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| Publications of Kathleen A. Welsh-Bohmer :chronological alphabetical combined listing:
%% Journal Articles
@article{fds374980,
Author = {Farrer, TJ and Bigler, ED and Tsui-Caldwell, YHW and Abildskov, TJ and Tschanz, JT and Welsh-Bohmer, KA},
Title = {Scheltens ratings, clinical white matter hyperintensities
and executive functioning in the Cache County Memory
Study.},
Journal = {Appl Neuropsychol Adult},
Pages = {1-7},
Year = {2023},
Month = {December},
url = {http://dx.doi.org/10.1080/23279095.2023.2287140},
Abstract = {OBJECTIVE: Examine the association between
neuropsychologically assessed executive function and
clinically identifiable white matter burden from magnetic
resonance imaging, using a visual rating system (Scheltens
Rating System) applied to the Cache County Memory Study
(CCMS) archival database. METHOD: We used the Scheltens
Ratings Scale to quantify white matter lesion burden in the
CCMS sample and used this metric as a predictor of executive
function. The sample included 60 individuals with dementia
and 13 healthy controls. RESULTS: Higher Scheltens ratings
were associated with poorer task performance on an Executive
Function composite score of common neuropsychological tests.
This association held true for both controls and dementing
cases. CONCLUSIONS: The current findings support extensive
prior literature demonstrating the association between brain
vascular health determined by white matter burden and
clinical outcomes based on neuropsychological assessment of
cognitive performance.},
Doi = {10.1080/23279095.2023.2287140},
Key = {fds374980}
}
@article{fds370292,
Author = {Blair, EM and Reale, BK and Zahuranec, DB and Forman, J and Langa, KM and Giordani, BJ and Plassman, BL and Welsh-Bohmer, KA and Wang, J and Kollman, CD and Levine, DA},
Title = {Influence of mild cognitive impairment on patient and care
partner decision-making for acute ischemic
stroke.},
Journal = {J Stroke Cerebrovasc Dis},
Volume = {32},
Number = {6},
Pages = {107068},
Year = {2023},
Month = {June},
url = {http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2023.107068},
Abstract = {GOALS: Evidence suggests that patients with mild cognitive
impairment (MCI) receive fewer treatments for acute ischemic
stroke and other cardiovascular diseases than patients with
normal cognition. Little is known about how patient and care
partner preferences for ischemic stroke treatment differ
between the patient population with MCI and the population
with normal cognition. This study aimed to understand how
patient MCI diagnosis influences patient and care partner
decision-making for acute ischemic stroke treatments.
METHODS: Multi-center qualitative study using in-person
semi-structured interviews with 20 MCI and normal cognition
patient-care partner dyads using a standard guide. The
present study reports results on patient and care partner
preferences for a clinical vignette patient to receive three
non-invasive treatments (intravenous tissue plasminogen
activator, inpatient rehabilitation, and secondary
preventive medications) and two invasive treatments (feeding
tube and carotid endarterectomy) after acute ischemic
stroke. We used qualitative content analysis to identify
themes. FINDINGS: We identified three major themes: (1)
Patients with MCI desired non-invasive treatments after
stroke, similar to patients with normal cognition and for
similar reasons; (2) Patients with MCI expressed different
preferences than patients with normal cognition for two
invasive treatments after stroke: carotid endarterectomy and
feeding tube placement; and (3) Patients with MCI expressed
more skepticism of the stroke treatment options and less
decisiveness in decision-making than patients with normal
cognition. CONCLUSIONS: These results suggest that patient
MCI diagnosis may contribute to differences in patient and
care partner preferences for invasive treatments after
stroke, but not for non-invasive treatments.},
Doi = {10.1016/j.jstrokecerebrovasdis.2023.107068},
Key = {fds370292}
}
@article{fds371156,
Author = {Grazia, A and Altomare, D and Preis, L and Monsch, AU and Cappa, SF and Gauthier, S and Frölich, L and Winblad, B and Welsh-Bohmer, KA and Teipel, SJ and Boccardi, M and Consortium for the Harmonization of
Neuropsychological Assessment},
Title = {Feasibility of a standard cognitive assessment in European
academic memory clinics.},
Journal = {Alzheimers Dement},
Volume = {19},
Number = {6},
Pages = {2276-2286},
Year = {2023},
Month = {June},
url = {http://dx.doi.org/10.1002/alz.12830},
Abstract = {INTRODUCTION: Standardized cognitive assessment would
enhance diagnostic reliability across memory clinics. An
expert consensus adapted the Uniform Dataset (UDS)-3 for
European centers, the clinician's UDS (cUDS). This study
assessed its implementation acceptability and feasibility.
METHODS: We developed a survey investigating barriers,
facilitators, and willingness to implement the cUDS. With a
mixed-methods design, we analyzed data from academic memory
clinics. RESULTS: Seventy-eight percent of responding
clinicians were experienced neuropsychologists/psychologists
and 22% were medical specialists coming from 18 European
countries. Sixty-five percent clinicians were willing to
implement cUDS. General barriers related to implementation
(43%) and clinical-methodological domains (21%). Favorable
clinicians reported finances (15%) and digitalization (9%)
as facilitating, but unavailability of local norms (23%) as
hindering. Unfavorable clinicians reported logistical (23%)
and time issues (18%). DISCUSSION: Despite challenges, data
showed moderate clinicians' acceptability and requirements
to improve feasibility. Nonetheless, these results come from
academic clinicians. The next steps will require feasibility
evaluation in non-academic contexts.},
Doi = {10.1002/alz.12830},
Key = {fds371156}
}
@article{fds371673,
Author = {Huggins, LKL and Min, SH and Kaplan, S and Wei, J and Welsh-Bohmer, K and Xu, H},
Title = {Meta-Analysis of Variations in Association between APOE ɛ4
and Alzheimer's Disease and Related Dementias Across
Hispanic Regions of Origin.},
Journal = {J Alzheimers Dis},
Volume = {93},
Number = {3},
Pages = {1095-1109},
Year = {2023},
url = {http://dx.doi.org/10.3233/JAD-221167},
Abstract = {BACKGROUND: Emerging research has shown racial and ethnic
variations in the magnitude of association between the
apolipoprotein ɛ4 (APOE ɛ4) allele and the risk of
developing Alzheimer's disease and related dementias (ADRD).
Studies researching this association among Hispanic groups
within and outside of the United States have produced
inconsistent results. OBJECTIVE: To examine the association
between the APOE ɛ4 allele and the risk of developing ADRD
in global Hispanic populations from different ethnic regions
of origin. METHODS: PubMed, Embase, Scopus, and PsycInfo
were searched for studies relating to Hispanic/Latin
American origin, APOE ɛ4, and ADRD. Odds ratios (OR) of
ADRD risk for individuals with APOE ɛ4 versus those without
APOE ɛ4 were extracted and calculated using random effects
analysis. RESULTS: 20 eligible studies represented Caribbean
Hispanic, Mexican, South American, Spanish, and Cuban
groups. Overall, APOE ɛ4 was significantly associated with
increased risk of ADRD (Odds Ratio [OR] 3.80, 95% CI:
2.38-6.07). The association was only significant in the
South American (OR: 4.61, 95% CI: 2.74-7.75) subgroup.
CONCLUSION: There was an association between APOE ɛ4 and
increased ADRD risk for the South American subgroup. The
strength of this association varied across Hispanic
subgroups. Data is limited with more studies especially
needed for adjusted analysis on Spanish, Central American,
Cuban Hispanic, and Caribbean Hispanic groups. Results
suggest additional environmental or genetic risk factors are
associated with ethnic variations.},
Doi = {10.3233/JAD-221167},
Key = {fds371673}
}
@article{fds372749,
Author = {Zou, H and Luo, S and Liu, H and Lutz, MW and Bennett, DA and Plassman, BL and Welsh-Bohmer, KA},
Title = {Genotypic Effects of the TOMM40'523 Variant and APOE on
Longitudinal Cognitive Change over 4 Years: The TOMMORROW
Study.},
Journal = {J Prev Alzheimers Dis},
Volume = {10},
Number = {4},
Pages = {886-894},
Year = {2023},
url = {http://dx.doi.org/10.14283/jpad.2023.115},
Abstract = {BACKGROUND: The 523 poly-T length polymorphism (rs10524523)
in TOMM40 has been reported to influence longitudinal
cognitive test performance within APOE ε3/3 carriers. The
results from prior studies are inconsistent. It is also
unclear whether specific APOE and TOMM40 genotypes
contribute to heterogeneity in longitudinal cognitive
performance during the preclinical stages of AD. OBJECTIVES:
To determine the effects of these genes on longitudinal
cognitive change in early preclinical stages of AD, we used
the clinical trial data from the recently concluded
TOMMORROW study to examine the effects of APOE and TOMM40
genotypes on neuropsychological test performance. DESIGN: A
phase 3, double-blind, placebo-controlled, randomized
clinical trial. SETTING: Academic affiliated and private
research clinics in Australia, Germany, Switzerland, the UK,
and the USA. PARTICIPANTS: Cognitively normal older adults
aged 65 to 83. INTERVENTION: Pioglitazone tablet.
MEASUREMENTS: Participants from the TOMMORROW trial were
stratified based on APOE genotype (APOE ε3/3, APOE ε3/4,
APOE ε4/4). APOE ε3/3 carriers were further stratified by
TOMM40'523 genotype. The final analysis dataset consists of
1,330 APOE ε3/3 carriers and 7,001 visits. Linear mixed
models were used to compare the rates of decline in
cognition across APOE groups and the APOE ε3/3 carriers
with different TOMM40'523 genotypes. RESULTS: APOE ε3/4 and
APOE ε4/4 genotypes compared with the APOE ε3/3 genotype
were associated with worse performance on measures of global
cognition, episodic memory, and expressive language.
Further, over the four years of observation, the APOE ε3/3
carriers with the TOMM40'523-S/S genotype showed better
global cognition and accelerated rates of cognitive decline
on tests of global cognition, executive function, and
attentional processing compared to APOE ε3/3 carriers with
TOMM40'523-S/VL and VL/VL genotypes and compared to the APOE
ε3/4 and APOE ε4/4 carriers. CONCLUSIONS: We suggest that
both APOE and TOMM40 genotypes may independently contribute
to cognitive heterogeneity in the pre-MCI stages of AD.
Controlling for this genetic variability will be important
in clinical trials designed to slow the rate of cognitive
decline and/or prevent symptom onset in preclinical
AD.},
Doi = {10.14283/jpad.2023.115},
Key = {fds372749}
}
@article{fds373574,
Author = {Watts, A and Haneline, S and Welsh-Bohmer, KA and Wu, J and Alexander,
R and Swerdlow, RH and Burns, DK and Saunders, AM},
Title = {TOMM40 '523 Genotype Distinguishes Patterns of Cognitive
Improvement for Executive Function in APOEɛ3
Homozygotes.},
Journal = {J Alzheimers Dis},
Volume = {95},
Number = {4},
Pages = {1697-1707},
Year = {2023},
url = {http://dx.doi.org/10.3233/JAD-230066},
Abstract = {BACKGROUND: TOMM40 '523 has been associated with cognitive
performance and risk for developing Alzheimer's disease
independent of the effect of APOE genotype. Few studies have
considered the longitudinal effect of this genotype on
change in cognition over time. OBJECTIVE: Our objective was
to evaluate the relationship between TOMM40 genotype status
and change in cognitive performance in the TOMMORROW study,
which was designed to prospectively evaluate an algorithm
that includes TOMM40 '523 for genetic risk for conversion to
mild cognitive impairment. METHODS: We used latent growth
curve models to estimate the effect of TOMM40 allele carrier
(short, very long) status on the intercept and slope of
change in cognitive performance in four broad cognitive
domains (attention, memory, executive function, and
language) and a combined overall cognitive score over 30
months. RESULTS: TOMM40 very long allele carriers had
significantly lower baseline performance for the combined
overall cognitive function score (B = -0.088,
p = 0.034) and for the executive function domain score
(B = -0.143, p = 0.013). Slopes for TOMM40 very long
carriers had significantly greater increases over time for
the executive function domain score only. In sensitivity
analyses, the results for executive function were observed
in participants who remained clinically stable, but not in
those who progressed clinically over the study duration.
CONCLUSIONS: Our results add to the growing body of evidence
that TOMM40, in the absence of APOEɛ4, may contribute to
cognitive changes with aging and dementia and support the
view that mitochondrial function is an important contributor
to Alzheimer's disease risk.},
Doi = {10.3233/JAD-230066},
Key = {fds373574}
}
@article{fds373575,
Author = {Welsh-Bohmer, KA and Kerchner, GA and Dhadda, S and Garcia, M and Miller, DS and Natanegara, F and Raket, LL and Robieson, W and Siemers,
ER and Carrillo, MC and Weber, CJ},
Title = {Decision making in clinical trials: Interim analyses,
innovative design, and biomarkers.},
Journal = {Alzheimers Dement (N Y)},
Volume = {9},
Number = {4},
Pages = {e12421},
Year = {2023},
url = {http://dx.doi.org/10.1002/trc2.12421},
Abstract = {The efficient and accurate execution of clinical trials
testing novel treatments for Alzheimer's disease (AD) is a
critical component of the field's collective efforts to
develop effective disease-modifying treatments for AD. The
lengthy and heterogeneous nature of clinical progression in
AD contributes to the challenges inherent in demonstrating a
clinically meaningful benefit of any potential new AD
therapy. The failure of many large and expensive clinical
trials to date has prompted a focus on optimizing all
aspects of decision making, to not only expedite the
development of new treatments, but also maximize the value
of the information that each clinical trial yields, so that
all future clinical trials (including those that are
negative) will contribute toward advancing the field. To
address this important topic the Alzheimer's Association
Research Roundtable convened December 1-2, 2020. The goals
focused around identifying new directions and actionable
steps to enhance clinical trial decision making in planned
future studies.},
Doi = {10.1002/trc2.12421},
Key = {fds373575}
}
@article{fds365210,
Author = {Largent, EA and Walter, S and Childs, N and Dacks, PA and Dodge, S and Florian, H and Jackson, J and Llibre Guerra and JJ and Iturriaga, E and Miller, DS and Moreno, M and Nosheny, RL and Obisesan, TO and Portacolone, E and Siddiqi, B and Silverberg, N and Warren, RC and Welsh-Bohmer, KA and Edelmayer, RM and Participant FIRST Work
Group},
Title = {Putting participants and study partners FIRST when clinical
trials end early.},
Journal = {Alzheimers Dement},
Volume = {18},
Number = {12},
Pages = {2736-2746},
Year = {2022},
Month = {December},
url = {http://dx.doi.org/10.1002/alz.12732},
Abstract = {Between 2018 and 2019, multiple clinical trials ended
earlier than planned, resulting in calls to improve
communication with and support for participants and their
study partners ("dyads"). The multidisciplinary Participant
Follow-Up Improvement in Research Studies and Trials
(Participant FIRST) Work Group met throughout 2021. Its
goals were to identify best practices for communicating with
and supporting dyads affected by early trial stoppage. The
Participant FIRST Work Group identified 17 key
recommendations spanning the pre-trial, mid-trial, and
post-trial periods. These focus on prospectively allocating
sufficient resources for orderly closeout; developing
dyad-centered communication plans; helping dyads build and
maintain support networks; and, if a trial stops, informing
dyads rapidly. Participants and study partners invest time,
effort, and hope in their research participation. The
research community should take intentional steps toward
better communicating with and supporting participants when
clinical trials end early. The Participant FIRST
recommendations are a practical guide for embarking on that
journey.},
Doi = {10.1002/alz.12732},
Key = {fds365210}
}
@article{fds374098,
Author = {Baloni, P and Arnold, M and Buitrago, L and Nho, K and Moreno, H and Huynh,
K and Brauner, B and Louie, G and Kueider-Paisley, A and Suhre, K and Saykin, AJ and Ekroos, K and Meikle, PJ and Hood, L and Price, ND and Alzheimer’s Disease Metabolomics Consortium, and Doraiswamy,
PM and Funk, CC and Hernández, AI and Kastenmüller, G and Baillie, R and Han, X and Kaddurah-Daouk, R},
Title = {Multi-Omic analyses characterize the ceramide/sphingomyelin
pathway as a therapeutic target in Alzheimer's
disease.},
Journal = {Commun Biol},
Volume = {5},
Number = {1},
Pages = {1074},
Year = {2022},
Month = {October},
url = {http://dx.doi.org/10.1038/s42003-022-04011-6},
Abstract = {Dysregulation of sphingomyelin and ceramide metabolism have
been implicated in Alzheimer's disease. Genome-wide and
transcriptome-wide association studies have identified
various genes and genetic variants in lipid metabolism that
are associated with Alzheimer's disease. However, the
molecular mechanisms of sphingomyelin and ceramide
disruption remain to be determined. We focus on the
sphingolipid pathway and carry out multi-omics analyses to
identify central and peripheral metabolic changes in
Alzheimer's patients, correlating them to imaging features.
Our multi-omics approach is based on (a) 2114 human
post-mortem brain transcriptomics to identify differentially
expressed genes; (b) in silico metabolic flux analysis on
context-specific metabolic networks identified differential
reaction fluxes; (c) multimodal neuroimaging analysis on
1576 participants to associate genetic variants in
sphingomyelin pathway with Alzheimer's disease pathogenesis;
(d) plasma metabolomic and lipidomic analysis to identify
associations of lipid species with dysregulation in
Alzheimer's; and (e) metabolite genome-wide association
studies to define receptors within the pathway as a
potential drug target. We validate our hypothesis in
amyloidogenic APP/PS1 mice and show prolonged exposure to
fingolimod alleviated synaptic plasticity and cognitive
impairment in mice. Our integrative multi-omics approach
identifies potential targets in the sphingomyelin pathway
and suggests modulators of S1P metabolism as possible
candidates for Alzheimer's disease treatment.},
Doi = {10.1038/s42003-022-04011-6},
Key = {fds374098}
}
@article{fds356500,
Author = {Levine, DA and Galecki, AT and Plassman, BL and Fagerlin, A and Wallner,
LP and Langa, KM and Whitney, RT and Nallamothu, BK and Morgenstern, LB and Reale, BK and Blair, EM and Giordani, B and Welsh-Bohmer, KA and Kabeto,
MU and Zahuranec, DB},
Title = {The Association Between Mild Cognitive Impairment Diagnosis
and Patient Treatment Preferences: a Survey of Older
Adults.},
Journal = {J Gen Intern Med},
Volume = {37},
Number = {8},
Pages = {1925-1934},
Year = {2022},
Month = {June},
url = {http://dx.doi.org/10.1007/s11606-021-06839-w},
Abstract = {BACKGROUND: Older patients (65+) with mild cognitive
impairment (MCI) receive less guideline-concordant care for
cardiovascular disease (CVD) and other conditions than
patients with normal cognition (NC). One potential
explanation is that patients with MCI want less treatment
than patients with NC; however, the treatment preferences of
patients with MCI have not been studied. OBJECTIVE: To
determine whether patients with MCI have different treatment
preferences than patients with NC. DESIGN: Cross-sectional
survey conducted at two academic medical centers from
February to December 2019 PARTICIPANTS: Dyads of older
outpatients with MCI and NC and patient-designated
surrogates. MAIN MEASURES: The modified Life-Support
Preferences-Predictions Questionnaire score measured
patients' preferences for life-sustaining treatment
decisions in six health scenarios including stroke and acute
myocardial infarction (range, 0-24 treatments rejected with
greater scores indicating lower desire for treatment). KEY
RESULTS: The survey response rate was 73.4%. Of 136
recruited dyads, 127 (93.4%) completed the survey (66 MCI
and 61 NC). The median number of life-sustaining treatments
rejected across health scenarios did not differ
significantly between patients with MCI and patients with NC
(4.5 vs 6.0; P=0.55). Most patients with MCI (80%) and NC
(80%) desired life-sustaining treatments in their current
health (P=0.99). After adjusting for patient and surrogate
factors, the difference in mean counts of rejected
treatments between patients with MCI and patients with NC
was not statistically significant (adjusted ratio, 1.08, 95%
CI, 0.80-1.44; P=0.63). CONCLUSION: We did not find evidence
that patients with MCI want less treatment than patients
with NC. These findings suggest that other provider and
system factors might contribute to patients with MCI getting
less guideline-concordant care.},
Doi = {10.1007/s11606-021-06839-w},
Key = {fds356500}
}
@article{fds359831,
Author = {Hao, N and Wang, Z and Liu, P and Becker, R and Yang, S and Yang, K and Pei,
Z and Zhang, P and Xia, J and Shen, L and Wang, L and Welsh-Bohmer, KA and Sanders, L and Lee, LP and Huang, TJ},
Title = {Acoustofluidic multimodal diagnostic system for Alzheimer's
disease.},
Journal = {Biosens Bioelectron},
Volume = {196},
Pages = {113730},
Year = {2022},
Month = {January},
url = {http://dx.doi.org/10.1016/j.bios.2021.113730},
Abstract = {Alzheimer's disease (AD) is a progressive and irreversible
neurodegenerative brain disorder that affects tens of
millions of older adults worldwide and has significant
economic and societal impacts. Despite its prevalence and
severity, early diagnosis of AD remains a considerable
challenge. Here we report an integrated acoustofluidics-based
diagnostic system (ADx), which combines triple functions of
acoustics, microfluidics, and orthogonal biosensors for
clinically accurate, sensitive, and rapid detection of AD
biomarkers from human plasma. We design and fabricate a
surface acoustic wave-based acoustofluidic separation device
to isolate and purify AD biomarkers to increase the
signal-to-noise ratio. Multimodal biosensors within the
integrated ADx are fabricated by in-situ patterning of the
ZnO nanorod array and deposition of Ag nanoparticles onto
the ZnO nanorods for surface-enhanced Raman scattering
(SERS) and electrochemical immunosensors. We obtain the
label-free detections of SERS and electrochemical
immunoassay of clinical plasma samples from AD patients and
healthy controls with high sensitivity and specificity. We
believe that this efficient integration provides promising
solutions for the early diagnosis of AD.},
Doi = {10.1016/j.bios.2021.113730},
Key = {fds359831}
}
@article{fds362114,
Author = {Kimmel, HJ and Levine, DA and Whitney, RT and Forman, J and Plassman,
BL and Fagerlin, A and Welsh-Bohmer, KA and Reale, BK and Galecki, AT and Blair, E and Langa, KM and Giordani, B and Kollman, C and Wang, J and Zahuranec, DB},
Title = {A Mixed-Methods Study of the Impact of Mild Cognitive
Impairment Diagnosis on Patient and Care Partner Perception
of Health Risks.},
Journal = {J Alzheimers Dis},
Volume = {85},
Number = {3},
Pages = {1175-1187},
Year = {2022},
url = {http://dx.doi.org/10.3233/JAD-215155},
Abstract = {BACKGROUND: Older patients (≥65 years) with mild cognitive
impairment (MCI) are undertreated for cardiovascular disease
(CVD). One reason for this disparity could be that patients
with MCI might underestimate the chances of CVD and
overestimate dementia. OBJECTIVE: To compare conceptions of
health risk between older patients with MCI and normal
cognition (NC) and their care partners. METHODS: We
conducted a multi-center mixed-methods study of patient-care
partner dyads completing written quantitative surveys (73%
response rate; 127 dyads: 66 MCI and 61 NC) or
semi-structured interviews (20 dyads: 11 MCI, and 9 NC).
Surveys assessed two-year patient risks of dementia, heart
attack, stroke, and fall. Interviews assessed similar health
risks and reasons for risk perceptions. RESULTS: On surveys,
a similarly low proportion of MCI and NC patients felt they
were at risk of stroke (5% versus 2%; p = 0.62) and
heart attack (2% versus 0%; p = 0.99). More MCI than NC
patients perceived dementia risk (26% versus 2%;
p < 0.001). Care partners' survey findings were similar.
Interviews generally confirmed these patterns and also
identified reasons for future health concerns. For both MCI
and NC dyads, personal experience with cognitive decline or
CVD (personal or family history) increased concerns about
each disease. Additionally, perceptions of irreversibility
and lack of treatment for cognitive decline increased
concern about dementia. CONCLUSION: Less use of CVD
treatments in MCI seems unlikely to be driven by
differential perceptions of CVD risk. Future work to improve
awareness of CVD risks in older patients and dementia risk
in patients with MCI are warranted.},
Doi = {10.3233/JAD-215155},
Key = {fds362114}
}
@article{fds366215,
Author = {Schneider, LS and Bennett, DA and Farlow, MR and Peskind, ER and Raskind, MA and Sano, M and Stern, Y and Haneline, S and Welsh-Bohmer,
KA and O'Neil, J and Walter, R and Maresca, S and Culp, M and Alexander, R and Saunders, AM and Burns, DK and Chiang, C},
Title = {Adjudicating Mild Cognitive Impairment Due to Alzheimer's
Disease as a Novel Endpoint Event in the TOMMORROW
Prevention Clinical Trial.},
Journal = {J Prev Alzheimers Dis},
Volume = {9},
Number = {4},
Pages = {625-634},
Year = {2022},
url = {http://dx.doi.org/10.14283/jpad.2022.72},
Abstract = {BACKGROUND: The onset of mild cognitive impairment (MCI) is
an essential outcome in Alzheimer's disease (AD) prevention
trials and a compelling milestone for clinically meaningful
change. Determining MCI, however, may be variable and
subject to disagreement. Adjudication procedures may improve
the reliability of these determinations. We report the
performance of an adjudication committee for an AD
prevention trial. METHODS: The TOMMORROW prevention trial
selected cognitively normal participants at increased
genetic risk for AD and randomized them to low-dose
pioglitazone or placebo treatment. When adjudication
criteria were triggered, a participant's clinical
information was randomly assigned to a three-member panel of
a six-member independent adjudication committee.
Determination of whether or not a participant reached MCI
due to AD or AD dementia proceeded through up to three
review stages - independent review, collaborative review,
and full committee review - requiring a unanimous decision
and ratification by the chair. RESULTS: Of 3494 participants
randomized, the committee adjudicated on 648 cases from 386
participants, resulting in 96 primary endpoint events. Most
participants had cases that were adjudicated once (n = 235,
60.9%); the rest had cases that were adjudicated multiple
times. Cases were evenly distributed among the eight
possible three-member panels. Most adjudicated cases
(485/648, 74.8%) were decided within the independent review
(stage 1); 14.0% required broader collaborative review
(stage 2), and 11.1% needed full committee discussion (stage
3). The primary endpoint event decision rate was 39/485
(8.0%) for stage 1, 29/91 (31.9%) for stage 2, and 28/72
(38.9%) for stage 3. Agreement between the primary event
outcomes supported by investigators' clinical diagnoses and
the decisions of the adjudication committee increased from
50% to approximately 93% (after around 100 cases) before
settling at 80-90% for the remainder of the study.
CONCLUSIONS: The adjudication process was designed to
provide independent, consistent determinations of the trial
endpoints. These outcomes demonstrated the extent of
uncertainty among trial investigators and agreement between
adjudicators when the transition to MCI due to AD was
prospectively assessed. These methods may inform clinical
endpoint determination in future AD secondary prevention
studies. Reliable, accurate assessment of clinical events is
critical for prevention trials and may mean the difference
between success and failure.},
Doi = {10.14283/jpad.2022.72},
Key = {fds366215}
}
@article{fds371157,
Author = {Atkins, AS and Kraus, MS and Welch, M and Yuan, Z and Stevens, H and Welsh-Bohmer, KA and Keefe, RSE},
Title = {Remote self-administration of digital cognitive tests using
the Brief Assessment of Cognition: Feasibility, reliability,
and sensitivity to subjective cognitive decline.},
Journal = {Front Psychiatry},
Volume = {13},
Pages = {910896},
Year = {2022},
url = {http://dx.doi.org/10.3389/fpsyt.2022.910896},
Abstract = {Cognitive impairment is a common and pervasive feature of
etiologically diverse disorders of the central nervous
system, and a target indication for a growing number of
symptomatic and disease modifying drugs. Remotely acquired
digital endpoints have been recognized for their potential
in providing frequent, real-time monitoring of cognition,
but their ultimate value will be determined by the
reliability and sensitivity of measurement in the
populations of interest. To this end, we describe initial
validation of remote self-administration of cognitive tests
within a regulatorily compliant tablet-based platform.
Participants were 61 older adults (age 55+), including 20
individuals with subjective cognitive decline (SCD). To
allow comparison between remote (in-home) and site-based
testing, participants completed 2 testing sessions 1 week
apart. Results for three of four cognitive domains assessed
demonstrated equivalence between remote and site-based
tests, with high cross-modality ICCs (absolute agreement)
for Symbol Coding (ICC = 0.75), Visuospatial Working Memory
(ICC = 0.70) and Verbal Fluency (ICC > 0.73). Group
differences in these domains were significant and reflected
sensitivity to objective cognitive impairment in the SCD
group for both remote and site-based testing (p < 0.05). In
contrast, performance on tests of verbal episodic memory
suggested inflated performance during unmonitored testing
and indicate reliable use of remote cognitive assessments
may depend on the construct, as well as the population being
tested.},
Doi = {10.3389/fpsyt.2022.910896},
Key = {fds371157}
}
@article{fds372272,
Author = {Welsh-Bohmer, KA and Byrd, GS and Dewees, R and Bozoki, AC and Martin,
PM and Plassman, B and Price, SR},
Title = {Raising Awareness of Alzheimer's Disease and Dementia in
Native Americans in North Carolina.},
Journal = {N C Med J},
Volume = {83},
Number = {1},
Pages = {77-78},
Year = {2022},
url = {http://dx.doi.org/10.18043/ncm.83.1.77},
Doi = {10.18043/ncm.83.1.77},
Key = {fds372272}
}
@article{fds358313,
Author = {Shadyab, AH and LaCroix, AZ and Feldman, HH and van Dyck, CH and Okonkwo, OC and Tam, SP and Fairchild, JK and Welsh-Bohmer, KA and Matthews, G and Bennett, D and Shadyab, AA and Schafer, KA and Morrison,
RH and Kipperman, SA and Mason, J and Tan, D and Thomas, RG and Cotman, CW and Baker, LD and ADCS EXERT Study Group},
Title = {Recruitment of a multi-site randomized controlled trial of
aerobic exercise for older adults with amnestic mild
cognitive impairment: The EXERT trial.},
Journal = {Alzheimers Dement},
Volume = {17},
Number = {11},
Pages = {1808-1817},
Year = {2021},
Month = {November},
url = {http://dx.doi.org/10.1002/alz.12401},
Abstract = {INTRODUCTION: Effective strategies to recruit older adults
with mild cognitive impairment (MCI) into nonpharmacological
intervention trials are lacking. METHODS: Recruitment for
EXERT, a multisite randomized controlled 18-month trial
examining the effects of aerobic exercise on cognitive
trajectory in adults with amnestic MCI, involved a diverse
portfolio of strategies to enroll 296 participants. RESULTS:
Recruitment occurred September 2016 through March 2020 and
was initially slow. After mass mailings of 490,323 age- and
geo-targeted infographic postcards and brochures,
recruitment rates increased substantially, peaking at 16
randomizations/month in early 2020. Mass mailings accounted
for 52% of randomized participants, whereas 25% were
recruited from memory clinic rosters, electronic health
records, and national and local registries. Other sources
included news broadcasts, public service announcements
(PSA), local advertising, and community presentations.
DISCUSSION: Age- and geo-targeted mass mailing of
infographic materials was the most effective approach in
recruiting older adults with amnestic MCI into an 18-month
exercise trial.},
Doi = {10.1002/alz.12401},
Key = {fds358313}
}
@article{fds371158,
Author = {Burns, DK and Alexander, RC and Welsh-Bohmer, KA and Culp, M and Chiang,
C and O'Neil, J and Evans, RM and Harrigan, P and Plassman, BL and Burke,
JR and Wu, J and Lutz, MW and Haneline, S and Schwarz, AJ and Schneider,
LS and Yaffe, K and Saunders, AM and Ratti, E and TOMMORROW study
investigators},
Title = {Safety and efficacy of pioglitazone for the delay of
cognitive impairment in people at risk of Alzheimer's
disease (TOMMORROW): a prognostic biomarker study and a
phase 3, randomised, double-blind, placebo-controlled
trial.},
Journal = {Lancet Neurol},
Volume = {20},
Number = {7},
Pages = {537-547},
Year = {2021},
Month = {July},
url = {http://dx.doi.org/10.1016/S1474-4422(21)00043-0},
Abstract = {BACKGROUND: The identification of people at risk of
cognitive impairment is essential for improving recruitment
in secondary prevention trials of Alzheimer's disease. We
aimed to test and qualify a biomarker risk assignment
algorithm (BRAA) to identify participants at risk of
developing mild cognitive impairment due to Alzheimer's
disease within 5 years, and to evaluate the safety and
efficacy of low-dose pioglitazone to delay onset of mild
cognitive impairment in these at-risk participants. METHODS:
In this phase 3, multicentre, randomised, double-blind,
placebo-controlled, parallel-group study, we enrolled
cognitively healthy, community living participants aged
65-83 years from 57 academic affiliated and private research
clinics in Australia, Germany, Switzerland, the UK, and the
USA. By use of the BRAA, participants were grouped as high
risk or low risk. Participants at high risk were randomly
assigned 1:1 to receive oral pioglitazone (0·8 mg/day
sustained release) or placebo, and all low-risk participants
received placebo. Study investigators, site staff, sponsor
personnel, and study participants were masked to genotype,
risk assignment, and treatment assignment. The planned study
duration was the time to accumulate 202 events of mild
cognitive impairment due to Alzheimer's disease in White
participants who were at high risk (the population on whom
the genetic analyses that informed the BRAA development was
done). Primary endpoints were time-to-event comparisons
between participants at high risk and low risk given placebo
(for the BRAA objective), and between participants at high
risk given pioglitazone or placebo (for the efficacy
objective). The primary analysis included all participants
who were randomly assigned, received at least one dose of
study drug, and had at least one valid post-baseline visit,
with significance set at p=0·01. The safety analysis
included all participants who were randomly assigned and
received at least one dose of study medication. An efficacy
futility analysis was planned for when approximately 33% of
the anticipated events occurred in the high-risk, White,
non-Hispanic or Latino group. This trial is registered with
ClinicalTrials.gov, NCT01931566. FINDINGS: Between Aug 28,
2013, and Dec 21, 2015, we enrolled 3494 participants (3061
at high risk and 433 at low risk). Of those participants,
1545 were randomly assigned to pioglitazone and 1516 to
placebo. 1104 participants discontinued treatment (464
assigned to the pioglitazone group, 501 in the placebo high
risk group, and 139 in the placebo low risk group). 3399
participants had at least one dose of study drug or placebo
and at least one post-baseline follow-up visit, and were
included in the efficacy analysis. 3465 participants were
included in the safety analysis (1531 assigned to the
pioglitazone group, 1507 in the placebo high risk group, and
427 in the placebo low risk group). In the full analysis
set, 46 (3·3%) of 1406 participants at high risk given
placebo had mild cognitive impairment due to Alzheimer's
disease, versus four (1·0%) of 402 participants at low risk
given placebo (hazard ratio 3·26, 99% CI 0·85-12·45;
p=0·023). 39 (2·7%) of 1430 participants at high risk
given pioglitazone had mild cognitive impairment, versus 46
(3·3%) of 1406 participants at high risk given placebo
(hazard ratio 0·80, 99% CI 0·45-1·40; p=0·307). In the
safety analysis set, seven (0·5%) of 1531 participants at
high risk given pioglitazone died versus 21 (1·4%) of 1507
participants at high risk given placebo. There were no other
notable differences in adverse events between groups. The
study was terminated in January, 2018, after failing to meet
the non-futility threshold. INTERPRETATION: Pioglitazone did
not delay the onset of mild cognitive impairment. The
biomarker algorithm demonstrated a 3 times enrichment of
events in the high risk placebo group compared with the low
risk placebo group, but did not reach the pre-specified
significance threshold. Because we did not complete the
study as planned, findings can only be considered
exploratory. The conduct of this study could prove useful to
future clinical development strategies for Alzheimer's
disease prevention studies. FUNDING: Takeda and
Zinfandel.},
Doi = {10.1016/S1474-4422(21)00043-0},
Key = {fds371158}
}
@article{fds358002,
Author = {Clausen, AN and Bouchard, HC and VA Mid-Atlantic MIRECC Workgroup, and Welsh-Bohmer, KA and Morey, RA},
Title = {Assessment of Neuropsychological Function in Veterans With
Blast-Related Mild Traumatic Brain Injury and Subconcussive
Blast Exposure.},
Journal = {Front Psychol},
Volume = {12},
Pages = {686330},
Year = {2021},
url = {http://dx.doi.org/10.3389/fpsyg.2021.686330},
Abstract = {Objective: The majority of combat-related head injuries are
associated with blast exposure. While Veterans with mild
traumatic brain injury (mTBI) report cognitive complaints
and exhibit poorer neuropsychological performance, there is
little evidence examining the effects of subconcussive blast
exposure, which does not meet clinical symptom criteria for
mTBI during the acute period following exposure. We compared
chronic effects of combat-related blast mTBI and
combat-related subconcussive blast exposure on
neuropsychological performance in Veterans. Methods:
Post-9/11 Veterans with combat-related subconcussive blast
exposure (n = 33), combat-related blast mTBI (n = 26), and
controls (n = 33) without combat-related blast exposure,
completed neuropsychological assessments of intellectual and
executive functioning, processing speed, and working memory
via NIH toolbox, assessment of clinical psychopathology, a
retrospective account of blast exposures and
non-blast-related head injuries, and self-reported current
medication. Huber Robust Regressions were employed to
compare neuropsychological performance across groups.
Results: Veterans with combat-related blast mTBI and
subconcussive blast exposure displayed significantly slower
processing speed compared with controls. After adjusting for
post-traumatic stress disorder and depressive symptoms,
those with combat-related mTBI exhibited slower processing
speed than controls. Conclusion: Veterans in the
combat-related blast mTBI group exhibited slower processing
speed relative to controls even when controlling for PTSD
and depression. Cognition did not significantly differ
between subconcussive and control groups or subconcussive
and combat-related blast mTBI groups. Results suggest
neurocognitive assessment may not be sensitive enough to
detect long-term effects of subconcussive blast exposure, or
that psychiatric symptoms may better account for cognitive
sequelae following combat-related subconcussive blast
exposure or combat-related blast mTBI.},
Doi = {10.3389/fpsyg.2021.686330},
Key = {fds358002}
}
@article{fds351411,
Author = {Cocroft, S and Welsh-Bohmer, KA and Plassman, BL and Chanti-Ketterl,
M and Edmonds, H and Gwyther, L and McCart, M and MacDonald, H and Potter,
G and Burke, JR},
Title = {Racially diverse participant registries to facilitate the
recruitment of African Americans into presymptomatic
Alzheimer's disease studies.},
Journal = {Alzheimers Dement},
Volume = {16},
Number = {8},
Pages = {1107-1114},
Year = {2020},
Month = {August},
url = {http://dx.doi.org/10.1002/alz.12048},
Abstract = {INTRODUCTION: The Alzheimer's Disease Prevention Registry
(ADPR) of the Joseph and Kathleen Bryan Alzheimer's Disease
Research Center at Duke University has been successful in
achieving a racially diverse and "research ready" cohort of
cognitively healthy volunteers. METHODS: The ADPR is based
on an infrastructure that includes: (1) an administrative
leadership team; (2) a coordinating center; (3) an IT
management team; (4) a community engagement team; and (5)
collaborations with study partners across disciplines.
RESULTS: The ADPR currently has more than 4677 members, 26%
of whom are African American. The ADPR has supported 21
studies including 8 biomarker studies, 7 clinical trials, 4
cognitive neuroscience studies, and 2 studies assessing
novel computerized measures. DISCUSSION: We describe our
experiences establishing and maintaining a diverse ADPR as
well as insights on recruitment strategies to increase the
representation of African Americans in Alzheimer's disease
studies.},
Doi = {10.1002/alz.12048},
Key = {fds351411}
}
@article{fds347140,
Author = {Blumenthal, JA and Smith, PJ and Mabe, S and Hinderliter, A and Welsh-Bohmer, K and Browndyke, JN and Doraiswamy, PM and Lin, P-H and Kraus, WE and Burke, JR and Sherwood, A},
Title = {Longer Term Effects of Diet and Exercise on Neurocognition:
1-Year Follow-up of the ENLIGHTEN Trial.},
Journal = {J Am Geriatr Soc},
Volume = {68},
Number = {3},
Pages = {559-568},
Year = {2020},
Month = {March},
url = {http://dx.doi.org/10.1111/jgs.16252},
Abstract = {OBJECTIVES: To evaluate the longer term changes in executive
functioning among participants with cardiovascular disease
(CVD) risk factors and cognitive impairments with no
dementia (CIND) randomized to a diet and exercise
intervention. DESIGN: A 2 (Exercise) × 2 (Dietary
Approaches to Stop Hypertension [DASH] eating plan)
factorial randomized clinical trial. SETTING: Academic
tertiary care medical center. PARTICIPANTS: Volunteer sample
of 160 older sedentary adults with CIND and at least one
additional CVD risk factor enrolled in the ENLIGHTEN trial
between December 2011 and March 2016. INTERVENTIONS: Six
months of aerobic exercise (AE), DASH diet counseling,
combined AE + DASH, or health education (HE) controls.
MEASUREMENTS: Neurocognitive battery recommended by the
Neuropsychological Working Group for Vascular Cognitive
Disorders including measures of executive function, memory,
and language/verbal fluency. Secondary outcomes included the
Clinical Dementia Rating-Sum of Boxes (CDR-SB), Six-Minute
Walk Distance (6MWD), and CVD risk including blood pressure,
body weight, and CVD medication burden. RESULTS: Despite
discontinuation of lifestyle changes, participants in the
exercise groups retained better executive function 1 year
post-intervention (P = .041) compared with non-exercise
groups, with a similar, albeit weaker, pattern in the DASH
groups (P = .054), without variation over time
(P's > .867). Participants in the exercise groups also
achieved greater sustained improvements in 6MWD compared
with non-Exercise participants (P < .001). Participants
in the DASH groups exhibited lower CVD risk relative to
non-DASH participants (P = .032); no differences in CVD risk
were observed for participants in the Exercise groups
compared with non-Exercise groups (P = .711). In post hoc
analyses, the AE + DASH group had better performance on
executive functioning (P < .001) and CDR-SB (P = .011)
compared with HE controls. CONCLUSION: For participants with
CIND and CVD risk factors, exercise for 6 months promoted
better executive functioning compared with non-exercisers
through 1-year post-intervention, although its clinical
significance is uncertain. J Am Geriatr Soc 68:559-568,
2020.},
Doi = {10.1111/jgs.16252},
Key = {fds347140}
}
@article{fds352912,
Author = {Smith, PJ and Mabe, SM and Sherwood, A and Doraiswamy, PM and Welsh-Bohmer, KA and Burke, JR and Kraus, WE and Lin, P-H and Browndyke,
JN and Babyak, MA and Hinderliter, AL and Blumenthal,
JA},
Title = {Metabolic and Neurocognitive Changes Following Lifestyle
Modification: Examination of Biomarkers from the ENLIGHTEN
Randomized Clinical Trial.},
Journal = {J Alzheimers Dis},
Volume = {77},
Number = {4},
Pages = {1793-1803},
Year = {2020},
url = {http://dx.doi.org/10.3233/JAD-200374},
Abstract = {BACKGROUND: Previous studies have demonstrated that aerobic
exercise (AE) and the Dietary Approaches to Stop
Hypertension (DASH) diet can improve neurocognition.
However, the mechanisms by which lifestyle improves
neurocognition have not been widely studied. We examined the
associations between changes in metabolic, neurotrophic, and
inflammatory biomarkers with executive functioning among
participants from the Exercise and Nutritional Interventions
for Neurocognitive Health Enhancement (ENLIGHTEN) trial.
OBJECTIVE: To examine the association between changes in
metabolic function and neurocognition among older adults
with cognitive impairment, but without dementia (CIND)
participating in a comprehensive lifestyle intervention.
METHODS: ENLIGHTEN participants were randomized using a 2×2
factorial design to receive AE, DASH, both AE+DASH, or a
health education control condition (HE) for six months.
Metabolic biomarkers included insulin resistance
(homeostatic model assessment [HOMA-IR]), leptin, and
insulin-like growth factor (IGF-1); neurotrophic biomarkers
included brain derived neurotrophic factor (BDNF) and
vascular endothelial growth factor (VEGF); and inflammatory
biomarkers included interleukin-6 (IL-6) and C-Reactive
Protein (CRP). RESULTS: Participants included 132 sedentary
older adults (mean age = 65 [SD = 7]) with CIND.
Results demonstrated that both AE (d = 0.48,
p = 0.015) and DASH improved metabolic function
(d = 0.37, p = 0.039), without comparable
improvements in neurotrophic or inflammatory biomarkers.
Greater improvements in metabolic function, including
reduced HOMA-IR (B = -2.3 [-4.3, -0.2], p = 0.033)
and increased IGF-1 (B = 3.4 [1.2, 5.7], p = 0.004),
associated with increases in Executive Function. CONCLUSION:
Changes in neurocognition after lifestyle modification are
associated with improved metabolic function.},
Doi = {10.3233/JAD-200374},
Key = {fds352912}
}
@article{fds365162,
Author = {Dodge, HH and Goldstein, FC and Wakim, NI and Gefen, T and Teylan, M and Chan, KCG and Kukull, WA and Barnes, LL and Giordani, B and Hughes, TM and Kramer, JH and Loewenstein, DA and Marson, DC and Mungas, DM and Mattek,
N and Sachs, BC and Salmon, DP and Willis-Parker, M and Welsh-Bohmer,
KA and Wild, KV and Morris, JC and Weintraub, S and National Alzheimer's
Coordinating Center (NACC)},
Title = {Differentiating among stages of cognitive impairment in
aging: Version 3 of the Uniform Data Set (UDS)
neuropsychological test battery and MoCA index
scores.},
Journal = {Alzheimers Dement (N Y)},
Volume = {6},
Number = {1},
Pages = {e12103},
Year = {2020},
url = {http://dx.doi.org/10.1002/trc2.12103},
Abstract = {INTRODUCTION: Federally funded Alzheimer's Disease Centers
in the United States have been using a standardized
neuropsychological test battery as part of the National
Alzheimer's Coordinating Center Uniform Data Set (UDS) since
2005. Version 3 (V3) of the UDS replaced the previous
version (V2) in 2015. We compared V2 and V3
neuropsychological tests with respect to their ability to
distinguish among the Clinical Dementia Rating (CDR) global
scores of 0, 0.5, and 1. METHODS: First, we matched
participants receiving V2 tests (V2 cohort) and V3 tests (V3
cohort) in their cognitive functions using tests common to
both versions. Then, we compared receiver-operating
characteristic (ROC) area under the curve in differentiating
CDRs for the remaining tests. RESULTS: Some V3 tests
performed better than V2 tests in differentiating between
CDR 0.5 and 0, but the improvement was limited to Caucasian
participants. DISCUSSION: Further efforts to improve the
ability for early identification of cognitive decline among
diverse racial groups are required.},
Doi = {10.1002/trc2.12103},
Key = {fds365162}
}
@article{fds371159,
Author = {Ma, Y and Jun, GR and Zhang, X and Chung, J and Naj, AC and Chen, Y and Bellenguez, C and Hamilton-Nelson, K and Martin, ER and Kunkle, BW and Bis, JC and Debette, S and DeStefano, AL and Fornage, M and Nicolas, G and van Duijn, C and Bennett, DA and De Jager and PL and Mayeux, R and Haines,
JL and Pericak-Vance, MA and Seshadri, S and Lambert, J-C and Schellenberg, GD and Lunetta, KL and Farrer, LA and Alzheimer’s
Disease Sequencing Project and Alzheimer’s Disease Exome
Sequencing–France Project},
Title = {Analysis of Whole-Exome Sequencing Data for Alzheimer
Disease Stratified by APOE Genotype.},
Journal = {JAMA Neurol},
Volume = {76},
Number = {9},
Pages = {1099-1108},
Year = {2019},
Month = {September},
url = {http://dx.doi.org/10.1001/jamaneurol.2019.1456},
Abstract = {IMPORTANCE: Previous genome-wide association studies of
common variants identified associations for Alzheimer
disease (AD) loci evident only among individuals with
particular APOE alleles. OBJECTIVE: To identify APOE
genotype-dependent associations with infrequent and rare
variants using whole-exome sequencing. DESIGN, SETTING, AND
PARTICIPANTS: The discovery stage included 10 441
non-Hispanic white participants in the Alzheimer Disease
Sequencing Project. Replication was sought in 2 independent,
whole-exome sequencing data sets (1766 patients with AD,
2906 without AD [controls]) and a chip-based genotype
imputation data set (8728 patients with AD, 9808 controls).
Bioinformatics and functional analyses were conducted using
clinical, cognitive, neuropathologic, whole-exome
sequencing, and gene expression data obtained from a
longitudinal cohort sample including 402 patients with AD
and 647 controls. Data were analyzed between March 2017 and
September 2018. MAIN OUTCOMES AND MEASURES: Score, Firth,
and sequence kernel association tests were used to test the
association of AD risk with individual variants and genes in
subgroups of APOE ε4 carriers and noncarriers. Results with
P ≤ 1 × 10-5 were further evaluated in the
replication data sets and combined by meta-analysis.
RESULTS: Among 3145 patients with AD and 4213 controls
lacking ε4 (mean [SD] age, 83.4 [7.6] years; 4363 [59.3.%]
women), novel genome-wide significant associations were
obtained in the discovery sample with rs536940594 in
AC099552 (odds ratio [OR], 88.0; 95% CI, 9.08-852.0;
P = 2.22 × 10-7) and rs138412600 in GPAA1 (OR,
1.78; 95% CI, 1.44-2.2; meta-P = 7.81 × 10-8).
GPAA1 was also associated with expression in the brain of
GPAA1 (β = -0.08; P = .03) and its repressive
transcription factor, FOXG1 (β = 0.13; P = .003),
and global cognition function (β = -0.53;
P = .009). Significant gene-wide associations (threshold
P ≤ 6.35 × 10-7) were observed for OR8G5
(P = 4.67 × 10-7), IGHV3-7 (P = 9.75 × 10-16),
and SLC24A3 (P = 2.67 × 10-12) in 2377 patients
with AD and 706 controls with ε4 (mean [SD] age, 75.2 [9.6]
years; 1668 [54.1%] women). CONCLUSIONS AND RELEVANCE: The
study identified multiple possible novel associations for AD
with individual and aggregated rare variants in groups of
individuals with and without APOE ε4 alleles that reinforce
known and suggest additional pathways leading to
AD.},
Doi = {10.1001/jamaneurol.2019.1456},
Key = {fds371159}
}
@article{fds371160,
Author = {Kunkle, BW and Grenier-Boley, B and Sims, R and Bis, JC and Damotte, V and Naj, AC and Boland, A and Vronskaya, M and van der Lee, SJ and Amlie-Wolf, A and Bellenguez, C and Frizatti, A and Chouraki, V and Martin, ER and Sleegers, K and Badarinarayan, N and Jakobsdottir, J and Hamilton-Nelson, KL and Moreno-Grau, S and Olaso, R and Raybould, R and Chen, Y and Kuzma, AB and Hiltunen, M and Morgan, T and Ahmad, S and Vardarajan, BN and Epelbaum, J and Hoffmann, P and Boada, M and Beecham,
GW and Garnier, J-G and Harold, D and Fitzpatrick, AL and Valladares, O and Moutet, M-L and Gerrish, A and Smith, AV and Qu, L and Bacq, D and Denning,
N and Jian, X and Zhao, Y and Del Zompo and M and Fox, NC and Choi, S-H and Mateo, I and Hughes, JT and Adams, HH and Malamon, J and Sanchez-Garcia,
F and Patel, Y and Brody, JA and Dombroski, BA and Naranjo, MCD and Daniilidou, M and Eiriksdottir, G and Mukherjee, S and Wallon, D and Uphill, J and Aspelund, T and Cantwell, LB and Garzia, F and Galimberti,
D and Hofer, E and Butkiewicz, M and Fin, B and Scarpini, E and Sarnowski,
C and Bush, WS and Meslage, S and Kornhuber, J and White, CC and Song, Y and Barber, RC and Engelborghs, S and Sordon, S and Voijnovic, D and Adams,
PM and Vandenberghe, R and Mayhaus, M and Cupples, LA and Albert, MS and De
Deyn, PP and Gu, W and Himali, JJ and Beekly, D and Squassina, A and Hartmann, AM and Orellana, A and Blacker, D and Rodriguez-Rodriguez,
E and Lovestone, S and Garcia, ME and Doody, RS and Munoz-Fernadez, C and Sussams, R and Lin, H and Fairchild, TJ and Benito, YA and Holmes, C and Karamujić-Čomić, H and Frosch, MP and Thonberg, H and Maier, W and Roshchupkin, G and Ghetti, B and Giedraitis, V and Kawalia, A and Li, S and Huebinger, RM and Kilander, L and Moebus, S and Hernández, I and Kamboh, MI and Brundin, R and Turton, J and Yang, Q and Katz, MJ and Concari, L and Lord, J and Beiser, AS and Keene, CD and Helisalmi, S and Kloszewska, I and Kukull, WA and Koivisto, AM and Lynch, A and Tarraga,
L and Larson, EB and Haapasalo, A and Lawlor, B and Mosley, TH and Lipton,
RB and Solfrizzi, V and Gill, M and Longstreth, WT and Montine, TJ and Frisardi, V and Diez-Fairen, M and Rivadeneira, F and Petersen, RC and Deramecourt, V and Alvarez, I and Salani, F and Ciaramella, A and Boerwinkle, E and Reiman, EM and Fievet, N and Rotter, JI and Reisch,
JS and Hanon, O and Cupidi, C and Uitterlinden, AGA and Royall, DR and Dufouil, C and Maletta, RG and de Rojas, I and Sano, M and Brice, A and Cecchetti, R and George-Hyslop, PS and Ritchie, K and Tsolaki, M and Tsuang, DW and Dubois, B and Craig, D and Wu, C-K and Soininen, H and Avramidou, D and Albin, RL and Fratiglioni, L and Germanou, A and Apostolova, LG and Keller, L and Koutroumani, M and Arnold, SE and Panza, F and Gkatzima, O and Asthana, S and Hannequin, D and Whitehead,
P and Atwood, CS and Caffarra, P and Hampel, H and Quintela, I and Carracedo, Á and Lannfelt, L and Rubinsztein, DC and Barnes, LL and Pasquier, F and Frölich, L and Barral, S and McGuinness, B and Beach,
TG and Johnston, JA and Becker, JT and Passmore, P and Bigio, EH and Schott, JM and Bird, TD and Warren, JD and Boeve, BF and Lupton, MK and Bowen, JD and Proitsi, P and Boxer, A and Powell, JF and Burke, JR and Kauwe, JSK and Burns, JM and Mancuso, M and Buxbaum, JD and Bonuccelli,
U and Cairns, NJ and McQuillin, A and Cao, C and Livingston, G and Carlson,
CS and Bass, NJ and Carlsson, CM and Hardy, J and Carney, RM and Bras, J and Carrasquillo, MM and Guerreiro, R and Allen, M and Chui, HC and Fisher,
E and Masullo, C and Crocco, EA and DeCarli, C and Bisceglio, G and Dick,
M and Ma, L and Duara, R and Graff-Radford, NR and Evans, DA and Hodges, A and Faber, KM and Scherer, M and Fallon, KB and Riemenschneider, M and Fardo, DW and Heun, R and Farlow, MR and Kölsch, H and Ferris, S and Leber, M and Foroud, TM and Heuser, I and Galasko, DR and Giegling, I and Gearing, M and Hüll, M and Geschwind, DH and Gilbert, JR and Morris, J and Green, RC and Mayo, K and Growdon, JH and Feulner, T and Hamilton, RL and Harrell, LE and Drichel, D and Honig, LS and Cushion, TD and Huentelman,
MJ and Hollingworth, P and Hulette, CM and Hyman, BT and Marshall, R and Jarvik, GP and Meggy, A and Abner, E and Menzies, GE and Jin, L-W and Leonenko, G and Real, LM and Jun, GR and Baldwin, CT and Grozeva, D and Karydas, A and Russo, G and Kaye, JA and Kim, R and Jessen, F and Kowall,
NW and Vellas, B and Kramer, JH and Vardy, E and LaFerla, FM and Jöckel,
K-H and Lah, JJ and Dichgans, M and Leverenz, JB and Mann, D and Levey, AI and Pickering-Brown, S and Lieberman, AP and Klopp, N and Lunetta, KL and Wichmann, H-E and Lyketsos, CG and Morgan, K and Marson, DC and Brown,
K and Martiniuk, F and Medway, C and Mash, DC and Nöthen, MM and Masliah,
E and Hooper, NM and McCormick, WC and Daniele, A and McCurry, SM and Bayer, A and McDavid, AN and Gallacher, J and McKee, AC and van den
Bussche, H and Mesulam, M and Brayne, C and Miller, BL and Riedel-Heller, S and Miller, CA and Miller, JW and Al-Chalabi, A and Morris, JC and Shaw, CE and Myers, AJ and Wiltfang, J and O'Bryant, S and Olichney, JM and Alvarez, V and Parisi, JE and Singleton, AB and Paulson, HL and Collinge, J and Perry, WR and Mead, S and Peskind, E and Cribbs, DH and Rossor, M and Pierce, A and Ryan, NS and Poon, WW and Nacmias, B and Potter, H and Sorbi, S and Quinn, JF and Sacchinelli, E and Raj, A and Spalletta, G and Raskind, M and Caltagirone, C and Bossù, P and Orfei, MD and Reisberg, B and Clarke, R and Reitz, C and Smith, AD and Ringman, JM and Warden, D and Roberson, ED and Wilcock, G and Rogaeva,
E and Bruni, AC and Rosen, HJ and Gallo, M and Rosenberg, RN and Ben-Shlomo, Y and Sager, MA and Mecocci, P and Saykin, AJ and Pastor, P and Cuccaro, ML and Vance, JM and Schneider, JA and Schneider, LS and Slifer, S and Seeley, WW and Smith, AG and Sonnen, JA and Spina, S and Stern, RA and Swerdlow, RH and Tang, M and Tanzi, RE and Trojanowski,
JQ and Troncoso, JC and Van Deerlin and VM and Van Eldik and LJ and Vinters,
HV and Vonsattel, JP and Weintraub, S and Welsh-Bohmer, KA and Wilhelmsen, KC and Williamson, J and Wingo, TS and Woltjer, RL and Wright, CB and Yu, C-E and Yu, L and Saba, Y and Alzheimer Disease
Genetics Consortium (ADGC), and European Alzheimer’s Disease
Initiative (EADI), and Cohorts for Heart and Aging Research in
Genomic Epidemiology Consortium (CHARGE), and Genetic and Environmental Risk in AD/Defining Genetic and Polygenic and Environmental Risk for Alzheimer’s Disease Consortium
(GERAD/PERADES), and Pilotto, A and Bullido, MJ and Peters, O and Crane, PK and Bennett, D and Bosco, P and Coto, E and Boccardi, V and De
Jager, PL and Lleo, A and Warner, N and Lopez, OL and Ingelsson, M and Deloukas, P and Cruchaga, C and Graff, C and Gwilliam, R and Fornage, M and Goate, AM and Sanchez-Juan, P and Kehoe, PG and Amin, N and Ertekin-Taner, N and Berr, C and Debette, S and Love, S and Launer, LJ and Younkin, SG and Dartigues, J-F and Corcoran, C and Ikram, MA and Dickson, DW and Nicolas, G and Campion, D and Tschanz, J and Schmidt, H and Hakonarson, H and Clarimon, J and Munger, R and Schmidt, R and Farrer,
LA and Van Broeckhoven and C and O'Donovan, MC and DeStefano, AL and Jones,
L and Haines, JL and Deleuze, J-F and Owen, MJ and Gudnason, V and Mayeux,
R and Escott-Price, V and Psaty, BM and Ramirez, A and Wang, L-S and Ruiz,
A and van Duijn, CM and Holmans, PA and Seshadri, S and Williams, J and Amouyel, P and Schellenberg, GD and Lambert, J-C and Pericak-Vance,
MA},
Title = {Author Correction: Genetic meta-analysis of diagnosed
Alzheimer's disease identifies new risk loci and implicates
Aβ, tau, immunity and lipid processing.},
Journal = {Nat Genet},
Volume = {51},
Number = {9},
Pages = {1423-1424},
Year = {2019},
Month = {September},
url = {http://dx.doi.org/10.1038/s41588-019-0495-7},
Abstract = {An amendment to this paper has been published and can be
accessed via a link at the top of the paper.},
Doi = {10.1038/s41588-019-0495-7},
Key = {fds371160}
}
@article{fds345607,
Author = {Mathew, JP and Welsh-Bohmer, KA and Newman, MF},
Title = {Nomenclature for Perioperative Cognitive Disorders:
Comment.},
Journal = {Anesthesiology},
Volume = {131},
Number = {2},
Pages = {443-444},
Year = {2019},
Month = {August},
url = {http://dx.doi.org/10.1097/ALN.0000000000002831},
Doi = {10.1097/ALN.0000000000002831},
Key = {fds345607}
}
@article{fds371161,
Author = {Ma, Y and Jun, GR and Chung, J and Zhang, X and Kunkle, BW and Naj, AC and White, CC and Bennett, DA and De Jager and PL and Alzheimer’s Disease
Genetics Consortium, and Mayeux, R and Haines, JL and Pericak-Vance,
MA and Schellenberg, GD and Farrer, LA and Lunetta,
KL},
Title = {CpG-related SNPs in the MS4A region have a dose-dependent
effect on risk of late-onset Alzheimer disease.},
Journal = {Aging Cell},
Volume = {18},
Number = {4},
Pages = {e12964},
Year = {2019},
Month = {August},
url = {http://dx.doi.org/10.1111/acel.12964},
Abstract = {CpG-related single nucleotide polymorphisms (CGS) have the
potential to perturb DNA methylation; however, their effects
on Alzheimer disease (AD) risk have not been evaluated
systematically. We conducted a genome-wide association study
using a sliding-window approach to measure the combined
effects of CGSes on AD risk in a discovery sample of 24
European ancestry cohorts (12,181 cases, 12,601 controls)
from the Alzheimer's Disease Genetics Consortium (ADGC) and
replication sample of seven European ancestry cohorts (7,554
cases, 27,382 controls) from the International Genomics of
Alzheimer's Project (IGAP). The potential functional
relevance of significant associations was evaluated by
analysis of methylation and expression levels in brain
tissue of the Religious Orders Study and the Rush Memory and
Aging Project (ROSMAP), and in whole blood of Framingham
Heart Study participants (FHS). Genome-wide significant
(p < 5 × 10-8 ) associations were identified with 171
1.0 kb-length windows spanning 932 kb in the APOE region
(top p < 2.2 × 10-308 ), five windows at BIN1 (top
p = 1.3 × 10-13 ), two windows at MS4A6A (top
p = 2.7 × 10-10 ), two windows near MS4A4A (top
p = 6.4 × 10-10 ), and one window at PICALM
(p = 6.3 × 10-9 ). The total number of CGS-derived CpG
dinucleotides in the window near MS4A4A was associated with
AD risk (p = 2.67 × 10-10 ), brain DNA methylation
(p = 2.15 × 10-10 ), and gene expression in brain
(p = 0.03) and blood (p = 2.53 × 10-4 ). Pathway
analysis of the genes responsive to changes in the
methylation quantitative trait locus signal at MS4A4A
(cg14750746) showed an enrichment of methyltransferase
functions. We confirm the importance of CGS in AD and the
potential for creating a functional CpG dosage-derived
genetic score to predict AD risk.},
Doi = {10.1111/acel.12964},
Key = {fds371161}
}
@article{fds343521,
Author = {Klinger, RY and Cooter, M and Bisanar, T and Terrando, N and Berger, M and Podgoreanu, MV and Stafford-Smith, M and Newman, MF and Mathew, JP and Neurologic Outcomes Research Group of the Duke Heart
Center},
Title = {Intravenous Lidocaine Does Not Improve Neurologic Outcomes
after Cardiac Surgery: A Randomized Controlled
Trial.},
Journal = {Anesthesiology},
Volume = {130},
Number = {6},
Pages = {958-970},
Year = {2019},
Month = {June},
url = {http://dx.doi.org/10.1097/ALN.0000000000002668},
Abstract = {BACKGROUND: Cognitive decline after cardiac surgery occurs
frequently and persists in a significant proportion of
patients. Preclinical studies and human trials suggest that
intravenous lidocaine may confer protection in the setting
of neurologic injury. It was hypothesized that lidocaine
administration would reduce cognitive decline after cardiac
surgery compared to placebo. METHODS: After institutional
review board approval, 478 patients undergoing cardiac
surgery were enrolled into this multicenter, prospective,
randomized, double-blinded, placebo-controlled, parallel
group trial. Subjects were randomized to lidocaine 1 mg/kg
bolus after the induction of anesthesia followed by a
continuous infusion (48 μg · kg · min for the first hour,
24 μg · kg · min for the second hour, and 10 μg · kg ·
min for the next 46 h) or saline with identical volume and
rate changes to preserve blinding. Cognitive function was
assessed preoperatively and at 6 weeks and 1 yr
postoperatively using a standard neurocognitive test
battery. The primary outcome was change in cognitive
function between baseline and 6 weeks postoperatively,
adjusting for age, years of education, baseline cognition,
race, and procedure type. RESULTS: Among the 420 allocated
subjects who returned for 6-week follow-up (lidocaine: N =
211; placebo: N = 209), there was no difference in the
continuous cognitive score change (adjusted mean difference
[95% CI], 0.02 (-0.05, 0.08); P = 0.626). Cognitive deficit
(greater than 1 SD decline in at least one cognitive domain)
at 6 weeks occurred in 41% (87 of 211) in the lidocaine
group versus 40% (83 of 209) in the placebo group (adjusted
odds ratio [95% CI], 0.94 [0.63, 1.41]; P = 0.766). There
were no differences in any quality of life outcomes between
treatment groups. At the 1-yr follow-up, there continued to
be no difference in cognitive score change, cognitive
deficit, or quality of life. CONCLUSIONS: Intravenous
lidocaine administered during and after cardiac surgery did
not reduce postoperative cognitive decline at 6
weeks.},
Doi = {10.1097/ALN.0000000000002668},
Key = {fds343521}
}
@article{fds371162,
Author = {Goudey, B and Fung, BJ and Schieber, C and Faux, NG and Alzheimer’s
Disease Metabolomics Consortium, and Alzheimer’s Disease
Neuroimaging Initiative},
Title = {A blood-based signature of cerebrospinal fluid Aβ1-42
status.},
Journal = {Sci Rep},
Volume = {9},
Number = {1},
Pages = {4163},
Year = {2019},
Month = {March},
url = {http://dx.doi.org/10.1038/s41598-018-37149-7},
Abstract = {It is increasingly recognized that Alzheimer's disease (AD)
exists before dementia is present and that shifts in amyloid
beta occur long before clinical symptoms can be detected.
Early detection of these molecular changes is a key aspect
for the success of interventions aimed at slowing down rates
of cognitive decline. Recent evidence indicates that of the
two established methods for measuring amyloid, a decrease in
cerebrospinal fluid (CSF) amyloid β1-42 (Aβ1-42) may be an
earlier indicator of Alzheimer's disease risk than measures
of amyloid obtained from Positron Emission Tomography (PET).
However, CSF collection is highly invasive and expensive. In
contrast, blood collection is routinely performed, minimally
invasive and cheap. In this work, we develop a blood-based
signature that can provide a cheap and minimally invasive
estimation of an individual's CSF amyloid status using a
machine learning approach. We show that a Random Forest
model derived from plasma analytes can accurately predict
subjects as having abnormal (low) CSF Aβ1-42 levels
indicative of AD risk (0.84 AUC, 0.78 sensitivity, and 0.73
specificity). Refinement of the modeling indicates that only
APOEε4 carrier status and four plasma analytes (CGA,
Aβ1-42, Eotaxin 3, APOE) are required to achieve a high
level of accuracy. Furthermore, we show across an
independent validation cohort that individuals with
predicted abnormal CSF Aβ1-42 levels transitioned to an AD
diagnosis over 120 months significantly faster than those
with predicted normal CSF Aβ1-42 levels and that the
resulting model also validates reasonably across PET Aβ1-42
status (0.78 AUC). This is the first study to show that a
machine learning approach, using plasma protein levels, age
and APOEε4 carrier status, is able to predict CSF Aβ1-42
status, the earliest risk indicator for AD, with high
accuracy.},
Doi = {10.1038/s41598-018-37149-7},
Key = {fds371162}
}
@article{fds371163,
Author = {Kunkle, BW and Grenier-Boley, B and Sims, R and Bis, JC and Damotte, V and Naj, AC and Boland, A and Vronskaya, M and van der Lee, SJ and Amlie-Wolf, A and Bellenguez, C and Frizatti, A and Chouraki, V and Martin, ER and Sleegers, K and Badarinarayan, N and Jakobsdottir, J and Hamilton-Nelson, KL and Moreno-Grau, S and Olaso, R and Raybould, R and Chen, Y and Kuzma, AB and Hiltunen, M and Morgan, T and Ahmad, S and Vardarajan, BN and Epelbaum, J and Hoffmann, P and Boada, M and Beecham,
GW and Garnier, J-G and Harold, D and Fitzpatrick, AL and Valladares, O and Moutet, M-L and Gerrish, A and Smith, AV and Qu, L and Bacq, D and Denning,
N and Jian, X and Zhao, Y and Del Zompo and M and Fox, NC and Choi, S-H and Mateo, I and Hughes, JT and Adams, HH and Malamon, J and Sanchez-Garcia,
F and Patel, Y and Brody, JA and Dombroski, BA and Naranjo, MCD and Daniilidou, M and Eiriksdottir, G and Mukherjee, S and Wallon, D and Uphill, J and Aspelund, T and Cantwell, LB and Garzia, F and Galimberti,
D and Hofer, E and Butkiewicz, M and Fin, B and Scarpini, E and Sarnowski,
C and Bush, WS and Meslage, S and Kornhuber, J and White, CC and Song, Y and Barber, RC and Engelborghs, S and Sordon, S and Voijnovic, D and Adams,
PM and Vandenberghe, R and Mayhaus, M and Cupples, LA and Albert, MS and De
Deyn, PP and Gu, W and Himali, JJ and Beekly, D and Squassina, A and Hartmann, AM and Orellana, A and Blacker, D and Rodriguez-Rodriguez,
E and Lovestone, S and Garcia, ME and Doody, RS and Munoz-Fernadez, C and Sussams, R and Lin, H and Fairchild, TJ and Benito, YA and Holmes, C and Karamujić-Čomić, H and Frosch, MP and Thonberg, H and Maier, W and Roshchupkin, G and Ghetti, B and Giedraitis, V and Kawalia, A and Li, S and Huebinger, RM and Kilander, L and Moebus, S and Hernández, I and Kamboh, MI and Brundin, R and Turton, J and Yang, Q and Katz, MJ and Concari, L and Lord, J and Beiser, AS and Keene, CD and Helisalmi, S and Kloszewska, I and Kukull, WA and Koivisto, AM and Lynch, A and Tarraga,
L and Larson, EB and Haapasalo, A and Lawlor, B and Mosley, TH and Lipton,
RB and Solfrizzi, V and Gill, M and Longstreth, WT and Montine, TJ and Frisardi, V and Diez-Fairen, M and Rivadeneira, F and Petersen, RC and Deramecourt, V and Alvarez, I and Salani, F and Ciaramella, A and Boerwinkle, E and Reiman, EM and Fievet, N and Rotter, JI and Reisch,
JS and Hanon, O and Cupidi, C and Andre Uitterlinden and AG and Royall, DR and Dufouil, C and Maletta, RG and de Rojas, I and Sano, M and Brice, A and Cecchetti, R and George-Hyslop, PS and Ritchie, K and Tsolaki, M and Tsuang, DW and Dubois, B and Craig, D and Wu, C-K and Soininen, H and Avramidou, D and Albin, RL and Fratiglioni, L and Germanou, A and Apostolova, LG and Keller, L and Koutroumani, M and Arnold, SE and Panza, F and Gkatzima, O and Asthana, S and Hannequin, D and Whitehead,
P and Atwood, CS and Caffarra, P and Hampel, H and Quintela, I and Carracedo, Á and Lannfelt, L and Rubinsztein, DC and Barnes, LL and Pasquier, F and Frölich, L and Barral, S and McGuinness, B and Beach,
TG and Johnston, JA and Becker, JT and Passmore, P and Bigio, EH and Schott, JM and Bird, TD and Warren, JD and Boeve, BF and Lupton, MK and Bowen, JD and Proitsi, P and Boxer, A and Powell, JF and Burke, JR and Kauwe, JSK and Burns, JM and Mancuso, M and Buxbaum, JD and Bonuccelli,
U and Cairns, NJ and McQuillin, A and Cao, C and Livingston, G and Carlson,
CS and Bass, NJ and Carlsson, CM and Hardy, J and Carney, RM and Bras, J and Carrasquillo, MM and Guerreiro, R and Allen, M and Chui, HC and Fisher,
E and Masullo, C and Crocco, EA and DeCarli, C and Bisceglio, G and Dick,
M and Ma, L and Duara, R and Graff-Radford, NR and Evans, DA and Hodges, A and Faber, KM and Scherer, M and Fallon, KB and Riemenschneider, M and Fardo, DW and Heun, R and Farlow, MR and Kölsch, H and Ferris, S and Leber, M and Foroud, TM and Heuser, I and Galasko, DR and Giegling, I and Gearing, M and Hüll, M and Geschwind, DH and Gilbert, JR and Morris, J and Green, RC and Mayo, K and Growdon, JH and Feulner, T and Hamilton, RL and Harrell, LE and Drichel, D and Honig, LS and Cushion, TD and Huentelman,
MJ and Hollingworth, P and Hulette, CM and Hyman, BT and Marshall, R and Jarvik, GP and Meggy, A and Abner, E and Menzies, GE and Jin, L-W and Leonenko, G and Real, LM and Jun, GR and Baldwin, CT and Grozeva, D and Karydas, A and Russo, G and Kaye, JA and Kim, R and Jessen, F and Kowall,
NW and Vellas, B and Kramer, JH and Vardy, E and LaFerla, FM and Jöckel,
K-H and Lah, JJ and Dichgans, M and Leverenz, JB and Mann, D and Levey, AI and Pickering-Brown, S and Lieberman, AP and Klopp, N and Lunetta, KL and Wichmann, H-E and Lyketsos, CG and Morgan, K and Marson, DC and Brown,
K and Martiniuk, F and Medway, C and Mash, DC and Nöthen, MM and Masliah,
E and Hooper, NM and McCormick, WC and Daniele, A and McCurry, SM and Bayer, A and McDavid, AN and Gallacher, J and McKee, AC and van den
Bussche, H and Mesulam, M and Brayne, C and Miller, BL and Riedel-Heller, S and Miller, CA and Miller, JW and Al-Chalabi, A and Morris, JC and Shaw, CE and Myers, AJ and Wiltfang, J and O'Bryant, S and Olichney, JM and Alvarez, V and Parisi, JE and Singleton, AB and Paulson, HL and Collinge, J and Perry, WR and Mead, S and Peskind, E and Cribbs, DH and Rossor, M and Pierce, A and Ryan, NS and Poon, WW and Nacmias, B and Potter, H and Sorbi, S and Quinn, JF and Sacchinelli, E and Raj, A and Spalletta, G and Raskind, M and Caltagirone, C and Bossù, P and Orfei, MD and Reisberg, B and Clarke, R and Reitz, C and Smith, AD and Ringman, JM and Warden, D and Roberson, ED and Wilcock, G and Rogaeva,
E and Bruni, AC and Rosen, HJ and Gallo, M and Rosenberg, RN and Ben-Shlomo, Y and Sager, MA and Mecocci, P and Saykin, AJ and Pastor, P and Cuccaro, ML and Vance, JM and Schneider, JA and Schneider, LS and Slifer, S and Seeley, WW and Smith, AG and Sonnen, JA and Spina, S and Stern, RA and Swerdlow, RH and Tang, M and Tanzi, RE and Trojanowski,
JQ and Troncoso, JC and Van Deerlin and VM and Van Eldik and LJ and Vinters,
HV and Vonsattel, JP and Weintraub, S and Welsh-Bohmer, KA and Wilhelmsen, KC and Williamson, J and Wingo, TS and Woltjer, RL and Wright, CB and Yu, C-E and Yu, L and Saba, Y and Pilotto, A and Bullido,
MJ and Peters, O and Crane, PK and Bennett, D and Bosco, P and Coto, E and Boccardi, V and De Jager and PL and Lleo, A and Warner, N and Lopez, OL and Ingelsson, M and Deloukas, P and Cruchaga, C and Graff, C and Gwilliam,
R and Fornage, M and Goate, AM and Sanchez-Juan, P and Kehoe, PG and Amin,
N and Ertekin-Taner, N and Berr, C and Debette, S and Love, S and Launer,
LJ and Younkin, SG and Dartigues, J-F and Corcoran, C and Ikram, MA and Dickson, DW and Nicolas, G and Campion, D and Tschanz, J and Schmidt, H and Hakonarson, H and Clarimon, J and Munger, R and Schmidt, R and Farrer,
LA and Van Broeckhoven and C and C O'Donovan and M and DeStefano, AL and Jones, L and Haines, JL and Deleuze, J-F and Owen, MJ and Gudnason, V and Mayeux, R and Escott-Price, V and Psaty, BM and Ramirez, A and Wang,
L-S and Ruiz, A and van Duijn, CM and Holmans, PA and Seshadri, S and Williams, J and Amouyel, P and Schellenberg, GD and Lambert, J-C and Pericak-Vance, MA and Alzheimer Disease Genetics Consortium
(ADGC),, and European Alzheimer’s Disease Initiative
(EADI),, and Cohorts for Heart and Aging Research in Genomic
Epidemiology Consortium (CHARGE),, and Genetic and Environmental Risk in AD/Defining Genetic and Polygenic and Environmental Risk for Alzheimer’s Disease Consortium
(GERAD/PERADES)},
Title = {Genetic meta-analysis of diagnosed Alzheimer's disease
identifies new risk loci and implicates Aβ, tau, immunity
and lipid processing.},
Journal = {Nat Genet},
Volume = {51},
Number = {3},
Pages = {414-430},
Year = {2019},
Month = {March},
url = {http://dx.doi.org/10.1038/s41588-019-0358-2},
Abstract = {Risk for late-onset Alzheimer's disease (LOAD), the most
prevalent dementia, is partially driven by genetics. To
identify LOAD risk loci, we performed a large genome-wide
association meta-analysis of clinically diagnosed LOAD
(94,437 individuals). We confirm 20 previous LOAD risk loci
and identify five new genome-wide loci (IQCK, ACE, ADAM10,
ADAMTS1, and WWOX), two of which (ADAM10, ACE) were
identified in a recent genome-wide association
(GWAS)-by-familial-proxy of Alzheimer's or dementia.
Fine-mapping of the human leukocyte antigen (HLA) region
confirms the neurological and immune-mediated disease
haplotype HLA-DR15 as a risk factor for LOAD. Pathway
analysis implicates immunity, lipid metabolism, tau binding
proteins, and amyloid precursor protein (APP) metabolism,
showing that genetic variants affecting APP and Aβ
processing are associated not only with early-onset
autosomal dominant Alzheimer's disease but also with LOAD.
Analyses of risk genes and pathways show enrichment for rare
variants (P = 1.32 × 10-7), indicating that
additional rare variants remain to be identified. We also
identify important genetic correlations between LOAD and
traits such as family history of dementia and
education.},
Doi = {10.1038/s41588-019-0358-2},
Key = {fds371163}
}
@article{fds371164,
Author = {Hu, Y and Li, M and Lu, Q and Weng, H and Wang, J and Zekavat, SM and Yu, Z and Li, B and Gu, J and Muchnik, S and Shi, Y and Kunkle, BW and Mukherjee, S and Natarajan, P and Naj, A and Kuzma, A and Zhao, Y and Crane, PK and Alzheimer’s Disease Genetics Consortium,, and Lu, H and Zhao,
H},
Title = {A statistical framework for cross-tissue transcriptome-wide
association analysis.},
Journal = {Nat Genet},
Volume = {51},
Number = {3},
Pages = {568-576},
Year = {2019},
Month = {March},
url = {http://dx.doi.org/10.1038/s41588-019-0345-7},
Abstract = {Transcriptome-wide association analysis is a powerful
approach to studying the genetic architecture of complex
traits. A key component of this approach is to build a model
to impute gene expression levels from genotypes by using
samples with matched genotypes and gene expression data in a
given tissue. However, it is challenging to develop robust
and accurate imputation models with a limited sample size
for any single tissue. Here, we first introduce a multi-task
learning method to jointly impute gene expression in 44
human tissues. Compared with single-tissue methods, our
approach achieved an average of 39% improvement in
imputation accuracy and generated effective imputation
models for an average of 120% more genes. We describe a
summary-statistic-based testing framework that combines
multiple single-tissue associations into a powerful metric
to quantify the overall gene-trait association. We applied
our method, called UTMOST (unified test for molecular
signatures), to multiple genome-wide-association results and
demonstrate its advantages over single-tissue
strategies.},
Doi = {10.1038/s41588-019-0345-7},
Key = {fds371164}
}
@article{fds341018,
Author = {Blumenthal, JA and Smith, PJ and Mabe, S and Hinderliter, A and Lin,
P-H and Liao, L and Welsh-Bohmer, KA and Browndyke, JN and Kraus, WE and Doraiswamy, PM and Burke, JR and Sherwood, A},
Title = {Lifestyle and neurocognition in older adults with cognitive
impairments: A randomized trial.},
Journal = {Neurology},
Volume = {92},
Number = {3},
Pages = {e212-e223},
Year = {2019},
Month = {January},
url = {http://dx.doi.org/10.1212/WNL.0000000000006784},
Abstract = {OBJECTIVE: To determine the independent and additive effects
of aerobic exercise (AE) and the Dietary Approaches to Stop
Hypertension (DASH) diet on executive functioning in adults
with cognitive impairments with no dementia (CIND) and risk
factors for cardiovascular disease (CVD). METHODS: A 2-by-2
factorial (exercise/no exercise and DASH diet/no DASH diet)
randomized clinical trial was conducted in 160 sedentary men
and women (age >55 years) with CIND and CVD risk factors.
Participants were randomly assigned to 6 months of AE, DASH
diet nutritional counseling, a combination of both AE and
DASH, or health education (HE). The primary endpoint was a
prespecified composite measure of executive function;
secondary outcomes included measures of language/verbal
fluency, memory, and ratings on the modified Clinical
Dementia Rating Scale. RESULTS: Participants who engaged in
AE (d = 0.32, p = 0.046) but not those who consumed the DASH
diet (d = 0.30, p = 0.059) demonstrated significant
improvements in the executive function domain. The largest
improvements were observed for participants randomized to
the combined AE and DASH diet group (d = 0.40, p = 0.012)
compared to those receiving HE. Greater aerobic fitness (b =
2.3, p = 0.049), reduced CVD risk (b = 2.6, p = 0.042), and
reduced sodium intake (b = 0.18, p = 0.024) were associated
with improvements in executive function. There were no
significant improvements in the memory or language/verbal
fluency domains. CONCLUSIONS: These preliminary findings
show that AE promotes improved executive functioning in
adults at risk for cognitive decline. CLINICALTRIALSGOV
IDENTIFIER: NCT01573546. CLASSIFICATION OF EVIDENCE: This
study provides Class I evidence that for adults with CIND,
AE but not the DASH diet significantly improves executive
functioning.},
Doi = {10.1212/WNL.0000000000006784},
Key = {fds341018}
}
@article{fds341567,
Author = {Tsui-Caldwell, YHW and Farrer, TJ and McDonnell, Z and Christensen,
Z and Finuf, C and Bigler, ED and Tschanz, JT and Norton, MC and Welsh-Bohmer, KA},
Title = {MRI Clinical Ratings and Cognitive Function in a
Cross-Sectional Population Study of Dementia: The Cache
County Memory Study.},
Journal = {J Prev Alzheimers Dis},
Volume = {6},
Number = {2},
Pages = {100-107},
Year = {2019},
url = {http://dx.doi.org/10.14283/jpad.2019.1},
Abstract = {BACKGROUND: White matter integrity in aging populations is
associated with increased risk of cognitive decline,
dementia diagnosis, and mortality. Population-based data can
elucidate this association. OBJECTIVES: To examine the
association between white matter integrity, as measured by a
clinical rating scale of hyperintensities, and mental status
in older adults including advanced aging. DESIGN: Scheltens
Ratings Scale was used to qualitatively assess white matter
(WM) hyperintensities in participants of the Cache County
Memory Study (CCMS), an epidemiological study of Alzheimer's
disease in an exceptionally long-lived population. Further,
the relation between Mini-Mental State Exam (MMSE) and WM
hyperintensities were explored. METHOD: Participants
consisted of 415 individuals with dementia and 22 healthy
controls. RESULTS: CCMS participants, including healthy
controls, had high levels of WM pathology as measured by
Scheltens Ratings Scale score. While age did not
significantly relate to WM pathology, higher Scheltens
Ratings Scale scores were associated with lower MMSE
findings (correlation between -0.14 and -0.22; p < .05).
CONCLUSIONS: WM pathology was common in this county-wide
population sample of those ranging in age from 65 to 106.
