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1.  Incidence Rates of Dementia, Alzheimer’s disease and Vascular Dementia in the Japanese American Population in Seattle, WA: The Kame Project 
There are few dementia incidence studies in representative minority populations in the U.S., and no population-based studies of Japanese American women. We identified 3,045 individuals aged 65+ with at least 1 parent of Japanese descent living in King County, WA in 1992–4, of which 1,836 were dementia-free and were examined every two years (1994–2001) to identify incident cases of all dementias, Alzheimer’s disease (AD), vascular dementia (VaD) and other dementias. Cox regression was used to examine associations with age, sex, years of education and Apolipoprotein (APOE)-ε4. Among 173 incident cases of dementia, the overall rate was 14.4/1,000/yr, with rates being slightly higher among women (15.9/1,000) than men (12.5/1,000). Rates roughly doubled every 5 years for dementia and AD; the age trend for VaD and other dementias was less consistent. Sex was not significantly related to incidence of dementia or its subtypes in adjusted models. There was a trend for an inverse association with increasing years of education. APOE-ε4 was a strong risk factor for all dementias (HR=2.89, 95% CI 1.88–4.46), AD (HR=3.27, 95% CI 2.03–5.28) and VaD (HR=3.33, 95% CI 1.34–8.27). This study is the first to report population-based incidence rates for both Japanese American men and women.
PMCID: PMC4036673  PMID: 24045327
Incidence rates; population-based cohort studies; risk factors; Alzheimer’s disease; vascular dementia; dementias
2.  Pulse Wave Velocity and Cognitive Function in Older Adults 
Arterial stiffness may be associated with cognitive function. In this study, pulse wave velocity (PWV) was measured from the carotid to femoral (CF-PWV) and from the carotid to radial (CR-PWV) with the Complior SP System (Alam Medical, Vincennes, France). Cognitive function was measured by six tests of executive function, psychomotor speed, memory, and language fluency. A total of 1433 participants were included (mean age 75 years, 43% men). Adjusting for age, sex, education, pulse rate, hemoglobin A1C, HDL cholesterol, hypertension, CVD history, smoking ,drinking, and depression symptoms, a CF-PWV > 12 m/s was associated with a lower Mini-Mental State Examination score (coefficient: −0.31, se: 0.11, p=0.005), fewer words recalled on Auditory Verbal Learning Test (coefficient: −1.10, se: 0.43, p=0.01), and lower score on the composite cognition score (coefficient: −0.10, se: 0.05, p=0.04) and marginally significantly associated with longer time to complete Trail Making Test-B (coefficient: 6.30, se: 3.41, p=0.06), CF-PWV was not associated with Trail Making Test-A, Digit Symbol Substation Test, or Verbal Fluency Test. No associations were found between CR-PWV and cognitive performance measures. Higher large artery stiffness was associated with worse cognitive function, and longitudinal studies are needed to confirm these associations.
PMCID: PMC3778043  PMID: 23632267
pulse wave velocity; cognitive function; epidemiology; arterial stiffness
3.  Physical Activity and Cognitive Trajectories in Cognitively Normal Adults: The Adult Children Study 
Increased physical activity may protect against cognitive decline, the primary symptom of Alzheimer's disease (AD). In this study, we examined the relationship between physical activity and trajectories of cognitive functioning over serial assessments. Cognitively normal (Clinical Dementia Rating 0) middle aged and older adults (N=173, mean age 60.7 +/- 7.8 years) completed a self-report measure of physical activity and a battery of standard neuropsychological tests assessing processing speed, attention, executive functioning, and verbal memory. At baseline, individuals with higher physical activity levels performed better on tests of episodic memory and visuospatial functioning. Over subsequent follow-up visits, higher physical activity was associated with small performance gains on executive functioning and working memory tasks in participants with one or more copy of the apolipoprotein ε4 allele (APOE4). In APOE4 non-carriers, slopes of cognitive performance over time were not related to baseline physical activity. Our results suggest that cognitively normal older adults who report higher levels of physical activity may have slightly better cognitive performance, but the potential cognitive benefits of higher levels of physical activity over time may be most evident in individuals at genetic risk for AD.