Increased WM burden was found to be significantly associated
with decreased overall MMSE performance.},
Doi = {10.14283/jpad.2019.1},
Key = {fds341567}
}
@article{fds344656,
Author = {Knodt, AR and Burke, JR and Welsh-Bohmer, KA and Plassman, BL and Burns,
DK and Brannan, SK and Kukulka, M and Wu, J and Hariri,
AR},
Title = {Effects of pioglitazone on mnemonic hippocampal function: A
blood oxygen level-dependent functional magnetic resonance
imaging study in elderly adults.},
Journal = {Alzheimers Dement (N Y)},
Volume = {5},
Pages = {254-263},
Year = {2019},
url = {http://dx.doi.org/10.1016/j.trci.2019.05.004},
Abstract = {INTRODUCTION: Mitochondrial dysfunction is implicated in the
pathophysiology of Alzheimer's disease (AD). Accordingly,
drugs that positively influence mitochondrial function are
being evaluated in delay-of-onset clinical trials with
at-risk individuals. Such ongoing clinical research can be
advanced by developing a better understanding of how these
drugs affect intermediate brain phenotypes associated with
both AD risk and pathophysiology. METHODS: Using a
randomized, parallel-group, placebo-controlled design in 55
healthy elderly volunteers, we explored the effects of oral,
low-dose pioglitazone, a thiazolidinedione with
promitochondrial effects, on hippocampal activity measured
with functional magnetic resonance imaging during the
encoding of novel face-name pairs. RESULTS: Compared with
placebo, 0.6 mg of pioglitazone (but not 2.1 mg, 3.9 mg,
or 6.0 mg) administered daily for 14 days was associated
with significant increases in right hippocampal activation
during encoding of novel face-name pairs at day 7 and day
14, relative to baseline. DISCUSSION: Our exploratory
analyses suggest that low-dose pioglitazone has measurable
effects on mnemonic brain function associated with AD risk
and pathophysiology.},
Doi = {10.1016/j.trci.2019.05.004},
Key = {fds344656}
}
@article{fds346727,
Author = {Smith, PJ and Mabe, S and Sherwood, A and Babyak, MA and Doraiswamy, PM and Welsh-Bohmer, KA and Kraus, W and Burke, J and Hinderliter, A and Blumenthal, JA},
Title = {Association Between Insulin Resistance, Plasma Leptin, and
Neurocognition in Vascular Cognitive Impairment.},
Journal = {J Alzheimers Dis},
Volume = {71},
Number = {3},
Pages = {921-929},
Year = {2019},
url = {http://dx.doi.org/10.3233/JAD-190569},
Abstract = {BACKGROUND: Greater body weight has been associated
impairments in neurocognition and greater dementia risk,
although the mechanisms linking weight and neurocognition
have yet to be adequately delineated. OBJECTIVE: To examine
metabolic mechanisms underlying the association between
obesity and neurocognition. METHODS: We conducted a
secondary analysis of weight, neurocognition, and the
potentially mediating role of metabolic and inflammatory
biomarkers among 160 participants from the ENLIGHTEN trial
of vascular cognitive impairment, no dementia (CIND).
Neurocognition was assessed using a 45-minute assessment
battery assessing Executive Function, Verbal and Visual
Memory. We considered three metabolic biomarkers: insulin
resistance (homeostatic model assessment [HOMA-IR]), plasma
leptin, and insulin-like growth factor (IGF-1). Inflammation
was assessed using C-reactive protein. Multiple regression
analyses were used. RESULTS: Participants included 160
sedentary older adults with CIND. Participants tended to be
overweight or obese (mean BMI = 32.5 [SD = 4.8]).
Women exhibited higher BMI (p = 0.043), CRP
(p < 0.001), and leptin (p < 0.001) compared with
men. Higher BMI levels were associated with worse
performance on measures of Executive Function (β= -0.16,
p = 0.024) and Verbal Memory (β= -0.16,
p = 0.030), but not Visual Memory (β= 0.05,
p = 0.500). Worse metabolic biomarker profiles also were
associated with lower Executive Function (β= -0.12,
p = 0.050). Mediation analyses suggested leptin was a
plausible candidate as a mediator between BMI and Executive
Function. CONCLUSIONS: In overweight and obese adults with
vascular CIND, the association between greater weight and
poorer executive function may be mediated by higher leptin
resistance.},
Doi = {10.3233/JAD-190569},
Key = {fds346727}
}
@article{fds346902,
Author = {Burns, DK and Chiang, C and Welsh-Bohmer, KA and Brannan, SK and Culp,
M and O'Neil, J and Runyan, G and Harrigan, P and Plassman, BL and Lutz, M and Lai, E and Haneline, S and Yarnall, D and Yarbrough, D and Metz, C and Ponduru, S and Sundseth, S and Saunders, AM},
Title = {The TOMMORROW study: Design of an Alzheimer's disease
delay-of-onset clinical trial.},
Journal = {Alzheimers Dement (N Y)},
Volume = {5},
Pages = {661-670},
Year = {2019},
url = {http://dx.doi.org/10.1016/j.trci.2019.09.010},
Abstract = {INTRODUCTION: Alzheimer's disease (AD) is a continuum with
neuropathologies manifesting years before clinical symptoms;
thus, AD research is attempting to identify more
disease-modifying approaches to test treatments administered
before full disease expression. Designing such trials in
cognitively normal elderly individuals poses unique
challenges. METHODS: The TOMMORROW study was a phase 3
double-blind, parallel-group study designed to support
qualification of a novel genetic biomarker risk assignment
algorithm (BRAA) and to assess efficacy and safety of
low-dose pioglitazone to delay onset of mild cognitive
impairment due to AD. Eligible participants were stratified
based on the BRAA (using TOMM40 rs 10524523 genotype,
Apolipoprotein E genotype, and age), with high-risk
individuals receiving low-dose pioglitazone or placebo and
low-risk individuals receiving placebo. The primary endpoint
was time to the event of mild cognitive impairment due to
AD. The primary objectives were to compare the primary
endpoint between high- and low-risk placebo groups (for BRAA
qualification) and between high-risk pioglitazone and
high-risk placebo groups (for pioglitazone efficacy).
Approximately 300 individuals were also asked to participate
in a volumetric magnetic resonance imaging substudy at
selected sites. RESULTS: The focus of this paper is on the
design of the study; study results will be presented in a
separate paper. DISCUSSION: The design of the TOMMORROW
study addressed many key challenges to conducting a
dual-objective phase 3 pivotal AD clinical trial in
presymptomatic individuals. Experiences from planning and
executing the TOMMORROW study may benefit future AD
prevention/delay-of-onset trials.},
Doi = {10.1016/j.trci.2019.09.010},
Key = {fds346902}
}
@article{fds351449,
Author = {Gauthier, S and Alam, J and Fillit, H and Iwatsubo, T and Liu-Seifert,
H and Sabbagh, M and Salloway, S and Sampaio, C and Sims, JR and Sperling,
B and Sperling, R and Welsh-Bohmer, KA and Touchon, J and Vellas, B and Aisen, P},
Title = {Combination Therapy for Alzheimer's Disease: Perspectives of
the EU/US CTAD Task Force.},
Journal = {J Prev Alzheimers Dis},
Volume = {6},
Number = {3},
Pages = {164-168},
Year = {2019},
url = {http://dx.doi.org/10.14283/jpad.2019.12},
Abstract = {Combination therapy is expected to play an important role
for the treatment of Alzheimer's disease (AD). In October
2018, the European Union-North American Clinical Trials in
Alzheimer's Disease Task Force (EU/US CTAD Task Force) met
to discuss scientific, regulatory, and logistical challenges
to the development of combination therapy for AD and current
efforts to address these challenges. Task Force members
unanimously agreed that successful treatment of AD will
likely require combination therapy approaches that target
multiple mechanisms and pathways. They further agreed on the
need for global collaboration and sharing of data and
resources to accelerate development of such
approaches.},
Doi = {10.14283/jpad.2019.12},
Key = {fds351449}
}
@article{fds340273,
Author = {Deming, Y and Dumitrescu, L and Barnes, LL and Thambisetty, M and Kunkle, B and Gifford, KA and Bush, WS and Chibnik, LB and Mukherjee, S and De Jager and PL and Kukull, W and Huentelman, M and Crane, PK and Resnick,
SM and Keene, CD and Montine, TJ and Schellenberg, GD and Haines, JL and Zetterberg, H and Blennow, K and Larson, EB and Johnson, SC and Albert,
M and Moghekar, A and Del Aguila and JL and Fernandez, MV and Budde, J and Hassenstab, J and Fagan, AM and Riemenschneider, M and Petersen, RC and Minthon, L and Chao, MJ and Van Deerlin and VM and Lee, VM-Y and Shaw, LM and Trojanowski, JQ and Peskind, ER and Li, G and Davis, LK and Sealock, JM and Cox, NJ and Alzheimer’s Disease Neuroimaging Initiative
(ADNI), and Alzheimer Disease Genetics Consortium (ADGC), and Goate, AM and Bennett, DA and Schneider, JA and Jefferson, AL and Cruchaga, C and Hohman, TJ},
Title = {Sex-specific genetic predictors of Alzheimer's disease
biomarkers.},
Journal = {Acta Neuropathol},
Volume = {136},
Number = {6},
Pages = {857-872},
Publisher = {Springer Nature},
Year = {2018},
Month = {December},
url = {http://dx.doi.org/10.1007/s00401-018-1881-4},
Abstract = {Cerebrospinal fluid (CSF) levels of amyloid-β 42 (Aβ42)
and tau have been evaluated as endophenotypes in Alzheimer's
disease (AD) genetic studies. Although there are sex
differences in AD risk, sex differences have not been
evaluated in genetic studies of AD endophenotypes. We
performed sex-stratified and sex interaction genetic
analyses of CSF biomarkers to identify sex-specific
associations. Data came from a previous genome-wide
association study (GWAS) of CSF Aβ42 and tau (1527 males,
1509 females). We evaluated sex interactions at previous
loci, performed sex-stratified GWAS to identify sex-specific
associations, and evaluated sex interactions at sex-specific
GWAS loci. We then evaluated sex-specific associations
between prefrontal cortex (PFC) gene expression at relevant
loci and autopsy measures of plaques and tangles using data
from the Religious Orders Study and Rush Memory and Aging
Project. In Aβ42, we observed sex interactions at one
previous and one novel locus: rs316341 within SERPINB1
(p = 0.04) and rs13115400 near LINC00290
(p = 0.002). These loci showed stronger associations
among females (β = - 0.03, p = 4.25 × 10-8;
β = 0.03, p = 3.97 × 10-8) than males
(β = - 0.02, p = 0.009; β = 0.01,
p = 0.20). Higher levels of expression of SERPINB1,
SERPINB6, and SERPINB9 in PFC was associated with higher
levels of amyloidosis among females (corrected p
values < 0.02) but not males (p > 0.38). In total
tau, we observed a sex interaction at a previous locus,
rs1393060 proximal to GMNC (p = 0.004), driven by a
stronger association among females (β = 0.05,
p = 4.57 × 10-10) compared to males (β = 0.02,
p = 0.03). There was also a sex-specific association
between rs1393060 and tangle density at autopsy
(pfemale = 0.047; pmale = 0.96), and higher levels
of expression of two genes within this locus were associated
with lower tangle density among females (OSTN p = 0.006;
CLDN16 p = 0.002) but not males (p ≥ 0.32).
Results suggest a female-specific role for SERPINB1 in
amyloidosis and for OSTN and CLDN16 in tau pathology.
Sex-specific genetic analyses may improve understanding of
AD's genetic architecture.},
Doi = {10.1007/s00401-018-1881-4},
Key = {fds340273}
}
@article{fds339515,
Author = {Hohman, TJ and Dumitrescu, L and Barnes, LL and Thambisetty, M and Beecham, G and Kunkle, B and Gifford, KA and Bush, WS and Chibnik, LB and Mukherjee, S and De Jager and PL and Kukull, W and Crane, PK and Resnick,
SM and Keene, CD and Montine, TJ and Schellenberg, GD and Haines, JL and Zetterberg, H and Blennow, K and Larson, EB and Johnson, SC and Albert,
M and Bennett, DA and Schneider, JA and Jefferson, AL and Alzheimer’s
Disease Genetics Consortium and the Alzheimer’s Disease
Neuroimaging Initiative},
Title = {Sex-Specific Association of Apolipoprotein E With
Cerebrospinal Fluid Levels of Tau.},
Journal = {JAMA Neurol},
Volume = {75},
Number = {8},
Pages = {989-998},
Year = {2018},
Month = {August},
url = {http://dx.doi.org/10.1001/jamaneurol.2018.0821},
Abstract = {IMPORTANCE: The strongest genetic risk factor for Alzheimer
disease (AD), the apolipoprotein E (APOE) gene, has a
stronger association among women compared with men. Yet
limited work has evaluated the association between APOE
alleles and markers of AD neuropathology in a sex-specific
manner. OBJECTIVE: To evaluate sex differences in the
association between APOE and markers of AD neuropathology
measured in cerebrospinal fluid (CSF) during life or in
brain tissue at autopsy. DESIGN, SETTING, AND PARTICIPANTS:
This multicohort study selected data from 10 longitudinal
cohort studies of normal aging and AD. Cohorts had variable
recruitment criteria and follow-up intervals and included
population-based and clinic-based samples. Inclusion in our
analysis required APOE genotype data and either CSF data
available for analysis. Analyses began on November 6, 2017,
and were completed on December 20, 2017. MAIN OUTCOMES AND
MEASURES: Biomarker analyses included levels of β-amyloid
42, total tau, and phosphorylated tau measured in CSF.
Autopsy analyses included Consortium to Establish a Registry
for Alzheimer's Disease staging for neuritic plaques and
Braak staging for neurofibrillary tangles. RESULTS: Of the
1798 patients in the CSF biomarker cohort, 862 were women,
226 had AD, 1690 were white, and the mean (SD) age was 70
[9] years. Of the 5109 patients in the autopsy cohort, 2813
were women, 4953 were white, and the mean (SD) age was 84
(9) years. After correcting for multiple comparisons using
the Bonferroni procedure, we observed a statistically
significant interaction between APOE-ε4 and sex on CSF
total tau (β = 0.41; 95% CI, 0.27-0.55; P < .001)
and phosphorylated tau (β = 0.24; 95% CI, 0.09-0.38;
P = .001), whereby APOE showed a stronger association
among women compared with men. Post hoc analyses suggested
this sex difference was present in amyloid-positive
individuals (β = 0.41; 95% CI, 0.20-0.62; P < .001)
but not among amyloid-negative individuals (β = 0.06;
95% CI, -0.18 to 0.31; P = .62). We did not observe sex
differences in the association between APOE and β-amyloid
42, neuritic plaque burden, or neurofibrillary tangle
burden. CONCLUSIONS AND RELEVANCE: We provide robust
evidence of a stronger association between APOE-ε4 and CSF
tau levels among women compared with men across multiple
independent data sets. Interestingly, APOE-ε4 is not
differentially associated with autopsy measures of
neurofibrillary tangles. Together, the sex difference in the
association between APOE and CSF measures of tau and the
lack of a sex difference in the association with
neurofibrillary tangles at autopsy suggest that APOE may
modulate risk for neurodegeneration in a sex-specific
manner, particularly in the presence of amyloidosis.},
Doi = {10.1001/jamaneurol.2018.0821},
Key = {fds339515}
}
@article{fds330585,
Author = {Browndyke, JN and Berger, M and Smith, PJ and Harshbarger, TB and Monge,
ZA and Panchal, V and Bisanar, TL and Glower, DD and Alexander, JH and Cabeza, R and Welsh-Bohmer, K and Newman, MF and Mathew, JP and Duke
Neurologic Outcomes Research Group (NORG)},
Title = {Task-related changes in degree centrality and local
coherence of the posterior cingulate cortex after major
cardiac surgery in older adults.},
Journal = {Hum Brain Mapp},
Volume = {39},
Number = {2},
Pages = {985-1003},
Year = {2018},
Month = {February},
url = {http://dx.doi.org/10.1002/hbm.23898},
Abstract = {OBJECTIVES: Older adults often display postoperative
cognitive decline (POCD) after surgery, yet it is unclear to
what extent functional connectivity (FC) alterations may
underlie these deficits. We examined for postoperative
voxel-wise FC changes in response to increased working
memory load demands in cardiac surgery patients and
nonsurgical controls. EXPERIMENTAL DESIGN: Older cardiac
surgery patients (n = 25) completed a verbal N-back
working memory task during MRI scanning and cognitive
testing before and 6 weeks after surgery; nonsurgical
controls with cardiac disease (n = 26) underwent these
assessments at identical time intervals. We measured
postoperative changes in degree centrality, the number of
edges attached to a brain node, and local coherence, the
temporal homogeneity of regional functional correlations,
using voxel-wise graph theory-based FC metrics. Group ×
time differences were evaluated in these FC metrics
associated with increased N-back working memory load
(2-back > 1-back), using a two-stage partitioned
variance, mixed ANCOVA. PRINCIPAL OBSERVATIONS: Cardiac
surgery patients demonstrated postoperative working memory
load-related degree centrality increases in the left dorsal
posterior cingulate cortex (dPCC; p < .001, cluster
p-FWE < .05). The dPCC also showed a postoperative
increase in working memory load-associated local coherence
(p < .001, cluster p-FWE < .05). dPCC degree
centrality and local coherence increases were inversely
associated with global cognitive change in surgery patients
(p < .01), but not in controls. CONCLUSIONS: Cardiac
surgery patients showed postoperative increases in working
memory load-associated degree centrality and local coherence
of the dPCC that were inversely associated with
postoperative global cognitive outcomes and independent of
perioperative cerebrovascular damage.},
Doi = {10.1002/hbm.23898},
Key = {fds330585}
}
@article{fds339675,
Author = {Peloso, GM and van der Lee, SJ and Sims, R and Naj, AC and Bellenguez,
C and Badarinarayan, N and Jakobsdottir, J and Kunkle, BW and Boland, A and Raybould, R and Bis, JC and Martin, ER and Grenier-Boley, B and Heilmann-Heimbach, S and Chouraki, V and Kuzma, AB and Sleegers, K and Vronskaya, M and Ruiz, A and Graham, RR and Olaso, R and Hoffmann, P and Grove, ML and Vardarajan, BN and Hiltunen, M and Nöthen, MM and White,
CC and Hamilton-Nelson, KL and Epelbaum, J and Maier, W and Choi, SH and Beecham, GW and Dulary, C and Herms, S and Smith, AV and Funk, CC and Derbois, and Forstner, AJ and Ahmad, S and Li, H and Bacq, D and Harold,
D and Satizabal, CL and Valladares, O and Squassina, A and Thomas, R and Brody, JA and Qu, L and Sánchez-Juan, P and Morgan, T and Wolters, FJ and Zhao, Y and Garcia, FS and Denning, N and Fornage, M and Malamon, J and Naranjo, MCD and Majounie, E and Mosley, TH and Dombroski, B and Wallon,
D and Lupton, MK and Dupuis, J and Whitehead, P and Fratiglioni, L and Medway, C and Jian, X and Mukherjee, S and Keller, L and Brown, K and Lin,
H and Cantwell, LB and Panza, F and McGuinness, B and Moreno-Grau, S and Burgess, JD and Solfrizzi, V and Proitsi, P and Adams, HH and Allen, M and Seripa, D and Pastor, P and Cupples, LA and Price, ND and Hannequin, D and Frank-García, A and Levy, D and Chakrabarty, P and Caffarra, P and Giegling, I and Beiser, AS and Giedraitis, V and Hampel, H and Garcia,
ME and Wang, X and Lannfelt, L and Mecocci, P and Eiriksdottir, G and Crane, PK},
Title = {Genetically elevated high-density lipoprotein cholesterol
through the cholesteryl ester transfer protein gene does not
associate with risk of Alzheimer's disease},
Journal = {Alzheimer's and Dementia: Diagnosis, Assessment and Disease
Monitoring},
Volume = {10},
Pages = {595-598},
Publisher = {Elsevier BV},
Year = {2018},
Month = {January},
url = {http://dx.doi.org/10.1016/j.dadm.2018.08.008},
Abstract = {Introduction: There is conflicting evidence whether
high-density lipoprotein cholesterol (HDL-C) is a risk
factor for Alzheimer's disease (AD) and dementia. Genetic
variation in the cholesteryl ester transfer protein (CETP)
locus is associated with altered HDL-C. We aimed to assess
AD risk by genetically predicted HDL-C. Methods: Ten single
nucleotide polymorphisms within the CETP locus predicting
HDL-C were applied to the International Genomics of
Alzheimer's Project (IGAP) exome chip stage 1 results in up
16,097 late onset AD cases and 18,077 cognitively normal
elderly controls. We performed instrumental variables
analysis using inverse variance weighting, weighted median,
and MR-Egger. Results: Based on 10 single nucleotide
polymorphisms distinctly predicting HDL-C in the CETP locus,
we found that HDL-C was not associated with risk of AD (P
>.7). Discussion: Our study does not support the role of
HDL-C on risk of AD through HDL-C altered by CETP. This
study does not rule out other mechanisms by which HDL-C
affects risk of AD.},
Doi = {10.1016/j.dadm.2018.08.008},
Key = {fds339675}
}
@article{fds339320,
Author = {Atkins, AS and Khan, A and Ulshen, D and Vaughan, A and Balentin, D and Dickerson, H and Liharska, LE and Plassman, B and Welsh-Bohmer, K and Keefe, RSE},
Title = {Assessment of Instrumental Activities of Daily Living in
Older Adults with Subjective Cognitive Decline Using the
Virtual Reality Functional Capacity Assessment Tool
(VRFCAT).},
Journal = {J Prev Alzheimers Dis},
Volume = {5},
Number = {4},
Pages = {216-234},
Year = {2018},
url = {http://dx.doi.org/10.14283/jpad.2018.28},
Abstract = {BACKGROUND: Continuing advances in the understanding of
Alzheimer's disease progression have inspired development of
disease-modifying therapeutics intended for use in
preclinical populations. However, identification of
clinically meaningful cognitive and functional outcomes for
individuals who are, by definition, asymptomatic remains a
significant challenge. Clinical trials for prevention and
early intervention require measures with increased
sensitivity to subtle deficits in instrumental activities of
daily living (IADL) that comprise the first functional
declines in prodromal disease. Validation of potential
endpoints is required to ensure measure sensitivity and
reliability in the populations of interest. OBJECTIVES: The
present research validates use of the Virtual Reality
Functional Capacity Assessment Tool (VRFCAT) for
performance-based assessment of IADL functioning in older
adults (age 55+) with subjective cognitive decline. DESIGN:
Cross-sectional validation study. SETTING: All participants
were evaluated on-site at NeuroCog Trials, Durham, NC, USA.
PARTICIPANTS: Participants included 245 healthy younger
adults ages 20-54 (131 female), 247 healthy older adults
ages 55-91 (151 female) and 61 older adults with subjective
cognitive decline (SCD) ages 56-97 (45 female). MEASURES:
Virtual Reality Functional Capacity Assessment Tool; Brief
Assessment of Cognition App; Alzheimer's Disease Cooperative
Study Prevention Instrument Project - Mail-In Cognitive
Function Screening Instrument; Alzheimer's Disease
Cooperative Study Instrumental Activities of Daily Living -
Prevention Instrument, University of California, San Diego
Performance-Based Skills Assessment - Validation of
Intermediate Measures; Montreal Cognitive Assessment; Trail
Making Test- Part B. RESULTS: Participants with SCD
performed significantly worse than age-matched normative
controls on all VRFCAT endpoints, including total completion
time, errors and forced progressions (p≤0001 for all,
after Bonferonni correction). Consistent with prior
findings, both groups performed significantly worse than
healthy younger adults (age 20-54). Participants with SCD
also performed significantly worse than controls on
objective cognitive measures. VRFCAT performance was
strongly correlated with cognitive performance. In the SCD
group, VRFCAT performance was strongly correlated with
cognitive performance across nearly all tests with
significant correlation coefficients ranging from 0.3 to
0.7; VRFCAT summary measures all had correlations greater
than r=0.5 with MoCA performance and BAC App Verbal Memory
(p<0.01 for all). CONCLUSIONS: Findings suggest the VRFCAT
provides a sensitive tool for evaluation of IADL functioning
in individuals with subjective cognitive decline. Strong
correlations with cognition across groups suggest the VRFCAT
may be uniquely suited for clinical trials in preclinical
AD, as well as longitudinal investigations of the
relationship between cognition and function.},
Doi = {10.14283/jpad.2018.28},
Key = {fds339320}
}
@article{fds337115,
Author = {Romero, HR and Monsch, AU and Hayden, KM and Plassman, BL and Atkins,
AS and Keefe, RSE and Brewster, S and Chiang, C and O'Neil, J and Runyan,
G and Atkinson, MJ and Crawford, S and Budur, K and Burns, DK and Welsh-Bohmer, KA},
Title = {TOMMORROW neuropsychological battery: German language
validation and normative study.},
Journal = {Alzheimers Dement (N Y)},
Volume = {4},
Pages = {314-323},
Year = {2018},
url = {http://dx.doi.org/10.1016/j.trci.2018.06.009},
Abstract = {INTRODUCTION: Assessment of preclinical Alzheimer's disease
(AD) requires reliable and validated methods to detect
subtle cognitive changes. The battery of standardized
cognitive assessments that is used for diagnostic criteria
for mild cognitive impairment due to AD in the TOMMORROW
study have only been fully validated in English-speaking
countries. We conducted a validation and normative study of
the German language version of the TOMMORROW
neuropsychological test battery, which tests episodic
memory, language, visuospatial ability, executive function,
and attention. METHODS: German-speaking cognitively healthy
controls (NCs) and subjects with AD were recruited from a
memory clinic at a Swiss medical center. Construct validity,
test-retest, and alternate form reliability were assessed in
NCs. Criterion and discriminant validities of the cognitive
measures were tested using logistic regression and
discriminant analysis. Cross-cultural equivalency of
performance of the German language tests was compared with
English language tests. RESULTS: A total of 198 NCs and 25
subjects with AD (aged 65-88 years) were analyzed. All
German language tests discriminated NCs from persons with
AD. Episodic memory tests had the highest potential to
discriminate with almost twice the predictive power of any
other domain. Test-retest reliability of the test battery
was adequate, and alternate form reliability for episodic
memory tests was supported. For most tests, age was a
significant predictor of group effect sizes; therefore,
normative data were stratified by age. Validity and
reliability results were similar to those in the published
US cognitive testing literature. DISCUSSION: This study
establishes the reliability and validity of the German
language TOMMORROW test battery, which performed similarly
to the English language tests. Some variations in test
performance underscore the importance of regional normative
values. The German language battery and normative data will
improve the precision of measuring cognition and diagnosing
incident mild cognitive impairment due to AD in clinical
settings in German-speaking countries.},
Doi = {10.1016/j.trci.2018.06.009},
Key = {fds337115}
}
@article{fds333554,
Author = {Weintraub, S and Carrillo, MC and Farias, ST and Goldberg, TE and Hendrix, JA and Jaeger, J and Knopman, DS and Langbaum, JB and Park, DC and Ropacki, MT and Sikkes, SAM and Welsh-Bohmer, KA and Bain, LJ and Brashear, R and Budur, K and Graf, A and Martenyi, F and Storck, MS and Randolph, C},
Title = {Measuring cognition and function in the preclinical stage of
Alzheimer's disease.},
Journal = {Alzheimers Dement (N Y)},
Volume = {4},
Pages = {64-75},
Year = {2018},
url = {http://dx.doi.org/10.1016/j.trci.2018.01.003},
Abstract = {The Alzheimer's Association's Research Roundtable met in
November 2016 to explore how best to measure changes in
cognition and function in the preclinical stage of
Alzheimer's disease. This review will cover the tools and
instruments currently available to identify populations for
prevention trials, and measure subtle disease progression in
the earliest stages of Alzheimer's disease, and will include
discussions of suitable cognitive, behavioral, functional,
composite, and biological endpoints for prevention trials.
Current prevention trials are reviewed including TOMMOROW,
Alzheimer's Prevention Initiative Autosomal Dominant
Alzheimer's Disease Trial, the Alzheimer's Prevention
Initiative Generation Study, and the Anti-Amyloid Treatment
in Asymptomatic Alzheimer's to compare current approaches
and tools that are being developed.},
Doi = {10.1016/j.trci.2018.01.003},
Key = {fds333554}
}
@article{fds332791,
Author = {Weintraub, S and Besser, L and Dodge, HH and Teylan, M and Ferris, S and Goldstein, FC and Giordani, B and Kramer, J and Loewenstein, D and Marson, D and Mungas, D and Salmon, D and Welsh-Bohmer, K and Zhou, X-H and Shirk, SD and Atri, A and Kukull, WA and Phelps, C and Morris,
JC},
Title = {Version 3 of the Alzheimer Disease Centers'
Neuropsychological Test Battery in the Uniform Data Set
(UDS).},
Journal = {Alzheimer Dis Assoc Disord},
Volume = {32},
Number = {1},
Pages = {10-17},
Year = {2018},
url = {http://dx.doi.org/10.1097/WAD.0000000000000223},
Abstract = {INTRODUCTION: The neuropsychological battery of the Uniform
Data Set (UDSNB) was implemented in 2005 by the National
Institute on Aging (NIA) Alzheimer Disease Centers program
to measure cognitive performance in dementia and mild
cognitive impairment due to Alzheimer Disease. This paper
describes a revision, the UDSNB 3.0. METHODS: The
Neuropsychology Work Group of the NIA Clinical Task Force
recommended revisions through a process of due diligence to
address shortcomings of the original battery. The UDSNB 3.0
covers episodic memory, processing speed, executive
function, language, and constructional ability. Data from
3602 cognitively normal participants in the National
Alzheimer Coordinating Center database were analyzed.
RESULTS: Descriptive statistics are presented. Multivariable
linear regression analyses demonstrated score differences by
age, sex, and education and were also used to create a
normative calculator available online. DISCUSSION: The UDSNB
3.0 neuropsychological battery provides a valuable non
proprietary resource for conducting research on cognitive
aging and dementia.},
Doi = {10.1097/WAD.0000000000000223},
Key = {fds332791}
}
@article{fds342566,
Author = {Whitson, HE and Potter, GG and Feld, JA and Plassman, BL and Reynolds,
K and Sloane, R and Welsh-Bohmer, KA},
Title = {Dual-Task Gait and Alzheimer's Disease Genetic Risk in
Cognitively Normal Adults: A Pilot Study.},
Journal = {J Alzheimers Dis},
Volume = {64},
Number = {4},
Pages = {1137-1148},
Year = {2018},
url = {http://dx.doi.org/10.3233/JAD-180016},
Abstract = {BACKGROUND: Dual-task paradigms, in which an individual
performs tasks separately and then concurrently, often
demonstrate that people with neurodegenerative disorders
experience more dual-task interference, defined as worse
performance in the dual-task condition compared to the
single-task condition. OBJECTIVE: To examine how
gait-cognition dual-task performance differs between
cognitively normal older adults with and without an APOE ɛ4
allele. METHODS: Twenty-nine individuals ages 60 to 72 with
normal cognition completed a dual-task protocol in which
walking and cognitive tasks (executive function, memory)
were performed separately and concurrently. Fourteen
participants carried APOE ɛ4 alleles (ɛ3/ɛ4 or ɛ2/ɛ4);
fifteen had APOE genotypes (ɛ2/ɛ2, ɛ2/ɛ3, or ɛ3/ɛ3)
associated with lower risk of Alzheimer's disease (AD).
RESULTS: The two risk groups did not differ by age, sex,
race, education, or gait or cognitive measures under
single-task conditions. Compared to low risk participants,
APOE ɛ4 carriers tended to exhibit greater dual-task
interference. Both the memory and executive function tasks
resulted in dual-task interference on gait, but effect sizes
for a group difference were larger when the cognitive task
was executive function. In the dual-task protocol that
combined walking and the executive function task, effect
sizes for group difference in gait interference were larger
(0.62- 0.70) than for cognitive interference (0.45- 0.47).
DISCUSSION: Dual-task paradigms may reveal subtle changes in
brain function in asymptomatic individuals at heightened
risk of AD.},
Doi = {10.3233/JAD-180016},
Key = {fds342566}
}
@article{fds339676,
Author = {Morrison, RL and Pei, H and Novak, G and Kaufer, DI and Welsh-Bohmer,
KA and Ruhmel, S and Narayan, VA},
Title = {A computerized, self-administered test of verbal episodic
memory in elderly patients with mild cognitive impairment
and healthy participants: A randomized, crossover,
validation study.},
Journal = {Alzheimers Dement (Amst)},
Volume = {10},
Pages = {647-656},
Year = {2018},
url = {http://dx.doi.org/10.1016/j.dadm.2018.08.010},
Abstract = {INTRODUCTION: Performance of "Revere", a novel
iPad-administered word-list recall (WLR) test, in
quantifying deficits in verbal episodic memory, was
evaluated versus examiner-administered Rey Auditory Verbal
Learning Test (RAVLT) in patients with mild cognitive
impairment and cognitively normal participants. METHODS:
Elderly patients with clinically diagnosed mild cognitive
impairment (Montreal Cognitive Assessment score 24-27) and
cognitively normal (Montreal Cognitive Assessment score
≥28) were administered RAVLT or Revere in a randomized
crossover design. RESULTS: A total of 153/161 participants
(Revere/RAVLT n = 75; RAVLT/Revere n = 78) were
randomized; 148 (97%) completed study; 121 patients (mean
[standard deviation] age: 70.4 [7.84] years) were included
for analysis. Word-list recall scores (8 trials) were
comparable between Revere and RAVLT (Pearson's correlation
coefficients: 0.12-0.70; least square mean difference
[Revere-RAVLT]: -0.84 [90% CI, -1.15; -0.54]). Model factor
estimates indicated trial (P < .001), period (P < .001)
and evaluation sequence (P = .038) as significant factors.
Learning over trials index and serial position effects were
comparable. DISCUSSION: Participants' verbal recall
performance on Revere and RAVLT were equivalent.},
Doi = {10.1016/j.dadm.2018.08.010},
Key = {fds339676}
}
@article{fds328886,
Author = {Sims, R and van der Lee, SJ and Naj, AC and Bellenguez, C and Badarinarayan, N and Jakobsdottir, J and Kunkle, BW and Boland, A and Raybould, R and Bis, JC and Martin, ER and Grenier-Boley, B and Heilmann-Heimbach, S and Chouraki, V and Kuzma, AB and Sleegers, K and Vronskaya, M and Ruiz, A and Graham, RR and Olaso, R and Hoffmann, P and Grove, ML and Vardarajan, BN and Hiltunen, M and Nöthen, MM and White,
CC and Hamilton-Nelson, KL and Epelbaum, J and Maier, W and Choi, S-H and Beecham, GW and Dulary, C and Herms, S and Smith, AV and Funk, CC and Derbois, C and Forstner, AJ and Ahmad, S and Li, H and Bacq, D and Harold,
D and Satizabal, CL and Valladares, O and Squassina, A and Thomas, R and Brody, JA and Qu, L and Sánchez-Juan, P and Morgan, T and Wolters, FJ and Zhao, Y and Garcia, FS and Denning, N and Fornage, M and Malamon, J and Naranjo, MCD and Majounie, E and Mosley, TH and Dombroski, B and Wallon,
D and Lupton, MK and Dupuis, J and Whitehead, P and Fratiglioni, L and Medway, C and Jian, X and Mukherjee, S and Keller, L and Brown, K and Lin,
H and Cantwell, LB and Panza, F and McGuinness, B and Moreno-Grau, S and Burgess, JD and Solfrizzi, V and Proitsi, P and Adams, HH and Allen, M and Seripa, D and Pastor, P and Cupples, LA and Price, ND and Hannequin, D and Frank-García, A and Levy, D and Chakrabarty, P and Caffarra, P and Giegling, I and Beiser, AS and Giedraitis, V and Hampel, H and Garcia,
ME and Wang, X and Lannfelt, L and Mecocci, P and Eiriksdottir, G and Crane, PK and Pasquier, F and Boccardi, V and Henández, I and Barber,
RC and Scherer, M and Tarraga, L and Adams, PM and Leber, M and Chen, Y and Albert, MS and Riedel-Heller, S and Emilsson, V and Beekly, D and Braae,
A and Schmidt, R and Blacker, D and Masullo, C and Schmidt, H and Doody,
RS and Spalletta, G and Longstreth, WT and Fairchild, TJ and Bossù, P and Lopez, OL and Frosch, MP and Sacchinelli, E and Ghetti, B and Yang, Q and Huebinger, RM and Jessen, F and Li, S and Kamboh, MI and Morris, J and Sotolongo-Grau, O and Katz, MJ and Corcoran, C and Dunstan, M and Braddel, A and Thomas, C and Meggy, A and Marshall, R and Gerrish, A and Chapman, J and Aguilar, M and Taylor, S and Hill, M and Fairén, MD and Hodges, A and Vellas, B and Soininen, H and Kloszewska, I and Daniilidou, M and Uphill, J and Patel, Y and Hughes, JT and Lord, J and Turton, J and Hartmann, AM and Cecchetti, R and Fenoglio, C and Serpente, M and Arcaro, M and Caltagirone, C and Orfei, MD and Ciaramella, A and Pichler, S and Mayhaus, M and Gu, W and Lleó, A and Fortea, J and Blesa, R and Barber, IS and Brookes, K and Cupidi, C and Maletta, RG and Carrell, D and Sorbi, S and Moebus, S and Urbano, M and Pilotto, A and Kornhuber, J and Bosco, P and Todd, S and Craig, D and Johnston, J and Gill, M and Lawlor, B and Lynch, A and Fox, NC and Hardy,
J and ARUK Consortium, and Albin, RL and Apostolova, LG and Arnold, SE and Asthana, S and Atwood, CS and Baldwin, CT and Barnes, LL and Barral, S and Beach, TG and Becker, JT and Bigio, EH and Bird, TD and Boeve, BF and Bowen, JD and Boxer, A and Burke, JR and Burns, JM and Buxbaum, JD and Cairns, NJ and Cao, C and Carlson, CS and Carlsson, CM and Carney, RM and Carrasquillo, MM and Carroll, SL and Diaz, CC and Chui, HC and Clark,
DG and Cribbs, DH and Crocco, EA and DeCarli, C and Dick, M and Duara, R and Evans, DA and Faber, KM and Fallon, KB and Fardo, DW and Farlow, MR and Ferris, S and Foroud, TM and Galasko, DR and Gearing, M and Geschwind,
DH and Gilbert, JR and Graff-Radford, NR and Green, RC and Growdon, JH and Hamilton, RL and Harrell, LE and Honig, LS and Huentelman, MJ and Hulette, CM and Hyman, BT and Jarvik, GP and Abner, E and Jin, L-W and Jun,
G and Karydas, A and Kaye, JA and Kim, R and Kowall, NW and Kramer, JH and LaFerla, FM and Lah, JJ and Leverenz, JB and Levey, AI and Li, G and Lieberman, AP and Lunetta, KL and Lyketsos, CG and Marson, DC and Martiniuk, F and Mash, DC and Masliah, E and McCormick, WC and McCurry,
SM and McDavid, AN and McKee, AC and Mesulam, M and Miller, BL and Miller,
CA and Miller, JW and Morris, JC and Murrell, JR and Myers, AJ and O'Bryant, S and Olichney, JM and Pankratz, VS and Parisi, JE and Paulson, HL and Perry, W and Peskind, E and Pierce, A and Poon, WW and Potter, H and Quinn, JF and Raj, A and Raskind, M and Reisberg, B and Reitz, C and Ringman, JM and Roberson, ED and Rogaeva, E and Rosen, HJ and Rosenberg, RN and Sager, MA and Saykin, AJ and Schneider, JA and Schneider, LS and Seeley, WW and Smith, AG and Sonnen, JA and Spina, S and Stern, RA and Swerdlow, RH and Tanzi, RE and Thornton-Wells, TA and Trojanowski, JQ and Troncoso, JC and Van Deerlin and VM and Van Eldik,
LJ and Vinters, HV and Vonsattel, JP and Weintraub, S and Welsh-Bohmer,
KA and Wilhelmsen, KC and Williamson, J and Wingo, TS and Woltjer, RL and Wright, CB and Yu, C-E and Yu, L and Garzia, F and Golamaully, F and Septier, G and Engelborghs, S and Vandenberghe, R and De Deyn and PP and Fernadez, CM and Benito, YA and Thonberg, H and Forsell, C and Lilius,
L and Kinhult-Stählbom, A and Kilander, L and Brundin, R and Concari,
L and Helisalmi, S and Koivisto, AM and Haapasalo, A and Dermecourt, V and Fievet, N and Hanon, O and Dufouil, C and Brice, A and Ritchie, K and Dubois, B and Himali, JJ and Keene, CD and Tschanz, J and Fitzpatrick,
AL and Kukull, WA and Norton, M and Aspelund, T and Larson, EB and Munger,
R and Rotter, JI and Lipton, RB and Bullido, MJ and Hofman, A and Montine,
TJ and Coto, E and Boerwinkle, E and Petersen, RC and Alvarez, V and Rivadeneira, F and Reiman, EM and Gallo, M and O'Donnell, CJ and Reisch,
JS and Bruni, AC and Royall, DR and Dichgans, M and Sano, M and Galimberti,
D and St George-Hyslop and P and Scarpini, E and Tsuang, DW and Mancuso, M and Bonuccelli, U and Winslow, AR and Daniele, A and Wu, C-K and GERAD/PERADES, CHARGE and ADGC, EADI and Peters, O and Nacmias, B and Riemenschneider, M and Heun, R and Brayne, C and Rubinsztein, DC and Bras, J and Guerreiro, R and Al-Chalabi, A and Shaw, CE and Collinge, J and Mann, D and Tsolaki, M and Clarimón, J and Sussams, R and Lovestone, S and O'Donovan, MC and Owen, MJ and Behrens, TW and Mead, S and Goate, AM and Uitterlinden, AG and Holmes, C and Cruchaga, C and Ingelsson, M and Bennett, DA and Powell, J and Golde, TE and Graff, C and De Jager and PL and Morgan, K and Ertekin-Taner, N and Combarros, O and Psaty, BM and Passmore, P and Younkin, SG and Berr, C and Gudnason, V and Rujescu, D and Dickson, DW and Dartigues, J-F and DeStefano, AL and Ortega-Cubero,
S and Hakonarson, H and Campion, D and Boada, M and Kauwe, JK and Farrer,
LA and Van Broeckhoven and C and Ikram, MA and Jones, L and Haines, JL and Tzourio, C and Launer, LJ and Escott-Price, V and Mayeux, R and Deleuze,
J-F and Amin, N and Holmans, PA and Pericak-Vance, MA and Amouyel, P and van Duijn, CM and Ramirez, A and Wang, L-S and Lambert, J-C and Seshadri, S and Williams, J and Schellenberg, GD},
Title = {Rare coding variants in PLCG2, ABI3, and TREM2 implicate
microglial-mediated innate immunity in Alzheimer's
disease.},
Journal = {Nat Genet},
Volume = {49},
Number = {9},
Pages = {1373-1384},
Year = {2017},
Month = {September},
url = {http://dx.doi.org/10.1038/ng.3916},
Abstract = {We identified rare coding variants associated with
Alzheimer's disease in a three-stage case-control study of
85,133 subjects. In stage 1, we genotyped 34,174 samples
using a whole-exome microarray. In stage 2, we tested
associated variants (P < 1 × 10-4) in 35,962 independent
samples using de novo genotyping and imputed genotypes. In
stage 3, we used an additional 14,997 samples to test the
most significant stage 2 associations (P < 5 × 10-8) using
imputed genotypes. We observed three new genome-wide
significant nonsynonymous variants associated with
Alzheimer's disease: a protective variant in PLCG2
(rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR)
= 0.68, minor allele frequency (MAF)cases = 0.0059,
MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338:
p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases = 0.011,
MAFcontrols = 0.008), and a new genome-wide significant
variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 ×
10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089),
a known susceptibility gene for Alzheimer's disease. These
protein-altering changes are in genes highly expressed in
microglia and highlight an immune-related protein-protein
interaction network enriched for previously identified risk
genes in Alzheimer's disease. These genetic findings provide
additional evidence that the microglia-mediated innate
immune response contributes directly to the development of
Alzheimer's disease.},
Doi = {10.1038/ng.3916},
Key = {fds328886}
}
@article{fds327422,
Author = {Jun, GR and Chung, J and Mez, J and Barber, R and Beecham, GW and Bennett,
DA and Buxbaum, JD and Byrd, GS and Carrasquillo, MM and Crane, PK and Cruchaga, C and De Jager and P and Ertekin-Taner, N and Evans, D and Fallin, MD and Foroud, TM and Friedland, RP and Goate, AM and Graff-Radford, NR and Hendrie, H and Hall, KS and Hamilton-Nelson,
KL and Inzelberg, R and Kamboh, MI and Kauwe, JSK and Kukull, WA and Kunkle, BW and Kuwano, R and Larson, EB and Logue, MW and Manly, JJ and Martin, ER and Montine, TJ and Mukherjee, S and Naj, A and Reiman, EM and Reitz, C and Sherva, R and St George-Hyslop and PH and Thornton, T and Younkin, SG and Vardarajan, BN and Wang, L-S and Wendlund, JR and Winslow, AR and Alzheimer's Disease Genetics Consortium, and Haines, J and Mayeux, R and Pericak-Vance, MA and Schellenberg, G and Lunetta, KL and Farrer, LA},
Title = {Transethnic genome-wide scan identifies novel Alzheimer's
disease loci.},
Journal = {Alzheimers Dement},
Volume = {13},
Number = {7},
Pages = {727-738},
Year = {2017},
Month = {July},
url = {http://dx.doi.org/10.1016/j.jalz.2016.12.012},
Abstract = {INTRODUCTION: Genetic loci for Alzheimer's disease (AD) have
been identified in whites of European ancestry, but the
genetic architecture of AD among other populations is less
understood. METHODS: We conducted a transethnic genome-wide
association study (GWAS) for late-onset AD in Stage 1 sample
including whites of European Ancestry, African-Americans,
Japanese, and Israeli-Arabs assembled by the Alzheimer's
Disease Genetics Consortium. Suggestive results from Stage 1
from novel loci were followed up using summarized results in
the International Genomics Alzheimer's Project GWAS dataset.
RESULTS: Genome-wide significant (GWS) associations in
single-nucleotide polymorphism (SNP)-based tests (P < 5 ×
10-8) were identified for SNPs in PFDN1/HBEGF,
USP6NL/ECHDC3, and BZRAP1-AS1 and for the interaction of the
(apolipoprotein E) APOE ε4 allele with NFIC SNP. We also
obtained GWS evidence (P < 2.7 × 10-6) for gene-based
association in the total sample with a novel locus, TPBG
(P = 1.8 × 10-6). DISCUSSION: Our findings highlight the
value of transethnic studies for identifying novel AD
susceptibility loci.},
Doi = {10.1016/j.jalz.2016.12.012},
Key = {fds327422}
}
@article{fds322219,
Author = {Browndyke, JN and Berger, M and Harshbarger, TB and Smith, PJ and White,
W and Bisanar, TL and Alexander, JH and Gaca, JG and Welsh-Bohmer, K and Newman, MF and Mathew, JP},
Title = {Resting-State Functional Connectivity and Cognition After
Major Cardiac Surgery in Older Adults without Preoperative
Cognitive Impairment: Preliminary Findings.},
Journal = {J Am Geriatr Soc},
Volume = {65},
Number = {1},
Pages = {e6-e12},
Year = {2017},
Month = {January},
url = {http://dx.doi.org/10.1111/jgs.14534},
Abstract = {OBJECTIVES: To look for changes in intrinsic functional
brain connectivity associated with postoperative changes in
cognition, a common complication in seniors undergoing major
surgery, using resting-state functional magnetic resonance
imaging. DESIGN: Objective cognitive testing and functional
brain imaging were prospectively performed at preoperative
baseline and 6 weeks after surgery and at the same time
intervals in nonsurgical controls. SETTING: Academic medical
center. PARTICIPANTS: Older adults undergoing cardiac
surgery (n = 12) and nonsurgical older adult controls with a
history of coronary artery disease (n = 12); no participants
had cognitive impairment at preoperative baseline
(Mini-Mental State Examination score >27). MEASUREMENTS:
Differences in resting-state functional connectivity (RSFC)
and global cognitive change relationships were assessed
using a voxel-wise intrinsic connectivity method,
controlling for demographic factors and pre- and
perioperative cerebral white matter disease volume. Analyses
were corrected for multiple comparisons (false discovery
rate P < .01). RESULTS: Global cognitive change after
cardiac surgery was significantly associated with intrinsic
RSFC changes in regions of the posterior cingulate cortex
and right superior frontal gyrus-anatomical and functional
locations of the brain's default mode network (DMN). No
statistically significant relationships were found between
global cognitive change and RSFC change in nonsurgical
controls. CONCLUSION: Clinicians have long known that some
older adults develop postoperative cognitive dysfunction
(POCD) after anesthesia and surgery, yet the neurobiological
correlates of POCD are not well defined. The current results
suggest that altered RSFC in specific DMN regions is
positively correlated with global cognitive change 6 weeks
after cardiac surgery, suggesting that DMN activity and
connectivity could be important diagnostic markers of POCD
or intervention targets for potential POCD treatment
efforts.},
Doi = {10.1111/jgs.14534},
Key = {fds322219}
}
@article{fds339373,
Author = {Aisen, P and Touchon, J and Amariglio, R and Andrieu, S and Bateman, R and Breitner, J and Donohue, M and Dunn, B and Doody, R and Fox, N and Gauthier, S and Grundman, M and Hendrix, S and Ho, C and Isaac, M and Raman, R and Rosenberg, P and Schindler, R and Schneider, L and Sperling, R and Tariot, P and Welsh-Bohmer, K and Weiner, M and Vellas,
B},
Title = {EU/US/CTAD Task Force: Lessons Learned from Recent and
Current Alzheimer's Prevention Trials.},
Journal = {J Prev Alzheimers Dis},
Volume = {4},
Number = {2},
Pages = {116-124},
Year = {2017},
url = {http://dx.doi.org/10.14283/jpad.2017.13},
Abstract = {At a meeting of the EU/US/Clinical Trials in Alzheimer's
Disease (CTAD) Task Force in December 2016, an international
group of investigators from industry, academia, and
regulatory agencies reviewed lessons learned from ongoing
and planned prevention trials, which will help guide future
clinical trials of AD treatments, particularly in the
pre-clinical space. The Task Force discussed challenges that
need to be addressed across all aspects of clinical trials,
calling for innovation in recruitment and retention,
infrastructure development, and the selection of outcome
measures. While cognitive change provides a marker of
disease progression across the disease continuum, there
remains a need to identify the optimal assessment tools that
provide clinically meaningful endpoints. Patient- and
informant-reported assessments of cognition and function may
be useful but present additional challenges. Imaging and
other biomarkers are also essential to maximize the
efficiency of and the information learned from clinical
trials.},
Doi = {10.14283/jpad.2017.13},
Key = {fds339373}
}
@article{fds326771,
Author = {Blumenthal, JA and Smith, PJ and Mabe, S and Hinderliter, A and Welsh-Bohmer, K and Browndyke, JN and Lin, P-H and Kraus, W and Doraiswamy, PM and Burke, J and Sherwood, A},
Title = {Lifestyle and Neurocognition in Older Adults With
Cardiovascular Risk Factors and Cognitive
Impairment.},
Journal = {Psychosom Med},
Volume = {79},
Number = {6},
Pages = {719-727},
Year = {2017},
url = {http://dx.doi.org/10.1097/PSY.0000000000000474},
Abstract = {OBJECTIVE: The aim of the study was to determine the
relationship of lifestyle factors and neurocognitive
functioning in older adults with vascular risk factors and
cognitive impairment, no dementia (CIND). METHODS: One
hundred sixty adults (M [SD] = 65.4 [6.8] years) with CIND
completed neurocognitive assessments of executive function,
processing speed, and memory. Objective measures of physical
activity using accelerometry, aerobic capacity determined by
exercise testing, and dietary habits quantified by the Food
Frequency Questionnaire and 4-Day Food Diary to assess
adherence to the Mediterranean and Dietary Approaches to
Stop Hypertension (DASH) diets were obtained to assess
direct effects with neurocognition. Potential indirect
associations of high-sensitivity C-reactive protein and the
Framingham Stroke Risk Profile also were examined. RESULTS:
Greater aerobic capacity (β = 0.24) and daily physical
activity (β = 0.15) were associated with better executive
functioning/processing speed and verbal memory (βs = 0.24;
0.16). Adherence to the DASH diet was associated with better
verbal memory (β = 0.17). Greater high-sensitivity
C-reactive protein (βs = -0.14; -0.21) and Framingham
Stroke Risk Profile (β = -0.18; -0.18) were associated with
poorer executive functioning/processing speed and verbal
memory. Greater stroke risk partially mediated the
association of aerobic capacity with executive
functioning/processing speed, and verbal memory and greater
inflammation partially mediated the association of physical
activity and aerobic fitness, with verbal memory.
CONCLUSIONS: Higher levels of physical activity, aerobic
fitness, and adherence to the DASH diet are associated with
better neurocognitive performance in adults with CIND. These
findings suggest that the adoption of healthy lifestyle
habits could reduce the risk of neurocognitive decline in
vulnerable older adults. CLINICAL TRIAL REGISTRATION:
NCT01573546.},
Doi = {10.1097/PSY.0000000000000474},
Key = {fds326771}
}
@article{fds322773,
Author = {Weninger, S and Carrillo, MC and Dunn, B and Aisen, PS and Bateman, RJ and Kotz, JD and Langbaum, JB and Mills, SL and Reiman, EM and Sperling, R and Santacruz, AM and Tariot, PN and Welsh-Bohmer,
KA},
Title = {Collaboration for Alzheimer's Prevention: Principles to
guide data and sample sharing in preclinical Alzheimer's
disease trials.},
Journal = {Alzheimers Dement},
Volume = {12},
Number = {5},
Pages = {631-632},
Year = {2016},
Month = {May},
url = {http://dx.doi.org/10.1016/j.jalz.2016.04.001},
Doi = {10.1016/j.jalz.2016.04.001},
Key = {fds322773}
}
@article{fds322221,
Author = {Ridge, PG and Hoyt, KB and Boehme, K and Mukherjee, S and Crane, PK and Haines, JL and Mayeux, R and Farrer, LA and Pericak-Vance, MA and Schellenberg, GD and Kauwe, JSK and Alzheimer's Disease Genetics
Consortium (ADGC)},
Title = {Assessment of the genetic variance of late-onset Alzheimer's
disease.},
Journal = {Neurobiol Aging},
Volume = {41},
Pages = {200.e13-200.e20},
Year = {2016},
Month = {May},
url = {http://dx.doi.org/10.1016/j.neurobiolaging.2016.02.024},
Abstract = {Alzheimer's disease (AD) is a complex genetic disorder with
no effective treatments. More than 20 common markers have
been identified, which are associated with AD. Recently,
several rare variants have been identified in Amyloid
Precursor Protein (APP), Triggering Receptor Expressed On
Myeloid Cells 2 (TREM2) and Unc-5 Netrin Receptor C (UNC5C)
that affect risk for AD. Despite the many successes, the
genetic architecture of AD remains unsolved. We used
Genome-wide Complex Trait Analysis to (1) estimate
phenotypic variance explained by genetics; (2) calculate
genetic variance explained by known AD single nucleotide
polymorphisms (SNPs); and (3) identify the genomic locations
of variation that explain the remaining unexplained genetic
variance. In total, 53.24% of phenotypic variance is
explained by genetics, but known AD SNPs only explain 30.62%
of the genetic variance. Of the unexplained genetic
variance, approximately 41% is explained by unknown SNPs in
regions adjacent to known AD SNPs, and the remaining
unexplained genetic variance outside these
regions.},
Doi = {10.1016/j.neurobiolaging.2016.02.024},
Key = {fds322221}
}
@article{fds322220,
Author = {Lutz, MW and Crenshaw, D and Welsh-Bohmer, KA and Burns, DK and Roses,
AD},
Title = {New Genetic Approaches to AD: Lessons from APOE-TOMM40
Phylogenetics.},
Journal = {Curr Neurol Neurosci Rep},
Volume = {16},
Number = {5},
Pages = {48},
Year = {2016},
Month = {May},
url = {http://dx.doi.org/10.1007/s11910-016-0643-8},
Abstract = {Clinical trials for Alzheimer's disease are now focusing on
the earliest stages of the disease with the goal of delaying
dementia onset. There is great utility in using genetic
variants to identify individuals at high age-dependent risk
when the goal is to begin treatment before the development
of any cognitive symptoms. Genetic variants identified
through large-scale genome-wide association studies have not
substantially improved the accuracy provided by APOE
genotype to identify people at high risk of late-onset
Alzheimer's disease (LOAD). We describe novel approaches,
focused on molecular phylogenetics, to finding genetic
variants that predict age at LOAD onset with sufficient
accuracy and precision to be useful. We highlight the
discovery of a polymorphism in TOMM40 that, in addition to
APOE, may improve risk prediction and review how TOMM40
genetic variants may impact the develop of LOAD
independently from APOE. The analysis methods described in
this review may be useful for other genetically complex
human diseases.},
Doi = {10.1007/s11910-016-0643-8},
Key = {fds322220}
}
@article{fds327247,
Author = {Perry, DC and Sturm, VE and Peterson, MJ and Pieper, CF and Bullock, T and Boeve, BF and Miller, BL and Guskiewicz, KM and Berger, MS and Kramer,
JH and Welsh-Bohmer, KA},
Title = {Association of traumatic brain injury with subsequent
neurological and psychiatric disease: a meta-analysis.},
Journal = {J Neurosurg},
Volume = {124},
Number = {2},
Pages = {511-526},
Year = {2016},
Month = {February},
url = {http://dx.doi.org/10.3171/2015.2.JNS14503},
Abstract = {OBJECTIVE: Mild traumatic brain injury (TBI) has been
proposed as a risk factor for the development of Alzheimer's
disease, Parkinson's disease, depression, and other
illnesses. This study's objective was to determine the
association of prior mild TBI with the subsequent diagnosis
(that is, at least 1 year postinjury) of neurological or
psychiatric disease. METHODS: All studies from January 1995
to February 2012 reporting TBI as a risk factor for
diagnoses of interest were identified by searching PubMed,
study references, and review articles. Reviewers abstracted
the data and assessed study designs and characteristics.
RESULTS: Fifty-seven studies met the inclusion criteria. A
random effects meta-analysis revealed a significant
association of prior TBI with subsequent neurological and
psychiatric diagnoses. The pooled odds ratio (OR) for the
development of any illness subsequent to prior TBI was 1.67
(95% CI 1.44-1.93, p < 0.0001). Prior TBI was independently
associated with both neurological (OR 1.55, 95% CI
1.31-1.83, p < 0.0001) and psychiatric (OR 2.00, 95% CI
1.50-2.66, p < 0.0001) outcomes. Analyses of individual
diagnoses revealed higher odds of Alzheimer's disease,
Parkinson's disease, mild cognitive impairment, depression,
mixed affective disorders, and bipolar disorder in
individuals with previous TBI as compared to those without
TBI. This association was present when examining only
studies of mild TBI and when considering the influence of
study design and characteristics. Analysis of a subset of
studies demonstrated no evidence that multiple TBIs were
associated with higher odds of disease than a single TBI.
CONCLUSIONS: History of TBI, including mild TBI, is
associated with the development of neurological and
psychiatric illness. This finding indicates that either TBI
is a risk factor for heterogeneous pathological processes or
that TBI may contribute to a common pathological
mechanism.},
Doi = {10.3171/2015.2.JNS14503},
Key = {fds327247}
}
@article{fds327851,
Author = {Jun, G and Ibrahim-Verbaas, CA and Vronskaya, M and Lambert, J-C and Chung, J and Naj, AC and Kunkle, BW and Wang, L-S and Bis, JC and Bellenguez, C and Harold, D and Lunetta, KL and Destefano, AL and Grenier-Boley, B and Sims, R and Beecham, GW and Smith, AV and Chouraki,
V and Hamilton-Nelson, KL and Ikram, MA and Fievet, N and Denning, N and Martin, ER and Schmidt, H and Kamatani, Y and Dunstan, ML and Valladares, O and Laza, AR and Zelenika, D and Ramirez, A and Foroud,
TM and Choi, S-H and Boland, A and Becker, T and Kukull, WA and van der
Lee, SJ and Pasquier, F and Cruchaga, C and Beekly, D and Fitzpatrick,
AL and Hanon, O and Gill, M and Barber, R and Gudnason, V and Campion, D and Love, S and Bennett, DA and Amin, N and Berr, C and Tsolaki, M and Buxbaum,
JD and Lopez, OL and Deramecourt, V and Fox, NC and Cantwell, LB and Tárraga, L and Dufouil, C and Hardy, J and Crane, PK and Eiriksdottir,
G and Hannequin, D and Clarke, R and Evans, D and Mosley, TH and Letenneur,
L and Brayne, C and Maier, W and De Jager and P and Emilsson, V and Dartigues,
J-F and Hampel, H and Kamboh, MI and de Bruijn, RFAG and Tzourio, C and Pastor, P and Larson, EB and Rotter, JI and O'Donovan, MC and Montine,
TJ and Nalls, MA and Mead, S and Reiman, EM and Jonsson, PV and Holmes, C and St George-Hyslop and PH and Boada, M and Passmore, P and Wendland, JR and Schmidt, R and Morgan, K and Winslow, AR and Powell, JF and Carasquillo,
M and Younkin, SG and Jakobsdóttir, J and Kauwe, JSK and Wilhelmsen,
KC and Rujescu, D and Nöthen, MM and Hofman, A and Jones, L and IGAP
Consortium, and Haines, JL and Psaty, BM and Van Broeckhoven and C and Holmans, P and Launer, LJ and Mayeux, R and Lathrop, M and Goate, AM and Escott-Price, V and Seshadri, S and Pericak-Vance, MA and Amouyel, P and Williams, J and van Duijn, CM and Schellenberg, GD and Farrer,
LA},
Title = {A novel Alzheimer disease locus located near the gene
encoding tau protein.},
Journal = {Mol Psychiatry},
Volume = {21},
Number = {1},
Pages = {108-117},
Year = {2016},
Month = {January},
url = {http://dx.doi.org/10.1038/mp.2015.23},
Abstract = {APOE ɛ4, the most significant genetic risk factor for
Alzheimer disease (AD), may mask effects of other loci. We
re-analyzed genome-wide association study (GWAS) data from
the International Genomics of Alzheimer's Project (IGAP)
Consortium in APOE ɛ4+ (10 352 cases and 9207 controls)
and APOE ɛ4- (7184 cases and 26 968 controls) subgroups
as well as in the total sample testing for interaction
between a single-nucleotide polymorphism (SNP) and APOE ɛ4
status. Suggestive associations (P<1 × 10(-4)) in stage 1
were evaluated in an independent sample (stage 2) containing
4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE
ɛ4-: 718 cases and 1699 controls). Among APOE ɛ4-
subjects, novel genome-wide significant (GWS) association
was observed with 17 SNPs (all between KANSL1 and LRRC37A on
chromosome 17 near MAPT) in a meta-analysis of the stage 1
and stage 2 data sets (best SNP, rs2732703, P=5·8 ×
10(-9)). Conditional analysis revealed that rs2732703
accounted for association signals in the entire 100-kilobase
region that includes MAPT. Except for previously identified
AD loci showing stronger association in APOE ɛ4+ subjects
(CR1 and CLU) or APOE ɛ4- subjects (MS4A6A/MS4A4A/MS4A6E),
no other SNPs were significantly associated with AD in a
specific APOE genotype subgroup. In addition, the finding in
the stage 1 sample that AD risk is significantly influenced
by the interaction of APOE with rs1595014 in TMEM106B
(P=1·6 × 10(-7)) is noteworthy, because TMEM106B variants
have previously been associated with risk of frontotemporal
dementia. Expression quantitative trait locus analysis
revealed that rs113986870, one of the GWS SNPs near
rs2732703, is significantly associated with four KANSL1
probes that target transcription of the first translated
exon and an untranslated exon in hippocampus (P ⩽ 1.3 ×
10(-8)), frontal cortex (P ⩽ 1.3 × 10(-9)) and temporal
cortex (P⩽1.2 × 10(-11)). Rs113986870 is also strongly
associated with a MAPT probe that targets transcription of
alternatively spliced exon 3 in frontal cortex (P=9.2 ×
10(-6)) and temporal cortex (P=2.6 × 10(-6)). Our
APOE-stratified GWAS is the first to show GWS association
for AD with SNPs in the chromosome 17q21.31 region.
Replication of this finding in independent samples is needed
to verify that SNPs in this region have significantly
stronger effects on AD risk in persons lacking APOE ɛ4
compared with persons carrying this allele, and if this is
found to hold, further examination of this region and
studies aimed at deciphering the mechanism(s) are
warranted.},
Doi = {10.1038/mp.2015.23},
Key = {fds327851}
}
@article{fds322224,
Author = {Lutz, MW and Sundseth, SS and Burns, DK and Saunders, AM and Hayden, KM and Burke, JR and Welsh-Bohmer, KA and Roses, AD},
Title = {A Genetics-based Biomarker Risk Algorithm for Predicting
Risk of Alzheimer's Disease.},
Journal = {Alzheimers Dement (N Y)},
Volume = {2},
Number = {1},
Pages = {30-44},
Year = {2016},
Month = {January},
url = {http://dx.doi.org/10.1016/j.trci.2015.12.002},
Abstract = {BACKGROUND: A straightforward, reproducible blood-based test
that predicts age dependent risk of Alzheimer's disease (AD)
could be used as an enrichment tool for clinical development
of therapies. This study evaluated the prognostic
performance of a genetics-based biomarker risk algorithm
(GBRA) established on a combination of Apolipoprotein E
(APOE)/Translocase of outer mitochondrial membrane 40
homolog (TOMM40) genotypes and age, then compare it to
cerebrospinal fluid (CSF) biomarkers, neuroimaging and
neurocognitive tests using data from two independent AD
cohorts. METHODS: The GBRA was developed using data from the
prospective Bryan-ADRC study (n=407; 86 conversion events
(mild cognitive impairment (MCI) or late onset Alzheimer's
disease (LOAD)). The performance of the algorithm was tested
using data from the ADNI study (n=660; 457 individuals
categorized as MCI or LOAD). RESULTS: The positive
predictive values (PPV) and negative predictive values (NPV)
of the GBRA are in the range of 70-80%. The relatively high
odds ratio (approximately 3-5) and significant net
reclassification index (NRI) scores comparing the GBRA to a
version based on APOE and age alone support the value of the
GBRA in risk prediction for MCI due to LOAD. Performance of
the GBRA compares favorably with CSF and imaging (fMRI)
biomarkers. In addition, the GBRA "high" and "low" AD-risk
categorizations correlated well with pathological CSF
biomarker levels, PET amyloid burden and neurocognitive
scores. CONCLUSIONS: Unlike dynamic markers (i.e., imaging,
protein or lipid markers) that may be influenced by factors
unrelated to disease, genomic DNA is easily collected,
stable, and the technical methods for measurement are
robust, inexpensive, and widely available. The performance
characteristics of the GBRA support its use as a
pharmacogenetic enrichment tool for LOAD delay of onset
clinical trials, and merits further evaluation for its
clinical utility in evaluating therapeutic
efficacy.},
Doi = {10.1016/j.trci.2015.12.002},
Key = {fds322224}
}
@article{fds322774,
Author = {Reiman, EM and Langbaum, JB and Tariot, PN and Lopera, F and Bateman,
RJ and Morris, JC and Sperling, RA and Aisen, PS and Roses, AD and Welsh-Bohmer, KA and Carrillo, MC and Weninger,
S},
Title = {CAP--advancing the evaluation of preclinical Alzheimer
disease treatments.},
Journal = {Nat Rev Neurol},
Volume = {12},
Number = {1},
Pages = {56-61},
Year = {2016},
Month = {January},
url = {http://dx.doi.org/10.1038/nrneurol.2015.177},
Abstract = {If we are to find treatments to postpone, reduce the risk
of, or completely prevent the clinical onset of Alzheimer
disease (AD), we need faster methods to evaluate promising
preclinical AD treatments, new ways to work together in
support of common goals, and a determination to expedite the
initiation and performance of preclinical AD trials. In this
article, we note some of the current challenges,
opportunities and emerging strategies in preclinical AD
treatment. We describe the Collaboration for Alzheimer's
Prevention (CAP)-a convening, harmonizing and
consensus-building initiative to help stakeholders advance
AD prevention research with rigour, care and maximal
impact-and we demonstrate the impact of CAP on the goals and
design of new preclinical AD trials.},
Doi = {10.1038/nrneurol.2015.177},
Key = {fds322774}
}
@article{fds371165,
Author = {Morrison, R and Pei, H and Novak, G and Kaufer, D and Welsh-Bohmer, K and Ruhmel, S and Narayan, VA},
Title = {Validation of a Novel Computerized Self-Administered
Memory-Screening Test With Automated Reporting (SAMSTAR) in
Patients With Mild Cognitive Impairment and Normal Control
Participants: A Randomized, Crossover, Controlled
Study},
Journal = {NEUROPSYCHOPHARMACOLOGY},
Volume = {41},
Pages = {S345-S346},
Year = {2016},
Key = {fds371165}
}
@article{fds322222,
Author = {Karch, CM and Ezerskiy, LA and Bertelsen, S and Alzheimer’s Disease
Genetics Consortium (ADGC), and Goate, AM},
Title = {Alzheimer's Disease Risk Polymorphisms Regulate Gene
Expression in the ZCWPW1 and the CELF1 Loci.},
Journal = {PLoS One},
Volume = {11},
Number = {2},
Pages = {e0148717},
Editor = {Huang, Q},
Year = {2016},
url = {http://dx.doi.org/10.1371/journal.pone.0148717},
Abstract = {Late onset Alzheimer's disease (LOAD) is a genetically
complex and clinically heterogeneous disease. Recent
large-scale genome wide association studies (GWAS) have
identified more than twenty loci that modify risk for AD.
Despite the identification of these loci, little progress
has been made in identifying the functional variants that
explain the association with AD risk. Thus, we sought to
determine whether the novel LOAD GWAS single nucleotide
polymorphisms (SNPs) alter expression of LOAD GWAS genes and
whether expression of these genes is altered in AD brains.
The majority of LOAD GWAS SNPs occur in gene dense regions
under large linkage disequilibrium (LD) blocks, making it
unclear which gene(s) are modified by the SNP. Thus, we
tested for brain expression quantitative trait loci (eQTLs)
between LOAD GWAS SNPs and SNPs in high LD with the LOAD
GWAS SNPs in all of the genes within the GWAS loci. We found
a significant eQTL between rs1476679 and PILRB and GATS,
which occurs within the ZCWPW1 locus. PILRB and GATS
expression levels, within the ZCWPW1 locus, were also
associated with AD status. Rs7120548 was associated with
MTCH2 expression, which occurs within the CELF1 locus.
Additionally, expression of several genes within the CELF1
locus, including MTCH2, were highly correlated with one
another and were associated with AD status. We further
demonstrate that PILRB, as well as other genes within the
GWAS loci, are most highly expressed in microglia. These
findings together with the function of PILRB as a DAP12
receptor supports the critical role of microglia and
neuroinflammation in AD risk.},
Doi = {10.1371/journal.pone.0148717},
Key = {fds322222}
}
@article{fds322223,
Author = {Foster, CM and Addis, DR and Ford, JH and Kaufer, DI and Burke, JR and Browndyke, JN and Welsh-Bohmer, KA and Giovanello,
KS},
Title = {Prefrontal contributions to relational encoding in amnestic
mild cognitive impairment.},
Journal = {Neuroimage Clin},
Volume = {11},
Pages = {158-166},
Year = {2016},
url = {http://dx.doi.org/10.1016/j.nicl.2016.01.008},
Abstract = {Relational memory declines are well documented as an early
marker for amnestic mild cognitive impairment (aMCI).
Episodic memory formation relies on relational processing
supported by two mnemonic mechanisms, generation and
binding. Neuroimaging studies using functional magnetic
resonance imaging (fMRI) have primarily focused on binding
deficits which are thought to be mediated by medial temporal
lobe dysfunction. In this study, prefrontal contributions to
relational encoding were also investigated using fMRI by
parametrically manipulating generation demands during the
encoding of word triads. Participants diagnosed with aMCI
and healthy control subjects encoded word triads consisting
of a category word with either, zero, one, or two
semantically related exemplars. As the need to generate
increased (i.e., two- to one- to zero-link triads), both
groups recruited a core set of regions associated with the
encoding of word triads including the parahippocampal gyrus,
superior temporal gyrus, and superior parietal lobule.
Participants diagnosed with aMCI also parametrically
recruited several frontal regions including the inferior
frontal gyrus and middle frontal gyrus as the need to
generate increased, whereas the control participants did not
show this modulation. While there is some functional overlap
in regions recruited by generation demands between the
groups, the recruitment of frontal regions in the aMCI
participants coincides with worse memory performance, likely
representing a form of neural inefficiency associated with
Alzheimer's disease.},
Doi = {10.1016/j.nicl.2016.01.008},
Key = {fds322223}
}
@article{fds322775,
Author = {Monsell, SE and Dodge, HH and Zhou, X-H and Bu, Y and Besser, LM and Mock,
C and Hawes, SE and Kukull, WA and Weintraub, S and Neuropsychology Work
Group Advisory to the Clinical Task Force},
Title = {Results From the NACC Uniform Data Set Neuropsychological
Battery Crosswalk Study.},
Journal = {Alzheimer Dis Assoc Disord},
Volume = {30},
Number = {2},
Pages = {134-139},
Year = {2016},
url = {http://dx.doi.org/10.1097/WAD.0000000000000111},
Abstract = {INTRODUCTION: Four new nonproprietary tests were recommended
for use in the National Alzheimer's Coordinating Center's
Uniform Data Set Neuropsychological Battery. These tests are
similar to previous tests but also allow for continuity of
longitudinal data collection and wide dissemination among
research collaborators. METHODS: A Crosswalk Study was
conducted in early 2014 to assess the correlation between
each set of new and previous tests. Tests with good
correlation were equated using equipercentile equating. The
resulting conversion tables allow scores on the new tests to
be converted to equivalent scores on the previous tests.
RESULTS: All pairs of tests had good correlation (ρ=0.68 to
0.78). Learning effects were detected for Logical Memory
only. Confidence intervals were narrow at each point
estimate, and prediction accuracy was high. DISCUSSION: The
recommended new tests are well correlated with the previous
tests. The equipercentile equating method produced
conversion tables that provide a useful reference for
clinicians and researchers.},
Doi = {10.1097/WAD.0000000000000111},
Key = {fds322775}
}
@article{fds322225,
Author = {Mukherjee, S and Walter, S and Kauwe, JSK and Saykin, AJ and Bennett,
DA and Larson, EB and Crane, PK and Glymour, MM and Adult Changes in
Thought Study Investigators, and Religious Orders Study/Memory and Aging Project Investigators, and Alzheimer's Disease
Genetics Consortium},
Title = {Genetically predicted body mass index and Alzheimer's
disease-related phenotypes in three large samples: Mendelian
randomization analyses.},
Journal = {Alzheimers Dement},
Volume = {11},
Number = {12},
Pages = {1439-1451},
Year = {2015},
Month = {December},
url = {http://dx.doi.org/10.1016/j.jalz.2015.05.015},
Abstract = {Observational research shows that higher body mass index
(BMI) increases Alzheimer's disease (AD) risk, but it is
unclear whether this association is causal. We applied
genetic variants that predict BMI in Mendelian randomization
analyses, an approach that is not biased by reverse
causation or confounding, to evaluate whether higher BMI
increases AD risk. We evaluated individual-level data from
the AD Genetics Consortium (ADGC: 10,079 AD cases and 9613
controls), the Health and Retirement Study (HRS: 8403
participants with algorithm-predicted dementia status), and
published associations from the Genetic and Environmental
Risk for AD consortium (GERAD1: 3177 AD cases and 7277
controls). No evidence from individual single-nucleotide
polymorphisms or polygenic scores indicated BMI increased AD
risk. Mendelian randomization effect estimates per BMI point
(95% confidence intervals) were as follows: ADGC, odds ratio
(OR) = 0.95 (0.90-1.01); HRS, OR = 1.00 (0.75-1.32); GERAD1,
OR = 0.96 (0.87-1.07). One subscore (cellular processes not
otherwise specified) unexpectedly predicted lower AD
risk.},
Doi = {10.1016/j.jalz.2015.05.015},
Key = {fds322225}
}
@article{fds322226,
Author = {Ghani, M and Reitz, C and Cheng, R and Vardarajan, BN and Jun, G and Sato,
C and Naj, A and Rajbhandary, R and Wang, L-S and Valladares, O and Lin,
C-F and Larson, EB and Graff-Radford, NR and Evans, D and De Jager and PL and Crane, PK and Buxbaum, JD and Murrell, JR and Raj, T and Ertekin-Taner,
N and Logue, M and Baldwin, CT and Green, RC and Barnes, LL and Cantwell,
LB and Fallin, MD and Go, RCP and Griffith, PA and Obisesan, TO and Manly,
JJ and Lunetta, KL and Kamboh, MI and Lopez, OL and Bennett, DA and Hendrie, H and Hall, KS and Goate, AM and Byrd, GS and Kukull, WA and Foroud, TM and Haines, JL and Farrer, LA and Pericak-Vance, MA and Lee,
JH and Schellenberg, GD and St George-Hyslop and P and Mayeux, R and Rogaeva, E and Alzheimer’s Disease Genetics
Consortium},
Title = {Association of Long Runs of Homozygosity With Alzheimer
Disease Among African American Individuals.},
Journal = {JAMA Neurol},
Volume = {72},
Number = {11},
Pages = {1313-1323},
Year = {2015},
Month = {November},
url = {http://dx.doi.org/10.1001/jamaneurol.2015.1700},
Abstract = {IMPORTANCE: Mutations in known causal Alzheimer disease (AD)
genes account for only 1% to 3% of patients and almost all
are dominantly inherited. Recessive inheritance of complex
phenotypes can be linked to long (>1-megabase [Mb]) runs of
homozygosity (ROHs) detectable by single-nucleotide
polymorphism (SNP) arrays. OBJECTIVE: To evaluate the
association between ROHs and AD in an African American
population known to have a risk for AD up to 3 times higher
than white individuals. DESIGN, SETTING, AND PARTICIPANTS:
Case-control study of a large African American data set
previously genotyped on different genome-wide SNP arrays
conducted from December 2013 to January 2015. Global and
locus-based ROH measurements were analyzed using raw or
imputed genotype data. We studied the raw genotypes from 2
case-control subsets grouped based on SNP array: Alzheimer's
Disease Genetics Consortium data set (871 cases and 1620
control individuals) and Chicago Health and Aging
Project-Indianapolis Ibadan Dementia Study data set (279
cases and 1367 control individuals). We then examined the
entire data set using imputed genotypes from 1917 cases and
3858 control individuals. MAIN OUTCOMES AND MEASURES: The
ROHs larger than 1 Mb, 2 Mb, or 3 Mb were investigated
separately for global burden evaluation, consensus regions,
and gene-based analyses. RESULTS: The African American
cohort had a low degree of inbreeding (F ~ 0.006). In
the Alzheimer's Disease Genetics Consortium data set, we
detected a significantly higher proportion of cases with
ROHs greater than 2 Mb (P = .004) or greater than 3 Mb
(P = .02), as well as a significant 114-kilobase
consensus region on chr4q31.3 (empirical P value
2 = .04; ROHs >2 Mb). In the Chicago Health and Aging
Project-Indianapolis Ibadan Dementia Study data set, we
identified a significant 202-kilobase consensus region on
Chr15q24.1 (empirical P value 2 = .02; ROHs >1 Mb) and a
cluster of 13 significant genes on Chr3p21.31 (empirical P
value 2 = .03; ROHs >3 Mb). A total of 43 of 49
nominally significant genes common for both data sets also
mapped to Chr3p21.31. Analyses of imputed SNP data from the
entire data set confirmed the association of AD with global
ROH measurements (12.38 ROHs >1 Mb in cases vs 12.11 in
controls; 2.986 Mb average size of ROHs >2 Mb in cases vs
2.889 Mb in controls; and 22% of cases with ROHs >3 Mb vs
19% of controls) and a gene-cluster on Chr3p21.31 (empirical
P value 2 = .006-.04; ROHs >3 Mb). Also, we detected a
significant association between AD and CLDN17 (empirical P
value 2 = .01; ROHs >1 Mb), encoding a protein from the
Claudin family, members of which were previously suggested
as AD biomarkers. CONCLUSIONS AND RELEVANCE: To our
knowledge, we discovered the first evidence of increased
burden of ROHs among patients with AD from an outbred
African American population, which could reflect either the
cumulative effect of multiple ROHs to AD or the contribution
of specific loci harboring recessive mutations and risk
haplotypes in a subset of patients. Sequencing is required
to uncover AD variants in these individuals.},
Doi = {10.1001/jamaneurol.2015.1700},
Key = {fds322226}
}
@article{fds325786,
Author = {Cao, L and Pokorney, SD and Hayden, K and Welsh-Bohmer, K and Newby,
LK},
Title = {Cognitive Function: Is There More to Anticoagulation in
Atrial Fibrillation Than Stroke?},
Journal = {J Am Heart Assoc},
Volume = {4},
Number = {8},
Pages = {e001573},
Year = {2015},
Month = {August},
url = {http://dx.doi.org/10.1161/JAHA.114.001573},
Doi = {10.1161/JAHA.114.001573},
Key = {fds325786}
}
@article{fds276902,
Author = {Mistridis, P and Egli, SC and Iverson, GL and Berres, M and Willmes, K and Welsh-Bohmer, KA and Monsch, AU},
Title = {Considering the base rates of low performance in cognitively
healthy older adults improves the accuracy to identify
neurocognitive impairment with the Consortium to Establish a
Registry for Alzheimer's Disease-Neuropsychological
Assessment Battery (CERAD-NAB).},
Journal = {Eur Arch Psychiatry Clin Neurosci},
Volume = {265},
Number = {5},
Pages = {407-417},
Year = {2015},
Month = {August},
ISSN = {0940-1334},
url = {http://dx.doi.org/10.1007/s00406-014-0571-z},
Abstract = {It is common for some healthy older adults to obtain low
test scores when a battery of neuropsychological tests is
administered, which increases the risk of the clinician
misdiagnosing cognitive impairment. Thus, base rates of
healthy individuals' low scores are required to more
accurately interpret neuropsychological results. At present,
this information is not available for the German version of
the Consortium to Establish a Registry for Alzheimer's
Disease-Neuropsychological Assessment Battery (CERAD-NAB), a
frequently used battery in the USA and in German-speaking
Europe. This study aimed to determine the base rates of low
scores for the CERAD-NAB and to tabulate a summary figure of
cut-off scores and numbers of low scores to aid in clinical
decision making. The base rates of low scores on the ten
German CERAD-NAB subscores were calculated from the German
CERAD-NAB normative sample (N = 1,081) using six different
cut-off scores (i.e., 1st, 2.5th, 7th, 10th, 16th, and 25th
percentile). Results indicate that high percentages of one
or more "abnormal" scores were obtained, irrespective of the
cut-off criterion. For example, 60.6% of the normative
sample obtained one or more scores at or below the 10th
percentile. These findings illustrate the importance of
considering the prevalence of low scores in healthy
individuals. The summary figure of CERAD-NAB base rates is
an important supplement for test interpretation and can be
used to improve the diagnostic accuracy of neurocognitive
disorders.},
Doi = {10.1007/s00406-014-0571-z},
Key = {fds276902}
}
@article{fds327852,
Author = {Østergaard, SD and Mukherjee, S and Sharp, SJ and Proitsi, P and Lotta,
LA and Day, F and Perry, JRB and Boehme, KL and Walter, S and Kauwe, JS and Gibbons, LE and Alzheimer’s Disease Genetics Consortium, and GERAD1 Consortium, and EPIC-InterAct Consortium, and Larson, EB and Powell, JF and Langenberg, C and Crane, PK and Wareham, NJ and Scott,
RA},
Title = {Associations between Potentially Modifiable Risk Factors and
Alzheimer Disease: A Mendelian Randomization
Study.},
Journal = {PLoS Med},
Volume = {12},
Number = {6},
Pages = {e1001841},
Year = {2015},
Month = {June},
url = {http://dx.doi.org/10.1371/journal.pmed.1001841},
Abstract = {BACKGROUND: Potentially modifiable risk factors including
obesity, diabetes, hypertension, and smoking are associated
with Alzheimer disease (AD) and represent promising targets
for intervention. However, the causality of these
associations is unclear. We sought to assess the causal
nature of these associations using Mendelian randomization
(MR). METHODS AND FINDINGS: We used SNPs associated with
each risk factor as instrumental variables in MR analyses.
We considered type 2 diabetes (T2D, NSNPs = 49), fasting
glucose (NSNPs = 36), insulin resistance (NSNPs = 10), body
mass index (BMI, NSNPs = 32), total cholesterol (NSNPs =
73), HDL-cholesterol (NSNPs = 71), LDL-cholesterol (NSNPs =
57), triglycerides (NSNPs = 39), systolic blood pressure
(SBP, NSNPs = 24), smoking initiation (NSNPs = 1), smoking
quantity (NSNPs = 3), university completion (NSNPs = 2), and
years of education (NSNPs = 1). We calculated MR estimates
of associations between each exposure and AD risk using an
inverse-variance weighted approach, with summary statistics
of SNP-AD associations from the International Genomics of
Alzheimer's Project, comprising a total of 17,008
individuals with AD and 37,154 cognitively normal elderly
controls. We found that genetically predicted higher SBP was
associated with lower AD risk (odds ratio [OR] per standard
deviation [15.4 mm Hg] of SBP [95% CI]: 0.75 [0.62-0.91]; p
= 3.4 × 10(-3)). Genetically predicted higher SBP was also
associated with a higher probability of taking
antihypertensive medication (p = 6.7 × 10(-8)). Genetically
predicted smoking quantity was associated with lower AD risk
(OR per ten cigarettes per day [95% CI]: 0.67 [0.51-0.89]; p
= 6.5 × 10(-3)), although we were unable to stratify by
smoking history; genetically predicted smoking initiation
was not associated with AD risk (OR = 0.70 [0.37, 1.33]; p =
0.28). We saw no evidence of causal associations between
glycemic traits, T2D, BMI, or educational attainment and
risk of AD (all p > 0.1). Potential limitations of this
study include the small proportion of intermediate trait
variance explained by genetic variants and other implicit
limitations of MR analyses. CONCLUSIONS: Inherited lifetime
exposure to higher SBP is associated with lower AD risk.