PMCID: PMC3778080  PMID: 23739296
Alzheimer's disease; dementia; memory; physical activity; exercise; apolipoprotein E
We examined several vascular factors in relation to rates of decline in five cognitive domains in a population-based cohort. In an age-stratified random sample (N=1982) aged 65+ years, we assessed at baseline the cognitive domains of attention, executive function, memory, language, and visuospatial function, and also vascular, inflammatory, and metabolic indices. Random effects models generated slopes of cognitive decline over the next four years; linear models identified vascular factors associated with these slopes, adjusting for demographics, baseline cognition, and potential interactions. Several vascular risk factors (history of stroke, diabetes, central obesity, C-Reactive Protein), although associated with lower baseline cognitive performance, did not predict rate of subsequent decline. APOE*4 genotype was associated with accelerated decline in language, memory, and executive functions. Homocysteine elevation was associated with faster decline in executive function. Hypertension (history or systolic blood pressure >140 mm) was associated with slower decline in memory. Baseline alcohol consumption was associated with slower decline in attention, language, and memory. Different indices of vascular risk are associated with low performance and with rates of decline in different cognitive domains. Cardiovascular mechanisms explain at least some of the variance in cognitive decline. Selective survival may also play a role.
PMCID: PMC3945071  PMID: 24126216
5.  Midlife Cardiovascular Risk Impacts Executive Function: Framingham Offspring Study 
Novel error scores and traditional indices of executive function (EF) were related to cardiovascular risk factors (CVRF) measured 10–15 years earlier.
From 1991–1995, the Framingham Stroke Risk Profile (FSRP), a composite score of cardiovascular risk, was ascertained in 1755 Framingham Offspring participants (54% women, mean age= 54 ± 9 years). Participants were administered EF tests: FAS and Animals Fluency tests, Trail Making Test B (TrB), and Digit Span-Backwards (DS-B) in 2005–2009. Linear and logistic regression were used to relate the FSRP and its components to both error responses and traditional scores.
Consistent with previous findings, the FSRP and the individual components diabetes and sex were associated with several traditional measures of EF. Of interest were relationships between the FSRP score and TrB Total Errors (p=0.04), DS-B % Total Errors (p=0.02) and DS-B Capacity Score (p=0.03), and prevalent CVD related to making FAS Perseverations in the 75th percentile (p=0.03). By comparison, FSRP and CVD were not related to the traditional DS-B or FAS scores. Additionally, age was associated with higher Animals % Total Errors and % Perseverations among ApoE4+ individuals and with higher TrB Total Errors among ApoE4− individuals.
For those middle-aged and healthy, including those ApoE4+, CVRF are related to impairments in EF as ascertained by novel errors as well as traditional measures.
PMCID: PMC3945114  PMID: 23995818
Neuropsychological assessment; Executive function; Mild cognitive impairment; ApolipoproteinE allele 4
Alzheimer’s disease (AD) research faces challenges to successful enrollment, especially to clinical trials and biomarker studies. Failure to recruit the planned number of participants in a timely fashion threatens the internal validity and success of clinical research, raising concerns about external validity and generalizability of results, and possibly leading to disparities in disease treatment. Methods to improve recruitment exist, but require varying levels of staff effort and financial resources and evidence of effectiveness is often lacking or inconsistent. In this review, we summarize some of the available methods to improve AD research recruitment, the available literature to support or refute these strategies, and some of the experiences at the authors’ AD Research Centers. We discuss the use of community-based participatory research principles and participant registries as a means to enhance research enrollment and increase diversity of research samples.