These findings suggest that higher blood pressure--or some
environmental exposure associated with higher blood
pressure, such as use of antihypertensive medications--may
reduce AD risk.},
Doi = {10.1371/journal.pmed.1001841},
Key = {fds327852}
}
@article{fds276903,
Author = {Wang, L-S and Naj, AC and Graham, RR and Crane, PK and Kunkle, BW and Cruchaga, C and Murcia, JDG and Cannon-Albright, L and Baldwin, CT and Zetterberg, H and Blennow, K and Kukull, WA and Faber, KM and Schupf, N and Norton, MC and Tschanz, JT and Munger, RG and Corcoran, CD and Rogaeva,
E and Alzheimer's Disease Genetics Consortium, and Lin, C-F and Dombroski, BA and Cantwell, LB and Partch, A and Valladares, O and Hakonarson, H and St George-Hyslop and P and Green, RC and Goate, AM and Foroud, TM and Carney, RM and Larson, EB and Behrens, TW and Kauwe, JSK and Haines, JL and Farrer, LA and Pericak-Vance, MA and Mayeux, R and Schellenberg, GD and National Institute on Aging-Late-Onset
Alzheimer’s Disease (NIA-LOAD) Family Study, and Albert, MS and Albin, RL and Apostolova, LG and Arnold, SE and Barber, R and Barmada,
M and Barnes, LL and Beach, TG and Becker, JT and Beecham, GW and Beekly,
D and Bennett, DA and Bigio, EH and Bird, TD and Blacker, D and Boeve, BF and Bowen, JD and Boxer, A and Burke, JR and Buxbaum, JD and Cairns, NJ and Cao, C and Carlson, CS and Carroll, SL and Chui, HC and Clark, DG and Cribbs, DH and Crocco, EA and DeCarli, C and DeKosky, ST and Demirci,
FY and Dick, M and Dickson, DW and Duara, R and Ertekin-Taner, N and Fallon, KB and Farlow, MR and Ferris, S and Frosch, MP and Galasko, DR and Ganguli, M and Gearing, M and Geschwind, DH and Ghetti, B and Gilbert,
JR and Glass, JD and Graff-Radford, NR and Growdon, JH and Hamilton, RL and Hamilton-Nelson, KL and Harrell, LE and Head, E and Honig, LS and Hulette, CM and Hyman, BT and Jarvik, GP and Jicha, GA and Jin, L-W and Jun, G and Kamboh, MI and Karydas, A and Kaye, JA and Kim, R and Koo, EH and Kowall, NW and Kramer, JH and LaFerla, FM and Lah, JJ and Leverenz, JB and Levey, AI and Li, G and Lieberman, AP and Lopez, OL and Lunetta, KL and Lyketsos, CG and Mack, WJ and Marson, DC and Martin, ER and Martiniuk,
F and Mash, DC and Masliah, E and McCormick, WC and McCurry, SM and McDavid, AN and McKee, AC and Mesulam, WM and Miller, BL and Miller, CA and Miller, JW and Montine, TJ and Morris, JC and Murrell, JR and Olichney,
JM and Parisi, JE and Perry, W and Peskind, E and Petersen, RC and Pierce,
A and Poon, WW and Potter, H and Quinn, JF and Raj, A and Raskind, M and Reiman, EM and Reisberg, B and Reitz, C and Ringman, JM and Roberson,
ED and Rosen, HJ and Rosenberg, RN and Sano, M and Saykin, AJ and Schneider, JA and Schneider, LS and Seeley, WW and Smith, AG and Sonnen,
JA and Spina, S and Stern, RA and Tanzi, RE and Thornton-Wells, TA and Trojanowski, JQ and Troncoso, JC and Tsuang, DW and Van Deerlin and VM and Van Eldik and LJ and Vardarajan, BN and Vinters, HV and Vonsattel, JP and Weintraub, S and Welsh-Bohmer, KA and Williamson, J and Wishnek, S and Woltjer, RL and Wright, CB and Younkin, SG and Yu, C-E and Yu,
L},
Title = {Rarity of the Alzheimer disease-protective APP A673T variant
in the United States.},
Journal = {JAMA Neurol},
Volume = {72},
Number = {2},
Pages = {209-216},
Year = {2015},
Month = {February},
ISSN = {2168-6149},
url = {http://dx.doi.org/10.1001/jamaneurol.2014.2157},
Abstract = {IMPORTANCE: Recently, a rare variant in the amyloid
precursor protein gene (APP) was described in a population
from Iceland. This variant, in which alanine is replaced by
threonine at position 673 (A673T), appears to protect
against late-onset Alzheimer disease (AD). We evaluated the
frequency of this variant in AD cases and cognitively normal
controls to determine whether this variant will
significantly contribute to risk assessment in individuals
in the United States. OBJECTIVE: To determine the frequency
of the APP A673T variant in a large group of elderly
cognitively normal controls and AD cases from the United
States and in 2 case-control cohorts from Sweden. DESIGN,
SETTING, AND PARTICIPANTS: Case-control association analysis
of variant APP A673T in US and Swedish white individuals
comparing AD cases with cognitively intact elderly controls.
Participants were ascertained at multiple
university-associated medical centers and clinics across the
United States and Sweden by study-specific sampling methods.
They were from case-control studies, community-based
prospective cohort studies, and studies that ascertained
multiplex families from multiple sources. MAIN OUTCOMES AND
MEASURES: Genotypes for the APP A673T variant were
determined using the Infinium HumanExome V1 Beadchip
(Illumina, Inc) and by TaqMan genotyping (Life
Technologies). RESULTS: The A673T variant genotypes were
evaluated in 8943 US AD cases, 10 480 US cognitively
normal controls, 862 Swedish AD cases, and 707 Swedish
cognitively normal controls. We identified 3 US individuals
heterozygous for A673T, including 1 AD case (age at onset,
89 years) and 2 controls (age at last examination, 82 and 77
years). The remaining US samples were homozygous for the
alanine (A673) allele. In the Swedish samples, 3 controls
were heterozygous for A673T and all AD cases were homozygous
for the A673 allele. We also genotyped a US family
previously reported to harbor the A673T variant and found a
mother-daughter pair, both cognitively normal at ages 72 and
84 years, respectively, who were both heterozygous for
A673T; however, all individuals with AD in the family were
homozygous for A673. CONCLUSIONS AND RELEVANCE: The A673T
variant is extremely rare in US cohorts and does not play a
substantial role in risk for AD in this population. This
variant may be primarily restricted to Icelandic and
Scandinavian populations.},
Doi = {10.1001/jamaneurol.2014.2157},
Key = {fds276903}
}
@article{fds371166,
Author = {Budur, K and Martenyi, F and Welsh-Bohmer, KA and Burns, DK and Chiang,
C and O'Neil, J and Runyan, G and Schuster, J and Crenshaw, DG and Lutz,
MW and Metz, CA and Saunders, AM and Yarbrough, D and Yarnall, D and Lai,
E and Brannan, SK and Roses, AD},
Title = {A Pharmacogenetics Supported Clinical Trial to Delay Onset
of Mild Cognitive Impairment due to Alzheimer's Disease
Using Low Dose Pioglitazone: The Tommorrow
Study},
Journal = {NEUROPSYCHOPHARMACOLOGY},
Volume = {39},
Pages = {S342-S342},
Publisher = {NATURE PUBLISHING GROUP},
Year = {2014},
Month = {December},
Key = {fds371166}
}
@article{fds276898,
Author = {Chuang, Y-F and Breitner, JCS and Chiu, Y-L and Khachaturian, A and Hayden, K and Corcoran, C and Tschanz, J and Norton, M and Munger, R and Welsh-Bohmer, K and Zandi, PP and Cache County
Investigators},
Title = {Use of diuretics is associated with reduced risk of
Alzheimer's disease: the Cache County Study.},
Journal = {Neurobiol Aging},
Volume = {35},
Number = {11},
Pages = {2429-2435},
Year = {2014},
Month = {November},
ISSN = {0197-4580},
url = {http://dx.doi.org/10.1016/j.neurobiolaging.2014.05.002},
Abstract = {Although the use of antihypertensive medications has been
associated with reduced risk of Alzheimer's disease (AD), it
remains unclear which class provides the most benefit. The
Cache County Study of Memory Health and Aging is a
prospective longitudinal cohort study of dementing illnesses
among the elderly population of Cache County, Utah. Using
waves I to IV data of the Cache County Study, 3417
participants had a mean of 7.1 years of follow-up.
Time-varying use of antihypertensive medications including
different class of diuretics, angiotensin converting enzyme
inhibitors, β-blockers, and calcium channel blockers was
used to predict the incidence of AD using Cox proportional
hazards analyses. During follow-up, 325 AD cases were
ascertained with a total of 23,590 person-years. Use of any
antihypertensive medication was associated with lower
incidence of AD (adjusted hazard ratio [aHR], 0.77; 95%
confidence interval [CI], 0.61-0.97). Among different
classes of antihypertensive medications, thiazide (aHR, 0.7;
95% CI, 0.53-0.93), and potassium-sparing diuretics (aHR,
0.69; 95% CI, 0.48-0.99) were associated with the greatest
reduction of AD risk. Thiazide and potassium-sparing
diuretics were associated with decreased risk of AD. The
inverse association of potassium-sparing diuretics confirms
an earlier finding in this cohort, now with longer
follow-up, and merits further investigation.},
Doi = {10.1016/j.neurobiolaging.2014.05.002},
Key = {fds276898}
}
@article{fds276904,
Author = {Naj, AC and Jun, G and Reitz, C and Kunkle, BW and Perry, W and Park, YS and Beecham, GW and Rajbhandary, RA and Hamilton-Nelson, KL and Wang,
L-S and Kauwe, JSK and Huentelman, MJ and Myers, AJ and Bird, TD and Boeve,
BF and Baldwin, CT and Jarvik, GP and Crane, PK and Rogaeva, E and Barmada,
MM and Demirci, FY and Cruchaga, C and Kramer, PL and Ertekin-Taner, N and Hardy, J and Graff-Radford, NR and Green, RC and Larson, EB and St
George-Hyslop, PH and Buxbaum, JD and Evans, DA and Schneider, JA and Lunetta, KL and Kamboh, MI and Saykin, AJ and Reiman, EM and De Jager,
PL and Bennett, DA and Morris, JC and Montine, TJ and Goate, AM and Blacker, D and Tsuang, DW and Hakonarson, H and Kukull, WA and Foroud,
TM and Martin, ER and Haines, JL and Mayeux, RP and Farrer, LA and Schellenberg, GD and Pericak-Vance, MA and Alzheimer Disease
Genetics Consortium, and Albert, MS and Albin, RL and Apostolova,
LG and Arnold, SE and Barber, R and Barnes, LL and Beach, TG and Becker,
JT and Beekly, D and Bigio, EH and Bowen, JD and Boxer, A and Burke, JR and Cairns, NJ and Cantwell, LB and Cao, C and Carlson, CS and Carney, RM and Carrasquillo, MM and Carroll, SL and Chui, HC and Clark, DG and Corneveaux, J and Cribbs, DH and Crocco, EA and DeCarli, C and DeKosky,
ST and Dick, M and Dickson, DW and Duara, R and Faber, KM and Fallon, KB and Farlow, MR and Ferris, S and Frosch, MP and Galasko, DR and Ganguli, M and Gearing, M and Geschwind, DH and Ghetti, B and Gilbert, JR and Glass,
JD and Growdon, JH and Hamilton, RL and Harrell, LE and Head, E and Honig,
LS and Hulette, CM and Hyman, BT and Jicha, GA and Jin, L-W and Karydas, A and Kaye, JA and Kim, R and Koo, EH and Kowall, NW and Kramer, JH and LaFerla,
FM and Lah, JJ and Leverenz, JB and Levey, AI and Li, G and Lieberman, AP and Lin, C-F and Lopez, OL and Lyketsos, CG and Mack, WJ and Martiniuk, F and Mash, DC and Masliah, E and McCormick, WC and McCurry, SM and McDavid,
AN and McKee, AC and Mesulam, M and Miller, BL and Miller, CA and Miller,
JW and Murrell, JR and Olichney, JM and Pankratz, VS and Parisi, JE and Paulson, HL and Peskind, E and Petersen, RC and Pierce, A and Poon, WW and Potter, H and Quinn, JF and Raj, A and Raskind, M and Reisberg, B and Ringman, JM and Roberson, ED and Rosen, HJ and Rosenberg, RN and Sano,
M and Schneider, LS and Seeley, WW and Smith, AG and Sonnen, JA and Spina,
S and Stern, RA and Tanzi, RE and Thornton-Wells, TA and Trojanowski,
JQ and Troncoso, JC and Valladares, O and Van Deerlin and VM and Van Eldik,
LJ and Vardarajan, BN and Vinters, HV and Vonsattel, JP and Weintraub,
S and Welsh-Bohmer, KA and Williamson, J and Wishnek, S and Woltjer, RL and Wright, CB and Younkin, SG and Yu, C-E and Yu, L},
Title = {Effects of multiple genetic loci on age at onset in
late-onset Alzheimer disease: a genome-wide association
study.},
Journal = {JAMA Neurol},
Volume = {71},
Number = {11},
Pages = {1394-1404},
Year = {2014},
Month = {November},
ISSN = {2168-6149},
url = {http://dx.doi.org/10.1001/jamaneurol.2014.1491},
Abstract = {IMPORTANCE: Because APOE locus variants contribute to risk
of late-onset Alzheimer disease (LOAD) and to differences in
age at onset (AAO), it is important to know whether other
established LOAD risk loci also affect AAO in affected
participants. OBJECTIVES: To investigate the effects of
known Alzheimer disease risk loci in modifying AAO and to
estimate their cumulative effect on AAO variation using data
from genome-wide association studies in the Alzheimer
Disease Genetics Consortium. DESIGN, SETTING, AND
PARTICIPANTS: The Alzheimer Disease Genetics Consortium
comprises 14 case-control, prospective, and family-based
data sets with data on 9162 participants of white
race/ethnicity with Alzheimer disease occurring after age 60
years who also had complete AAO information, gathered
between 1989 and 2011 at multiple sites by participating
studies. Data on genotyped or imputed single-nucleotide
polymorphisms most significantly associated with risk at 10
confirmed LOAD loci were examined in linear modeling of AAO,
and individual data set results were combined using a
random-effects, inverse variance-weighted meta-analysis
approach to determine whether they contribute to variation
in AAO. Aggregate effects of all risk loci on AAO were
examined in a burden analysis using genotype scores weighted
by risk effect sizes. MAIN OUTCOMES AND MEASURES: Age at
disease onset abstracted from medical records among
participants with LOAD diagnosed per standard criteria.
RESULTS: Analysis confirmed the association of APOE with
earlier AAO (P = 3.3 × 10(-96)), with associations in CR1
(rs6701713, P = 7.2 × 10(-4)), BIN1 (rs7561528, P = 4.8 ×
10(-4)), and PICALM (rs561655, P = 2.2 × 10(-3)) reaching
statistical significance (P < .005). Risk alleles
individually reduced AAO by 3 to 6 months. Burden analyses
demonstrated that APOE contributes to 3.7% of the variation
in AAO (R(2) = 0.256) over baseline (R(2) = 0.221), whereas
the other 9 loci together contribute to 2.2% of the
variation (R(2) = 0.242). CONCLUSIONS AND RELEVANCE: We
confirmed an association of APOE (OMIM 107741) variants with
AAO among affected participants with LOAD and observed novel
associations of CR1 (OMIM 120620), BIN1 (OMIM 601248), and
PICALM (OMIM 603025) with AAO. In contrast to earlier
hypothetical modeling, we show that the combined effects of
Alzheimer disease risk variants on AAO are on the scale of,
but do not exceed, the APOE effect. While the aggregate
effects of risk loci on AAO may be significant, additional
genetic contributions to AAO are individually likely to be
small.},
Doi = {10.1001/jamaneurol.2014.1491},
Key = {fds276904}
}
@article{fds276906,
Author = {Roses, AD and Lutz, MW and Saunders, AM and Goldgaber, D and Saul, R and Sundseth, SS and Akkari, PA and Roses, SM and Gottschalk, WK and Whitfield, KE and Vostrov, AA and Hauser, MA and Allingham, RR and Burns, DK and Chiba-Falek, O and Welsh-Bohmer,
KA},
Title = {African-American TOMM40'523-APOE haplotypes are admixture of
West African and Caucasian alleles.},
Journal = {Alzheimers Dement},
Volume = {10},
Number = {6},
Pages = {592-601.e2},
Year = {2014},
Month = {November},
ISSN = {1552-5260},
url = {http://dx.doi.org/10.1016/j.jalz.2014.06.009},
Abstract = {BACKGROUND: Several studies have demonstrated a lower
apolipoprotein E4 (APOE ε4) allele frequency in
African-Americans, but yet an increased age-related
prevalence of AD. An algorithm for prevention clinical
trials incorporating TOMM40'523 (Translocase of Outer
Mitochondria Membrane) and APOE depends on accurate
TOMM40'523-APOE haplotypes. METHODS: We have compared the
APOE and TOMM40'523 phased haplotype frequencies of a 9.5 kb
TOMM40/APOE genomic region in West African, Caucasian, and
African-American cohorts. RESULTS: African-American
haplotype frequency scans of poly-T lengths connected in
phase with either APOE ε4 or APOE ε3 differ from both West
Africans and Caucasians and represent admixture of several
distinct West African and Caucasian haplotypes. A new West
African TOMM40'523 haplotype, with APOE ε4 connected to a
short TOMM40'523 allele, is observed in African-Americans
but not Caucasians. CONCLUSION: These data have therapeutic
implications for the age of onset risk algorithm estimates
and the design of a prevention trial for African-Americans
or other mixed ethnic populations.},
Doi = {10.1016/j.jalz.2014.06.009},
Key = {fds276906}
}
@article{fds276907,
Author = {Hayden, KM and Makeeva, OA and Newby, LK and Plassman, BL and Markova,
VV and Dunham, A and Romero, HR and Melikyan, ZA and Germain, CM and Welsh-Bohmer, KA and Roses, AD and TOMSK-DUKE Study Group
Investigators},
Title = {A comparison of neuropsychological performance between US
and Russia: preparing for a global clinical
trial.},
Journal = {Alzheimers Dement},
Volume = {10},
Number = {6},
Pages = {760-768.e1},
Year = {2014},
Month = {November},
ISSN = {1552-5260},
url = {http://dx.doi.org/10.1016/j.jalz.2014.02.008},
Abstract = {BACKGROUND: Understanding regional differences in cognitive
performance is important for interpretation of data from
large multinational clinical trials. METHODS: Data from
Durham and Cabarrus Counties in North Carolina, USA and
Tomsk, Russia (n = 2972) were evaluated. The Montreal
Cognitive Assessment (MoCA), Trail Making Test Part B
(Trails B), Consortium to Establish a Registry for
Alzheimer's Disease Word List Memory Test (WLM) delayed
recall, and self-report Alzheimer's Disease Cooperative
Studies Mail-In Cognitive Function Screening Instrument
(MCFSI) were administered at each site. Multilevel modeling
measured the variance explained by site and predictors of
cognitive performance. RESULTS: Site differences accounted
for 11% of the variation in the MoCA, 1.6% in Trails B, 1.7%
in WLM, and 0.8% in MCFSI scores. Prior memory testing was
significantly associated with WLM. Diabetes and stroke were
significantly associated with Trails B and MCFSI.
CONCLUSIONS: Sources of variation include cultural
differences, health conditions, and exposure to test
stimuli. Findings highlight the importance of local norms to
interpret test performance.},
Doi = {10.1016/j.jalz.2014.02.008},
Key = {fds276907}
}
@article{fds276916,
Author = {Hayden, KM and Kuchibhatla, M and Romero, HR and Plassman, BL and Burke,
JR and Browndyke, JN and Welsh-Bohmer, KA},
Title = {Pre-clinical cognitive phenotypes for Alzheimer disease: a
latent profile approach.},
Journal = {Am J Geriatr Psychiatry},
Volume = {22},
Number = {11},
Pages = {1364-1374},
Year = {2014},
Month = {November},
url = {http://www.ncbi.nlm.nih.gov/pubmed/24080384},
Abstract = {BACKGROUND: Cognitive profiles for pre-clinical Alzheimer
disease (AD) can be used to identify groups of individuals
at risk for disease and better characterize pre-clinical
disease. Profiles or patterns of performance as pre-clinical
phenotypes may be more useful than individual test scores or
measures of global decline. OBJECTIVE: To evaluate patterns
of cognitive performance in cognitively normal individuals
to derive latent profiles associated with later onset of
disease using a combination of factor analysis and latent
profile analysis. METHODS: The National Alzheimer
Coordinating Centers collect data, including a battery of
neuropsychological tests, from participants at 29 National
Institute on Aging-funded Alzheimer Disease Centers across
the United States. Prior factor analyses of this battery
demonstrated a four-factor structure comprising memory,
attention, language, and executive function. Factor scores
from these analyses were used in a latent profile approach
to characterize cognition among a group of cognitively
normal participants (N = 3,911). Associations between
latent profiles and disease outcomes an average of 3 years
later were evaluated with multinomial regression models.
Similar analyses were used to determine predictors of
profile membership. RESULTS: Four groups were identified;
each with distinct characteristics and significantly
associated with later disease outcomes. Two groups were
significantly associated with development of cognitive
impairment. In post hoc analyses, both the Trail Making Test
Part B, and a contrast score (Delayed Recall - Trails B),
significantly predicted group membership and later cognitive
impairment. CONCLUSIONS: Latent profile analysis is a useful
method to evaluate patterns of cognition in large samples
for the identification of preclinical AD phenotypes;
comparable results, however, can be achieved with very
sensitive tests and contrast scores.},
Doi = {10.1016/j.jagp.2013.07.008},
Key = {fds276916}
}
@article{fds276919,
Author = {Greene, D and Tschanz, JT and Smith, KR and Ostbye, T and Corcoran, C and Welsh-Bohmer, KA and Norton, MC and Cache County
Investigators},
Title = {Impact of offspring death on cognitive health in late life:
the Cache County study.},
Journal = {Am J Geriatr Psychiatry},
Volume = {22},
Number = {11},
Pages = {1307-1315},
Year = {2014},
Month = {November},
url = {http://www.ncbi.nlm.nih.gov/pubmed/23954042},
Abstract = {OBJECTIVE: Experiencing the death of a child is associated
with negative short-term mental health consequences, but
less is known about cognitive outcomes and whether such
associations extend to late life. We tested the hypothesis
that experiencing an offspring death (OD) is associated with
an increased rate of cognitive decline in late life.
METHODS: This population-based longitudinal study observed
four cognitive statuses spaced 3-4 years apart, linked to an
extensive database containing objective genealogic and vital
statistics data. Home visits were conducted with 3,174
residents of a rural county in northern Utah, initially
without dementia, aged 65-105. Cognitive status was measured
with the Modified Mini-Mental State Exam at baseline and at
3-, 7-, and 10-year follow-ups. OD was obtained from the
Utah Population Database, which contains statewide birth and
death records. RESULTS: In linear mixed models, controlling
for age, gender, education, and apolipoprotein E status,
subjects who experienced OD while younger than age 31 years
experienced a significantly faster rate of cognitive decline
in late life, but only if they had an ε4 allele.
Reclassifying all OD (regardless of age) according to
subsequent birth of another child, OD was only related to
faster cognitive decline when there were no subsequent
births. CONCLUSION: Experiencing OD in early adulthood has a
long-term association with cognitive functioning in late
life, with a gene-environment interaction at the
apolipoprotein E locus. Subsequent birth of another child
attenuates this association.},
Doi = {10.1016/j.jagp.2013.05.002},
Key = {fds276919}
}
@article{fds276910,
Author = {Linnertz, C and Lutz, MW and Ervin, JF and Allen, J and Miller, NR and Welsh-Bohmer, KA and Roses, AD and Chiba-Falek,
O},
Title = {The genetic contributions of SNCA and LRRK2 genes to Lewy
Body pathology in Alzheimer's disease.},
Journal = {Hum Mol Genet},
Volume = {23},
Number = {18},
Pages = {4814-4821},
Year = {2014},
Month = {September},
ISSN = {0964-6906},
url = {http://dx.doi.org/10.1093/hmg/ddu196},
Abstract = {The molecular genetic basis that leads to Lewy Body (LB)
pathology in 15-20% of Alzheimer disease cases (LBV/AD) was
largely unknown. Alpha-synuclein (SNCA) and Leucine-rich
repeat kinase2 (LRRK2) have been implicated in the
pathogenesis of Parkinson's disease (PD), the prototype of
LB spectrum disorders. We tested the association of SNCA
variants with LB pathology in AD. We then stratified the
SNCA association analyses by LRRK2 genotype. We also
investigated the expression regulation of SNCA and LRRK2 in
relation to LB pathology. We evaluated the differences in
SNCA-mRNA and LRRK2-mRNA levels as a function of LB
pathology in the temporal cortex (TC) from autopsy-confirmed
LBV/AD cases and AD controls. We further investigated the
cis-effect of the LB pathology-associated genetic variants
within the SNCA and LRRK2 loci on the mRNA expression of
these genes. SNCA SNPs rs3857059 and rs2583988 showed
significant associations with increased risk for LB
pathology. When the analyses were stratified by
LRRK2-rs1491923 genotype, the associations became stronger
for both SNPs and an association was also observed with
rs2619363. Expression analysis demonstrated that SNCA- and
LRRK2-mRNA levels were significantly higher in TC from
LBV/AD brains compared with AD controls. Furthermore,
SNCA-mRNA expression level in the TC was associated with
rs3857059; homozygotes for the minor allele showed
significant higher expression. LRRK2-transcript levels were
increased in carriers of rs1491923 minor allele. Our
findings demonstrated that SNCA contributes to LB pathology
in AD patients, possibly via interaction with LRRK2, and
suggested that expression regulation of these genes may be
the molecular basis underlying the observed LB
associations.},
Doi = {10.1093/hmg/ddu196},
Key = {fds276910}
}
@article{fds276913,
Author = {Linnertz, C and Anderson, L and Gottschalk, W and Crenshaw, D and Lutz,
MW and Allen, J and Saith, S and Mihovilovic, M and Burke, JR and Welsh-Bohmer, KA and Roses, AD and Chiba-Falek,
O},
Title = {The cis-regulatory effect of an Alzheimer's
disease-associated poly-T locus on expression of TOMM40 and
apolipoprotein E genes.},
Journal = {Alzheimers Dement},
Volume = {10},
Number = {5},
Pages = {541-551},
Year = {2014},
Month = {September},
ISSN = {1552-5260},
url = {http://dx.doi.org/10.1016/j.jalz.2013.08.280},
Abstract = {BACKGROUND: We investigated the genomic region spanning the
Translocase of the Outer Mitochondrial Membrane 40-kD
(TOMM40) and Apolipoprotein E (APOE) genes, that has been
associated with the risk and age of onset of late-onset
Alzheimer's disease (LOAD) to determine whether a highly
polymorphic, intronic poly-T within this region (rs10524523;
hereafter, 523) affects expression of the APOE and TOMM40
genes. Alleles of this locus are classified as S, short; L,
long; and VL, very long based on the number of T residues.
METHODS: We evaluated differences in APOE messenger RNA
(mRNA) and TOMM40 mRNA levels as a function of the 523
genotype in two brain regions from APOE ε3/ε3 white
autopsy-confirmed LOAD cases and normal controls. We further
investigated the effect of the 523 locus in its native
genomic context using a luciferase expression system.
RESULTS: The expression of both genes was significantly
increased with disease. Mean expression of APOE and TOMM40
mRNA levels were higher in VL homozygotes compared with S
homozygotes in the temporal and occipital cortexes from
normal and LOAD cases. Results of a luciferase reporter
system were consistent with the human brain mRNA analysis;
the 523 VL poly-T resulted in significantly higher
expression than the S poly-T. Although the effect of poly-T
length on reporter expression was the same in HepG2 hepatoma
and SH-SY5Y neuroblastoma cells, the magnitude of the effect
was greater in the neuroblastoma than in the hepatoma cells,
which implies tissue-specific modulation of the 523 poly-T.
CONCLUSIONS: These results suggest that the 523 locus may
contribute to LOAD susceptibility by modulating the
expression of TOMM40 and/or APOE transcription.},
Doi = {10.1016/j.jalz.2013.08.280},
Key = {fds276913}
}
@article{fds276922,
Author = {Peterson, D and Munger, C and Crowley, J and Corcoran, C and Cruchaga,
C and Goate, AM and Norton, MC and Green, RC and Munger, RG and Breitner,
JCS and Welsh-Bohmer, KA and Lyketsos, C and Tschanz, J and Kauwe, JSK and Alzheimer's Disease Neuroimaging Initiative},
Title = {Variants in PPP3R1 and MAPT are associated with more rapid
functional decline in Alzheimer's disease: the Cache County
Dementia Progression Study.},
Journal = {Alzheimers Dement},
Volume = {10},
Number = {3},
Pages = {366-371},
Year = {2014},
Month = {May},
url = {http://www.ncbi.nlm.nih.gov/pubmed/23727081},
Abstract = {BACKGROUND: Single-nucleotide polymorphisms (SNPs) located
in the gene encoding the regulatory subunit of the protein
phosphatase 2B (PPP3R1, rs1868402) and the
microtubule-associated protein tau (MAPT, rs3785883) gene
were recently associated with higher cerebrospinal fluid
(CSF) tau levels in samples from the Knight Alzheimer's
Disease Research Center at Washington University (WU) and
Alzheimer's Disease Neuroimaging Initiative (ADNI). In these
same samples, these SNPs were also associated with faster
functional decline, or progression of Alzheimer's disease
(AD) as measured by the Clinical Dementia Rating sum of
boxes scores (CDR-sb). We attempted to validate the latter
association in an independent, population-based sample of
incident AD cases from the Cache County Dementia Progression
Study (DPS). METHODS: All 92 AD cases from the DPS with a
global CDR-sb ≤1 (mild) at initial clinical assessment who
were later assessed on CDR-sb data on at least two other
time points were genotyped at the two SNPs of interest
(rs1868402 and rs3785883). We used linear mixed models to
estimate associations between these SNPs and CDR-sb
trajectory. All analyses were performed using Proc Mixed in
SAS. RESULTS: Although we observed no association between
rs3785883 or rs1868402 alone and change in CDR-sb (P > .10),
there was a significant association between a combined
genotype model and change in CDR-sb: carriers of the
high-risk genotypes at both loci progressed >2.9 times
faster than noncarriers (P = .015). When data from DPS were
combined with previously published data from WU and ADNI,
change in CDR-sb was 30% faster for each copy of the
high-risk allele at rs3785883 (P = .0082) and carriers of
both high-risk genotypes at both loci progressed 6 times
faster (P < .0001) than all others combined. CONCLUSIONS: We
replicate a previous report by Cruchaga et al that specific
variations in rs3785883 and rs1868402 are associated with
accelerated progression of AD. Further characterization of
this association will provide a better understanding of how
genetic factors influence the rate of progression of AD and
could provide novel insights into preventative and
therapeutic strategies.},
Doi = {10.1016/j.jalz.2013.02.010},
Key = {fds276922}
}
@article{fds276920,
Author = {Steinberg, M and Hess, K and Corcoran, C and Mielke, MM and Norton, M and Breitner, J and Green, R and Leoutsakos, J and Welsh-Bohmer, K and Lyketsos, C and Tschanz, J},
Title = {Vascular risk factors and neuropsychiatric symptoms in
Alzheimer's disease: the Cache County Study.},
Journal = {Int J Geriatr Psychiatry},
Volume = {29},
Number = {2},
Pages = {153-159},
Year = {2014},
Month = {February},
ISSN = {0885-6230},
url = {http://dx.doi.org/10.1002/gps.3980},
Abstract = {OBJECTIVE: Knowledge of potentially modifiable risk factors
for neuropsychiatric symptoms (NPS) in Alzheimer's disease
(AD) is important. This study longitudinally explores
modifiable vascular risk factors for NPS in AD. METHODS:
Participants enrolled in the Cache County Study on Memory in
Aging with no dementia at baseline were subsequently
assessed over three additional waves, and those with
incident (new onset) dementia were invited to join the
Dementia Progression Study for longitudinal follow-up. A
total of 327 participants with incident AD were identified
and assessed for the following vascular factors: atrial
fibrillation, hypertension, diabetes mellitus, angina,
coronary artery bypass surgery, myocardial infarction,
cerebrovascular accident, and use of antihypertensive or
diabetes medicines. A vascular index (VI) was also
calculated. NPS were assessed over time using the
Neuropsychiatric Inventory (NPI). Affective and Psychotic
symptom clusters were assessed separately. The association
between vascular factors and change in NPI total score was
analyzed using linear mixed model and in symptom clusters
using a random effects model. RESULTS: No individual
vascular risk factors or the VI significantly predicted
change in any individual NPS. The use of antihypertensive
medications more than four times per week was associated
with higher total NPI and Affective cluster scores.
CONCLUSIONS: Use of antihypertensive medication was
associated with higher total NPI and Affective cluster
scores. The results of this study do not otherwise support
vascular risk factors as modifiers of longitudinal change in
NPS in AD.},
Doi = {10.1002/gps.3980},
Key = {fds276920}
}
@article{fds276911,
Author = {Romero, HR and Welsh-Bohmer, KA and Gwyther, LP and Edmonds, HL and Plassman, BL and Germain, CM and McCart, M and Hayden, KM and Pieper, C and Roses, AD},
Title = {Community engagement in diverse populations for Alzheimer
disease prevention trials.},
Journal = {Alzheimer Dis Assoc Disord},
Volume = {28},
Number = {3},
Pages = {269-274},
Year = {2014},
ISSN = {0893-0341},
url = {http://dx.doi.org/10.1097/WAD.0000000000000029},
Abstract = {The recruitment of asymptomatic volunteers has been
identified as a critical factor that is delaying the
development and validation of preventive therapies for
Alzheimer disease (AD). Typical recruitment strategies
involve the use of convenience samples or soliciting
participation of older adults with a family history of AD
from clinics and outreach efforts. However, high-risk
groups, such as ethnic/racial minorities, are traditionally
less likely to be recruited for AD prevention studies, thus
limiting the ability to generalize findings for a
significant proportion of the aging population. A
community-engagement approach was used to create a registry
of 2311 research-ready, healthy adult volunteers who reflect
the ethnically diverse local community. Furthermore, the
registry's actual commitment to research was examined,
through demonstrated participation rates in a clinical
study. The approach had varying levels of success in
establishing a large, diverse pool of individuals who are
interested in participating in pharmacological prevention
trials and meet the criteria for primary prevention research
trials designed to delay the onset of AD. Our efforts
suggest that entry criteria for the clinical trials need to
be carefully considered to be inclusive of African
Americans, and that sustained effort is needed to engage
African Americans in pharmacological prevention
approaches.},
Doi = {10.1097/WAD.0000000000000029},
Key = {fds276911}
}
@article{fds276917,
Author = {Wengreen, H and Munger, RG and Cutler, A and Quach, A and Bowles, A and Corcoran, C and Tschanz, JT and Norton, MC and Welsh-Bohmer,
KA},
Title = {Prospective study of Dietary Approaches to Stop
Hypertension- and Mediterranean-style dietary patterns and
age-related cognitive change: the Cache County Study on
Memory, Health and Aging.},
Journal = {Am J Clin Nutr},
Volume = {98},
Number = {5},
Pages = {1263-1271},
Year = {2013},
Month = {November},
url = {http://www.ncbi.nlm.nih.gov/pubmed/24047922},
Abstract = {BACKGROUND: Healthy dietary patterns may protect against
age-related cognitive decline, but results of studies have
been inconsistent. OBJECTIVE: We examined associations
between Dietary Approaches to Stop Hypertension (DASH)- and
Mediterranean-style dietary patterns and age-related
cognitive change in a prospective, population-based study.
DESIGN: Participants included 3831 men and women ≥65 y of
age who were residents of Cache County, UT, in 1995.
Cognitive function was assessed by using the Modified
Mini-Mental State Examination (3MS) ≤4 times over 11 y.
Diet-adherence scores were computed by summing across the
energy-adjusted rank-order of individual food and nutrient
components and categorizing participants into quintiles of
the distribution of the diet accordance score. Mixed-effects
repeated-measures models were used to examine 3MS scores
over time across increasing quintiles of dietary accordance
scores and individual food components that comprised each
score. RESULTS: The range of rank-order DASH and
Mediterranean diet scores was 1661-25,596 and 2407-26,947,
respectively. Higher DASH and Mediterranean diet scores were
associated with higher average 3MS scores. People in
quintile 5 of DASH averaged 0.97 points higher than those in
quintile 1 (P = 0.001). The corresponding difference for
Mediterranean quintiles was 0.94 (P = 0.001). These
differences were consistent over 11 y. Higher intakes of
whole grains and nuts and legumes were also associated with
higher average 3MS scores [mean quintile 5 compared with 1
differences: 1.19 (P < 0.001), 1.22 (P < 0.001),
respectively]. CONCLUSIONS: Higher levels of accordance with
both the DASH and Mediterranean dietary patterns were
associated with consistently higher levels of cognitive
function in elderly men and women over an 11-y period. Whole
grains and nuts and legumes were positively associated with
higher cognitive functions and may be core neuroprotective
foods common to various healthy plant-centered diets around
the globe.},
Doi = {10.3945/ajcn.112.051276},
Key = {fds276917}
}
@article{fds276924,
Author = {Peters, ME and Rosenberg, PB and Steinberg, M and Norton, MC and Welsh-Bohmer, KA and Hayden, KM and Breitner, J and Tschanz, JT and Lyketsos, CG and Cache County Investigators},
Title = {Neuropsychiatric symptoms as risk factors for progression
from CIND to dementia: the Cache County Study.},
Journal = {Am J Geriatr Psychiatry},
Volume = {21},
Number = {11},
Pages = {1116-1124},
Year = {2013},
Month = {November},
url = {http://www.ncbi.nlm.nih.gov/pubmed/23567370},
Abstract = {OBJECTIVES: To examine the association of neuropsychiatric
symptom (NPS) severity with risk of transition to all-cause
dementia, Alzheimer disease (AD), and vascular dementia
(VaD). DESIGN: Survival analysis of time to dementia, AD, or
VaD onset. SETTING: Population-based study. PARTICIPANTS:
230 participants diagnosed with cognitive impairment, no
dementia (CIND) from the Cache County Study of Memory Health
and Aging were followed for a mean of 3.3 years.
MEASUREMENTS: The Neuropsychiatric Inventory (NPI) was used
to quantify the presence, frequency, and severity of NPS.
Chi-squared statistics, t-tests, and Cox proportional hazard
ratios were used to assess associations. RESULTS: The
conversion rate from CIND to all-cause dementia was 12% per
year, with risk factors including an APOE ε4 allele, lower
Mini-Mental State Examination, lower 3MS, and higher CDR
sum-of-boxes. The presence of at least one NPS was a risk
factor for all-cause dementia, as was the presence of NPS
with mild severity. Nighttime behaviors were a risk factor
for all-cause dementia and of AD, whereas hallucinations
were a risk factor for VaD. CONCLUSIONS: These data confirm
that NPS are risk factors for conversion from CIND to
dementia. Of special interest is that even NPS of mild
severity are a risk for all-cause dementia or
AD.},
Doi = {10.1016/j.jagp.2013.01.049},
Key = {fds276924}
}
@article{fds277148,
Author = {Tschanz, JT and Pfister, R and Wanzek, J and Corcoran, C and Smith, K and Tschanz, BT and Steffens, DC and Østbye, T and Welsh-Bohmer, KA and Norton, MC},
Title = {Stressful life events and cognitive decline in late life:
moderation by education and age. The Cache County
Study.},
Journal = {Int J Geriatr Psychiatry},
Volume = {28},
Number = {8},
Pages = {821-830},
Year = {2013},
Month = {August},
url = {http://www.ncbi.nlm.nih.gov/pubmed/23037866},
Abstract = {OBJECTIVE: Stressful life events (SLE) have been associated
with increased dementia risk, but their association with
cognitive decline has been inconsistent. In a longitudinal
population-based study of older individuals, we examined the
association between SLE and cognitive decline, and the role
of potential effect modifiers. METHODS: A total of 2665
non-demented participants of the Cache County Memory Study
completed an SLE questionnaire at Wave 2 and were revisited
4 and 7 years later. The events were represented via
several scores: total number, subjective rating (negative,
positive, and unexpected), and a weighted summary based on
their impact. Cognition was assessed at each visit with the
modified Mini-Mental State Exam. General linear models were
used to examine the association between SLE scores and
cognition. Effect modification by age, education, and APOE
genotype was tested. RESULTS: Years of formal education
(p = 0.006) modified the effect of number of SLE, and
age (p = 0.009) modified the effect of negative SLE on
the rate of cognitive decline. Faster decline was observed
among those with fewer years of education experiencing more
SLE and also among younger participants experiencing more
negative SLE. There was no association between other
indicators of SLE and cognitive decline. APOE genotype did
not modify any of the aforementioned associations.
CONCLUSIONS: The effects of SLE on cognition in late life
are complex and vary by individual factors such as age and
education. These results may explain some of the
contradictory findings in the literature.},
Doi = {10.1002/gps.3888},
Key = {fds277148}
}
@article{fds277104,
Author = {Browndyke, JN and Giovanello, K and Petrella, J and Hayden, K and Chiba-Falek, O and Tucker, KA and Burke, JR and Welsh-Bohmer,
KA},
Title = {Phenotypic regional functional imaging patterns during
memory encoding in mild cognitive impairment and Alzheimer's
disease.},
Journal = {Alzheimers Dement},
Volume = {9},
Number = {3},
Pages = {284-294},
Year = {2013},
Month = {May},
url = {http://www.ncbi.nlm.nih.gov/pubmed/22841497},
Abstract = {BACKGROUND: Reliable blood-oxygen-level-dependent (BOLD)
functional magnetic resonance imaging (fMRI) phenotypic
biomarkers of Alzheimer's disease (AD) or mild cognitive
impairment (MCI) are likely to emerge only from a
systematic, quantitative, and aggregate examination of the
functional neuroimaging research literature. METHODS: A
series of random-effects activation likelihood estimation
(ALE) meta-analyses were conducted on studies of episodic
memory encoding operations in AD and MCI samples relative to
normal controls. ALE analyses were based on a thorough
literature search for all task-based functional neuroimaging
studies in AD and MCI published up to January 2010. Analyses
covered 16 fMRI studies, which yielded 144 distinct foci for
ALE meta-analysis. RESULTS: ALE results indicated several
regional task-based BOLD consistencies in MCI and AD
patients relative to normal control subjects across the
aggregate BOLD functional neuroimaging research literature.
Patients with AD and those at significant risk (MCI) showed
statistically significant consistent activation differences
during episodic memory encoding in the medial temporal lobe,
specifically parahippocampal gyrus, as well superior frontal
gyrus, precuneus, and cuneus, relative to normal control
subjects. CONCLUSIONS: ALE consistencies broadly support the
presence of frontal compensatory activity, medial temporal
lobe activity alteration, and posterior midline "default
mode" hyperactivation during episodic memory encoding
attempts in the diseased or prospective predisease
condition. Taken together, these robust commonalities may
form the foundation for a task-based fMRI phenotype of
memory encoding in AD.},
Doi = {10.1016/j.jalz.2011.12.006},
Key = {fds277104}
}
@article{fds371167,
Author = {Welsh-Bohmer, KA and Fillenbaum, GG and Morris,
JC},
Title = {Albert Heyman, MD (1916–2012)},
Journal = {Neurology},
Volume = {80},
Number = {13},
Pages = {1184-1185},
Publisher = {Ovid Technologies (Wolters Kluwer Health)},
Year = {2013},
Month = {March},
url = {http://dx.doi.org/10.1212/wnl.0b013e3182897160},
Doi = {10.1212/wnl.0b013e3182897160},
Key = {fds371167}
}
@article{fds276925,
Author = {Potter, GG and Wagner, HR and Burke, JR and Plassman, BL and Welsh-Bohmer, KA and Steffens, DC},
Title = {Neuropsychological predictors of dementia in late-life major
depressive disorder.},
Journal = {Am J Geriatr Psychiatry},
Volume = {21},
Number = {3},
Pages = {297-306},
Year = {2013},
Month = {March},
url = {http://www.ncbi.nlm.nih.gov/pubmed/23395197},
Abstract = {OBJECTIVE: Major depressive disorder is a likely risk factor
for dementia, but some cases of major depressive disorder in
older adults may actually represent a prodrome of this
condition. The purpose of this study was to use
neuropsychological test scores to predict conversion to
dementia in a sample of depressed older adults diagnosed as
nondemented at the time of neuropsychological testing.
DESIGN: Longitudinal, with mean follow-up of 5.45 years.
SETTING: Outpatient depression treatment study at Duke
University. PARTICIPANTS: Thirty nondemented individuals
depressed at the time of neuropsychological testing and
later diagnosed with incident dementia; 149 nondemented
individuals depressed at the time of neuropsychological
testing and a diagnosis of cognitively normal. METHODOLOGY:
All participants received clinical assessment of depression,
were assessed to rule out prevalent dementia at the time of
study enrollment, completed neuropsychological testing at
the time of study enrollment, and were diagnosed for
cognitive disorders on an annual basis. RESULTS:
Nondemented, acutely depressed older adults who converted to
dementia during the study period exhibited broadly lower
cognitive performances at baseline than acutely depressed
individuals who remained cognitively normal. Discriminant
function analysis indicated that 2 neuropsychological tests,
Recognition Memory (from the Consortium to Establish a
Registry for Alzheimer's Disease neuropsychological battery)
and Trail Making B, best predicted dementia conversion.
CONCLUSIONS: Depressed older adults with cognitive deficits
in the domains of memory and executive functions during
acute depression are at higher risk for developing dementia.
Some cases of late-life depression may reflect a prodrome of
dementia in which clinical manifestation of mood changes may
co-occur with emerging cognitive deficits.},
Doi = {10.1016/j.jagp.2012.12.009},
Key = {fds276925}
}
@article{fds276929,
Author = {Crenshaw, DG and Gottschalk, WK and Lutz, MW and Grossman, I and Saunders, AM and Burke, JR and Welsh-Bohmer, KA and Brannan, SK and Burns, DK and Roses, AD},
Title = {Using genetics to enable studies on the prevention of
Alzheimer's disease.},
Journal = {Clin Pharmacol Ther},
Volume = {93},
Number = {2},
Pages = {177-185},
Year = {2013},
Month = {February},
url = {http://www.ncbi.nlm.nih.gov/pubmed/23249780},
Abstract = {Curing Alzheimer's disease (AD) remains an elusive goal;
indeed, it may even prove to be impossible, given the nature
of the disease. Although modulating disease progression is
an attractive target and will alleviate the burden of the
most severe stages, this strategy will not reduce the
prevalence of the disease itself. Preventing or (as
described in this article) delaying the onset of cognitive
impairment and AD will provide the greatest benefit to
individuals and society by pushing the onset of disease into
the later years of life. Because of the high variability in
the age of onset of the disease, AD prevention studies that
do not stratify participants by age-dependent disease risk
will be operationally challenging, being large in size and
of long duration. We present a composite genetic biomarker
to stratify disease risk so as to facilitate clinical
studies in high-risk populations. In addition, we discuss
the rationale for the use of pioglitazone to delay the onset
of AD in individuals at high risk.},
Doi = {10.1038/clpt.2012.222},
Key = {fds276929}
}
@article{fds371168,
Author = {Foster, C and Addis, D and Ford, J and Kaufer, D and Browndyke, J and Welsh-Bohmer, K and Giovanello, K},
Title = {PREFRONTAL CONTRIBUTIONS TO RELATIONAL ENCODING IN HEALTHY
AGING AND MILD COGNITIVE IMPAIRMENT},
Journal = {JOURNAL OF COGNITIVE NEUROSCIENCE},
Pages = {197-197},
Publisher = {MIT PRESS},
Year = {2013},
Month = {January},
Key = {fds371168}
}
@article{fds277115,
Author = {Blumenthal, JA and Smith, PJ and Welsh-Bohmer, K and Babyak, MA and Browndyke, J and Lin, P-H and Doraiswamy, PM and Burke, J and Kraus, W and Hinderliter, A and Sherwood, A},
Title = {Can lifestyle modification improve neurocognition? Rationale
and design of the ENLIGHTEN clinical trial.},
Journal = {Contemp Clin Trials},
Volume = {34},
Number = {1},
Pages = {60-69},
Year = {2013},
Month = {January},
url = {http://www.ncbi.nlm.nih.gov/pubmed/23000080},
Abstract = {BACKGROUND: Risk factors for cardiovascular disease (CVD)
not only increase the risk for clinical CVD events, but also
are associated with a cascade of neurophysiologic and
neuroanatomic changes that increase the risk of cognitive
impairment and dementia. Although epidemiological studies
have shown that exercise and diet are associated with lower
CVD risk and reduced incidence of dementia, no randomized
controlled trial (RCT) has examined the independent effects
of exercise and diet on neurocognitive function among
individuals at risk for dementia. The ENLIGHTEN trial is a
RCT of patients with CVD risk factors who also are
characterized by subjective cognitive complaints and
objective evidence of neurocognitive impairment without
dementia (CIND) STUDY DESIGN: A 2 by 2 design will examine
the independent and combined effects of diet and exercise on
neurocognition. 160 participants diagnosed with CIND will be
randomly assigned to 6 months of aerobic exercise, the DASH
diet, or a combination of both exercise and diet; a
(control) group will receive health education but otherwise
will maintain their usual dietary and activity habits.
Participants will complete comprehensive assessments of
neurocognitive functioning along with biomarkers of CVD risk
including measures of blood pressure, glucose, endothelial
function, and arterial stiffness. CONCLUSION: The ENLIGHTEN
trial will (a) evaluate the effectiveness of aerobic
exercise and the DASH diet in improving neurocognitive
functioning in CIND patients with CVD risk factors; (b)
examine possible mechanisms by which exercise and diet
improve neurocognition; and (c) consider potential
moderators of treatment, including subclinical
CVD.},
Doi = {10.1016/j.cct.2012.09.004},
Key = {fds277115}
}
@article{fds276923,
Author = {Hendrix, SB and Welsh-Bohmer, KA},
Title = {Separation of cognitive domains to improve prediction of
progression from mild cognitive impairment to Alzheimer's
disease.},
Journal = {Alzheimers Res Ther},
Volume = {5},
Number = {3},
Pages = {22},
Year = {2013},
url = {http://www.ncbi.nlm.nih.gov/pubmed/23680123},
Abstract = {Addressing causes of heterogeneity in cognitive outcomes is
becoming more critical as Alzheimer's disease (AD) research
focuses on earlier disease. One of the causes of this
heterogeneity may be that individuals with deficiencies in
different cognitive domains may perform similarly on a
neuropsychological (NP) test for very different reasons.
Tatsuoka and colleagues have applied a Bayesian model in
order to integrate knowledge about cognitive domains
relevant to each NP test with the observed outcomes from the
Alzheimer's Disease Neuroimaging Initiative (ADNI) mild
cognitive impairment data. This approach resulted in better
prediction of AD diagnosis than more traditional
approaches.},
Doi = {10.1186/alzrt176},
Key = {fds276923}
}
@article{fds276927,
Author = {Whitcomb, DC and LaRusch, J and Krasinskas, AM and Klei, L and Smith,
JP and Brand, RE and Neoptolemos, JP and Lerch, MM and Tector, M and Sandhu, BS and Guda, NM and Orlichenko, L and Alzheimer's Disease
Genetics Consortium, and Alkaade, S and Amann, ST and Anderson, MA and Baillie, J and Banks, PA and Conwell, D and Coté, GA and Cotton, PB and DiSario, J and Farrer, LA and Forsmark, CE and Johnstone, M and Gardner,
TB and Gelrud, A and Greenhalf, W and Haines, JL and Hartman, DJ and Hawes,
RA and Lawrence, C and Lewis, M and Mayerle, J and Mayeux, R and Melhem,
NM and Money, ME and Muniraj, T and Papachristou, GI and Pericak-Vance,
MA and Romagnuolo, J and Schellenberg, GD and Sherman, S and Simon, P and Singh, VP and Slivka, A and Stolz, D and Sutton, R and Weiss, FU and Wilcox, CM and Zarnescu, NO and Wisniewski, SR and O'Connell, MR and Kienholz, ML and Roeder, K and Barmada, MM and Yadav, D and Devlin,
B},
Title = {Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci
alter risk for alcohol-related and sporadic
pancreatitis.},
Journal = {Nat Genet},
Volume = {44},
Number = {12},
Pages = {1349-1354},
Year = {2012},
Month = {December},
url = {http://www.ncbi.nlm.nih.gov/pubmed/23143602},
Abstract = {Pancreatitis is a complex, progressively destructive
inflammatory disorder. Alcohol was long thought to be the
primary causative agent, but genetic contributions have been
of interest since the discovery that rare PRSS1, CFTR and
SPINK1 variants were associated with pancreatitis risk. We
now report two associations at genome-wide significance
identified and replicated at PRSS1-PRSS2 (P < 1 × 10(-12))
and X-linked CLDN2 (P < 1 × 10(-21)) through a two-stage
genome-wide study (stage 1: 676 cases and 4,507 controls;
stage 2: 910 cases and 4,170 controls). The PRSS1 variant
likely affects disease susceptibility by altering expression
of the primary trypsinogen gene. The CLDN2 risk allele is
associated with atypical localization of claudin-2 in
pancreatic acinar cells. The homozygous (or hemizygous in
males) CLDN2 genotype confers the greatest risk, and its
alleles interact with alcohol consumption to amplify risk.
These results could partially explain the high frequency of
alcohol-related pancreatitis in men (male hemizygote
frequency is 0.26, whereas female homozygote frequency is
0.07).},
Doi = {10.1038/ng.2466},
Key = {fds276927}
}
@article{fds276972,
Author = {Rosenberg, PB and Mielke, MM and Han, D and Leoutsakos, JS and Lyketsos,
CG and Rabins, PV and Zandi, PP and Breitner, JCS and Norton, MC and Welsh-Bohmer, KA and Zuckerman, IH and Rattinger, GB and Green, RC and Corcoran, C and Tschanz, JT},
Title = {The association of psychotropic medication use with the
cognitive, functional, and neuropsychiatric trajectory of
Alzheimer's disease.},
Journal = {Int J Geriatr Psychiatry},
Volume = {27},
Number = {12},
Pages = {1248-1257},
Year = {2012},
Month = {December},
url = {http://www.ncbi.nlm.nih.gov/pubmed/22374884},
Abstract = {OBJECTIVE: The use of psychotropic medications in
Alzheimer's disease (AD) has been associated with both
deleterious and potentially beneficial outcomes. We examined
the longitudinal association of psychotropic medication use
with cognitive, functional, and neuropsychiatric symptom
(NPS) trajectories among community-ascertained incident AD
cases from the Cache County Dementia Progression Study.
METHODS: A total of 230 participants were followed for a
mean of 3.7 years. Persistency index (PI) was calculated for
all antidepressants, selective serotonin reuptake inhibitors
(SSRIs), antipsychotics (atypical and typical), and
benzodiazepines as the proportion of observed time of
medication exposure. Mixed-effects models were used to
examine the association between PI for each medication class
and Mini-Mental State Exam (MMSE), Clinical Dementia Rating
Sum of Boxes (CDR-Sum), and Neuropsychiatric Inventory -
Total (NPI-Total) trajectories, controlling for appropriate
demographic and clinical covariates. RESULTS: At baseline,
psychotropic medication use was associated with greater
severity of dementia and poorer medical status. Higher PI
for all medication classes was associated with a more rapid
decline in MMSE. For antidepressant, SSRI, benzodiazepine,
and typical antipsychotic use, a higher PI was associated
with a more rapid increase in CDR-Sum. For SSRIs,
antipsychotics, and typical antipsychotics, a higher PI was
associated with more rapid increase in NPI-Total.
CONCLUSIONS: Psychotropic medication use was associated with
more rapid cognitive and functional decline in AD, and not
with improved NPS. Clinicians may tend to prescribe
psychotropic medications to AD patients at risk of poorer
outcomes, but one cannot rule out the possibility of poorer
outcomes being caused by psychotropic medications.},
Doi = {10.1002/gps.3769},
Key = {fds276972}
}
@article{fds277070,
Author = {Sheline, YI and Disabato, BM and Hranilovich, J and Morris, C and D'Angelo, G and Pieper, C and Toffanin, T and Taylor, WD and MacFall,
JR and Wilkins, C and Barch, DM and Welsh-Bohmer, KA and Steffens, DC and Krishnan, RR and Doraiswamy, PM},
Title = {Treatment course with antidepressant therapy in late-life
depression.},
Journal = {Am J Psychiatry},
Volume = {169},
Number = {11},
Pages = {1185-1193},
Year = {2012},
Month = {November},
url = {http://www.ncbi.nlm.nih.gov/pubmed/23034601},
Abstract = {OBJECTIVE: In order to assess the effect of gray matter
volumes and cortical thickness on antidepressant treatment
response in late-life depression, the authors examined the
relationship between brain regions identified a priori and
Montgomery-Åsberg Depression Rating Scale (MADRS) scores
over the course of an antidepressant treatment trial.
METHOD: In a nonrandomized prospective trial, 168 patients
who were at least 60 years of age and met DSM-IV criteria
for major depression underwent MRI and were enrolled in a
12-week treatment study. Exclusion criteria included
cognitive impairment or severe medical disorders. The
volumes or cortical thicknesses of regions of interest that
differed between the depressed group and a comparison group
(N=50) were determined. These regions of interest were used
in analyses of the depressed group to predict antidepressant
treatment outcome. Mixed-model analyses adjusting for age,
education, age at depression onset, race, baseline MADRS
score, scanner, and interaction with time examined
predictors of MADRS scores over time. RESULTS: Smaller
hippocampal volumes predicted a slower response to
treatment. With the inclusion of white matter
hyper-intensity severity and neuropsychological factor
scores, the best model included hippocampal volume and
cognitive processing speed to predict rate of response over
time. A secondary analysis showed that hippocampal volume
and frontal pole thickness differed between patients who
achieved remission and those who did not. CONCLUSIONS: These
data expand our understanding of the prediction of treatment
course in late-life depression. The authors propose that the
primary variables of hippocampal volume and cognitive
processing speed, subsuming other contributing variables
(episodic memory, executive function, language processing)
predict antidepressant response.},
Doi = {10.1176/appi.ajp.2012.12010122},
Key = {fds277070}
}
@article{fds277050,
Author = {Shao, H and Breitner, JCS and Whitmer, RA and Wang, J and Hayden, K and Wengreen, H and Corcoran, C and Tschanz, J and Norton, M and Munger, R and Welsh-Bohmer, K and Zandi, PP and Cache County
Investigators},
Title = {Hormone therapy and Alzheimer disease dementia: new findings
from the Cache County Study.},
Journal = {Neurology},
Volume = {79},
Number = {18},
Pages = {1846-1852},
Year = {2012},
Month = {October},
ISSN = {0028-3878},
url = {http://dx.doi.org/10.1212/WNL.0b013e318271f823},
Abstract = {OBJECTIVES: Observational studies suggest reduced risk of
Alzheimer disease (AD) in users of hormone therapy (HT), but
trials show higher risk. We examined whether the association
of HT with AD varies with timing or type of HT use. METHODS:
Between 1995 and 2006, the population-based Cache County
Study followed 1,768 women who had provided a detailed
history on age at menopause and use of HT. During this
interval, 176 women developed incident AD. Cox proportional
hazard models evaluated the association of HT use with AD,
overall and in relation to timing, duration of use, and type
(opposed vs unopposed) of HT. RESULTS: Women who used any
type of HT within 5 years of menopause had 30% less risk of
AD (95% confidence interval 0.49-0.99), especially if use
was for 10 or more years. By contrast, AD risk was not
reduced among those who had initiated HT 5 or more years
after menopause. Instead, rates were increased among those
who began "opposed" estrogen-progestin compounds within the
3 years preceding the Cache County Study baseline (adjusted
hazard ratio 1.93; 95% confidence interval 0.94-3.96). This
last hazard ratio was similar to the ratio of 2.05 reported
in randomized trial participants assigned to opposed HT.
CONCLUSIONS: Association of HT use and risk of AD may depend
on timing of use. Although possibly beneficial if taken
during a critical window near menopause, HT (especially
opposed compounds) initiated in later life may be associated
with increased risk. The relation of AD risk to timing and
type of HT deserves further study.},
Doi = {10.1212/WNL.0b013e318271f823},
Key = {fds277050}
}
@article{fds276971,
Author = {Leoutsakos, J-MS and Han, D and Mielke, MM and Forrester, SN and Tschanz, JT and Corcoran, CD and Green, RC and Norton, MC and Welsh-Bohmer, KA and Lyketsos, CG},
Title = {Effects of general medical health on Alzheimer's
progression: the Cache County Dementia Progression
Study.},
Journal = {Int Psychogeriatr},
Volume = {24},
Number = {10},
Pages = {1561-1570},
Year = {2012},
Month = {October},
url = {http://www.ncbi.nlm.nih.gov/pubmed/22687143},
Abstract = {BACKGROUND: Several observational studies have suggested a
link between health status and rate of decline among
individuals with Alzheimer's disease (AD). We sought to
quantify the relationship in a population-based study of
incident AD, and to compare global comorbidity ratings to
counts of comorbid conditions and medications as predictors
of AD progression. METHODS: This was a case-only cohort
study arising from a population-based longitudinal study of
memory and aging, in Cache County, Utah. Participants
comprised 335 individuals with incident AD followed for up
to 11 years. Patient descriptors included sex, age,
education, dementia duration at baseline, and APOE genotype.
Measures of health status made at each visit included the
General Medical Health Rating (GMHR), number of comorbid
medical conditions, and number of non-psychiatric
medications. Dementia outcomes included the Mini-Mental
State Examination (MMSE), Clinical Dementia Rating - sum of
boxes (CDR-sb), and the Neuropsychiatric Inventory (NPI).
RESULTS: Health status tended to fluctuate over time within
individuals. None of the baseline medical variables (GMHR,
comorbidities, and non-psychiatric medications) was
associated with differences in rates of decline in
longitudinal linear mixed effects models. Over time, low
GMHR ratings, but not comorbidities or medications, were
associated with poorer outcomes (MMSE: β = -1.07 p = 0.01;
CDR-sb: β = 1.79 p < 0.001; NPI: β = 4.57 p = 0.01).
CONCLUSIONS: Given that time-varying GMHR, but not baseline
GMHR, was associated with the outcomes, it seems likely that
there is a dynamic relationship between medical and
cognitive health. GMHR is a more sensitive measure of health
than simple counts of comorbidities or medications. Since
health status is a potentially modifiable risk factor,
further study is warranted.},
Doi = {10.1017/S104161021200049X},
Key = {fds276971}
}
@article{fds276928,
Author = {Peters, ME and Rosenberg, PB and Steinberg, M and Norton, MC and Welsh-Bohmer, KA and Hayden, KM and Breitner, J and Tschanz, JT and Lyketsos, CG and the Cache County Investigators},
Title = {Neuropsychiatric Symptoms as Risk Factors for Progression
From CIND to Dementia: The Cache County Study.},
Journal = {Am J Geriatr Psychiatry},
Year = {2012},
Month = {September},
url = {http://www.ncbi.nlm.nih.gov/pubmed/22976786},
Abstract = {OBJECTIVES:: To examine the association of neuropsychiatric
symptom (NPS) severity with risk of transition to all-cause
dementia, Alzheimer disease (AD), and vascular dementia
(VaD). DESIGN:: Survival analysis of time to dementia, AD,
or VaD onset. SETTING:: Population-based study.
PARTICIPANTS:: 230 participants diagnosed with cognitive
impairment, no dementia (CIND) from the Cache County Study
of Memory Health and Aging were followed for a mean of 3.3
years. MEASUREMENTS:: The Neuropsychiatric Inventory (NPI)
was used to quantify the presence, frequency, and severity
of NPS. Chi-squared statistics, t-tests, and Cox
proportional hazard ratios were used to assess associations.
RESULTS:: The conversion rate from CIND to all-cause
dementia was 12% per year, with risk factors including an
APOE [Latin Small Letter Open E]4 allele, lower Mini-Mental
State Examination, lower 3MS, and higher CDR sum-of-boxes.
The presence of at least one NPS was a risk factor for
all-cause dementia, as was the presence of NPS with mild
severity. Nighttime behaviors were a risk factor for
all-cause dementia and of AD, whereas hallucinations were a
risk factor for VaD. CONCLUSIONS:: These data confirm that
NPS are risk factors for conversion from CIND to dementia.
Of special interest is that even NPS of mild severity are a
risk for all-cause dementia or AD.},
Doi = {10.1097/JGP.0b013e318267014b},
Key = {fds276928}
}
@article{fds277108,
Author = {Giovanello, KS and De Brigard and F and Hennessey Ford and J and Kaufer,
DI and Burke, JR and Browndyke, JN and Welsh-Bohmer,
KA},
Title = {Event-related functional magnetic resonance imaging changes
during relational retrieval in normal aging and amnestic
mild cognitive impairment.},
Journal = {J Int Neuropsychol Soc},
Volume = {18},
Number = {5},
Pages = {886-897},
Year = {2012},
Month = {September},
url = {http://www.ncbi.nlm.nih.gov/pubmed/22622022},
Abstract = {The earliest cognitive deficits observed in amnestic mild
cognitive impairment (aMCI) appear to center on memory tasks
that require relational memory (RM), the ability to link or
integrate unrelated pieces of information. RM impairments in
aMCI likely reflect neural changes in the medial temporal
lobe (MTL) and posterior parietal cortex (PPC). We tested
the hypothesis that individuals with aMCI, as compared to
cognitively normal (CN) controls, would recruit neural
regions outside of the MTL and PPC to support relational
memory. To this end, we directly compared the neural
underpinnings of successful relational retrieval in aMCI and
CN groups, using event-related functional magnetic resonance
imaging (fMRI), holding constant the stimuli and encoding
task. The fMRI data showed that the CN, compared to the
aMCI, group activated left precuneus, left angular gyrus,
right posterior cingulate, and right parahippocampal cortex
during relational retrieval, while the aMCI group, relative
to the CN group, activated superior temporal gyrus and
supramarginal gyrus for this comparison. Such findings
indicate an early shift in the functional neural
architecture of relational retrieval in aMCI, and may prove
useful in future studies aimed at capitalizing on
functionally intact neural regions as targets for treatment
and slowing of the disease course. (JINS, 2012, 18,
1-12).},
Doi = {10.1017/S1355617712000689},
Key = {fds277108}
}
@article{fds277118,
Author = {Hayden, KM and McEvoy, JM and Linnertz, C and Attix, D and Kuchibhatla,
M and Saunders, AM and Lutz, MW and Welsh-Bohmer, KA and Roses, AD and Chiba-Falek, O},
Title = {A homopolymer polymorphism in the TOMM40 gene contributes to
cognitive performance in aging.},
Journal = {Alzheimers Dement},
Volume = {8},
Number = {5},
Pages = {381-388},
Year = {2012},
Month = {September},
url = {http://www.ncbi.nlm.nih.gov/pubmed/22863908},
Abstract = {INTRODUCTION: A highly polymorphic T homopolymer was
recently found to be associated with late-onset Alzheimer's
disease risk and age of onset. OBJECTIVE: To explore the
effects of the polymorphic polyT tract (rs10524523, referred
as '523') on cognitive performance in cognitively healthy
elderly individuals. METHODS: One hundred eighty-one
participants were recruited from local independent-living
retirement communities. Informed consent was obtained, and
participants completed demographic questionnaires, a
conventional paper-and-pencil neuropsychological battery,
and the computerized Cambridge Neuropsychological Test
Automated Battery (CANTAB). Saliva samples were collected
for determination of the TOMM40 '523' (S, L, VL) and the
apolipoprotein E (APOE) (ɛ2, 3, 4) genotypes. From the
initial sample of 181 individuals, 127 were eligible for the
association analysis. Participants were divided into three
groups based on '523' genotypes (S/S, S/L-S/VL, and
L/L-L/VL-VL/VL). Generalized linear models were used to
evaluate the association between the '523' genotypes and
neuropsychological test performance. Analyses were adjusted
for age, sex, education, depression, and APOE ɛ4 status. A
planned subanalysis was undertaken to evaluate the
association between '523' genotypes and test performance in
a sample restricted to APOE ɛ3 homozygotes. RESULTS: The S
homozygotes performed better, although not significantly,
than the S/L-S/VL and the VL/L-L/VL-VL/VL genotype groups on
measures associated with memory (CANTAB Paired Associates
Learning, Verbal Recognition Memory free recall) and
executive function (CANTAB measures of Intra-Extra
Dimensional Set Shift). Follow-up analysis of APOE ɛ3
homozygotes only showed that the S/S group performed
significantly better than the S/VL group on measures of
episodic memory (CANTAB Paired Associates Learning and
Verbal Recognition Memory free recall), attention (CANTAB
Rapid Visual Information Processing latency), and executive
function (Digit Symbol Substitution). The S/S group
performed marginally better than the VL/VL group on
Intra-Extra Dimensional Set Shift. None of the associations
remained significant after applying a Bonferroni correction
for multiple testing. CONCLUSIONS: Results suggest important
APOE-independent associations between the TOMM40 '523'
polymorphism and specific cognitive domains of memory and
executive control that are preferentially affected in
early-stage Alzheimer's disease.},
Doi = {10.1016/j.jalz.2011.10.005},
Key = {fds277118}
}
@article{fds276926,
Author = {Coppola, G and Chinnathambi, S and Lee, JJ and Dombroski, BA and Baker,
MC and Soto-Ortolaza, AI and Lee, SE and Klein, E and Huang, AY and Sears,
R and Lane, JR and Karydas, AM and Kenet, RO and Biernat, J and Wang, L-S and Cotman, CW and Decarli, CS and Levey, AI and Ringman, JM and Mendez, MF and Chui, HC and Le Ber and I and Brice, A and Lupton, MK and Preza, E and Lovestone, S and Powell, J and Graff-Radford, N and Petersen, RC and Boeve, BF and Lippa, CF and Bigio, EH and Mackenzie, I and Finger, E and Kertesz, A and Caselli, RJ and Gearing, M and Juncos, JL and Ghetti, B and Spina, S and Bordelon, YM and Tourtellotte, WW and Frosch, MP and Vonsattel, JPG and Zarow, C and Beach, TG and Albin, RL and Lieberman,
AP and Lee, VM and Trojanowski, JQ and Van Deerlin and VM and Bird, TD and Galasko, DR and Masliah, E and White, CL and Troncoso, JC and Hannequin,
D and Boxer, AL and Geschwind, MD and Kumar, S and Mandelkow, E-M and Wszolek, ZK and Uitti, RJ and Dickson, DW and Haines, JL and Mayeux, R and Pericak-Vance, MA and Farrer, LA and Alzheimer's Disease Genetics
Consortium, and Ross, OA and Rademakers, R and Schellenberg, GD and Miller, BL and Mandelkow, E and Geschwind, DH},
Title = {Evidence for a role of the rare p.A152T variant in MAPT in
increasing the risk for FTD-spectrum and Alzheimer's
diseases.},
Journal = {Hum Mol Genet},
Volume = {21},
Number = {15},
Pages = {3500-3512},
Year = {2012},
Month = {August},
url = {http://www.ncbi.nlm.nih.gov/pubmed/22556362},
Abstract = {Rare mutations in the gene encoding for tau (MAPT,
microtubule-associated protein tau) cause frontotemporal
dementia-spectrum (FTD-s) disorders, including FTD,
progressive supranuclear palsy (PSP) and corticobasal
syndrome, and a common extended haplotype spanning across
the MAPT locus is associated with increased risk of PSP and
Parkinson's disease. We identified a rare tau variant
(p.A152T) in a patient with a clinical diagnosis of PSP and
assessed its frequency in multiple independent series of
patients with neurodegenerative conditions and controls, in
a total of 15 369 subjects. Tau p.A152T significantly
increases the risk for both FTD-s (n = 2139, OR = 3.0, CI:
1.6-5.6, P = 0.0005) and Alzheimer's disease (AD) (n = 3345,
OR = 2.3, CI: 1.3-4.2, P = 0.004) compared with 9047
controls. Functionally, p.A152T (i) decreases the binding of
tau to microtubules and therefore promotes microtubule
assembly less efficiently; and (ii) reduces the tendency to
form abnormal fibers. However, there is a pronounced
increase in the formation of tau oligomers. Importantly,
these findings suggest that other regions of the tau protein
may be crucial in regulating normal function, as the p.A152
residue is distal to the domains considered responsible for
microtubule interactions or aggregation. These data provide
both the first genetic evidence and functional studies
supporting the role of MAPT p.A152T as a rare risk factor
for both FTD-s and AD and the concept that rare variants can
increase the risk for relatively common, complex
neurodegenerative diseases, but since no clear significance
threshold for rare genetic variation has been established,
some caution is warranted until the findings are further
replicated.},
Doi = {10.1093/hmg/dds161},
Key = {fds276926}
}
@article{fds277069,
Author = {Barch, DM and DʼAngelo, G and Pieper, C and Wilkins, CH and Welsh-Bohmer, K and Taylor, W and Garcia, KS and Gersing, K and Doraiswamy, PM and Sheline, YI},
Title = {Cognitive improvement following treatment in late-life
depression: relationship to vascular risk and age of
onset.},
Journal = {Am J Geriatr Psychiatry},
Volume = {20},
Number = {8},
Pages = {682-690},
Year = {2012},
Month = {August},
url = {http://www.ncbi.nlm.nih.gov/pubmed/22430020},
Abstract = {OBJECTIVES: To test the hypothesis that the degree of
vascular burden and/or age of onset may influence the degree
to which cognition can improve during the course of
treatment in late-life depression. DESIGN: Measurement of
cognition both before and following 12 weeks of treatment
with sertraline. SETTING: University medical centers
(Washington University and Duke University). PARTICIPANTS:
One hundred sixty-six individuals with late-life depression.
INTERVENTION: Sertraline treatment. MEASUREMENTS: The
cognitive tasks were grouped into five domains (language,
processing speed, working memory, episodic memory, and
executive function). We measured vascular risk using the
Framingham Stroke Risk Profile measure. We measured T2-based
white matter hyperintensities using the Fazekas criteria.
RESULTS: Both episodic memory and executive function
demonstrated significant improvement among adults with
late-life depression during treatment with sertraline.
Importantly, older age, higher vascular risk scores, and
lower baseline Mini-Mental State Examination scores
predicted less change in working memory. Furthermore, older
age, later age of onset, and higher vascular risk scores
predicted less change in executive function. CONCLUSIONS:
These results have important clinical implications in that
they suggest that a regular assessment of vascular risk in
older adults with depression is necessary as a component of
treatment planning and in predicting prognosis, both for the
course of the depression itself and for the cognitive
impairments that often accompany depression in later
life.},
Doi = {10.1097/JGP.0b013e318246b6cb},
Key = {fds277069}
}
@article{fds277096,
Author = {McCarthy, JJ and Saith, S and Linnertz, C and Burke, JR and Hulette, CM and Welsh-Bohmer, KA and Chiba-Falek, O},
Title = {The Alzheimer's associated 5' region of the SORL1 gene cis
regulates SORL1 transcripts expression.},
Journal = {Neurobiol Aging},
Volume = {33},
Number = {7},
Pages = {1485.e1-1485.e8},
Year = {2012},
Month = {July},
url = {http://www.ncbi.nlm.nih.gov/pubmed/21185108},
Abstract = {SORL1 has been identified as a major contributor to late
onset Alzheimer's disease (LOAD). We test whether genetic
variability in the 5' of SORL1 gene modulates the risk to
develop LOAD via regulation of SORL1-messenger ribonucleic
acid (mRNA) expression and splicing. Two brain structures,
differentially vulnerable to LOAD pathology, were examined
in 144 brain samples from 92 neurologically normal
individuals. The temporal cortex, which is more susceptible
to Alzheimer's pathology, demonstrated ∼2-fold increase in
SORL1-mRNA levels in carriers of the minor alleles at single
nucleotide polymorphisms (SNPs), rs7945931 and rs2298525,
compared with noncarriers. No genetic effect on
total-SORL1-mRNA levels was detected in the frontal cortex.
However, rs11600875 minor allele was associated with
significantly increased levels of exon-2 skipping, but only
in frontal cortex. No correlation of SORL1-mRNAs expression
was found between frontal and temporal cortexes.
Collectively, these indicate the brain region specificity of
the genetic regulation of SORL1 expression. Our results
suggest that genetic regulation of SORL1 expression plays a
role in disease risk and may be responsible for the reported
LOAD associations. Further studies to detect the actual
pathogenic variant/s are necessary.},
Doi = {10.1016/j.neurobiolaging.2010.10.004},
Key = {fds277096}
}
@article{fds276970,
Author = {Mielke, MM and Leoutsakos, J-M and Corcoran, CD and Green, RC and Norton, MC and Welsh-Bohmer, KA and Tschanz, JT and Lyketsos,
CG},
Title = {Effects of Food and Drug Administration-approved medications
for Alzheimer's disease on clinical progression.},
Journal = {Alzheimers Dement},
Volume = {8},
Number = {3},
Pages = {180-187},
Year = {2012},
Month = {May},
url = {http://www.ncbi.nlm.nih.gov/pubmed/22301194},
Abstract = {BACKGROUND: Observational studies suggest that
cholinesterase inhibitors and/or memantine may delay
clinical progression of Alzheimer's disease (AD) in 40% of
individuals taking the medications. Given this response and
existence of side effects, we sought to quantify medication
use and benefits in a population-based study of incident AD
cases. METHODS: The Cache County Dementia Progression Study
enrolled and followed a cohort of 327 incident AD cases for
a maximum of 9 years. Drug exposure was expressed using a
persistency index (PI), calculated as total years of drug
use divided by total years of observation. Linear
mixed-effects models examined PI, and interactions with sex
and apolipoprotein E (APOE) as predictors of clinical
progression on the Mini-Mental State Examination and
Clinical Dementia Rating-Sum of Boxes. RESULTS: A total of
69 participants (21.1%) reported having ever used
cholinesterase inhibitors or memantine. There was a strong
three-way interaction between PI, sex, and time. Among
women, a higher PI (i.e., greater duration of use) of
cholinesterase inhibitors was associated with slower
progression on the Mini-Mental State Examination and
Clinical Dementia Rating-Sum of Boxes, particularly among
those with an APOE ɛ4 allele. In contrast, higher PI was
associated with faster progression in males. CONCLUSION: A
low percentage of individuals with AD in the community are
taking cholinesterase inhibitors or memantine. This study
suggests that women, particularly those with an APOE ɛ4
allele, may benefit the most from these medications. With
the newly approved increased dose of donepezil, it will be
imperative to determine whether a higher dose is needed in
men or whether other factors warrant consideration.},
Doi = {10.1016/j.jalz.2011.02.011},
Key = {fds276970}
}
@article{fds277049,
Author = {Peters, ME and Rosenberg, PB and Steinberg, M and Tschanz, JT and Norton, MC and Welsh-Bohmer, KA and Hayden, KM and Breitner, JCS and Lyketsos, CG and Cache County Investigators},
Title = {Prevalence of neuropsychiatric symptoms in CIND and its
subtypes: the Cache County Study.},
Journal = {Am J Geriatr Psychiatry},
Volume = {20},
Number = {5},
Pages = {416-424},
Year = {2012},
Month = {May},
url = {http://www.ncbi.nlm.nih.gov/pubmed/22522960},
Abstract = {OBJECTIVES: 1) To report rates of neuropsychiatric symptoms
(NPS) in cognitive impairment, no dementia (CIND). 2) To
compare the 30-day prevalence of NPS in CIND with that in
dementia and cognitively normal individuals. 3) To compare
the prevalence of NPS in amnestic MCI (aMCI) with other
predementia syndromes. DESIGN: Comparison of prevalence
proportions among several defined groups. SETTING:
Population-based study. PARTICIPANTS: A subsample of the
permanent residents of Cache County, Utah, aged 65 years or
older in January 1995 (N = 5092) and who had completed
clinical assessments and had an informant-completed
Neuropsychiatric Inventory. MEASUREMENTS: Chi-square
statistics, tests for trend, and logistic regression models
were used to analyze the three objectives listed earlier.
RESULTS: The most prevalent NPS in those with CIND were
depression (16.9%), irritability (9.8%), nighttime behaviors
(7.6%), apathy (6.9%), and anxiety (5.4%). Trend analyses
confirmed that the CIND group had NPS prevalence rates that
fell between the normal and dementia groups for most NPS.
Logistic regression models showed no significant difference
between aMCI and other CIND participants in the prevalence
of any NPS (lowest p: 0.316). CONCLUSIONS: These data
confirm the relatively high prevalence of NPS in CIND
reported by other studies, especially for affective
symptoms. No differences in NPS prevalence were found
between aMCI and other types of CIND.},
Doi = {10.1097/JGP.0b013e318211057d},
Key = {fds277049}
}
@article{fds371169,
Author = {Babyak, MA and Schwartz, S and Jiang, R and Brummett, B and Kauwe, JS and Corcoran, C and Munger, R and Welsh-Bohmer, K and Williams, RB and Norton, M},
Title = {PSYCHOSOCIAL STRESS IN MIDLIFE MAY MODERATE EFFECTS OF
APOE-TOMM40 RS157580 ON METABOLIC TRAITS IN LATE
LIFE},
Journal = {ANNALS OF BEHAVIORAL MEDICINE},
Volume = {43},
Pages = {S180-S180},
Publisher = {SPRINGER},
Year = {2012},
Month = {April},
Key = {fds371169}
}
@article{fds277095,
Author = {Potter, GG and Wagner, HR and Burke, JR and Plassman, BL and Welsh-Bohmer, KA and Steffens, DC},
Title = {Neuropsychological Predictors of Dementia in Late-Life Major
Depressive Disorder.},
Journal = {Am J Geriatr Psychiatry},
Year = {2012},
Month = {March},
url = {http://www.ncbi.nlm.nih.gov/pubmed/22415312},
Abstract = {OBJECTIVE:: Major depressive disorder is a likely risk
factor for dementia, but some cases of major depressive
disorder in older adults may actually represent a prodrome
of this condition. The purpose of this study was to use
neuropsychological test scores to predict conversion to
dementia in a sample of depressed older adults diagnosed as
nondemented at the time of neuropsychological testing.
DESIGN:: Longitudinal, with mean follow-up of 5.45 years.
SETTING:: Outpatient depression treatment study at Duke
University. PARTICIPANTS:: Thirty nondemented individuals
depressed at the time of neuropsychological testing and
later diagnosed with incident dementia; 149 nondemented
individuals depressed at the time of neuropsychological
testing and a diagnosis of cognitively normal. METHODOLOGY::
All participants received clinical assessment of depression,
were assessed to rule out prevalent dementia at the time of
study enrollment, completed neuropsychological testing at
the time of study enrollment, and were diagnosed for
cognitive disorders on an annual basis. RESULTS::
Nondemented, acutely depressed older adults who converted to
dementia during the study period exhibited broadly lower
cognitive performances at baseline than acutely depressed
individuals who remained cognitively normal. Discriminant
function analysis indicated that 2 neuropsychological tests,
Recognition Memory (from the Consortium to Establish a
Registry for Alzheimer's Disease neuropsychological battery)
and Trail Making B, best predicted dementia conversion.
CONCLUSIONS:: Depressed older adults with cognitive deficits
in the domains of memory and executive functions during
acute depression are at higher risk for developing dementia.
Some cases of late-life depression may reflect a prodrome of
dementia in which clinical manifestation of mood changes may
co-occur with emerging cognitive deficits.},
Doi = {10.1097/JGP.0b013e318248764e},
Key = {fds277095}
}
@article{fds276969,
Author = {Norton, MC and Dew, J and Smith, H and Fauth, E and Piercy, KW and Breitner, JCS and Tschanz, J and Wengreen, H and Welsh-Bohmer, K and Cache County Investigators},
Title = {Lifestyle behavior pattern is associated with different
levels of risk for incident dementia and Alzheimer's
disease: the Cache County study.},
Journal = {J Am Geriatr Soc},
Volume = {60},
Number = {3},
Pages = {405-412},
Year = {2012},
Month = {March},
ISSN = {0002-8614},
url = {http://dx.doi.org/10.1111/j.1532-5415.2011.03860.x},
Abstract = {OBJECTIVES: To identify distinct behavioral patterns of
diet, exercise, social interaction, church attendance,
alcohol consumption, and smoking and to examine their
association with subsequent dementia risk. DESIGN:
Longitudinal, population-based dementia study. SETTING:
Rural county in northern Utah, at-home evaluations.
PARTICIPANTS: Two thousand four hundred ninety-one
participants without dementia (51% male, average age 73.0 ±
5,7; average education 13.7 ± 4.1 years) initially reported
no problems in activities of daily living and no stroke or
head injury within the past 5 years. MEASUREMENTS: Six
dichotomized lifestyle behaviors were examined (diet: high
≥ median on the Dietary Approaches to Stop Hypertension
scale; exercise: ≥5 h/wk of light activity and at least
occasional moderate to vigorous activity; church attendance:
attending church services at least weekly; social
Interaction: spending time with family and friends at least
twice weekly; alcohol: currently drinking alcoholic
beverages ≥ 2 times/wk; nonsmoker: no current use or fewer
than 100 cigarettes ever). Latent class analysis (LCA) was
used to identify patterns among these behaviors.
Proportional hazards regression modeled time to dementia
onset as a function of behavioral class, age, sex,
education, and apolipoprotein E status. Follow-up averaged
6.3 ± 5.3 years, during which 278 cases of incident
dementia (200 Alzheimer's disease (AD)) were diagnosed.
RESULTS: LCA identified four distinct lifestyle classes.
Unhealthy-religious (UH-R; 11.5%), unhealthy-nonreligious
(UH-NR; 10.5%), healthy-moderately religious (H-MR; 38.5%),
and healthy-very religious (H-VR; 39.5%). UH-NR (hazard
ratio (HR) = 0.54, P = .028), H-MR (HR = 0.56, P = .003),
and H-VR (HR = 0.58, P = .005) had significantly lower
dementia risk than UH-R. Results were comparable for AD,
except that UH-NR was less definitive. CONCLUSION:
Functionally independent older adults appear to cluster into
subpopulations with distinct patterns of lifestyle behaviors
with different levels of risk for subsequent dementia and
AD.},
Doi = {10.1111/j.1532-5415.2011.03860.x},
Key = {fds276969}
}
@article{fds277106,
Author = {Wee, C-Y and Yap, P-T and Zhang, D and Denny, K and Browndyke, JN and Potter, GG and Welsh-Bohmer, KA and Wang, L and Shen,
D},
Title = {Identification of MCI individuals using structural and
functional connectivity networks.},
Journal = {Neuroimage},
Volume = {59},
Number = {3},
Pages = {2045-2056},
Year = {2012},
Month = {February},
url = {http://www.ncbi.nlm.nih.gov/pubmed/22019883},
Abstract = {Different imaging modalities provide essential complementary
information that can be used to enhance our understanding of
brain disorders. This study focuses on integrating multiple
imaging modalities to identify individuals at risk for mild
cognitive impairment (MCI). MCI, often an early stage of
Alzheimer's disease (AD), is difficult to diagnose due to
its very mild or insignificant symptoms of cognitive
impairment. Recent emergence of brain network analysis has
made characterization of neurological disorders at a
whole-brain connectivity level possible, thus providing new
avenues for brain diseases classification. Employing
multiple-kernel Support Vector Machines (SVMs), we attempt
to integrate information from diffusion tensor imaging (DTI)
and resting-state functional magnetic resonance imaging
(rs-fMRI) for improving classification performance. Our
results indicate that the multimodality classification
approach yields statistically significant improvement in
accuracy over using each modality independently. The
classification accuracy obtained by the proposed method is
96.3%, which is an increase of at least 7.4% from the single
modality-based methods and the direct data fusion method. A
cross-validation estimation of the generalization
performance gives an area of 0.953 under the receiver
operating characteristic (ROC) curve, indicating excellent
diagnostic power. The multimodality classification approach
hence allows more accurate early detection of brain
abnormalities with greater sensitivity.},
Doi = {10.1016/j.neuroimage.2011.10.015},
Key = {fds277106}
}
@article{fds276930,
Author = {Hayden, KM and Welsh-Bohmer, KA},
Title = {Epidemiology of cognitive aging and Alzheimer's disease:
contributions of the cache county utah study of memory,
health and aging.},
Journal = {Curr Top Behav Neurosci},
Volume = {10},
Pages = {3-31},
Year = {2012},
ISSN = {1866-3370},
url = {http://www.ncbi.nlm.nih.gov/pubmed/21809193},
Abstract = {Epidemiological studies of Alzheimer's disease (AD) provide
insights into changing public health trends and their
contribution to disease incidence. The current chapter
considers how the population-based approach has contributed
to our understanding of lifetime exposures that contribute
to later disease risk and may act to modify onset of
symptoms. We focus on the findings from a recent survey of
an exceptionally long-lived population, the Cache County
Utah Study of Memory, Health, and Aging. This study is
confined to a single geographic population has allowed
estimation of the genetic and environmental influences on AD
expression across the expected human lifespan of 95+ years.