PMCID: PMC3945167  PMID: 24322484
Alzheimer’s Disease; Recruitment; Registries; Clinical Trials; Community-Based Participatory Research; Research Participation
7.  Body Mass Index, Weight Change, and Clinical Progression in Mild Cognitive Impairment and Alzheimer’s Disease 
The speed and severity of clinical progression after Alzheimer’s Disease (AD) diagnosis varies and depends on multiple factors, most not well elucidated. We assessed whether body mass index (BMI) and one-year weight change (WC) are associated with clinical progression in amnestic mild cognitive impairment (aMCI) and early-stage AD. Longitudinal data comprising 2,268 aMCI and 1,506 AD participants in the National Alzheimer’s Coordinating Center’s Uniform Data Set were used to examine nuances of clinical progression by BMI and WC, as well as potential variations in associations by age, sex, BMI (WC model), or apolipoprotein E (APOE) genotype. In aMCI, high BMI (versus moderate BMI) was associated with slower progression; weight loss (versus no WC) was associated with faster progression. In AD, no significant differences were observed in clinical progression by BMI or WC. The association between BMI and clinical progression varied significantly by APOE genotype in AD, and the association between WC and clinical progression varied significantly by sex and BMI in aMCI. Baseline BMI and one-year WC in late-life may serve as early prognostic indicators in aMCI and early-stage AD. If replicated, these results may help in counseling patients on anticipated clinical progression and suggest windows of opportunity for intervention.
PMCID: PMC3945175  PMID: 24126214
Body Mass Index; Body Weight Changes; Weight Loss; Alzheimer Disease; Mild Cognitive Impairment; Disease Progression
8.  A Case of Globular Glial Tauopathy Presenting Clinically as Alzheimer Disease 
Alzheimer disease and associated disorders  2013;10.1097/WAD.0b013e318298e531.
PMCID: PMC3875620  PMID: 23751368
globular glial tauopathy; globular oligodendroglial inclusions; dementia; Alzheimer disease; neuropsychological testing
9.  Plasma proteomics for the identification of Alzheimer’s disease 
Alzheimer disease and associated disorders  2013;27(4):10.1097/WAD.0b013e31827b60d2.
Less invasive biomarkers for early Alzheimer’s disease (AD) are urgently needed. The present study aimed to establish a panel of plasma proteins that accurately distinguishes early AD from physiological aging and to compare the findings with previous reports. Fifty eight healthy controls (CON) and 109 patients with AD dementia were randomly split into a training (40%) and a test (60%) sample. Significant proteins to differentiate between the CON and the AD dementia groups were identified in a comprehensive panel of 107 plasma analytes in the training sample; the accuracy in differentiating these two groups was explored in the test sample. A set of five plasma proteins was identified, which differentiated the CON vs. the AD dementia with a sensitivity of 89.36% and a specificity of 79.17%. A biological pathway analysis showed that four of the five proteins belonged to a common network with amyloid precursor protein and tau. Apolipoprotein E was the only protein that was both significant in the present report and in one previous proteomic study. The study provides a piece of evidence in support of the feasibility of a blood-based biomarker approach in AD diagnostics; however, further research is required because of issues with replicability.
PMCID: PMC3626738  PMID: 23314060
Alzheimer’s disease; dementia; biomarker; early diagnosis; prognosis; proteomics
10.  Defining MCI in the Framingham Heart Study Offspring: Education vs. WRAT-based norms 
Alzheimer disease and associated disorders  2013;27(4):10.1097/WAD.0b013e31827bde32.
Psychometric definitions of mild cognitive impairment (MCI) typically use cut-off levels set at 1.5 standard deviations below age- and education-adjusted norms, assuming that the education adjustment accounts for premorbid abilities. However, non-cognitive factors impact educational attainment, potentially leading to incorrect categorization as MCI. We examined whether using an adjustment based on reading performance (Wide Range Achievement Test [WRAT] Reading) improved MCI diagnostic accuracy.
935 Framingham Offspring (mean age 72 ± 5) underwent tests of Memory, Executive Function, Abstraction, Language, and Visuospatial Function as part of a neuropsychological test battery. Domain-specific test scores were regressed onto age and WRAT score, or education, to define MCI. Survival analyses were used to relate baseline MCI to incident dementia.
The two MCI definitions differed most for the lowest and highest education groups. The WRAT definition was more strongly associated with incident dementia for all five tests. MCI-level Abstraction performance was associated with incident dementia using the WRAT definition (HR = 3.20, p = .033), but not the education definition (HR = 1.19, p = .814).
The WRAT should be considered along with the standard measure of years of education, as it may be a better surrogate marker of premorbid abilities.
PMCID: PMC3626741  PMID: 23314066
Mild cognitive impairment; premorbid abilities; neuropsychological assessment; Alzheimer's disease; longitudinal
11.  Differential Longitudinal Decline on the Mini-Mental State Examination in Frontotemporal Lobar Degeneration and Alzheimer's Disease 
Alzheimer disease and associated disorders  2013;27(4):10.1097/WAD.0b013e31827bdc6f.
To examine how phenotype affects longitudinal decline on the Mini-Mental State Examination (MMSE) in patients with frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD)
The MMSE is the most commonly administered assessment for dementia severity; however, the effects of phenotype on longitudinal MMSE performance in FTLD and AD have not been extensively studied.
Data from 185 patients diagnosed with AD (n=106) and three FTLD (n=79) phenotypes (behavioral variant frontotemporal dementia [bvFTD], nonfluent agrammatic variant of primary progressive aphasia [nfaPPA], and semantic variant PPA [svPPA]) were collected for up to 52 months since initial evaluation.
Differential rates of decline were noted in that MMSE scores declined more precipitously for AD and svPPA compared to bvFTD and nfaPPA patients (p=0.001). The absolute 4-year MMSE decline given median baseline MMSE for bvFTD (14.67, 95% confidence interval [CI]: 14.63-14.71) and nfaPPA (11.02, 95% CI: 10.98-11.06) were lower than svPPA (22.32, 95% CI: 22.29-22.34) or AD (22.24, 95% CI: 22.22-22.26).
These data suggest that within-group AD and FTLD phenotypes present distinct patterns of longitudinal decline on the MMSE. MMSE may not be adequately sensitive to track disease progression in some phenotypes of FTLD.
PMCID: PMC3648632  PMID: 23314064
MMSE; Alzheimer's disease; frontotemporal lobe dementia; longitudinal assessment
12.  Effect of Cognitive Reserve Markers on Alzheimer Pathological Progression 
Alzheimer disease and associated disorders  2013;27(4):10.1097/WAD.0b013e3182900b2b.
Education, occupation, premorbid intelligence and brain size are surrogate markers for cognitive reserve. Whether these markers have biological influence on Alzheimer disease (AD) pathology is not known. We thus aimed to investigate the effect of cognitive reserve proxies on longitudinal change of AD biomarkers. A total of 819 participants with normal cognition (NC), mild cognitive impairment (MCI) and mild AD were enrolled in the Alzheimer’s Disease Neuroimaging Initiative and followed up with repeated measures of CSF, PET and MRI biomarkers. Generalized estimating equations were employed to assess whether biomarker rates of change were modified by reserve proxies. CSF Aβ42 decline was slower in NC participants with higher cognitive reserve indexed by education, occupation and American National Adult Reading Test (ANART). The decline of [18F] fluorodeoxyglucose PET uptake was slower in AD participants with better performance on the ANART. Education, occupation and ANART did not modify the rates of MRI hippocampal atrophy in any group. These findings remained unchanged after accounting for APOE 4, longitudinal missing data and baseline cognitive performance. Higher levels of reserve markers may slow the rate of amyloid deposition before cognitive impairment and preserve glucose metabolism at the dementia stage over the course of AD pathological progression.
PMCID: PMC3745532  PMID: 23552443
cognitive reserve; Alzheimer disease; aging; biomarker; longitudinal study
13.  Neurodegenerative disease phenotypes in carriers of MAPT p.A152T, a risk factor for frontotemporal dementia spectrum disorders and Alzheimer's disease 
Alzheimer disease and associated disorders  2013;27(4):10.1097/WAD.0b013e31828cc357.
Recently, Coppola and colleagues demonstrated that a rare MAPT sequence variant, c.454G>A (p.A152T), significantly increases the risk of frontotemporal dementia (FTD) spectrum disorders and Alzheimer's disease (AD) in a screen of 15,369 subjects1. We describe clinical features of 9 patients with neurodegenerative disease (4 women) harboring p.A152T, aged 51 to 79 years at symptom onset. Seven developed FTD spectrum clinical syndromes, including progressive supranuclear palsy syndrome (PSP, n=2), behavioral variant FTD (bvFTD, n=1), nonfluent variant primary progressive aphasia (nfvPPA, n=2), and corticobasal syndrome (CBS, n=2); two patients were diagnosed with clinical AD. Thus, MAPT p.A152T is associated with a variety of FTD spectrum clinical presentations, although patients with clinical AD are also identified. These data warrant larger studies with clinicopathological correlation to elucidate the influence of this genetic variant on neurodegenerative disease.