Given the emphasis of this text on the behavioral
neurosciences of aging, we highlight within the current
chapter the particular contributions of this
population-based study to the neuropsychology of aging and
AD. We also discuss hypotheses generated from this survey
with respect to factors that may either accelerate or delay
symptom onset in AD and the conditions that appear to be
associated with successful cognitive aging.},
Doi = {10.1007/7854_2011_152},
Key = {fds276930}
}
@article{fds276968,
Author = {Tranel, D and Welsh-Bohmer, KA},
Title = {Pervasive olfactory impairment after bilateral limbic system
destruction.},
Journal = {J Clin Exp Neuropsychol},
Volume = {34},
Number = {2},
Pages = {117-125},
Year = {2012},
url = {http://www.ncbi.nlm.nih.gov/pubmed/22220560},
Abstract = {What pattern of brain damage could completely obliterate the
sense of olfaction in humans? We had an opportunity to
address this intriguing question in Patient B., who has
extensive bilateral damage to most of the limbic system,
including the medial and lateral temporal lobes, orbital
frontal cortex, insular cortex, anterior cingulate cortex,
and basal forebrain, caused by herpes simplex encephalitis.
The patient demonstrated profound impairments in odor
identification and recognition. Moreover, he could not
discriminate between olfactory stimuli, and he had severe
impairments in odor detection. Reliable stimulus detection
was obtained only for solutions of the organic solvent
acetone and highly concentrated solutions of ethanol. In
contrast to the more circumscribed olfactory deficits
demonstrated in patients with damage confined to either the
temporal lobes or orbitofrontal cortex (which tend to
involve odor identification but not odor detection), Patient
B. demonstrated a strikingly severe and complete anosmia.
This contrast in olfactory abilities and deficits as a
result of different anatomical pathology affords new
insights into the neural substrates of olfactory processing
in humans.},
Doi = {10.1080/13803395.2011.633897},
Key = {fds276968}
}
@article{fds277107,
Author = {Wee, C-Y and Yap, P-T and Denny, K and Browndyke, JN and Potter, GG and Welsh-Bohmer, KA and Wang, L and Shen, D},
Title = {Resting-state multi-spectrum functional connectivity
networks for identification of MCI patients.},
Journal = {PLoS One},
Volume = {7},
Number = {5},
Pages = {e37828},
Year = {2012},
url = {http://www.ncbi.nlm.nih.gov/pubmed/22666397},
Abstract = {In this paper, a high-dimensional pattern classification
framework, based on functional associations between brain
regions during resting-state, is proposed to accurately
identify MCI individuals from subjects who experience normal
aging. The proposed technique employs multi-spectrum
networks to characterize the complex yet subtle blood
oxygenation level dependent (BOLD) signal changes caused by
pathological attacks. The utilization of multi-spectrum
networks in identifying MCI individuals is motivated by the
inherent frequency-specific properties of BOLD spectrum. It
is believed that frequency specific information extracted
from different spectra may delineate the complex yet subtle
variations of BOLD signals more effectively. In the proposed
technique, regional mean time series of each
region-of-interest (ROI) is band-pass filtered (0.025 ≤ ƒ
≤ 0.100 Hz) before it is decomposed into five frequency
sub-bands. Five connectivity networks are constructed, one
from each frequency sub-band. Clustering coefficient of each
ROI in relation to the other ROIs are extracted as features
for classification. Classification accuracy was evaluated
via leave-one-out cross-validation to ensure generalization
of performance. The classification accuracy obtained by this
approach is 86.5%, which is an increase of at least 18.9%
from the conventional full-spectrum methods. A
cross-validation estimation of the generalization
performance shows an area of 0.863 under the receiver
operating characteristic (ROC) curve, indicating good
diagnostic power. It was also found that, based on the
selected features, portions of the prefrontal cortex,
orbitofrontal cortex, temporal lobe, and parietal lobe
regions provided the most discriminant information for
classification, in line with results reported in previous
studies. Analysis on individual frequency sub-bands
demonstrated that different sub-bands contribute differently
to classification, providing extra evidence regarding
frequency-specific distribution of BOLD signals. Our MCI
classification framework, which allows accurate early
detection of functional brain abnormalities, makes an
important positive contribution to the treatment management
of potential AD patients.},
Doi = {10.1371/journal.pone.0037828},
Key = {fds277107}
}
@article{fds277123,
Author = {Linnertz, C and Saunders, AM and Lutz, MW and Crenshaw, DM and Grossman,
I and Burns, DK and Whitfield, KE and Hauser, MA and McCarthy, JJ and Ulmer, M and Allingham, R and Welsh-Bohmer, KA and Roses, AD and Chiba-Falek, O},
Title = {Characterization of the poly-T variant in the TOMM40 gene in
diverse populations.},
Journal = {PLoS One},
Volume = {7},
Number = {2},
Pages = {e30994},
Year = {2012},
url = {http://www.ncbi.nlm.nih.gov/pubmed/22359560},
Abstract = {We previously discovered that a polymorphic,
deoxythymidine-homopolymer (poly-T, rs10524523) in intron 6
of the TOMM40 gene is associated with age-of-onset of
Alzheimer's disease and with cognitive performance in
elderly. Three allele groups were defined for rs10524523,
hereafter '523', based on the number of 'T'-residues:
'Short' (S, T≤19), 'Long' (L, 20≤T≤29) and 'Very Long'
(VL, T≥30). Homopolymers, particularly long homopolymers
like '523', are difficult to genotype because 'slippage'
occurs during PCR-amplification. We initially genotyped this
locus by PCR-amplification followed by Sanger-sequencing.
However, we recognized the need to develop a
higher-throughput genotyping method that is also accurate
and reliable. Here we describe a new '523' genotyping assay
that is simple and inexpensive to perform in a standard
molecular genetics laboratory. The assay is based on the
detection of differences in PCR-fragment length using
capillary electrophoresis. We discuss technical problems,
solutions, and the steps taken for validation. We employed
the novel assay to investigate the '523' allele frequencies
in different ethnicities. Whites and Hispanics have similar
frequencies of S/L/VL alleles (0.45/0.11/0.44 and
0.43/0.09/0.48, respectively). In African-Americans, the
frequency of the L-allele (0.10) is similar to Whites and
Hispanics; however, the S-allele is more prevalent (0.65)
and the VL-allele is concomitantly less frequent (0.25). The
allele frequencies determined using the new methodology are
compared to previous reports for Ghanaian, Japanese, Korean
and Han Chinese cohorts. Finally, we studied the linkage
pattern between TOMM40-'523' and APOE alleles. In Whites and
Hispanics, consistent with previous reports, the L is
primarily linked to ε4, while the majority of the VL and S
are linked to ε3. Interestingly, in African-Americans,
Ghanaians and Japanese, there is an increased frequency of
the '523'S-APOEε4 haplotype. These data may be used as
references for '523' allele and '523'-APOE haplotype
frequencies in diverse populations for the design of
research studies and clinical trials.},
Doi = {10.1371/journal.pone.0030994},
Key = {fds277123}
}
@article{fds276967,
Author = {Kramer, PL and Xu, H and Woltjer, RL and Westaway, SK and Clark, D and Erten-Lyons, D and Kaye, JA and Welsh-Bohmer, KA and Troncoso, JC and Markesbery, WR and Petersen, RC and Turner, RS and Kukull, WA and Bennett, DA and Galasko, D and Morris, JC and Ott,
J},
Title = {Alzheimer disease pathology in cognitively healthy elderly:
a genome-wide study.},
Journal = {Neurobiol Aging},
Volume = {32},
Number = {12},
Pages = {2113-2122},
Year = {2011},
Month = {December},
url = {http://www.ncbi.nlm.nih.gov/pubmed/20452100},
Abstract = {Many elderly individuals remain dementia-free throughout
their life. However, some of these individuals exhibit
Alzheimer disease neuropathology on autopsy, evidenced by
neurofibrillary tangles (NFTs) in AD-specific brain regions.
We conducted a genome-wide association study to identify
genetic mechanisms that distinguish non-demented elderly
with a heavy NFT burden from those with a low NFT burden.
The study included 299 non-demented subjects with autopsy
(185 subjects with low and 114 with high NFT levels). Both a
genotype test, using logistic regression, and an allele test
provided consistent evidence that variants in the RELN gene
are associated with neuropathology in the context of
cognitive health. Immunohistochemical data for reelin
expression in AD-related brain regions added support for
these findings. Reelin signaling pathways modulate
phosphorylation of tau, the major component of NFTs, either
directly or through β-amyloid pathways that influence tau
phosphorylation. Our findings suggest that up-regulation of
reelin may be a compensatory response to tau-related or
beta-amyloid stress associated with AD even prior to the
onset of dementia.},
Doi = {10.1016/j.neurobiolaging.2010.01.010},
Key = {fds276967}
}
@article{fds277097,
Author = {Fillenbaum, GG and Burchett, BM and Unverzagt, FW and Rexroth, DF and Welsh-Bohmer, K},
Title = {Norms for CERAD constructional praxis recall.},
Journal = {Clin Neuropsychol},
Volume = {25},
Number = {8},
Pages = {1345-1358},
Year = {2011},
Month = {November},
url = {http://www.ncbi.nlm.nih.gov/pubmed/21992077},
Abstract = {Recall of the four-item constructional praxis measure was a
later addition to the Consortium to Establish a Registry for
Alzheimer's Disease (CERAD) neuropsychological battery.
Norms for this measure, based on cognitively intact African
Americans age ≥70 (Indianapolis-Ibadan Dementia Project,
N=372), European American participants age ≥66 (Cache
County Study of Memory, Health and Aging, N=507), and
European American CERAD clinic controls age ≥50
(N = 182), are presented here. Performance varied by
site; by sex, education, and age (African Americans in
Indianapolis); education and age (Cache County European
Americans); and only age (CERAD European American controls).
Performance declined with increased age, within age with
less education, and was poorer for women. Means, standard
deviations, and percentiles are presented separately for
each sample.},
Doi = {10.1080/13854046.2011.614962},
Key = {fds277097}
}
@article{fds276982,
Author = {Norton, MC and Smith, KR and Østbye, T and Tschanz, JT and Schwartz, S and Corcoran, C and Breitner, JCS and Steffens, DC and Skoog, I and Rabins,
PV and Welsh-Bohmer, KA and Cache County Investigators},
Title = {Early parental death and remarriage of widowed parents as
risk factors for Alzheimer disease: the Cache County
study.},
Journal = {Am J Geriatr Psychiatry},
Volume = {19},
Number = {9},
Pages = {814-824},
Year = {2011},
Month = {September},
url = {http://www.ncbi.nlm.nih.gov/pubmed/21873837},
Abstract = {OBJECTIVES: Early parental death is associated with lifelong
tendencies toward depression and chronic stress. We tested
the hypothesis that early parental death is associated with
higher risk for Alzheimer disease (AD) in offspring. DESIGN:
A population-based epidemiological study of dementia with
detailed clinical evaluations, linked to one of the world's
richest sources of objective genealogical and vital
statistics data. SETTING: Home visits with residents of a
rural county in northern Utah. PARTICIPANTS: 4,108 subjects,
aged 65-105. MEASUREMENTS: Multistage dementia ascertainment
protocol implemented in four triennial waves, yielding
expert consensus diagnoses of 570 participants with AD and
3,538 without dementia. Parental death dates, socioeconomic
status, and parental remarriage after widowhood were
obtained from the Utah Population Database, a large
genealogical database linked to statewide birth and death
records. RESULTS: Mother's death during subject's
adolescence was significantly associated with higher rate of
AD in regression models that included age, gender,
education, APOE genotype, and socioeconomic status. Father's
death before subject age 5 showed a weaker association. In
stratified analyses, associations were significant only when
the widowed parent did not remarry. Parental death
associations were not moderated by gender or APOE genotype.
Findings were specific to AD and not found for non-AD
dementia. CONCLUSIONS: Parental death during childhood is
associated with higher prevalence of AD, with different
critical periods for father's versus mother's death, with
strength of these associations attenuated by remarriage of
the widowed parent.},
Doi = {10.1097/JGP.0b013e3182011b38},
Key = {fds276982}
}
@article{fds277094,
Author = {Plassman, BL and Langa, KM and McCammon, RJ and Fisher, GG and Potter,
GG and Burke, JR and Steffens, DC and Foster, NL and Giordani, B and Unverzagt, FW and Welsh-Bohmer, KA and Heeringa, SG and Weir, DR and Wallace, RB},
Title = {Incidence of dementia and cognitive impairment, not dementia
in the United States.},
Journal = {Ann Neurol},
Volume = {70},
Number = {3},
Pages = {418-426},
Year = {2011},
Month = {September},
url = {http://www.ncbi.nlm.nih.gov/pubmed/21425187},
Abstract = {OBJECTIVE: Estimates of incident dementia, and cognitive
impairment, not dementia (CIND) (or the related mild
cognitive impairment) are important for public health and
clinical care policy. In this paper, we report US national
incidence rates for dementia and CIND. METHODS: Participants
in the Aging, Demographic, and Memory Study (ADAMS) were
evaluated for cognitive impairment using a comprehensive
in-home assessment. A total of 456 individuals aged 72 years
and older, who were not demented at baseline, were followed
longitudinally from August 2001 to December 2009. An expert
consensus panel assigned a diagnosis of normal cognition,
CIND, or dementia and its subtypes. Using a
population-weighted sample, we estimated the incidence of
dementia, Alzheimer disease (AD), vascular dementia (VaD),
and CIND by age. We also estimated the incidence of
progression from CIND to dementia. RESULTS: The incidence of
dementia was 33.3 (standard error [SE], 4.2) per 1,000
person-years and 22.9 (SE, 2.9) per 1,000 person-years for
AD. The incidence of CIND was 60.4 (SE, 7.2) cases per 1,000
person-years. An estimated 120.3 (SE, 16.9) individuals per
1,000 person-years progressed from CIND to dementia. Over a
5.9-year period, about 3.4 million individuals aged 72 and
older in the United States developed incident dementia, of
whom approximately 2.3 million developed AD, and about
637,000 developed VaD. Over this same period, almost 4.8
million individuals developed incident CIND. INTERPRETATION:
The incidence of CIND is greater than the incidence of
dementia, and those with CIND are at high risk of
progressing to dementia, making CIND a potentially valuable
target for treatments aimed at slowing cognitive
decline.},
Doi = {10.1002/ana.22362},
Key = {fds277094}
}
@article{fds276965,
Author = {Treiber, KA and Carlson, MC and Corcoran, C and Norton, MC and Breitner,
JCS and Piercy, KW and Deberard, MS and Stein, D and Foley, B and Welsh-Bohmer, KA and Frye, A and Lyketsos, CG and Tschanz,
JT},
Title = {Cognitive stimulation and cognitive and functional decline
in Alzheimer's disease: the cache county dementia
progression study.},
Journal = {J Gerontol B Psychol Sci Soc Sci},
Volume = {66},
Number = {4},
Pages = {416-425},
Year = {2011},
Month = {July},
url = {http://www.ncbi.nlm.nih.gov/pubmed/21441386},
Abstract = {OBJECTIVES: To examine the association of engagement in
cognitively stimulating activities with cognitive and
functional decline in a population-based sample of incident
Alzheimer's disease (AD). METHOD: After diagnosis, 187
participants (65% females) were followed semiannually for a
mean 2.7 (SD = 0.4) years. Mean age and education were 84.6
(SD = 5.8) and 13.2 (SD = 2.9) years. Caregivers enumerated
cognitively stimulating leisure activities via the Lifestyle
Activities Questionnaire. Cognition was assessed using the
Mini-Mental State Examination and functional ability via the
Clinical Dementia Rating sum of boxes. Linear mixed models
tested the association between stimulating activities and
change over time in each outcome. Covariates were
demographic factors, estimated premorbid IQ,
presence/absence of the APOE ε4 allele, duration of
dementia, level of physical activity, and general health.
RESULTS: At initial assessment, 87% of participants were
engaged in one or more stimulating activities, with mean
(SD) activities = 4.0 (3.0). This number declined to 2.4
(2.0) at the final visit. There was a statistical
interaction between dementia duration and number of
activities in predicting rate of cognitive decline (p = .02)
and overall functional ability (p = .006). DISCUSSION:
Active involvement in cognitively stimulating pursuits may
be beneficial for persons with AD.},
Doi = {10.1093/geronb/gbr023},
Key = {fds276965}
}
@article{fds276966,
Author = {Tschanz, JT and Corcoran, CD and Schwartz, S and Treiber, K and Green,
RC and Norton, MC and Mielke, MM and Piercy, K and Steinberg, M and Rabins,
PV and Leoutsakos, J-M and Welsh-Bohmer, KA and Breitner, JCS and Lyketsos, CG},
Title = {Progression of cognitive, functional, and neuropsychiatric
symptom domains in a population cohort with Alzheimer
dementia: the Cache County Dementia Progression
study.},
Journal = {Am J Geriatr Psychiatry},
Volume = {19},
Number = {6},
Pages = {532-542},
Year = {2011},
Month = {June},
url = {http://www.ncbi.nlm.nih.gov/pubmed/21606896},
Abstract = {OBJECTIVES: Progression of Alzheimer dementia (AD) is highly
variable. Most estimates derive from convenience samples
from dementia clinics or research centers where there is
substantial potential for survival bias and other
distortions. In a population-based sample of incident AD
cases, we examined progression of impairment in cognition,
function, and neuropsychiatric symptoms, and the influence
of selected variables on these domains. DESIGN:
Longitudinal, prospective cohort study. SETTING: Cache
County (Utah). PARTICIPANTS: Three hundred twenty-eight
persons with a diagnosis of possible/probable AD.
MEASUREMENTS: Mini-Mental State Exam (MMSE), Clinical
Dementia Rating sum-of-boxes (CDR-sb), and Neuropsychiatric
Inventory (NPI). RESULTS: Over a mean follow-up of 3.80
(range: 0.07-12.90) years, the mean (SD) annual rates of
change were -1.53 (2.69) scale points on the MMSE, 1.44
(1.82) on the CDR-sb, and 2.55 (5.37) on the NPI. Among
surviving participants, 30% to 58% progressed less than 1
point per year on these measures, even 5 to 7 years after
dementia onset. Rates of change were correlated between MMSE
and CDR-sb (r = -0.62, df = 201, p < 0.001) and between the
CDR-sb and NPI (r = 0.20, df = 206, p < 0.004). Female
subjects (LR χ = 8.7, df = 2, p = 0.013) and those with
younger onset (likelihood ratio [LR] χ = 5.7, df = 2, p =
0.058) declined faster on the MMSE. Although one or more
apolipoprotein E ε 4 alleles and ever use of FDA-approved
antidementia medications were associated with initial MMSE
scores, neither was related to the rate of progression in
any domain. CONCLUSIONS: A significant proportion of persons
with AD progresses slowly. The results underscore
differences between population-based versus clinic-based
samples and suggest ongoing need to identify factors that
may slow the progression of AD.},
Doi = {10.1097/JGP.0b013e3181faec23},
Key = {fds276966}
}
@article{fds277120,
Author = {Swaminathan, M and Nicoara, A and Phillips-Bute, BG and Aeschlimann,
N and Milano, CA and Mackensen, GB and Podgoreanu, MV and Velazquez, EJ and Stafford-Smith, M and Mathew, JP and Cardiothoracic Anesthesia
Research Endeavors (CARE) Group},
Title = {Utility of a simple algorithm to grade diastolic dysfunction
and predict outcome after coronary artery bypass graft
surgery.},
Journal = {Ann Thorac Surg},
Volume = {91},
Number = {6},
Pages = {1844-1850},
Year = {2011},
Month = {June},
url = {http://www.ncbi.nlm.nih.gov/pubmed/21492828},
Abstract = {BACKGROUND: Inclusion of a measure of left ventricular
diastolic dysfunction (LVDD) may improve risk prediction
after cardiac surgery. Current LVDD grading guidelines rely
on echocardiographic variables that are not always available
or aligned to allow grading. We hypothesized that a
simplified algorithm involving fewer variables would enable
more patients to be assigned a LVDD grade compared with a
comprehensive algorithm, and also be valid in identifying
patients at risk of long-term major adverse cardiac events
(MACE). METHODS: Intraoperative transesophageal
echocardiography data were gathered on 905 patients
undergoing coronary artery bypass graft surgery, including
flow and tissue Doppler-based measurements. Two algorithms
were constructed to categorize LVDD: a comprehensive
four-variable algorithm, A, was compared with a simplified
version, B, with only two variables-transmitral early flow
velocity and early mitral annular tissue velocity-for ease
of grading and association with MACE. RESULTS: Using
algorithm A, only 563 patients (62%) could be graded,
whereas 895 patients (99%) received a grade with algorithm
B. Over the median follow-up period of 1,468 days, Cox
modeling showed that LVDD was significantly associated with
MACE when graded with algorithm B (p=0.013), but not
algorithm A (p=0.79). Patients with the highest incidence of
MACE could not be graded with algorithm A. CONCLUSIONS: We
found that an LVDD algorithm with fewer variables enabled
grading of a significantly greater number of coronary artery
bypass graft patients, and was valid, as evidenced by
worsening grades being associated with MACE. This simplified
algorithm could be extended to similar populations as a
valid method of characterizing LVDD.},
Doi = {10.1016/j.athoracsur.2011.02.008},
Key = {fds277120}
}
@article{fds277092,
Author = {Kaddurah-Daouk, R and Rozen, S and Matson, W and Han, X and Hulette, CM and Burke, JR and Doraiswamy, PM and Welsh-Bohmer,
KA},
Title = {Metabolomic changes in autopsy-confirmed Alzheimer's
disease.},
Journal = {Alzheimers Dement},
Volume = {7},
Number = {3},
Pages = {309-317},
Year = {2011},
Month = {May},
url = {http://www.ncbi.nlm.nih.gov/pubmed/21075060},
Abstract = {BACKGROUND: Metabolomics, the global science of
biochemistry, provides powerful tools to map perturbations
in the metabolic network and enables simultaneous
quantification of several metabolites to identify metabolic
perturbances that might provide insights into disease.
METHODS: In this pilot study, we took a targeted
electrochemistry-based metabolomics approach where liquid
chromatography followed by coulometric array detection
enables quantification of over 30 metabolites within key
neurotransmitter pathways (dopamine and serotonin) and
pathways involved in oxidative stress. RESULTS: Using
samples from postmortem ventricular cerebrospinal fluid (15
Alzheimer's disease [AD] and 15 nondemented subjects with
autopsy-confirmed diagnoses) and by using regression models,
correlations, Wilcoxon rank-sum tests, and t-tests we
identified alterations in tyrosine, tryptophan, purine, and
tocopherol pathways in patients with AD. Reductions in
norepinephrine and its related metabolites were also seen,
consistent with previously published data. CONCLUSIONS:
These data support further investigation of metabolomics in
larger samples of clinical AD as well as in those with
preclinical disease for use as biomarkers.},
Doi = {10.1016/j.jalz.2010.06.001},
Key = {fds277092}
}
@article{fds277093,
Author = {Naj, AC and Jun, G and Beecham, GW and Wang, L-S and Vardarajan, BN and Buros, J and Gallins, PJ and Buxbaum, JD and Jarvik, GP and Crane, PK and Larson, EB and Bird, TD and Boeve, BF and Graff-Radford, NR and De
Jager, PL and Evans, D and Schneider, JA and Carrasquillo, MM and Ertekin-Taner, N and Younkin, SG and Cruchaga, C and Kauwe, JSK and Nowotny, P and Kramer, P and Hardy, J and Huentelman, MJ and Myers, AJ and Barmada, MM and Demirci, FY and Baldwin, CT and Green, RC and Rogaeva,
E and St George-Hyslop and P and Arnold, SE and Barber, R and Beach, T and Bigio, EH and Bowen, JD and Boxer, A and Burke, JR and Cairns, NJ and Carlson, CS and Carney, RM and Carroll, SL and Chui, HC and Clark, DG and Corneveaux, J and Cotman, CW and Cummings, JL and DeCarli, C and DeKosky, ST and Diaz-Arrastia, R and Dick, M and Dickson, DW and Ellis,
WG and Faber, KM and Fallon, KB and Farlow, MR and Ferris, S and Frosch,
MP and Galasko, DR and Ganguli, M and Gearing, M and Geschwind, DH and Ghetti, B and Gilbert, JR and Gilman, S and Giordani, B and Glass, JD and Growdon, JH and Hamilton, RL and Harrell, LE and Head, E and Honig, LS and Hulette, CM and Hyman, BT and Jicha, GA and Jin, L-W and Johnson, N and Karlawish, J and Karydas, A and Kaye, JA and Kim, R and Koo, EH and Kowall,
NW and Lah, JJ and Levey, AI and Lieberman, AP and Lopez, OL and Mack, WJ and Marson, DC and Martiniuk, F and Mash, DC and Masliah, E and McCormick,
WC and McCurry, SM and McDavid, AN and McKee, AC and Mesulam, M and Miller,
BL and Miller, CA and Miller, JW and Parisi, JE and Perl, DP and Peskind,
E and Petersen, RC and Poon, WW and Quinn, JF and Rajbhandary, RA and Raskind, M and Reisberg, B and Ringman, JM and Roberson, ED and Rosenberg, RN and Sano, M and Schneider, LS and Seeley, W and Shelanski,
ML and Slifer, MA and Smith, CD and Sonnen, JA and Spina, S and Stern, RA and Tanzi, RE and Trojanowski, JQ and Troncoso, JC and Van Deerlin and VM and Vinters, HV and Vonsattel, JP and Weintraub, S and Welsh-Bohmer, KA and Williamson, J and Woltjer, RL and Cantwell, LB and Dombroski, BA and Beekly, D and Lunetta, KL and Martin, ER and Kamboh, MI and Saykin, AJ and Reiman, EM and Bennett, DA and Morris, JC and Montine, TJ and Goate, AM and Blacker, D and Tsuang, DW and Hakonarson, H and Kukull, WA and Foroud,
TM and Haines, JL and Mayeux, R and Pericak-Vance, MA and Farrer, LA and Schellenberg, GD},
Title = {Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are
associated with late-onset Alzheimer's disease.},
Journal = {Nat Genet},
Volume = {43},
Number = {5},
Pages = {436-441},
Year = {2011},
Month = {May},
url = {http://www.ncbi.nlm.nih.gov/pubmed/21460841},
Abstract = {The Alzheimer Disease Genetics Consortium (ADGC) performed a
genome-wide association study of late-onset Alzheimer
disease using a three-stage design consisting of a discovery
stage (stage 1) and two replication stages (stages 2 and 3).
Both joint analysis and meta-analysis approaches were used.
We obtained genome-wide significant results at MS4A4A
(rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 ×
10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2
and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2
and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2
and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1,
2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous
associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J)
= 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8),
P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 ×
10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) =
7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2,
to late-onset Alzheimer's disease susceptibility.},
Doi = {10.1038/ng.801},
Key = {fds277093}
}
@article{fds277026,
Author = {Tate, DF and Neeley, ES and Norton, MC and Tschanz, JT and Miller, MJ and Wolfson, L and Hulette, C and Leslie, C and Welsh-Bohmer, KA and Plassman, B and Bigler, ED},
Title = {Intracranial volume and dementia: some evidence in support
of the cerebral reserve hypothesis.},
Journal = {Brain Res},
Volume = {1385},
Pages = {151-162},
Year = {2011},
Month = {April},
url = {http://www.ncbi.nlm.nih.gov/pubmed/21172323},
Abstract = {The brain reserve hypothesis has been posited as being one
important mediating factor for developing dementia,
especially Alzheimer's disease (AD). Evidence for this
hypothesis is mixed though different methodologies have made
these findings difficult to interpret. We examined imaging
data from a large cohort (N=194) of mixed dementia patients
and controls, 65years old and older from the Cache County,
Utah Study of Memory and Aging for evidence of the brain
reserve hypothesis using total intracranial volume (TICV) as
a quantitative measure of pre-morbid brain size and a
vicarious indicator of reserve. A broader spectrum of
non-demented elderly control subjects from previous studies
was also included for comparison (N=423). In addition,
non-parametric Classification and Regression Tree (CART)
analyses were performed to model group heterogeneity and
identify any subgroups of patients where TICV might be an
important predictor of dementia. Parametrically, no main
effect was found for TICV when predicting a dementia
diagnosis; however, the CART analysis did reveal important
TICV subgroups, including a sex differential wherein ε4
APOE allele presence in males and low TICV predicted AD
classification. TICV, APOE, and other potential
mediator/moderator variables are discussed in the context of
the brain reserve hypothesis.},
Doi = {10.1016/j.brainres.2010.12.038},
Key = {fds277026}
}
@article{fds277090,
Author = {McCarthy, JJ and Linnertz, C and Saucier, L and Burke, JR and Hulette,
CM and Welsh-Bohmer, KA and Chiba-Falek, O},
Title = {The effect of SNCA 3' region on the levels of SNCA-112
splicing variant.},
Journal = {Neurogenetics},
Volume = {12},
Number = {1},
Pages = {59-64},
Year = {2011},
Month = {February},
url = {http://www.ncbi.nlm.nih.gov/pubmed/21046180},
Abstract = {Genetic variability at the 3' region of SNCA locus has been
repeatedly associated with susceptibility to sporadic
Parkinson's disease (PD). Accumulated evidence emphasizes
the importance of SNCA dosage and expression levels in PD
pathogenesis. However, the mechanism through which the 3'
region of SNCA gene modulates the risk to develop sporadic
PD remained elusive. We studied the effect of PD
risk-associated variants at SNCA 3' regions on SNCA112-mRNA
(exon 5 in-frame skipping) levels in vivo in 117
neuropathologically normal, human brain frontal cortex
samples. SNPs tagging the SNCA 3' showed significant effects
on the relative levels of SNCA112-mRNA from total SNCA
transcripts levels. The "risk" alleles were correlated with
increased expression ratio of SNCA112-mRNA from total. We
provide evidence for functional consequences of
PD-associated SNCA gene variants at the 3' region,
suggesting that genetic regulation of SNCA splicing plays an
important role in the development of the disease. Further
studies to determine the definite functional variant/s
within SNCA 3'and to establish their association with PD
pathology are necessary.},
Doi = {10.1007/s10048-010-0263-4},
Key = {fds277090}
}
@article{fds277103,
Author = {Wee, C-Y and Yap, P-T and Li, W and Denny, K and Browndyke, JN and Potter,
GG and Welsh-Bohmer, KA and Wang, L and Shen, D},
Title = {Enriched white matter connectivity networks for accurate
identification of MCI patients.},
Journal = {Neuroimage},
Volume = {54},
Number = {3},
Pages = {1812-1822},
Year = {2011},
Month = {February},
url = {http://www.ncbi.nlm.nih.gov/pubmed/20970508},
Abstract = {Mild cognitive impairment (MCI), often a prodromal phase of
Alzheimer's disease (AD), is frequently considered to be a
good target for early diagnosis and therapeutic
interventions of AD. Recent emergence of reliable network
characterization techniques has made it possible to
understand neurological disorders at a whole-brain
connectivity level. Accordingly, we propose an effective
network-based multivariate classification algorithm, using a
collection of measures derived from white matter (WM)
connectivity networks, to accurately identify MCI patients
from normal controls. An enriched description of WM
connections, utilizing six physiological parameters, i.e.,
fiber count, fractional anisotropy (FA), mean diffusivity
(MD), and principal diffusivities(λ(1), λ(2), and λ(3)),
results in six connectivity networks for each subject to
account for the connection topology and the biophysical
properties of the connections. Upon parcellating the brain
into 90 regions-of-interest (ROIs), these properties can be
quantified for each pair of regions with common traversing
fibers. For building an MCI classifier, clustering
coefficient of each ROI in relation to the remaining ROIs is
extracted as feature for classification. These features are
then ranked according to their Pearson correlation with
respect to the clinical labels, and are further sieved to
select the most discriminant subset of features using an
SVM-based feature selection algorithm. Finally, support
vector machines (SVMs) are trained using the selected subset
of features. Classification accuracy was evaluated via
leave-one-out cross-validation to ensure generalization of
performance. The classification accuracy given by our
enriched description of WM connections is 88.9%, which is an
increase of at least 14.8% from that using simple WM
connectivity description with any single physiological
parameter. A cross-validation estimation of the
generalization performance shows an area of 0.929 under the
receiver operating characteristic (ROC) curve, indicating
excellent diagnostic power. It was also found, based on the
selected features, that portions of the prefrontal cortex,
orbitofrontal cortex, parietal lobe and insula regions
provided the most discriminant features for classification,
in line with results reported in previous studies. Our MCI
classification framework, especially the enriched
description of WM connections, allows accurate early
detection of brain abnormalities, which is of paramount
importance for treatment management of potential AD
patients.},
Doi = {10.1016/j.neuroimage.2010.10.026},
Key = {fds277103}
}
@article{fds277048,
Author = {Mayeux, R and Reitz, C and Brickman, AM and Haan, MN and Manly, JJ and Glymour, MM and Weiss, CC and Yaffe, K and Middleton, L and Hendrie, HC and Warren, LH and Hayden, KM and Welsh-Bohmer, KA and Breitner, JCS and Morris, JC},
Title = {Operationalizing diagnostic criteria for Alzheimer's disease
and other age-related cognitive impairment-Part
1.},
Journal = {Alzheimers Dement},
Volume = {7},
Number = {1},
Pages = {15-34},
Year = {2011},
Month = {January},
url = {http://www.ncbi.nlm.nih.gov/pubmed/21255741},
Abstract = {In this article, the challenges faced by several noted
population studies for Alzheimer dementia in
operationalizing current clinical diagnostic criteria for
Alzheimer's disease (AD) have been reviewed. Differences in
case ascertainment, methodological biases, cultural and
educational influences on test performance, inclusion of
special populations such as underrepresented minorities and
the oldest old, and detection of the earliest symptomatic
stages of underlying AD have been considered. Classification
of Alzheimer dementia may be improved by the incorporation
of biomarkers for AD if the sensitivity, specificity, and
predictive value of the biomarkers are established and if
they are appropriate for epidemiological studies, as may
occur should a plasma biomarker be developed. Biomarkers for
AD could also facilitate studies of the interactions of
various forms of neurodegenerative disorders with
cerebrovascular disease, resulting in "mixed
dementia".},
Doi = {10.1016/j.jalz.2010.11.005},
Key = {fds277048}
}
@article{fds371170,
Author = {Norton, MC and Franklin, LM and Bingham, D and Steffens, DC and Welsh-Bohmer, K},
Title = {INDIVIDUAL RELIGIOUS BEHAVIORS ARE INVERSELY ASSOCIATED WITH
SUBSEQUENT GERIATRIC DEPRESSION},
Journal = {GERONTOLOGIST},
Volume = {51},
Pages = {32-32},
Year = {2011},
Key = {fds371170}
}
@article{fds277091,
Author = {Han, X and Rozen, S and Boyle, SH and Hellegers, C and Cheng, H and Burke,
JR and Welsh-Bohmer, KA and Doraiswamy, PM and Kaddurah-Daouk,
R},
Title = {Metabolomics in early Alzheimer's disease: identification of
altered plasma sphingolipidome using shotgun
lipidomics.},
Journal = {PLoS One},
Volume = {6},
Number = {7},
Pages = {e21643},
Year = {2011},
url = {http://www.ncbi.nlm.nih.gov/pubmed/21779331},
Abstract = {BACKGROUND: The development of plasma biomarkers could
facilitate early detection, risk assessment and therapeutic
monitoring in Alzheimer's disease (AD). Alterations in
ceramides and sphingomyelins have been postulated to play a
role in amyloidogensis and inflammatory stress related
neuronal apoptosis; however few studies have conducted a
comprehensive analysis of the sphingolipidome in AD plasma
using analytical platforms with accuracy, sensitivity and
reproducibility. METHODS AND FINDINGS: We prospectively
analyzed plasma from 26 AD patients (mean MMSE 21) and 26
cognitively normal controls in a non-targeted approach using
multi-dimensional mass spectrometry-based shotgun lipidomics
to determine the levels of over 800 molecular species of
lipids. These data were then correlated with diagnosis,
apolipoprotein E4 genotype and cognitive performance. Plasma
levels of species of sphingolipids were significantly
altered in AD. Of the 33 sphingomyelin species tested, 8
molecular species, particularly those containing long
aliphatic chains such as 22 and 24 carbon atoms, were
significantly lower (p<0.05) in AD compared to controls.
Levels of 2 ceramide species (N16:0 and N21:0) were
significantly higher in AD (p<0.05) with a similar, but
weaker, trend for 5 other species. Ratios of ceramide to
sphingomyelin species containing identical fatty acyl chains
differed significantly between AD patients and controls.
MMSE scores were correlated with altered mass levels of both
N20:2 SM and OH-N25:0 ceramides (p<0.004) though lipid
abnormalities were observed in mild and moderate AD. Within
AD subjects, there were also genotype specific differences.
CONCLUSIONS: In this prospective study, we used a sensitive
multimodality platform to identify and characterize an
essentially uniform but opposite pattern of disruption in
sphingomyelin and ceramide mass levels in AD plasma. Given
the role of brain sphingolipids in neuronal function, our
findings provide new insights into the AD sphingolipidome
and the potential use of metabolomic signatures as
peripheral biomarkers.},
Doi = {10.1371/journal.pone.0021643},
Key = {fds277091}
}
@article{fds277105,
Author = {Hayden, KM and Jones, RN and Zimmer, C and Plassman, BL and Browndyke,
JN and Pieper, C and Warren, LH and Welsh-Bohmer,
KA},
Title = {Factor structure of the National Alzheimer's Coordinating
Centers uniform dataset neuropsychological battery: an
evaluation of invariance between and within groups over
time.},
Journal = {Alzheimer Dis Assoc Disord},
Volume = {25},
Number = {2},
Pages = {128-137},
Year = {2011},
url = {http://www.ncbi.nlm.nih.gov/pubmed/21606904},
Abstract = {The neuropsychological battery from the National Alzheimer's
Disease Coordinating Center is designed to provide a
sensitive assessment of mild cognitive disorders for
multicenter investigations. Comprising 8 common
neuropsychological tests (12 measures), the battery assesses
cognitive domains affected early in the course of Alzheimer
disease. We examined the factor structure of the battery
across levels of cognition [normal, mild cognitive
impairment, dementia] based on Clinical Dementia Rating
scores to determine cognitive domains tapped by the battery.
Using data pooled from 29 Alzheimer's Disease Centers funded
by National Institute on Aging, exploratory factor analysis
was used to derive a general model using half of the sample;
4 factors representing memory, attention, executive
function, and language were identified. Confirmatory factor
analysis was used on the second half of the sample to
evaluate invariance between groups and within groups over 1
year. Factorial invariance testing included systematic
addition of constraints and comparisons of nested models.
The general confirmatory factor analysis model had a good
fit. As constraints were added, model fit deteriorated
slightly. Comparisons within groups showed stability over 1
year. In a range of cognition from normal to dementia,
factor structures and factor loadings will vary little.
Further work is needed to determine whether domains become
more or less distinct in severely cognitively compromised
individuals.},
Doi = {10.1097/WAD.0b013e3181ffa76d},
Key = {fds277105}
}
@article{fds276915,
Author = {Romero, HR and Hayes, SM and Welsh-bohmer, KA},
Title = {Cognitive Domains Affected by Conditions of Ageing and the
Role of Neuropsychological Testing},
Pages = {389-396},
Publisher = {JOHN WILEY & SONS LTD},
Year = {2010},
Month = {December},
url = {http://dx.doi.org/10.1002/9780470669600.ch62},
Abstract = {Determining the presence of a memory disorder in older
patients can be challenging given the similarity between the
complaints of benign brain aging and early brain diseases,
such as Alzheimer's disease. In this chapter is we provide
an overview of the cognitive domains assessed by a standard
neuropsychological evaluation with focused consideration of
the cognitive profiles common to normal brain aging,
Alzheimer's disease, and geriatric depression. An
understanding of the domains affected in these clinical
contexts and the application of targeted neurocognitive
measures of memory and executive processes can augment
routine screening for neurodegenerative conditions and
geriatric depression © 2011 John Wiley & Sons,
Ltd.},
Doi = {10.1002/9780470669600.ch62},
Key = {fds276915}
}
@article{fds276991,
Author = {Wee, CY and Yap, PT and Brownyke, JN and Potter, GG and Steffens, DC and Welsh-Bohmer, K and Wang, L and Shen, D},
Title = {Accurate identification of MCI patients via enriched
white-matter connectivity network},
Journal = {Lecture Notes in Computer Science (including subseries
Lecture Notes in Artificial Intelligence and Lecture Notes
in Bioinformatics)},
Volume = {6357 LNCS},
Pages = {140-147},
Publisher = {Springer Berlin Heidelberg},
Year = {2010},
Month = {October},
ISSN = {0302-9743},
url = {http://dx.doi.org/10.1007/978-3-642-15948-0_18},
Abstract = {Mild cognitive impairment (MCI), often a prodromal phase of
Alzheimer's disease (AD), is frequently considered to be a
good target for early diagnosis and therapeutic
interventions of AD. Recent emergence of reliable network
characterization techniques have made understanding
neurological disorders at a whole brain connectivity level
possible. Accordingly, we propose a network-based
multivariate classification algorithm, using a collection of
measures derived from white-matter (WM) connectivity
networks, to accurately identify MCI patients from normal
controls. An enriched description of WM connections,
utilizing six physiological parameters, i.e., fiber
penetration count, fractional anisotropy (FA), mean
diffusivity (MD), and principal diffusivities (λ 1, λ 2,
λ 3), results in six connectivity networks for each subject
to account for the connection topology and the biophysical
properties of the connections. Upon parcellating the brain
into 90 regions-of-interest (ROIs), the average statistics
of each ROI in relation to the remaining ROIs are extracted
as features for classification. These features are then
sieved to select the most discriminant subset of features
for building an MCI classifier via support vector machines
(SVMs). Cross-validation results indicate better diagnostic
power of the proposed enriched WM connection description
than simple description with any single physiological
parameter. © 2010 Springer-Verlag Berlin
Heidelberg.},
Doi = {10.1007/978-3-642-15948-0_18},
Key = {fds276991}
}
@article{fds276964,
Author = {Roses, AD and Lutz, MW and Amrine-Madsen, H and Saunders, AM and Crenshaw, DG and Sundseth, SS and Huentelman, MJ and Welsh-Bohmer,
KA and Reiman, EM},
Title = {A TOMM40 variable-length polymorphism predicts the age of
late-onset Alzheimer's disease.},
Journal = {Pharmacogenomics J},
Volume = {10},
Number = {5},
Pages = {375-384},
Year = {2010},
Month = {October},
url = {http://www.ncbi.nlm.nih.gov/pubmed/20029386},
Abstract = {The ɛ4 allele of the apolipoprotein E (APOE) gene is
currently the strongest and most highly replicated genetic
factor for risk and age of onset of late-onset Alzheimer's
disease (LOAD). Using phylogenetic analysis, we have
identified a polymorphic poly-T variant, rs10524523, in the
translocase of outer mitochondrial membrane 40 homolog
(TOMM40) gene that provides greatly increased precision in
the estimation of age of LOAD onset for APOE ɛ3 carriers.
In two independent clinical cohorts, longer lengths of
rs10524523 are associated with a higher risk for LOAD. For
APOE ɛ3/4 patients who developed LOAD after 60 years of
age, individuals with long poly-T repeats linked to APOE ɛ3
develop LOAD on an average of 7 years earlier than
individuals with shorter poly-T repeats linked to APOE ɛ3
(70.5 ± 1.2 years versus 77.6 ± 2.1 years, P=0.02, n=34).
Independent mutation events at rs10524523 that occurred
during Caucasian evolution have given rise to multiple
categories of poly-T length variants at this locus. On
replication, these results will have clinical utility for
predictive risk estimates for LOAD and for enabling clinical
disease prevention studies. In addition, these results show
the effective use of a phylogenetic approach for analysis of
haplotypes of polymorphisms, including structural
polymorphisms, which contribute to complex
diseases.},
Doi = {10.1038/tpj.2009.69},
Key = {fds276964}
}
@article{fds371171,
Author = {Bradford, D and Smith, K and Schwartz, S and Tschanz, J and Ostbye, T and Corcoran, C and Welsh-Bohmer, K and Norton, MC},
Title = {TIMING OF OFFSPRING DEATH IN PARENTS' LIVES AND LATE-LIFE
COGNITIVE DECLINE. THE CACHE COUNTY STUDY},
Journal = {GERONTOLOGIST},
Volume = {50},
Pages = {462-462},
Publisher = {OXFORD UNIV PRESS INC},
Year = {2010},
Month = {October},
Key = {fds371171}
}
@article{fds371172,
Author = {Norton, MC and Bradford, D and Smith, K and Schwartz, S and Tschanz, J and Ostbye, T and Corcoran, C and Welsh-Bohmer, K},
Title = {FAMILY SIZE MODERATES THE ASSOCIATION BETWEEN OFFSPRING
DEATH AND RATE OF COGNITIVE DECLINE. THE CACHE COUNTY
STUDY},
Journal = {GERONTOLOGIST},
Volume = {50},
Pages = {464-464},
Publisher = {OXFORD UNIV PRESS INC},
Year = {2010},
Month = {October},
Key = {fds371172}
}
@article{fds371173,
Author = {Tschanz, J and Pfister, R and Steffens, DC and Corcoran, C and Smith, K and Ostbye, T and Welsh-Bohmer, K and Norton, MC},
Title = {STRESSFUL EVENTS IN LATE-LIFE: EFFECTS ON COGNITIVE DECLINE.
THE CACHE COUNTY STUDY},
Journal = {GERONTOLOGIST},
Volume = {50},
Pages = {354-354},
Publisher = {OXFORD UNIV PRESS INC},
Year = {2010},
Month = {October},
Key = {fds371173}
}
@article{fds277047,
Author = {Hayden, KM and Breitner, JCS and Welsh-Bohmer,
KA},
Title = {Apolipoprotein E ε4 status and cognitive decline with and
without dementia - Reply},
Journal = {Archives of Neurology},
Volume = {67},
Number = {8},
Pages = {1036-1037},
Publisher = {American Medical Association (AMA)},
Year = {2010},
Month = {August},
ISSN = {0003-9942},
url = {http://dx.doi.org/10.1001/archneurol.2010.164},
Doi = {10.1001/archneurol.2010.164},
Key = {fds277047}
}
@article{fds276963,
Author = {Buckley, T and Norton, MC and Deberard, MS and Welsh-Bohmer, KA and Tschanz, JT},
Title = {A brief metacognition questionnaire for the elderly:
comparison with cognitive performance and informant ratings
the Cache County Study.},
Journal = {Int J Geriatr Psychiatry},
Volume = {25},
Number = {7},
Pages = {739-747},
Year = {2010},
Month = {July},
url = {http://www.ncbi.nlm.nih.gov/pubmed/19823990},
Abstract = {OBJECTIVE: To examine the utility of a brief, metacognition
questionnaire by examining its association with objective
cognitive testing and informant ratings. We hypothesized
that the association between self-ratings of change and both
outcomes would be greater among individuals without dementia
than among those with dementia. METHODS: Participants were
535 persons without dementia and 152 with dementia from the
Cache County Memory Study who had completed a metacognition
questionnaire, two administrations of the Modified
Mini-Mental State Exam (3 MS) and who had data on the
Informant Questionnaire of Cognitive Decline in the Elderly
(IQCODE). Cronbach's alpha was calculated as a measure of
internal consistency of the metacognition questionnaire.
Multiple regression was used to examine the relationship
between metacognition and 3 MS change. Logistic regression
was used to examine the relationship between metacognition
and IQCODE ratings (no change vs. worse). RESULTS:
Cronbach's alpha was 0.75. Among individuals without
dementia, metacognition significantly predicted 3 MS change
(p = .027) and IQCODE ratings (OR = 4.0, 95% CI = 1.2-13.8,
p = .029), suggesting consistency among measures. For those
with dementia, there was a weak, inverse relationship
between 3 MS change and metacognition (r = -0.16, p = .056).
IQCODE ratings were not significantly associated with
metacognition (p = .729). Degree of dementia severity did
not modify the relationship between metacognition and either
outcome (p > .05). CONCLUSIONS: We demonstrated adequate
internal consistency and evidence for validity of a brief
metacognition questionnaire. The questionnaire may provide a
useful adjunct to memory and functional assessments for
assessing anosognosia in elderly populations.},
Doi = {10.1002/gps.2416},
Key = {fds276963}
}
@article{fds277102,
Author = {Dennis, NA and Browndyke, JN and Stokes, J and Need, A and Burke, JR and Welsh-Bohmer, KA and Cabeza, R},
Title = {Temporal lobe functional activity and connectivity in young
adult APOE varepsilon4 carriers.},
Journal = {Alzheimers Dement},
Volume = {6},
Number = {4},
Pages = {303-311},
Year = {2010},
Month = {July},
url = {http://www.ncbi.nlm.nih.gov/pubmed/19744893},
Abstract = {BACKGROUND: We sought to determine if the APOE epsilon4
allele influences both the functional activation and
connectivity of the medial temporal lobes (MTLs) during
successful memory encoding in young adults. METHODS:
Twenty-four healthy young adults, i.e., 12 carriers and 12
noncarriers of the APOE epsilon4 allele, were scanned in a
subsequent-memory paradigm, using event-related functional
magnetic resonance imaging. The neuroanatomic correlates of
successful encoding were measured as greater neural activity
for subsequently remembered versus forgotten task items, or
in short, encoding success activity (ESA). Group differences
in ESA within the MTLs, as well as whole-brain functional
connectivity with the MTLs, were assessed. RESULTS: In the
absence of demographic or performance differences, APOE
epsilon4 allele carriers exhibited greater bilateral MTL
activity relative to noncarriers while accomplishing the
same encoding task. Moreover, whereas epsilon4 carriers
demonstrated a greater functional connectivity of
ESA-related MTL activity with the posterior cingulate and
other peri-limbic regions, reductions in overall
connectivity were found across the anterior and posterior
cortices. CONCLUSIONS: These results suggest that the APOE
varepsilon4 allele may influence not only functional
activations within the MTL, but functional connectivity of
the MTLs to other regions implicated in memory encoding.
Enhanced functional connectivity of the MTLs with the
posterior cingulate in young adult epsilon4 carriers
suggests that APOE may be expressed early in brain regions
known to be involved in Alzheimer's disease, long before
late-onset dementia is a practical risk or consideration.
These functional connectivity differences may also reflect
pleiotropic effects of APOE during early
development.},
Doi = {10.1016/j.jalz.2009.07.003},
Key = {fds277102}
}
@article{fds277114,
Author = {Smith, PJ and Blumenthal, JA and Babyak, MA and Craighead, L and Welsh-Bohmer, KA and Browndyke, JN and Strauman, TA and Sherwood,
A},
Title = {Effects of the dietary approaches to stop hypertension diet,
exercise, and caloric restriction on neurocognition in
overweight adults with high blood pressure.},
Journal = {Hypertension},
Volume = {55},
Number = {6},
Pages = {1331-1338},
Year = {2010},
Month = {June},
url = {http://www.ncbi.nlm.nih.gov/pubmed/20305128},
Abstract = {High blood pressure increases the risks of stroke, dementia,
and neurocognitive dysfunction. Although aerobic exercise
and dietary modifications have been shown to reduce blood
pressure, no randomized trials have examined the effects of
aerobic exercise combined with dietary modification on
neurocognitive functioning in individuals with high blood
pressure (ie, prehypertension and stage 1 hypertension). As
part of a larger investigation, 124 participants with
elevated blood pressure (systolic blood pressure 130 to 159
mm Hg or diastolic blood pressure 85 to 99 mm Hg) who were
sedentary and overweight or obese (body mass index: 25 to 40
kg/m(2)) were randomized to the Dietary Approaches to Stop
Hypertension (DASH) diet alone, DASH combined with a
behavioral weight management program including exercise and
caloric restriction, or a usual diet control group.
Participants completed a battery of neurocognitive tests of
executive function-memory-learning and psychomotor speed at
baseline and again after the 4-month intervention.
Participants on the DASH diet combined with a behavioral
weight management program exhibited greater improvements in
executive function-memory-learning (Cohen's D=0.562;
P=0.008) and psychomotor speed (Cohen's D=0.480; P=0.023),
and DASH diet alone participants exhibited better
psychomotor speed (Cohen's D=0.440; P=0.036) compared with
the usual diet control. Neurocognitive improvements appeared
to be mediated by increased aerobic fitness and weight loss.
Also, participants with greater intima-medial thickness and
higher systolic blood pressure showed greater improvements
in executive function-memory-learning in the group on the
DASH diet combined with a behavioral weight management
program. In conclusion, combining aerobic exercise with the
DASH diet and caloric restriction improves neurocognitive
function among sedentary and overweight/obese individuals
with prehypertension and hypertension.},
Doi = {10.1161/HYPERTENSIONAHA.109.146795},
Key = {fds277114}
}
@article{fds277073,
Author = {Hayden, KM and Norton, MC and Darcey, D and Ostbye, T and Zandi, PP and Breitner, JCS and Welsh-Bohmer, KA and Cache County Study
Investigators},
Title = {Occupational exposure to pesticides increases the risk of
incident AD: the Cache County study.},
Journal = {Neurology},
Volume = {74},
Number = {19},
Pages = {1524-1530},
Year = {2010},
Month = {May},
url = {http://www.ncbi.nlm.nih.gov/pubmed/20458069},
Abstract = {BACKGROUND: Commonly used organophosphate and organochlorine
pesticides inhibit acetylcholinesterase at synapses in the
somatic, autonomic, and central nervous systems and may
therefore have lasting effects on the nervous system. Few
studies have examined the relationship of pesticide exposure
and risk of dementia or Alzheimer disease (AD). We sought to
examine the association of occupational pesticide exposure
and the risk of incident dementia and AD in later life.
METHODS: Residents of the agricultural community of Cache
County, UT, who were aged 65 years and older as of January
1995, were invited to participate in the study. At baseline,
participants completed detailed occupational history
questionnaires that included information about exposures to
various types of pesticides. Cognitive status was assessed
at baseline and after 3, 7, and 10 years. Standardized
methods were used for detection and diagnosis of dementia
and AD. Cox proportional hazards survival analyses were used
to evaluate the risk of incident dementia and AD associated
with pesticide exposure. RESULTS: Among 3,084 enrollees
without dementia, more men than women reported pesticide
exposure (p < 0.0001). Exposed individuals (n = 572) had
more years of education (p < 0.01) but did not differ from
others in age. Some 500 individuals developed incident
dementia, 344 with AD. After adjustment for baseline age,
sex, education, APOE epsilon4 status, and baseline Modified
Mini-Mental State Examination scores, Cox proportional
hazards models showed increased risks among
pesticide-exposed individuals for all-cause dementia, with
hazard ratio (HR) 1.38 and 95% confidence interval (CI)
1.09-1.76, and for AD (HR 1.42, 95% CI 1.06-1.91). The risk
of AD associated with organophosphate exposure (HR 1.53, 95%
CI 1.05-2.23) was slightly higher than the risk associated
with organochlorines (HR 1.49, 95% CI 0.99-2.24), which was
nearly significant. CONCLUSIONS: Pesticide exposure may
increase the risk of dementia and Alzheimer disease in late
life.},
Doi = {10.1212/WNL.0b013e3181dd4423},
Key = {fds277073}
}
@article{fds276981,
Author = {Norton, MC and Smith, KR and Østbye, T and Tschanz, JT and Corcoran, C and Schwartz, S and Piercy, KW and Rabins, PV and Steffens, DC and Skoog, I and Breitner, JCS and Welsh-Bohmer, KA and Cache County
Investigators},
Title = {Greater risk of dementia when spouse has dementia? The Cache
County study.},
Journal = {J Am Geriatr Soc},
Volume = {58},
Number = {5},
Pages = {895-900},
Year = {2010},
Month = {May},
url = {http://www.ncbi.nlm.nih.gov/pubmed/20722820},
Abstract = {OBJECTIVES: To examine the effects of caring for a spouse
with dementia on the caregiver's risk for incident dementia.
DESIGN: Population-based study of incident dementia in
spouses of persons with dementia. SETTING: Rural county in
northern Utah. PARTICIPANTS: Two thousand four hundred
forty-two subjects (1,221 married couples) aged 65 and
older. MEASUREMENTS: Incident dementia was diagnosed in 255
subjects, with onset defined as age when subject met
Diagnostic and Statistical Manual of Mental Disorders, Third
Edition, Revised, criteria for dementia. Cox proportional
hazards regression tested the effect of time-dependent
exposure to dementia in one's spouse, adjusted for potential
confounders. RESULTS: A subject whose spouse experienced
incident dementia onset had a six times greater risk for
incident dementia as subjects whose spouses were dementia
free (hazard rate ratio (HRR)=6.0, 95% confidence interval
(CI)=2.2-16.2, P<.001). In sex-specific analyses, husbands
had higher risks (HRR=11.9, 95% CI=1.7-85.5, P=.01) than
wives (HRR=3.7, 95% CI=1.2-11.6, P=.03). CONCLUSION: The
chronic and often severe stress associated with dementia
caregiving may exert substantial risk for the development of
dementia in spouse caregivers. Additional (not mutually
exclusive) explanations for findings are
discussed.},
Doi = {10.1111/j.1532-5415.2010.02806.x},
Key = {fds276981}
}
@article{fds277112,
Author = {Smith, PJ and Blumenthal, JA and Hoffman, BM and Cooper, H and Strauman,
TA and Welsh-Bohmer, K and Browndyke, JN and Sherwood,
A},
Title = {Aerobic exercise and neurocognitive performance: a
meta-analytic review of randomized controlled
trials.},
Journal = {Psychosom Med},
Volume = {72},
Number = {3},
Pages = {239-252},
Year = {2010},
Month = {April},
url = {http://www.ncbi.nlm.nih.gov/pubmed/20223924},
Abstract = {OBJECTIVES: To assess the effects of aerobic exercise
training on neurocognitive performance. Although the effects
of exercise on neurocognition have been the subject of
several previous reviews and meta-analyses, they have been
hampered by methodological shortcomings and are now outdated
as a result of the recent publication of several
large-scale, randomized, controlled trials (RCTs). METHODS:
We conducted a systematic literature review of RCTs
examining the association between aerobic exercise training
on neurocognitive performance between January 1966 and July
2009. Suitable studies were selected for inclusion according
to the following criteria: randomized treatment allocation;
mean age > or =18 years of age; duration of treatment >1
month; incorporated aerobic exercise components; supervised
exercise training; the presence of a nonaerobic-exercise
control group; and sufficient information to derive effect
size data. RESULTS: Twenty-nine studies met inclusion
criteria and were included in our analyses, representing
data from 2049 participants and 234 effect sizes.
Individuals randomly assigned to receive aerobic exercise
training demonstrated modest improvements in attention and
processing speed (g = 0.158; 95% confidence interval [CI];
0.055-0.260; p = .003), executive function (g = 0.123; 95%
CI, 0.021-0.225; p = .018), and memory (g = 0.128; 95% CI,
0.015-0.241; p = .026). CONCLUSIONS: Aerobic exercise
training is associated with modest improvements in attention
and processing speed, executive function, and memory,
although the effects of exercise on working memory are less
consistent. Rigorous RCTs are needed with larger samples,
appropriate controls, and longer follow-up
periods.},
Doi = {10.1097/PSY.0b013e3181d14633},
Key = {fds277112}
}
@article{fds277025,
Author = {Van Deerlin and VM and Sleiman, PMA and Martinez-Lage, M and Chen-Plotkin, A and Wang, L-S and Graff-Radford, NR and Dickson, DW and Rademakers, R and Boeve, BF and Grossman, M and Arnold, SE and Mann,
DMA and Pickering-Brown, SM and Seelaar, H and Heutink, P and van
Swieten, JC and Murrell, JR and Ghetti, B and Spina, S and Grafman, J and Hodges, J and Spillantini, MG and Gilman, S and Lieberman, AP and Kaye,
JA and Woltjer, RL and Bigio, EH and Mesulam, M and Al-Sarraj, S and Troakes, C and Rosenberg, RN and White, CL and Ferrer, I and Lladó, A and Neumann, M and Kretzschmar, HA and Hulette, CM and Welsh-Bohmer, KA and Miller, BL and Alzualde, A and Lopez de Munain and A and McKee, AC and Gearing, M and Levey, AI and Lah, JJ and Hardy, J and Rohrer, JD and Lashley, T and Mackenzie, IRA and Feldman, HH and Hamilton, RL and Dekosky, ST and van der Zee, J and Kumar-Singh, S and Van
Broeckhoven, C and Mayeux, R and Vonsattel, JPG and Troncoso, JC and Kril, JJ and Kwok, JBJ and Halliday, GM and Bird, TD and Ince, PG and Shaw,
PJ and Cairns, NJ and Morris, JC and McLean, CA and DeCarli, C and Ellis,
WG and Freeman, SH and Frosch, MP and Growdon, JH and Perl, DP and Sano, M and Bennett, DA and Schneider, JA and Beach, TG and Reiman, EM and Woodruff,
BK and Cummings, J and Vinters, HV and Miller, CA and Chui, HC and Alafuzoff, I and Hartikainen, P and Seilhean, D and Galasko, D and Masliah, E and Cotman, CW and Tuñón, MT and Martínez, MCC and Munoz,
DG and Carroll, SL and Marson, D and Riederer, PF and Bogdanovic, N and Schellenberg, GD and Hakonarson, H and Trojanowski, JQ and Lee,
VM-Y},
Title = {Common variants at 7p21 are associated with frontotemporal
lobar degeneration with TDP-43 inclusions.},
Journal = {Nat Genet},
Volume = {42},
Number = {3},
Pages = {234-239},
Year = {2010},
Month = {March},
url = {http://www.ncbi.nlm.nih.gov/pubmed/20154673},
Abstract = {Frontotemporal lobar degeneration (FTLD) is the second most
common cause of presenile dementia. The predominant
neuropathology is FTLD with TAR DNA-binding protein (TDP-43)
inclusions (FTLD-TDP). FTLD-TDP is frequently familial,
resulting from mutations in GRN (which encodes progranulin).
We assembled an international collaboration to identify
susceptibility loci for FTLD-TDP through a genome-wide
association study of 515 individuals with FTLD-TDP. We found
that FTLD-TDP associates with multiple SNPs mapping to a
single linkage disequilibrium block on 7p21 that contains
TMEM106B. Three SNPs retained genome-wide significance
following Bonferroni correction (top SNP rs1990622, P = 1.08
x 10(-11); odds ratio, minor allele (C) 0.61, 95% CI
0.53-0.71). The association replicated in 89 FTLD-TDP cases
(rs1990622; P = 2 x 10(-4)). TMEM106B variants may confer
risk of FTLD-TDP by increasing TMEM106B expression. TMEM106B
variants also contribute to genetic risk for FTLD-TDP in
individuals with mutations in GRN. Our data implicate
variants in TMEM106B as a strong risk factor for FTLD-TDP,
suggesting an underlying pathogenic mechanism.},
Doi = {10.1038/ng.536},
Key = {fds277025}
}
@article{fds277068,
Author = {Sheline, YI and Pieper, CF and Barch, DM and Welsh-Bohmer, K and McKinstry, RC and MacFall, JR and D'Angelo, G and Garcia, KS and Gersing, K and Wilkins, C and Taylor, W and Steffens, DC and Krishnan,
RR and Doraiswamy, PM},
Title = {Support for the vascular depression hypothesis in late-life
depression: results of a 2-site, prospective, antidepressant
treatment trial.},
Journal = {Arch Gen Psychiatry},
Volume = {67},
Number = {3},
Pages = {277-285},
Year = {2010},
Month = {March},
url = {http://www.ncbi.nlm.nih.gov/pubmed/20194828},
Abstract = {CONTEXT: Research on vascular depression has used 2
approaches to subtype late-life depression, based on
executive dysfunction or white matter hyperintensity
severity. OBJECTIVE: To evaluate the relationship of
neuropsychological performance and white matter
hyperintensity with clinical response in late-life
depression. DESIGN: Two-site, prospective, nonrandomized
controlled trial. SETTING: Outpatient clinics at Washington
University and Duke University. PARTICIPANTS: A total of 217
subjects aged 60 years or older met DSM-IV criteria for
major depression, scored 20 or more on the Montgomery-Asberg
Depression Rating Scale (MADRS), and received vascular risk
factor scores, neuropsychological testing, and magnetic
resonance imaging; they were excluded for cognitive
impairment or severe medical disorders. Fazekas rating was
conducted to grade white matter hyperintensity lesions.
Intervention Twelve weeks of sertraline treatment, titrated
by clinical response. Main Outcome Measure Participants'
MADRS scores over time. RESULTS: Baseline neuropsychological
factor scores correlated negatively with baseline Fazekas
scores. A mixed model examined effects of predictor
variables on MADRS scores over time. Baseline episodic
memory (P = .002), language (P = .007), working memory (P =
.01), processing speed (P < .001), executive function factor
scores (P = .002), and categorical Fazekas ratings (P = .05)
predicted MADRS scores, controlling for age, education, age
of onset, and race. Controlling for baseline MADRS scores,
these factors remained significant predictors of decrease in
MADRS scores, except for working memory and Fazekas ratings.
Thirty-three percent of subjects achieved remission (MADRS <
or =7). Remitters differed from nonremitters in baseline
cognitive processing speed, executive function, language,
episodic memory, and vascular risk factor scores.
CONCLUSIONS: Comprehensive neuropsychological function and
white matter hyperintensity severity predicted MADRS scores
prospectively over a 12-week treatment course with selective
serotonin reuptake inhibitors in late-life depression.
Baseline neuropsychological function differentiated
remitters from nonremitters and predicted time to remission
in a proportional hazards model. Predictor variables
correlated highly with vascular risk factor severity. These
data support the vascular depression hypothesis and
highlight the importance of linking subtypes based on
neuropsychological function and white matter integrity.
TRIAL REGISTRATION: clinicaltrials.gov Identifier:
NCT00045773.},
Doi = {10.1001/archgenpsychiatry.2009.204},
Key = {fds277068}
}
@article{fds277045,
Author = {Welsh-Bohmer, KA and Plassman, BL and Hayden, KM},
Title = {Genetic and environmental contributions to cognitive decline
in aging and Alzheimer's disease},
Journal = {Annual Review of Gerontology and Geriatrics},
Volume = {30},
Number = {1},
Pages = {81-114},
Publisher = {Springer Publishing Company},
Year = {2010},
Month = {January},
ISSN = {0198-8794},
url = {http://dx.doi.org/10.1891/0198-8794.30.81},
Abstract = {Inheritance appears to play a strong role in terms of human
longevity and also in risk for chronic neurodegenerative
diseases of late life such as Alzheimer's disease (AD).
Understanding the role of genes in normal biological aging
of the nervous system and in the expression of AD
pathological changes is important for developing useful
disease targets for clinical intervention and treatment. The
extent to which gene expression can be altered through
environmental exposures may also provide important clues for
disease prevention. In this chapter, we consider the role of
genetic and environmental factors in AD risk and in
age-related cognitive decline. We focus, in particular, on
targets that are potentially modifiable with respect to
exerting positive effects on cognition and AD risk. In this
context, we conclude the chapter by considering lifestyle
approaches to disease prevention and enhancement of
successful cognitive aging that extend from the current
state of evidence and discuss areas for future research
development. © 2010 Springer Publishing
Company.},
Doi = {10.1891/0198-8794.30.81},
Key = {fds277045}
}
@article{fds371174,
Author = {Romero, HR and Browndyke, JN and Burke, JR and Hayden, KM and Welsh-Bohmer, KA},
Title = {Executive Measures are Related to Functional Ability in an
Ethnically Diverse Cohort},
Journal = {CLINICAL NEUROPSYCHOLOGIST},
Volume = {24},
Number = {4},
Pages = {599-600},
Publisher = {TAYLOR & FRANCIS INC},
Year = {2010},
Month = {January},
Key = {fds371174}
}
@article{fds277046,
Author = {Chuang, Y-F and Hayden, KM and Norton, MC and Tschanz, J and Breitner,
JCS and Welsh-Bohmer, KA and Zandi, PP},
Title = {Association between APOE epsilon4 allele and vascular
dementia: The Cache County study.},
Journal = {Dement Geriatr Cogn Disord},
Volume = {29},
Number = {3},
Pages = {248-253},
Year = {2010},
url = {http://www.ncbi.nlm.nih.gov/pubmed/20375505},
Abstract = {BACKGROUND: The APOE epsilon4 allele is an established risk
factor for Alzheimer's disease, but reports of its
association with vascular dementia (VaD) have been
inconsistent. We examined the relationship between APOE
epsilon4 allele and the risk of incident VaD in a large,
population-based cohort of elderly adults with up to 10
years of follow-up between 1995 and 2005. METHODS: A total
of 3,424 elderly men and women free of dementia were
genotyped at the baseline assessment. Incident VaD was
identified through standardized procedures administered at 3
follow-up assessments. Cox proportional hazards models were
used to evaluate the risk of VaD associated with APOE
epsilon4. RESULTS: The adjusted hazard ratio was 1.6 for the
participants with 1 APOE epsilon4 allele (95% CI: 0.9-2.7; p
= 0.083) and 4.4 for those with 2 APOE epsilon4 alleles (95%
CI: 1.6-12.5; p = 0.005). The increased risk did not appear
to be mediated by vascular risk factors. CONCLUSIONS: The
APOE epsilon4 allele is associated with an increased risk of
VaD in a dose-dependent fashion and accounts for almost 20%
of VaD in the population.},
Doi = {10.1159/000285166},
Key = {fds277046}
}
@article{fds277089,
Author = {Heinzen, EL and Need, AC and Hayden, KM and Chiba-Falek, O and Roses,
AD and Strittmatter, WJ and Burke, JR and Hulette, CM and Welsh-Bohmer,
KA and Goldstein, DB},
Title = {Genome-wide scan of copy number variation in late-onset
Alzheimer's disease.},
Journal = {J Alzheimers Dis},
Volume = {19},
Number = {1},
Pages = {69-77},
Year = {2010},
url = {http://www.ncbi.nlm.nih.gov/pubmed/20061627},
Abstract = {Alzheimer's disease is a complex and progressive
neurodegenerative disease leading to loss of memory,
cognitive impairment, and ultimately death. To date, six
large-scale genome-wide association studies have been
conducted to identify SNPs that influence disease
predisposition. These studies have confirmed the well-known
APOE epsilon4 risk allele, identified a novel variant that
influences disease risk within the APOE epsilon4 population,
found a SNP that modifies the age of disease onset, as well
as reported the first sex-linked susceptibility variant.
Here we report a genome-wide scan of Alzheimer's disease in
a set of 331 cases and 368 controls, extending analyses for
the first time to include assessments of copy number
variation. In this analysis, no new SNPs show genome-wide
significance. We also screened for effects of copy number
variation, and while nothing was significant, a duplication
in CHRNA7 appears interesting enough to warrant further
investigation.},
Doi = {10.3233/JAD-2010-1212},
Key = {fds277089}
}
@article{fds376500,
Author = {Sheline, and Welsh-Bohmer, K},
Title = {Support for the Vascular Depression Hypothesis in Late-Life
Depression: Results of a 2-Site, Prospective, Antidepressant
Treatment Trial (vol 67, pg 277, 2010)},
Journal = {ARCHIVES OF GENERAL PSYCHIATRY},
Volume = {67},
Number = {10},
Pages = {1043-1043},
Year = {2010},
Key = {fds376500}
}
@article{fds277044,
Author = {Hayden, KM and Zandi, PP and West, NA and Tschanz, JT and Norton, MC and Corcoran, C and Breitner, JCS and Welsh-Bohmer, KA and Cache County
Study Group},
Title = {Effects of family history and apolipoprotein E epsilon4
status on cognitive decline in the absence of Alzheimer
dementia: the Cache County Study.},
Journal = {Arch Neurol},
Volume = {66},
Number = {11},
Pages = {1378-1383},
Year = {2009},
Month = {November},
url = {http://www.ncbi.nlm.nih.gov/pubmed/19901170},
Abstract = {OBJECTIVE: To evaluate the influences of a family history of
Alzheimer dementia (FHxAD) and the apolipoprotein E epsilon4
genotype (APOE epsilon4) on cognitive decline. DESIGN,
SETTING, AND PARTICIPANTS: Residents of Cache County, Utah,
aged 65 years or older, were invited to participate. At
baseline, 2957 participants provided DNA for genotyping of
APOE and a detailed FHxAD. They also completed the Modified
Mini-Mental State Examination. Cognitive status was
reexamined after 3 and 7 years. We used mixed-effects models
to examine the association among FHxAD, APOE epsilon4, and
cognitive trajectories. MAIN OUTCOME MEASURE: Modified
Mini-Mental State Examination score trajectories over time.
RESULTS: Compared with participants who did not have APOE
epsilon4 or an FHxAD, those with APOE epsilon4 scored lower
on the Modified Mini-Mental State Examination at baseline
(-0.70 points; 95% confidence interval [CI], -1.15 to
-0.24). Participants with an FHxAD and APOE epsilon4
differed less, if at all, in baseline score (-0.46 points;
95% CI, -1.09 to 0.16) but declined faster during the 7-year
study (-9.75 points [95% CI, -10.82 to -8.67] vs -2.91
points [95% CI, -3.37 to -2.44]). After exclusion of
participants who developed prodromal AD or incident
dementia, the group with an FHxAD and APOE epsilon4 declined
much less during the 7-year study (-1.54; 95% CI, -2.59 to
-0.50). CONCLUSIONS: Much of the association among FHxAD,
APOE epsilon4, and cognitive decline may be attributed to
undetected incipient (latent) disease. In the absence of
latent disease, the 2 factors do not appear individually to
be associated with cognitive decline, although they may be
additive.},
Doi = {10.1001/archneurol.2009.237},
Key = {fds277044}
}
@article{fds277101,
Author = {Linnertz, C and Saucier, L and Ge, D and Cronin, KD and Burke, JR and Browndyke, JN and Hulette, CM and Welsh-Bohmer, KA and Chiba-Falek,
O},
Title = {Genetic regulation of alpha-synuclein mRNA expression in
various human brain tissues.},
Journal = {PLoS One},
Volume = {4},
Number = {10},
Pages = {e7480},
Year = {2009},
Month = {October},
url = {http://www.ncbi.nlm.nih.gov/pubmed/19834617},
Abstract = {Genetic variability across the SNCA locus has been
repeatedly associated with susceptibility to sporadic
Parkinson's disease (PD). Accumulated evidence emphasizes
the importance of SNCA dosage and expression levels in PD
pathogenesis. However whether genetic variability in the
SNCA gene modulates the risk to develop sporadic PD via
regulation of SNCA expression remained elusive. We studied
the effect of PD risk-associated variants at SNCA 5' and
3'regions on SNCA-mRNA levels in vivo in 228 human brain
samples from three structures differentially vulnerable to
PD pathology (substantia-nigra, temporal- and
frontal-cortex) obtained from 144 neurologically normal
cadavers. The extensively characterized PD-associated
promoter polymorphism, Rep1, had an effect on SNCA-mRNA
levels. Homozygous genotype of the 'protective', Rep1-259 bp
allele, was associated with lower levels of SNCA-mRNA
relative to individuals that carried at least one copy of
the PD-risk associated alleles, amounting to an average
decrease of approximately 40% and >50% in temporal-cortex
and substantia-nigra, respectively. Furthermore, SNPs
tagging the SNCA 3'-untranslated-region also showed effects
on SNCA-mRNA levels in both the temporal-cortex and the
substantia-nigra, although, in contrast to Rep1, the
'decreased-risk' alleles were correlated with increased
SNCA-mRNA levels. Similar to Rep1 findings, no difference in
SNCA-mRNA level was seen with different SNCA 3'SNP alleles
in the frontal-cortex, indicating there is brain-region
specificity of the genetic regulation of SNCA expression. We
provide evidence for functional consequences of
PD-associated SNCA gene variants in disease relevant brain
tissues, suggesting that genetic regulation of SNCA
expression plays an important role in the development of the
disease.},
Doi = {10.1371/journal.pone.0007480},
Key = {fds277101}
}
@article{fds276990,
Author = {Potter, GG and Taylor, WD and McQuoid, DR and Steffens, DC and Welsh-Bohmer, KA and Krishnan, KRR},
Title = {The COMT Val158Met polymorphism and cognition in depressed
and nondepressed older adults.},
Journal = {Int J Geriatr Psychiatry},
Volume = {24},
Number = {10},
Pages = {1127-1133},
Year = {2009},
Month = {October},
url = {http://www.ncbi.nlm.nih.gov/pubmed/19296553},
Abstract = {OBJECTIVE: The objective of the current study was to examine
the relationship between the COMT Val(158)Met polymorphism
and neuropsychological performance in depressed and
nondepressed older adults. METHODS: One hundred and
twenty-six clinically depressed older adults and 105
nondepressed comparison participants were compared on
neuropsychological performance and COMT Val(158)Met
(Val/Val, Val/Met, Met/Met). RESULTS: Based on multivariate
regression models, the COMT Val(158)Met polymorphism was not
associated with cognitive performance among depressed or
nondepressed individuals, nor did this polymorphism account
for the fact that depressed individuals performed worse than
nondepressed individuals on several neuropsychological tests
that are typically affected by depression. There was also no
difference in frequency of the COMT Val(158)Met alleles
between depressed and nondepressed individuals. CONCLUSIONS:
Although the current study found no association between COMT
Val(158)Met polymorphism on a number of clinical
neuropsychological tests that are typically found to be
sensitive to depression, differential effects of the COMT
Val(158)Met polymorphism on dopamine transmission in
psychiatric and non-psychiatric populations may be further
clarified by clinical research with neuroscience-based
paradigms that segregate cognitive tasks into component
processes with precise neural substrates, particularly with
respect to the complex functions of the prefrontal cortex.
Negative results can be important to narrowing down target
processes and understanding the influence of clinical and
demographic characteristics in studies of psychiatric
genetics.},
Doi = {10.1002/gps.2235},
Key = {fds276990}
}
@article{fds276961,
Author = {Norton, MC and Piercy, KW and Rabins, PV and Green, RC and Breitner,
JCS and Ostbye, T and Corcoran, C and Welsh-Bohmer, KA and Lyketsos, CG and Tschanz, JT},
Title = {Caregiver-recipient closeness and symptom progression in
Alzheimer disease. The Cache County Dementia Progression
Study.},
Journal = {J Gerontol B Psychol Sci Soc Sci},
Volume = {64},
Number = {5},
Pages = {560-568},
Year = {2009},
Month = {September},
url = {http://www.ncbi.nlm.nih.gov/pubmed/19564210},
Abstract = {Applying Rusbult's investment model of dyadic relationships,
we examined the effect of caregiver-care recipient
relationship closeness (RC) on cognitive and functional
decline in Alzheimer's disease. After diagnosis, 167
participants completed up to six visits, observed over an
average of 20 months. Participants were 64% women, had a
mean age of 86 years, and mean dementia duration of 4 years.
Caregiver-rated closeness was measured using a six-item
scale. In mixed models adjusted for dementia severity, dyads
with higher levels of closeness (p < .05) and with spouse
caregivers (p = .01) had slower cognitive decline. Effect of
higher RC on functional decline was greater with spouse
caregivers (p = .007). These findings of attenuated
Alzheimer's dementia (AD) decline with closer relationships,
particularly with spouse caregivers, are consistent with
investment theory. Future interventions designed to enhance
the caregiving dyadic relationship may help slow decline in
AD.},
Doi = {10.1093/geronb/gbp052},
Key = {fds276961}
}
@article{fds277043,
Author = {Levin, ED and Aschner, M and Heberlein, U and Ruden, D and Welsh-Bohmer,
KA and Bartlett, S and Berger, K and Chen, L and Corl, AB and Eddins, D and French, R and Hayden, KM and Helmcke, K and Hirsch, HVB and Linney, E and Lnenicka, G and Page, GP and Possidente, D and Possidente, B and Kirshner, A},
Title = {Genetic aspects of behavioral neurotoxicology.},
Journal = {Neurotoxicology},
Volume = {30},
Number = {5},
Pages = {741-753},
Year = {2009},
Month = {September},
url = {http://www.ncbi.nlm.nih.gov/pubmed/19647018},
Abstract = {Considerable progress has been made over the past couple of
decades concerning the molecular bases of neurobehavioral
function and dysfunction. The field of neurobehavioral
genetics is becoming mature. Genetic factors contributing to
neurologic diseases such as Alzheimer's disease have been
found and evidence for genetic factors contributing to other
diseases such as schizophrenia and autism are likely. This
genetic approach can also benefit the field of behavioral
neurotoxicology. It is clear that there is substantial
heterogeneity of response with behavioral impairments
resulting from neurotoxicants. Many factors contribute to
differential sensitivity, but it is likely that genetic
variability plays a prominent role. Important discoveries
concerning genetics and behavioral neurotoxicity are being
made on a broad front from work with invertebrate and
piscine mutant models to classic mouse knockout models and
human epidemiologic studies of polymorphisms. Discovering
genetic factors of susceptibility to neurobehavioral
toxicity not only helps identify those at special risk, it
also advances our understanding of the mechanisms by which
toxicants impair neurobehavioral function in the larger
population. This symposium organized by Edward Levin and
Annette Kirshner, brought together researchers from the
laboratories of Michael Aschner, Douglas Ruden, Ulrike
Heberlein, Edward Levin and Kathleen Welsh-Bohmer conducting
studies with Caenorhabditis elegans, Drosophila, fish,
rodents and humans studies to determine the role of genetic
factors in susceptibility to behavioral impairment from
neurotoxic exposure.},
Doi = {10.1016/j.neuro.2009.07.014},
Key = {fds277043}
}
@article{fds277088,
Author = {Hulette, CM and Ervin, JF and Edmonds, Y and Antoine, S and Stewart, N and Szymanski, MH and Hayden, KM and Pieper, CF and Burke, JR and Welsh-Bohmer, KA},
Title = {Cerebrovascular smooth muscle actin is increased in
nondemented subjects with frequent senile plaques at
autopsy: implications for the pathogenesis of Alzheimer
disease.},
Journal = {J Neuropathol Exp Neurol},
Volume = {68},
Number = {4},
Pages = {417-424},
Year = {2009},
Month = {April},
ISSN = {0022-3069},
url = {http://www.ncbi.nlm.nih.gov/pubmed/19287310},
Abstract = {We previously found that vascular smooth muscle actin (SMA)
is reduced in the brains of patients with late stage
Alzheimer disease (AD) compared with brains of nondemented,
neuropathologically normal subjects. To assess the
pathogenetic significance and disease specificity of this
finding, we studied 3 additional patient groups: nondemented
subjects without significant AD type pathology ("Normal"; n
= 20), nondemented subjects with frequent senile plaques at
autopsy ("Preclinical AD"; n = 20), and subjects with
frontotemporal dementia ("FTD"; n = 10). The groups were
matched for sex and age with those previously reported; SMA
immunohistochemistry and image analysis were performed as
previously described. Surprisingly, SMA expression in
arachnoid, cerebral cortex, and white matter arterioles was
greater in the Preclinical AD group than in the Normal and
FTD groups. The plaques were not associated with amyloid
angiopathy or other vascular disease in this group. Smooth
muscle actin expression in the brains of the Normal group
was intermediate between the Preclinical AD and FTD groups.
All 3 groups exhibited much greater SMA expression than in
our previous report. The presence of frequent plaques and
increased arteriolar SMA expression in the brains of
nondemented subjects suggest that increased SMA expression
might represent a physiological response to
neurodegeneration that could prevent or delay overt
expression dementia in AD.},
Doi = {10.1097/NEN.0b013e31819e6334},
Key = {fds277088}
}
@article{fds371175,
Author = {Norton, MC and Tschanz, JT and Steffens, DC and Skoog, I and Welsh-Bohmer, KA and Munger, R and Breitner, JCS},
Title = {Age Moderates the Effect of Late-life Depression on Incident
Alzheimer's Disease Risk},
Journal = {AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY},
Volume = {17},
Number = {3},
Pages = {A72-A72},
Publisher = {LIPPINCOTT WILLIAMS & WILKINS},
Year = {2009},
Month = {March},
Key = {fds371175}
}
@article{fds276989,
Author = {Potter, GG and McQuoid, DR and Steffens, DC and Welsh-Bohmer, KA and Krishnan, KRR},
Title = {Neuropsychological correlates of magnetic resonance
imaging-defined subcortical ischemic depression.},
Journal = {Int J Geriatr Psychiatry},
Volume = {24},
Number = {3},
Pages = {219-225},
Year = {2009},
Month = {March},
url = {http://www.ncbi.nlm.nih.gov/pubmed/18655212},
Abstract = {OBJECTIVE: The goal of the current study was to examine the
neuropsychological profile of magnetic resonance imaging
(MRI)-defined subcortical ischemic depression (SID).