PMCID: PMC3796183  PMID: 23518664
All Cognitive Disorders/Dementia; Alzheimer's disease; Frontotemporal Dementia; Corticobasal degeneration; Progressive Supranuclear Palsy
14.  Hospital and Nursing Home Use from 2002 to 2008 among U.S. Older Adults with Cognitive Impairment, Not dementia in 2002 
Alzheimer disease and associated disorders  2013;27(4):10.1097/WAD.0b013e318276994e.
Little is known about health care use in the cognitive impairment, not dementia (CIND) subpopulation. Using a cohort of 7,130 persons aged 71 years or over from the Health and Retirement Survey we compared mean and total health care use from 2002–2008 for those with no cognitive impairment [CI], CIND, or dementia in 2002.
Cognitive status was determined using a validated method based on self or proxy interview measures. Health care use was also based on self or proxy reports.
Based on the HRS, the CIND subpopulation in 2002 was 5.3 million; or 23% of the total population 71 years of age or over. Mean hospital nights was similar and mean nursing home nights was less in persons with CIND compared to persons with dementia. The CIND subpopulation, however, had more total hospital and nursing home nights; 71,000 total hospital nights and 223,000 total nursing home nights versus 32,000 hospital nights and 138,000 nursing home nights in the dementia subpopulation.
A relatively large population and high health care use result in a large health care impact of the CIND subpopulation.
PMCID: PMC3607633  PMID: 23151595
Older Adults; Cognitive Impairment; Health Services Use
15.  Developing Dementia Prevention Trials: Baseline Report of the Home-Based Assessment Study 
This report describes the baseline experience of the multi-center, Home Based Assessment (HBA) study, designed to develop methods for dementia prevention trials using novel technologies for test administration and data collection. Non-demented individuals ≥ 75 years old were recruited and evaluated in-person using established clinical trial outcomes of cognition and function, and randomized to one of 3 assessment methodologies: 1) mail-in questionnaire/live telephone interviews (MIP); 2) automated telephone with interactive voice recognition (IVR); and 3) internet-based computer Kiosk (KIO). Brief versions of cognitive and non-cognitive outcomes, were adapted to each methodology and administered at baseline and repeatedly over a 4-year period. “Efficiency” measures assessed the time from screening to baseline, and staff time required for each methodology. 713 individuals signed consent and were screened; 640 met eligibility and were randomized to one of 3 assessment arms and 581 completed baseline. Drop out, time from screening to baseline and total staff time were highest among those assigned to KIO. However efficiency measures were driven by non-recurring start-up activities suggesting that differences may be mitigated over a long trial. Performance among HBA instruments collected via different technologies will be compared to established outcomes over this 4 year study.
PMCID: PMC3943465  PMID: 23151596
Alzheimer’s disease; clinical trials; in-home assessment; prevention studies
16.  Extrapyramidal signs by dementia severity in Alzheimer’s disease and dementia with Lewy bodies 
Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) are common etiologies of dementia with overlapping clinical features. Our objective was to determine which extrapyramidal signs (EPS) are most helpful in identifying DLB. We analyzed data from the National Alzheimer’s Coordinating Center, including demographics, Unified Parkinson’s Disease Rating Scale (UPDRS) scores, Mini Mental State Exam (MMSE) scores, and clinical diagnosis. The subjects were divided into three groups: AD, DLB or LBV (Lewy body variant). The UPDRS motor scores were totaled and analyzed within and across MMSE strata using regression techniques. Next, we divided UPDRS subscores into 9 EPS, dichotomized as either present or absent. Logistic regression analysis was used to compare each of the EPS in the AD and LB (DLB+LBV) groups. DLB subjects (n=130) were more likely to be male, younger, and have higher MMSE scores (p<0.001) than AD (n=1,826) or LBV (n=105) subjects. Differences were found for total UPDRS score and number of EPS (p<0.001), after controlling for age, gender and MMSE. Logistic regression models demonstrated that masked facies best differentiated AD from LB (OR=6.5, p<0.001, 95% CI: 3.8–11.1). If these findings are neuropathologically validated, then the presence of specific EPS may help clinicians better differentiate AD and DLB.
PMCID: PMC3562426  PMID: 23023095
17.  The Demographic and Medical Correlates of Plasma Aβ40 and Aβ42 
Plasma amyloid beta-42 (Aβ42) and Aβ42/Aβ40 are increasingly recognized as biomarkers for dementia, with low levels indicating increased risk. Little is known about the demographic and medical correlates of plasma Aβ40 or Aβ42. In 997 community-dwelling, non-demented older adults from the Health, Aging and Body Composition Study, we determined the cross-sectional association between a wide range of demographic and medical variables with Aβ40 and Aβ42. In multivariate stepwise linear regression models, Aβ40 was significantly associated with race (β=−14.70, F=22.01, p<0.0001), age (β=1.34, F=6.39, p=0.01), creatinine (β=52.91, F=151.77, p<0.0001), and serum brain-derived neurotrophic factor (BDNF) (β=−0.0004, F=7.34, p=0.007); Aβ42 was significantly associated with race (β=−3.72, F=30.83, p<0.0001), sex (β=1.39, F=4.32, p=0.04), education (β=1.50, F=4.78, p=0.03), Apolipoprotein E (APOE) e4 allele status (β=−2.82, F=16.57, p<0.0001), and creatinine (β=9.32, F=120.09, p<0.0001). These correlates should be considered as potential confounders in future studies investigating plasma Aβ as a biomarker of dementia. Understanding fully how these correlates mediate or modify the association between plasma Aβ and dementia will be a fundamental step in determining the biological pathways through which plasma Aβ40 and Aβ42 are associated with dementia, and in determining their full potential as biomarkers.
PMCID: PMC3473156  PMID: 22732677
Plasma amyloid beta; dementia; cognitive decline; biomarker; epidemiology
18.  Big 5 Personality changes in Greek bvFTD, AD, and MCI patients 
Patients with neurodegenerative disease show distinct patterns of personality change, some of which may be traced to focal neurologic damage, while others may be mediated by cultural reactions to functional impairment. While such changes are early and pervasive in behavioral variant frontotemporal dementia (bvFTD), and milder changes are seen in Alzheimer’s (AD), no study has examined all Big 5 factors of personality in mild cognitive impairment (MCI) patients. Also, the influence of culture and ethnicity on disease-related personality changes has seldom been examined. Premorbid and current personality were measured in 47 Greek patients with bvFTD, AD, and MCI according to informant reports using the TPQue5, a 5-factor inventory in the Greek language and accounting for Greek cultural factors. bvFTDs showed greater decreases in conscientiousness than ADs and MCIs. ADs and MCIs showed increased neuroticism, while the bvFTD patients were rated as having become much less neurotic in the course of their disease. The pattern of personality change in MCIs was very similar to that of ADs, supporting recent evidence that personality changes occur as early as the MCI disease stage. In all groups, personality changes were similar to those previously described in non-Mediterranean cultures, supporting the hypothesis that they may result directly from disease-specific neurologic processes.
PMCID: PMC3553233  PMID: 23060360
personality; frontotemporal dementia; Alzheimer’s disease; mild cognitive impairment; Big Five
19.  Combining direct and proxy assessments to reduce attrition bias in a longitudinal study 
Retaining severely impaired individuals poses a major challenge in longitudinal studies of determinants of dementia or memory decline. In the Health and Retirement Study (HRS), participants complete direct memory assessments biennially until they are too impaired to complete the interview. Thereafter, proxy informants, typically spouses, assess the subject’s memory and cognitive function using standardized instruments. Because there is no common scale for direct memory assessments and proxy assessments, proxy reports are often excluded from longitudinal analyses. The Aging and Demographics Memory Study (ADAMS) implemented full neuropsychological exams on a subsample (n=856) of HRS participants, including respondents with direct or proxy cognitive assessments in the prior HRS core interview. Using data from ADAMS, we developed an approach to estimating a dementia probability and a composite memory score based on either proxy or direct assessments in HRS core interviews. The prediction model achieved a c-statistic of 94.3% for DSM diagnosed dementia in the ADAMS sample. We applied these scoring rules to HRS core sample respondents born 1923 or earlier (n=5,483) for biennial assessments 1995-2008. Compared to estimates excluding proxy respondents in the full cohort, incorporating information from proxy respondents increased estimated prevalence of dementia by 12 percentage points in 2008 (average age = 89) and suggested accelerated rates of memory decline over time.