METHODS: Clinically depressed older adults with MRI-defined
SID (n = 70) and depressed elders without SID (n = 75) were
compared on neuropsychological performance, depression
symptoms, and medical burden. RESULTS: Group comparisons
revealed that the SID was associated with worse performance
on all neuropsychological measures, but also with greater
age, higher cardiac illness burden, and greater deficits in
the depression symptoms of self-initiation and
concentration. In multivariate regression models, auditory
working memory and nonverbal memory remained worse among the
SID group after controlling for contributions of age,
cardiovascular risk, and depression symptoms. CONCLUSIONS:
Although auditory working memory span and nonverbal memory
appear to be specifically associated with the ischemic
pathology that defines SID, the typical individual with SID
is also likely to have a broader profile of
neuropsychological deficits than those without SID because
they are typically older and have specific depression
symptoms that predispose them to compromised neurocognitive
performance.},
Doi = {10.1002/gps.2093},
Key = {fds276989}
}
@article{fds276962,
Author = {Welsh-Bohmer, KA and White, CL},
Title = {Alzheimer disease: what changes in the brain cause
dementia?},
Journal = {Neurology},
Volume = {72},
Number = {4},
Pages = {e21},
Year = {2009},
Month = {January},
url = {http://www.ncbi.nlm.nih.gov/pubmed/19171824},
Doi = {10.1212/01.wnl.0000343818.11392.d9},
Key = {fds276962}
}
@article{fds277042,
Author = {Welsh-Bohmer, KA and Ostbye, T and Sanders, L and Pieper, CF and Hayden,
KM and Tschanz, JT and Norton, MC and Cache Country Study
Group},
Title = {Neuropsychological performance in advanced age: influences
of demographic factors and Apolipoprotein E: findings from
the Cache County Memory Study.},
Journal = {Clin Neuropsychol},
Volume = {23},
Number = {1},
Pages = {77-99},
Year = {2009},
Month = {January},
url = {http://www.ncbi.nlm.nih.gov/pubmed/18609337},
Abstract = {The Cache County Study of Memory in Aging (CCMS) is an
epidemiological study of Alzheimer's disease (AD), mild
cognitive disorders, and aging in a population of
exceptionally long-lived individuals (7th to 11th decade).
Observation of population members without dementia provides
an opportunity for establishing the range of normal
neurocognitive performance in a representative sample of the
very old. We examined neurocognitive performance of the
normal participants undergoing full clinical evaluations (n
= 507) and we tested the potential modifying effects of
apolipoprotein E (APOE) genotype, a known genetic risk
factor for the later development of AD. The results indicate
that advanced age and low education are related to lower
test scores across nearly all of the neurocognitive
measures. Gender and APOE epsilon4 both had negligible and
inconsistent influences, affecting only isolated measures of
memory and expressive speech (in case of gender). The gender
and APOE effects disappeared once age and education were
controlled. The study of this exceptionally long-lived
population provides useful normative information regarding
the broad range of "normal" cognition seen in advanced age.
Among elderly without dementia or other cognitive
impairment, APOE does not appear to exert any major effects
on cognition once other demographic influences are
controlled.},
Doi = {10.1080/13854040801894730},
Key = {fds277042}
}
@article{fds371176,
Author = {Peters, ME and Rosenberg, P and Steinberg, M and Tschanz, J and Welsh-Bohmer, K and Hayden, K and Breitner, J and Lyketsos,
CG},
Title = {Prevalence of Neuropsychiatric Symptoms in CIND and its
Subtypes: Cache County Study},
Journal = {AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY},
Volume = {17},
Number = {3},
Pages = {A117-A118},
Year = {2009},
Key = {fds371176}
}
@article{fds277072,
Author = {Heinzen, EL and Ge, D and Cronin, KD and Maia, JM and Shianna, KV and Gabriel, WN and Welsh-Bohmer, KA and Hulette, CM and Denny, TN and Goldstein, DB},
Title = {Tissue-specific genetic control of splicing: implications
for the study of complex traits.},
Journal = {PLoS Biol},
Volume = {6},
Number = {12},
Pages = {e1},
Year = {2008},
Month = {December},
url = {http://www.ncbi.nlm.nih.gov/pubmed/19222302},
Abstract = {Numerous genome-wide screens for polymorphisms that
influence gene expression have provided key insights into
the genetic control of transcription. Despite this work, the
relevance of specific polymorphisms to in vivo expression
and splicing remains unclear. We carried out the first
genome-wide screen, to our knowledge, for SNPs that
associate with alternative splicing and gene expression in
human primary cells, evaluating 93 autopsy-collected
cortical brain tissue samples with no defined
neuropsychiatric condition and 80 peripheral blood
mononucleated cell samples collected from living healthy
donors. We identified 23 high confidence associations with
total expression and 80 with alternative splicing as
reflected by expression levels of specific exons. Fewer than
50% of the implicated SNPs however show effects in both
tissue types, reflecting strong evidence for distinct
genetic control of splicing and expression in the two tissue
types. The data generated here also suggest the possibility
that splicing effects may be responsible for up to 13 out of
84 reported genome-wide significant associations with human
traits. These results emphasize the importance of
establishing a database of polymorphisms affecting splicing
and expression in primary tissue types and suggest that
splicing effects may be of more phenotypic significance than
overall gene expression changes.},
Doi = {10.1371/journal.pbio.1000001},
Key = {fds277072}
}
@article{fds277041,
Author = {Rosenberg, PB and Mielke, MM and Tschanz, J and Cook, L and Corcoran, C and Hayden, KM and Norton, M and Rabins, PV and Green, RC and Welsh-Bohmer,
KA and Breitner, JCS and Munger, R and Lyketsos, CG},
Title = {Effects of cardiovascular medications on rate of functional
decline in Alzheimer disease.},
Journal = {Am J Geriatr Psychiatry},
Volume = {16},
Number = {11},
Pages = {883-892},
Year = {2008},
Month = {November},
url = {http://www.ncbi.nlm.nih.gov/pubmed/18978249},
Abstract = {BACKGROUND: Evidence suggests that cardiovascular
medications, including statins and antihypertensive
medications, may delay cognitive decline in patients with
Alzheimer dementia (AD). We examined the association of
cardiovascular medication use and rate of functional decline
in a population-based cohort of individuals with incident
AD. METHODS: In the Dementia Progression Study of the Cache
County Study on Memory, Health, and Aging, 216 individuals
with incident AD were identified and followed longitudinally
with in-home visits for a mean of 3.0 years and 2.1
follow-up visits. The Clinical Dementia Rating (CDR) was
completed at each follow-up. Medication use was inventoried
during in-home visits. Generalized least-squares
random-effects regression was performed with CDR Sum of
Boxes (CDR-Sum) as the outcome and cardiovascular medication
use as the major predictors. RESULTS: CDR-Sum increased an
average of 1.69 points annually, indicating a steady decline
in functioning. After adjustment for demographic variables
and the baseline presence of cardiovascular conditions, use
of statins (p = 0.03) and beta-blockers (p = 0.04) was
associated with a slower annual rate of increase in CDR-Sum
(slower rate of functional decline) of 0.75 and 0.68 points
respectively, while diuretic use was associated with a
faster rate of increase in CDR-Sum (p = 0.01; 0.96 points
annually). Use of calcium-channel blockers,
angiotensin-converting enzyme inhibitors, digoxin, or
nitrates did not affect the rate of functional decline.
CONCLUSIONS: In this population-based study of individuals
with incident AD, use of statins and beta-blockers was
associated with delay of functional decline. Further studies
are needed to confirm these results and to determine whether
treatment with these medications may help delay AD
progression.},
Doi = {10.1097/JGP.0b013e318181276a},
Key = {fds277041}
}
@article{fds276960,
Author = {Welsh-Bohmer, K},
Title = {Neuropsychological characterization of dementia
patients},
Journal = {Primary Psychiatry},
Volume = {15},
Number = {10 SUPPL. 6},
Pages = {10-13},
Year = {2008},
Month = {October},
ISSN = {1082-6319},
Key = {fds276960}
}
@article{fds277117,
Author = {Story, TJ and Potter, GG and Attix, DK and Welsh-Bohmer, KA and Steffens, DC},
Title = {Neurocognitive correlates of response to treatment in
late-life depression.},
Journal = {Am J Geriatr Psychiatry},
Volume = {16},
Number = {9},
Pages = {752-759},
Year = {2008},
Month = {September},
url = {http://www.ncbi.nlm.nih.gov/pubmed/18697883},
Abstract = {UNLABELLED: Depression is often associated with
neurocognitive deficits in older adults, particularly in the
domains of information processing speed, episodic memory,
and executive functions. Greater neurocognitive dysfunction
while depressed is associated with a less effective
treatment response; however, questions remain about the
specific variables that characterize patients showing low
treatment response and persistent cognitive deficiencies.
OBJECTIVES: The authors examined neurocognitive variables
that differentiated patients who showed robust versus weak
responses to antidepressant therapy. PARTICIPANTS: The
baseline sample included 110 women and 67 men, with a mean
age of 69.1 years (SD = 6.9) and mean education of 14 years
(SD = 3.3). DESIGN: Patients enrolled in a treatment study
completed both a structured diagnostic assessment for
depression and neuropsychological testing at study entry and
1-year follow-up. MEASUREMENTS: Clinicians rated patient
depression using the Montgomery-Asberg Depression Rating
Scale. Neuropsychological assessments consisted of prose
recall and percent retention (Wechsler Memory Scale -III
Logical Memory), word-list recall, attention and visuomotor
processing speed (Trail Making A, Symbol Digit Modalities
Test), and mental flexibility (Trail Making B).
INTERVENTIONS: Patients underwent treatment for depression
following the guidelines of the Duke Somatic Treatment
Algorithm for Geriatric Depression approach. RESULTS:
Individuals who demonstrated the greatest improvement in
mood symptoms at follow-up exhibited better prose recall and
faster processing speed at baseline than individuals who
demonstrated weaker treatment responses. These differences
remained after controlling for depression severity at both
time-points. CONCLUSION: The current results suggest that
better pretreatment cognitive function, particularly in
verbal memory, is associated with a greater treatment
response in late-life depression.},
Doi = {10.1097/JGP.0b013e31817e739a},
Key = {fds277117}
}
@article{fds277024,
Author = {Carney, RM and Slifer, MA and Lin, PI and Gaskell, PC and Scott, WK and Potocky, CF and Hulette, CM and Welsh-Bohmer, KA and Schmechel, DE and Vance, JM and Pericak-Vance, MA},
Title = {Longitudinal follow-up of late-onset Alzheimer disease
families.},
Journal = {Am J Med Genet B Neuropsychiatr Genet},
Volume = {147B},
Number = {5},
Pages = {571-578},
Year = {2008},
Month = {July},
url = {http://www.ncbi.nlm.nih.gov/pubmed/18361431},
Abstract = {Historically, data for genetic studies are collected at one
time point. However, for diseases with late onset or with
complex phenotypes, such as Alzheimer disease (AD),
restricting diagnosis to a single ascertainment contact may
not be sufficient. Affection status may change over time and
some initial diagnoses may be inconclusive. Follow-up
provides the opportunity to resolve these complications.
However, to date, previous studies have not formally
demonstrated that longitudinally re-contacting families is
practical or productive. To update data initially collected
for linkage analysis of late-onset Alzheimer disease (LOAD),
we successfully re-contacted 63 of 81 (78%) multiplex
families (two to 17 years after ascertainment). Clinical
status changed for 73 of the 230 (32%) non-affected
participants. Additionally, expanded family history
identified 20 additional affected individuals to supplement
the data set. Furthermore, fostering ongoing relationships
with participating families helped recruit 101 affected
participants into an autopsy and tissue donation program.
Despite similar presentations, discordance between clinical
diagnosis and neuropathologic diagnosis was observed in 28%
of those with tissue diagnoses. Most of the families were
successfully re-contacted, and significant refinement and
supplementation of the data was achieved. We concluded that
serial contact with longitudinal evaluation of families has
significant implications for genetic analyses.},
Doi = {10.1002/ajmg.b.30590},
Key = {fds277024}
}
@article{fds276957,
Author = {Szekely, CA and Green, RC and Breitner, JCS and Østbye, T and Beiser,
AS and Corrada, MM and Dodge, HH and Ganguli, M and Kawas, CH and Kuller,
LH and Psaty, BM and Resnick, SM and Wolf, PA and Zonderman, AB and Welsh-Bohmer, KA and Zandi, PP},
Title = {No advantage of A beta 42-lowering NSAIDs for prevention of
Alzheimer dementia in six pooled cohort studies.},
Journal = {Neurology},
Volume = {70},
Number = {24},
Pages = {2291-2298},
Year = {2008},
Month = {June},
url = {http://www.ncbi.nlm.nih.gov/pubmed/18509093},
Abstract = {INTRODUCTION: Observational studies show reduced incidence
of Alzheimer dementia (AD) in users of nonsteroidal
anti-inflammatory drugs (NSAIDs). One hypothesis holds that
the subset of NSAIDs known as selective A beta(42)-lowering
agents (SALAs) is responsible for this apparent reduction in
AD risk. METHODS: We pooled individual-level data from six
prospective studies to obtain a sufficient sample to examine
AD risk in users of SALA vs non-SALA NSAIDs. RESULTS: Of
13,499 initially dementia-free participants (70,863
person-years), 820 developed incident AD. Users of NSAIDs
(29.6%) showed reduced risk of AD (adjusted hazard ratio
[aHR] 0.77, 95% CI 0.65-0.91). The point estimates were
similar for SALAs (aHR 0.87, CI 0.72-1.04) and non-SALAs
(aHR 0.75, CI 0.56-1.01). Because 573 NSAID users (14.5%)
reported taking both a SALA and non-SALA, we examined their
use alone and in combination. Resulting aHRs were 0.82 (CI
0.67-0.99) for SALA only, 0.60 (CI 0.40-0.90) for non-SALA
only, and 0.87 (CI 0.57-1.33) for both NSAIDs (Wald test for
differences, p = 0.32). The 40.7% of participants who used
aspirin also showed reduced risk of AD, even when they used
no other NSAIDs (aHR 0.78, CI 0.66-0.92). By contrast, there
was no association with use of acetaminophen (aHR 0.93, CI
0.76-1.13). CONCLUSIONS: In this pooled dataset,
nonsteroidal anti-inflammatory drug (NSAID) use reduced the
risk of Alzheimer dementia (AD). However, there was no
apparent advantage in AD risk reduction for the subset of
NSAIDs shown to selectively lower A beta(42), suggesting
that all conventional NSAIDs including aspirin have a
similar protective effect in humans.},
Doi = {10.1212/01.wnl.0000313933.17796.f6},
Key = {fds276957}
}
@article{fds276958,
Author = {Treiber, KA and Lyketsos, CG and Corcoran, C and Steinberg, M and Norton, M and Green, RC and Rabins, P and Stein, DM and Welsh-Bohmer,
KA and Breitner, JCS and Tschanz, JT},
Title = {Vascular factors and risk for neuropsychiatric symptoms in
Alzheimer's disease: the Cache County Study.},
Journal = {Int Psychogeriatr},
Volume = {20},
Number = {3},
Pages = {538-553},
Year = {2008},
Month = {June},
ISSN = {1041-6102},
url = {http://www.ncbi.nlm.nih.gov/pubmed/18289451},
Abstract = {OBJECTIVE: To examine, in an exploratory analysis, the
association between vascular conditions and the occurrence
of neuropsychiatric symptoms (NPS) in a population-based
sample of incident Alzheimer's disease (AD). METHODS: The
sample consisted of 254 participants, identified through two
waves of assessment. NPS were assessed using the
Neuropsychiatric Inventory. Prior to the onset of AD, data
regarding a history of stroke, hypertension, hyperlipidemia,
heart attack or coronary artery bypass graft (CABG), and
diabetes were recorded. Logistic regression procedures were
used to examine the relationship of each vascular condition
to individual neuropsychiatric symptoms. Covariates
considered were age, gender, education, APOE genotype,
dementia severity, and overall health status. RESULTS: One
or more NPS were observed in 51% of participants. Depression
was most common (25.8%), followed by apathy (18.6%), and
irritability (17.7%). Least common were elation (0.8%),
hallucinations (5.6%), and disinhibition (6.0%). Stroke
prior to the onset of AD was associated with increased risk
of delusions (OR = 4.76, p = 0.02), depression (OR = 3.87, p
= 0.03), and apathy (OR = 4.48, p = 0.02). Hypertension was
associated with increased risk of delusions (OR = 2.34, p =
0.02), anxiety (OR = 4.10, p = 0.002), and
agitation/aggression (OR = 2.82, p = 0.01). No associations
were observed between NPS and diabetes, hyperlipidemia,
heart attack or CABG, or overall health. CONCLUSIONS:
Results suggest that a history of stroke and hypertension
increase the risk of specific NPS in patients with AD. These
conditions may disrupt neural circuitry in brain areas
involved in NPS. Findings may provide an avenue for
reduction in occurrence of NPS through the treatment or
prevention of vascular risk conditions.},
Doi = {10.1017/S1041610208006704},
Key = {fds276958}
}
@article{fds277100,
Author = {Browndyke, JN and Paskavitz, J and Sweet, LH and Cohen, RA and Tucker,
KA and Welsh-Bohmer, KA and Burke, JR and Schmechel,
DE},
Title = {Neuroanatomical correlates of malingered memory impairment:
event-related fMRI of deception on a recognition memory
task.},
Journal = {Brain Inj},
Volume = {22},
Number = {6},
Pages = {481-489},
Year = {2008},
Month = {June},
url = {http://www.ncbi.nlm.nih.gov/pubmed/18465389},
Abstract = {PRIMARY OBJECTIVE: Event-related, functional magnetic
resonance imaging (fMRI) data were acquired in healthy
participants during purposefully malingered and normal
recognition memory performances to evaluate the neural
substrates of feigned memory impairment. METHODS AND
PROCEDURES: Pairwise, between-condition contrasts of neural
activity associated with discrete recognition memory
responses were conducted to isolate dissociable neural
activity between normal and malingered responding while
simultaneously controlling for shared stimulus familiarity
and novelty effects. Response timing characteristics were
also examined for any association with observed
between-condition activity differences. OUTCOMES AND
RESULTS: Malingered recognition memory errors, regardless of
type, were associated with inferior parietal and superior
temporal activity relative to normal performance, while
feigned recognition target misses produced additional
dorsomedial frontal activation and feigned foil false alarms
activated bilateral ventrolateral frontal regions.
Malingered response times were associated with activity in
the dorsomedial frontal, temporal and inferior parietal
regions. Normal memory responses were associated with
greater inferior occipitotemporal and dorsomedial parietal
activity, suggesting greater reliance upon
visual/attentional networks for proper task performance.
CONCLUSIONS: The neural substrates subserving feigned
recognition memory deficits are influenced by response
demand and error type, producing differential activation of
cortical regions important to complex visual processing,
executive control, response planning and working memory
processes.},
Doi = {10.1080/02699050802084894},
Key = {fds277100}
}
@article{fds276956,
Author = {Hallam, BJ and Brown, WS and Ross, C and Buckwalter, JG and Bigler, ED and Tschanz, JT and Norton, MC and Welsh-Bohmer, KA and Breitner,
JCS},
Title = {Regional atrophy of the corpus callosum in
dementia.},
Journal = {J Int Neuropsychol Soc},
Volume = {14},
Number = {3},
Pages = {414-423},
Year = {2008},
Month = {May},
url = {http://www.ncbi.nlm.nih.gov/pubmed/18419840},
Abstract = {The regional distribution of degeneration of the corpus
callosum (CC) in dementia is not yet clear. This study
compared regional CC size in participants (n = 179) from the
Cache County Memory and Aging Study. Participants
represented a range of cognitive function: Alzheimer's
disease (AD), vascular dementia (VaD), mild ambiguous
(MA-cognitive problems, but not severe enough for diagnosis
of dementia), and healthy older adults. CC outlines obtained
from midsagittal magnetic resonance images were divided into
99 equally spaced widths. Factor analysis of these callosal
widths identified 10 callosal regions. Multivariate analysis
of variance revealed significant group differences for
anterior and posterior callosal regions. Post-hoc pairwise
comparisons of CC regions in patient groups as compared to
the control group (controlling for age) revealed trends
toward smaller anterior and posterior regions, but not all
were statistically significant. As compared to controls,
significantly smaller anterior and posterior CC regions were
found in the AD group; significantly smaller anterior CC
regions in the VaD group; but no significant CC regional
differences in the MA group. Findings suggest that
dementia-related CC atrophy occurs primarily in the anterior
and posterior portions.},
Doi = {10.1017/S1355617708080533},
Key = {fds276956}
}
@article{fds276980,
Author = {Norton, MC and Singh, A and Skoog, I and Corcoran, C and Tschanz, JT and Zandi, PP and Breitner, JCS and Welsh-Bohmer, KA and Steffens, DC and Cache County Investigators},
Title = {Church attendance and new episodes of major depression in a
community study of older adults: the Cache County
Study.},
Journal = {J Gerontol B Psychol Sci Soc Sci},
Volume = {63},
Number = {3},
Pages = {P129-P137},
Year = {2008},
Month = {May},
ISSN = {1079-5014},
url = {http://www.ncbi.nlm.nih.gov/pubmed/18559677},
Abstract = {We examined the relation between church attendance,
membership in the Church of Jesus Christ of Latter-Day
Saints (LDS), and major depressive episode, in a
population-based study of aging and dementia in Cache
County, Utah. Participants included 2,989 nondemented
individuals aged between 65 and 100 years who were
interviewed initially in 1995 to 1996 and again in 1998 to
1999. LDS church members reported twice the rate of major
depression that non-LDS members did (odds ratio = 2.56, 95%
confidence interval = 1.07-6.08). Individuals attending
church weekly or more often had a significantly lower risk
for major depression. After controlling for demographic and
health variables and the strongest predictor of future
episodes of depression, a prior depression history, we found
that church attendance more often than weekly remained a
significant protectant (odds ratio = 0.51, 95% confidence
interval = 0.28-0.92). Results suggest that there may be a
threshold of church attendance that is necessary for a
person to garner long-term protection from depression. We
discuss sociological factors relevant to LDS
culture.},
Doi = {10.1093/geronb/63.3.p129},
Key = {fds276980}
}
@article{fds277040,
Author = {Fotuhi, M and Zandi, PP and Hayden, KM and Khachaturian, AS and Szekely,
CA and Wengreen, H and Munger, RG and Norton, MC and Tschanz, JT and Lyketsos, CG and Breitner, JCS and Welsh-Bohmer,
K},
Title = {Better cognitive performance in elderly taking antioxidant
vitamins E and C supplements in combination with
nonsteroidal anti-inflammatory drugs: the Cache County
Study.},
Journal = {Alzheimers Dement},
Volume = {4},
Number = {3},
Pages = {223-227},
Year = {2008},
Month = {May},
url = {http://www.ncbi.nlm.nih.gov/pubmed/18631971},
Abstract = {Studies have shown less cognitive decline and lower risk of
Alzheimer's disease in elderly individuals consuming either
antioxidant vitamins or nonsteroidal anti-inflammatory drugs
(NSAIDs). The potential of added benefit from their combined
use has not been studied. We therefore analyzed data from
3,376 elderly participants of the Cache County Study who
were given the Modified Mini-Mental State examination up to
three times during a period of 8 years. Those who used a
combination of vitamins E and C supplements and NSAIDs at
baseline declined by an average 0.96 fewer points every 3
years than nonusers (P < .05). This apparent effect was
attributable entirely to participants with the APOE epsilon4
allele, whose users declined by 2.25 fewer points than
nonusers every 3 years (P < .05). These results suggest that
among elderly individuals with an APOE epsilon4 allele,
there is an association between using antioxidant
supplements in combination with NSAIDs and less cognitive
decline over time.},
Doi = {10.1016/j.jalz.2008.01.004},
Key = {fds277040}
}
@article{fds276954,
Author = {Martini, B and Buffington, ALH and Welsh-Bohmer, KA and Brandt, J and ADAPT Research Group},
Title = {Time of day affects episodic memory in older
adults.},
Journal = {Neuropsychol Dev Cogn B Aging Neuropsychol
Cogn},
Volume = {15},
Number = {2},
Pages = {146-164},
Year = {2008},
Month = {March},
url = {http://www.ncbi.nlm.nih.gov/pubmed/17851985},
Abstract = {The neuropsychological test scores of 2030 cognitively
normal older adults were examined to evaluate performance
patterns as they related to time of day (TOD) at which
testing was initiated. Multiple regression analyses were
used to examine the association of TOD with scores on seven
neuropsychological tests used in the clinical evaluation of
dementia. Episodic memory performance was significantly
related to TOD, while memory span and verbal fluency were
not. Best performance occurred during early morning hours
and late afternoon; worst performance occurred mid-day
(i.e., noon). These findings may have implications for
clinical assessment, the design of research on dementia, and
the daily functioning of older adults.},
Doi = {10.1080/13825580601186643},
Key = {fds276954}
}
@article{fds276955,
Author = {Welsh-Bohmer, KA},
Title = {Defining "prodromal" Alzheimer's disease, frontotemporal
dementia, and Lewy body dementia: are we there
yet?},
Journal = {Neuropsychol Rev},
Volume = {18},
Number = {1},
Pages = {70-72},
Year = {2008},
Month = {March},
ISSN = {1040-7308},
url = {http://www.ncbi.nlm.nih.gov/pubmed/18327642},
Doi = {10.1007/s11065-008-9057-y},
Key = {fds276955}
}
@article{fds277062,
Author = {Fillenbaum, GG and van Belle, G and Morris, JC and Mohs, RC and Mirra,
SS and Davis, PC and Tariot, PN and Silverman, JM and Clark, CM and Welsh-Bohmer, KA and Heyman, A},
Title = {Consortium to Establish a Registry for Alzheimer's Disease
(CERAD): the first twenty years.},
Journal = {Alzheimers Dement},
Volume = {4},
Number = {2},
Pages = {96-109},
Year = {2008},
Month = {March},
url = {http://www.ncbi.nlm.nih.gov/pubmed/18631955},
Abstract = {The Consortium to Establish a Registry for Alzheimer's
Disease (CERAD) was funded by the National Institute on
Aging in 1986 to develop standardized, validated measures
for the assessment of Alzheimer's disease (AD). The present
report describes the measures that CERAD developed during
its first decade and their continued use in their original
and translated forms. These measures include clinical,
neuropsychological, neuropathologic, and behavioral
assessments of AD and also assessment of family history and
parkinsonism in AD. An approach to evaluating neuroimages
did not meet the standards desired. Further evaluations that
could not be completed because of lack of funding (but where
some materials are available) include evaluation of very
severe AD and of service use and need by patient and
caregiver. The information that was developed in the U.S.
and abroad permits standardized assessment of AD in clinical
practice, facilitates epidemiologic studies, and provides
information valuable for individual and public health
planning. CERAD materials and data remain available for
those wishing to use them.},
Doi = {10.1016/j.jalz.2007.08.005},
Key = {fds277062}
}
@article{fds277087,
Author = {Steinberg, M and Shao, H and Zandi, P and Lyketsos, CG and Welsh-Bohmer,
KA and Norton, MC and Breitner, JCS and Steffens, DC and Tschanz, JT and Cache County Investigators},
Title = {Point and 5-year period prevalence of neuropsychiatric
symptoms in dementia: the Cache County Study.},
Journal = {Int J Geriatr Psychiatry},
Volume = {23},
Number = {2},
Pages = {170-177},
Year = {2008},
Month = {February},
ISSN = {0885-6230},
url = {http://www.ncbi.nlm.nih.gov/pubmed/17607801},
Abstract = {BACKGROUND: Neuropsychiatric symptoms are nearly universal
in dementia, yet little is known about their longitudinal
course in the community. OBJECTIVE: To estimate point and
5-year period prevalence of neuropsychiatric symptoms in an
incident sample of 408 dementia participants from the Cache
County Study. METHODS: The Neuropsychiatric Inventory
assessed symptoms at baseline and at 1.5 years, 3.0 years,
4.1 years, and 5.3 years. Point prevalence, period
prevalence and mean symptom severity at each time point were
estimated. RESULTS: Point prevalence for delusions was 18%
at baseline and 34-38% during the last three visits;
hallucinations, 10% at baseline and 19-24% subsequently;
agitation/aggression fluctuated between 13% and 24%;
depression 29% at baseline and 41-47% subsequently; apathy
increased from 20% at baseline to 51% at 5.3 years; elation
never rose above 1%; anxiety 14% at baseline and 24-32%
subsequently; disinhibition fluctuated between 2% and 15%;
irritability between 17% and 27%; aberrant motor behavior
gradually increased from 7% at baseline to 29% at 5.3 years.
Point prevalence for any symptom was 56% at baseline and
76-87% subsequently. Five-year period prevalence was
greatest for depression (77%), apathy (71%), and anxiety
(62%); lowest for elation (6%), and disinhibition (31%).
Ninety-seven percent experienced at least one symptom.
Symptom severity was consistently highest for apathy.
CONCLUSIONS: Participants were most likely to develop
depression, apathy, or anxiety, and least likely to develop
elation or disinhibition. Give converging evidence that
syndromal definitions may more accurately capture
neuropsychiatric co-morbidity in dementia, future efforts to
validate such syndromes are warranted.},
Doi = {10.1002/gps.1858},
Key = {fds277087}
}
@article{fds276959,
Author = {Welsh-Bohmer, K},
Title = {Neuropsychological characterization of dementia
patients},
Journal = {CNS Spectrums},
Volume = {13},
Number = {10 SUPPL. 16},
Pages = {10-13},
Year = {2008},
ISSN = {1092-8529},
url = {http://dx.doi.org/10.1017/s1092852900026973},
Doi = {10.1017/s1092852900026973},
Key = {fds276959}
}
@article{fds277071,
Author = {Heinzen, EL and Ge, D and Cronin, KD and Maia, JM and Shianna, KV and Gabriel, WN and Welsh-Bohmer, KA and Hulette, CM and Denny, TN and Goldstein, DB},
Title = {Tissue-specific genetic control of splicing: Implications
for the study of complex traits},
Journal = {PLoS Biology},
Volume = {6},
Number = {12},
Pages = {2869-2879},
Year = {2008},
ISSN = {1544-9173},
url = {http://dx.doi.org/10.1371/journal.pbio.1000001},
Abstract = {Numerous genome-wide screens for polymorphisms that
influence gene expression have provided key insights into
the genetic control of transcription. Despite this work, the
relevance of specific polymorphisms to in vivo expression
and splicing remains unclear. We carried out the first
genome-wide screen, to our knowledge, for SNPs that
associate with alternative splicing and gene expression in
human primary cells, evaluating 93 autopsy-collected
cortical brain tissue samples with no defined
neuropsychiatric condition and 80 peripheral blood
mononucleated cell samples collected from living healthy
donors. We identified 23 high confidence associations with
total expression and 80 with alternative splicing as
reflected by expression levels of specific exons. Fewer than
50% of the implicated SNPs however show effects in both
tissue types, reflecting strong evidence for distinct
genetic control of splicing and expression in the two tissue
types. The data generated here also suggest the possibility
that splicing effects may be responsible for up to 13 out of
84 reported genome-wide significant associations with human
traits. These results emphasize the importance of
establishing a database of polymorphisms affecting splicing
and expression in primary tissue types and suggest that
splicing effects may be of more phenotypic significance than
overall gene expression changes. © 2008 Heinzen et
al.},
Doi = {10.1371/journal.pbio.1000001},
Key = {fds277071}
}
@article{fds277086,
Author = {Ervin, JF and Heinzen, EL and Cronin, KD and Goldstein, D and Szymanski,
MH and Burke, JR and Welsh-Bohmer, KA and Hulette,
CM},
Title = {Postmortem delay has minimal effect on brain RNA
integrity.},
Journal = {J Neuropathol Exp Neurol},
Volume = {66},
Number = {12},
Pages = {1093-1099},
Year = {2007},
Month = {December},
ISSN = {0022-3069},
url = {http://www.ncbi.nlm.nih.gov/pubmed/18090918},
Abstract = {The Bryan Alzheimer Disease Research Center obtains
postmortem human brain tissue from patients with Alzheimer
disease (AD) and cognitively normal control subjects for
molecular and genetic research programs. A growing body of
research suggests that variations in gene transcript levels
may contribute to the onset and progression of disease.
Identifying how the regulation of gene expression may affect
AD requires the use of high-quality mRNA from banked human
brains. The present study was conducted to establish the
quality and suitability of available banked brain tissue for
future gene expression studies. We chose 32 AD cases with
Braak stage IV, V, or VI. These AD cases were matched to 36
normal control cases by age and sex when possible. Multiple
regions from each brain were sampled, including frontal
cortex, temporal cortex, occipital cortex, and cerebellum.
Hippocampus was also available for study from 14 control
cases. A comparison of several antemortem and postmortem
variables, such as postmortem interval, agonal state,
ventricular cerebrospinal fluid pH, and cause of death were
analyzed. RNA was isolated from at least 1 area from every
brain and most brains yielded intact RNA from all regions
tested. Analysis of the clinical variables did not reveal
any features that correlated with the ability to recover
intact mRNA. We conclude that undegraded mRNA may be
isolated from most brain regions many hours postmortem and
that neither the pH of ventricular fluid nor postmortem
interval is predictive of mRNA integrity.},
Doi = {10.1097/nen.0b013e31815c196a},
Key = {fds277086}
}
@article{fds277039,
Author = {Mielke, MM and Rosenberg, PB and Tschanz, J and Cook, L and Corcoran, C and Hayden, KM and Norton, M and Rabins, PV and Green, RC and Welsh-Bohmer,
KA and Breitner, JCS and Munger, R and Lyketsos, CG},
Title = {Vascular factors predict rate of progression in Alzheimer
disease.},
Journal = {Neurology},
Volume = {69},
Number = {19},
Pages = {1850-1858},
Year = {2007},
Month = {November},
url = {http://www.ncbi.nlm.nih.gov/pubmed/17984453},
Abstract = {BACKGROUND: While there is considerable epidemiologic
evidence that cardiovascular risk factors increase risk of
incident Alzheimer disease (AD), few studies have examined
their effect on progression after an established AD
diagnosis. OBJECTIVE: To examine the effect of vascular
factors, and potential age modification, on rate of
progression in a longitudinal study of incident dementia.
METHODS: A total of 135 individuals with incident AD,
identified in a population-based sample of elderly persons
in Cache County, UT, were followed with in-home visits for a
mean of 3.0 years (range: 0.8 to 9.5) and 2.1 follow-up
visits (range: 1 to 5). The Clinical Dementia Rating (CDR)
Scale and Mini-Mental State Examination (MMSE) were
administered at each visit. Baseline vascular factors were
determined by interview and physical examination.
Generalized least-squares random-effects regression was
performed with CDR Sum of Boxes (CDR-Sum) or MMSE as the
outcome, and vascular index or individual vascular factors
as independent variables. RESULTS: Atrial fibrillation,
systolic hypertension, and angina were associated with more
rapid decline on both the CDR-Sum and MMSE, while history of
coronary artery bypass graft surgery, diabetes, and
antihypertensive medications were associated with a slower
rate of decline. There was an age interaction such that
systolic hypertension, angina, and myocardial infarction
were associated with greater decline with increasing
baseline age. CONCLUSION: Atrial fibrillation, hypertension,
and angina were associated with a greater rate of decline
and may represent modifiable risk factors for secondary
prevention in Alzheimer disease. The attenuated decline for
diabetes and coronary artery bypass graft surgery may be due
to selective survival. Some of these effects appear to vary
with age.},
Doi = {10.1212/01.wnl.0000279520.59792.fe},
Key = {fds277039}
}
@article{fds277012,
Author = {Potter, GG and Blackwell, AD and McQuoid, DR and Payne, ME and Steffens,
DC and Sahakian, BJ and Welsh-Bohmer, KA and Krishnan,
KRR},
Title = {Prefrontal white matter lesions and prefrontal task
impersistence in depressed and nondepressed
elders.},
Journal = {Neuropsychopharmacology},
Volume = {32},
Number = {10},
Pages = {2135-2142},
Year = {2007},
Month = {October},
ISSN = {0893-133X},
url = {http://www.ncbi.nlm.nih.gov/pubmed/17299509},
Abstract = {Poor task persistence is often observed among depressed
individuals, and may be associated with some of the same
frontal regions that are involved in depression. The current
study explored the association between white-matter lesion
volume in prefrontal cortex and noncompletion rates on a
complex neurocognitive task among older adults in a
treatment study for depression. Older adults in treatment
for depression (n=83) and nondepressed (n=47) elders were
administered the Stockings of Cambridge subtest (SoC) of the
Cambridge Automated Neuropsychological Testing Battery
(CANTAB) and completed a brain magnetic resonance imaging
scan as part of an ongoing research study. Noncompletion of
the SoC occurred in approximately 19% of depressed
participants (16/83) and only 2% of nondepressed
participants (1/47), which was statistically significant. In
multivariate models, failure to complete the SoC was
consistently and significantly associated with greater
volume of white matter lesions in the anterior-most region
of prefrontal cortex, particularly in the left hemisphere,
and with greater age. Although SoC completion was not
significantly associated with depression severity,
noncompletion rates were significantly higher among
unremitted individuals and those with comorbid anxiety at
study entry. The inability to initiate behavior sufficient
to sustain a complex neurocognitive task is a characteristic
of geriatric depression which may be associated with
integrity of left-prefrontal regions. Future research should
investigate whether task impersistence is a construct that
generalizes to other neurocognitive tasks, and if it is
associated with other adverse outcomes in geriatric
depression related to cerebrovascular pathology, such as
poor treatment response.},
Doi = {10.1038/sj.npp.1301339},
Key = {fds277012}
}
@article{fds277085,
Author = {Steffens, DC and Potter, GG and McQuoid, DR and MacFall, JR and Payne,
ME and Burke, JR and Plassman, BL and Welsh-Bohmer,
KA},
Title = {Longitudinal magnetic resonance imaging vascular changes,
apolipoprotein E genotype, and development of dementia in
the neurocognitive outcomes of depression in the elderly
study.},
Journal = {Am J Geriatr Psychiatry},
Volume = {15},
Number = {10},
Pages = {839-849},
Year = {2007},
Month = {October},
ISSN = {1064-7481},
url = {http://www.ncbi.nlm.nih.gov/pubmed/17623814},
Abstract = {OBJECTIVE: Several studies suggest that depression is a risk
factor for development of dementia in the elderly. In a
study of older depressed individuals, the authors examined
both neuroimaging and genetic factors in development of
dementia. The authors hypothesized that change in
subcortical gray matter and white matter hyperintensity
volumes would be associated with development of dementia, as
would presence of an apolipoprotein E (APOE) epsilon 4
allele. METHODS: The sample consisted of 161 older depressed
subjects without dementia who had magnetic resonance imaging
scans at baseline and at two years. Blood samples were also
taken to determine APOE genotype. All participants were
treated with antidepressants using a guideline-based
treatment algorithm. Their cognitive status was evaluated
annually. A consensus panel of experts evaluated each case
to determine cognitive status and assign a diagnosis.
RESULTS: Twenty subjects became demented over the follow-up
period (5.4 years on average). Change in white matter
hyperintensity volume was significantly associated with
development of dementia, especially among non-Alzheimer
dementias. There was a trend for change in subcortical gray
matter hyperintensity volume to be associated with incident
dementia. APOE genotype was not associated with onset of
dementia. CONCLUSION: Worsening cerebrovascular disease in
older depressed adults is associated with cognitive decline
and dementia, particularly of the non-Alzheimer disease
type. The association of change in white matter lesion
volume and incident dementia among depressed elders extends
the vascular depression hypothesis of geriatric depression
to include cognitive outcomes of depression in the
elderly.},
Doi = {10.1097/JGP.0b013e318048a1a0},
Key = {fds277085}
}
@article{fds277037,
Author = {Hayden, KM and Zandi, PP and Khachaturian, AS and Szekely, CA and Fotuhi, M and Norton, MC and Tschanz, JT and Pieper, CF and Corcoran, C and Lyketsos, CG and Breitner, JCS and Welsh-Bohmer, KA and Cache County
Investigators},
Title = {Does NSAID use modify cognitive trajectories in the elderly?
The Cache County study.},
Journal = {Neurology},
Volume = {69},
Number = {3},
Pages = {275-282},
Year = {2007},
Month = {July},
url = {http://www.ncbi.nlm.nih.gov/pubmed/17636065},
Abstract = {BACKGROUND: Epidemiologic studies have suggested that
nonsteroidal anti-inflammatory drugs (NSAIDs) may be useful
for the prevention of Alzheimer disease (AD). By contrast,
clinical trials have not supported NSAID use to delay or
treat AD. Few studies have evaluated cognitive trajectories
of NSAID users over time. METHODS: Residents of Cache
County, UT, aged 65 or older on January 1, 1995, were
invited to participate in the study. At baseline,
participants provided a detailed inventory of their
medications and completed a revised Modified Mini-Mental
State Examination (3MS). Participants (n = 3,383) who were
cognitively normal at baseline were re-examined after 3 and
8 years. The association between NSAID use and 3MS scores
over time was estimated using random effects modeling.
RESULTS: Associations depended upon when NSAIDs were started
and APOE genotype. In participants who started NSAID use
prior to age 65, those with no APOE epsilon4 alleles
performed similarly to nonusers (a difference of 0.10 points
per year; p = 0.19), while those with one or more epsilon4
allele(s) showed more protection (0.40 points per year; p =
0.0005). Among participants who first used NSAIDs at or
after age 65, those with one or more epsilon4 alleles had
higher baseline scores (0.95 points; p = 0.03) but did not
show subsequent difference in change in score over time
(0.06 points per year; p = 0.56). Those without an epsilon4
allele who started NSAID use after age 65 showed greater
decline than nonusers (-0.16 points per year; p = 0.02).
CONCLUSIONS: Nonsteroidal anti-inflammatory drug use may
help to prevent cognitive decline in older adults if started
in midlife rather than late life. This effect may be more
notable in those who have one or more APOE epsilon4
alleles.},
Doi = {10.1212/01.wnl.0000265223.25679.2a},
Key = {fds277037}
}
@article{fds277084,
Author = {Fearing, MA and Bigler, ED and Norton, M and Tschanz, JA and Hulette, C and Leslie, C and Welsh-Bohmer, K and Cache County
Investigators},
Title = {Autopsy-confirmed Alzheimer's disease versus clinically
diagnosed Alzheimer's disease in the Cache County Study on
Memory and Aging: a comparison of quantitative MRI and
neuropsychological findings.},
Journal = {J Clin Exp Neuropsychol},
Volume = {29},
Number = {5},
Pages = {553-560},
Year = {2007},
Month = {July},
ISSN = {1380-3395},
url = {http://www.ncbi.nlm.nih.gov/pubmed/17564920},
Abstract = {Atrophy of specific, regional, and generalized brain
structures occurs as a result of the Alzheimer's disease
(AD) process. Comparing AD patients with histopathological
confirmation of the disease at autopsy to those without
autopsy but who were clinically diagnosed using the same
antemortem criteria will provide further evidence of the
utility and accuracy of neuropsychological assessments at
the time of diagnosis, as well as the efficacy of
quantitative magnetic resonance imaging (qMRI) in
demonstrating gross neuropathological changes associated
with the disease. The Cache County Study of Aging provides a
unique opportunity to determine how closely AD subjects with
only the clinical diagnosis match similarly diagnosed AD
subjects but with postmortem confirmation of the disease.
qMRI volumes of various brain structures, as well as
neuropsychological outcome measures from an expanded
battery, were obtained in 31 autopsy-confirmed AD subjects
and 45 clinically diagnosed AD subjects. Of the various qMRI
variables examined, only total temporal lobe volume was
different, where those with postmortem confirmation had
reduced volume. No significant differences between the two
groups were found with any of the neuropsychological outcome
measures. These findings confirm the similarity in
neuroimaging and neuropsychological assessment findings
between those with just the clinical diagnosis of AD and
those with an autopsy-confirmed diagnosis in the
moderate-to-severe stage of the disease at the time of
diagnosis.},
Doi = {10.1080/13803390600826579},
Key = {fds277084}
}
@article{fds371177,
Author = {Hulette, CM and Ervin, JF and Steed, E and Szymanski, M and Burke, J and Welsh-Bohmer, K},
Title = {Arteriolar ApoE expression is increased Alzheimer disease
cortex},
Journal = {Journal of Neuropathology and Experimental
Neurology},
Volume = {66},
Number = {5},
Pages = {433-433},
Publisher = {Oxford University Press (OUP)},
Year = {2007},
Month = {May},
url = {http://dx.doi.org/10.1097/01.jnen.0000268866.50903.81},
Doi = {10.1097/01.jnen.0000268866.50903.81},
Key = {fds371177}
}
@article{fds276952,
Author = {Onyike, CU and Sheppard, J-ME and Tschanz, JT and Norton, MC and Green,
RC and Steinberg, M and Welsh-Bohmer, KA and Breitner, JC and Lyketsos,
CG},
Title = {Epidemiology of apathy in older adults: the Cache County
Study.},
Journal = {Am J Geriatr Psychiatry},
Volume = {15},
Number = {5},
Pages = {365-375},
Year = {2007},
Month = {May},
ISSN = {1064-7481},
url = {http://www.ncbi.nlm.nih.gov/pubmed/17463187},
Abstract = {OBJECTIVES: The objectives of this study are to describe the
distribution of apathy in community-based older adults and
to investigate its relationships with cognition and
day-to-day functioning. METHODS: Data from the Cache County
Study on Memory, Health and Aging were used to estimate the
frequency of apathy in groups of elders defined by
demographic, cognitive, and functional status and to examine
the associations of apathy with impairments of cognition and
day-to-day functioning. RESULTS: Apathy was measured with
the Neuropsychiatric Inventory. Clinical apathy
(Neuropsychiatric Inventory score > or = 4) was found in
1.4% of individuals classified as cognitively normal, 3.1%
of those with a mild cognitive syndrome, and 17.3% of those
with dementia. Apathy status was associated with cognitive
and functional impairments and higher levels of stress
experienced by caregivers. Among participants with normal
cognition, apathy was associated with worse performance on
the Mini-Mental State Examination, the Boston Naming and
Animal Fluency tests, and the Trail Making Test-Part B. The
association of apathy with cognitive impairment was
independent of its association with Neuropsychiatric
Inventory depression. CONCLUSIONS: In a cohort of
community-based older adults, the frequency and severity of
apathy is positively correlated with the severity of
cognitive impairment. In addition, apathy is associated with
cognitive and functional impairments in elders adjudged to
have normal cognition. The results suggest that apathy is an
early sign of cognitive decline and that delineating
phenotypes in which apathy and a mild cognitive syndrome
co-occur may facilitate earlier identification of
individuals at risk for dementia.},
Doi = {10.1097/01.JGP.0000235689.42910.0d},
Key = {fds276952}
}
@article{fds371178,
Author = {Hulette, CM and Ervin, JF and Steed, E and Szymanski, M and Burke, J and Welsh-Bohmer, K},
Title = {Arteriolar ApoE expression is increased Alzheimer disease
cortex.},
Journal = {FASEB JOURNAL},
Volume = {21},
Number = {5},
Pages = {A72-A72},
Publisher = {FEDERATION AMER SOC EXP BIOL},
Year = {2007},
Month = {April},
Key = {fds371178}
}
@article{fds276951,
Author = {Sugarman, J and Roter, D and Cain, C and Wallace, R and Schmechel, D and Welsh-Bohmer, KA},
Title = {Proxies and consent discussions for dementia
research.},
Journal = {J Am Geriatr Soc},
Volume = {55},
Number = {4},
Pages = {556-561},
Year = {2007},
Month = {April},
ISSN = {0002-8614},
url = {http://www.ncbi.nlm.nih.gov/pubmed/17397434},
Abstract = {OBJECTIVES: To better understand the nature of informed
consent encounters for research involving patients with
dementia that requires proxy consent. DESIGN: Audiotaping of
informed-consent encounters for a study of genetic markers
for sporadic Alzheimer's disease. SETTING: Outpatients at an
Alzheimer's disease research center. PARTICIPANTS: Patients
with dementia and their companions. MEASUREMENTS: Audiotapes
were analyzed to characterize communication style and
coverage of the standard elements of informed consent and,
using the Roter Interaction Analysis System, to capture the
dynamics of three-way interaction between the patient, their
companion, and the physician investigator. RESULTS: Of 26
informed consent encounters, all involved a patient, a
companion, and a physician. Patients had a mean Mini-Mental
State Examination (MMSE) score of 21.8. For patients, 49% of
their interactions involved agreement and approval (positive
statements), 16% psychosocial information, 7% biomedical
information, 7% asking questions, and 7% expressing emotion.
Companion interactions involved 37% positive statements and
19% biomedical information. Physician interactions involved
emotional expressiveness (30%) and positive statements
(19%). Discussion length was positively related to MMSE
score (Spearman rho=0.45; P<.02). Coverage of required
elements of informed consent was fairly comprehensive and
had no relationship to patients' MMSE scores. CONCLUSION:
These data should inform policies regarding the ethically
appropriate ways of conducting research with cognitively
impaired adults. For example, patients in this study were
more silent than their companions and the physician, but
when patients spoke, they primarily agreed with what was
said. Although this might first seem to signal assent, such
an interpretation should be made with caution for persons
with dementia. In addition, previous work on informed
consent has focused on its cognitive aspects, but these data
reveal that the emotional and social dimensions warrant
attention.},
Doi = {10.1111/j.1532-5415.2007.01101.x},
Key = {fds276951}
}
@article{fds277023,
Author = {Hulette, CM and Welsh-Bohmer, K},
Title = {Coronary artery disease is associated with Alzheimer disease
neuropathology in APOE4 carriers.},
Journal = {Neurology},
Volume = {68},
Number = {6},
Pages = {471},
Year = {2007},
Month = {February},
url = {http://www.ncbi.nlm.nih.gov/pubmed/17283328},
Doi = {10.1212/01.wnl.0000256286.78188.dd},
Key = {fds277023}
}
@article{fds276988,
Author = {Lee, JS and Potter, GG and Wagner, HR and Welsh-Bohmer, KA and Steffens,
DC},
Title = {Persistent mild cognitive impairment in geriatric
depression.},
Journal = {Int Psychogeriatr},
Volume = {19},
Number = {1},
Pages = {125-135},
Year = {2007},
Month = {February},
ISSN = {1041-6102},
url = {http://www.ncbi.nlm.nih.gov/pubmed/16834811},
Abstract = {BACKGROUND: Cognitive impairment often occurs with geriatric
depression and impairments may persist despite remission of
depression. Although clinical definitions of mild cognitive
impairment (MCI) have typically excluded depression, a
neuropsychological model of MCI in depression has utility
for identifying individuals whose cognitive impairments may
persist or progress to dementia. METHODS: At baseline and
1-year follow-up, 67 geriatric patients with depression had
a comprehensive clinical examination that included
depression assessment and neuropsychological testing. We
defined MCI by a neuropsychological algorithm and examined
the odds of MCI classification at Year 1 for remitted
depressed individuals with baseline MCI, and examined
clinical, functional and genetic factors associated with
MCI. RESULTS: Fifty-four percent of the sample had MCI at
baseline. Odds of MCI classification at Year 1 were four
times greater among patients with baseline MCI than those
without. Instrumental activities of daily living were
associated with MCI at Year 1, while age and APOE genotype
was not. CONCLUSIONS: These results confirm previous
observations that MCI is highly prevalent among older
depressed adults and that cognitive impairment occurring
during acute depression may persist after depression remits.
Self-reported decline in functional activities may be a
marker for persistent cognitive impairment, which suggests
that assessments of both neuropsychological and functional
status are important prognostic factors in the evaluation of
geriatric depression.},
Doi = {10.1017/S1041610206003607},
Key = {fds276988}
}
@article{fds277036,
Author = {Hayden, KM and Welsh-Bohmer, KA and Wengreen, HJ and Zandi, PP and Lyketsos, CG and Breitner, JCS and Cache County
Investigators},
Title = {Risk of mortality with vitamin E supplements: the Cache
County study.},
Journal = {Am J Med},
Volume = {120},
Number = {2},
Pages = {180-184},
Year = {2007},
Month = {February},
url = {http://www.ncbi.nlm.nih.gov/pubmed/17275460},
Abstract = {PURPOSE: A recent meta-analysis reported increased mortality
in clinical trial participants randomized to high-dose
vitamin E. We sought to determine whether these mortality
risks with vitamin E reflect adverse consequences of its use
in the presence of cardiovascular disease. METHODS: In a
defined population aged 65 years or older, baseline
interviews captured self- or proxy-reported history of
cardiovascular illness. A medicine cabinet inventory
verified nutritional supplement and medication use. Three
sources identified subsequent deaths. Cox proportional
hazards methods examined the association between vitamin E
use and mortality. RESULTS: After adjustment for age and
sex, there was no association in this population between
vitamin E use and mortality (adjusted hazard ratio [aHR]
0.93; 95% confidence interval [CI], 0.74-1.15). Predictably,
deaths were more frequent with a history of diabetes,
stroke, coronary artery bypass graft surgery, or myocardial
infarction, and with the use of warfarin, nitrates, or
diuretics. None of these conditions or treatments altered
the null main effect with vitamin E, but mortality was
increased in vitamin E users who had a history of stroke
(aHR 3.64; CI, 1.73-7.68), coronary bypass graft surgery
(aHR 4.40; CI, 2.83-6.83), or myocardial infarction (aHR
1.95; CI, 1.29-2.95) and, independently, in those taking
nitrates (aHR 3.95; CI, 2.04-7.65), warfarin (aHR 3.71; CI,
2.22-6.21), or diuretics (aHR 1.83; CI, 1.35-2.49). Although
not definitive, a consistent trend toward reduced mortality
was seen in vitamin E users without these conditions or
treatments. CONCLUSIONS: In this population-based study,
vitamin E use was unrelated to mortality, but this
apparently null finding seems to represent a combination of
increased mortality in those with severe cardiovascular
disease and a possible protective effect in those
without.},
Doi = {10.1016/j.amjmed.2006.03.039},
Key = {fds277036}
}
@article{fds277022,
Author = {Trembath, D and Ervin, JF and Broom, L and Szymanski, M and Welsh-Bohmer, K and Pieper, C and Hulette, CM},
Title = {The distribution of cerebrovascular amyloid in Alzheimer's
disease varies with ApoE genotype.},
Journal = {Acta Neuropathol},
Volume = {113},
Number = {1},
Pages = {23-31},
Year = {2007},
Month = {January},
ISSN = {0001-6322},
url = {http://www.ncbi.nlm.nih.gov/pubmed/17089130},
Abstract = {We performed a comparative study to assess cerebral amyloid
angiopathy and ApoE genotype in cases of Alzheimer's disease
(AD). Ten ApoE 3,3 and ten ApoE 4,4 AD brains, as well as
ten normal control brains, were selected after matching for
age, sex, and duration of disease. Sections of middle
frontal and inferior parietal cortex including white matter
sections were stained with an antibody against amyloid beta
(Abeta), and extensive analysis of arteriolar Abeta
deposition was performed using digital image analysis.
Quantification of the staining revealed a larger
cross-section of arteriolar walls occupied by Abeta in ApoE
4,4 and ApoE 3,3 AD subjects compared to controls. Our
results show Abeta deposition in gray matter and white
matter arterioles was predominantly found in ApoE 4,4 brains
and, overall, Abeta deposition was greatest in these cases.
This observation implies that there is greater vascular
amyloid deposition (particularly in the white matter
arterioles) in ApoE 4,4 AD individuals compared to ApoE 3,3
AD. These observations may give insight into the etiology
behind the increased risk for AD associated with the
ApoE-epsilon4 allele and the pathogenesis of vascular Abeta
deposition.},
Doi = {10.1007/s00401-006-0162-9},
Key = {fds277022}
}
@article{fds276953,
Author = {Beekly, DL and Ramos, EM and Lee, WW and Deitrich, WD and Jacka, ME and Wu,
J and Hubbard, JL and Koepsell, TD and Morris, JC and Kukull, WA and NIA
Alzheimer's Disease Centers},
Title = {The National Alzheimer's Coordinating Center (NACC)
database: the Uniform Data Set.},
Journal = {Alzheimer Dis Assoc Disord},
Volume = {21},
Number = {3},
Pages = {249-258},
Year = {2007},
ISSN = {0893-0341},
url = {http://dx.doi.org/10.1097/WAD.0b013e318142774e},
Abstract = {The National Alzheimer's Coordinating Center (NACC) is
responsible for developing and maintaining a database of
participant information collected from the 29 Alzheimer's
Disease Centers (ADCs) funded by the National Institute on
Aging (NIA). The NIA appointed the ADC Clinical Task Force
to determine and define an expanded, standardized clinical
data set, called the Uniform Data Set (UDS). The goal of the
UDS is to provide ADC researchers a standard set of
assessment procedures, collected longitudinally, to better
characterize ADC participants with mild Alzheimer disease
and mild cognitive impairment in comparison with nondemented
controls. NACC implemented the UDS (September 2005) by
developing data collection forms for initial and follow-up
visits based on Clinical Task Force definitions, a
relational database, and a data submission system accessible
by all ADCs. The NIA requires ADCs to submit UDS data to
NACC for all their Clinical Core participants. Thus, the
NACC web site (https://www.alz.washington.edu) was enhanced
to provide efficient and secure access data submission and
retrieval systems.},
Doi = {10.1097/WAD.0b013e318142774e},
Key = {fds276953}
}
@article{fds277038,
Author = {Wengreen, HJ and Munger, RG and Corcoran, CD and Zandi, P and Hayden,
KM and Fotuhi, M and Skoog, I and Norton, MC and Tschanz, J and Breitner,
JCS and Welsh-Bohmer, KA},
Title = {Antioxidant intake and cognitive function of elderly men and
women: the Cache County Study.},
Journal = {J Nutr Health Aging},
Volume = {11},
Number = {3},
Pages = {230-237},
Year = {2007},
ISSN = {1279-7707},
url = {http://www.ncbi.nlm.nih.gov/pubmed/17508099},
Abstract = {OBJECTIVE: We prospectively examined associations between
intakes of antioxidants (vitamins C, vitamin E, and
carotene) and cognitive function and decline among elderly
men and women of the Cache County Study on Memory and Aging
in Utah. PARTICIPANTS AND DESIGN: In 1995, 3831 residents 65
years of age or older completed a baseline survey that
included a food frequency questionnaire and cognitive
assessment. Cognitive function was assessed using an adapted
version of the Modified Mini-Mental State examination (3MS)
at baseline and at three subsequent follow-up interviews
spanning approximately 7 years. Multivariable-mixed models
were used to estimate antioxidant nutrient effects on
average 3MS score over time. RESULTS: Increasing quartiles
of vitamin C intake alone and combined with vitamin E were
associated with higher baseline average 3MS scores (p-trend
= 0.013 and 0.02 respectively); this association appeared
stronger for food sources compared to supplement or food and
supplement sources combined. Study participants with lower
levels of intake of vitamin C, vitamin E and carotene had a
greater acceleration of the rate of 3MS decline over time
compared to those with higher levels of intake. CONCLUSION:
High antioxidant intake from food and supplement sources of
vitamin C, vitamin E, and carotene may delay cognitive
decline in the elderly.},
Key = {fds277038}
}
@article{fds277083,
Author = {Heinzen, EL and Yoon, W and Weale, ME and Sen, A and Wood, NW and Burke,
JR and Welsh-Bohmer, KA and Hulette, CM and Sisodiya, SM and Goldstein,
DB},
Title = {Alternative ion channel splicing in mesial temporal lobe
epilepsy and Alzheimer's disease.},
Journal = {Genome Biol},
Volume = {8},
Number = {3},
Pages = {R32},
Year = {2007},
url = {http://www.ncbi.nlm.nih.gov/pubmed/17343748},
Abstract = {BACKGROUND: Alternative gene transcript splicing permits a
single gene to produce multiple proteins with varied
functions. Bioinformatic investigations have identified
numerous splice variants, but whether these transcripts are
translated to functional proteins and the physiological
significance of these alternative proteins are largely
unknown. Through direct identification of splice variants
associated with disease states, we can begin to address
these questions and to elucidate their roles in disease
predisposition and pathophysiology. This work specifically
sought to identify disease-associated alternative splicing
patterns in ion channel genes by comprehensively screening
affected brain tissue collected from patients with mesial
temporal lobe epilepsy and Alzheimer's disease. New
technology permitting the screening of alternative splice
variants in microarray format was employed. Real time
quantitative PCR was used to verify observed splice variant
patterns. RESULTS: This work shows for the first time that
two common neurological conditions are associated with
extensive changes in gene splicing, with 25% and 12% of the
genes considered having significant changes in splicing
patterns associated with mesial temporal lobe epilepsy and
Alzheimer's disease, respectively. Furthermore, these
changes were found to exhibit unique and consistent patterns
within the disease groups. CONCLUSION: This work has
identified a set of disease-associated, alternatively
spliced gene products that represent high priorities for
detailed functional investigations into how these changes
impact the pathophysiology of mesial temporal lobe epilepsy
and Alzheimer's disease.},
Doi = {10.1186/gb-2007-8-3-r32},
Key = {fds277083}
}
@article{fds371179,
Author = {Khachaturian, AS and Zandi, PP and Lyketsos, CG and Hayden, KM and Skoog, I and Norton, MC and Tschanz, JT and Mayer, L and Welsh-Bohmer,
KA and Breitner, JC},
Title = {Antihypertensive medication use and incident Alzheimer
disease: The cache county study},
Journal = {NEUROPSYCHOPHARMACOLOGY},
Volume = {31},
Pages = {S39-S39},
Publisher = {NATURE PUBLISHING GROUP},
Year = {2006},
Month = {December},
Key = {fds371179}
}
@article{fds277082,
Author = {Plassman, BL and Steffens, DC and Burke, JR and Welsh-Bohmer, KA and Newman, TN and Drosdick, D and Helms, MJ and Potter, GG and Breitner,
JCS},
Title = {Duke Twins Study of Memory in Aging in the NAS-NRC Twin
Registry.},
Journal = {Twin Res Hum Genet},
Volume = {9},
Number = {6},
Pages = {950-957},
Year = {2006},
Month = {December},
ISSN = {1832-4274},
url = {http://www.ncbi.nlm.nih.gov/pubmed/17254435},
Abstract = {The Duke Twins Study of Memory in Aging is an ongoing,
longitudinal study of cognitive change and dementia in the
population-based National Academy of Sciences-National
Research Council (NAS-NRC) Twin Registry of World War II
Male Veterans. The primary goal of this study has been to
estimate the overall genetic and environmental contributions
to dementia with a specific focus on Alzheimer's disease. An
additional goal has been to examine specific genetic and
environmental antecedents of cognitive decline and dementia.
Since 1989, we have completed 4 waves of data collection.
Each wave included a 2-phase telephone cognitive screening
protocol, followed by an in-home standardized clinical
assessment for those with suspected dementia. For many
participants, we have obtained postmortem neuropathological
confirmation of the diagnosis of dementia. In addition to
data on cognition, we have also collected information on
occupational history, medical history, medications and other
lifetime experiences that may influence cognitive function
in late life. We provide an overview of the study's
methodology and describe the focus of recent
research.},
Doi = {10.1375/183242706779462381},
Key = {fds277082}
}
@article{fds371180,
Author = {Ervin, JF and Heinzen, EL and Goldstein, D and Szymanski, MH and Burke,
JR and Welsh-Bohmer, KA and Hulette, CM},
Title = {Human brain tissue may be retrieved up to 30 hours
post-mortem with little effect on RNA or protein
integrity},
Journal = {BRAIN PATHOLOGY},
Volume = {16},
Pages = {S125-S125},
Publisher = {BLACKWELL PUBLISHING},
Year = {2006},
Month = {September},
Key = {fds371180}
}
@article{fds276978,
Author = {Steinberg, M and Corcoran, C and Tschanz, JT and Huber, C and Welsh-Bohmer, K and Norton, MC and Zandi, P and Breitner, JCS and Steffens, DC and Lyketsos, CG},
Title = {Risk factors for neuropsychiatric symptoms in dementia: the
Cache County Study.},
Journal = {Int J Geriatr Psychiatry},
Volume = {21},
Number = {9},
Pages = {824-830},
Year = {2006},
Month = {September},
ISSN = {0885-6230},
url = {http://dx.doi.org/10.1002/gps.1567},
Abstract = {OBJECTIVE: To investigate the probability of individual
neuropsychiatric symptoms in dementia patients as a function
of eight risk factors. METHODS: In the Cache County Study,
we administered the Neuropsychiatric Inventory (NPI) to 328
dementia patients at baseline. Approximately 18 months
later, we re-administered the NPI to 184 participants
available for follow-up. Generalized estimating equation
methods were used to model the probability of individual
neuropsychiatric symptoms as a function of: gender, age,
education, dementia type and severity, APOE status, time of
observation, and general medical health. RESULTS: Women
showed increased tendency toward anxiety, [odds ratio (OR)
2.22, 95% confidence interval (CI) 1.31-3.76] and delusions
(OR 2.15, CI 1.22-3.78), but older persons of both sexes
showed less tendency toward anxiety. Dementia severity
increased the tendency toward hallucinations and agitation
(OR 2.42, CI 1.81-3.23) and decreased risk of depression.
Positive APOE epsilon4 status increased the tendency toward
aberrant motor behavior (OR 1.84, CI 1.05-3.22). Among
dementia diagnoses, those with Alzheimer's disease showed
decreased tendency toward agitation (OR 0.58, CI 0.35-0.95),
depression (OR 0.56, CI 0.33-0.96) and disinhibition (OR
0.46, CI 0.24-0.88). Later time of observation increased
risk of aberrant motor behavior and delusions, and more
serious medical comorbidity increased risk of, agitation,
irritability, disinhibition, and aberrant motor behavior.
CONCLUSIONS: Gender, age, dementia severity, APOE epsilon4,
dementia diagnosis, time of observation, and general medical
health appear to influence the occurrence of individual
neuropsychiatric symptoms.},
Doi = {10.1002/gps.1567},
Key = {fds276978}
}
@article{fds277111,
Author = {Newman, MF and Mathew, JP and Grocott, HP and Mackensen, GB and Monk, T and Welsh-Bohmer, KA and Blumenthal, JA and Laskowitz, DT and Mark,
DB},
Title = {Central nervous system injury associated with cardiac
surgery.},
Journal = {Lancet},
Volume = {368},
Number = {9536},
Pages = {694-703},
Year = {2006},
Month = {August},
url = {http://www.ncbi.nlm.nih.gov/pubmed/16920475},
Abstract = {Millions of individuals with coronary artery or valvular
heart disease have been given a new chance at life by heart
surgery, but the potential for neurological injury is an
Achilles heel. Technological advancements and innovations in
surgical and anaesthetic technique have allowed us to offer
surgical treatment to patients at the extremes of age and
infirmity-the group at greatest risk for neurological
injury. Neurocognitive dysfunction is a complication of
cardiac surgery that can restrict the improved quality of
life that patients usually experience after heart surgery.
With a broader understanding of the frequency and effects of
neurological injury from cardiac surgery and its
implications for patients in both the short term and the
long term, we should be able to give personalised treatments
and thus preserve both their quantity and quality of life.
We describe these issues and the controversies that merit
continued investigation.},
Doi = {10.1016/S0140-6736(06)69254-4},
Key = {fds277111}
}
@article{fds277067,
Author = {Li, Y-J and Scott, WK and Zhang, L and Lin, P-I and Oliveira, SA and Skelly, T and Doraiswamy, MP and Welsh-Bohmer, KA and Martin, ER and Haines, JL and Pericak-Vance, MA and Vance, JM},
Title = {Revealing the role of glutathione S-transferase omega in
age-at-onset of Alzheimer and Parkinson diseases.},
Journal = {Neurobiol Aging},
Volume = {27},
Number = {8},
Pages = {1087-1093},
Year = {2006},
Month = {August},
url = {http://www.ncbi.nlm.nih.gov/pubmed/15985314},
Abstract = {We previously reported a linkage region on chromosome 10q
for age-at-onset (AAO) of Alzheimer (AD) and Parkinson (PD)
diseases. Glutathione S-transferase, omega-1 (GSTO1) and the
adjacent gene GSTO2, located in this linkage region, were
then reported to associate with AAO of AD and PD. To examine
whether GSTO1 and GSTO2 (hereafter referred to as GSTO1h)
are responsible for the linkage evidence, we identified 39
families in AD that lead to our previous linkage and
association findings. The evidence of linkage and
association was markedly diminished after removing these 39
families from the analyses, thus providing support that
GSTO1h drives the original linkage results. The maximum
average AAO delayed by GSTO1h SNP 7-1 (rs4825, A nucleotide)
was 6.8 (+/-4.41) years for AD and 8.6(+/-5.71) for PD,
respectively. This is comparable to the magnitude of AAO
difference by APOE-4 in these same AD and PD families. These
findings suggest the presence of genetic heterogeneity for
GSTO1h's effect on AAO, and support GSTO1h's role in
modifying AAO in these two disorders.},
Doi = {10.1016/j.neurobiolaging.2005.05.013},
Key = {fds277067}
}
@article{fds277035,
Author = {Tschanz, JT and Welsh-Bohmer, KA and Lyketsos, CG and Corcoran, C and Green, RC and Hayden, K and Norton, MC and Zandi, PP and Toone, L and West,
NA and Breitner, JCS and Cache County Investigators},
Title = {Conversion to dementia from mild cognitive disorder: the
Cache County Study.},
Journal = {Neurology},
Volume = {67},
Number = {2},
Pages = {229-234},
Year = {2006},
Month = {July},
url = {http://www.ncbi.nlm.nih.gov/pubmed/16864813},
Abstract = {OBJECTIVE: To examine 3-year rates of conversion to
dementia, and risk factors for such conversion, in a
population-based sample with diverse types of cognitive
impairment. METHODS: All elderly (aged 65 or older)
residents of Cache County, UT, were invited to undergo two
waves of dementia screening and assessment. Three-year
follow-up data were available for 120 participants who had
some form of mild cognitive impairment at baseline. Of
these, 51 had been classified at baseline with prodromal
Alzheimer disease (proAD), and 69 with other cognitive
syndromes (CS). RESULTS: Three-year rates of conversion to
dementia were 46% among those with cognitive impairment at
baseline. By comparison, 3.3% without impairment converted
to dementia in the interval. Among converters, AD was the
most common type of dementia. In individuals with at least
one APOE epsilon4 allele, those with proAD or CS exhibited a
22- to 25-fold higher risk of dementia than cognitively
unimpaired individuals (vs 5- to 10-fold higher risk in
those without epsilon4). CONCLUSIONS: Individuals with all
types of mild cognitive impairment have an elevated risk of
dementia over 3 years, more so in those with an APOE
epsilon4 allele. These results suggest value in dementia
surveillance for broad groups of cognitively impaired
individuals beyond any specific category, and utility of
APOE genotyping as a prognostic method.},
Doi = {10.1212/01.wnl.0000224748.48011.84},
Key = {fds277035}
}
@article{fds276950,
Author = {Lin, PI and Martin, ER and Bronson, PG and Browning-Large, C and Small,
GW and Schmechel, DE and Welsh-Bohmer, KA and Haines, JL and Gilbert,
JR and Pericak-Vance, MA},
Title = {Exploring the association of glyceraldehyde-3-phosphate
dehydrogenase gene and Alzheimer disease.},
Journal = {Neurology},
Volume = {67},
Number = {1},
Pages = {64-68},
Year = {2006},
Month = {July},
url = {http://www.ncbi.nlm.nih.gov/pubmed/16832079},
Abstract = {BACKGROUND: Previous linkage studies have shown that
chromosome 12 harbors susceptibility genes for late-onset
Alzheimer disease (LOAD). However, association studies of
several candidate genes on this chromosome region have
produced ambiguous results. A recent study reported the
association between the glyceraldehyde-3-phosphate
dehydrogenase (GAPD) gene on chromosome 12p and the risk of
LOAD. METHODS: The authors conducted family-based and
case-control association studies in two independent LOAD
data sets on 12 single-nucleotide polymorphisms (SNPs) in
the GAPD gene and its paralogs. RESULTS: No association was
found of the GAPD gene with LOAD in the family-based data
set, but marginal evidence of association was seen in the
later-onset subgroup when age at onset was stratified. The
SNP rs2029721 in one GAPD pseudogene was also found to be
associated with risk for LOAD in the unrelated case-control
data set (p = 0.003). CONCLUSIONS: The GAPD gene and its
pseudogene may play a role in the development of late-onset
Alzheimer disease. However, the effect, if any, is likely to
be limited.},
Doi = {10.1212/01.wnl.0000223438.90113.4e},
Key = {fds276950}
}
@article{fds277034,
Author = {Welsh-Bohmer, KA and Breitner, JCS and Hayden, KM and Lyketsos, C and Zandi, PP and Tschanz, JT and Norton, MC and Munger,
R},
Title = {Modifying dementia risk and trajectories of cognitive
decline in aging: the Cache County Memory
Study.},
Journal = {Alzheimers Dement},
Volume = {2},
Number = {3},
Pages = {257-260},
Year = {2006},
Month = {July},
url = {http://www.ncbi.nlm.nih.gov/pubmed/19595895},
Abstract = {The Cache County Study of Memory, Health, and Aging, more
commonly referred to as the "Cache County Memory Study
(CCMS)" is a longitudinal investigation of aging and
Alzheimer's disease (AD) based in an exceptionally
long-lived population residing in northern Utah. The study
begun in 1994 has followed an initial cohort of 5,092 older
individuals (many over age 84) and has examined the
development of cognitive impairment and dementia in relation
to genetic and environmental antecedents. This article
summarizes the major contributions of the CCMS towards the
understanding of mild cognitive disorders and AD across the
lifespan, underscoring the role of common health exposures
in modifying dementia risk and trajectories of cognitive
change. The study now in its fourth wave of ascertainment
illustrates the role of population-based approaches in
informing testable models of cognitive aging and Alzheimer's
disease.},
Doi = {10.1016/j.jalz.2006.04.011},
Key = {fds277034}
}
@article{fds277065,
Author = {Sheline, YI and Barch, DM and Garcia, K and Gersing, K and Pieper, C and Welsh-Bohmer, K and Steffens, DC and Doraiswamy,
PM},
Title = {Cognitive function in late life depression: relationships to
depression severity, cerebrovascular risk factors and
processing speed.},
Journal = {Biol Psychiatry},
Volume = {60},
Number = {1},
Pages = {58-65},
Year = {2006},
Month = {July},
ISSN = {0006-3223},
url = {http://www.ncbi.nlm.nih.gov/pubmed/16414031},
Abstract = {BACKGROUND: A number of studies have examined clinical
factors linked to worse neuropsychological performance in
late life depression (LLD). To understand the influence of
LLD on cognition, it is important to determine if deficits
in a number of cognitive domains are relatively independent,
or mediated by depression- related deficits in a basic
domain such as processing speed. METHODS: Patients who met
DSM-IV criteria for major depression (n = 155) were
administered a comprehensive neuropsychological battery of
tasks grouped into episodic memory, language, working
memory, executive function, and processing speed domains.
Multiple regression analyses were conducted to determine
contributions of predictor variables to cognitive domains.
RESULTS: Age, depression severity, education, race and
vascular risk factors all made significant and independent
contributions to one or more domains of cognitive function,
with all five making independent contributions to processing
speed. Age of onset made no independent contribution, after
accounting for age and vascular risk factors. Of the five
cognitive domains investigated, changes in processing speed
were found to most fully mediate the influence of predictor
variables on all other cognitive domains. CONCLUSIONS: While
slowed processing speed appears to be the most core
cognitive deficit in LLD, it was closely followed by
executive function as a core cognitive deficit. Future
research is needed to help clarify mechanisms leading to
LLD- related changes in processing speed, including the
potential role of white matter abnormalities.},
Doi = {10.1016/j.biopsych.2005.09.019},
Key = {fds277065}
}
@article{fds277066,
Author = {Lin, P-I and Martin, ER and Browning-Large, CA and Schmechel, DE and Welsh-Bohmer, KA and Doraiswamy, PM and Gilbert, JR and Haines, JL and Pericak-Vance, MA},
Title = {Parsing the genetic heterogeneity of chromosome 12q
susceptibility genes for Alzheimer disease by family-based
association analysis.},
Journal = {Neurogenetics},
Volume = {7},
Number = {3},
Pages = {157-165},
Year = {2006},
Month = {July},
ISSN = {1364-6745},
url = {http://www.ncbi.nlm.nih.gov/pubmed/16770605},
Abstract = {Previous linkage studies have suggested that chromosome 12
may harbor susceptibility genes for late-onset Alzheimer
disease (LOAD). No risk genes on chromosome 12 have been
conclusively identified yet. We have reported that the
linkage evidence for LOAD in a 12q region was significantly
increased in autopsy-confirmed families particularly for
those showing no linkage to alpha-T catenin gene, a LOAD
candidate gene on chromosome 10 [LOD score increased from
0.1 in the autopsy-confirmed subset to 4.19 in the unlinked
subset (optimal subset); p<0.0001 for the increase in LOD
score], indicating a one-LOD support interval spanning 6 Mb.
To further investigate this finding and to identify
potential candidate LOAD risk genes for follow-up analysis,
we analyzed 99 single nucleotide polymorphisms in this
region, for the overall sample, the autopsy-confirmed
subset, and the optimal subset, respectively, for
comparison. We saw no significant association (p<0.01) in
the overall sample. In the autopsy-confirmed subset, the
best finding was obtained in the activation transcription
factor 7 (ATF7) gene (single-locus association, p=0.002;
haplotype association global, p=0.007). In the optimal
subset, the best finding was obtained in the hypothetical
protein FLJ20436 (FLJ20436) gene (single-locus association,
p=0.0026). These results suggest that subset and covariate
analyses may be one approach to help identify novel
susceptibility genes on chromosome 12q for
LOAD.},
Doi = {10.1007/s10048-006-0047-z},
Key = {fds277066}
}
@article{fds277099,
Author = {Akomolafe, A and Lunetta, KL and Erlich, PM and Cupples, LA and Baldwin,
CT and Huyck, M and Green, RC and Farrer, LA and MIRAGE Study
Group},
Title = {Genetic association between endothelial nitric oxide
synthase and Alzheimer disease.},
Journal = {Clin Genet},
Volume = {70},
Number = {1},
Pages = {49-56},
Year = {2006},
Month = {July},
ISSN = {0009-9163},
url = {http://dx.doi.org/10.1111/j.1399-0004.2006.00638.x},
Abstract = {Evidence suggests that vascular and inflammatory factors may
be important in the etiology of Alzheimer disease (AD). The
Glu/Glu genotype at the Glu298Asp variant of the endothelial
nitric oxide synthase (NOS3) gene has been tested for
association with AD in several Caucasian and Asian
populations, with conflicting results. We tested the
Glu298Asp variant for association in African American and
Caucasian AD patients, unaffected siblings, and unrelated
controls from the MIRAGE Study. To explore whether the
inconsistent results in previous studies might be due to
linkage disequilibrium with a polymorphism or haplotype not
previously tested, we genotyped 10 additional NOS3 single
nucleotide polymorphisms (SNPs) spanning 25.3 kb. Finally,
we compiled results of previous studies of Glu298Asp using
meta-analysis, to determine whether the aggregate studies
support an association between Glu298Asp and AD. We found
that the Glu298 allele was associated with higher risk of AD
in the MIRAGE African American (p = 0.002) but not Caucasian
(p = 0.9) groups. None of the additional SNPs were
associated with AD in the Caucasians, whereas two showed
evidence for association in the African Americans. The
meta-analysis showed a small effect of the Glu298Asp GG
genotype on AD risk across all studies (summary odds ratio =
1.15, 95% confidence interval: 0.97-1.35) and significant
heterogeneity of this association among studies (p =
0.02).},
Doi = {10.1111/j.1399-0004.2006.00638.x},
Key = {fds277099}
}
@article{fds277011,
Author = {Lyketsos, CG and Toone, L and Tschanz, J and Corcoran, C and Norton, M and Zandi, P and Munger, R and Breitner, JCS and Welsh-Bohmer, K and Cache
County Study Group},
Title = {A population-based study of the association between coronary
artery bypass graft surgery (CABG) and cognitive decline:
the Cache County study.},
Journal = {Int J Geriatr Psychiatry},
Volume = {21},
Number = {6},
Pages = {509-518},
Year = {2006},
Month = {June},
ISSN = {0885-6230},
url = {http://dx.doi.org/10.1002/gps.1502},
Abstract = {BACKGROUND: The relationship between coronary artery bypass
graft (CABG) surgery and cognitive decline remains
uncertain, in particular with regard to whether there is
delayed cognitive decline associated with this procedure.
METHODS: This was a population-based cohort study involving
participants in the Cache County Study of Memory Health and
Aging. At baseline the study enrolled 5,092 persons age 65
and older and followed them up three years later and again
four years after that. Individuals who reported having
undergone CABG surgery at study baseline or had this surgery
in between follow-up waves were compared to individuals who
never reported having the surgery. The main outcome measure
was the Modified Mini Mental State (3MS). Multilevel models
were used to examine the relationship between CABG surgery
and cognitive decline over time. RESULTS: Study participants
who had CABG surgery evidenced 0.95 points of greater
decline relative to baseline on the 3MS at the first
follow-up interview after CABG, and an average of 1.9 points
of greater decline at the second follow-up interview, than
those without CABG (t = -2.51, df = 2,316, p = 0.0121),
after adjusting for several covariates, including number of
vascular conditions. This decline was restricted to
individuals who were more than five years past the procedure
and was not evident in the early years after the surgery.
CONCLUSIONS: CABG surgery is associated with accelerated
cognitive decline more than five years after the procedure
in a long-lived population. This decline is small and its
clinical significance is uncertain. We could not find an
association between CABG and decline in the first five
post-operative years.},
Doi = {10.1002/gps.1502},
Key = {fds277011}
}
@article{fds276977,
Author = {Norton, MC and Skoog, I and Franklin, LM and Corcoran, C and Tschanz,
JT and Zandi, PP and Breitner, JCS and Welsh-Bohmer, KA and Steffens,
DC and Cache County Investigators},
Title = {Gender differences in the association between religious
involvement and depression: the Cache County (Utah)
study.},
Journal = {J Gerontol B Psychol Sci Soc Sci},
Volume = {61},
Number = {3},
Pages = {P129-P136},
Year = {2006},
Month = {May},
ISSN = {1079-5014},
url = {http://www.ncbi.nlm.nih.gov/pubmed/16670181},
Abstract = {We examined the relation between religious involvement,
membership in the Church of Jesus Christ of Latter-Day
Saints, and major depression in a population-based study of
aging and dementia in Cache County, Utah. Participants
included 4,468 nondemented individuals between the ages of
65 and 100 years who were interviewed in person. In logistic
regression models adjusting for demographic and health
variables, frequent church attendance was associated with a
reduced prevalence of depression in women but increased
prevalence in men. Social role loss and the potential impact
of organizational power differential by sex are discussed.
Though causality cannot be determined here, these findings
suggest that the association between religious involvement
and depression may differ substantially between men and
women.},
Doi = {10.1093/geronb/61.3.p129},
Key = {fds276977}
}
@article{fds277033,
Author = {Khachaturian, AS and Zandi, PP and Lyketsos, CG and Hayden, KM and Skoog, I and Norton, MC and Tschanz, JT and Mayer, LS and Welsh-Bohmer,
KA and Breitner, JCS},
Title = {Antihypertensive medication use and incident Alzheimer
disease: the Cache County Study.},
Journal = {Arch Neurol},
Volume = {63},
Number = {5},
Pages = {686-692},
Year = {2006},
Month = {May},
ISSN = {0003-9942},
url = {http://www.ncbi.nlm.nih.gov/pubmed/16533956},
Abstract = {BACKGROUND: Recent reports suggest that antihypertensive
(AH) medications may reduce the risk of dementing illnesses.
OBJECTIVES: To examine the relationship of AH medication use
with incidence of Alzheimer disease (AD) among the elderly
population (aged 65 years and older) of Cache County, Utah,
and to examine whether the relationship varies with
different classes of AH medications. METHODS: After an
initial (wave 1) multistage assessment (1995 through 1997)
to identify prevalent cases of dementia, we used similar
methods 3 years later (wave 2) to identify 104 incident
cases of AD among the 3308 survivors. At the baseline
assessment, we obtained a detailed drug inventory from the
study participants. We carried out discrete time survival
analyses to examine the association between the use of AH
medications (including angiotensin converting enzyme
inhibitors, beta-blockers, calcium channel blockers, and
diuretics) at baseline with subsequent risk of AD. RESULTS:
Use of any AH medication at baseline was associated with
lower incidence of AD (adjusted hazard ratio, 0.64; 95%
confidence interval, 0.41-0.98). Examination of medication
subclasses showed that use of diuretics (adjusted hazard
ratio, 0.57; 95% confidence interval, 0.33-0.94), and
specifically potassium-sparing diuretics (adjusted hazard
ratio, 0.26; 95% confidence interval, 0.08-0.64), was
associated with the greatest reduction in risk of AD.
Corresponding analysis with a fully examined subsample
controlling for blood pressure measurements did not
substantially change our findings. CONCLUSIONS: These data
suggest that AH medications, and specifically
potassium-sparing diuretics, are associated with reduced
incidence of AD. Because the latter association is a new
finding, it requires confirmation in further
study.},
Doi = {10.1001/archneur.63.5.noc60013},
Key = {fds277033}
}
@article{fds277064,
Author = {Slifer, MA and Martin, ER and Bronson, PG and Browning-Large, C and Doraiswamy, PM and Welsh-Bohmer, KA and Gilbert, JR and Haines, JL and Pericak-Vance, MA},
Title = {Lack of association between UBQLN1 and Alzheimer
disease.},
Journal = {Am J Med Genet B Neuropsychiatr Genet},
Volume = {141B},
Number = {3},
Pages = {208-213},
Year = {2006},
Month = {April},
ISSN = {1552-4841},
url = {http://www.ncbi.nlm.nih.gov/pubmed/16526030},
Abstract = {Alzheimer disease (AD) is heterogeneous and complex with a
strong genetic diathesis. It is the most common cause of
dementia affecting the elderly. Linkage studies [Kehoe et
al., 1999; Hum Mol Genet 8: 237-245]; [Pericak-Vance et al.,
2000; Exp Gerontol 35: 1343-1352]; [Myers et al., 2002; Am J
Med Genet 114: 235-244]; [Blacker et al., 2003; Hum Mol
Genet 12: 23-32] identified chromosome 9q as a region
containing a possible AD candidate gene. Functional protein
studies [Mah et al., 2000; J Cell Biol 151: 847-862]; [Ko et
al., 2002; J Biol Chem 277: 35386-35392] identified the
UBQLN1 gene on chromosome 9q that encodes ubiquilin as a
likely candidate for a role in late-onset AD pathogenesis. A
recent family-based study by [Bertram et al., 2005; N Engl J
352: 884-894] reported genetic association and expression
evidence for a putative AD risk allele of an intronic single
nucleotide polymorphism (SNP) within the UBQLN1 gene. In
this study, we comprehensively assessed whether any of seven
polymorphisms located across the UBQLN1 gene are associated
with AD in another large family-based data set and an
independent case-control data set. We found no significant
association of AD risk with any of the seven SNPs genotyped
(including those SNPs previously reported by Bertram et al.)
in either the family-based or case-control data set.
Age-specific analyses and analyses conditional on
Apolipoprotein E (ApoE) genotype and sex also revealed no
significant associations to AD risk in either data set.