PMCID: PMC3731387  PMID: 22992720
Dementia; Memory decline; HRS; Cognitive assessments; Proxy informants
20.  Dysexecutive versus amnestic Alzheimer’s disease subgroups: Analysis of demographic, genetic, and vascular factors 
The objective of this study was to compare demographic and vascular characteristics and APOE genotypes of a dysexecutive subgroup of Alzheimer’s disease (AD) with an amnestic subgroup of AD early in the disease course. 2,224 participants from the National Alzheimer’s Coordinating Center (NACC) database who carried a diagnosis of MCI (n=1,188) or mild AD (clinical dementia rating ≤1) (n=1,036) were included in this study. A subset of the MCI (n=61) and mild AD (n=79) participants underwent autopsy. A dysexecutive subgroup (n=587) was defined as having executive performance >1 SD worse than memory performance and an amnestic subgroup (n=549) was defined conversely. Among the autopsy subset, the likelihood of an AD pathologic diagnosis was compared in the two subgroups. Demographics, APOEε4 status, and vascular risk factors were compared in the two subgroups. Among the autopsy subset, the likelihood of having an AD pathologic diagnosis did not differ between the dysexecutive and amnestic subgroups. Under an additive model, participants in the dysexecutive subgroup possessed the APOEε4 allele less frequently than those in the amnestic subgroup. The dysexecutive subgroup had a history of hypertension less frequently than the amnestic subgroup. These distinct characteristics add to accumulating evidence that a dysexecutive subgroup of AD may have a unique underlying pathophysiology.
PMCID: PMC3748394  PMID: 23954887
21.  Comparative Analysis of the Alzheimer’s Questionnaire (AQ) with the CDR Sum of Boxes, MoCA, and MMSE 
Alzheimer disease and associated disorders  2012;10.1097/WAD.0b013e3182769731.
The Alzheimer’s Questionnaire (AQ) has been established as a valid and accurate informant-based screening questionnaire for Alzheimer’s disease (AD) and amnestic mild cognitive impairment (aMCI). Although the AQ’s validity and diagnostic accuracy has been established, its performance in comparison to other instruments has not. 39 amnestic mild cognitive impairment (aMCI) cases and 34 Alzheimer’s disease (AD) cases were matched on age, education, and gender to 73 cognitively normal individuals. The sample had a mean age of 82.54±7.77 and a mean education level of 14.61±2.61 years. The diagnostic accuracy of the CDR Sum of Boxes, Mini Mental State Exam (MMSE), Montreal Cognitive Assessment (MoCA), were compared to the AQ. The AQ correlated strongly with the CDR Sum of Boxes (r = .79) and demonstrated similar diagnostic accuracy with the MoCA and MMSE. These results suggest that the AQ is comparable to other established informant-based and patient-based measures.
PMCID: PMC3584226  PMID: 23138174
cognitive screening; mild cognitive impairment; neuropsychological tests; dementia screening
22.  Cultural Diversity and Views on Alzheimer’s Disease in Older African Americans 
Cultural constructs prevalent in older African Americans may influence their risk perceptions and knowledge of Alzheimer’s disease (AD). To examine this issue, we administered 3 sociocultural scales, the Alzheimer’s Disease Knowledge Scale, and a Risk Perception questionnaire to 271 older African Americans who were recruited from a large community senior center and local churches. Higher Present Time Orientation was significantly related to perceptions of having little control over risks to health (p = .004), God’s Will in determining AD (p = .001), and lower AD knowledge (p < .0001), and marginally related to having little control over developing AD (p = .052). Religiosity was marginally related to having little control over risks to health (p = .055) and getting AD″ (p =.057). Post hoc inter-group comparisons found significant differences in the highest vs. lowest scoring Religiosity groups. There were no significant differences by Future Time Orientation. Most subjects (57.6%) were unaware that African Americans were at higher risk for AD than whites. These data indicate that cultural diversity within older African Americans may shape health perceptions and knowledge of AD. This diversity may contribute to disparities in the detection and treatment of AD in this high risk population.