Using age at onset (AAO) as a quantitative trait revealed a
modest age modifying association; however, the results were
inconsistent between the data sets. Our results suggest that
UBQLN1 variants do not increase risk for AD in these
data.},
Doi = {10.1002/ajmg.b.30298},
Key = {fds277064}
}
@article{fds371181,
Author = {Fotuhi, M and Zandi, PP and Hayden, KM and Khachaturian, AS and Wengreen, H and Munger, R and Norton, MC and Tschanz, JT and Lyketsos,
CG and Breitner, JCS and Welsh-Bohmer, KA},
Title = {Better cognitive performance in elderly taking vitamins E
and C in combination with NSAIDs: The Cache County
study},
Journal = {NEUROLOGY},
Volume = {66},
Number = {5},
Pages = {A217-A217},
Publisher = {LIPPINCOTT WILLIAMS & WILKINS},
Year = {2006},
Month = {March},
Key = {fds371181}
}
@article{fds276949,
Author = {Hahs, DW and McCauley, JL and Crunk, AE and McFarland, LL and Gaskell,
PC and Jiang, L and Slifer, SH and Vance, JM and Scott, WK and Welsh-Bohmer, KA and Johnson, SR and Jackson, CE and Pericak-Vance,
MA and Haines, JL},
Title = {A genome-wide linkage analysis of dementia in the
Amish.},
Journal = {Am J Med Genet B Neuropsychiatr Genet},
Volume = {141B},
Number = {2},
Pages = {160-166},
Year = {2006},
Month = {March},
ISSN = {1552-4841},
url = {http://www.ncbi.nlm.nih.gov/pubmed/16389594},
Abstract = {Susceptibility genes for Alzheimer's disease are proving to
be highly challenging to detect and verify. Population
heterogeneity may be a significant confounding factor
contributing to this difficulty. To increase the power for
disease susceptibility gene detection, we conducted a
genome-wide genetic linkage screen using individuals from
the relatively isolated, genetically homogeneous, Amish
population. Our genome linkage analysis used a
407-microsatellite-marker map (average density 7 cM) to
search for autosomal genes linked to dementia in five Amish
families from four Midwestern U.S. counties. Our highest
two-point lod score (3.01) was observed at marker D4S1548 on
chromosome 4q31. Five other regions (10q22, 3q28, 11p13,
4q28, 19p13) also demonstrated suggestive linkage with
markers having two-point lod scores >2.0. While two of these
regions are novel (4q31 and 11p13), the other regions lie
close to regions identified in previous genome scans in
other populations. Our results identify regions of the
genome that may harbor genes involved in a subset of
dementia patients, in particular the North American Amish
community.},
Doi = {10.1002/ajmg.b.30257},
Key = {fds276949}
}
@article{fds276948,
Author = {McCauley, JL and Hahs, DW and Jiang, L and Scott, WK and Welsh-Bohmer,
KA and Jackson, CE and Vance, JM and Pericak-Vance, MA and Haines,
JL},
Title = {Combinatorial Mismatch Scan (CMS) for loci associated with
dementia in the Amish.},
Journal = {BMC Med Genet},
Volume = {7},
Pages = {19},
Year = {2006},
Month = {March},
url = {http://www.ncbi.nlm.nih.gov/pubmed/16515697},
Abstract = {BACKGROUND: Population heterogeneity may be a significant
confounding factor hampering detection and verification of
late onset Alzheimer's disease (LOAD) susceptibility genes.
The Amish communities located in Indiana and Ohio are
relatively isolated populations that may have increased
power to detect disease susceptibility genes. METHODS: We
recently performed a genome scan of dementia in this
population that detected several potential loci. However,
analyses of these data are complicated by the highly
consanguineous nature of these Amish pedigrees. Therefore we
applied the Combinatorial Mismatch Scanning (CMS) method
that compares identity by state (IBS) (under the presumption
of identity by descent (IBD)) sharing in distantly related
individuals from such populations where standard linkage and
association analyses are difficult to implement. CMS
compares allele sharing between individuals in affected and
unaffected groups from founder populations. Comparisons
between cases and controls were done using two Fisher's
exact tests, one testing for excess in IBS allele frequency
and the other testing for excess in IBS genotype frequency
for 407 microsatellite markers. RESULTS: In all, 13 dementia
cases and 14 normal controls were identified who were not
related at least through the grandparental generation. The
examination of allele frequencies identified 24 markers (6%)
nominally (p < or = 0.05) associated with dementia; the most
interesting (empiric p < or = 0.005) markers were D3S1262,
D5S211, and D19S1165. The examination of genotype
frequencies identified 21 markers (5%) nominally (p < or =
0.05) associated with dementia; the most significant markers
were both located on chromosome 5 (D5S1480 and D5S211).
Notably, one of these markers (D5S211) demonstrated
differences (empiric p < or = 0.005) under both tests.
CONCLUSION: Our results provide the initial groundwork for
identifying genes involved in late-onset Alzheimer's disease
within the Amish community. Genes identified within this
isolated population will likely play a role in a subset of
late-onset AD cases across more general populations. Regions
highlighted by markers demonstrating suggestive allelic
and/or genotypic differences will be the focus of more
detailed examination to characterize their involvement in
dementia.},
Doi = {10.1186/1471-2350-7-19},
Key = {fds276948}
}
@article{fds276976,
Author = {Norton, MC and Skoog, I and Toone, L and Corcoran, C and Tschanz, JT and Lisota, RD and Hart, AD and Zandi, PP and Breitner, JCS and Welsh-Bohmer, KA and Steffens, DC and Cache County
Investigators},
Title = {Three-year incidence of first-onset depressive syndrome in a
population sample of older adults: the Cache County
study.},
Journal = {Am J Geriatr Psychiatry},
Volume = {14},
Number = {3},
Pages = {237-245},
Year = {2006},
Month = {March},
ISSN = {1064-7481},
url = {http://www.ncbi.nlm.nih.gov/pubmed/16505128},
Abstract = {OBJECTIVE: Estimates of incidence of late-life depression
vary greatly with few studies excluding demented cases
through in-depth evaluation and most studies failing to
control for the effect of mortality and interval treatment.
In a large population-based study, the authors examined the
effect on incidence of first-onset depressive syndrome to
determine whether any gender or age differences in incidence
are attenuated with inclusion of these additional measures.
METHOD: Incidence rates of depressive syndrome per 1,000
person-years are presented for 2,877 nondemented elderly
(ages 65 to 100 years) residents of Cache County, Utah.
Cases are identified by direct interview methods, by
inference from prescription antidepressant medicine use, and
by postmortem informant interview for decedents. RESULTS:
In-person interviews yielded incidence rates of first-onset
depressive disorder (any type) of 13.09 for men and 19.44
for women. Inclusion of antidepressant users increased these
figures to 15.55 for men and 23.30 for women. Addition of
postmortem interview data yielded rates of 20.66 for men and
26.29 for women. Individuals with no history of depression
had rates for major depression of 7.88 for men and 8.75 for
women; minor depression rates were 19.23 for men and 24.46
for women (p = 0.691; effect for minor depression p
<0.0001). Age did not predict incidence. CONCLUSIONS:
Incidence of first-onset major depression varies with data
source and prior lifetime history of depression. Gender
effects apparent in interview data are attenuated when
postmortem information and pharmacotherapy were
considered.},
Doi = {10.1097/01.JGP.0000196626.34881.42},
Key = {fds276976}
}
@article{fds276975,
Author = {Steffens, DC and Otey, E and Alexopoulos, GS and Butters, MA and Cuthbert, B and Ganguli, M and Geda, YE and Hendrie, HC and Krishnan,
RR and Kumar, A and Lopez, OL and Lyketsos, CG and Mast, BT and Morris, JC and Norton, MC and Peavy, GM and Petersen, RC and Reynolds, CF and Salloway,
S and Welsh-Bohmer, KA and Yesavage, J},
Title = {Perspectives on depression, mild cognitive impairment, and
cognitive decline.},
Journal = {Arch Gen Psychiatry},
Volume = {63},
Number = {2},
Pages = {130-138},
Year = {2006},
Month = {February},
ISSN = {0003-990X},
url = {http://www.ncbi.nlm.nih.gov/pubmed/16461855},
Abstract = {CONTEXT: The public health implications of depression and
cognitive impairment in late life are enormous. Cognitive
impairment and late-life depression are associated with
increased risk for subsequent dementia; however,
investigations of these phenomena appear to be proceeding
along separate tracks. OBJECTIVES AND DATA SOURCE: The
National Institute of Mental Health organized the conference
"Perspectives on Depression, Mild Cognitive Impairment, and
Cognitive Decline" to consider how the varied perspectives
might be better integrated to examine the associations among
depression, mild cognitive impairment, and cognitive decline
and to illuminate the common or distinct mechanisms involved
in these associations. DATA SYNTHESIS: The following 2 broad
questions were addressed: (1) What gaps in our knowledge
have the greatest public health significance? (2) Can we
more efficiently use our research dollars and participant
resources to fill these gaps? Meeting participants included
grantees from the National Institute of Mental Health and
the National Institute on Aging and program staff from the
National Institute of Mental Health, the National Institute
on Aging, and the National Institute of Neurological
Disorders and Stroke. CONCLUSIONS: One of the most important
recommendations to emerge from the meeting discussions is
for increased collaboration among clinical and
epidemiological investigators whose work focuses in the area
of depression with those working primarily in the area of
memory disorders. Directions for future research were
identified.},
Doi = {10.1001/archpsyc.63.2.130},
Key = {fds276975}
}
@article{fds277032,
Author = {Østbye, T and Krause, KM and Norton, MC and Tschanz, J and Sanders, L and Hayden, K and Pieper, C and Welsh-Bohmer, KA and Cache County
Investigators},
Title = {Ten dimensions of health and their relationships with
overall self-reported health and survival in a predominately
religiously active elderly population: the cache county
memory study.},
Journal = {J Am Geriatr Soc},
Volume = {54},
Number = {2},
Pages = {199-209},
Year = {2006},
Month = {February},
ISSN = {0002-8614},
url = {http://www.ncbi.nlm.nih.gov/pubmed/16460369},
Abstract = {OBJECTIVES: To document the extent of healthy aging along 10
different dimensions in a population known for its
longevity. DESIGN: A cohort study with baseline measures of
overall self-reported health and health along 10 specific
dimensions; analyses investigated the 10 dimensions as
predictors of self-reported health and 10-year mortality.
SETTING: Cache County, Utah, which is among the areas with
the highest conditional life expectancy at age 65 in the
United States. PARTICIPANTS: Inhabitants of Cache County
aged 65 and older (January 1, 1995). MEASUREMENTS:
Self-reported overall health and 10 specific dimensions of
healthy aging: independent living, vision, hearing,
activities of daily living, instrumental activities of daily
living, absence of physical illness, cognition, healthy
mood, social support and participation, and religious
participation and spirituality. RESULTS: This elderly
population was healthy overall. With few exceptions, 80% to
90% of persons aged 65 to 75 were healthy according to each
measure used. Prevalence of excellent and good self-reported
health decreased with age, to approximately 60% in those
aged 85 and older. Even in the oldest old, the majority of
respondents were independent in activities of daily living.
Although vision, hearing, and mood were significant
predictors of overall self-reported health in the final
models, age, sex, and cognition were significant only in the
final survival models. CONCLUSION: This population has a
high prevalence of most factors representing healthy aging.
The predictors of overall self-reported health are distinct
from the predictors of survival in this age group and, being
potentially modifiable, are amenable to clinical and public
health efforts.},
Doi = {10.1111/j.1532-5415.2005.00583.x},
Key = {fds277032}
}
@article{fds277081,
Author = {Plassman, BL and Khachaturian, AS and Townsend, JJ and Ball, MJ and Steffens, DC and Leslie, CE and Tschanz, JT and Norton, MC and Burke,
JR and Welsh-Bohmer, KA and Hulette, CM and Nixon, RR and Tyrey, M and Breitner, JCS},
Title = {Comparison of clinical and neuropathologic diagnoses of
Alzheimer's disease in 3 epidemiologic samples.},
Journal = {Alzheimers Dement},
Volume = {2},
Number = {1},
Pages = {2-11},
Year = {2006},
Month = {January},
url = {http://www.ncbi.nlm.nih.gov/pubmed/19595851},
Abstract = {BACKGROUND: Studies of dementia in populations avoid many of
the selection biases in clinical samples but require special
evaluation and diagnostic methods to obtain high
participation rates. To address this issue, we developed a
unique in-home dementia assessment. We assessed validity of
these assessments using neuropathologic confirmation of the
clinical diagnosis in 3 epidemiologic samples. METHODS:
Subjects were 175 participants in 3 ongoing studies of
dementia. Two were population based and identified dementia
by cognitive screening. The third study sought volunteers
via advertisements. Dementia evaluations were then conducted
at the participants' residences by specially trained nurses
and psychometricians. Evaluation results were interpreted,
and preliminary diagnoses were assigned by a
geropsychiatrist or neurologist and a psychologist. Final
diagnoses were assigned by a consensus panel of
neurologists, geropsychiatrists, and psychologists. We
compared the clinical diagnoses with the gold-standard
neuropathologic diagnoses for those participants who
subsequently underwent autopsy. RESULTS: Among the demented,
the sensitivity of a clinical diagnosis of probable or
possible Alzheimer's disease (AD) was 93% across the 3
studies. The rate of overall diagnostic agreement was 81%.
Measures of agreement did not differ meaningfully across
varying levels of dementia severity. CONCLUSIONS: Rates of
neuropathologic confirmation for clinical AD diagnoses in
these studies were similar to those reported from
clinic-based samples. These results support the validity of
clinical diagnoses of AD from a structured in-home
assessment of community dwelling and institutionalized
individuals using relatively economical methods of dementia
screening and assessment.},
Doi = {10.1016/j.jalz.2005.11.001},
Key = {fds277081}
}
@article{fds277098,
Author = {Erlich, PM and Lunetta, KL and Cupples, LA and Huyck, M and Green, RC and Baldwin, CT and Farrer, LA and MIRAGE Study Group},
Title = {Polymorphisms in the PON gene cluster are associated with
Alzheimer disease.},
Journal = {Hum Mol Genet},
Volume = {15},
Number = {1},
Pages = {77-85},
Year = {2006},
Month = {January},
ISSN = {0964-6906},
url = {http://dx.doi.org/10.1093/hmg/ddi428},
Abstract = {Paraoxonase is an arylesterase enzyme that is expressed in
the liver and found in the circulation in association with
apoA1 and the high-density lipoprotein, and prevents the
accumulation of oxidized lipids in low-density lipoproteins
in vitro. Common polymorphisms in genes encoding paraoxonase
are established risk factors in a variety of vascular
disorders including coronary artery disease and carotid
artery stenosis, but their association with Alzheimer
disease (AD) is controversial. We tested the association of
29 SNPs in PON1, PON2 and PON3 with AD in 730 Caucasian and
467 African American participants of the MIRAGE Study, an
ongoing multi-center family-based genetic epidemiology study
of AD. Eight SNPs were associated with AD in the African
American families (0.0001< or =P< or =0.04) and two SNPs
were associated with AD in Caucasian families (0.01< or =P<
or =0.04). Of note, the pattern of association for the PON1
promoter SNP -161[C/T] was the same in both ethnic groups
(P=0.006). Haplotype analysis using sliding windows revealed
11 contiguous SNP combinations spanning the three PON genes
with significant global test scores (0.006< or =P< or =0.04)
in the two ethnic groups combined. The most significantly
associated haplotype comprised SNPs in the region spanning
the -161[C/T] SNP (P=0.00009). Our results demonstrate
association between AD and variants in the PON gene cluster
in Caucasians and African Americans.},
Doi = {10.1093/hmg/ddi428},
Key = {fds277098}
}
@article{fds276979,
Author = {Sair, HI and Welsh-Bohmer, KA and Wagner, HR and Steffens,
DC},
Title = {Ascending digits task as a measure of executive function in
geriatric depression.},
Journal = {J Neuropsychiatry Clin Neurosci},
Volume = {18},
Number = {1},
Pages = {117-120},
Year = {2006},
ISSN = {0895-0172},
url = {http://www.ncbi.nlm.nih.gov/pubmed/16525080},
Abstract = {The authors hypothesized that older depressed patients would
perform more poorly on the Ascending Digits Task (ADT) when
matched against a nondepressed elderly comparison group. In
a novel measure, the ADT, 129 older depressives scored more
poorly than 129 comparison subjects in bivariate analyses
and models controlling for demographic variables. The ADT
may be a good measure of executive function in older
adults.},
Doi = {10.1176/jnp.18.1.117},
Key = {fds276979}
}
@article{fds277030,
Author = {Hayden, KM and Zandi, PP and Lyketsos, CG and Khachaturian, AS and Bastian, LA and Charoonruk, G and Tschanz, JT and Norton, MC and Pieper,
CF and Munger, RG and Breitner, JCS and Welsh-Bohmer, KA and Cache
County Investigators},
Title = {Vascular risk factors for incident Alzheimer disease and
vascular dementia: the Cache County study.},
Journal = {Alzheimer Dis Assoc Disord},
Volume = {20},
Number = {2},
Pages = {93-100},
Year = {2006},
ISSN = {0893-0341},
url = {http://www.ncbi.nlm.nih.gov/pubmed/16772744},
Abstract = {Vascular risk factors for Alzheimer disease (AD) and
vascular dementia (VaD) have been evaluated; however, few
studies have compared risks by dementia subtypes and sex. We
evaluated relationships between cardiovascular risk factors
(hypertension, high cholesterol, diabetes mellitus, and
obesity), events (stroke, coronary artery bypass graft
surgery, and myocardial infarction), and subsequent risk of
AD and VaD by sex in a community-based cohort of 3264 Cache
County residents aged 65 or older. Cardiovascular history
was ascertained by self-report or proxy-report in detailed
interviews. AD and VaD were diagnosed using standard
criteria. Estimates from discrete-time survival models
showed no association between self-reported history of
hypertension and high cholesterol and AD after adjustments.
Hypertension increased the risk of VaD [adjusted hazard
ratio (aHR) 2.42, 95% confidence interval (CI) 0.95-7.44].
Obesity increased the risk of AD in females (aHR 2.23, 95%
CI 1.09-4.30) but not males. Diabetes increased the risk of
VaD in females after adjustments (aHR 3.33, 95% CI
1.03-9.78) but not males. The risk of VaD after stroke was
increased in females (aHR 16.90, 95% CI 5.58-49.03) and
males (aHR 10.95, 95% CI 2.48-44.78). The results indicate
that vascular factors increase risks for AD and VaD
differentially by sex. Future studies should focus on
specific causal pathways for each of these factors with
regard to sex to determine if sex differences in the
prevalence of vascular factors have an influence on sex
differences in dementia risk.},
Doi = {10.1097/01.wad.0000213814.43047.86},
Key = {fds277030}
}
@article{fds371182,
Author = {Lin, PI and Martin, ER and Bronson, PG and Browning-Large, CA and Small,
GW and Schmechel, DE and Welsh-Bohmer, KA and Haines, JL and Gilbert,
JR and Pericak-Vance, MA},
Title = {Exploring the effect of interactions of GAPD genes on
late-onset al.zheimer disease},
Journal = {GENETIC EPIDEMIOLOGY},
Volume = {29},
Number = {3},
Pages = {264-265},
Publisher = {WILEY-LISS},
Year = {2005},
Month = {November},
Key = {fds371182}
}
@article{fds277145,
Author = {van der Walt, JM and Scott, WK and Slifer, S and Gaskell, PC and Martin,
ER and Welsh-Bohmer, K and Creason, M and Crunk, A and Fuzzell, D and McFarland, L and Kroner, CC and Jackson, CE and Haines, JL and Pericak-Vance, MA},
Title = {Maternal lineages and Alzheimer disease risk in the Old
Order Amish.},
Journal = {Hum Genet},
Volume = {118},
Number = {1},
Pages = {115-122},
Year = {2005},
Month = {October},
ISSN = {0340-6717},
url = {http://www.ncbi.nlm.nih.gov/pubmed/16078048},
Abstract = {Old Order Amish, founded by a small number of Swiss
immigrants, exist in culturally isolated communities across
rural North America. The consequences of genetic isolation
and inbreeding within this group are evident by increased
frequencies of many monogenic diseases and several complex
disorders. Conversely, the prevalence of Alzheimer disease
(AD), the most common form of dementia, is lower in the
Amish than in the general American population. Since
mitochondrial dysfunction has been proposed as an underlying
cause of AD and a specific haplogroup was found to affect AD
susceptibility in Caucasians, we investigated whether
inherited mitochondrial haplogroups affect risk of
developing AD dementia in Ohio and Indiana Amish
communities. Ninety-five independent matrilines were
observed across six large pedigrees and three small
pedigrees then classified into seven major European
haplogroups. Haplogroup T is the most frequent haplogroup
represented overall in these maternal lines (35.4%) while
observed in only 10.6% in outbred American and European
populations. Furthermore, haplogroups J and K are less
frequent (1.0%) than in the outbred data set (9.4-11.2%).
Affected case matrilines and unaffected control lines were
chosen from pedigrees to test whether specific haplogroups
and their defining SNPs confer risk of AD. We did not
observe frequency differences between AD cases compared to
controls overall or when stratified by sex. Therefore, we
suggest that the genetic effect responsible for AD dementia
in the affected Amish pedigrees is unlikely to be of
mitochondrial origin and may be caused by nuclear genetic
factors.},
Doi = {10.1007/s00439-005-0032-x},
Key = {fds277145}
}
@article{fds277146,
Author = {Lyketsos, CG and Toone, L and Tschanz, J and Rabins, PV and Steinberg,
M and Onyike, CU and Corcoran, C and Norton, M and Zandi, P and Breitner,
JCS and Welsh-Bohmer, K and Anthony, J and Østbye, T and Bigler, E and Pieper, C and Burke, J and Plassman, B and Green, RC and Steffens, DC and Klein, L and Leslie, C and Townsend, JJ and Wyse, BW and Munger, R and Williams, M and Cache County Study Group},
Title = {Population-based study of medical comorbidity in early
dementia and "cognitive impairment, no dementia (CIND)":
association with functional and cognitive impairment: The
Cache County Study.},
Journal = {Am J Geriatr Psychiatry},
Volume = {13},
Number = {8},
Pages = {656-664},
Year = {2005},
Month = {August},
ISSN = {1064-7481},
url = {http://www.ncbi.nlm.nih.gov/pubmed/16085781},
Abstract = {OBJECTIVE: Authors investigated medical comorbidity in
persons with dementia and "Cognitive Impairment, No
Dementia" (CIND). METHODS: The Cache County Study is an
ongoing population-based study of the epidemiology of
dementia, the risk factors for conversion from CIND to
dementia, and the progression of dementia. As part of the
study's first incidence wave, persons with dementia (N=149),
CIND (N=225), or without cognitive impairment (N=321) were
identified and studied. Participants received comprehensive
clinical evaluations and were rated on the General Medical
Health Rating (GMHR), a global measure of seriousness of
medical comorbidity. Participants and informants also
completed the Mini-Mental State Exam and provided
self-report information about comorbid medical conditions
and functioning in activities of daily living. RESULTS:
There were few differences in number or type of comorbid
medical conditions between persons with CIND and dementia,
but persons with dementia were prescribed more medications.
Stroke was more common in dementia participants, but other
illnesses common in old age were not significantly different
across cognitive groups. Medical comorbidity was more
serious in both dementia and CIND, such that both groups
were less likely to have "little to no" comorbidity.
Seriousness of medical comorbidity was significantly
associated with worse day-to-day functioning and cognition.
CONCLUSIONS: Persons with CIND and dementia have more
serious medical comorbidity than comparable persons without
cognitive impairment. This comorbidity may play a role in
the progression of CIND and dementia. Future studies should
investigate the role of medical comorbidity and its
treatment on dementia onset or progression, as well as the
mechanisms mediating its neuropathologic
effects.},
Doi = {10.1176/appi.ajgp.13.8.656},
Key = {fds277146}
}
@article{fds277031,
Author = {Hayden, KM and Warren, LH and Pieper, CF and Østbye, T and Tschanz, JT and Norton, MC and Breitner, JCS and Welsh-Bohmer,
KA},
Title = {Identification of VaD and AD prodromes: the Cache County
Study.},
Journal = {Alzheimers Dement},
Volume = {1},
Number = {1},
Pages = {19-29},
Year = {2005},
Month = {July},
url = {http://www.ncbi.nlm.nih.gov/pubmed/19595812},
Abstract = {BACKGROUND: It is unclear whether vascular dementia (VaD)
has a cognitive prodrome, akin to the mild cognitive
impairment (MCI) prodrome to Alzheimer's dementia (AD). To
evaluate whether VaD has a cognitive prodrome, and if it can
be differentiated from prodromal AD, we examined
neuropsychological test performance of participants in a
nested case-control study within a population-based cohort
aged 65 or older. METHODS: Participants (n = 485) were
identified from the Cache County Study, a large
population-based study of aging and dementia. After an
average of 3 years of follow-up, a total of 62 incident
dementia cases were identified (14 VaD, 48 AD). We
identified a number of neuropsychological tests (executive
and memory) that discriminated between diagnosed VaD and AD
cases. Multivariate analyses sought to differentiate between
these same groups 3 years before clinical diagnosis.
RESULTS: The Consortium to Establish a Registry for
Alzheimer's Disease Word List Recognition Test correct
recognition of foils (mean difference, 1.25; 95% confidence
interval [CI], 0.42 to 2.07; p < 0.01), Logical Memory I
(mean difference, 7.16; 95% CI, 0.78 to 13.55, p < 0.05),
Logical Memory II delayed recall (mean difference, 8.67; 95%
CI, 1.59 to 15.74, p < 0.05), and percent savings (mean
difference, 51.07; 95% CI, 32.58 to 69.56, p < 0.0001)
differentiated VaD from AD cases after adjustment for age,
sex, education, and dementia severity. Three years before
dementia diagnosis, word list recognition ("no" responses
mean difference, 1.40; 95% CI, 0.64 to 2.17; p < 0.001, and
"yes" responses mean difference, -1.14; 95% CI, -2.14 to
-0.13; p < 0.03) discriminated between prodromal VaD and AD.
CONCLUSION: These results suggest that VaD has a prodromal
syndrome, the cognitive features of which are
distinguishable from the cognitive prodrome of
AD.},
Doi = {10.1016/j.jalz.2005.06.002},
Key = {fds277031}
}
@article{fds277028,
Author = {Hayden, KM and Zandi, PP and Lyketsos, CG and Tschanz, JT and Norton,
MC and Khachaturian, AS and Pieper, CF and Welsh-Bohmer, KA and Breitner, JCS and Cache County Investigators},
Title = {Apolipoprotein E genotype and mortality: findings from the
Cache County Study.},
Journal = {J Am Geriatr Soc},
Volume = {53},
Number = {6},
Pages = {935-942},
Year = {2005},
Month = {June},
ISSN = {0002-8614},
url = {http://www.ncbi.nlm.nih.gov/pubmed/15935014},
Abstract = {OBJECTIVES: To evaluate the association between
apolipoprotein E (apo E) epsilon4 and mortality, the
population attributable risk for mortality with epsilon4,
and relative contributions of cardiovascular disease (CVD)
and Alzheimer's disease (AD). DESIGN: Population-based
cohort study. SETTING: Community-based. PARTICIPANTS:
Permanent residents of Cache County, Utah, aged 65 and older
as of January 1, 1995. MEASUREMENTS: Participants were
genotyped at the apo E locus using buccal-swab
deoxyribonucleic acid. Cardiovascular health was ascertained
using self- or proxy-report interviews at participants'
residences. AD was diagnosed according to Diagnostic and
Statistical Manual of Mental Disorders, Third Edition,
Revised, and National Institute of Neurological and
Communicative Disorders and Stroke-Alzheimer's Disease and
Related Disorders criteria. Utah Department of Vital
Statistics quarterly reports were reviewed to identify
participants who died. RESULTS: Crude evaluations showed
nonsignificantly greater risk of death for epsilon2/2
(hazard ratio (HR)=1.66, 95% confidence interval
(CI)=0.92-2.76) and epsilon3/4 (HR=1.11, 95% CI=0.97-1.26)
genotypes and significantly greater risk for epsilon4/4
(HR=1.48, 95% CI=1.09-1.96). After adjustment for age,
age(2), sex, and education, risks increased to 1.98 (95%
CI=1.08-3.35), 1.28 (95% CI=1.12-1.46), and 2.02 (95%
CI=1.47-2.71), respectively, compared with epsilon3/3
genotypes. Adjustment for presence of any CVD did not change
the risk of death for epsilon3/4 and epsilon4/4. Adjustment
for AD reduced the risk of death for epsilon3/4 (HR=1.13,
95% CI=0.99-1.30) and epsilon4/4 (HR=1.59, 95%
CI=1.15-2.14). The population attributable risk of death for
epsilon3/4 and epsilon4/4 genotypes combined is estimated at
9.6%. CONCLUSION: These findings suggested that the
epsilon2/2, epsilon3/4, and epsilon4/4 genotypes have
greater early mortality risks. Further analyses showed that
AD partially mediates the association between epsilon3/4,
epsilon4/4, and death.},
Doi = {10.1111/j.1532-5415.2005.53301.x},
Key = {fds277028}
}
@article{fds277119,
Author = {Ashley-Koch, AE and Shao, Y and Rimmler, JB and Gaskell, PC and Welsh-Bohmer, KA and Jackson, CE and Scott, WK and Haines, JL and Pericak-Vance, MA},
Title = {An autosomal genomic screen for dementia in an extended
Amish family.},
Journal = {Neurosci Lett},
Volume = {379},
Number = {3},
Pages = {199-204},
Year = {2005},
Month = {May},
ISSN = {0304-3940},
url = {http://www.ncbi.nlm.nih.gov/pubmed/15843063},
Abstract = {Apolipoprotein E (APOE) is the only universally confirmed
susceptibility gene for late-onset Alzheimer disease (LOAD),
although many loci are believed to modulate LOAD risk. The
genetic homogeneity of isolated populations, such as the
Amish, potentially provide increased power to identify LOAD
susceptibility genes. Population homogeneity in these
special populations may reduce the total number of
susceptibility genes contributing to the complex disorder,
thereby increasing the ability to identify any one
susceptibility gene. Dementia in the Amish is clinically
indistinguishable from LOAD in the general population.
Previous studies in the Amish demonstrated a significantly
decreased frequency of the APOE-4 susceptibility allele, but
significant familial clustering of dementia [M.A.
Pericak-Vance, C.C. Johnson, J.B. Rimmler, A.M. Saunders,
L.C. Robinson, E.G. D'Hondt, C.E. Jackson, J.L. Haines,
Alzheimer's disease and apolipoprotein E-4 allele in an
Amish population, Ann. Neurol. 39 (1996) 700-704]. These
data suggested that a genetic etiology independent of APOE
may underlie the dementia observed in this population. In
the present analysis, we focused on a large, multiplex,
inbred Amish family (24 sampled individuals; 10 of whom are
affected). We completed a genomic screen to identify novel
LOAD loci (n=316 genetic markers), using both
model-dependent "affecteds-only" analysis (dominant and
recessive) and model-independent affected relative pair
analysis. Interesting results (lod>1.5 or p<0.01) were
obtained for markers on eight chromosomes (2q, 5q, 6q, 7p,
8p, 8q, 11p, 18p, 18q, and 19q). The highest overall score
was a multipoint lod score of 3.1 on chromosome 11p. Most
regions we identified were not previously detected by
genomic screens of outbred populations and may represent
population-specific susceptibilities to LOAD. These loci are
currently under further investigation in a study of LOAD
including additional Amish families.},
Doi = {10.1016/j.neulet.2004.12.065},
Key = {fds277119}
}
@article{fds371183,
Author = {Hulette, CM and Ervin, JF and Edmonds, Y and Stewart, N and Welsh-Bohmer, K and Pieper, CF and Szymanski, MH and Schmechel,
DE},
Title = {Cerebrovascular smooth muscle actin is increased in possible
Azheimer disease brain tissue: A controlled autopsy
study.},
Journal = {JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL
NEUROLOGY},
Volume = {64},
Number = {5},
Pages = {467-467},
Publisher = {LIPPINCOTT WILLIAMS & WILKINS},
Year = {2005},
Month = {May},
Key = {fds371183}
}
@article{fds277144,
Author = {Zandi, PP and Sparks, DL and Khachaturian, AS and Tschanz, J and Norton,
M and Steinberg, M and Welsh-Bohmer, KA and Breitner, JCS and Cache
County Study investigators},
Title = {Do statins reduce risk of incident dementia and Alzheimer
disease? The Cache County Study.},
Journal = {Arch Gen Psychiatry},
Volume = {62},
Number = {2},
Pages = {217-224},
Year = {2005},
Month = {February},
ISSN = {0003-990X},
url = {http://www.ncbi.nlm.nih.gov/pubmed/15699299},
Abstract = {BACKGROUND: Prior reports suggest reduced occurrence of
dementia and Alzheimer disease (AD) in statin users, but, to
our knowledge, no prospective studies relate statin use and
dementia incidence. OBJECTIVE: To examine the association of
statin use with both prevalence and incidence of dementia
and AD. DESIGN: Cross-sectional studies of prevalence and
incidence and a prospective study of incidence of dementia
and AD among 5092 elderly residents (aged 65 years or older)
of a single county. Participants were assessed at home in
1995-1997 and again in 1998-2000. A detailed visual
inventory of medicines, including statins and other
lipid-lowering agents, was collected at both assessments.
MAIN OUTCOME MEASURES: Diagnosis of dementia and of AD.
RESULTS: From 4895 participants with data sufficient to
determine cognitive status, we identified 355 cases of
prevalent dementia (200 with AD) at initial assessment.
Statin use was inversely associated with prevalence of
dementia (adjusted odds ratio, 0.44; 95% confidence
interval, 0.17-0.94). Three years later, we identified 185
cases of incident dementia (104 with AD) among 3308
survivors at risk. Statin use at baseline did not predict
incidence of dementia or AD (adjusted hazard ratio for
dementia, 1.19; 95% confidence interval, 0.53-2.34; adjusted
hazard ratio for AD, 1.19; 95% confidence interval,
0.35-2.96), nor did statin use at follow-up (adjusted odds
ratio for dementia, 1.04; 95% confidence interval,
0.56-1.81; adjusted odds ratio for AD, 0.85; 95% confidence
interval, 0.32-1.88). CONCLUSIONS: Although statin use might
be less frequent in those with prevalent dementia, we found
no association between statin use and subsequent onset of
dementia or AD. Further research is warranted before costly
dementia prevention trials with statins are
undertaken.},
Doi = {10.1001/archpsyc.62.2.217},
Key = {fds277144}
}
@article{fds277079,
Author = {LaBar, KS and Torpey, DC and Cook, CA and Johnson, SR and Warren, LH and Burke, JR and Welsh-Bohmer, KA},
Title = {Emotional enhancement of perceptual priming is preserved in
aging and early-stage Alzheimer's disease.},
Journal = {Neuropsychologia},
Volume = {43},
Number = {12},
Pages = {1824-1837},
Year = {2005},
ISSN = {0028-3932},
url = {http://www.ncbi.nlm.nih.gov/pubmed/16154458},
Abstract = {Perceptual priming for emotionally-negative and neutral
scenes was tested in early-stage Alzheimer's disease (AD)
patients and healthy younger, middle-aged and older adults.
In the study phase, participants rated the scenes for their
arousal properties. In the test phase, studied and novel
scenes were initially presented subliminally, and the
exposure duration was gradually increased until a valence
categorization was made. The difference in exposure duration
required to categorize novel versus studied items was the
dependent measure of priming. Aversive content increased the
magnitude of priming, an effect that was preserved in
healthy aging and AD. Results from an immediate recognition
memory test showed that the priming effects could not be
attributable to enhanced explicit memory for the aversive
scenes. These findings implicate a dissociation between the
modulatory effect of emotion across implicit and explicit
forms of memory in aging and early-stage
AD.},
Doi = {10.1016/j.neuropsychologia.2005.01.018},
Key = {fds277079}
}
@article{fds277080,
Author = {Tschanz, JT and Treiber, K and Norton, MC and Welsh-Bohmer, KA and Toone, L and Zandi, PP and Szekely, CA and Lyketsos, C and Breitner,
JCS and Cache County Study Group},
Title = {A population study of Alzheimer's disease: findings from the
Cache County Study on Memory, Health, and
Aging.},
Journal = {Care Manag J},
Volume = {6},
Number = {2},
Pages = {107-114},
Year = {2005},
ISSN = {1521-0987},
url = {http://www.ncbi.nlm.nih.gov/pubmed/16544872},
Abstract = {There are several population-based studies of aging, memory,
and dementia being conducted worldwide. Of these, the Cache
County Study on Memory, Health and Aging is noteworthy for
its large number of "oldest-old" members. This study, which
has been following an initial cohort of 5,092 seniors since
1995, has reported among its major findings the role of the
Apolipoprotein E gene on modifying the risk for Alzheimer's
disease (AD) in males and females and identifying
pharmacologic compounds that may act to reduce AD risk. This
article summarizes the major findings of the Cache County
study to date, describes ongoing investigations, and reports
preliminary analyses on the outcome of the oldest-old in
this population, the subgroup of participants who were over
age 84 at the study's inception.},
Doi = {10.1891/cmaj.6.2.107},
Key = {fds277080}
}
@article{fds277010,
Author = {Potter, GG and Plassman, BL and Helms, MJ and Steffens, DC and Welsh-Bohmer, KA},
Title = {Age effects of coronary artery bypass graft on cognitive
status change among elderly male twins.},
Journal = {Neurology},
Volume = {63},
Number = {12},
Pages = {2245-2249},
Year = {2004},
Month = {December},
url = {http://www.ncbi.nlm.nih.gov/pubmed/15623681},
Abstract = {BACKGROUND: Research regarding long-term cognitive outcome
following coronary artery bypass graft (CABG) is
inconsistent, which may be due in part to differential
genetic and environmental influences within most study
samples. METHODS: The authors examined the effect of CABG on
cognitive status change scores in members of the National
Academy of Sciences-National Research Council Twins Registry
of World War II veterans. Subjects were administered the
modified Telephone Interview for Cognitive Status (TICS-m)
at approximately 3-year intervals between 1990 and 2002 as
part of an epidemiologic study of dementia. RESULTS: Based
on co-twin control analyses using a repeated-measures
analysis of variance matching twins discordant for CABG
within the pair (n = 464 individuals) across three age
categories (63 to 70, 71 to 73, 74 to 83), the authors found
at follow-up that men who had CABG between ages 63 and 70
showed an increase in TICS-m scores and performed better
than their co-twin who did not have the procedure. No
significant differences were found within twin pairs for the
older two age groups following CABG surgery. This age effect
was replicated when comparing individuals positive for CABG
surgery with nonfamilial, age- and education-matched
controls who were negative for CABG. CONCLUSIONS: In this
study of twin pairs who share many genetic and environmental
risks for cerebrovascular problems, the results suggest that
timing of the CABG procedure may be important to predicting
positive cognitive outcomes.},
Doi = {10.1212/01.wnl.0000147291.49404.0a},
Key = {fds277010}
}
@article{fds277113,
Author = {Steffens, DC and Welsh-Bohmer, KA and Burke, JR and Plassman, BL and Beyer, JL and Gersing, KR and Potter, GG},
Title = {Methodology and preliminary results from the neurocognitive
outcomes of depression in the elderly study.},
Journal = {J Geriatr Psychiatry Neurol},
Volume = {17},
Number = {4},
Pages = {202-211},
Year = {2004},
Month = {December},
ISSN = {0891-9887},
url = {http://www.ncbi.nlm.nih.gov/pubmed/15533991},
Abstract = {A methodology is presented for following a cohort of older
depressed patients to examine neurocognitive outcomes of
depression. A total of 265 depressed individuals and 138
healthy, nondepressed controls age 60 and older who
completed at least 1 year of follow-up data underwent
periodic clinical evaluation by a geriatric psychiatrist. A
subset of 141 patients and 137 controls had
neuropsychological testing. A consensus panel of experts
reviewed 63 depressed subjects with suspected cognitive
impairment. Twenty-seven individuals in the depressed group
were assigned diagnoses of dementia, including 11 with
Alzheimer's disease, 8 with vascular dementia, and 8 with
dementia of undetermined etiology. In addition, 25
individuals had other forms of cognitive impairment, and 11
were considered cognitively normal. Among elderly controls,
2 developed substantial cognitive impairment with clinical
diagnoses of dementia. Among the depressed group, the
incidence rates for dementia for this age are much higher
than would be expected. These results are consistent with
prior evidence linking depression and later dementia. Future
studies are needed to examine neuroimaging and genetic,
clinical, and social predictors of neurocognitive decline in
depression.},
Doi = {10.1177/0891988704269819},
Key = {fds277113}
}
@article{fds277143,
Author = {Nicodemus, KK and Stenger, JE and Schmechel, DE and Welsh-Bohmer, KA and Saunders, AM and Roses, AD and Gilbert, JR and Vance, JM and Haines, JL and Pericak-Vance, MA and Martin, ER},
Title = {Comprehensive association analysis of APOE regulatory region
polymorphisms in Alzheimer disease.},
Journal = {Neurogenetics},
Volume = {5},
Number = {4},
Pages = {201-208},
Year = {2004},
Month = {December},
ISSN = {1364-6745},
url = {http://www.ncbi.nlm.nih.gov/pubmed/15455263},
Abstract = {Several recent case-control studies have examined the
association between single nucleotide polymorphisms (SNPs)
in the promoter region of the apolipoprotein E gene (APOE)
and risk of Alzheimer disease (AD), with conflicting
results. We assessed the relation between five APOE region
SNPs and risk of AD in both case-control and family-based
analyses. We observed a statistically significant
association with the +5361T allele in the overall
case-control analysis (P value=0.04) after adjusting for the
known effect of the APOE-4 allele. Further analysis revealed
this association to be limited to carriers of the APOE-4
allele. Age-stratified analyses in the patients with age at
onset of 80 years or greater and age-matched controls showed
that the -219T allele (P value=0.009) and the +113C allele
(P value=0.03) are associated with increased risk of AD.
Despite these findings, haplotype and family-based
association analyses were unable to provide evidence that
the APOE region SNPs influenced risk of AD independent of
the APOE-4 allele. In addition to risk, we tested for
association between the SNPs and age at onset of AD, but
found no association in the case-control or family based
analyses. In conclusion, SNPs +5361, or a SNP in strong
linkage disequilibrium, may confer some additional risk for
developing AD beyond the risk due to APOE-4; however, the
effect independent of APOE-4 is likely to be
small.},
Doi = {10.1007/s10048-004-0189-9},
Key = {fds277143}
}
@article{fds277017,
Author = {Labar, KS and Cook, CA and Torpey, DC and Welsh-Bohmer,
KA},
Title = {Impact of healthy aging on awareness and fear
conditioning.},
Journal = {Behav Neurosci},
Volume = {118},
Number = {5},
Pages = {905-915},
Year = {2004},
Month = {October},
ISSN = {0735-7044},
url = {http://www.ncbi.nlm.nih.gov/pubmed/15506873},
Abstract = {Fear conditioning has provided a useful model system for
studying associative emotional learning, but the impact of
healthy aging has gone relatively unexplored. The present
study investigated fear conditioning across the adult life
span in humans. A delay discrimination task was employed
using visual conditioned stimuli and an auditory
unconditioned stimulus. Awareness of the reinforcement
contingencies was assessed in a postexperimental interview.
Compared with young adult participants, middle-aged and
older adults displayed reductions in unconditioned
responding, discriminant conditioning, and contingency
awareness. When awareness and overall arousability were
taken into consideration, there were no residual effects of
aging on conditioning. These results highlight the
importance of considering the influence of declarative
knowledge when interpreting age-associated changes in
discriminative conditioned learning.},
Doi = {10.1037/0735-7044.118.5.905},
Key = {fds277017}
}
@article{fds277063,
Author = {van der Walt, JM and Dementieva, YA and Martin, ER and Scott, WK and Nicodemus, KK and Kroner, CC and Welsh-Bohmer, KA and Saunders, AM and Roses, AD and Small, GW and Schmechel, DE and Murali Doraiswamy and P and Gilbert, JR and Haines, JL and Vance, JM and Pericak-Vance,
MA},
Title = {Analysis of European mitochondrial haplogroups with
Alzheimer disease risk.},
Journal = {Neurosci Lett},
Volume = {365},
Number = {1},
Pages = {28-32},
Year = {2004},
Month = {July},
ISSN = {0304-3940},
url = {http://www.ncbi.nlm.nih.gov/pubmed/15234467},
Abstract = {We examined the association of mtDNA variation with
Alzheimer disease (AD) risk in Caucasians (989 cases and 328
controls) testing the effect of individual haplogroups and
single nucleotide polymorphisms (SNPs). Logistic regression
analyses were used to assess risk of haplogroups and SNPs
with AD in both main effects and interaction models. Males
classified as haplogroup U showed an increase in risk (OR =
2.30; 95% CI, 1.03-5.11; P = 0.04) of AD relative to the
most common haplogroup H, while females demonstrated a
significant decrease in risk with haplogroup U (OR = 0.44 ;
95% CI, 0.24-0.80; P = 0.007). Our results were independent
of APOE genotype, demonstrating that the effect of mt
variation is not confounded by APOE4 carrier status. We
suggest that variations within haplogroup U may be involved
in AD expression in combination with environmental exposures
or nuclear proteins other than APOE.},
Doi = {10.1016/j.neulet.2004.04.051},
Key = {fds277063}
}
@article{fds371184,
Author = {Martin, E and Bronson, P and Jiang, L and Welsh-Bohmer, K and Schmechel,
D and Small, G and Haines, J and Gilbert, J and Pericak-Vance, M and Moore,
J},
Title = {P4-134 A multilocus association analysis of APOE, LRP1 and
A2M in Alzheimer disease},
Journal = {Neurobiology of Aging},
Volume = {25},
Pages = {S513-S513},
Publisher = {Elsevier BV},
Year = {2004},
Month = {July},
url = {http://dx.doi.org/10.1016/s0197-4580(04)81692-0},
Doi = {10.1016/s0197-4580(04)81692-0},
Key = {fds371184}
}
@article{fds371185,
Author = {Steinberg, M and Corcoran, C and Huber, C and Welsh-Bohmer, K and Norton, M and Zandi, P and Breitner, J and Tschanz, J and Lyketsos,
C},
Title = {P2-333 A longitudinal model for neuropsychiatric symptoms in
dementia: the Cache County Study},
Journal = {Neurobiology of Aging},
Volume = {25},
Pages = {S327-S328},
Publisher = {Elsevier BV},
Year = {2004},
Month = {July},
url = {http://dx.doi.org/10.1016/s0197-4580(04)81076-5},
Doi = {10.1016/s0197-4580(04)81076-5},
Key = {fds371185}
}
@article{fds371186,
Author = {Tschanz, J and Klein, E and Treiber, K and Corcoran, C and Norton, M and Toone, L and Welsh-Bohmer, K and Steinberg, M and Munger, R and Pieper,
C and Breitner, J and Zandi, P and Lyketsos, C},
Title = {P2-288 Neuropsychiatric symptoms in mild cognitive
impairment and dementia: prevalence and relationship to
cognitive and functional impairment. The Cache County
Study},
Journal = {Neurobiology of Aging},
Volume = {25},
Pages = {S314-S314},
Publisher = {Elsevier BV},
Year = {2004},
Month = {July},
url = {http://dx.doi.org/10.1016/s0197-4580(04)81033-9},
Doi = {10.1016/s0197-4580(04)81033-9},
Key = {fds371186}
}
@article{fds371187,
Author = {Toone, L and Tschanz, J and Rabins, PV and Steinberg, M and Onyike, C and Corcoran, C and Norton, M and Welsh-Bohmer, K and Breitner, J and Zandi,
P and Lyketsos, CG},
Title = {P2-247 A population based study of medical co-morbidity in
early dementia and mild cognitive syndrome: association with
functional and cognitive impairment},
Journal = {Neurobiology of Aging},
Volume = {25},
Pages = {S302-S302},
Publisher = {Elsevier BV},
Year = {2004},
Month = {July},
url = {http://dx.doi.org/10.1016/s0197-4580(04)80993-x},
Doi = {10.1016/s0197-4580(04)80993-x},
Key = {fds371187}
}
@article{fds371188,
Author = {Klein, E and Corcoran, C and Tschanz, J and Norton, M and Welsh-Bohmer,
K and Breitner, J and Zandi, P and Lyketsos, C},
Title = {P1-051 Survival from memory symptom onset: a comparison of
individuals with dementia and cognitive impairment. The
cache county study},
Journal = {Neurobiology of Aging},
Volume = {25},
Pages = {S109-S109},
Publisher = {Elsevier BV},
Year = {2004},
Month = {July},
url = {http://dx.doi.org/10.1016/s0197-4580(04)80365-8},
Doi = {10.1016/s0197-4580(04)80365-8},
Key = {fds371188}
}
@article{fds371189,
Author = {Plassman, BL and Steffens, DC and Burke, JR and Welsh-Bohmer, KA and Helms, MJ and Breitner, JC},
Title = {P4-137 Alzheimer's disease in the NAS-NRC twin registry of
WWII veterans},
Journal = {Neurobiology of Aging},
Volume = {25},
Pages = {S514-S514},
Publisher = {Elsevier BV},
Year = {2004},
Month = {July},
url = {http://dx.doi.org/10.1016/s0197-4580(04)81695-6},
Doi = {10.1016/s0197-4580(04)81695-6},
Key = {fds371189}
}
@article{fds371190,
Author = {Pericak-Vance, MA and Bronson, P and Martin, ER and Browning, C and Rayner, M and Xu, P and Small, GW and Roses, AD and Schmechel, DE and Doraiswamy, PM and Welsh-Bohmer, KA and Haines, JL and Gilbert,
JR},
Title = {P4-080 Genetic studies of Alzheimer disease on chromosome
9P},
Journal = {Neurobiology of Aging},
Volume = {25},
Pages = {S497-S497},
Publisher = {Elsevier BV},
Year = {2004},
Month = {July},
url = {http://dx.doi.org/10.1016/s0197-4580(04)81638-5},
Doi = {10.1016/s0197-4580(04)81638-5},
Key = {fds371190}
}
@article{fds371191,
Author = {Hayden, KM and Norton, MC and Tschanz, JT and Zandi, PP and Lyketsos,
CG and Khachaturian, AS and Pieper, CF and Welsh-Bohmer, KA and Breitner, JC},
Title = {P3-116 The complex role of cardiovascular risk factors,
cerebrovascular disease, and gender, with the incidence of
Alzheimer's disease: findings from the Cache County
Study},
Journal = {Neurobiology of Aging},
Volume = {25},
Pages = {S388-S388},
Publisher = {Elsevier BV},
Year = {2004},
Month = {July},
url = {http://dx.doi.org/10.1016/s0197-4580(04)81268-5},
Doi = {10.1016/s0197-4580(04)81268-5},
Key = {fds371191}
}
@article{fds371192,
Author = {Khachaturian, AS and Zandi, PP and Hayden, KM and Lyketsos, CG and Mayer, LS and Skoog, I and Tschanz, JT and Norton, MC and Welsh-Bohmer,
KA and Breitner, JCS},
Title = {O3-01-07 Anti-hypertensive medication use may reduce risk of
incident Alzheimer's disease. The Cache County
Study},
Journal = {Neurobiology of Aging},
Volume = {25},
Pages = {S53-S53},
Publisher = {Elsevier BV},
Year = {2004},
Month = {July},
url = {http://dx.doi.org/10.1016/s0197-4580(04)80181-7},
Doi = {10.1016/s0197-4580(04)80181-7},
Key = {fds371192}
}
@article{fds371193,
Author = {Browning, C and Vance, DD and Bronson, PG and Schmechel, D and Welsh-Bohmer, K and Scott, W and Haines, JL and Vance, JM and Pericak-Vance, MA},
Title = {P4-072 Follow-up analysis of chromosome 2 linkage in
early-onset Alzheimer disease},
Journal = {Neurobiology of Aging},
Volume = {25},
Pages = {S494-S494},
Publisher = {Elsevier BV},
Year = {2004},
Month = {July},
url = {http://dx.doi.org/10.1016/s0197-4580(04)81630-0},
Doi = {10.1016/s0197-4580(04)81630-0},
Key = {fds371193}
}
@article{fds371194,
Author = {Quan, H and Haines, JL and Sanchez-Boutard, N and Small, G and Roses, A and Schmechel, D and Welsh-Bohmer, K and Xu, P-T and Li, Y-J and Gilbert,
JR and Vance, JM and Pericak-Vance, MA},
Title = {P4-138 Genomic convergence on chromosome 12 in Alzheimer's
disease},
Journal = {Neurobiology of Aging},
Volume = {25},
Pages = {S514-S514},
Publisher = {Elsevier BV},
Year = {2004},
Month = {July},
url = {http://dx.doi.org/10.1016/s0197-4580(04)81696-8},
Doi = {10.1016/s0197-4580(04)81696-8},
Key = {fds371194}
}
@article{fds371195,
Author = {Li, Y-J and Oliveira, SA and Qin, X-J and Roses, AD and Schmechel, D and Welsh-Bohmer, KA and Haines, JL and Pericak-Vance, MA and Vance,
JM},
Title = {P4-088 Association analysis of interleukin 1 (IL-1)
polymorphisms with age-at-onset and risk of Alzheimer
disease},
Journal = {Neurobiology of Aging},
Volume = {25},
Pages = {S499-S499},
Publisher = {Elsevier BV},
Year = {2004},
Month = {July},
url = {http://dx.doi.org/10.1016/s0197-4580(04)81646-4},
Doi = {10.1016/s0197-4580(04)81646-4},
Key = {fds371195}
}
@article{fds371196,
Author = {Haines, JL and Crunk, A and McFarland, L and Gaskell, P and Fuzzell, D and Creason, M and Jiang, L and Jackson, CE and Scott, WK and A.
Welsh-Bohmer, K and Pericak-Vance, MA},
Title = {S2-01-01 Dementia in mid-Western U.S. amish
families},
Journal = {Neurobiology of Aging},
Volume = {25},
Pages = {S24-S25},
Publisher = {Elsevier BV},
Year = {2004},
Month = {July},
url = {http://dx.doi.org/10.1016/s0197-4580(04)80079-4},
Doi = {10.1016/s0197-4580(04)80079-4},
Key = {fds371196}
}
@article{fds371197,
Author = {Norton, MC and Steffens, DC and Toone, L and Tschanz, JT and Hayden, K and Corcoran, C and Klein, L and Zandi, P and Breitner, JCS and Welsh-Bohmer, KA},
Title = {P3-108 Late-life depression, mild cognitive impairment, APOE
and their interactive effects on conversion to dementia in a
population-based study. The Cache County
Study},
Journal = {Neurobiology of Aging},
Volume = {25},
Pages = {S385-S386},
Publisher = {Elsevier BV},
Year = {2004},
Month = {July},
url = {http://dx.doi.org/10.1016/s0197-4580(04)81260-0},
Doi = {10.1016/s0197-4580(04)81260-0},
Key = {fds371197}
}
@article{fds371198,
Author = {Zandi, PP and Szekely, CA and Green, RC and Breitner, JC and Welsh-Bohmer, KA},
Title = {S1-03-03 Pooled analysis of the association between
different NSAIDS and AD: preliminary findings},
Journal = {Neurobiology of Aging},
Volume = {25},
Pages = {S5-S6},
Publisher = {Elsevier BV},
Year = {2004},
Month = {July},
url = {http://dx.doi.org/10.1016/s0197-4580(04)80018-6},
Doi = {10.1016/s0197-4580(04)80018-6},
Key = {fds371198}
}
@article{fds277021,
Author = {Ervin, JF and Pannell, C and Szymanski, M and Welsh-Bohmer, K and Schmechel, DE and Hulette, CM},
Title = {Vascular smooth muscle actin is reduced in Alzheimer disease
brain: a quantitative analysis.},
Journal = {J Neuropathol Exp Neurol},
Volume = {63},
Number = {7},
Pages = {735-741},
Year = {2004},
Month = {July},
ISSN = {0022-3069},
url = {http://www.ncbi.nlm.nih.gov/pubmed/15290898},
Abstract = {We analyzed smooth muscle actin (SMA) immunoreactivity in
brain blood vessels of 10 ApoE 4,4 Alzheimer disease (AD)
patients and 10 ApoE 3,3 AD patients matched for age, sex,
and duration of dementia. We also examined 10 cognitively
and neuropathologically normal controls matched for age and
sex. Vascular SMA immunoreactivity in the arachnoid, grey
matter, and white matter was quantified by image analysis.
There was less SMA immunoreactivity in blood vessels of all
AD patients when compared to cognitively and
neuropathologically normal controls (p < 0.001). In
addition, arachnoidal vessels of ApoE 4,4 AD patients had
less SMA immunoreactivity than ApoE 3,3 AD patients (p <
0.05). There is decreased vascular SMA density in arachnoid,
grey matter, and white matter blood vessels in patients with
AD when compared to age matched, cognitively and
neuropathologically normal controls. The severity of the
loss of SMA within the AD group may depend on ApoE
type.},
Doi = {10.1093/jnen/63.7.735},
Key = {fds277021}
}
@article{fds277029,
Author = {Hayden, KM and Pieper, CF and Welsh-Bohmer, KA and Breitner, JCS and Norton, MC and Munger, R},
Title = {Self- or proxy-reported stroke and the risk of Alzheimer
disease.},
Journal = {Arch Neurol},
Volume = {61},
Number = {6},
Pages = {982},
Year = {2004},
Month = {June},
ISSN = {0003-9942},
url = {http://www.ncbi.nlm.nih.gov/pubmed/15210546},
Doi = {10.1001/archneur.61.6.982},
Key = {fds277029}
}
@article{fds277142,
Author = {Bigler, ED and Neeley, ES and Miller, MJ and Tate, DF and Rice, SA and Cleavinger, H and Wolfson, L and Tschanz, J and Welsh-Bohmer,
K},
Title = {Cerebral volume loss, cognitive deficit and
neuropsychological performance: comparative measures of
brain atrophy: I. Dementia.},
Journal = {J Int Neuropsychol Soc},
Volume = {10},
Number = {3},
Pages = {442-452},
Year = {2004},
Month = {May},
url = {http://dx.doi.org/10.1017/S1355617704103111},
Abstract = {There are several magnetic resonance (MR) imaging methods to
measure brain volume and cerebral atrophy; however, the best
measure for examining potential relationships between such
measures and neuropsychological performance has not been
established. Relationships between seven measures of MR
derived brain volume or indices of atrophy and
neuropsychological performance in the elderly subjects of
the population-based Cache County, Utah Study of Aging and
Memory (n = 195) were evaluated. The seven MR measures
included uncorrected total brain volume (TBV), TBV corrected
by total intracranial volume (TICV), TBV corrected by the
ratio of the individuals TICV by group TICV (TBVC), a
ventricle-to-brain ratio (VBR), total ventricular volume
(TVV), TVV corrected by TICV, and a measure of parenchymal
volume loss. The cases from the Cache County Study were
comprised of elderly individuals classified into one of four
subject groups based on a consensus diagnostic process,
independent of quantitative MR imaging findings. The groups
included subjects with Alzheimer's disease (AD, n = 85), no
dementia but mild/ambiguous (M/A) deficits (n = 30), a group
of subjects with non-AD dementia or neuropsychiatric
disorder including vascular dementia (n = 60), and control
subjects (n = 20). Neuropsychological performance was based
on the Mini-Mental Status Exam (MMSE) and an expanded
neuropsychological test battery (consortium to establish a
registry for Alzheimer's disease (CERAD). The results
demonstrated that the various quantitative MR measures were
highly interrelated and no single measure was statistically
superior. However, TBVC, TBV/TICV and VBR consistently
exhibited the more robust relationships with
neuropsychological performance. These results suggest that a
single corrected brain volume measure or index is sufficient
in studies examining global MR indicators of cerebral
atrophy in relation to cognitive function and recommends use
of either TBVC, TBV/TICV, or VBR.},
Doi = {10.1017/S1355617704103111},
Key = {fds277142}
}
@article{fds277027,
Author = {Tschanz, JT and Corcoran, C and Skoog, I and Khachaturian, AS and Herrick, J and Hayden, KM and Welsh-Bohmer, KA and Calvert, T and Norton, MC and Zandi, P and Breitner, JCS and Cache County Study
Group},
Title = {Dementia: the leading predictor of death in a defined
elderly population: the Cache County Study.},
Journal = {Neurology},
Volume = {62},
Number = {7},
Pages = {1156-1162},
Year = {2004},
Month = {April},
url = {http://www.ncbi.nlm.nih.gov/pubmed/15079016},
Abstract = {OBJECTIVE: To examine the relative risk and population
attributable risk (PAR) of death with dementia of varying
type and severity and other risk factors in a population of
exceptional longevity. METHODS: Deaths were monitored over 5
years using vital statistics records and newspaper
obituaries in 355 individuals with prevalent dementia and
4,328 without in Cache County, UT. Mean age was 83.3 (SD
7.0) years with dementia and 73.7 (SD 6.8) years without.
History of coronary artery disease, hypertension, diabetes,
and other life-shortening illness was ascertained from
interviews. RESULTS: Death certificates implicated dementia
as an important cause of death, but other data suggested a
stronger association. Adjusted Cox relative hazard and PAR
of death were higher with dementia than with any other
illness studied. Relative hazard of death with dementia was
highest at ages 65 to 74, but the high prevalence of
dementia after age 85 resulted in 27% PAR among the oldest
old. Mortality increased substantially with severity of
dementia. Alzheimer disease shortened survival time most
dramatically in younger participants, but vascular dementia
posed a greater mortality risk among the oldest old.
CONCLUSION: In this population, dementia was the strongest
predictor of mortality, with a risk two to three times those
of other life-shortening illnesses.},
Doi = {10.1212/01.wnl.0000118210.12660.c2},
Key = {fds277027}
}
@article{fds277051,
Author = {Li, YL and Oliveira, SA and Xu, P and Martin, ER and Stenger, JE and Hulette, C and Scherzer, CR and Hauser, MA and Scott, WK and Small, GW and Nance, MA and Watts, RL and Hubble, JP and Koller, WC and Pahwa, R and Stern, MB and Hiner, BC and Jankovic, J and Goetz, CG and Mastaglia, F and Middleton, LT and Roses, AD and Saunders, AM and Welsh-Bohmer, KA and Schmechel, DE and Gullans, SR and Haines, JL and Gilbert, JR and Vance,
JM and Pericak-Vance, MA},
Title = {Erratum: Glutathione S-transferase omega-1 modifies
age-at-onset of Alzheimer disease and Parkinson disease
(Human Molecular Genetics (2003) vol. 12
(3259-3267))},
Journal = {Human Molecular Genetics},
Volume = {13},
Number = {5},
Pages = {573},
Publisher = {Oxford University Press (OUP)},
Year = {2004},
Month = {March},
url = {http://dx.doi.org/10.1093/hmg/ddh059},
Doi = {10.1093/hmg/ddh059},
Key = {fds277051}
}
@article{fds277141,
Author = {Zandi, PP and Anthony, JC and Khachaturian, AS and Stone, SV and Gustafson, D and Tschanz, JT and Norton, MC and Welsh-Bohmer, KA and Breitner, JCS and Cache County Study Group},
Title = {Reduced risk of Alzheimer disease in users of antioxidant
vitamin supplements: the Cache County Study.},
Journal = {Arch Neurol},
Volume = {61},
Number = {1},
Pages = {82-88},
Year = {2004},
Month = {January},
ISSN = {0003-9942},
url = {http://www.ncbi.nlm.nih.gov/pubmed/14732624},
Abstract = {BACKGROUND: Antioxidants may protect the aging brain against
oxidative damage associated with pathological changes of
Alzheimer disease (AD). OBJECTIVE: To examine the
relationship between antioxidant supplement use and risk of
AD. DESIGN: Cross-sectional and prospective study of
dementia. Elderly (65 years or older) county residents were
assessed in 1995 to 1997 for prevalent dementia and AD, and
again in 1998 to 2000 for incident illness. Supplement use
was ascertained at the first contact. SETTING: Cache County,
Utah. PARTICIPANTS: Among 4740 respondents (93%) with data
sufficient to determine cognitive status at the initial
assessment, we identified 200 prevalent cases of AD. Among
3227 survivors at risk, we identified 104 incident AD cases
at follow-up. MAIN OUTCOME MEASURE: Diagnosis of AD by means
of multistage assessment procedures. RESULTS: Analyses of
prevalent and incident AD yielded similar results. Use of
vitamin E and C (ascorbic acid) supplements in combination
was associated with reduced AD prevalence (adjusted odds
ratio, 0.22; 95% confidence interval, 0.05-0.60) and
incidence (adjusted hazard ratio, 0.36; 95% confidence
interval, 0.09-0.99). A trend toward lower AD risk was also
evident in users of vitamin E and multivitamins containing
vitamin C, but we saw no evidence of a protective effect
with use of vitamin E or vitamin C supplements alone, with
multivitamins alone, or with vitamin B-complex supplements.
CONCLUSIONS: Use of vitamin E and vitamin C supplements in
combination is associated with reduced prevalence and
incidence of AD. Antioxidant supplements merit further study
as agents for the primary prevention of AD.},
Doi = {10.1001/archneur.61.1.82},
Key = {fds277141}
}
@article{fds371199,
Author = {Norton, M and Klein, L and Welsh-Bohmer, K and Tschanz, J and Toone, L and Steffens, D and Zandi, P and Corcoran, C and Hayden, K and Breitner,
J},
Title = {Late-life depression, mild cognitive impairment, APOE and
their interactive effects on 3-year conversion to
dementia},
Journal = {GERONTOLOGIST},
Volume = {44},
Pages = {219-219},
Year = {2004},
Key = {fds371199}
}
@article{fds371200,
Author = {Klein, E and Tschanz, J and Corcoran, C and Norton, M and Welsh-Bohmer,
K and Breitner, J and Zandi, P and Lyketsos, CC},
Title = {Estimating survival duration from memory symptom onset: A
comparison of methods. The Cache County Study.},
Journal = {AMERICAN JOURNAL OF EPIDEMIOLOGY},
Volume = {159},
Number = {11},
Pages = {S3-S3},
Year = {2004},
Key = {fds371200}
}
@article{fds371201,
Author = {Norton, M and Skoog, I and Toone, L and Tschanz, J and Corcoran, C and Zandi, P and Hart, A and Breitner, J and Welsh-Bohmer, K and Steffens,
D},
Title = {Improving assessment of incidence of first-onset geriatric
depression in population-based studies.},
Journal = {AMERICAN JOURNAL OF EPIDEMIOLOGY},
Volume = {159},
Number = {11},
Pages = {S2-S2},
Year = {2004},
Key = {fds371201}
}
@article{fds276974,
Author = {Steffens, DC and McQuoid, DR and Welsh-Bohmer, KA and Krishnan,
KRR},
Title = {Left orbital frontal cortex volume and performance on the
benton visual retention test in older depressives and
controls.},
Journal = {Neuropsychopharmacology},
Volume = {28},
Number = {12},
Pages = {2179-2183},
Year = {2003},
Month = {December},
ISSN = {0893-133X},
url = {http://www.ncbi.nlm.nih.gov/pubmed/14532909},
Abstract = {Changes within the prefrontal cortex (PFC) have been
associated with both mood disorders and with specific
impairments in cognitive testing. The left PFC has been
implicated in relational processing, that is, binding
different pieces of information. We hypothesized that among
older depressives and elderly controls, lower performance on
one test of relational processing would be associated with
smaller volume of the orbital frontal cortex (OFC). A total
of 30 depressed and 40 control subjects were included in the
study. All subjects were administered the Benton Visual
Retention Test (BVRT). Subjects received a standardized
magnetic resonance imaging, for which volumes of the OFC and
total brain were calculated. We found that, controlling for
age and education, total correct on BVRT was associated with
left OFC volume normalized for total brain volume among the
entire sample. For the depressed sample only, the number of
perseverative errors was negatively associated with left OFC
volume normalized for total brain volume after controlling
for age and education. These results add to the literature
linking mood and cognitive disturbances to the PFC. Future
studies with a larger sample employing functional measures
are warranted.},
Doi = {10.1038/sj.npp.1300285},
Key = {fds276974}
}
@article{fds371202,
Author = {Vance, JM and Li, Y and Oliveira, AS and Hauser, MA and Martin, ER and Scott, WK and Stenger, JE and Scherzer, C and Gullans, SR and Small, GW and Roses, AD and Saunders, AM and Schmechel, DE and Welsh-Bohmer, KA and Hulette, C and Haines, JL and Gilbert, JR and Pericak-Vance,
MA},
Title = {Glutathione S-transferase, omega-1 (GSTO1) modifies age at
onset of Alzheimer disease and Parkinson
disease.},
Journal = {AMERICAN JOURNAL OF HUMAN GENETICS},
Volume = {73},
Number = {5},
Pages = {182-182},
Publisher = {UNIV CHICAGO PRESS},
Year = {2003},
Month = {November},
Key = {fds371202}
}
@article{fds277052,
Author = {Scott, WK and Hauser, ER and Schmechel, DE and Welsh-Bohmer, KA and Small, GW and Roses, AD and Saunders, AM and Gilbert, JR and Vance, JM and Haines, JL and Pericak-Vance, MA},
Title = {Ordered-subsets linkage analysis detects novel Alzheimer
disease loci on chromosomes 2q34 and 15q22.},
Journal = {Am J Hum Genet},
Volume = {73},
Number = {5},
Pages = {1041-1051},
Year = {2003},
Month = {November},
ISSN = {0002-9297},
url = {http://www.ncbi.nlm.nih.gov/pubmed/14564669},
Abstract = {Alzheimer disease (AD) is a complex disorder characterized
by a wide range, within and between families, of ages at
onset of symptoms. Consideration of age at onset as a
covariate in genetic-linkage studies may reduce genetic
heterogeneity and increase statistical power.
Ordered-subsets analysis includes continuous covariates in
linkage analysis by rank ordering families by a covariate
and summing LOD scores to find a subset giving a
significantly increased LOD score relative to the overall
sample. We have analyzed data from 336 markers in 437
multiplex (>/=2 sampled individuals with AD) families
included in a recent genomic screen for AD loci. To identify
genetic heterogeneity by age at onset, families were ordered
by increasing and decreasing mean and minimum ages at onset.
Chromosomewide significance of increases in the LOD score in
subsets relative to the overall sample was assessed by
permutation. A statistically significant increase in the
nonparametric multipoint LOD score was observed on
chromosome 2q34, with a peak LOD score of 3.2 at D2S2944
(P=.008) in 31 families with a minimum age at onset between
50 and 60 years. The LOD score in the chromosome 9p region
previously linked to AD increased to 4.6 at D9S741 (P=.01)
in 334 families with minimum age at onset between 60 and 75
years. LOD scores were also significantly increased on
chromosome 15q22: a peak LOD score of 2.8 (P=.0004) was
detected at D15S1507 (60 cM) in 38 families with minimum age
at onset >/=79 years, and a peak LOD score of 3.1 (P=.0006)
was obtained at D15S153 (62 cM) in 43 families with mean age
at onset >80 years. Thirty-one families were contained in
both 15q22 subsets, indicating that these results are likely
detecting the same locus. There is little overlap in these
subsets, underscoring the utility of age at onset as a
marker of genetic heterogeneity. These results indicate that
linkage to chromosome 9p is strongest in late-onset AD and
that regions on chromosome 2q34 and 15q22 are linked to
early-onset AD and very-late-onset AD, respectively.},
Doi = {10.1086/379083},
Key = {fds277052}
}
@article{fds277122,
Author = {Mackensen, GB and Ti, LK and Phillips-Bute, BG and Mathew, JP and Newman, MF and Grocott, HP and Neurologic Outcome Research Group
(NORG)},
Title = {Cerebral embolization during cardiac surgery: impact of
aortic atheroma burden.},
Journal = {Br J Anaesth},
Volume = {91},
Number = {5},
Pages = {656-661},
Year = {2003},
Month = {November},
ISSN = {0007-0912},
url = {http://www.ncbi.nlm.nih.gov/pubmed/14570786},
Abstract = {BACKGROUND: Aortic atheromatous disease is known to be
associated with an increased risk of perioperative stroke in
the setting of cardiac surgery. In this study, we sought to
determine the relationship between cerebral microemboli and
aortic atheroma burden in patients undergoing cardiac
surgery. METHODS: Transoesophageal echocardiographic images
of the ascending, arch and descending aorta were evaluated
in 128 patients to determine the aortic atheroma burden.
Transcranial Doppler (TCD) of the right middle cerebral
artery was performed in order to measure cerebral embolic
load during surgery. Using multivariate linear regression,
the numbers of emboli were compared with the atheroma
burden. RESULTS: After controlling for age, cardiopulmonary
bypass time and the number of bypass grafts, cerebral emboli
were significantly associated with atheroma in the ascending
aorta (R2=0.11, P=0.02) and aortic arch (P=0.013). However,
there was no association between emboli and descending
aortic atheroma burden (R2=0.05, P=0.20). CONCLUSIONS: We
demonstrate a positive relationship between TCD-detected
cerebral emboli and the atheromatous burden of the ascending
aorta and aortic arch. Previously demonstrated associations
between TCD-detectable cerebral emboli and adverse cerebral
outcome may be related to the presence of significant aortic
atheromatous disease.},
Doi = {10.1093/bja/aeg234},
Key = {fds277122}
}
@article{fds277009,
Author = {Bigler, ED and Lowry, CM and Kerr, B and Tate, DF and Hessel, CD and Earl,
HD and Miller, MJ and Rice, SA and Smith, KH and Tschanz, JT and Welsh-Bohmer, K and Plassman, B and Victoroff,
J},
Title = {Role of white matter lesions, cerebral atrophy, and APOE on
cognition in older persons with and without dementia: the
Cache County, Utah, study of memory and aging.},
Journal = {Neuropsychology},
Volume = {17},
Number = {3},
Pages = {339-352},
Year = {2003},
Month = {July},
url = {http://dx.doi.org/10.1037/0894-4105.17.3.339},
Abstract = {Neuropsychological, qualitative, and quantitative magnetic
resonance imaging findings were examined in subjects with
Alzheimer's disease (AD), non-AD dementia or mixed
neuropsychiatric disorder, subjects characterized as
mild/ambiguous, and controls, all with known apolipoprotein
E (APOE) genotype. Neuropsychological tasks included an
expanded Consortium to Establish a Registery for Alzheimer's
Disease (J. T. Tschanz et al., 2000; K. A. Welsh, J. M.
Hoffman, N. L. Earl, & M. W. Hanson 1994) battery and the
Mini-Mental Status Examination (M. F. Folstein, S. E.
Folstein, & P. R. McHugh, 1975). Periventricular white
matter lesions were the most clinically salient, and
generalized measures of cerebral atrophy were the most
significant quantitative indicators. APOE genotype was
unrelated to imaging or neuropsychological performance.
Neuropsychological relationships with neuroimaging findings
depend on the qualitative or quantitative method
used.},
Doi = {10.1037/0894-4105.17.3.339},
Key = {fds277009}
}
@article{fds277078,
Author = {Steffens, DC and Norton, MC and Hart, AD and Skoog, I and Corcoran, C and Breitner, JCS and Cache County Study Group},
Title = {Apolipoprotein E genotype and major depression in a
community of older adults. The Cache County
Study.},
Journal = {Psychol Med},
Volume = {33},
Number = {3},
Pages = {541-547},
Year = {2003},
Month = {April},
ISSN = {0033-2917},
url = {http://www.ncbi.nlm.nih.gov/pubmed/12701674},
Abstract = {BACKGROUND: The role of allelic variation in APOE, the
genetic locus for apolipoprotein E, in geriatric depression
is poorly understood. There are conflicting reports as to an
association between the epsilon4 allele and depression in
late life. METHOD: Using a community based study of
non-demented elders in Cache County, Utah, that included
many very old individuals, we examined the relationship
between APOE and late-onset (age > 60) depression, with
particular attention to possible age effects. RESULTS: There
was no overall association between APOE and depression.
However, there was a significant interaction effect of APOE
and age such that the relationship of late-onset depression
with respect to presence of the epsilon4 allele was larger
among those 80 and older compared with those below age 80.
Consistent with previous studies, women were more likely to
experience late-onset depression than men. CONCLUSIONS:
Because we excluded prevalent cases of dementia, this
pattern of relative risk with age may reflect the appearance
of depressive symptoms as a prodrome of Alzheimer's disease
or vascular dementia. Longitudinal studies should help to
confirm or refute this explanation of the
data.},
Doi = {10.1017/s0033291702007201},
Key = {fds277078}
}
@article{fds371203,
Author = {Welsh-Bohmer, KA},
Title = {Defining "prodromal" Alzheimer's disease and the factors
that modify its trajectory to dementia: Clues from
population based studies},
Journal = {CLINICAL NEUROPSYCHOLOGIST},
Volume = {17},
Number = {1},
Pages = {97-97},
Publisher = {SWETS ZEITLINGER PUBLISHERS},
Year = {2003},
Month = {February},
Key = {fds371203}
}
@article{fds371204,
Author = {Broadbent, D and Norton, M and Tschanz, J and Welsh-Bohmer, K and Breitner, J},
Title = {Effect of prior and recent health problems on performance of
activities of daily living by the elderly: The cache county
study},
Journal = {GERONTOLOGIST},
Volume = {43},
Pages = {458-459},
Year = {2003},
Key = {fds371204}
}
@article{fds371205,
Author = {Franklin, L and Norton, M and Steffens, D and Tschanz, J and Welsh-Bohmer, K and Breitner, J},
Title = {Couples' religious parity, their depression history and
social support, as predictors of new-onset major depression
in elderly wives. The Cache County Study.},
Journal = {GERONTOLOGIST},
Volume = {43},
Pages = {392-392},
Year = {2003},
Key = {fds371205}
}
@article{fds371206,
Author = {Hayden, K and Zandi, P and Tschanz, J and Khachaturian, A and Garrett,
K and Welsh-Bohmer, K and Breitner, J},
Title = {APOE genotype and mortality: The Cache County
study},
Journal = {GERONTOLOGIST},
Volume = {43},
Pages = {8-8},
Year = {2003},
Key = {fds371206}
}
@article{fds371207,
Author = {Yoash-Gantz, RE and DiPersio, DA and Fahey, F and Welsh-Bohmer,
K},
Title = {Asymmetry of hemispheric function in MCI as measured by
FDG-PET},
Journal = {ARCHIVES OF CLINICAL NEUROPSYCHOLOGY},
Volume = {18},
Number = {7},
Pages = {694-694},
Year = {2003},
Key = {fds371207}
}
@article{fds371208,
Author = {Johnson, S and Welsh-Bohmer, K and Wagner, RH and Steffens,
DC},
Title = {Expression of geriatric depression in African-Americans and
Caucasians},
Journal = {CLINICAL NEUROPSYCHOLOGIST},
Volume = {17},
Number = {1},
Pages = {113-113},
Year = {2003},
Key = {fds371208}
}
@article{fds277110,
Author = {Phillips Bute and B and Mathew, J and Blumenthal, JA and Welsh-Bohmer,
K and White, WD and Mark, D and Landolfo, K and Newman,
MF},
Title = {Female gender is associated with impaired quality of life 1
year after coronary artery bypass surgery.},
Journal = {Psychosom Med},
Volume = {65},
Number = {6},
Pages = {944-951},
Year = {2003},
url = {http://www.ncbi.nlm.nih.gov/pubmed/14645771},
Abstract = {OBJECTIVE: To evaluate gender-related differences in quality
of life (QOL) and cognitive function 1 year after coronary
artery bypass surgery (CABG) after adjusting for known
baseline differences. MATERIALS AND METHODS: Two hundred
eighty patients (96 women and 184 men) underwent
neurocognitive and QOL evaluation at baseline
(preoperatively) and at 1 year after CABG. Multivariable
linear regression was used to assess the relationship of
gender to follow-up QOL and cognitive function. Measures
used to evaluate QOL were IADL, DASI, work activities
(SF-36), social activities, social support, general health
perception (SF-36), CESD, STAI, and symptom limitations.
Cognitive function was measured with a battery of
performance-based neuropsychological tests, reduced to a
four-cognitive domain scores with factor analysis, and a
self-report measure of cognitive difficulties. Covariates in
multiple regression models included age, years of education,
marital status, Charlson Comorbidity Index, hypertension,
diabetes, race, and baseline QOL/cognitive status. RESULTS:
Female patients showed significantly worse outcome than male
patients at 1 year follow-up in several key areas of QOL.
After adjusting for baseline differences, women are at
greater risk for increased cognitive difficulties (p= 0.04)
and anxiety (p= 0.03), as well as impaired DASI (p= 0.02),
IADL (p= 0.03), and work activities (p= 0.02). Cognitive
sequelae attributable to bypass surgery were similar between
men and women. CONCLUSIONS: Even after adjusting for known
risk factors for compromised QOL and cognitive functioning,
women do not show the same long-term quality benefits of
CABG surgery that men do.},
Doi = {10.1097/01.psy.0000097342.24933.a2},
Key = {fds277110}
}
@article{fds277008,
Author = {Zandi, PP and Carlson, MC and Plassman, BL and Welsh-Bohmer, KA and Mayer, LS and Steffens, DC and Breitner, JCS and Cache County Memory
Study Investigators},
Title = {Hormone replacement therapy and incidence of Alzheimer
disease in older women: the Cache County
Study.},
Journal = {JAMA},
Volume = {288},
Number = {17},
Pages = {2123-2129},
Year = {2002},
Month = {November},
ISSN = {0098-7484},
url = {http://www.ncbi.nlm.nih.gov/pubmed/12413371},
Abstract = {CONTEXT: Previous studies have shown a sex-specific
increased risk of Alzheimer disease (AD) in women older than
80 years. Basic neuroscience findings suggest that hormone
replacement therapy (HRT) could reduce a woman's risk of AD.
Epidemiologic findings on AD and HRT are mixed. OBJECTIVE:
To examine the relationship between use of HRT and risk of
AD among elderly women. DESIGN, SETTING, AND PARTICIPANTS:
Prospective study of incident dementia among 1357 men (mean
age, 73.2 years) and 1889 women (mean age, 74.5 years)
residing in a single county in Utah. Participants were first
assessed in 1995-1997, with follow-up conducted in
1998-2000. History of women's current and former use of HRT,
as well as of calcium and multivitamin supplements, was
ascertained at the initial contact. MAIN OUTCOME MEASURE:
Diagnosis of incident AD. RESULTS: Thirty-five men (2.6%)
and 88 women (4.7%) developed AD between the initial
interview and time of the follow-up (3 years). Incidence
among women increased after age 80 years and exceeded the
risk among men of similar age (adjusted hazard ratio [HR],
2.11; 95% confidence interval [CI], 1.22-3.86). Women who
used HRT had a reduced risk of AD (26 cases among 1066
women) compared with non-HRT users (58 cases among 800
women) (adjusted HR, 0.59; 95% CI, 0.36-0.96). Risk varied
with duration of HRT use, so that a woman's sex-specific
increase in risk disappeared entirely with more than 10
years of treatment (7 cases among 427 women). Adjusted HRs
were 0.41 (95% CI, 0.17-0.86) for HRT users compared with
nonusers and 0.77 (95% CI, 0.31-1.67) compared with men. No
similar effect was seen with calcium or multivitamin use.
Almost all of the HRT-related reduction in incidence
reflected former use of HRT (9 cases among 490 women;
adjusted HR, 0.33 [95% CI, 0.15-0.65]). There was no effect
with current HRT use (17 cases among 576 women; adjusted HR,
1.08 [95% CI, 0.59-1.91]) unless duration of treatment
exceeded 10 years (6 cases among 344 women; adjusted HR,
0.55 [95% CI, 0.21-1.23]). CONCLUSIONS: Prior HRT use is
associated with reduced risk of AD, but there is no apparent
benefit with current HRT use unless such use has exceeded 10
years.},
Doi = {10.1001/jama.288.17.2123},
Key = {fds277008}
}
@article{fds277007,
Author = {Bigler, ED and Tate, DF and Miller, MJ and Rice, SA and Hessel, CD and Earl, HD and Tschanz, JT and Plassman, B and Welsh-Bohmer,
KA},
Title = {Dementia, asymmetry of temporal lobe structures, and
apolipoprotein E genotype: relationships to cerebral atrophy
and neuropsychological impairment.},
Journal = {J Int Neuropsychol Soc},
Volume = {8},
Number = {7},
Pages = {925-933},
Year = {2002},
Month = {November},
ISSN = {1355-6177},
url = {http://www.ncbi.nlm.nih.gov/pubmed/12405544},
Abstract = {We examined asymmetry of hippocampal volume as well as other
temporal lobe structures (temporal lobe, temporal horn of
the lateral ventricular system, parahippocampal and fusiform
gyri) in 194 subjects from the Cache County, Utah study,
with varying disorders [85 with Alzheimer's disease (AD), 59
with some cognitive or neuropsychiatric disorder-referenced
as a Mixed Neuropsychiatric group, 30 with mild
ambiguous/mild cognitive impairment (MA/MCI) and 20
controls] and APOE genotypes. Asymmetry was determined by
subtracting left-side volume from the right corrected by
total intracranial volume. No significant asymmetry was
observed to be associated with presence of the epsilon4
allele. Since the AD-epsilon4 allele risk effect may be
expressed early in the course of the disorder, we also
examined asymmetry indices in AD, MA/MCI and Mixed
Neuropsychiatric subjects early in the course of their
disorder (2 years or less) to those with longer duration
illness (greater than 2 years). We observed a leftward
asymmetry (i.e., left side larger) regardless of APOE
genotype in hippocampal volume where both AD and MCI
subjects demonstrated a leftward shift in hippocampal size
when length of disease (LOD) was less but not more than 2
years. Leftward asymmetry was not associated with LOD in the
Mixed Neuropsychiatric group. These findings do not support
an association between epsilon4 and hippocampal asymmetry in
dementia. We also examined whether asymmetry influenced
neuropsychological performance, but minimal effects were
observed. Where significance or strong trends were observed,
better neuropsychological performance was associated with
larger parenchymal volume of temporal lobe structures. These
findings were interpreted as representing cognitive reserve
effects where larger volume was protective against
impairment. The role of asymmetry research in understanding
neuropsychological performance in dementia is
discussed.},
Doi = {10.1017/s1355617702870072},
Key = {fds277007}
}
@article{fds277121,
Author = {Swaminathan, M and McCreath, BJ and Phillips-Bute, BG and Newman, MF and Mathew, JP and Smith, PK and Blumenthal, JA and Stafford-Smith, M and Perioperative Outcomes Research Group},
Title = {Serum creatinine patterns in coronary bypass surgery
patients with and without postoperative cognitive
dysfunction.},
Journal = {Anesth Analg},
Volume = {95},
Number = {1},
Pages = {1-8},
Year = {2002},
Month = {July},
ISSN = {0003-2999},
url = {http://www.ncbi.nlm.nih.gov/pubmed/12088934},
Abstract = {UNLABELLED: Renal dysfunction is common after coronary
artery bypass graft (CABG) surgery. We have previously shown
that CABG procedures complicated by stroke have a threefold
greater peak serum creatinine level relative to
uncomplicated surgery. However, postoperative creatinine
patterns for procedures complicated by cognitive dysfunction
are unknown. Therefore, we tested the hypothesis that
postoperative cognitive dysfunction is associated with acute
perioperative renal injury after CABG surgery. Data were
prospectively gathered for 282 elective CABG surgery
patients. Psychometric tests were performed at baseline and
6 wk after surgery. Cognitive dysfunction was defined both
as a dichotomous variable (cognitive deficit [CD]) and as a
continuous variable (cognitive index). Forty percent of
patients had CD at 6 wk. However, the association between
peak percentage change in postoperative creatinine and CD
(parameter estimate = -0.41; P = 0.91) or cognitive index
(parameter estimate = -1.29; P = 0.46) was not significant.
These data indicate that postcardiac surgery cognitive
dysfunction, unlike stroke, is not associated with major
increases in postoperative renal dysfunction. IMPLICATIONS:
We previously noted that patients with postcardiac surgery
stroke also have greater acute renal injury than unaffected
patients. However, in the same setting, we found no
difference in renal injury between patients with and without
cognitive dysfunction. Factors responsible for subtle
postoperative cognitive dysfunction do not appear to be
associated with clinically important renal
effects.},
Doi = {10.1097/00000539-200207000-00001},
Key = {fds277121}
}
@article{fds371209,
Author = {Li, YJ and Scott, WK and Hedges, DK and Zhang, FY and Gaskell, PC and Stajich, JM and Saunders, AM and Scott, BL and Schmechel, DE and Welsh-Bohmer, KA and Conneally, PM and Gilbert, JR and Vance, JM and Pericak-Vance, MA and Nance, MA and Watts, RL and Hubble, JP and Koller,
WC and Pahwa, R and Stern, MB and Hiner, BC and Jankovic, J and Allen, FH and Goetz, CG and Mastaglia, F and Gibson, RA and Middelton, LT and Small,
GW and Roses, AD and Haines, JL},
Title = {Location of common age-at onset genes in Alzheimer and
Parkinson diseases},
Journal = {NEUROBIOLOGY OF AGING},
Volume = {23},
Number = {1},
Pages = {S317-S317},
Publisher = {ELSEVIER SCIENCE INC},
Year = {2002},
Month = {July},
Key = {fds371209}
}
@article{fds276986,
Author = {Li, Y-J and Scott, WK and Hedges, DJ and Zhang, F and Gaskell, PC and Nance, MA and Watts, RL and Hubble, JP and Koller, WC and Pahwa, R and Stern, MB and Hiner, BC and Jankovic, J and Allen, FA and Goetz, CG and Mastaglia, F and Stajich, JM and Gibson, RA and Middleton, LT and Saunders, AM and Scott, BL and Small, GW and Nicodemus, KK and Reed, AD and Schmechel, DE and Welsh-Bohmer, KA and Conneally, PM and Roses, AD and Gilbert, JR and Vance, JM and Haines, JL and Pericak-Vance,
MA},
Title = {Age at onset in two common neurodegenerative diseases is
genetically controlled.},
Journal = {Am J Hum Genet},
Volume = {70},
Number = {4},
Pages = {985-993},
Year = {2002},
Month = {April},
ISSN = {0002-9297},
url = {http://www.ncbi.nlm.nih.gov/pubmed/11875758},
Abstract = {To identify genes influencing age at onset (AAO) in two
common neurodegenerative diseases, a genomic screen was
performed for AAO in families with Alzheimer disease (AD;
n=449) and Parkinson disease (PD; n=174). Heritabilities
between 40%--60% were found in both the AD and PD data sets.
For PD, significant evidence for linkage to AAO was found on
chromosome 1p (LOD = 3.41). For AD, the AAO effect of APOE
(LOD = 3.28) was confirmed. In addition, evidence for AAO
linkage on chromosomes 6 and 10 was identified independently
in both the AD and PD data sets. Subsequent unified analyses
of these regions identified a single peak on chromosome 10q
between D10S1239 and D10S1237, with a maximum LOD score of
2.62. These data suggest that a common gene affects AAO in
these two common complex neurodegenerative
diseases.},
Doi = {10.1086/339815},
Key = {fds276986}
}
@article{fds371210,
Author = {Norton, MC and Steffens, DC and Skoog, I and Welsh-Bohmer, KA and Wyse,
BW and Breitner, JC},
Title = {Relation of functional impairment, social support, and
religious involvement to incident depression over a
three-year interval.},
Journal = {AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY},
Volume = {10},
Number = {2},
Pages = {76-76},
Publisher = {AMER PSYCHIATRIC PRESS, INC},
Year = {2002},
Month = {March},
Key = {fds371210}
}
@article{fds277077,
Author = {Tschanz, JT and Welsh-Bohmer, KA and Plassman, BL and Norton, MC and Wyse, BW and Breitner, JCS and Cache County Study
Group},
Title = {An adaptation of the modified mini-mental state examination:
analysis of demographic influences and normative data: the
cache county study.},
Journal = {Neuropsychiatry Neuropsychol Behav Neurol},
Volume = {15},
Number = {1},
Pages = {28-38},
Year = {2002},
Month = {March},
ISSN = {0894-878X},
url = {http://www.ncbi.nlm.nih.gov/pubmed/11877549},
Abstract = {OBJECTIVES: To present a new version of the Modified
Mini-Mental State Examination (3MS-R), provide normative
information extending to individuals in the 10th decade, and
examine the effects of demographic variables on test
performance. BACKGROUND: The Modified Mini-Mental State
Examination, based originally on the Mini-Mental State
Examination, has been used to screen populations for
dementia. Providing normative information and an analysis of
demographic variables on test performance for this version
would support broader use in clinical and other settings.
METHODS: Two thousand, nine hundred thirteen elderly
individuals determined to be free of dementia and other
neurologic and psychiatric conditions served as subjects. An
analysis of variance was conducted to examine the effects of
age, gender, and education on test performance. Descriptive
statistics (means, standard deviations, and percentile
ranks) were calculated to summarize the range of normal
performance. To examine the sensitivity/specificity of the
suggested cut-off points at the 7th and 10th percentiles,
two subsamples of elderly individuals, on whom clinical
dementia assessments were available, were used to classify
individuals with regard to dementia status. RESULTS: Lower
age, higher education, and female gender were associated
with higher 3MS-R scores. Gender effects were among the
weakest, but most important at lower levels of education.
Education effects were most prominent in the youngest age
groups. Selection of a cut-off point at the 7th percentile
revealed 69%-70% sensitivity for detecting dementia, and
higher sensitivity for individuals in the youngest age
groups. Specificity at this cut-off point was 89%. Raising
the cut-off point to the 10th percentile improved
sensitivity to 73%-76%, but reduced specificity to 85%-86%.
CONCLUSION: We present a version of the Modified Mini-Mental
State Examination that has demonstrated utility in screening
a population for dementia. An analysis of normative
information and the effects of demographic influences
suggest that the 7th percentile cut-off point performs very
well in detecting dementia in 65-79-year-old individuals but
less well for individuals in their 80s and 90s. To increase
the sensitivity of the 3MS-R to detect dementia or other
forms of cognitive impairment, particularly among the
"old-old," the test user may wish to raise the cut-off point
for impairment in some demographic groups or to supplement
the test with additional cognitive measures.},
Key = {fds277077}
}
@article{fds371211,
Author = {Norton, M and Tschanz, J and Corcoran, C and Mumford, S and Welsh-Bohmer, K and Breitner, J},
Title = {Apolipoprotein ε4 interacts with mild cognitive deficit to
shorten time to dementia onset},
Journal = {NEUROBIOLOGY OF AGING},
Volume = {23},
Number = {1},
Pages = {S299-S299},
Year = {2002},
Key = {fds371211}
}
@article{fds371212,
Author = {Tschanz, J and Norton, M and Corcoran, C and LaCaille, R and Welsh-Bohmer, K and Breitner, J},
Title = {Cognitive screening and self-perception of memory problems
predict mild cognitive impairment and dementia},
Journal = {NEUROBIOLOGY OF AGING},
Volume = {23},
Number = {1},
Pages = {S262-S262},
Year = {2002},
Key = {fds371212}
}
@article{fds371213,
Author = {Lisota, R and Tschanz, J and Norton, M and Corcoran, C and Leslie, C and Lyketsos, C and Steinberg, M and Breitner, J and Welsh-Bohmer,
K},
Title = {Differential impact of genetic and demographic variables on
clinical course of dementia and Alzheimer's
disease},
Journal = {NEUROBIOLOGY OF AGING},
Volume = {23},
Number = {1},
Pages = {S152-S153},
Year = {2002},
Key = {fds371213}
}
@article{fds371214,
Author = {Gaskell, PC and Hulette, C and Welsh-Bohmer, K and Schmechel, D and Pericak-Vance, M and Roses, A},
Title = {Followup of multiplex Alzheimer disease (AD) families:
Presentation of data and discussion of their importance in
genetic analysis},
Journal = {NEUROBIOLOGY OF AGING},
Volume = {23},
Number = {1},
Pages = {S323-S323},
Year = {2002},
Key = {fds371214}
}
@article{fds276946,
Author = {Carlson, MC and Tschanz, JT and Norton, MC and Welsh-Bohmer, K and Martin, BK and Breitner, JCS},
Title = {H2 histamine receptor blockade in the treatment of Alzheimer
disease: a randomized, double-blind, placebo-controlled
trial of nizatidine.},
Journal = {Alzheimer Dis Assoc Disord},
Volume = {16},
Number = {1},
Pages = {24-30},
Year = {2002},
ISSN = {0893-0341},
url = {http://dx.doi.org/10.1097/00002093-200201000-00004},
Abstract = {OBJECTIVES: To evaluate the efficacy of nizatidine, a
histamine H2-blocking drug, in delaying the progression of
cognitive impairment in older adults with Alzheimer disease
(AD). DESIGN: A one-year, randomized, double-blind,
placebo-controlled trial. PARTICIPANTS: Fifty-one older men
and women aged 67 to 96 years with AD were recruited from
the Cache County Study on Memory in Aging. METHODS: Patients
were stratified by age and by the presence of one or more
epsilon 4 alleles at the APOE locus, then randomized to
receive nizatidine 75 mg (Axid ARTM, Whitehall Robins) or a
matching placebo tablet twice daily. Cognitive outcomes were
assessed at baseline, six, and twelve months after
enrollment using tests from the CERAD battery and additional
measures of visuospatial memory, verbal memory, and verbal
fluency. RESULTS: Subjects showed significant declines in
language, fluency, and praxis but most measures of memory
had already "bottomed out." Intention-to-treat and
compliance-based analyses showed no effect of nizatidine on
any of the cognitive outcome measures over the one-year
study interval. CONCLUSIONS: These results do not support
claims for the efficacy of nizatidine in over-the-counter
dosages as a means of preventing symptom progression in
AD.},
Doi = {10.1097/00002093-200201000-00004},
Key = {fds276946}
}
@article{fds276947,
Author = {Schiffman, SS and Graham, BG and Sattely-Miller, EA and Zervakis, J and Welsh-Bohmer, K},
Title = {Taste, smell and neuropsychological performance of
individuals at familial risk for Alzheimer's
disease.},
Journal = {Neurobiol Aging},
Volume = {23},
Number = {3},
Pages = {397-404},
Year = {2002},
ISSN = {0197-4580},
url = {http://dx.doi.org/10.1016/s0197-4580(01)00337-2},
Abstract = {The purpose of the study was to determine whether there are
chemosensory and neuropsychological changes that predate the
onset of Alzheimer's disease in individuals at enhanced risk
of developing the condition. To study this question, a
unique sample of individuals (n = 33) was studied who were
genetically at-risk for AD by virtue of documented
multigenerational evidence of the disease (so-called
multiplex families). The performance of at-risk individuals
was evaluated on various smell, taste, and
neuropsychological measures at baseline and 18 months later.
Their performance was compared to a control group (n = 32)
that was matched in age, gender, education, and race. At
baseline the at-risk group performed worse than the control
group on the chemosensory measures of phenethyl alcohol
smell detection, smell memory, and taste memory, and on a
memory measure involving recall of narrative information
(Logical Memory I from the Wechsler Memory Scale- Revised).
Across both sessions, the at-risk group had lower smell
memory scores than the control group. At-risk status was not
significantly associated with APOE status. The results of
this and other studies suggest that individuals who are
genetically at risk for developing AD may perform more
poorly on memory and smell measures compared to those not at
risk. This effect may be separate from one known genetic
risk factor of AD, APOE, and supports that multiple genes
are likely responsible for the disease and its associated
memory and other neurocognitive symptoms.},
Doi = {10.1016/s0197-4580(01)00337-2},
Key = {fds276947}
}
@article{fds277016,
Author = {Steffens, DC and Payne, ME and Greenberg, DL and Byrum, CE and Welsh-Bohmer, KA and Wagner, HR and MacFall, JR},
Title = {Hippocampal volume and incident dementia in geriatric
depression.},
Journal = {Am J Geriatr Psychiatry},
Volume = {10},
Number = {1},
Pages = {62-71},
Year = {2002},
ISSN = {1064-7481},
url = {http://www.ncbi.nlm.nih.gov/pubmed/11790636},
Abstract = {The authors investigated the role of baseline hippocampal
volume on later clinical emergence of dementia in a group of
older, non-demented depressed individuals. Subjects were 115
depressed, non-demented participants in a mental health
clinical research center. All subjects were screened for
dementia and agreed to have a magnetic resonance imaging
(MRI) brain scan at baseline. Subjects were clinically
evaluated by geriatric psychiatrists quarterly for up to 5
years and received annual neuropsychological testing.
Bivariate analyses examined age, gender, race, educational
level, baseline depression severity, age at depression
onset, baseline Mini-Mental State Exam (MMSE), left and
right hippocampal volume, and total cerebral volume. Age,
baseline MMSE, total cerebral volume, and having a small
left hippocampal volume were associated with later dementia
and were included in subsequent survival analysis. Small
left hippocampal volume was significantly associated with
later dementia (hazard ratio=2.762). Small left hippocampal
size on neuroimaging may be a marker for dementia in
depressed patients who have not yet met criteria for a
clinical diagnosis of a dementing disorder.},
Doi = {10.1176/appi.ajgp.10.1.62},
Key = {fds277016}
}
@article{fds277006,
Author = {Carlson, MC and Zandi, PP and Plassman, BL and Tschanz, JT and Welsh-Bohmer, KA and Steffens, DC and Bastian, LA and Mehta, KM and Breitner, JC and Cache County Study Group},
Title = {Hormone replacement therapy and reduced cognitive decline in
older women: the Cache County Study.},
Journal = {Neurology},
Volume = {57},
Number = {12},
Pages = {2210-2216},
Year = {2001},
Month = {December},
ISSN = {0028-3878},
url = {http://www.ncbi.nlm.nih.gov/pubmed/11756599},
Abstract = {OBJECTIVE: To examine the association between postmenopausal
hormone replacement therapy (HRT) and the trajectory of
global cognitive change with age. METHODS: The Modified
Mini-Mental State Examination (MMSE) was administered to a
population sample of 2,073 nondemented, community-dwelling
female residents of Cache County, UT, aged 65 and older.
Current and past HRT and other medications at a baseline
interview and at follow-up 3 years later were assessed.
Between interviews, a telephone Women's Health Questionnaire
was administered to assess initial exposure, duration, and
recency of HRT. Generalized estimating equation marginal
models were used to evaluate the cross-sectional and
longitudinal relations of HRT and modified MMSE score. Also
assessed were effects with multivitamins and calcium
supplements as exposures likely to reflect a "healthy
lifestyle" among HRT users. Model covariates included the
presence of APOE epsilon4 alleles, age, education,
concurrent depression, several chronic diseases, and
self-perceived general health. RESULTS: Age, lower
education, depression, and APOE epsilon4 were all associated
with lower baseline modified MMSE scores. With these
covariates in the model, lifetime HRT use was associated
with better baseline modified MMSE scores and a slower rate
of decline. Stratification by APOE genotype did not alter
these effects. Apparent benefits with HRT were attenuated
but remained significant after elimination of scores from
participants with incident dementia. A significant
interaction between age and HRT indicated the strongest
effects in women aged 85 and older. Measures of age at
initial use of HRT, duration, and recency of exposure did
not improve the models. No effects were seen with the
"healthy lifestyle" control exposures. CONCLUSIONS: In a
population cohort of older women, lifetime HRT exposure was
associated with improved global cognition and attenuated
decline over a 3-year interval. Improvements were greatest
in the oldest old.},
Doi = {10.1212/wnl.57.12.2210},
Key = {fds277006}
}
@article{fds276945,
Author = {Silverman, DH and Small, GW and Chang, CY and Lu, CS and Kung De Aburto,
MA and Chen, W and Czernin, J and Rapoport, SI and Pietrini, P and Alexander, GE and Schapiro, MB and Jagust, WJ and Hoffman, JM and Welsh-Bohmer, KA and Alavi, A and Clark, CM and Salmon, E and de Leon,
MJ and Mielke, R and Cummings, JL and Kowell, AP and Gambhir, SS and Hoh,
CK and Phelps, ME},
Title = {Positron emission tomography in evaluation of dementia:
Regional brain metabolism and long-term outcome.},
Journal = {JAMA},
Volume = {286},
Number = {17},
Pages = {2120-2127},
Year = {2001},
Month = {November},
ISSN = {0098-7484},
url = {http://www.ncbi.nlm.nih.gov/pubmed/11694153},
Abstract = {CONTEXT: Deficits in cerebral glucose utilization have been
identified in patients with cognitive dysfunction attributed
to various disease processes, but their prognostic and
diagnostic value remains to be defined. OBJECTIVE: To assess
the sensitivity and specificity with which cerebral
metabolic patterns at a single point in time forecast
subsequent documentation of progressive dementia. DESIGN,
SETTING, AND PATIENTS: Positron emission tomography (PET)
studies of [(18)F]fluorodeoxyglucose in 146 patients
undergoing evaluation for dementia with at least 2 years'
follow-up for disease progression at the University of
California, Los Angeles, from 1991 to 2000, and PET studies
in 138 patients undergoing evaluation for dementia at an
international consortium of facilities, with
histopathological diagnoses an average of 2.9 years later,
conducted from 1984 to 2000. MAIN OUTCOME MEASURES: Regional
distribution of [(18)F]fluorodeoxyglucose in each patient,
classified by criteria established a priori as positive or
negative for presence of a progressive neurodegenerative
disease in general and of Alzheimer disease (AD)
specifically, compared with results of longitudinal or
neuropathologic analyses. RESULTS: Progressive dementia was
detected by PET with a sensitivity of 93% (191/206) and a
specificity of 76% (59/78). Among patients with
neuropathologically based diagnoses, PET identified patients
with AD and patients with any neurodegenerative disease with
a sensitivity of 94% and specificities of 73% and 78%,
respectively. The negative likelihood ratio of experiencing
a progressive vs nonprogressive course over the several
years following a single negative brain PET scan was 0.10
(95% confidence interval, 0.06-0.16), and the initial
pattern of cerebral metabolism was significantly associated
with the subsequent course of progression overall (P<.001).
CONCLUSION: In patients presenting with cognitive symptoms
of dementia, regional brain metabolism was a sensitive
indicator of AD and of neurodegenerative disease in general.
A negative PET scan indicated that pathologic progression of
cognitive impairment during the mean 3-year follow-up was
unlikely to occur.},
Doi = {10.1001/jama.286.17.2120},
Key = {fds276945}
}
@article{fds276944,
Author = {Sugarman, J and Cain, C and Wallace, R and Welsh-Bohmer,
KA},
Title = {How proxies make decisions about research for patients with
Alzheimer's disease.},
Journal = {J Am Geriatr Soc},
Volume = {49},
Number = {8},
Pages = {1110-1119},
Year = {2001},
Month = {August},
ISSN = {0002-8614},
url = {http://www.ncbi.nlm.nih.gov/pubmed/11555076},
Abstract = {We examined the proxy decision-making and informed consent
processes for clinical research involving 49
patient-subjects with dementia in an outpatient setting by
performing serial in-depth, structured, open-ended telephone
interviews. Interviews were tape recorded and transcribed.
Transcripts were then coded and analyzed. Although in all
cases proxy consent was obtained for research from a legally
authorized representative, proxies reported considerable
ambiguity regarding who made the decision to participate in
research, or to what degree the decision was that of the
proxy or of the patient. Reasons proxies gave for
participating in research included: hope of direct or
indirect benefits to the patient, caregiver, or patient's
descendents; desperation; trust in the investigator; belief
in the goodness of research; and altruism. These reasons
varied according to the type of research. For instance, in
drug trials hope of direct benefit prevailed; in studies not
evaluating a potential therapy more altruistic concerns
predominated. Being a proxy decision maker for research can
be burdensome. The degree of burden related to making a
decision to participate in research seems influenced by a
number of intersecting factors, most importantly, the risk
and nature of the study, the extent to which patients were
able to participate in the decision, and the duration and
severity of dementia. Proxy decision-making concerning
participation in research for patients with dementia can be
a difficult task. The process might be improved by
emphasizing that proxy consent is being sought because the
nature of the patient's underlying medical condition can
preclude the ability to make meaningful decisions. In
addition, clinical researchers should recognize that giving
proxy consent might place additional burdens on caregivers
and discuss this explicitly when proxy consent is
solicited.},
Doi = {10.1046/j.1532-5415.2001.49218.x},
Key = {fds276944}
}
@article{fds277116,
Author = {Koltai, DC and Welsh-Bohmer, KA and Schmechel,
DE},
Title = {Influence of anosognosia on treatment outcome among dementia
patients},
Journal = {Neuropsychological Rehabilitation},
Volume = {11},
Number = {3-4},
Pages = {455-475},
Publisher = {Informa UK Limited},
Year = {2001},
Month = {July},
ISSN = {0960-2011},
url = {http://dx.doi.org/10.1080/09602010042000097},
Abstract = {This study was a preliminary investigation of the effects of
a Memory and Coping Program among mild to moderate dementia
patients. A total of 24 elderly participants were randomly
assigned to treatment and waiting-list control conditions. A
pre-test, post-test design was used, with group comparisons
of change scores on objective cognitive tests and subjective
ratings of mood and memory. While encouraging trends emerged
suggesting improvement among those who received treatment,
group differences did not reach statistical significance.
However, when outcomes were compared by treatment subgroups
with and without anosognosia, significant differences
emerged. Participants with insight made significantly
greater gains in perceived memory functioning that those
without insight. In contrast, informants perceived greater
gains among treatment subjects relative to controls
independent of insight status. The need for additional
research to further delineate the influences of anosognia,
baseline cognition, and affective status, and other
potential intervention outcome modifiers is discussed, with
attention to instrumentation and methodological
considerations.},
Doi = {10.1080/09602010042000097},
Key = {fds277116}
}
@article{fds372627,
Author = {Grundman, M and Kim, HT and Salmon, D and Storandt, M and Smith, G and Ferris, S and Mohs, R and Brandt, J and Doody, R and Welsh‐Bohmer, K and Saxton, J and Saine, K and Schmitt, F and Ogrocki, P and Johnson, N and Howieson, D and Papka, M and Green, J and Gamst, A and Kukull, W and Thal,
LJ},
Title = {The Alzheimer's Disease Centers' Neuropsychological Database
Initiative: A Resource for Alzheimer's Disease Prevention
Trials},
Pages = {129-140},
Publisher = {Wiley},
Year = {2001},
Month = {March},
ISBN = {9780471521761},
url = {http://dx.doi.org/10.1002/0470846453.ch13},
Doi = {10.1002/0470846453.ch13},
Key = {fds372627}
}
@article{fds372476,
Author = {Welsh‐Bohmer, KA and Hulette, C and Schmechel, D and Burke, J and Saunders, A},
Title = {Neuropsychological Detection of Preclinical Alzheimer's
Disease: Results of a Neuropathological Series of
‘Normal’ Controls},
Pages = {111-122},
Publisher = {Wiley},
Year = {2001},
Month = {March},
ISBN = {9780471521761},
url = {http://dx.doi.org/10.1002/0470846453.ch11},
Doi = {10.1002/0470846453.ch11},
Key = {fds372476}
}
@article{fds277015,
Author = {Steffens, DC and MacFall, JR and Payne, ME and Welsh-Bohmer, KA and Krishnan, KR},
Title = {Grey-matter lesions and dementia.},
Journal = {Lancet},
Volume = {356},
Number = {9242},
Pages = {1686-1687},
Year = {2000},
Month = {November},
ISSN = {0140-6736},
url = {http://www.ncbi.nlm.nih.gov/pubmed/11089848},
Doi = {10.1016/S0140-6736(05)70393-7},
Key = {fds277015}
}
@article{fds277055,
Author = {Hoffman, JM and Welsh-Bohmer, KA and Hanson, M and Crain, B and Hulette,
C and Earl, N and Coleman, RE},
Title = {FDG PET imaging in patients with pathologically verified
dementia.},
Journal = {J Nucl Med},
Volume = {41},
Number = {11},
Pages = {1920-1928},
Year = {2000},
Month = {November},
ISSN = {0161-5505},
url = {http://www.ncbi.nlm.nih.gov/pubmed/11079505},
Abstract = {UNLABELLED: The purpose of this study was to confirm with
pathologic verification 2 beliefs related to Alzheimer's
disease (AD): (a) the long-standing impression that
bilateral temporo-parietal hypometabolism, as noted on FDG
PET imaging, is the metabolic abnormality associated with
Alzheimer's disease (AD) and (b) that the sensitivity,
specificity, and diagnostic accuracy of the metabolic
pattern of bilateral temporo-parietal hypometabolism allows
differentiation between other degenerative causes of
dementia. METHODS: Twenty two individuals (8 women, 14 men)
with difficult-to-characterize memory loss or dementia
(using standard clinical criteria), and who eventually
received pathologic confirmation of diagnosis, were
evaluated. FDG PET brain scans were obtained and visually
graded by an experienced nuclear medicine physician as to
the presence of classic bilateral temporo-parietal
hypometabolism as seen in Alzheimer's type dementia.
Sensitivity, specificity, positive predictive value,
negative predictive value, and diagnostic accuracy of the
metabolic pattern of bilateral temporo-parietal
hypometabolism were determined using pathologic diagnosis as
the gold standard. RESULTS: The clinical diagnosis of
possible or probable AD was determined as the primary cause
of dementia in 12 patients. The sensitivity and specificity
of the clinical diagnosis for probable AD were 63% and 100%,
respectively. The sensitivity and specificity of the
clinical diagnosis for possible and probable AD were 75% and
100%, respectively. The sensitivity, specificity, and
diagnostic accuracy of bilateral temporo-parietal
hypometabolism being associated with AD were 93%, 63%, and
82%, respectively. CONCLUSION: This study confirms that
bilateral temporo-parietal hypometabolism is indeed the
classic metabolic abnormality associated with AD.
Furthermore, in individuals with dementia whose FDG PET
scans indicated a metabolic pattern other than bilateral
temporo-parietal hypometabolism, a cause of dementia other
than AD should be suspected. These observations may be of
clinical importance in differentiating dementia syndromes.
The sensitivity, specificity, and diagnostic accuracy of FDG
PET are acceptable as tests to be used in the evaluation of
dementia and particularly to confirm the clinical suspicion
of AD.},
Key = {fds277055}
}
@article{fds277076,
Author = {Plassman, BL and Havlik, RJ and Steffens, DC and Helms, MJ and Newman,
TN and Drosdick, D and Phillips, C and Gau, BA and Welsh-Bohmer, KA and Burke, JR and Guralnik, JM and Breitner, JC},
Title = {Documented head injury in early adulthood and risk of
Alzheimer's disease and other dementias.},
Journal = {Neurology},
Volume = {55},
Number = {8},
Pages = {1158-1166},
Year = {2000},
Month = {October},
ISSN = {0028-3878},
url = {http://www.ncbi.nlm.nih.gov/pubmed/11071494},
Abstract = {BACKGROUND: The association between antecedent head injury
and AD is inconsistent. OBJECTIVE: To examine the
association between early adult head injury, as documented
by military hospital records, and dementia in late life; and
to evaluate the interaction between head injury and APOE
epsilon4 as risk factors for dementia. METHODS: The study
had a population-based prospective historical cohort design.
It included men who were World War II Navy and Marine
veterans, and were hospitalized during their military
service with a diagnosis of either a nonpenetrating head
injury or another unrelated condition. In 1996 to 1997,
military medical records were abstracted to document the
occurrence and details of closed head injury. The entire
sample was then evaluated for dementia and AD using a
multistage procedure. There were 548 veterans with head
injury and 1228 without head injury who completed all
assigned stages of the study. The authors estimated risk of
dementia, specifically AD, using proportional hazards
models. RESULTS: Both moderate head injury (hazard ratio
[HR] = 2.32; CI = 1.04 to 5.17) and severe head injury (HR =
4.51; CI = 1.77 to 11.47) were associated with increased
risk of AD. Results were similar for dementia in general.
The results for mild head injury were inconclusive. When the
authors stratified by the number of APOE epsilon4 alleles,
they observed a nonsignificant trend toward a stronger
association between AD and head injury in men with more
epsilon4 alleles. CONCLUSIONS: Moderate and severe head
injuries in young men may be associated with increased risk
of AD and other dementias in late life. However, the authors
cannot exclude the possibility that other unmeasured factors
may be influencing this association.},
Doi = {10.1212/wnl.55.8.1158},
Key = {fds277076}
}
@article{fds277004,
Author = {Steffens, DC and Skoog, I and Norton, MC and Hart, AD and Tschanz, JT and Plassman, BL and Wyse, BW and Welsh-Bohmer, KA and Breitner,
JC},
Title = {Prevalence of depression and its treatment in an elderly
population: the Cache County study.},
Journal = {Arch Gen Psychiatry},
Volume = {57},
Number = {6},
Pages = {601-607},
Year = {2000},
Month = {June},
ISSN = {0003-990X},
url = {http://www.ncbi.nlm.nih.gov/pubmed/10839339},
Abstract = {BACKGROUND: Previous estimates of the prevalence of
geriatric depression have varied. There are few large
population-based studies; most of these focused on
individuals younger than 80 years. No US studies have been
published since the advent of the newer antidepressant
agents. METHODS: In 1995 through 1996, as part of a large
population study, we examined the current and lifetime
prevalence of depressive disorders in 4,559 nondemented
individuals aged 65 to 100 years. This sample represented
90% of the elderly population of Cache County, Utah. Using a
modified version of the Diagnostic Interview Schedule, we
ascertained past and present DSM-IV major depression,
dysthymia, and subclinical depressive disorders. Medication
use was determined through a structured interview and a
"medicine chest inventory." RESULTS: Point prevalence of
major depression was estimated at 4.4% in women and 2.7% in
men (P= .003). Other depressive syndromes were surprisingly
uncommon (combined point prevalence, 1.6%). Among subjects
with current major depression, 35.7% were taking an
antidepressant (mostly selective serotonin reuptake
inhibitors) and 27.4% a sedative/hypnotic. The current
prevalence of major depression did not change appreciably
with age. Estimated lifetime prevalence of major depression
was 20.4% in women and 9.6% in men (P<.001), decreasing with
age. CONCLUSIONS: These estimates for prevalence of major
depression are higher than those reported previously in
North American studies. Treatment with antidepressants was
more common than reported previously, but was still lacking
in most individuals with major depression. The prevalence of
subsyndromal depressive symptoms was low, possibly because
of unusual characteristics of the population.},
Doi = {10.1001/archpsyc.57.6.601},
Key = {fds277004}
}
@article{fds276943,
Author = {Tschanz, JT and Welsh-Bohmer, KA and Skoog, I and West, N and Norton,
MC and Wyse, BW and Nickles, R and Breitner, JC},
Title = {Dementia diagnoses from clinical and neuropsychological data
compared: the Cache County study.},
Journal = {Neurology},
Volume = {54},
Number = {6},
Pages = {1290-1296},
Year = {2000},
Month = {March},
ISSN = {0028-3878},
url = {http://www.ncbi.nlm.nih.gov/pubmed/10746600},
Abstract = {OBJECTIVE: To validate a neuropsychological algorithm for
dementia diagnosis. METHODS: We developed a
neuropsychological algorithm in a sample of 1,023 elderly
residents of Cache County, UT. We compared algorithmic and
clinical dementia diagnoses both based on DSM-III-R
criteria. The algorithm diagnosed dementia when there was
impairment in memory and at least one other cognitive
domain. We also tested a variant of the algorithm that
incorporated functional measures that were based on
structured informant reports. RESULTS: Of 1,023
participants, 87% could be classified by the basic
algorithm, 94% when functional measures were considered.
There was good concordance between basic psychometric and
clinical diagnoses (79% agreement, kappa = 0.57). This
improved after incorporating functional measures (90%
agreement, kappa = 0.76). CONCLUSIONS: Neuropsychological
algorithms may reasonably classify individuals on dementia
status across a range of severity levels and ages and may
provide a useful adjunct to clinical diagnoses in population
studies.},
Doi = {10.1212/wnl.54.6.1290},
Key = {fds276943}
}
@article{fds277005,
Author = {Steffens, DC and Plassman, BL and Helms, MJ and Welsh-Bohmer, KA and Newman, TT and Breitner, JC},
Title = {APOE and AD concordance in twin pairs as predictors of AD in
first-degree relatives.},
Journal = {Neurology},
Volume = {54},
Number = {3},
Pages = {593-598},
Year = {2000},
Month = {February},
ISSN = {0028-3878},
url = {http://www.ncbi.nlm.nih.gov/pubmed/10680788},
Abstract = {OBJECTIVE: To examine the independent effects of the APOE
genotype (APOE) and concordance for AD in twin pairs on the
occurrence of AD in first-degree relatives. BACKGROUND:
Studies of twins have been undertaken to investigate the
influence of genes in a variety of conditions, including AD.
A previous study, performed before reports linking APOE to
AD, demonstrated an increase in AD among first-degree
relatives of twins concordant for AD compared with relatives
of discordant twins. METHODS: In a sample of 94 twin pairs
the authors examined the association between concordance for
AD within the twin pair and family history of AD among
first-degree relatives of twins. They then examined the
extent to which the presence of the APOE epsilon4 allele in
the twin pair explains the association between concordance
for AD within the twin pair and family history of AD.
RESULTS: Concordance among twins was associated with
increased risk of AD among relatives (logrank test, chi2 =
12.558; p = 0.0004), and the presence of at least one APOE
epsilon4 allele in each member of the twin pair is also
associated with increased risk of AD among family members
(logrank test, chi2 = 7.712; p = 0.0055). CONCLUSIONS: APOE
genotype explains much but not all of the association
between concordance among twins and increased familial risk
of AD.},
Doi = {10.1212/wnl.54.3.593},
Key = {fds277005}
}
@article{fds277109,
Author = {Clark, LM and Bosworth, HB and Welsh-Bohmer, KA and Dawson, DV and Siegler, IC},
Title = {Relation between informant-rated personality and
clinician-rated depression in patients with memory
disorders.},
Journal = {Neuropsychiatry Neuropsychol Behav Neurol},
Volume = {13},
Number = {1},
Pages = {39-47},
Year = {2000},
Month = {January},
ISSN = {0894-878X},
url = {http://www.ncbi.nlm.nih.gov/pubmed/10645735},
Abstract = {OBJECTIVE: The goal of this study was to examine the
convergent validity of informant-rated changes in depressive
and related personality traits with clinician-assessed
depression in memory-disordered patients. BACKGROUND:
Depressive symptoms are frequent complications in persons
with dementias such as Alzheimer disease, and caregiver
informants consistently report changes in depression and
related neurotic traits on the NEO Personality Inventory
(NEO-PI) in dementia patients. METHODS: In 78 patients
undergoing evaluation of memory complaints at an Alzheimer
disease clinic, depression was characterized by clinical
diagnosis, a clinician-rated scale, and informant ratings of
premorbid versus current depression, anxiety, vulnerability,
and neuroticism on the NEO-PI. RESULTS: The diagnostic
groups differed in meaningful patterns on the NEO-PI
measures. Those with a diagnosis of major depression
differed from never-depressed patients in all personality
areas, although those with depressed mood differed only on
NEO-PI depression. The clinician-rated depression scale
correlated modestly with current personality and change from
baseline personality. CONCLUSIONS: The NEO-PI provides a
useful measure of informants' perspectives on depressive
personality changes in patients with memory disorders but
does not correspond fully with a clinical syndrome of
depression.},
Key = {fds277109}
}
@article{fds276985,
Author = {Dawson, DV and Welsh-Bohmer, KA and Siegler, IC},
Title = {Premorbid personality predicts level of rated personality
change in patients with Alzheimer disease.},
Journal = {Alzheimer Dis Assoc Disord},
Volume = {14},
Number = {1},
Pages = {11-19},
Year = {2000},
ISSN = {0893-0341},
url = {http://www.ncbi.nlm.nih.gov/pubmed/10718200},
Abstract = {Multiple studies of individuals with Alzheimer disease have
substantiated significant levels of informant-rated change
in several domains and facets of the Neuroticism-Extraversion-Openness
Personality Inventory, including increases in Neuroticism
and decreases in Extraversion and Conscientiousness relative
to premorbid personality traits. Decline in Openness was
cited in some reports, and replicable changes were
identified in several facets. Current and premorbid
personality of 50 patients with Alzheimer disease were rated
by informants using the Neuroticism-Extraversion-Openness
Personality Inventory. Multiple regression analysis was used
to assess possible relationships of levels of reported
change with covariates, including premorbid rating,
education, duration of dementia, age, gender, and
Mini-Mental State Examination score. Premorbid rating was
the only significant predictor of reported change for
Neuroticism, Extraversion, Conscientiousness, and the facets
Anxiety (N1), Assertiveness (E3), and Activity (E4). Rated
change in Depression was also found to be related to
duration of dementia, change in Vulnerability was influenced
by gender, and reported change in both Openness and Ideas
showed a relationship to level of education.},
Doi = {10.1097/00002093-200001000-00002},
Key = {fds276985}
}
@article{fds371215,
Author = {Yuspeh, RL and Koltai, DC and Welsh-Bohmer, KA},
Title = {Learning over trials: Normative data for an index of verbal
learning for the CERAD Word List Learning
Task},
Journal = {Archives of Clinical Neuropsychology},
Volume = {14},
Number = {8},
Pages = {670-670},
Publisher = {Oxford University Press (OUP)},
Year = {1999},
Month = {November},
url = {http://dx.doi.org/10.1093/arclin/14.8.670},
Doi = {10.1093/arclin/14.8.670},
Key = {fds371215}
}
@article{fds277013,
Author = {Welsh-Bohmer, KA and Morgenlander, JC},
Title = {Determining the cause of memory loss in the elderly. From
in-office screening to neuropsychological
referral.},
Journal = {Postgrad Med},
Volume = {106},
Number = {5},
Pages = {99-passim},
Year = {1999},
Month = {October},
ISSN = {0032-5481},
url = {http://www.ncbi.nlm.nih.gov/pubmed/10560471},
Abstract = {Improved understanding of neurobehavior in normal aging,
Alzheimer's disease, and late-life depression makes early
detection of neurodegenerative conditions possible. Primary
care physicians can screen patients' mental status and mood
states with simple in-office tests. When screening results
or the clinical picture is ambiguous or complex,
neuropsychological evaluation is useful in making an early,
reliable differentiation between dementia and normal aging.
Early identification of neurologic problems provides an
opportunity to enhance quality of life and long-term care.
Medical interventions, such as a trial of donepezil
hydrochloride (Aricept) or other memory-enhancing
medications as they become available, can be started when
results are likely to be optimal. Common coexisting problems
(e.g., depression, falls) can be sought and managed.
Additional important medical decisions (e.g., elective
surgeries) may be considered differently when dementia is
diagnosed early.},
Doi = {10.3810/pgm.1999.10.15.747},
Key = {fds277013}
}
@article{fds277002,
Author = {Norton, MC and Tschanz, JA and Fan, X and Plassman, BL and Welsh-Bohmer,
KA and West, N and Wyse, BW and Breitner, JC},
Title = {Telephone adaptation of the Modified Mini-Mental State Exam
(3MS). The Cache County Study.},
Journal = {Neuropsychiatry Neuropsychol Behav Neurol},
Volume = {12},
Number = {4},
Pages = {270-276},
Year = {1999},
Month = {October},
ISSN = {0894-878X},
url = {http://www.ncbi.nlm.nih.gov/pubmed/10527112},
Abstract = {OBJECTIVE: To examine the concurrent validity of a newly
developed telephone adaptation of the Modified Mini-Mental
State Exam. BACKGROUND: Longitudinal studies of cognition
may be advantaged by availability of assessment instruments
that can be used over the telephone, as well as in person.
METHOD: Subjects were 263 noninstitutionalized elderly
residents of a rural community in southern Idaho, aged 65 to
93, who had little or no cognitive difficulty. At an average
interval of four weeks, we administered the Modified
Mini-Mental State Exam (3MS) and the newly adapted Telephone
Modified Mini-Mental State Exam (T3MS). Order of
administration was randomly assigned. RESULTS: Agreement
between scores on the two instruments was good (r = 0.82, p
< 0.001). When we applied various cutoff scores to the
instruments, thereby generating assignments of individuals
to "screen positive" and "screen negative" groups, the
percent agreement in screening results ranged from 80% to
96% as we reduced the cutoff scores from 90 to 74 (100
points possible). CONCLUSIONS: At least among subjects
without major cognitive syndromes, the Telephone Modified
Mini-Mental State Exam provides a reasonable substitute for
the more costly in-person 3MS. The telephone instrument
should now be tested over a broader range of cognitive
abilities in order to assess its validity in more impaired
subjects, e.g., by studying an institutionalized
sample.},
Key = {fds277002}
}
@article{fds277003,
Author = {Steffens, DC and Norton, MC and Plassman, BL and Tschanz, JT and Wyse,
BW and Welsh-Bohmer, KA and Anthony, JC and Breitner,
JC},
Title = {Enhanced cognitive performance with estrogen use in
nondemented community-dwelling older women.},
Journal = {J Am Geriatr Soc},
Volume = {47},
Number = {10},
Pages = {1171-1175},
Year = {1999},
Month = {October},
ISSN = {0002-8614},
url = {http://www.ncbi.nlm.nih.gov/pubmed/10522948},
Abstract = {OBJECTIVE: To examine the association between history of
postmenopausal estrogen use and cognitive function in a
large sample of nondemented community-dwelling older women.
SETTING: A community of older residents in Cache County,
Utah. PARTICIPANTS: A total of 2338 nondemented women aged
65 and older. MEASUREMENTS: All subjects were administered
the Modified Mini-Mental State Examination (3MSE).
Self-reported information on current and past use of
estrogen after menopause was also obtained using a
structured interview. Estrogen use was trichotomized as: no
use, past use, and current use. Apolipoprotein E (APOE)
genotype was determined and was dichotomized by the presence
of an epsilon4 allele. A series of variance/covariance
models was conducted with the 3MSE score as the dependent
variable, first considering estrogen use alone, then adding,
sequentially as covariates, education, age, health status,
APOE genotype, current depression status, and history of
head injury. RESULTS: In the simplest bivariate model, the
3MSE means (and confidence intervals) were 92.1 (91.7-92.4),
93.5 (93.1-93.9), and 94.4 (94.0-94.7) for never-, past-,
and current users, respectively. In the final model (R2 =
0.28), no use of estrogen replacement therapy (P = .006),
lower education (P < .001), poorer perceived health status
(P = .035), current depression (P = .014), and presence of
at least one APOE epsilon4 allele (P < .001) each
independently predicted lower 3MSE score. Both current and
past estrogen users had significantly higher 3MSE scores
than never-users (P = .0063 and P = .0096, respectively).
CONCLUSIONS: In this large community study, women who had
used estrogen after menopause scored higher on the 3MSE.
This finding remained, even after controlling for the
effects of age, education, APOE genotype, and other
variables that may affect cognition. These data support
studies reporting a beneficial role of estrogen on cognition
in postmenopausal women, particularly among current estrogen
users.},
Doi = {10.1111/j.1532-5415.1999.tb05195.x},
Key = {fds277003}
}
@article{fds277020,
Author = {Hulette, CM and Pericak-Vance, MA and Roses, AD and Schmechel, DE and Yamaoka, LH and Gaskell, PC and Welsh-Bohmer, KA and Crowther, RA and Spillantini, MG},
Title = {Neuropathological features of frontotemporal dementia and
parkinsonism linked to chromosome 17q21-22 (FTDP-17): Duke
Family 1684.},
Journal = {J Neuropathol Exp Neurol},
Volume = {58},
Number = {8},
Pages = {859-866},
Year = {1999},
Month = {August},
ISSN = {0022-3069},
url = {http://www.ncbi.nlm.nih.gov/pubmed/10446810},
Abstract = {Frontotemporal dementia with parkinsonism (FTDP-17) is an
autosomal dominant disorder that presents clinically with
dementia, extrapyramidal signs, and behavioral disturbances
in mid-life and progresses to death within 5 to 10 years.
Pathologically, the disorder is characterized by variable
neuronal loss and gliosis in the frontal and temporal lobes,
limbic structures, and the midbrain. Autopsied individuals
from some kindreds display abundant neurofibrillary change
while others, including a single affected individual from
Duke Family 1684, lack distinctive histological features and
exhibit only mild neuronal loss and gliosis in limbic
structures and subcortical nuclei when examined by routine
silver stain. Recently, mutations in the microtubule
associated protein tau have been shown to segregate with the
disease in this family and in many other affected kindreds.
In order to examine the distribution of tau deposits, we
performed tau immunohistochemistry, immunoblotting, and
immunoelectron microscopy of tau-containing filaments.
Immunohistochemistry revealed numerous tau deposits within
glial cells and within neurons. Twisted ribbon-like
filaments observed by immunoelectron microscopy were
immunodecorated with tau AT8 antibody. Sarkosyl-insoluble
tau extracted from the hippocampus and cortex migrated as 2
major bands at 64 and 68 kilodaltons and a minor band at 72
kilodaltons, which after alkaline phosphatase treatment
appeared to contain mainly tau isoforms with 4 repeats.
Furthermore, the ratio of soluble tau with 4 to 3
microtubule-binding repeats was increased. The role of tau
mutations in this disorder is discussed in this
paper.},
Doi = {10.1097/00005072-199908000-00008},
Key = {fds277020}
}
@article{fds277000,
Author = {Breitner, JC and Wyse, BW and Anthony, JC and Welsh-Bohmer, KA and Steffens, DC and Norton, MC and Tschanz, JT and Plassman, BL and Meyer,
MR and Skoog, I and Khachaturian, A},
Title = {APOE-epsilon4 count predicts age when prevalence of AD
increases, then declines: the Cache County
Study.},
Journal = {Neurology},
Volume = {53},
Number = {2},
Pages = {321-331},
Year = {1999},
Month = {July},
ISSN = {0028-3878},
url = {http://dx.doi.org/10.1212/wnl.53.2.321},
Abstract = {OBJECTIVE: To examine the prevalence of Alzheimer's disease
(AD) and other dementias in relation to age, education, sex,
and genotype at APOE. Recent studies suggest age
heterogeneity in the risk of AD associated with the APOE
genotype and a possible interaction between APOE-epsilon4
and female sex as risk factors. We studied these topics in
the 5,677 elderly residents of Cache County, Utah, a
population known for long life expectancy and high
participation rates. METHODS: We screened for dementia with
a brief cognitive test and structured telephone Dementia
Questionnaire, then examined all individuals with apparent
cognitive symptoms and a sample of others. We estimated
age-specific prevalence of AD and other dementias and used
multiple logistic regression models to describe relation of
AD prevalence to age, sex, education, and APOE genotype.
RESULTS: We found 335 demented individuals, 230 (69%) with
definite, probable, or possible AD (positive predictive
value versus autopsy confirmation 85%). The adjusted
prevalence estimate for AD was 6.5% and for all dementias
9.6%. After age 90, the adjusted prevalence estimate for AD
was 28% and for all dementias 38%. Regression models showed
strong variation in AD prevalence with age, sex, education,
and number of epsilon4 alleles (effect of epsilon2 not
significant). Models were improved by a term for age-squared
(negative coefficient) and by separate terms for interaction
of age with presence of one or two epsilon4 alleles. An
association of AD with female sex was ascribable entirely to
individuals with epsilon4. CONCLUSIONS: In participants with
no epsilon4 alleles, the age-specific prevalence of AD
reached a maximum and then declined after age 95. In
epsilon4 heterozygotes a similar maximum was noted earlier
at age 87, in homozygotes at age 73. Female sex was a risk
factor for AD only in those with epsilon4. The epsilon4
allele accounted for 70% of the population attributable risk
for AD.},
Doi = {10.1212/wnl.53.2.321},
Key = {fds277000}
}
@article{fds277061,
Author = {Heyman, A and Fillenbaum, GG and Gearing, M and Mirra, SS and Welsh-Bohmer, KA and Peterson, B and Pieper, C},
Title = {Comparison of Lewy body variant of Alzheimer's disease with
pure Alzheimer's disease: Consortium to Establish a Registry
for Alzheimer's Disease, Part XIX.},
Journal = {Neurology},
Volume = {52},
Number = {9},
Pages = {1839-1844},
Year = {1999},
Month = {June},
ISSN = {0028-3878},
url = {http://www.ncbi.nlm.nih.gov/pubmed/10371532},
Abstract = {OBJECTIVE: To compare the clinical, neuropsychological, and
neuropathologic findings in patients with AD alone with
those in patients with the Lewy body variant of AD (LBV).
BACKGROUND: Prior studies indicate that patients with LBV
not only have distinct clinical and neuropsychological
differences from those with AD alone, but have a poorer
prognosis with shorter survival time. METHODS: The authors
evaluated 74 patients with autopsy-confirmed AD alone and 27
patients with LBV, and compared demographic characteristics
and clinical, neuropsychological, and neuropathologic
findings. RESULTS: The two groups of patients were
equivalent with respect to age at time of entry into the
study, years of education, and sex. Two or more
extrapyramidal clinical manifestations were found in 44% of
patients with LBV, compared with 16% of patients with AD
alone (p = 0.02). Duration of survival after entry into the
study was similar in both groups, with a mean survival of
3.6 (+/-2.1) years for AD alone versus 3.8 (+/-1.9) years
for LBV. Of the various neuropsychological tests
administered at the last Consortium to Establish a Registry
for Alzheimer's Disease evaluation, only delayed recall of a
learned word list was significantly different in the two
groups, with 32% of patients with LBV versus 15% of patients
with AD alone recalling any items (p = 0.04).
Neuropathologic findings confirmed those of previous studies
and showed that neurofibrillary tangles were significantly
less frequent in the neocortex of patients with LBV than in
those with AD alone. CONCLUSION: Compared with patients with
AD alone, those with LBV had a greater frequency of
extrapyramidal manifestations, somewhat better recall on a
selected memory task at their final evaluation, and a
significantly lower frequency of neocortical neurofibrillary
tangles at autopsy. There were no differences between the
two groups, however, in survival time from entry into the
study.},
Doi = {10.1212/wnl.52.9.1839},
Key = {fds277061}
}
@article{fds276987,
Author = {Watson, ME and Welsh-Bohmer, KA and Hoffman, JM and Lowe, V and Rubin,
DC},
Title = {The neural basis of naming impairments in Alzheimer's
disease revealed through positron emission
tomography.},
Journal = {Arch Clin Neuropsychol},
Volume = {14},
Number = {4},
Pages = {347-357},
Year = {1999},
Month = {May},
ISSN = {0887-6177},
url = {http://www.ncbi.nlm.nih.gov/pubmed/14590589},
Abstract = {The naming impairments in Alzheimer's disease (AD) have been
attributed to a variety of cognitive processing deficits,
including impairments in semantic memory, visual perception,
and lexical access. To further understand the underlying
biological basis of the naming failures in AD, the present
investigation examined the relationship of various classes
of naming errors to regional brain measures of cerebral
glucose metabolism as measured with 18 F-Fluoro-2-deoxyglucose
(FDG) and positron emission tomography (PET). Errors
committed on a visual naming test were categorized according
to a cognitive processing schema and then examined in
relationship to metabolism within specific brain regions.
The results revealed an association of semantic errors with
glucose metabolism in the frontal and temporal regions.
Language access errors, such as circumlocutions, and word
blocking nonresponses were associated with decreased
metabolism in areas within the left hemisphere.
Visuoperceptive errors were related to right inferior
parietal metabolic function. The findings suggest that
specific brain areas mediate the perceptual, semantic, and
lexical processing demands of visual naming and that visual
naming problems in dementia are related to dysfunction in
specific neural circuits.},
Doi = {10.1016/s0887-6177(98)00027-4},
Key = {fds276987}
}
@article{fds277140,
Author = {McKinney, CJ and MacCormac, ER and Welsh-Bohmer,
KA},
Title = {Hardware and software for tachistoscopy: how to make
accurate measurements on any PC utilizing the Microsoft
Windows operating system.},
Journal = {Behav Res Methods Instrum Comput},
Volume = {31},
Number = {1},
Pages = {129-136},
Year = {1999},
Month = {February},
ISSN = {0743-3808},
url = {http://www.ncbi.nlm.nih.gov/pubmed/10495844},
Abstract = {Methods for automated stimulus display and accurate response
time measurement with IBM-compatible PCs are of great
importance in cognitive research designs. Accurate
measurements of reaction times are required to interpolate
other measures, such as speed of mental processing. We
present a description of hardware and software that displays
stimulus images and performs reaction timing that is not
dependent on PC performance characteristics. This is
accomplished by electronically bypassing timing errors
normally inherent to the operation of the computer. A
high-precision external timer measures the time between
stimulus onset and a subject's push-button response while a
video blanking circuit controls the video presented to the
monitor screen. Two options for accurately detecting
stimulus onset are presented: (1) A photodetector can be
used to sense the actual onset of the stimulus on a
secondary video monitor screen; (2) the video blanking
circuit can provide a signal coincident with the initiation
of video to the monitor. Both methods result in a system
timing accuracy of 100 microseconds.},
Doi = {10.3758/bf03207703},
Key = {fds277140}
}
@article{fds277014,
Author = {Madden, DJ and Welsh-Bohmer, KA and Tupler, LA},
Title = {Task complexity and signal detection analyses of lexical
decision performance in Alzheimer's disease},
Journal = {Developmental Neuropsychology},
Volume = {16},
Number = {1},
Pages = {1-18},
Publisher = {Informa UK Limited},
Year = {1999},
Month = {January},
url = {http://dx.doi.org/10.1207/S15326942DN160101},
Abstract = {This experiment addressed the issue of whether the changes
in semantic memory performance associated with Alzheimer's
disease (AD) could be distinguished from a generalized
cognitive slowing. Young adults, healthy older adults, and
AD patients performed 3 different reaction time (RT) tasks
involving yes-no responses to visually presented letter
strings. Task complexity analyses indicated that performance
in the semantic task (lexical decision) was consistent with
a generalized slowing of cognitive function that was greater
in magnitude for AD than for normal aging. Signal detection
analyses of the lexical decision data demonstrated
AD-related changes in word-nonword discrimination, response
bias, and the relation between discrimination and RT. The
general cognitive slowing associated with AD was accompanied
by additional changes specific to the performance of this
semantic memory task.},
Doi = {10.1207/S15326942DN160101},
Key = {fds277014}
}
@article{fds371216,
Author = {Koltai, DC and Welsh-Bohmer, KA and Schmechel,
DE},
Title = {Subjective appraisals of memory functioning in dementia:
Validity and cautions},
Journal = {Archives of Clinical Neuropsychology},
Volume = {14},
Number = {1},
Pages = {82-82},
Publisher = {Oxford University Press (OUP)},
Year = {1999},
Month = {January},
url = {http://dx.doi.org/10.1093/arclin/14.1.82},
Doi = {10.1093/arclin/14.1.82},
Key = {fds371216}
}
@article{fds277019,
Author = {Hulette, CM and Welsh-Bohmer, KA and Murray, MG and Saunders, AM and Mash, DC and McIntyre, LM},
Title = {Neuropathological and neuropsychological changes in "normal"
aging: evidence for preclinical Alzheimer disease in
cognitively normal individuals.},
Journal = {J Neuropathol Exp Neurol},
Volume = {57},
Number = {12},
Pages = {1168-1174},
Year = {1998},
Month = {December},
ISSN = {0022-3069},
url = {http://www.ncbi.nlm.nih.gov/pubmed/9862640},
Abstract = {The presence of diffuse or primitive senile plaques in the
neocortex of cognitively normal elderly at autopsy has been
presumed to represent normal aging. Alternatively, these
patients may have developed dementia and clinical Alzheimer
disease (AD) if they had survived. In this setting, these
patients could be subjects for cognitive or pharmacologic
intervention to delay disease onset. We have thus followed a
cohort of cognitively normal elderly subjects with a
Clinical Dementia Rating (CDR) of 0 at autopsy. Thirty-one
brains were examined at postmortem according to Consortium
to Establish a Registry for Alzheimer Disease (CERAD)
criteria and staged according to Braak. Ten patients were
pathologically normal according to CERAD criteria (1a). Two
of these patients were Braak Stage II. Seven very elderly
subjects exhibited a few primitive neuritic plaques in the
cortex and thus represented CERAD 1b. These individuals
ranged in age from 85 to 105 years and were thus older than
the CERAD la group that ranged in age from 72 to 93.
Fourteen patients displayed Possible AD according to CERAD
with ages ranging from 66 to 95. Three of these were Braak
Stage I, 4 were Braak Stage II, and 7 were Braak Stage III.
The Apolipoprotein E4 allele was over-represented in this
possible AD group. Neuropsychological data were available on
12 individuals. In these 12 individuals, Possible AD at
autopsy could be predicted by cognitive deficits in 1 or
more areas including savings scores on memory testing and
overall performance on some measures of frontal executive
function.},
Doi = {10.1097/00005072-199812000-00009},
Key = {fds277019}
}
@article{fds276984,
Author = {Clark, LM and McDonald, WM and Welsh-Bohmer, KA and Siegler, IC and Dawson, DV and Tupler, LA and Krishnan, KR},
Title = {Magnetic resonance imaging correlates of depression in
early- and late-onset Alzheimer's disease.},
Journal = {Biol Psychiatry},
Volume = {44},
Number = {7},
Pages = {592-599},
Year = {1998},
Month = {October},
ISSN = {0006-3223},
url = {http://www.ncbi.nlm.nih.gov/pubmed/9787883},
Abstract = {BACKGROUND: Depressive symptoms are frequent complications
of Alzheimer's disease (AD). We hypothesized that AD
patients with depression would be more likely than
nondepressed AD patients to show deep white-matter,
subcortical gray-matter, and periventricular
hyperintensities on magnetic resonance imaging (MRI).
METHODS: In a retrospective study of 31 AD patients,
depression was characterized by clinical diagnosis
(DSM-III-R major depression, depressive symptoms, or no
depression), a clinician-rated depression scale, and
informant ratings of premorbid (before memory disorder) as
well as current depression using the NEO Personality
Inventory (NEO-PI), and related to qualitative and
quantitative ratings of MRI hyperintensities. RESULTS: In
contrast to reports in nondemented elderly patients, there
was no relationship between clinical diagnosis of major
depressive episode and hyperintensities; however,
clinician-rated depressive symptoms were higher in subjects
with large anterior hyperintensities. In the early-onset AD
group only, MRI abnormalities were related to greater
premorbid depression, and less increase in depression after
the onset of dementia, as rated by informants on the NEO-PI.
CONCLUSIONS: Results highlight the need to consider early-
and late-onset AD separately when assessing relationships
between personality and MRI abnormalities, and to consider
premorbid personality style when drawing conclusions about
the etiology of depressive features seen in
AD.},
Doi = {10.1016/s0006-3223(98)00106-1},
Key = {fds276984}
}
@article{fds277147,
Author = {Meyer, MR and Tschanz, JT and Norton, MC and Welsh-Bohmer, KA and Steffens, DC and Wyse, BW and Breitner, JC},
Title = {APOE genotype predicts when--not whether--one is predisposed
to develop Alzheimer disease.},
Journal = {Nat Genet},
Volume = {19},
Number = {4},
Pages = {321-322},
Year = {1998},
Month = {August},
ISSN = {1061-4036},
url = {http://www.ncbi.nlm.nih.gov/pubmed/9697689},
Doi = {10.1038/1206},
Key = {fds277147}
}
@article{fds277139,
Author = {Bass, MP and Yamaoka, LH and Scott, WK and Gaskell, PC and Welsh-Bohmer,
KA and Roses, AD and Saunders, AM and Haines, JL and Pericak-Vance,
MA},
Title = {No association of alpha1-antichymotrypsin flanking region
polymorphism and Alzheimer disease risk in early- and
late-onset Alzheimer disease patients.},
Journal = {Neurosci Lett},
Volume = {250},
Number = {2},
Pages = {79-82},
Year = {1998},
Month = {July},
ISSN = {0304-3940},
url = {http://www.ncbi.nlm.nih.gov/pubmed/9697923},
Abstract = {The alpha1-antichymotrypsin (AACT)-155 allele was found
elsewhere to have a significant effect on Alzheimer disease
(AD) risk in individuals with at least one APOE-4 allele. We
compared AACT genotypes of 284 cases of sporadic AD and 172
controls. The frequency of the AACT-155 allele did not
differ significantly between cases and controls, either
overall or when restricted to subjects with at least one
APOE-4 allele. Logistic regression controlling for age and
sex failed to show an effect due to AACT either alone or
acting with APOE. There was no evidence of an interaction
between APOE-4 and the AACT-155 allele to reduce age at
onset. Thus, our data do not support an association of
AACT-155 with risk or age at onset in AD.},
Doi = {10.1016/s0304-3940(98)00398-x},
Key = {fds277139}
}
@article{fds277059,
Author = {Fillenbaum, GG and Peterson, B and Welsh-Bohmer, KA and Kukull, WA and Heyman, A},
Title = {Progression of Alzheimer's disease in black and white
patients: the CERAD experience, part XVI. Consortium to
Establish a Registry for Alzheimer's Disease.},
Journal = {Neurology},
Volume = {51},
Number = {1},
Pages = {154-158},
Publisher = {Ovid Technologies (Wolters Kluwer Health)},
Year = {1998},
Month = {July},
ISSN = {0028-3878},
url = {http://dx.doi.org/10.1212/wnl.51.1.154},
Abstract = {We compared the progression of Alzheimer's disease (AD) in
CERAD-enrolled black and white patients, as indicated by
changes in selected clinical and neuropsychology measures,
over a 1-year time interval. Of 225 black and 935 white AD
patients who were enrolled, 148 (66%) black and 770 (82%)
white patients remained in the study. Of these, 82 black and
532 white patients provided complete in-person information
on first annual re-evaluation. Overall, with age, education,
initial level of performance on each measure, and stage of
disease at entry controlled, race had a very mild effect on
change in disease (8 df multivariate analysis of variance
[MANOVA], p < 0.047). Black patients showed less decline
than white patients, most notably for the CERAD Boston
Naming test (p < 0.02) and the third and final trial of the
10-item Word List Learning task (p < 0.003). Although
unadjusted data indicate that black and white patients
appear to differ notably at entry, our findings indicated
that differences in progression of the dementing process are
minor, suggesting that course of AD is comparable in these
racial groups. Examination over a longer period is difficult
because of the high attrition rate of black
patients.},
Doi = {10.1212/wnl.51.1.154},
Key = {fds277059}
}
@article{fds277060,
Author = {Heyman, A and Fillenbaum, GG and Welsh-Bohmer, KA and Gearing, M and Mirra, SS and Mohs, RC and Peterson, BL and Pieper,
CF},
Title = {Cerebral infarcts in patients with autopsy-proven
Alzheimer's disease: CERAD, part XVIII. Consortium to
Establish a Registry for Alzheimer's Disease.},
Journal = {Neurology},
Volume = {51},
Number = {1},
Pages = {159-162},
Publisher = {Ovid Technologies (Wolters Kluwer Health)},
Year = {1998},
Month = {July},
ISSN = {0028-3878},
url = {http://dx.doi.org/10.1212/wnl.51.1.159},
Abstract = {OBJECTIVE: To study the relation between cerebral infarction
and clinical and neuropsychologic manifestations in patients
with autopsy-proven Alzheimer's disease (AD) enrolled in the
Consortium to Establish a Registry for Alzheimer's Disease
(CERAD). BACKGROUND: Prior studies report that subjects with
neuropathologic evidence of AD and concomitant brain
infarcts had poorer cognitive function and higher frequency
of dementia than those with AD alone. METHODS: Clinical and
neuropsychologic manifestations of dementia were studied in
74 subjects with neuropathologic findings of AD alone and 32
with AD and concomitant cerebral infarcts or lacunar
lesions. RESULTS: The 32 patients with both AD and vascular
lesions were significantly older at time of death (median
age, 81 years) than the 74 patients with AD alone (76 years;
p = 0.02). At the final follow-up visit, the severity of the
dementia was greater in AD patients with vascular lesions
(median Clinical Dementia Rating [CDR] = 3) than in those
with AD alone (CDR = 2; p = 0.03). Patients with AD and
vascular lesions performed significantly worse on verbal
fluency, Boston Naming, and Mini-Mental State Examination
(MMSE) tests. No differences between the groups were
observed, however, in the semiquantitative measures of
frequency of neuritic plaques or neurofibrillary tangles.
CONCLUSIONS: The clinical-neuropathologic correlations in
CERAD patients generally confirm those in prior studies,
indicating that the presence of cerebral infarction in
patients with AD is associated with greater overall severity
of clinical dementia and poorer performance on specific
tests of language and cognitive function.},
Doi = {10.1212/wnl.51.1.159},
Key = {fds277060}
}
@article{fds371217,
Author = {Welsh-Bohmer, KA and Plassman, BL and Tschanz, JT and Norton, MC and Helms, MJ and Wyse, BW and Breitner, JCS},
Title = {Cognitive decline in aging: What is the role of
education?},
Journal = {CLINICAL NEUROPSYCHOLOGIST},
Volume = {12},
Number = {2},
Pages = {265-265},
Publisher = {SWETS ZEITLINGER PUBLISHERS},
Year = {1998},
Month = {May},
Key = {fds371217}
}
@article{fds371218,
Author = {Lowry, CM and Bigler, ED and Plassman, BL and Tshcantz, J and Welsh-Bohmer, KA and Saunders, AM and Breitner,
JCS},
Title = {A new method for quantifying cerebral atrophy in Alzheimer's
disease},
Journal = {CLINICAL NEUROPSYCHOLOGIST},
Volume = {12},
Number = {2},
Pages = {258-258},
Publisher = {SWETS ZEITLINGER PUBLISHERS},
Year = {1998},
Month = {May},
Key = {fds371218}
}
@article{fds277138,
Author = {Ikeuchi, T and Sanpei, K and Takano, H and Sasaki, H and Tashiro, K and Cancel, G and Brice, A and Bird, TD and Schellenberg, GD and Pericak-Vance, MA and Welsh-Bohmer, KA and Clark, LN and Wilhelmsen,
K and Tsuji, S},
Title = {A novel long and unstable CAG/CTG trinucleotide repeat on
chromosome 17q.},
Journal = {Genomics},
Volume = {49},
Number = {2},
Pages = {321-326},
Year = {1998},
Month = {April},
ISSN = {0888-7543},
url = {http://www.ncbi.nlm.nih.gov/pubmed/9598323},
Abstract = {Using the direct identification of repeat expansion and
cloning technique, we cloned a novel long CAG/CTG
trinucleotide repeat on chromosome 17. Using radiation
hybrid panels, the CAG/CTG repeat was mapped to chromosome
17q. The CAG/CTG repeat is highly polymorphic, with a
heterozygosity of 85%, and exhibits a bimodal distribution
(allele S, 10-26 repeat units, and allele L, 50-92 repeat
units). The CAG/CTG repeat of allele L exhibited
intergenerational instabilities, which are more prominent in
maternal transmission than in paternal transmission.
Analyses of Northern blot and RT-PCR indicate that the
repeat is transcribed. Although the size of the CAG/CTG
repeat of allele L is within the range of the expanded CAG
repeat of disease-causing genes, we did not detect any
association of allele L with various neurodegenerative
diseases, including frontotemporal dementia and
parkinsonism, mapped to 17q21-q23.},
Doi = {10.1006/geno.1998.5266},
Key = {fds277138}
}
@article{fds371219,
Author = {Pericak-Vance, MA and Rimmler, JB and Gaskell, PC and Abou-Donia, S and Welsh-Bohmer, KA and Jackson, CE and Schamel, MA and Yamaoka, LH and Haines, JL},
Title = {A genomic screen in extended Amish families with Alzheimer's
disease supports a locus on chromosome 12},
Journal = {NEUROLOGY},
Volume = {50},
Number = {4},
Pages = {A356-A356},
Publisher = {LIPPINCOTT WILLIAMS & WILKINS},
Year = {1998},
Month = {April},
Key = {fds371219}
}
@article{fds371220,
Author = {Meyer, MR and Breitner, JCS and Steffens, DC and Anthony, JC and Norton,
MA and Tschanz, JT and Wyse, BW and Welsh-Bohmer, KA and Plassman,
BL},
Title = {196. Onset of alzheimer's disease in susceptible subjects:
Influence of APOE},
Journal = {Biological Psychiatry},
Volume = {43},
Number = {8},
Pages = {S58-S58},
Publisher = {Elsevier BV},
Year = {1998},
Month = {April},
url = {http://dx.doi.org/10.1016/s0006-3223(98)90644-8},
Doi = {10.1016/s0006-3223(98)90644-8},
Key = {fds371220}
}
@article{fds277001,
Author = {Breitner, JC and Jarvik, GP and Plassman, BL and Saunders, AM and Welsh,
KA},
Title = {Risk of Alzheimer disease with the epsilon4 allele for
apolipoprotein E in a population-based study of men aged
62-73 years.},
Journal = {Alzheimer Dis Assoc Disord},
Volume = {12},
Number = {1},
Pages = {40-44},
Year = {1998},
Month = {March},
ISSN = {0893-0341},
url = {http://www.ncbi.nlm.nih.gov/pubmed/9539409},
Abstract = {The epsilon4 allele at APOE, the polymorphic locus for
apolipoprotein E, increases the risk of Alzheimer disease
(AD), especially among those with the homozygous
epsilon4/epsilon4 genotype. In family studies, epsilon4
homozygotes typically develop AD at 55-75 years, an age
range when AD is otherwise relatively infrequent.
Population-based studies of the AD risk associated with
allele epsilon4 (and especially with genotype
epsilon4/epsilon4) are limited in number, and most such
studies have included few AD cases between the ages of 55
and 75 years. In a large population-based twin registry, the
screening of 12,709 men who were 62-73 years old yielded 38
prevalent cases of AD whose onset age ranged from 54 to 73.
Genotype at APOE was determined for 37 of these cases and
independently, for a similarly aged probability sample of
344 men from the same registry. The epsilon4 allele
frequencies among the AD cases and the population samples
were 0.39 and 0.15, respectively. The odds ratios (ORs) for
AD were 17.7 for genotype epsilon4/epsilon4 versus
epsilon3/epsilon3 and 13.8 for epsilon4/epsilon4 versus all
remaining genotypes. By contrast, the ORs with heterozygous
epsilon4/epsilon3 were only 2.76 versus epsilon3/epsilon3
and 2.01 versus all genotypes other than epsilon4/epsilon3
(p for homozygote vs. heterozygote ORs=0.002). The estimated
etiologic fraction for AD with homozygous epsilon4 among men
in their mid-50s to mid 70s is therefore 0.20; for the much
more common heterozygous genotype epsilon4/epsilon3, the
fraction is 0.18. In combination with other studies that
have adjusted statistically for age, these results suggest
that the effect of the epsilon4 allele dose is neither
linear nor homogeneous for age. Homozygous epsilon4/epsilon4
appears to confer an extreme risk of AD at the age when
onset with this genotype is most likely. These results are
consistent with the view that individual genotypes modify
risk by predisposing to substantially different
distributions of AD onsets.},
Doi = {10.1097/00002093-199803000-00006},
Key = {fds277001}
}
@article{fds371221,
Author = {Heyman, A and Fillenbaum, G and Welsh-Bohmer, K and Gearing, M and Mirra, SS and Mohs, R and Peterson, B and Pieper,
C},
Title = {Clinical and neuropsychological findings in patients with
autopsy evidence of Alzheimer's disease with and without
cerebral infarction: The CERAD experience},
Journal = {NEUROLOGY},
Volume = {50},
Number = {4},
Pages = {A408-A408},
Year = {1998},
Key = {fds371221}
}
@article{fds277136,
Author = {Welsh-Bohmer, KA and Gearing, M and Saunders, AM and Roses, AD and Mirra, S},
Title = {Apolipoprotein E genotypes in a neuropathological series
from the Consortium to Establish a Registry for Alzheimer's
Disease.},
Journal = {Ann Neurol},
Volume = {42},
Number = {3},
Pages = {319-325},
Year = {1997},
Month = {September},
ISSN = {0364-5134},
url = {http://www.ncbi.nlm.nih.gov/pubmed/9307253},
Abstract = {We evaluated the sensitivity, specificity, and predictive
value of the apolipoprotein E (ApoE) epsilon4 allele for the
neuropathological diagnosis of Alzheimer disease (AD) in a
clinical series of well-characterized AD patients and
controls followed longitudinally in the multicenter study of
the Consortium to Establish a Registry for Alzheimer's
Disease (CERAD). In the 162 patients for whom autopsy and
ApoE genotype data were available, the clinical diagnosis of
AD was verified as the primary cause of dementia in 139
cases (139 of 162, or 86%). The sensitivity and specificity
of the epsilon4 allele for AD were both 83%. The positive
predictive value of the epsilon4 allele was very high at 97%
(115 of 119); whereas, the negative predictive value was 44%
(19 of 43), providing no useful information for diagnosis of
AD when the epsilon4 allele is not present. Of the cases
where AD was not considered the primary or sole cause of
dementia (n = 23), 6 cases exhibited concomitant
neuropathological findings of definite or probable AD and 2
of these 6 cases had at least one epsilon4 allele. These
multicenter data extend previous observations reported from
smaller case series of single laboratories and demonstrate
that once the clinical diagnosis of AD is established, the
presence of an epsilon4 allele reliably predicts the
ultimate CERAD neuropathological diagnosis of AD. The
findings also suggest that ApoE genotype information is
useful clinically in bolstering diagnostic confidence when
an epsilon4 allele is present and in identifying a group of
patients for whom additional diagnostic evaluations may be
warranted when the epsilon4 allele is absent.},
Doi = {10.1002/ana.410420308},
Key = {fds277136}
}
@article{fds277137,
Author = {Welsh-Bohmer, KA and Mohs, RC},
Title = {Neuropsychological assessment of Alzheimer's
disease.},
Journal = {Neurology},
Volume = {49},
Number = {3 Suppl 3},
Pages = {S11-S13},
Year = {1997},
Month = {September},
ISSN = {0028-3878},
url = {http://dx.doi.org/10.1212/wnl.49.3_suppl_3.s11},
Abstract = {The CERAD neuropsychological battery has been found to be a
valuable tool for clinical as well as research
investigations and has contributed considerably to the
identification and clinical understanding of AD. The CERAD
data addressing effects of age, education, sex, race, and
culture on neuropsychological performance are important in
the clinical interpretation of cognitive performance in the
elderly. Information on the performance of AD patients at
different levels of severity of dementia has enhanced the
reliability of clinical detection and staging of AD dementia
over time. Studies addressing longitudinal changes on the
CERAD neuropsychological measures have also helped to define
the natural history of AD and provide insights into the
limitations of various neuropsychological measures at
different stages of the illness. The neuropsychological
battery, although designed to assess AD, may be valuable in
differential diagnosis of some dementias.},
Doi = {10.1212/wnl.49.3_suppl_3.s11},
Key = {fds277137}
}
@article{fds277018,
Author = {Hulette, CM and Welsh-Bohmer, KA and Crain, B and Szymanski, MH and Sinclaire, NO and Roses, AD},
Title = {Rapid brain autopsy. The Joseph and Kathleen Bryan
Alzheimer's Disease Research Center experience.},
Journal = {Arch Pathol Lab Med},
Volume = {121},
Number = {6},
Pages = {615-618},
Year = {1997},
Month = {June},
ISSN = {0003-9985},
url = {http://www.ncbi.nlm.nih.gov/pubmed/9199629},
Abstract = {OBJECTIVE: To develop a system for retrieving brain tissue
within 1 hour after death in an effective and useful manner.
DESIGN: Nurse clinicians were employed as study
co-ordinators and were available to families 24 hours each
day. SETTING: Autopsies were performed at Duke University
Medical Center, Durham, NC, from 1985 through 1995.
PARTICIPANTS: Neuropathology faculty, fellows, and
residents, autopsy technicians; and brain bank staff.
RESULTS: Fifty-one rapid autopsies with a postmortem
interval of less than 1 hour have been performed. Four of
these were normal controls, three were disease controls, and
44 represented Alzheimer's disease patients. Tissue
retrieved at rapid autopsy has been distributed to 93
research teams, 30 of these located at Duke University
Medical Center. Many researchers have received multiple
shipments of tissue. CONCLUSIONS: The Bryan Alzheimer's
Disease Research Center Rapid Autopsy Program at Duke
University Medical Center has been successful in retrieving
tissue from individuals with dementia and also from controls
within 1 hour of death. The critical features of the success
of this program have been the use of nurse clinicians who
work closely with patients and their families to ensure a
successful autopsy at the time of death and the maintenance
of a 24-hour call schedule for nurses and neuropathology
staff. Similar programs can be implemented for experimental
work into the pathogenesis of a wide variety of human
diseases in which the examination of human tissue is
required.},
Key = {fds277018}
}
@article{fds276999,
Author = {Steffens, DC and Plassman, BL and Helms, MJ and Welsh-Bohmer, KA and Saunders, AM and Breitner, JC},
Title = {A twin study of late-onset depression and apolipoprotein E
epsilon 4 as risk factors for Alzheimer's
disease.},
Journal = {Biol Psychiatry},
Volume = {41},
Number = {8},
Pages = {851-856},
Year = {1997},
Month = {April},
ISSN = {0006-3223},
url = {http://www.ncbi.nlm.nih.gov/pubmed/9099411},
Abstract = {A prior history of depression and the epsilon 4 allele of
apolipoprotein E (APOE) have each been associated with
development of Alzheimer's disease (AD). In a sample of 142
elderly twins from a large study of dementia, we examined
the relation of major depression, APOE genotype and AD using
time-dependent proportional hazards models. Compared against
the risk for AD with no history of depression and no epsilon
4 allele, the risk ratio for AD with two epsilon 4 alleles
was 2.87 (C.I. = 1.56-5.28), with one epsilon 4 allele, 1.82
(C.I. = 1.09-3.04) and with late-onset depression and no
epsilon 4 allele, 2.95 (C.I. = 1.55-5.62). There was no
suggestion of an interaction between prior depression and
APOE genotype in their effects on AD risk. Results were
similar when the sample was stratified by twin pair, so that
a single genetic marker is unlikely to explain the relation
among depression, APOE, and dementia. Risk ratios declined
substantially with increasing intervals between the onset of
depression and AD. Thus, for many individuals, the
association of depression and AD may reflect the occurrence
of prodromal depressive symptoms rather than a true risk
relationship.},
Doi = {10.1016/S0006-3223(96)00247-8},
Key = {fds276999}
}
@article{fds276998,
Author = {Plassman, BL and Welsh-Bohmer, KA and Bigler, ED and Johnson, SC and Anderson, CV and Helms, MJ and Saunders, AM and Breitner,
JC},
Title = {Apolipoprotein E epsilon 4 allele and hippocampal volume in
twins with normal cognition.},
Journal = {Neurology},
Volume = {48},
Number = {4},
Pages = {985-989},
Year = {1997},
Month = {April},
ISSN = {0028-3878},
url = {http://www.ncbi.nlm.nih.gov/pubmed/9109888},
Abstract = {We examined the relation of APOE-epsilon 4, hippocampal
volume, and cognitive performance in ten pairs of
cognitively normal twins who had a mean age of 62.5 years
(SD = 7.8). There were no significant differences in
neuropsychological measures of the groups categorized by the
presence of an epsilon 4 allele. However, the mean
normalized right and left hippocampal volumes were smaller
in the epsilon 4 groups compared to the group without
epsilon 4. Combined with prior reports, these findings
suggest that epsilon 4 is associated with differences in
brain morphology that may be evident when no symptoms of
dementia are present.},
Doi = {10.1212/wnl.48.4.985},
Key = {fds276998}
}
@article{fds371222,
Author = {Rimmler, JB and Gaskell, PC and Aboudonia, S and Welsh-Bohmer, K and Jackson, CE and Schamel, M and Yamaoka, L and Haines, JL and Pericak-Vance, MA},
Title = {A genomic screen in extended Amish families supports a locus
on chromosome 12 for Alzheimer disease (AD).},
Journal = {AMERICAN JOURNAL OF HUMAN GENETICS},
Volume = {61},
Number = {4},
Pages = {A292-A292},
Year = {1997},
Key = {fds371222}
}
@article{fds277149,
Author = {Yamaoka, LH and Welsh-Bohmer, KA and Hulette, CM and Gaskell, PC and Murray, M and Rimmler, JL and Helms, BR and Guerra, M and Roses, AD and Schmechel, DE and Pericak-Vance, MA},
Title = {Linkage of frontotemporal dementia to chromosome 17:
clinical and neuropathological characterization of
phenotype.},
Journal = {Am J Hum Genet},
Volume = {59},
Number = {6},
Pages = {1306-1312},
Year = {1996},
Month = {December},
ISSN = {0002-9297},
url = {http://www.ncbi.nlm.nih.gov/pubmed/8940276},
Abstract = {Frontotemporal dementia is a behavioral disorder of
insidious onset and variable progression. Clinically, its
early features reflect frontal lobe dysfunction
characterized by personality change, deterioration in memory
and executive functions, and stereotypical and perseverative
behaviors. Pathologically, there is degeneration of the
neocortex and subcortical nuclei, without distinctive
features such as plaques, neurofibrillary tangles, or Pick
or Lewy bodies. Within-family variation in neuropathology
and clinical phenotype is observed. In cases where family
aggregation is observed, it is inherited as an autosomal
dominant, age-dependent disorder. Family studies recently
have identified two dementia loci: chromosome 17 for
disinhibition-dementia-parkinsonism-amyotrophic complex and
pallido-ponto-nigral degeneration and chromosome 3 for
familial nonspecific dementia. We describe a family
(DUK1684) with clinically and neuropathologically confirmed,
autosomal dominant, non-Alzheimer disease dementia. Linkage
analysis of this family showed evidence for linkage to
chromosome 17q21, with a multipoint location score (log10)
of 5.52. A comparison of the clinical and pathological
features in DUK1684 with those of the other chromosome
17-linked families, together with the linkage data, suggests
that these families are allelic. These studies emphasize
that genetic linkage analysis remains a useful tool for
differentiating disease loci in clinically complex
traits.},
Key = {fds277149}
}
@article{fds277135,
Author = {Davidson, M and Harvey, P and Welsh, KA and Powchik, P and Putnam, KM and Mohs, RC},
Title = {Cognitive functioning in late-life schizophrenia: a
comparison of elderly schizophrenic patients and patients
with Alzheimer's disease.},
Journal = {Am J Psychiatry},
Volume = {153},
Number = {10},
Pages = {1274-1279},
Year = {1996},
Month = {October},
ISSN = {0002-953X},
url = {http://dx.doi.org/10.1176/ajp.153.10.1274},
Abstract = {OBJECTIVE: Previous studies have suggested that geriatric
inpatients with chronic schizophrenia manifest profound
cognitive impairments. This study investigated how these
cognitive impairments resemble those seen in degenerative
dementing conditions. METHOD: The neuropsychological battery
of the Consortium to Establish a Registry for Alzheimer's
Disease (CERAD), widely used to characterize the cognitive
deficits of patients with Alzheimer's disease, was used to
compare patterns of cognitive impairment in 66 triads of
subjects consisting of one elderly patient with Alzheimer's
disease, one elderly, institutionalized patient with chronic
schizophrenia, and one elderly, cognitively normal
comparison subject who were matched on age, gender, and
education. For some analyses, the two groups of patients
were divided into subgroups according to the degree of their
cognitive impairment (mild, moderate, or severe) as
determined by their scores on the Mini-Mental State
examination. RESULTS: Relative to the comparison subjects,
both groups of patients showed cognitive deficits on each of
the neuropsychological measures. The schizophrenic patients
performed worse than the patients with Alzheimer's disease
on tests of naming and constructional praxis but were less
impaired on the test of delayed word recall. These
differences were consistent across all levels of severity of
globally measured cognitive impairment. CONCLUSIONS:
Consistent with earlier findings from postmortem studies,
these findings suggest that major differences exist in the
neurobiologic mechanisms responsible for cognitive
impairment in schizophrenia and Alzheimer's disease. Effects
directly attributable to social and environmental
differences between these two groups of patients may also
play a role.},
Doi = {10.1176/ajp.153.10.1274},
Key = {fds277135}
}
@article{fds277075,
Author = {Saunders, AM and Hulette, O and Welsh-Bohmer, KA and Schmechel, DE and Crain, B and Burke, JR and Alberts, MJ and Strittmatter, WJ and Breitner, JC and Rosenberg, C},
Title = {Specificity, sensitivity, and predictive value of
apolipoprotein-E genotyping for sporadic Alzheimer's
disease.},
Journal = {Lancet},
Volume = {348},
Number = {9020},
Pages = {90-93},
Year = {1996},
Month = {July},
ISSN = {0140-6736},
url = {http://www.ncbi.nlm.nih.gov/pubmed/8676723},
Abstract = {BACKGROUND: We aimed to determine the specificity,
sensitivity, and predictive value of apolipoprotein E (APOE)
genotyping in 67 consecutive patients with clinical
diagnoses of sporadic Alzheimer's disease (AD) who underwent
necropsy. METHODS: We studied patients who attended the Duke
Memory Disorders Clinic and were diagnosed as having
probable AD. These patients were followed up until they
died. APOE genotyping was done during life in most cases,
but in some brain tissue obtained at necropsy was used.
Members of known AD families were excluded. FINDINGS: After
neuropathological examination 57 (85%) of 67 of our patients
were confirmed as having AD including all 43 who had at
least one APOE-epsilon 4 allele. None of the patients found
not to have AD carried an epsilon 4 allele. In this series,
the specificity of the epsilon 4 allele was 100%, the
sensitivity 75%, the positive predictive value 100%, and the
negative predictive value 42%. In this necropsy-confirmed
series, the epsilon 4/epsilon 4 genotype predicted AD with
100% accuracy. The epsilon 3/epsilon 4 and epsilon 2/epsilon
4 genotypes were also unexpectedly highly specific for AD.