PMCID: PMC3492535  PMID: 22828323
Cultural Diversity; Alzheimer’s Disease; African Americans
23.  Ventricular atrophy and its clinical correlates in the imaging cohort from the ADCS MCI Donepezil/Vitamin E study 
We analyzed the baseline and 3-year T1-weighted magnetic resonance imaging data of 110 amnestic mild cognitive impairment (MCI) participants with minimal hippocampal atrophy at baseline from the Alzheimer’s Disease Cooperative Study group (ADCS) MCI Donepezil/Vitamin E trial. 46 subjects converted to AD (MCIc) while 64 remained stable (MCInc). We used the radial distance technique to examine the differences in lateral ventricle shape and size between MCIc and MCInc and the associations between ventricular enlargement and cognitive decline.
MCIc group had significantly larger frontal and right body/occipital horns relative to MCInc at baseline and significantly larger bilateral frontal, body/occipital and left temporal horns at follow-up. Global cognitive decline measured with ADAScog and MMSE and decline in activities of daily living (ADL) were associated with posterior lateral ventricle enlargement. Decline in ADAScog and ADL were associated with left temporal and decline in MMSE with right temporal horn enlargement. After correction for baseline hippocampal volume decline in ADL showed a significant association with right frontal horn enlargement. Executive decline was associated with right frontal and left temporal horn enlargement.
PMCID: PMC3662002  PMID: 23694947
Alzheimer’s disease; AD; mild cognitive impairment; MCI; imaging; MRI; brain atrophy; ventricular enlargement
24.  Caregiver burden, health utilities and institutional service costs among community-dwelling paients with Alzheimer's disease 
This study examined the moderating effect of caregiver burden on the relationship between patients’ health status and institutional costs in Alzheimer's disease (AD). Data were obtained on whether 421 community-dwelling patients with AD in the CATIE-AD trial received institutional services in the month preceding baseline and at 3-, 6-, and 9-months follow-up. All participants had a caregiver who lived with or visited them regularly. Outcome variables include hospital, nursing home, residential, and combined institutional costs. Mixed models were employed to estimate the interaction of Health Utility Index (HUI)-III scores (a health status measure) and five measures of caregiver burden. Wherever significant, results indicate that greater caregiver burden weakens the inverse relationship between health utilities and institutional costs, leading to greater costs than would be expected at a given level of health. Altogether 45.0% of the models (9/20) showed this effect (positive coefficient on the burden-HUI interaction term). Interventions should be based on caregiver burden, regardless of care recipient health status, for even seemingly manageable patients may be at heightened risk for institutionalization if caregivers experience sufficiently high levels of burden.
PMCID: PMC3951163  PMID: 20625266
Alzheimer's disease; costs; caregiver burden; Health Utilities Index; correlates; institutions
25.  Polyadenylated Messenger RNA in Paired Helical Filament-Immunoreactive Neurons in Alzheimer Disease 
An antibody raised against isolated paired helical filaments (PHF) was used to identify tangle-bearing (PHF+) neurons in autopsy brain tissue from six Alzheimer disease (AD) patients and six age-matched controls (AMC). A comparison of the levels of polyadenylated messenger RNA [poly(A)+ mRNA] in PHF+ and PHF− neurons of similar cross-sectional area in temporal and parietal lobe and cerebellum from four AD and four AMC brains was made by analysis of in situ hybridization of [3H] polyuridylate [poly(U)] to intracellular poly(A)+ mRNA. In PHF+ neurons, the level of poly(A)+. mRNA was approximately two-thirds that in similar-sized PHF− neurons in either AD or AMC. The level of poly(A)+ mRNA in PHF− neurons in regions of the brain that have more of the histopathologically defined effects in AD was similar to that in regions with less effects.
PMCID: PMC3886638  PMID: 1972628
Paired helical filament; Tangle-bearing neurons; Alzheimer disease; Polyadenylated messenger RNA

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