INTERPRETATION: Data from hundreds of necropsy-confirmed
non-AD patients in other longitudinal necropsy series will
allow the predictive value of APOE genotypes to be assessed
with useful confidence limits.},
Doi = {10.1016/s0140-6736(96)01251-2},
Key = {fds277075}
}
@article{fds277054,
Author = {Hoffman, JM and Hanson, MW and Welsh, KA and Earl, N and Paine, S and Delong, D and Coleman, RE},
Title = {Interpretation variability of 18FDG-positron emission
tomography studies in dementia.},
Journal = {Invest Radiol},
Volume = {31},
Number = {6},
Pages = {316-322},
Year = {1996},
Month = {June},
ISSN = {0020-9996},
url = {http://www.ncbi.nlm.nih.gov/pubmed/8761863},
Abstract = {RATIONALE AND OBJECTIVES: Functional imaging studies such as
18F-fluoro-18-labeled-deoxyglucose-positron emission
tomography (18FDG-PET) are being used increasingly in the
evaluation of patients with dementia. The authors evaluate
inter- and intraobserver interpretation agreement in a
diverse group of patients with clinically diagnosed dementia
and subjective memory complaints, as well as two healthy
control subjects. METHODS: Ninety-six patients with clinical
diagnoses of probable Alzheimer's disease (n = 18), possible
Alzheimer's disease (n = 33), dementia (n = 26), and mild
memory impairment (n = 17), as well as two healthy control
subjects were studied using 18FDG-PET. Three observers
graded all studies for regional 18FDG uptake in the
temporal, parietal, and frontal regions bilaterally. The
studies also were interpreted for the presence of bilateral
temporoparietal hypometabolism, which typically is present
in Alzheimer's disease. The kappa statistic was used to
determine intra- and interobserver agreement for regional
18FDG uptake and bilateral temporoparietal hypometabolism.
RESULTS: There was excellent intraobserver (kappa = .56, P <
0.0005) and interobserver (kappa = .51, P < 0.0005)
interpretation agreement for bilateral temporoparietal
hypometabolism. There also was excellent intraobserver
(kappa = .61, P < 0.000) and interobserver (kappa = .55, P <
0.000) interpretation agreement of regional 18FDG uptake.
Interobserver agreement was extremely high in those patients
who were considered clinically to have possible (kappa =
.42, P < 0.001) or probable (kappa = .42, P < 0.01)
Alzheimer's disease. CONCLUSIONS: Results confirm that
bilateral temporoparietal hypometabolism is the metabolic
abnormality associated with the diagnosis of probable
Alzheimer's disease. Furthermore, intra- and interobserver
agreement of visual interpretation of 18FDG-PET images
indicates that 18FDG-PET is acceptable as an imaging
technique in the clinical evaluation of the dementia
patient.},
Doi = {10.1097/00004424-199606000-00002},
Key = {fds277054}
}
@article{fds277074,
Author = {Steffens, DC and Welsh, KA and Burke, JR and Helms, MJ and Folstein, MF and Brandt, J and McDonald, WM and Breitner, JCS},
Title = {Diagnosis of Alzheimer's disease in epidemiologic studies by
staged review of clinical data},
Journal = {Neuropsychiatry, Neuropsychology and Behavioral
Neurology},
Volume = {9},
Number = {2},
Pages = {107-113},
Year = {1996},
Month = {April},
Abstract = {We explored the inter-rater agreement and validity of
diagnoses of Alzheimer's disease (AD) and other dementias
made in an epidemiological study. A previously described
protocol for cognitive screening and clinical assessment was
applied to a large registry of twins. An expert panel then
reviewed results from the assessment of 41 subjects whose
screening results suggested the presence of AD. After review
of the information at each of four stages of data
collection, we assessed inter-rater agreement among the
experts as well as their individual agreement with the final
consensus diagnosis. We investigated these measures to
assess the amount and quality, respectively, of new and
diagnostically useful information that was revealed at each
stage. A new scheme of weighted differences among the
available diagnostic categories was developed for these
analyses. As expected, incremental information from
successive stages of data collection enabled the panel to
increase their diagnostic agreement and rates of 'correct'
diagnoses. Over half of the total information was available,
however, after review of only the initial telephone
screening results (stage 1). A brief standardized videotape
segment of the mental status and neurologic examinations
provided substantial additional information. We were able to
compare the final consensus diagnoses with autopsy results
from seven individuals who had consensus clinical diagnoses
of Probable or Possible AD (n = 6) or 'demented,
questionable etiology' (n = 1). All these subjects had
Definite AD.},
Key = {fds277074}
}
@article{fds277058,
Author = {Welsh, KA and Fillenbaum, G and Wilkinson, W and Heyman, A and Mohs, RC and Stern, Y and Harrell, L and Edland, SD and Beekly,
D},
Title = {Neuropsychological test performance in African-American and
white patients with Alzheimer's disease.},
Journal = {Neurology},
Volume = {45},
Number = {12},
Pages = {2207-2211},
Year = {1995},
Month = {December},
ISSN = {0028-3878},
url = {http://dx.doi.org/10.1212/wnl.45.12.2207},
Abstract = {Little information exists on the performance of black versus
white patients with Alzheimer's disease on
neuropsychological tests for dementia. In this study, we
compared performance on the CERAD (Consortium to Establish a
Registry for Alzheimer's Disease) neuropsychological battery
between white (n = 830) and black (n = 158) patients with
Alzheimer's disease enrolled in the CERAD study at 23
university medical centers in the United States. The black
patients were older, had fewer years of formal education,
and were more impaired in their activities of daily living
than were the white patients. After controlling for these
characteristics and for duration of the disease and severity
of dementia, there were differences in the performance of
black and white patients on several of the cognitive
measures. Black patients scored lower than whites on tests
of visual naming and constructional praxis and on the
Mini-Mental State Examination. There were no statistical
differences in performance on tests of fluency and word list
memory. These findings suggest that cultural or experiential
differences may modify performance on specific
neuropsychological tests. These factors, in addition to age
and educational background, should be considered when
interpreting performance on neuropsychological tests in
elderly black patients with dementia.},
Doi = {10.1212/wnl.45.12.2207},
Key = {fds277058}
}
@article{fds276897,
Author = {Deguchi, A and Ohnishi, K and Nakagawa, H and Hamaguchi, H and Shiku, H and Deguchi, K},
Title = {Lipoprotein(A) and effective renal plasma flow rate in older
patients with arteriosclerotic diseases.},
Journal = {J Am Geriatr Soc},
Volume = {43},
Number = {9},
Pages = {1067-1068},
Year = {1995},
Month = {September},
ISSN = {0002-8614},
url = {http://dx.doi.org/10.1111/j.1532-5415.1995.tb05582.x},
Doi = {10.1111/j.1532-5415.1995.tb05582.x},
Key = {fds276897}
}
@article{fds276973,
Author = {Tupler, LA and Welsh, KA and Asare-Aboagye, Y and Dawson,
DV},
Title = {Reliability of the Rey-Osterrieth Complex Figure in use with
memory-impaired patients.},
Journal = {J Clin Exp Neuropsychol},
Volume = {17},
Number = {4},
Pages = {566-579},
Year = {1995},
Month = {August},
ISSN = {1380-3395},
url = {http://www.ncbi.nlm.nih.gov/pubmed/7593476},
Abstract = {Rater reliability was evaluated for the system most widely
used to assess copy and recall of the Rey Complex Figure:
the Osterrieth (1944) 18-item scoring system. The study
sample consisted of 95 subjects (49 males, 46 females), most
of whom were elderly individuals (M = 59.83, SD = 15.21
years) suffering from memory impairment. Four raters rated
copy and delayed-recall protocols, and three raters re-rated
the protocols after an interval of 3 months. Results
revealed excellent inter- and intra-rater reliability
coefficients (.85-.97) for total scores. However,
reliabilities for the 18 individual items ranged from poor
(.14) to excellent (.96). Differences in both reliability
and level of subject performance were observed as a function
of item and conditions of copy versus recall. It is
concluded that the Osterrieth scoring system supports
excellent reliability in use with memory-impaired patients
using total scores. Nevertheless, individual-item
reliability would benefit from enhancement, for example, via
amplified delineation of relevant decision
criteria.},
Doi = {10.1080/01688639508405146},
Key = {fds276973}
}
@article{fds276995,
Author = {Breitner, JC and Welsh, KA and Gau, BA and McDonald, WM and Steffens,
DC and Saunders, AM and Magruder, KM and Helms, MJ and Plassman, BL and Folstein, MF},
Title = {Alzheimer's disease in the National Academy of
Sciences-National Research Council Registry of Aging Twin
Veterans. III. Detection of cases, longitudinal results, and
observations on twin concordance.},
Journal = {Arch Neurol},
Volume = {52},
Number = {8},
Pages = {763-771},
Year = {1995},
Month = {August},
ISSN = {0003-9942},
url = {http://www.ncbi.nlm.nih.gov/pubmed/7639628},
Abstract = {OBJECTIVES: To detect cases of Alzheimer's disease (AD) in a
large population of twins living throughout the United
States and to examine concordance for AD in twins as a
function of age and genotype for apolipoprotein E (APOE).
SETTING: Nationwide survey. DESIGN: Multistage screening and
field evaluation beginning with two telephone interviews and
culminating with laboratory tests, longitudinal
neuropsychological measures, physician examination, and
diagnostic consensus among experts. PARTICIPANTS: Membership
in 1990-1991 of intact pairs in the National Academy of
Sciences--National Research Council Registry of veteran
twins, then aged 62 to 73 years. MAIN OUTCOME MEASURES:
Completeness of case detection was examined in collateral
studies. Zygosity and APOE genotypes were determined by
restriction mapping. Concordance was calculated by the
proband method. RESULTS: Ninety subjects who screened
positively for AD were studied in person, and 60 whose
differential diagnoses included AD were followed up, as were
their co-twins. Sensitivity of screening was estimated at
greater than 99%, but 24% of subjects refused participation
after initial screening. Seven of 38 diagnoses of AD have
been confirmed at autopsy, and 31 other subjects eventually
met criteria for probable or possible AD (prevalence
estimate, 0.42%, 95% confidence interval, 0.29% to 0.56%),
with good interrater reliability (intraclass r = .86).
Excluding one discordant pair with unknown zygosity,
concordance rates were 21.1% (4/19) for monozygotic and
11.1% (2/18) for dizygotic probands. Concordance was 50% for
twins sharing the epsilon 4/epsilon 4 genotype at APOE, but
there were no affected co-twins of 15 probands with onset
before age 70 years, no epsilon 4 allele, and no family
history of AD. The mean (SD) period of discordance in the
latter pairs was 11.3 (3.3) years. CONCLUSIONS: The
multistage case-detection approach achieved reliable and
valid diagnoses of AD with high apparent sensitivity but
substantial attrition after initial screening. Genetic
influences in AD at this age are limited, except among
homozygotes for allele epsilon 4 at APOE. Subjects with
early-onset AD who lack the epsilon 4 allele are not rare,
and their condition appears to have little genetic
influence. They should be ideal for studies on environmental
cause of AD.},
Doi = {10.1001/archneur.1995.00540320035011},
Key = {fds276995}
}
@article{fds276997,
Author = {Plassman, BL and Welsh, KA and Helms, M and Brandt, J and Page, WF and Breitner, JC},
Title = {Intelligence and education as predictors of cognitive state
in late life: a 50-year follow-up.},
Journal = {Neurology},
Volume = {45},
Number = {8},
Pages = {1446-1450},
Year = {1995},
Month = {August},
ISSN = {0028-3878},
url = {http://www.ncbi.nlm.nih.gov/pubmed/7644038},
Abstract = {We evaluated the relation of education and intelligence in
early adult life to cognitive function in a group of elderly
male twins. The Army General Classification Test (AGCT) was
administered to US armed forces inductees in the early
1940s. Fifty years later, as part of a study of dementia in
twins, we tested the cognitive status of 930 of these men
using the modified Telephone Interview for Cognitive Status
(TICS-m). TICS-m scores obtained in later life were
correlated with AGCT scores (r = 0.457) and with years of
education (r = 0.408). Thus, in univariate analyses, the
AGCT score accounted for 20.6% and education accounted for
16.7% of variance in cognitive status. However, these two
effects were not fully independent. A multivariable model
using AGCT score, education, and the interaction of the two
variables as predictors of the TICS-m score explained 24.8%
of the variance, a slightly but significantly greater
proportion than was explained by either factor alone. In a
separate analysis based on 604 pairs of twins who took the
AGCT, heritability of intelligence (estimated by AGCT score)
was 0.503. Although this study does not address the issue of
education and premorbid IQ as risk factors for dementia, the
findings suggest that basic cognitive abilities in late life
are related to cognitive performance measures from early
adult life (ie, education and IQ).},
Doi = {10.1212/wnl.45.8.1446},
Key = {fds276997}
}
@article{fds276996,
Author = {Smith, CJ and Lippiello, PM and Ashford, JW},
Title = {Smoking, Alzheimer's disease, and confounding with
genes.},
Journal = {Lancet},
Volume = {345},
Number = {8956},
Pages = {1054},
Year = {1995},
Month = {April},
url = {http://dx.doi.org/10.1016/s0140-6736(95)90796-3},
Doi = {10.1016/s0140-6736(95)90796-3},
Key = {fds276996}
}
@article{fds276993,
Author = {Plassman, BL and Helms, MJ and Welsh, KA and Saunders, AM and Breitner,
JC},
Title = {Smoking, Alzheimer's disease, and confounding with
genes.},
Journal = {Lancet},
Volume = {345},
Number = {8946},
Pages = {387},
Year = {1995},
Month = {February},
ISSN = {0140-6736},
url = {http://www.ncbi.nlm.nih.gov/pubmed/7772122},
Doi = {10.1016/s0140-6736(95)90374-7},
Key = {fds276993}
}
@article{fds277134,
Author = {Breitner, JC and Welsh, KA},
Title = {Diagnosis and management of memory loss and cognitive
disorders among elderly persons.},
Journal = {Psychiatr Serv},
Volume = {46},
Number = {1},
Pages = {29-35},
Year = {1995},
Month = {January},
url = {http://dx.doi.org/10.1176/ps.46.1.29},
Abstract = {Memory loss and other cognitive dysfunctions, although
common in elderly persons, are not universal features of old
age. Instead they herald the presence of various
neuropsychiatric diseases, which are first recognized as
syndromes. The two most common neuropsychiatric syndromes,
dementia and delirium, produce global changes in cognition
and other capacities. They are differentiated by the
patient's level of consciousness, which is impaired in
delirium but intact in dementia. Delirium is generally
reversible and often indicates serious physical illness.
Although dementia is occasionally reversible, the mainstays
of its management and treatment are palliative. Comorbid
psychiatric symptoms are common in patients with both
delirium or dementia, and their recognition and treatment
constitute an important task for the geropsychiatrist. The
differential diagnosis of primary dementing illness and
other psychiatric illnesses such as depression is complex,
because symptoms of the two kinds of disorders often coexist
and common pathogenetic mechanisms may underlie both
syndromes.},
Doi = {10.1176/ps.46.1.29},
Key = {fds277134}
}
@article{fds276941,
Author = {Breitner, JC and Welsh, KA},
Title = {Genes and recent developments in the epidemiology of
Alzheimer's disease and related dementia.},
Journal = {Epidemiol Rev},
Volume = {17},
Number = {1},
Pages = {39-47},
Year = {1995},
url = {http://dx.doi.org/10.1093/oxfordjournals.epirev.a036184},
Abstract = {In the search for cause or prevention of Alzheimer's
disease, the traditional aims of analytic epidemiology have
been hindered by several technical difficulties. The
heterogeneous genetic influences on Alzheimer's disease have
probably contributed substantially to difficulties in the
detection of host or environmental factors associated with
modified disease risk. We have discussed five areas of
improved technical or theoretical approach, each of which
has materially improved the prospects for future success in
this endeavor. Improved methods of diagnosis have yielded
purer samples of "cases" and have made it more practical to
undertake population-based studies. Genetic determinants of
Alzheimer's disease risk are being understood with
increasing sophistication. A growing recognition of the
time-dependent nature of the Alzheimer process has led to
new and heuristically valuable ways of thinking about the
disease, its causes (genetic and otherwise), and its
prevention. While there is a growing consensus that
Alzheimer's disease is probably not one disease but several,
the limited success of efforts to identify distinguishable
phenotypes has largely given way to the identification of
those with various measures of disease risk and (probably)
mechanisms on the basis of identifiable genotypic variation.
Thus, several forms of this disease may soon be segregated
for separate analysis. Two of the predisposing genes have
apparent implications for disease pathogenesis; others
remain identified only as anonymous "loci" implicated by
linkage analyses. The greater understanding of genetic
mechanisms serves to enable not only studies of gene effects
in pathogenesis, but also the influence of various
environmental factors that may modify the effects.(ABSTRACT
TRUNCATED AT 250 WORDS)},
Doi = {10.1093/oxfordjournals.epirev.a036184},
Key = {fds276941}
}
@article{fds276942,
Author = {Breitner, JC and Welsh, KA and Helms, MJ and Gaskell, PC and Gau, BA and Roses, AD and Pericak-Vance, MA and Saunders, AM},
Title = {Delayed onset of Alzheimer's disease with nonsteroidal
anti-inflammatory and histamine H2 blocking
drugs.},
Journal = {Neurobiol Aging},
Volume = {16},
Number = {4},
Pages = {523-530},
Year = {1995},
ISSN = {0197-4580},
url = {http://www.ncbi.nlm.nih.gov/pubmed/8544901},
Abstract = {Factors that modify onset of Alzheimer's disease (AD) may be
revealed by comparing environmental exposures in affected
and unaffected members of discordant twin pairs or sibships.
Among siblings at high risk of AD, sustained use of
nonsteroidal anti-inflammatory drugs (NSAIDs) was associated
with delayed onset and reduced risk of AD. After adjustment
for use of NSAIDs, there was minimal effect on onset with
reported history of any of three common illnesses
(arthritis, diabetes, or acid-peptic disease). However,
independent of exposure to NSAIDs, onset was unexpectedly
delayed in those reporting extended use of histamine H2
blocking drugs. Randomized clinical trials will be needed to
affirm the utility of these drugs for prevention, but the
present findings may have implications for pathogenesis:
because NSAIDs block the calcium-dependent postsynaptic
cascade that induces excitotoxic cell death in NMDA-reactive
neurons, and because histamine potentiates such events,
excitotoxicity may deserve additional investigation in
AD.},
Doi = {10.1016/0197-4580(95)00049-k},
Key = {fds276942}
}
@article{fds276937,
Author = {Reed, T and Carmelli, D and Swan, GE and Breitner, JC and Welsh, KA and Jarvik, GP and Deeb, S and Auwerx, J},
Title = {Lower cognitive performance in normal older adult male twins
carrying the apolipoprotein E epsilon 4 allele.},
Journal = {Arch Neurol},
Volume = {51},
Number = {12},
Pages = {1189-1192},
Year = {1994},
Month = {December},
ISSN = {0003-9942},
url = {http://dx.doi.org/10.1001/archneur.1994.00540240033012},
Abstract = {OBJECTIVE: Given the strong association of the
apolipoprotein E (apoE) allele epsilon 4 with late-onset
Alzheimer dementia or multi-infarct dementia, we tested
whether normal older adult men with at least one epsilon 4
allele demonstrate subclinical changes in cognition and
perform more poorly on tests of cognitive function compared
with subjects without the epsilon 4 allele. DESIGN:
Matched-pair design of normal adult male (average age, 63
years) fraternal twins. SETTING: Subjects voluntarily
participated on an outpatient basis at a research or medical
center facility. PARTICIPANTS: Members of the National
Heart, Lung, and Blood Institute twin panel third
examination previously genotyped for apoE. MAIN OUTCOME
MEASURE: Education-adjusted scores on several
neuropsychological tests were compared in twins discordant
for the apoE epsilon 4 allele. Subjects with documented
cerebrovascular disease were excluded. RESULTS: Among 20
fraternal twin pairs discordant for the presence of epsilon
4, twins with the epsilon 4 allele demonstrated poorer mean
performance than their co-twins without the epsilon 4
allele. This relationship was also noted cross-sectionally
where age- and education-adjusted scores of 50 individual
twin subjects with at least one epsilon 4 allele
demonstrated poorer performance compared with 138 individual
twins without an epsilon 4 allele. CONCLUSIONS: The apoE
epsilon 4 allele may be associated with decreased cognitive
function in discordant twin pairs. Our results suggest that
epsilon 4 may represent a potential marker for accelerated
cognitive aging and such individuals may be at greater risk
for development of late-onset Alzheimer dementia or
multi-infarct dementia.},
Doi = {10.1001/archneur.1994.00540240033012},
Key = {fds276937}
}
@article{fds276938,
Author = {Norton, MC and Breitner, JC and Welsh, KA and Wyse,
BW},
Title = {Characteristics of nonresponders in a community survey of
the elderly.},
Journal = {J Am Geriatr Soc},
Volume = {42},
Number = {12},
Pages = {1252-1256},
Year = {1994},
Month = {December},
url = {http://dx.doi.org/10.1111/j.1532-5415.1994.tb06506.x},
Abstract = {OBJECTIVE: To identify predictors of nonresponse in a
community survey of cognitive status in the elderly. DESIGN:
Cross-sectional community survey with two stages of
recruitment: an initial, less-intensive method, followed by
a more aggressive approach that included face-to-face
contact. Characteristics of initial nonresponders and
responders were compared. SETTING: A close-knit rural
community with higher than usual proportions of elderly,
especially the very old. Subjects were interviewed in their
homes. Collateral informants were subsequently interviewed
by telephone. PARTICIPANTS: Utah heads of household aged 75
and older who resided in a noninstitutionalized setting.
MEASUREMENTS: Mini-Mental State Examination (MMSE), Dementia
Questionnaire, and an autobiographical risk factor and
family history questionnaire provided measures for all
independent variables. The dependent variable was status as
initial responders or initial nonresponders. RESULTS: An
initial participation rate of 63% was achieved, but a final
rate of 93% was achieved when initial nonresponders were
contacted later face-to-face. MMSE score was significantly
related to responder status when analyzed alone (beta =
-.19, P = 0.02) and remained a significant predictor after
adjusting for education and whether born in Cache County
(beta = -.16, P = 0.041) or current drinking, diabetes, or
"other" health problems (beta = -.18, P = 0.028). After
controlling for the informant report of subject's problems
with activities of daily living, MMSE score fell just below
statistical significance (beta = -.16, P = 0.079).
CONCLUSIONS: Nonresponders in community surveys of the
elderly appear to be disproportionately cognitively
impaired. The increase in participation rates achieved after
more persistent recruitment suggests that many initial
nonresponders can still be recruited if intensive methods
are used.},
Doi = {10.1111/j.1532-5415.1994.tb06506.x},
Key = {fds276938}
}
@article{fds277053,
Author = {Welsh, KA and Hoffman, JM and Earl, NL and Hanson,
MW},
Title = {Neural correlates of dementia: regional brain metabolism
(FDG-PET) and the CERAD neuropsychological
battery.},
Journal = {Arch Clin Neuropsychol},
Volume = {9},
Number = {5},
Pages = {395-409},
Year = {1994},
Month = {October},
ISSN = {0887-6177},
url = {http://www.ncbi.nlm.nih.gov/pubmed/14589655},
Abstract = {The present Investigation examined the biological correlates
of the cognitive deficits of Alzheimer's disease and related
dementias using the neuropsychological assessment battery of
the Consortium to Establish a Registry of Alzheimer's
Disease (CERAD) and positron emission tomography (PET).
Resting state cerebral glucose metabolism was measured using
the labelled radiotracer, [18F] Fluoro-2-deoxyglucose (FDG),
in a sample of patients with mild to moderate dementia (n =
66). Specific and predictable relationships were seen
between regional brain metabolism (left and right, frontal,
temporal, and parietal lobes) and the neuropsychological
measures of verbal fluency, constructional praxis, and
verbal list learning. On tests of naming and delayed verbal
recall only diminished FDG uptake in the left frontal lobe
and the left temporal lobe, respectively, approached
significance. This study demonstrates the expected
relationships between neuropsychological performance and
regional cerebral metabolism, thereby providing support for
the CERAD battery as a valid measure in the clinical
evaluation of dementia and for the use of FDG-PET in
brain-behavior studies of dementia.},
Doi = {10.1093/arclin/9.5.395},
Key = {fds277053}
}
@article{fds276983,
Author = {Siegler, IC and Dawson, DV and Welsh, KA},
Title = {Caregiver ratings of personality change in Alzheimer's
disease patients: a replication.},
Journal = {Psychol Aging},
Volume = {9},
Number = {3},
Pages = {464-466},
Year = {1994},
Month = {September},
ISSN = {0882-7974},
url = {http://www.ncbi.nlm.nih.gov/pubmed/7999331},
Abstract = {Caregivers of 26 patients with Alzheimer's disease (AD)
rated current and premorbid personality patterns with the
NEO Personality Inventory. Results replicated previous
findings on the degree of change reported in a previous
group of patients with mixed memory disorder diagnoses.
After a diagnosis of AD, the patients were rated as
significantly more neurotic, less extraverted, less open,
and less conscientious. There were no rated differences of
changes in the personality domain of Agreeableness. These
results strengthen the usefulness of caregiver ratings of
personality change of patients with memory problems who
cannot be useful informants on their own
behalf.},
Doi = {10.1037//0882-7974.9.3.464},
Key = {fds276983}
}
@article{fds277056,
Author = {Fillenbaum, GG and Wilkinson, WE and Welsh, KA and Mohs,
RC},
Title = {Discrimination between stages of Alzheimer's disease with
subsets of Mini-Mental State Examination items. An analysis
of Consortium to Establish a Registry for Alzheimer's
Disease data.},
Journal = {Arch Neurol},
Volume = {51},
Number = {9},
Pages = {916-921},
Year = {1994},
Month = {September},
ISSN = {0003-9942},
url = {http://www.ncbi.nlm.nih.gov/pubmed/8080392},
Abstract = {OBJECTIVE: To identify minimal sets of Mini-Mental State
Examination (MMSE) items that can distinguish normal control
subjects from patients with mild Alzheimer's disease (AD),
patients with mild from those with moderate AD, and those
with moderate from those with severe AD. DESIGN: Two
randomly selected equivalent half samples. Results of
logistic regression analysis from data from the first half
of the sample were confirmed by receiver operating
characteristic curves on the second half. SETTING: Memory
disorders clinics at major medical centers in the United
States affiliated with the Consortium to establish a
Registry for Alzheimer's Disease (CERAD). PARTICIPANTS:
White, normal control subjects (n = 412) and patients with
AD (n = 621) who met CERAD criteria; nonwhite subjects (n =
165) and persons with missing data (n = 27) were excluded.
MAIN OUTCOME MEASURES: Three four-item sets of MMSE items
that discriminate, respectively, (1) normal controls from
patients with mild AD, (2) patients with mild from those
with moderate AD, and (3) patients with moderate from those
with severe AD. RESULTS: The MMSE items discriminating
normal controls from patients with mild AD were day, date,
recall of apple, and recall of penny; those discriminating
patients with mild from those with moderate AD were month,
city, spelling world backward, and county, and those
discriminating patients with moderate from those with severe
AD were floor of building, repeating the word table, naming
watch, and folding paper in half. Performance on the first
two four-item sets was comparable with that of the full
MMSE; the third set distinguished patients with moderate
from those with severe AD better than chance. CONCLUSIONS: A
minimum set of MMSE items can effectively discriminate
normal controls from patients with mild AD and between
successive levels of severity of AD. Data apply only to
white patients with AD. Performance in minorities, more
heterogeneous groups, or normal subjects with questionable
cognitive status has not been assessed.},
Doi = {10.1001/archneur.1994.00540210088017},
Key = {fds277056}
}
@article{fds277057,
Author = {Welsh, KA and Butters, N and Mohs, RC and Beekly, D and Edland, S and Fillenbaum, G and Heyman, A},
Title = {The Consortium to Establish a Registry for Alzheimer's
Disease (CERAD). Part V. A normative study of the
neuropsychological battery.},
Journal = {Neurology},
Volume = {44},
Number = {4},
Pages = {609-614},
Year = {1994},
Month = {April},
ISSN = {0028-3878},
url = {http://dx.doi.org/10.1212/wnl.44.4.609},
Abstract = {The neuropsychological tests developed for the Consortium to
Establish a Registry for Alzheimer's Disease (CERAD) are
currently used to measure cognitive impairments of
Alzheimer's disease (AD) in clinical investigations of this
disorder. This report presents the normative information for
the CERAD battery, obtained in a large sample (n = 413) of
control subjects (ages 50 to 89) who were enrolled in 23
university medical centers in the United States
participating in the CERAD study from 1987 to 1992. We
compared separately the performance of subjects with high (>
or = 12) and low (< 12) years of formal education. For many
of the individual cognitive measures in the highly educated
group, we observed significant age and gender effects. Only
the praxis measure showed a significant age effect in the
low-education group. Delayed recall, when adjusted for
amount of material acquired (savings), was relatively
unaffected by age, gender, and level of education. Our
findings suggest that the savings scores, in particular, may
be useful in distinguishing between AD and normal
aging.},
Doi = {10.1212/wnl.44.4.609},
Key = {fds277057}
}
@article{fds276994,
Author = {Breitner, JC and Gau, BA and Welsh, KA and Plassman, BL and McDonald,
WM and Helms, MJ and Anthony, JC},
Title = {Inverse association of anti-inflammatory treatments and
Alzheimer's disease: initial results of a co-twin control
study.},
Journal = {Neurology},
Volume = {44},
Number = {2},
Pages = {227-232},
Year = {1994},
Month = {February},
ISSN = {0028-3878},
url = {http://www.ncbi.nlm.nih.gov/pubmed/8309563},
Abstract = {We conducted a co-twin control study among 50 elderly twin
pairs with onsets of Alzheimer's disease (AD) separated by 3
or more years. Twenty-three male pairs (46%) were screened
from the (U.S.) National Academy of Sciences-National
Research Council Registry (NAS-NRC Registry) of World War II
veteran twins; others (mostly women) had responded to
advertisements or were referred from AD clinics. Twenty-six
pairs (52%) were monozygous. The onset of AD was inversely
associated with prior use of corticosteroids or ACTH (odds
ratio [OR], 0.25; 95% confidence interval [CI], 0.06 to
0.95; p = 0.04). Similar but weaker trends were present
among pairs discordant for history of arthritis or for prior
daily use of nonsteroidal anti-inflammatory drugs (NSAIDs)
or aspirin. The association was strongest when we combined
use of steroids/ACTH or NSAIDs post hoc into a single
variable of anti-inflammatory drugs (AIs) (OR, 0.24; CI,
0.07 to 0.74; p = 0.01). The inverse relation was strong in
female (volunteer) twin pairs but was not present in the
younger men from the NAS-NRC Registry. AIs had typically
been taken for arthritis or related conditions, but a
similar result was apparent after controlling statistically
for the arthritis variable (OR, 0.08; CI, 0.01 to 0.69; p =
0.02). AIs have been proposed as a means of retarding the
progression of AD symptoms, and these data suggest that AIs
may also prevent or delay the initial onset of AD symptoms.
Because of limitations in the case-control method, our
results require corroboration with hypothesis-driven
research designed to control bias and confounding.},
Doi = {10.1212/wnl.44.2.227},
Key = {fds276994}
}
@article{fds276992,
Author = {Plassman, BL and Newman, TT and Welsh, KA and Helms, M and Breitner,
JCS},
Title = {Properties of the telephone interview for cognitive status:
Application in epidemiological and longitudinal
studies},
Journal = {Neuropsychiatry, Neuropsychology and Behavioral
Neurology},
Volume = {7},
Number = {3},
Pages = {235-241},
Year = {1994},
Month = {January},
ISSN = {0894-878X},
Abstract = {We evaluated the utility of telephone screening for dementia
in epidemiologic research by comparing performance on the
modified Telephone Interview for Cognitive Status (TICS-m)
with results from in-person neuropsychological measures in
67 elderly males. Longitudinal performance on the TICS-m was
also evaluated over an average of 15 months in the same
subjects. After comprehensive clinical evaluation, subjects
were assigned to one of three diagnostic groups: normal,
demented, or "mild-ambiguous" cognitive syndrome. As
expected, the normal group scored highest on the TICS-m,
followed in turn by the mild-ambiguous and demented groups.
Among various neuropsychological measures, the Mini-Mental
State Examination correlated most strongly with the TICS-m.
The scores on the first and second administration of the
TICS-m were significantly correlated for both the normal and
demented groups. The normal and mild-ambiguous groups showed
slight improvement on the second administration of the
TICS-m, but the demented group showed a slight decline in
their scores. Thus, the TICS-m is able to detect dementia
and decline in cognitive function over time, and therefore
appears useful for population studies as an economical
alternative to standard in-person screening. © 1994 Raven
Press, Ltd., New York.},
Key = {fds276992}
}
@article{fds276939,
Author = {Breitner, JC and Welsh, KA and Robinette, CD and Gau, BA and Folstein,
MF and Brandt, J},
Title = {Alzheimer's disease in the NAS-NRC registry of aging twin
veterans. II. Longitudinal findings in a pilot series.
National Academy of Sciences. National Research Council
Registry.},
Journal = {Dementia},
Volume = {5},
Number = {2},
Pages = {99-105},
Year = {1994},
url = {http://dx.doi.org/10.1159/000106703},
Abstract = {Over 3 years we followed 8 pairs of male twins one or both
of whom had suspected Alzheimer's disease (AD) including
'mild/ambiguous' changes suggestive of incident AD. These
pairs were screened in 1988 and 1989 from 339 pairs in the
(US) National Academy of Sciences-National Research Council
Registry (NASR) of aging veteran twins, then 61-72 years of
age. Most of the suspected cases (10 of 12) had
mild/ambiguous changes. Including these subjects, we had
estimated the prevalence of AD in the NASR as about 2%. We
now describe briefly the longitudinal evaluation of these 8
pairs. Only 1 of the 10 individuals with mild/ambiguous
changes has progressed to show well-defined clinical
symptoms of AD. Two others remain in their original research
category, while 7 clearly do not have AD. Thus, we now
estimate the 1988-1989 prevalence of AD in the NASR as 0.5%.
These results contrast with other follow-up studies of mild
cases from a university-based Alzheimer's clinic. We suggest
that the contrasting findings reflect the nature of the
samples studied, and we show that the present results are
predicted by Bayesian reasoning.},
Doi = {10.1159/000106703},
Key = {fds276939}
}
@article{fds276940,
Author = {Welsh, KA and Ballard, E and Nash, F and Raiford, K and Harrell,
L},
Title = {Issues affecting minority participation in research studies
of Alzheimer disease.},
Journal = {Alzheimer Dis Assoc Disord},
Volume = {8},
Number = {Suppl. 4},
Pages = {38-48},
Year = {1994},
Abstract = {Despite the need for minority subjects in research studies
of Alzheimer disease (AD), the successful involvement of
minority patients in such studies has been difficult. This
report discusses the many societal, economic, logistical,
and attitudinal barriers that have inhibited the
participation of minority patients and their families in
medical research programs of AD. Special consideration is
given to the unique cultural issues that arise when
conducting studies involving African-American elderly
subjects. Methods are considered for overcoming the barriers
to participation gleaned from the national study CERAD
(Consortium to Establish a Registry of Alzheimer Disease)
and other investigations of AD. Recommendations are made for
future research programs targeted on the specific health
care needs and concerns of the minority segments of our
population.},
Key = {fds276940}
}
@article{fds277131,
Author = {Brandt, J and Welsh, KA and Breitner, JC and Folstein, MF and Helms, M and Christian, JC},
Title = {Hereditary influences on cognitive functioning in older men.
A study of 4000 twin pairs.},
Journal = {Arch Neurol},
Volume = {50},
Number = {6},
Pages = {599-603},
Year = {1993},
Month = {June},
url = {http://dx.doi.org/10.1001/archneur.1993.00540060039014},
Abstract = {OBJECTIVE: To determine the contribution of genetic factors
to cognitive functioning in older men. DESIGN: Cognitive
testing by telephone interview in an epidemiologically
defined population. PARTICIPANTS: 2077 monozygotic and 2225
dizygotic male twin pairs, all between the ages of 62 and 73
years, recruited from the National Academy of Sciences twin
registry. MAIN OUTCOME MEASURES: The Telephone Interview for
Cognitive Status--Modified total score and factor scores
were analyzed. The Falconer heritability statistic and
maximum likelihood estimates of genetic and environmental
components were computed. RESULTS: Heritability of the total
Telephone Interview for Cognitive Status--Modified score was
estimated to be 30%. Shared environmental effects accounted
for an additional 18% of the variance; most of this was
related to years of education. Of the four cognitive factors
derived, the language/attention factor had the highest
heritability estimate. CONCLUSIONS: Genetic factors and
educational achievement together account for almost half of
the variance in the cognitive functioning of older men.
Studies of the genetics of dementing illnesses need to
consider the degree to which cognitive capacities are
themselves under genetic control.},
Doi = {10.1001/archneur.1993.00540060039014},
Key = {fds277131}
}
@article{fds277132,
Author = {Breitner, JC and Gatz, M and Bergem, AL and Christian, JC and Mortimer,
JA and McClearn, GE and Heston, LL and Welsh, KA and Anthony, JC and Folstein, MF},
Title = {Use of twin cohorts for research in Alzheimer's
disease.},
Journal = {Neurology},
Volume = {43},
Number = {2},
Pages = {261-267},
Year = {1993},
Month = {February},
url = {http://dx.doi.org/10.1212/wnl.43.2.261},
Abstract = {The causes of Alzheimer's disease (AD) remain a mystery
despite the recent identification of several putative
environmental risk factors and the discovery of several
linked genetic loci and point mutations associated with the
disease. Particularly uncertain is the generalizability of
the genetic findings to the common forms of disease
encountered in clinical practice or population research.
Twin studies of AD can illuminate causal mechanisms, both
genetic and environmental. This consensus document explores
the rationale for such twin studies, as well as a number of
methodologic problems that render them difficult to
implement or interpret. We review existing twin studies of
AD and note several ambitious new studies. Finally, we
delineate several practical strategies for the near future
of twin research in AD.},
Doi = {10.1212/wnl.43.2.261},
Key = {fds277132}
}
@article{fds276936,
Author = {Welsh, KA and Hoffman, JM and McDonald, WM and Earl, NL and Breitner,
JCS},
Title = {Concordant but Different: Cognitive Function, Cerebral
Anatomy, and Metabolism in Monozygotic Twins With
Alzheimer's Disease},
Journal = {Neuropsychology},
Volume = {7},
Number = {2},
Pages = {158-171},
Publisher = {American Psychological Association (APA)},
Year = {1993},
Month = {January},
ISSN = {0894-4105},
url = {http://dx.doi.org/10.1037/0894-4105.7.2.158},
Abstract = {To illustrate the utility of the twin method in Alzheimer's
disease (AD) research, we studied in detail a pair of
monozygotic twins concordant for the disease but markedly
different in their clinical presentations.
Neuropsychological evaluation, magnetic resonance brain
imaging, and cerebral glucose metabolic studies revealed a
typical behavioral presentation for AD in Twin A. In
contrast, Twin B showed prominent visuospatial impairments.
Although there was no identified cause for the disparate
presentations, a close correspondence was observed between
the neuropsychological findings and the regional brain
measures. The results suggest that the trajectory of AD may
vary widely even in genetically identical individuals.
Factors accounting for the variability include potential
intrauterine, early developmental, and environmental
differences.},
Doi = {10.1037/0894-4105.7.2.158},
Key = {fds276936}
}
@article{fds277133,
Author = {Welsh, KA and Breitner, JCS and Magruder-Habib,
KM},
Title = {Detection of dementia in the elderly using telephone
screening of cognitive status},
Journal = {Neuropsychiatry, Neuropsychology and Behavioral
Neurology},
Volume = {6},
Number = {2},
Pages = {103-110},
Year = {1993},
Month = {January},
Abstract = {Detection of dementia in large, geographically dispersed
populations is difficult. Conventional in-person
neuropsychological assessment techniques, no matter how
brief, are too costly to be practical for this purpose.
Telephone interviewing is an obvious alternative for
cognitive screening, but its practical utility is relatively
unexplored. We therefore investigated the performance
characteristics of a telephone screen for dementia in
elderly residents of congregate housing facilities. We
interviewed 209 subjects using the Telephone Interview for
Cognitive Status (TICS) and a modified version (TICS-m) that
includes items sensitive to early dementia (delayed recall)
and eliminates other items difficult to verify in survey
work. After the subjects received a brief in-person
neuropsychological assessment, TICS and TICS-m scores were
compared as predictors of the resulting clinical assignment
(normal, mildly impaired, or demented). Although the TICS-m
yielded slightly better results, both versions of the
instrument were sensitive and specific indicators of
dementia in this community sample. In a separate exercise,
both instruments also correctly identified 17 clinic
patients with carefully diagnosed Probable AD. Telephone
interviewing of cognitive function may therefore provide an
economical approach to mental status screening in research
studies where in-person assessment is impractical. © 1993
Raven Press, Ltd., New York.},
Key = {fds277133}
}
@article{fds277129,
Author = {Welsh, KA and Butters, N and Hughes, JP and Mohs, RC and Heyman,
A},
Title = {Detection and staging of dementia in Alzheimer's disease.
Use of the neuropsychological measures developed for the
Consortium to Establish a Registry for Alzheimer's
Disease.},
Journal = {Arch Neurol},
Volume = {49},
Number = {5},
Pages = {448-452},
Year = {1992},
Month = {May},
url = {http://dx.doi.org/10.1001/archneur.1992.00530290030008},
Abstract = {Our earlier studies using the Consortium to Establish a
Registry of Alzheimer's Disease neuropsychological battery
showed that delayed recall was a highly sensitive indicator
of early Alzheimer's disease. None of the learning and
memory measures in the battery were found to be useful in
staging the severity of this form of dementia. This study
explores the nonmemory functions (fluency, naming, and
praxis) of the Consortium to Establish a Registry of
Alzheimer's Disease battery and asks whether performance on
any of these measures adds to the detection of early
Alzheimer's disease or is sensitive to the later progression
of the illness. We stratified patients with this disease
according to severity (mild, moderate, severe), and compared
them with age-, education-, and gender-matched control
subjects (group N = 49 each). Multivariate procedures and
cutting scores were used to determine the efficacy of the
various measures in distinguishing between the cases and
control subjects. Impairment of delayed recall was again
found to be the best discriminator for detecting mild cases
of Alzheimer's disease. Confrontation naming was the only
nonmemory factor that assisted in this discrimination. For
staging the illness, a combination of measures including
fluency, praxis, and recognition memory best differentiated
cases with mild dementia from those with either moderate or
severe stages of disease. Measures of delayed recall quickly
"bottomed out" in the patients with Alzheimer's disease and
proved of little value in staging the disorder.(ABSTRACT
TRUNCATED AT 250 WORDS)},
Doi = {10.1001/archneur.1992.00530290030008},
Key = {fds277129}
}
@article{fds277126,
Author = {Pericak-Vance, MA and Bebout, JL and Gaskell, PC and Yamaoka, LH and Hung, WY and Alberts, MJ and Walker, AP and Bartlett, RJ and Haynes, CA and Welsh, KA},
Title = {Linkage studies in familial Alzheimer disease: evidence for
chromosome 19 linkage.},
Journal = {Am J Hum Genet},
Volume = {48},
Number = {6},
Pages = {1034-1050},
Year = {1991},
Month = {June},
ISSN = {0002-9297},
url = {http://www.ncbi.nlm.nih.gov/pubmed/2035524},
Abstract = {A genetic component in the etiology of Alzheimer disease
(AD) has been supported by indirect evidence for several
years, with autosomal dominant inheritance with
age-dependent penetrance being suggested to explain the
familial aggregation of affecteds. St. George Hyslop et al.
reported linkage of familial AD (FAD) in four early-onset
families (mean age at onset [M] less than 50 years).
Subsequent studies have been inconsistent in their results;
Goate et al. also reported positive lod scores. However,
both Pericak-Vance et al.'s study of a series of mainly
late-onset FAD families (M greater than 60 years) and
Schellenberg et al.'s study failed to confirm linkage to
chromosome 21 (CH21). These various studies suggest the
possibility of genetic heterogeneity, with some families
linked to CH21 and others unlocalized. Recently, St. George
Hyslop et al. extended their analysis to include additional
families. The extended analyses supported their earlier
finding of linkage to CH21, while showing strong evidence of
heterogeneity between early-onset (M less than 65 years) and
late-onset (M greater than 60 years) FAD families. Because
our families did not show linkage to CH21, we undertook a
genomic search for an additional locus for FAD. Because of
both the confounding factor of late age at onset of FAD and
the lack of clear evidence of Mendelian transmission in some
of our families, we employed the affected-pedigree-member
(APM) method of linkage analysis as an initial screen for
possible linkage. Using this method, we identified two
regions suggesting linkage: the proximal long arm of
chromosome 19 (CH19) and the CH21 region of FAD linkage
reported by St. George Hyslop et al. Application of standard
likelihood (LOD score) analysis to these data support the
possibility of an FAD gene locate on CH19, particularly in
the late-onset FAD families. These data further suggest
genetic heterogeneity and delineate this region of CH19 as
an area needing additional investigation in
FAD.},
Key = {fds277126}
}
@article{fds277127,
Author = {Welsh, K and Butters, N and Hughes, J and Mohs, R and Heyman,
A},
Title = {Detection of abnormal memory decline in mild cases of
Alzheimer's disease using CERAD neuropsychological
measures.},
Journal = {Arch Neurol},
Volume = {48},
Number = {3},
Pages = {278-281},
Year = {1991},
Month = {March},
url = {http://dx.doi.org/10.1001/archneur.1991.00530150046016},
Abstract = {The present study was designed to determine which of the
memory tasks included in the CERAD (Consortium to Establish
a Registry for Alzheimer's Disease) neuropsychological
battery best differentiate patients with early Alzheimer's
disease from cognitively normal elderly control subjects and
also best distinguish between the various levels of severity
of the dementia process. A sample of CERAD patients with
Alzheimer's disease was stratified by disease severity into
those with mild, moderate, or severe dementia and matched
with control subjects for sex, age, and education. Using
multivariate procedures and cutting scores, the efficacy of
each memory measure in distinguishing between these groups
and control subjects was determined. The test for delayed
recall was found to be the best overall discriminatory
measure. The other tests of memory, ie, immediate recall,
intrusion errors, and recognition memory, had poor overall
discriminability. None of the CERAD memory measures were
found to be particularly powerful in staging the severity of
dementia. These findings suggest that tests for delayed
recall may be particularly useful in the early detection of
Alzheimer's disease and should be considered in screening
batteries for dementia in community surveys.},
Doi = {10.1001/archneur.1991.00530150046016},
Key = {fds277127}
}
@article{fds277128,
Author = {Schellenberg, GD and Pericak-Vance, MA and Wijsman, EM and Moore, DK and Gaskell, PC and Yamaoka, LA and Bebout, JL and Anderson, L and Welsh,
KA and Clark, CM},
Title = {Linkage analysis of familial Alzheimer disease, using
chromosome 21 markers.},
Journal = {Am J Hum Genet},
Volume = {48},
Number = {3},
Pages = {563-583},
Year = {1991},
Month = {March},
ISSN = {0002-9297},
url = {http://www.ncbi.nlm.nih.gov/pubmed/1998342},
Abstract = {Chromosome 21 markers were tested for linkage to familial
Alzheimer disease (FAD) in 48 kindreds. These families had
multiple cases of Alzheimer disease (AD) in 2 or more
generations with family age-at-onset means (M) ranging from
41 to 83 years. Included in this group are seven Volga
German families which are thought to be genetically
homogeneous with respect to FAD. Autopsy documentation of AD
was available for 32 families. Linkage to the 21 q11-q21
region was tested using D21S16, D21S13, D21S110, D21S1/S11,
and the APP gene as genetic markers. When linkage results
for all the families were summed, the LOD scores for these
markers were consistently negative and the entire region was
formally excluded. Linkage results were also summed for the
following family groups; late-onset (M greater than 60),
early-onset (M less than or equal to 60), Volga Germans (M =
56), and early-onset non-Volga Germans (M less than or equal
to 60). For the first three groups, LOD scores were negative
for this region. For the early-onset non-Volga German group
(six families), small positive LOD scores of Zmax = 0.78
(recombination fraction theta = .15), Zmax = 0.27 (theta =
.15), and Zmax = 0.64 (theta = .0), were observed for
D21S13, D21S16, and D21S110, respectively. The remainder of
the long arm of chromosome 21 was tested for linkage to FAD
using seven markers spanning the q22 region. Results for
these markers were also predominantly negative. Thus it is
highly unlikely that a chromosome 21 gene is responsible for
late-onset FAD and at least some forms of early-onset FAD
represented by the Volga German kindreds.},
Key = {fds277128}
}
@article{fds277130,
Author = {Welsh, KA},
Title = {Detection of early dementia in the elderly.},
Journal = {Experimental Aging Research},
Volume = {17},
Number = {2},
Pages = {101-},
Year = {1991},
Key = {fds277130}
}
@article{fds277150,
Author = {Siegler, IC and Welsh, KA and Dawson, DV and Fillenbaum, GG and Earl,
NL and Kaplan, EB and Clark, CM},
Title = {Ratings of personality change in patients being evaluated
for memory disorders.},
Journal = {Alzheimer Dis Assoc Disord},
Volume = {5},
Number = {4},
Pages = {240-250},
Year = {1991},
ISSN = {0893-0341},
url = {http://www.ncbi.nlm.nih.gov/pubmed/1781966},
Abstract = {Caregivers of 35 mildly to moderately memory-impaired
patients rated current and premorbid personalities with the
NEO Personality Inventory. We then examined changes in the
five domains of personality tapped by the NEO. There were
significant changes in four of the five domains of normal
personality functioning toward less conscientiousness, lower
extraversion, higher neuroticism, and lower openness. The
difference toward lower agreeableness was not significant
when controlling for multiple comparisons. Spearman rank
correlation coefficients indicated that changes in
conscientiousness and vulnerability were not related to
rated premorbid personality patterns and thus appear to
describe shifts for all patients evaluated for memory
disorders. These data suggest that personality inventories
may be helpful in characterizing caregivers' observations of
memory-impaired patients and thus represent a critical
source of information for the clinician in charge of
care.},
Doi = {10.1097/00002093-199100540-00003},
Key = {fds277150}
}
@article{fds276935,
Author = {Breitner, JCS and Welsh, KA and Magruder-Habib, KM and Churchill, CM and Robinette, CD and Folslein, MF and Murphy, EA and Priolo, CC and Brandt,
J},
Title = {Alzheimer’s disease in the national academy of sciences
registry of aging twin veterans: I. Pilot
investigations},
Journal = {Dementia and Geriatric Cognitive Disorders},
Volume = {1},
Number = {6},
Pages = {297-303},
Publisher = {S. Karger AG},
Year = {1990},
Month = {January},
url = {http://dx.doi.org/10.1159/000107157},
Abstract = {The (US) National Academy of Sciences Registry of aging twin
veterans contains 15.924 pairs of white male twins born
between 1917 and 1927. About 8.000 pairs are living today.
In preparation for a study of Alzheimer’s disease (AD) in
this Registry, we investigated 829 members of pairs living
in North and South Carolina. Virginia. in the District of
Columbia, and Maryland. A brief telephone interview for
cognitive symptoms was administered to 678 (91.4%) of 742
subjects located. Cognitive dysfunction was identified
initially in 124 individuals (18.3%). whose clinical
histories were then obtained over the telephone. Results
suggested that 108 subjects did not have AD. Ten (62.5%) of
the remaining 16 subjects underwent diagnostic evaluation
for dementia. One had cerebrovascular disease with concident
depression. Two others with probable AD were a monozygotic
(MZ) pair. The remaining 7 subjects had possible AD or a
mild but progressive cognitive disorder suggestive of early
AD. Upon subsequent examination, 3 of 4 MZ co-twins showed
significant symptoms that had not been detected during
screening procedures. None of 3 dizygotic co-twin showed any
significant abnormality. These results suggest: (1) that a
combination of mailed information, telephone interviews, and
clinical examination provides a feasible means of detecting
AD in the Registry. (2) that about 150 pairs with
presumptive AD in 1 or both subjects will be identified in a
full study of the Registry, (3) that concordance for AD in
MZ pairs may exceed prior estimates, but (4) that such rates
of concordance are apparent only upon detailed evaluation of
apparently normal co-twins as well as their impaired
brothers. Longitudinal observation of pairs with apparently
affected individuals will be required for definitive
conclusions. © 1990 S. Karger AG, Basel.},
Doi = {10.1159/000107157},
Key = {fds276935}
}
@article{fds277125,
Author = {Pericak-Vance, MA and Bebout, JL and Yamaoka, LA and Gaskell, PC and Hung, WY and Alberts, MJ and Clark, CM and Haynes, CS and Welsh, KA and Earl, NL and Heyman, A and Roses, AD},
Title = {Linkage studies in familial Alzheimer's disease, application
of the affected pedigree member (APM) method of linkage
analysis},
Journal = {Molecular biology and genetics of Alzheimer's disease:
proceedings of the International Symposium on Dementia:
Molecular Biology and Genetics of Alzheimer's Disease.
ICS884},
Pages = {215-228},
Year = {1990},
Month = {January},
Key = {fds277125}
}
@article{fds276934,
Author = {Gold, PE and Welsh, KA},
Title = {Regional brain catecholamines and memory: effects of
footshock, amygdala implantation, and stimulation.},
Journal = {Behav Neural Biol},
Volume = {47},
Number = {2},
Pages = {116-129},
Year = {1987},
Month = {March},
ISSN = {0163-1047},
url = {http://dx.doi.org/10.1016/s0163-1047(87)90215-9},
Abstract = {Previous findings have revealed a correlation between
post-training release of whole brain norepinephrine (NE) and
later retention performance. The present experiment examined
changes after a training footshock in NE levels, as well as
the levels of the major central NE metabolite,
3-methoxy-4-hydroxyphenylglycol (MHPG), dopamine (DA), and
epinephrine (EPI) in eight brain regions. Brain levels of
these amines and the metabolite were assessed 10 min after
training in a one-trial inhibitory (passive) avoidance task.
The results indicate that NE levels decreased significantly
in neocortex, neostriatum, hypothalamus, frontal pole,
septum, and brainstem, but not in hippocampus or thalamus.
The decreases in NE levels were generally accompanied by
increases in MHPG; the MHPG/NE ratio increased significantly
in all areas in which decreases in NE were observed. DA
levels decreased in neostriatum and increased in neocortex
and brainstem. Epinephrine levels decreased only in the
brainstem sample. Thus, the effects of training on NE are
widespread, probably reflecting the release of the amine in
most brain regions. Such findings are consistent with the
view that posttraining release of brain NE may modulate the
storage of new information in many brain regions. One
especially potent treatment for modulating memory storage is
electrical stimulation of the amygdala. Therefore, we also
examined the effects of amygdala implantation and
stimulation on brain catecholamine levels to determine
whether such changes might be correlated with the effects of
amygdala stimulation on memory. The results indicate that
electrode implantation into the amygdala results in
pervasive changes in NE levels in most brain regions tested.
Against this modified baseline, the results of training and
electrical stimulation were region specific and very
difficult to interpret. The major conclusion which can be
derived from this portion of the experiment is that the
amygdala damage produced by electrode implantation produces
a brain which is substantially different from that of intact
animals.},
Doi = {10.1016/s0163-1047(87)90215-9},
Key = {fds276934}
}
@article{fds276932,
Author = {Welsh, KA and Gold, PE},
Title = {Epinephrine proactive retardation of amygdala-kindled
epileptogenesis.},
Journal = {Behav Neurosci},
Volume = {100},
Number = {2},
Pages = {236-245},
Year = {1986},
Month = {April},
ISSN = {0735-7044},
url = {http://dx.doi.org/10.1037//0735-7044.100.2.236},
Abstract = {Recent findings indicate that a single injection (ip) of
epinephrine can proactively retard the development of
amygdala-kindled seizures. In these experiments, these
findings were extended by examining the dose and temporal
properties of this phenomenon. Rats were prepared with
stimulating electrodes placed in the amygdala. At 30 min or
24, 48, or 72 hr before the first kindling trial, the
animals received an epinephrine injection (0.01-1.0 mg/kg).
The results indicate that the high epinephrine dose delayed
the onset of kindling when injected within 24 hr before
kindling, the intermediate dose delayed kindling when
injected at 30 min before the first kindling trial, and the
low dose was ineffective at all intervals. Injections
administered after kindling had been established had no
effect on later seizures, although injections during early
kindling stages had a small effect on the further
development of seizures. Examination of the time courses of
increases in plasma catecholamine levels, blood pressure,
and heart rate demonstrated that long-term changes in these
measures cannot account for the retardation of kindling. The
findings of these experiments indicate that although
epinephrine does not directly affect seizure production with
these procedures, the hormone does have long-lasting
proactive effects on kindled epileptogenesis.},
Doi = {10.1037//0735-7044.100.2.236},
Key = {fds276932}
}
@article{fds276933,
Author = {Welsh, KA and Gold, PE},
Title = {Brain catecholamines and memory modulation: effects of
footshock, amygdala implantation, and stimulation.},
Journal = {Behav Neural Biol},
Volume = {43},
Number = {2},
Pages = {119-131},
Year = {1985},
Month = {March},
ISSN = {0163-1047},
url = {http://dx.doi.org/10.1016/s0163-1047(85)91317-2},
Abstract = {The results of previous studies indicate that the extent of
a transient decline in brain norepinephrine (NE) levels
shortly after training and administration of any of several
memory modulating treatments is correlated with later
retention performance. The present experiment assessed such
changes after one-trial inhibitory (passive) avoidance
training and, in addition, measured concentration changes in
3-methoxy-4-hydroxyphenylglycol (MHPG), the major metabolite
of brain NE, as well as dopamine (DA) and epinephrine (EPI)
levels. The results indicate that the decreases in brain NE
after footshock are accompanied by an increase in MHPG, thus
providing additional evidence that brain NE is released
after training. DA levels were unchanged after training;
brainstem EPI levels increased after the training footshock,
but forebrain EPI levels were unchanged. A second experiment
examined brain catecholamine levels in animals which
received post-training electrical stimulation of the
amygdala. The findings of this experiment indicate that the
amygdala damage which accompanies electrode implantation
apparently results in a chronic change in whole brain NE
levels and metabolism. After amygdala, NE concentrations in
both brainstem and forebrain samples were reduced by 20% and
MHPG was increased by 22-34%. Furthermore, NE levels were
not responsive to training in implanted animals. Thus, brain
NE levels after training were not predictive of retention
performance in amygdala-implanted or -stimulated animals.
However, the significance of such findings for understanding
the possible role of central NE in memory storage is
complicated by the severe modification of the dynamics of
brain aminergic systems in animals bearing amygdala
electrodes.},
Doi = {10.1016/s0163-1047(85)91317-2},
Key = {fds276933}
}
@article{fds276931,
Author = {Welsh, KA and Gold, PE},
Title = {Attenuation of epileptogenesis: proactive effect of a single
epinephrine injection of amygdaloid kindling.},
Journal = {Behav Neural Biol},
Volume = {40},
Number = {2},
Pages = {179-185},
Year = {1984},
Month = {March},
ISSN = {0163-1047},
url = {http://dx.doi.org/10.1016/s0163-1047(84)90279-6},
Abstract = {Repeated daily electrical stimulation of the amygdala can
lead to a progressive increase in brain and behavioral
seizures. This phenomenon, termed kindling, has been viewed
as a model for epileptogenesis. The results reported here
demonstrate that a single systemic epinephrine injection can
significantly retard such epileptogenesis for a period of at
least several days. These findings suggest that peripheral
catecholamines, responding either to stress near the time of
seizure initiation or to treatments administered at that
time, may be important in regulating the development of
epileptic states. In addition, the results indicate that an
acute episode of high plasma epinephrine levels may result
in a durable modification of brain function.},
Doi = {10.1016/s0163-1047(84)90279-6},
Key = {fds276931}
}
@article{fds277124,
Author = {Welsh, KA and Gold, PE},
Title = {Age-related changes in brain catecholamine responses to a
single footshock.},
Journal = {Neurobiol Aging},
Volume = {5},
Number = {1},
Pages = {55-59},
Year = {1984},
ISSN = {0197-4580},
url = {http://dx.doi.org/10.1016/0197-4580(84)90086-1},
Abstract = {The responses of forebrain and brainstem catecholamine
levels to a single footshock were studied in 70-day,
one-year, and two-year-old Fischer-344 rats. Brain
catecholamine concentrations were assessed 10 minutes after
a single 2 second footshock (0, 0.3, or 2.0 mA). In samples
taken from non-footshocked rats, only forebrain dopamine
concentrations showed a significant age-related decline.
However, because the net weights of both the forebrain and
the brainstem samples increased significantly with age, the
content of forebrain dopamine did not exhibit a significant
decline. Both norepinephrine and dopamine levels showed
age-related changes in responsiveness to footshock.
Norepinephrine concentrations were reduced in both the
forebrain and brainstem samples obtained 10 minutes after
the high footshock in both the 70-day and one-year-old
animals. In two-year-old rats, however, neither forebrain
nor brainstem norepinephrine concentrations were altered in
response to footshock. Seventy-day-old rats demonstrated
significant footshock-induced increases in brainstem
dopamine levels, one-year olds showed no appreciable change,
and two-year olds demonstrated a non-significant
footshock-induced decrease. Thus, both noradrenergic and
dopaminergic systems demonstrated age-related changes in
their responsiveness to a single brief footshock. These
alterations may contribute to the declining ability of the
senescent animals to adapt to stressful situations.},
Doi = {10.1016/0197-4580(84)90086-1},
Key = {fds277124}
}
%% Papers Published
@article{fds135091,
Title = {Silverman, D.H.S., Small, G.W., Chang, C.Y., Lu, C.S., Kung
de Aburto, M.A., Chen, W., Czernin, J., Rapoport, S.I.,
Pietrini, P., Alexander, G.E., Schapiro, M.B., Jagust, W.J.,
Hoffman, J.M., Welsh-Bohmer, K.A., ....& Phelps, M.E. (in
press). Neuroimaging in evaluation of dementia: Regional
brain metabolism and long-term outcome. Journal of the
American Medical Association.},
Year = {2001},
Key = {fds135091}
}
@article{fds135092,
Title = {Welsh-Bohmer, K.A. & Madden, D.J. (accepted). Benign
Senescent Forgetfulness, Age-Associated Memory Impairment,
and Age-related cognitive decline. In: J.Copeland, M.
Abou-Saleh, & D. Blazer (Eds). Principles and Practice of
Geriatric Psychiatry- 2nd Edition. Sussex, England: John
Wiley & Sons, Ltd.},
Year = {2001},
Key = {fds135092}
}
@article{fds135093,
Title = {Publications in print},
Year = {2001},
Key = {fds135093}
}
@article{fds135094,
Title = {Sugarman, J., Cain, C., Wallace, R., & Welsh-Bohmer, K.A.
(2001). How proxies make decisions about research for
patients with Alzheimer's disease. Journal of the American
Geriatrics Society, 49, 1110-1119.},
Year = {2001},
Key = {fds135094}
}
@article{fds135122,
Title = {Yi-Ju, L., Scott, W.K., Hedges, D.J., Zhang, F., Gaskell,
P.C., Nance, M.A., Watts, R.L., Hubble, J.P., Koller, W.C.,
Pahwa, R., Stern, M.B., Hiner, B.C., Jankovic, J., Allen
Jr., F.A., Goetz, C.G., Mastaglia, F., Stajich, J.M.,
Gibson, R.A., Middleton, L.T., Saunders, A.M., Scott, B.L.,
Small, G.W., Reed, A.D., Schmechel, D.E., Welsh-Bohmer,
K.A., Conneally, P.M., Roses, A.D., Gilbert, J.R., Vance,
J.M., Haines, J.L., Pericak-Vance, M.A.. (accepted). Onset
in neurodegenerative diseases is genetically controlled.
American Journal of Human Genetics.},
Year = {2001},
Key = {fds135122}
}
@article{fds135123,
Title = {Schiffman, S.S., Graham, B.G., Sattely-Miller, E.A.,
Zervakis, J., Welsh-Bohmer, K.A. (in press). Taste, smell,
and neuropsychological performance of individuals at risk
for Alzheimer's disease. Neurobiology of
Aging.},
Year = {2001},
Key = {fds135123}
}
@article{fds135124,
Title = {Steffens, D.C., Payne, M.E., Greenberg, D.L., Byrum, C.E.,
Welsh-Bohmer, K.A., Wagner, H.R., & MacFall, J.R.
(accepted). Hippocampal volume and incident dementia in
geriatric depression. American Journal of Geriatric
Psychiatry.},
Year = {2001},
Key = {fds135124}
}
@article{fds135125,
Title = {Welsh-Bohmer, K.A., Koltai, D.C., & Mason D.J. (accepted).
The clinical utility of neuropsychological evaluation of
patients with known or suspected dementia. In: G. Prigatano
& N. Pliskin (eds). Demonstrating Utility and Cost
Effectiveness in Clinical Neuropsychology. Philadelphia:
Psychology Press- Taylor & Francis Group.},
Year = {2001},
Key = {fds135125}
}
@article{fds135126,
Title = {Carlson, M., Tschanz, J., Norton, M., Welsh-Bohmer, K.A.,
Martin, B., Breitner, J.C.S. (accepted). H2 Histamine
receptor blockage in the treatment of Alzheimer's disease: A
randomized, double-blind, placebo-controlled trial of
nizatidine. Alzheimer's Disease and Associated
Disorders.},
Year = {2001},
Key = {fds135126}
}
@article{fds135127,
Title = {Koltai, D.C., Welsh-Bohmer, K.A., & Mason, D.J. (accepted).
Neuropsychological consultation and training of family
members with dementia. In: G. Prigatano & N. Pliskin (eds).
Demonstrating Utility and Cost Effectiveness in Clinical
Neuropsychology. Philadelphia: Psychology Press- Taylor &
Francis Group.},
Year = {2001},
Key = {fds135127}
}
@article{fds135128,
Title = {Fillenbaum, G.G., Unverzagt, F.W., Ganguli, M.,
Welsh-Bohmer, K.A. (accepted). The CERAD neuropsychological
battery: Performance of representative community and
tertiary care samples of African-American and European
American elderly. In: F.R. Ferraro (ed). Minority and
Cross-Cultural Aspects of Neuropsychological Assessment.
London: Swets & Zeitlineger.},
Year = {2001},
Key = {fds135128}
}
@article{fds135129,
Title = {Dawson, D.V., Welsh-Bohmer, K.A., Siegler, I.C. (accepted).
Premorbid personality predicts level of rated personality
change in AD patients. Alzheimer's Disease and Associated
Disorders.},
Year = {2001},
Key = {fds135129}
}
@article{fds135130,
Title = {Meich, R.A, Breitner, J.C.S., Zandi, P.P., Khachaturian,
A.S., Anthony, J.C., Mayer, L., for the Cache County Study
Group. (2002). Incidence of AD may decline in the early 90's
for men, later for women: The Cache County Study. Neurology,
58:209-218.},
Year = {2001},
Key = {fds135130}
}
@article{fds135131,
Title = {Carlson, M.C., Zandi, P.A., Plassman, B.L., Tschanz, J.T.,
Welsh-Bohmer, K.A. Steffens, D.C., Bastian, L, Mehta, K.M.,
& Breitner, J.C.S. for the Cache County Study Group (2002).
Hormone Replacement Therapy Predicts Improved Cognitive
Trajectory In Older Women. The Cache County Study.
Neurology, 57: 2210-2216},
Year = {2001},
Key = {fds135131}
}
@article{fds135132,
Title = {Koltai, D.C., Welsh-Bohmer, K.A., & Schmechel, D.E. (2001).
Influence of anosognosia on treatment outcome among dementia
patients. Neuropsychological Rehabilitation, 11:
455-475},
Year = {2001},
Key = {fds135132}
}
@article{fds135133,
Title = {Dawson, D.V., Welsh-Bohmer, K.A., & Siegler, I.C. (2001).
Informant rated personality change in Alzheimer's disease
patients: Replication, influence of premorbid profile, and
covariate relationships. Research and Practice in
Alzheimer's Disease. Volume 5. In: B. Vellas & J. Fitten
(Eds). Auzeville-Tolosane France: Serdi Press, pp
27-32.},
Year = {2001},
Key = {fds135133}
}
@article{fds135134,
Title = {Grundman, M., Kim, H.T., Salmon, D., Storandt, M., Smith,
G., Ferris, S., Mohs, R., Kawas, C., Doody, R.,
Welsh-Bohmer, K.A.,...Kukull, W., Thal, L.J. for
participants in the Alzheimer's Disease Centers'
Neuropsychological Database Initiative (2001). The
Alzheimer's Disease Centers' Neuropsychological Database
Initiative: A Resource for Alzheimer's Disease Prevention
Trials. In: K. Iqbal, S.S. Sisodia, and B. Winblad (eds)
Alzheimer's disease: Advances in etiology, pathogenesis and
therapeutics. The Proceedings of the 7th International
conference on Alzheimer's Disease and Related Disorders."
London: John Wiley & Son, pp129-140.},
Year = {2001},
Key = {fds135134}
}
@article{fds135135,
Title = {Welsh-Bohmer, K.A., Hulette, C., Schmechel, D., Burke, J. &
Saunders, A. (2001). Neuropsychological detection of
preclinical Alzheimer's disease: Results of a
neuropathological series of "normal" controls. In: K. Iqbal,
S.S. Sisodia, and B. Winblad (eds) Alzheimer's disease:
Advances in etiology, pathogenesis and therapeutics. The
Proceedings of the 7th International conference on
Alzheimer's Disease and Related Disorders." London: John
Wiley & Sons, pp 111-122.},
Year = {2001},
Key = {fds135135}
}
@article{fds135090,
Title = {Welsh-Bohmer, K.A. & Ogrocki, P. K. (1998). Clinical
differentiation of memory disorders in neurodegenerative
diseases. In: A.I. Troster (Ed), Memory in Neurodegenerative
Disease: Biological, Cognitive, and Clinical Perspectives.
Cambridge University Press, London, pp 290313.},
Year = {1998},
Key = {fds135090}
}
@article{fds135120,
Title = {Ogrocki, P.K. & Welsh-Bohmer, K.A. (accepted). Assessment of
Cognitive and Functional Impairment in the Elderly. In:
C.Clark (Ed) Neurodegenerative Dementia: Clinical Features
and Pathological Mechanisms. New York: McGraw
Hill.},
Year = {1998},
Key = {fds135120}
}
@article{fds135121,
Title = {Koltai, D.C. & Welsh-Bohmer, K.A. (accepted). Geriatric
Neuropsychological Assessment. In: R.D. Vanderploeg (Ed)
Clinician's Guide to Neuropsychological Assessment, 2nd
Edition. New Jersey: Lawrence Erlbaum Associates.},
Year = {1998},
Key = {fds135121}
}
@article{fds135096,
Title = {Welsh-Bohmer, K.A., Gearing, M., Saunders, A.M., Roses,
A.D., & Mirra, S.M. (1997). Apolipoprotein E genotypes in a
neuropathological series from the Consortium to Establish a
Registry for Alzheimer's Disease (CERAD). Annals of
Neurology, 42: 319-325.},
Year = {1997},
Key = {fds135096}
}
@article{fds135087,
Title = {Fillenbaum, G.G., Peterson, B., Welsh-Bohmer, K.A., Kukull,
W., Heyman, A. (accepted) Progression of Alzheimer's disease
in African-American and White patients: The CERAD
experience, Part XVI. Neurology.},
Year = {1996},
Key = {fds135087}
}
@article{fds135088,
Title = {Welsh-Bohmer, K.A. & Hoffman, J.M. (1996). Positron Emission
Tomography Neuroimaging in Dementia. In: E.Bigler (Ed),
Handbook of Human Brain Function. Plenum Press: New York,
pp. 185-222.},
Year = {1996},
Key = {fds135088}
}
@article{fds135089,
Title = {Siegler, I., Poon, L., Madden, D., & Welsh, K.A. (1996).
Psychological Aspects of Normal Aging. In: E.W. Busse & D.G.
Blazer (Eds). Geriatric Psychiatry, 2nd Edition. Washington
D.C.: American Psychatric Press, pp 105-127.},
Year = {1996},
Key = {fds135089}
}
@article{fds135095,
Title = {Yamaoka, L.H., Welsh-Bohmer, K.A., Hulette, C.M. Gaskell
Jr., P.C., Murray, M., Rimmler, J.L., Helms, B.R., Guerra,
M., Roses, A.D., Schmechel, D.E., Pericak-Vance, M.A.
(1996). Linkage of Frontotemporal dementia to Chromosome 17:
Clinical and neuropathological characterization of
phenotype. American Journal of Human Genetics, 59,
1306-1312.},
Year = {1996},
Key = {fds135095}
}
@article{fds135113,
Title = {Hulette, C., Welsh-Bohmer, K.A., Crain, B., Szymanski, M.H.,
Sinclaire, N.O.,& Roses, A.D. (accepted). Rapid brain
autopsy. The Bryan Alzheimer's Disease Research Center
Experience. Journal of Neuropathology. Plassman, B.L.,
Welsh-Bohmer, K.A., Bigler, E.D., Johnson, S.C., Anderson,
C.V., Helms, M.J., Breitner, J.C.S. (in press).
Apolipoprotein E e4 and hippocampal volume in twins with
normal cognition. Neurology},
Year = {1996},
Key = {fds135113}
}
@article{fds135114,
Title = {Yamaoka, L.H., Welsh-Bohmer, K.A., Hulette, C.M. Gaskell
Jr., P.C., Murray, M., Rimmler, J.L., Helms, B.R., Guerra,
M., Roses, A.D., Schmechel, D.E., Pericak-Vance, M.A.
Linkage of Frontotemporal dementia to Chromosome 17:
Clinical and neuropathological characterization of
phenotype. American Journal of Human Genetics.
(accepted).},
Year = {1996},
Key = {fds135114}
}
@article{fds135115,
Title = {Steffens, D.C., Plassman B.L., Helms M.J., Welsh, K.A.,
Saunders A.M., & Breitner J.C.S. A twin study of late-onset
depression and apolipoprotein E e4 as risk factors for
Alzheimer's disease. Biological Psychiatry
(accepted).},
Year = {1996},
Key = {fds135115}
}
@article{fds135116,
Title = {Davidson M., Harvey P.D., Welsh K.A., Powchik P., Putnam
K.M., Mohs R.C. (1996). Defining the dementia of old age
schizophrenia: Psychometric comparisons of schizophrenic
patients to patients with Alzheimer's disease. American
Journal of Psychiatry, 153, 1274-1279.},
Year = {1996},
Key = {fds135116}
}
@article{fds135117,
Title = {Hoffman, J.M., Hanson, M.W., Welsh, K.A., Earl, N.L., Paine,
S., Delong, D. & Coleman, R.E. (1996). Interpretation
variability of 18F-fluoro-2-deoxyglucose (FDG) Positron
Emission Tomography (PET) studies in dementia. Investigative
Radiology, 31, 316-322.},
Year = {1996},
Key = {fds135117}
}
@article{fds135118,
Title = {Saunders, A.M., Hulette, C., Welsh-Bohmer, K.A., Schmechel,
D.E., Crain, B., Burke, J.R., Alberts, M.A., Strittmatter,
W.J., Breitner, J.C.S., Earl, N., Clark, C., Heyman, A.,
Gaskell, P.C., Pericak-Vance, M.A., & Roses, A.D. (1996).
Specificity and sensitivity of apolipoprotein E genotyping
in a prospectively ascertained series of probable Alzheimer
disease patients with autopsy-confirmed diagnoses. Lancet,
348, 90-93.},
Year = {1996},
Key = {fds135118}
}
@article{fds135119,
Title = {Steffens, D.C., Welsh, K.A., Burke, J.R., Helms, M.J.,
Folstein, M.F., Brandt, J., McDonald, W.M., & Breitner,
J.C.S. (1996). Diagnosis of Alzheimer's disease in
epidemiological studies by staged review of clinical data.
Neuropsychiatry, Neuropsychology, and Behavioral Neurology,
9, 107-113.},
Year = {1996},
Key = {fds135119}
}
@article{fds135084,
Title = {1995},
Year = {1995},
Key = {fds135084}
}
@article{fds135085,
Title = {Tupler, L.A., Welsh, K.A., Asare-Aboagye, Y., Dawson, D.V.
(1995). Reliability of the Rey-Osterrieth Complex Figure in
use with memory impaired patients. Journal of Clinical and
Experimental Neuropsychology, 17, 566-579.},
Year = {1995},
Key = {fds135085}
}
@article{fds135086,
Title = {Plassman, B.L., Saunders, A.M., Helms, M.J., Breitner JCS, &
Welsh, K.A.,. (1995). Smoking, Alzheimer's disease, and
confounding with genes. Author's reply. Lancet, 345, 1054
.},
Year = {1995},
Key = {fds135086}
}
@article{fds135107,
Title = {Welsh, K.A., Fillenbaum, G., Wilkinson, W., Heyman, A.,
Mohs, R.C., Stern, Y., & Harrell, L. (1995).
Neuropsychological performance of black and white patients
with Alzheimer's disease. Neurology, 45:
2207-2211.},
Year = {1995},
Key = {fds135107}
}
@article{fds135108,
Title = {Breitner, J.C.S. & Welsh, K.A. (1995). Genes and recent
developments in the epidemiology of Alzheimer's disease and
related dementia. Epidemiology Reviews, 17,
39-47.},
Year = {1995},
Key = {fds135108}
}
@article{fds135109,
Title = {Plassman, B.L., Welsh, K.A., Helms, M., Brandt, J., Page,
W.F., & Breitner, J.C.S. (1995) Intelligence and education
as predictor of cognitive state in late life: A 50 year
follow-up. Neurology, 45: 1446-1450.},
Year = {1995},
Key = {fds135109}
}
@article{fds135110,
Title = {Breitner, J.C.S., Welsh, K.A., Gau, B.A., McDonald WM,
Steffens DC, Saunders AM, Magruder KM, Helms MJ, Blassman
BL, Folstein MF, Brandt J, Robinette CD, Page WF. (1995).
Alzheimer's disease in the National Academy of Sciences-
National Research Council Registry of Aging Twin Veterans.
III. Detection of Cases, longitudinal results, and
observations on twin concordance. Archives of Neurology, 52,
763-771.},
Year = {1995},
Key = {fds135110}
}
@article{fds135111,
Title = {Plassman, B.L., Breitner, J.C.S., Helms, M.J., Welsh, K.A.,
& Saunders, A.M. (1995) Confounding with genes may explain
the inverse association of smoking and Alzheimer's disease.
Lancet, 345, 387.},
Year = {1995},
Key = {fds135111}
}
@article{fds135112,
Title = {Breitner, J.C.S. & Welsh, K.A. (1995). An approach to
diagnosis and management of memory loss and other cognitive
syndromes of aging. Psychiatric Services: A Journal of the
American Psychiatric Association , 46, 29-35.},
Year = {1995},
Key = {fds135112}
}
@article{fds135080,
Title = {1994},
Year = {1994},
Key = {fds135080}
}
@article{fds135081,
Title = {Welsh K.A., Ballard E., Nash F., Raiford K., & Harrell L.
(1994). Issues affecting minority participation in studies
of Alzheimer's disease. Alzheimer's Disease and Associated
Disorders, 8 (Suppl 4), 38-48.},
Year = {1994},
Key = {fds135081}
}
@article{fds135082,
Title = {Reed T., Swan G., Carmeli D., Christian, J., Breitner
J.C.S., Welsh, K.A. (1994). Lower cognitive performance in
normal older adult male twins carrying the Apolipoprotein E
e4 allele. Archives of Neurology, 51, 1189-1192.},
Year = {1994},
Key = {fds135082}
}
@article{fds135083,
Title = {Welsh KA, Butters N, Mohs RC, Beekly D, Edland S, Fillenbaum
G, Heyman A: The consortius to establish a registry of
Alzheimer's disease (CERAD) Part V: A normative study of the
neuropsychological battery. Neurology 44: 609-614,
1994.},
Year = {1994},
Key = {fds135083}
}
@article{fds135100,
Title = {Norton M.C., Breitner, J.C.S., Welsh, K.A., & Wyse, B.W.
(1994). Characteristics of nonresponders in a community
survey of the elderly. Journal of the American Geriatrics
Society, 42: 1252-1256.},
Year = {1994},
Key = {fds135100}
}
@article{fds135101,
Title = {Fillenbaum, G. G., Burchett, B.M., & Welsh, K.A. The 20-item
word list as a measure of cognitive functioning in the
Health and Retirement Survey: Norms and validity for White,
Black, and Hispanic respondents. Health and Retirement Study
Working Paper Series, Paper #94-005. Institute for Social
Research at the University of Michigan & the National
Institute of Aging.},
Year = {1994},
Key = {fds135101}
}
@article{fds135102,
Title = {Welsh K.A., Hoffman J.M., Earl N.L., & Hansen, M. W. (1994)
Neural correlates of dementia: Regional brain metabolism
(FDG-PET) and the CERAD neuropsychological battery. Archives
of Clinical Neuropsychology, 9, 395-409.},
Year = {1994},
Key = {fds135102}
}
@article{fds135103,
Title = {Welsh K.A., Butters N., Mohs R.C., Beekly D., Edland S.,
Fillenbaum, G, & Heyman A.},
Year = {1994},
Key = {fds135103}
}
@article{fds135104,
Title = {Welsh KA, Hoffman JM, Earl NL, Hansen MW: Neural correlates
of dementia: Regional brain metabolism (FDG-PET) and the
CERAD neuropsychological battery. Archives of Clinical
Neuropsychology 9: 395-409, 1994.},
Year = {1994},
Key = {fds135104}
}
@article{fds135105,
Title = {Breitner JCS, Welsh KA, Robinette CD, Gau BA, Folstein MF,
Brandt J: Alzheimer's disease in the National Academy of
Sciences Registry of Aging Twin Veterans II. Longitudinal
findings in a pilot series. Dementia 5: 99-105,
1994.},
Year = {1994},
Key = {fds135105}
}
@article{fds135106,
Title = {Breitner JCS, Gau B, Welsh KA, Plassman B, Helms M, Anthony
J: Inverse association betrween anti-inflammatory agents and
Alzheimer's disease: Initial results of a co-twin control
study. Neurology 44: 227-232, 19994.},
Year = {1994},
Key = {fds135106}
}
@article{fds135136,
Title = {Welsh K.A., Hoffman J.M., Earl N.L., & Hansen, M. W. (1994)
Neural correlates of dementia: Regional brain metabolism
(FDG-PET) and the CERAD neuropsychological battery. Archives
of Clinical Neuropsychology, 9, 395-409.},
Year = {1994},
Key = {fds135136}
}
@article{fds135077,
Title = {1993},
Year = {1993},
Key = {fds135077}
}
@article{fds135078,
Title = {Welsh K.A., Breitner J.C.S., & Magruder-Habib, K.M. (1993).
Detection of dementia in community volunteers using
telephone screening of cognitive status. Neuropsychiatry,
Neuropsychology, and Behavioral Neurology, 6,
103-110.},
Year = {1993},
Key = {fds135078}
}
@article{fds135079,
Title = {Welsh K.A., Hoffman J.M., McDonald J.M., Earl N.L., &
Breitner J.C.S. (1993). Concordant but different: Cognitive
function, cerebral anatomy, and brain metabolism in
monozygotic twins with Alzheimer's disease. Neuropsychology,
7, 158-171.},
Year = {1993},
Key = {fds135079}
}
@article{fds135098,
Title = {Brandt J., Welsh K.A., Breitner J.C.S., Folstein, M.F.,
Helms, M, & Christian, J.C. (1993). Hereditary influences on
cognitive functioning in older men: A study of 4,000
twin-pairs. Archives of Neurology, 50, 599-603.},
Year = {1993},
Key = {fds135098}
}
@article{fds135099,
Title = {Breitner, J.C.S., Gatz, M., Bergem A.L.M., Christian J.C.,
Mortimer, J.A., McClearn, G.E., Heston L.L., Welsh, K.A.,
Anthony, J.C., Folstein, M.F., & Radebaugh, T.S. (1993). The
use of Twin Cohorts for Research in Alzheimer's Disease: A
consensus document sponsored by the NIA and Duke University
Collaborative Twin Studies. Neurology, 43,
261-267.},
Year = {1993},
Key = {fds135099}
}
@article{fds135076,
Title = {Welsh, K.A., Butters, N., Hughes, J.P., Mohs, R.C., and
Heyman, A. (1991) Detection of abnormal memory decline in
mild Alzheimer\'s disease using CERAD neuropsychological
measures. Archives of Neurology, 48, 278-281.},
Year = {1991},
Key = {fds135076}
}
@article{fds135097,
Title = {Hulette, C.M., Welsh-Bohmer, K.A., Murray, M.G., Mash, D.&
McIntyre, L.M. Neuropathological and neuropsychological
changes in "normal" aging: Evidence for preclinical
Alzheimer's disease. Journal of Neuropathology and
Experimental Neurology, 57, 1168-1174.},
Key = {fds135097}
}
%% Chapters in Books
@misc{fds364315,
Author = {Welsh-Bohmer, KA and Johnson, S},
Title = {Neuropsychological Assessment of Dementia},
Pages = {59-87},
Booktitle = {Handbook of Dementing Illnesses, Second Edition},
Year = {2006},
Month = {January},
ISBN = {9780824758387},
url = {http://dx.doi.org/10.3109/9780849354847-8},
Abstract = {Department of Psychiatry and Joseph and Kathleen Bryan
Alzheimer’s Disease Research Center-Division of Neurology,
Department of Medicine, Duke University Medical Center,
Durham, North Carolina, U.S.A. Neuropsychological assessment
plays an important part in the differential diagnosis of
dementing disorders, particularly in clinically ambiguous
situations (e.g., suspected early dementia) and in the
context of confounding factors, such as the presence of a
superimposed depression or advanced age (1, 2). Within the
medical evaluation of dementia, the neuropsychological
evaluation provides unique information in the form of a
“behavioral sample” that can be used to determine in an
objective, quantifiable manner the presence of cognitive
symptoms and their functional significance. To accomplish
these basic aims, the neuropsychological examination employs
rigorous, standardized psychometric tests of memory and
cognitive function and relies heavily on the application of
normative standards and on a fundamental understanding of
brain function. The examination results in metric values for
discrete cognitive and behavioral capacities, which can then
be used by the examining clinician to arrive at diagnostic
inferences, to make judgments of functional abilities, and
to establish a benchmark for monitoring future change and
responsiveness to medical treatments and
therapies.},
Doi = {10.3109/9780849354847-8},
Key = {fds364315}
}
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