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1.  COMBINING ISOTONIC REGRESSION AND EM ALGORITHM TO PREDICT GENETIC RISK UNDER MONOTONICITY CONSTRAINT 
The annals of applied statistics  2014;8(2):1182-1208.
In certain genetic studies, clinicians and genetic counselors are interested in estimating the cumulative risk of a disease for individuals with and without a rare deleterious mutation. Estimating the cumulative risk is difficult, however, when the estimates are based on family history data. Often, the genetic mutation status in many family members is unknown; instead, only estimated probabilities of a patient having a certain mutation status are available. Also, ages of disease-onset are subject to right censoring. Existing methods to estimate the cumulative risk using such family-based data only provide estimation at individual time points, and are not guaranteed to be monotonic, nor non-negative. In this paper, we develop a novel method that combines Expectation-Maximization and isotonic regression to estimate the cumulative risk across the entire support. Our estimator is monotonic, satisfies self-consistent estimating equations, and has high power in detecting differences between the cumulative risks of different populations. Application of our estimator to a Parkinson’s disease (PD) study provides the age-at-onset distribution of PD in PARK2 mutation carriers and non-carriers, and reveals a significant difference between the distribution in compound heterozygous carriers compared to non-carriers, but not between heterozygous carriers and non-carriers.
doi:10.1214/14-AOAS730
PMCID: PMC4231830  PMID: 25404955
Binomial likelihood; Parkinson’s disease; Pool adjacent violation algorithm; Self-consistency estimating equations
2.  Do neuropsychological tests have the same meaning in Spanish speakers as they do in English speakers? 
Neuropsychology  2010;24(3):402-411.
Objective
The purpose of this study was to examine whether neuropsychological tests translated into Spanish measure the same cognitive constructs as the original English versions.
Method
Older adult participants (N = 2,664), who did not exhibit dementia from the Washington Heights Inwood Columbia Aging Project (WHICAP), a community-based cohort from northern Manhattan, were evaluated with a comprehensive neuropsychological battery. The study cohort includes both English (n = 1,800) and Spanish speakers (n = 864) evaluated in their language of preference. Invariance analyses were conducted across language groups on a structural equation model comprising four neuropsychological factors (memory, language, visual-spatial ability, and processing speed).
Results
The results of the analyses indicated that the four-factor model exhibited partial measurement invariance, demonstrated by invariant factor structure and factor loadings but nonequivalent observed score intercepts.
Conclusion
The finding of invariant factor structure and factor loadings provides empirical evidence to support the implicit assumption that scores on neuropsychological tests are measuring equivalent psychological traits across these two language groups. At the structural level, the model exhibited invariant factor variances and covariances.
doi:10.1037/a0017515
PMCID: PMC3908788  PMID: 20438217
aging; cognition; cross-cultural; neuropsychology; measurement invariance; structural equation modeling
3.  Familial Aggregation of Dementia With Lewy Bodies 
Archives of Neurology  2011;68(1):90-93.
Background
Familial aggregation of dementia with Lewy bodies (DLB) remains unclear.
Objectives
To determine the degree of family aggregation of DLB by comparing DLB risk between siblings of probands with clinically diagnosed DLB and siblings of probands with clinically diagnosed Alzheimer disease in a cohort of Caribbean Hispanic families and to explore the degree of aggregation of specific clinical manifestations (ie, cognitive fluctuations, visual hallucinations, and parkinsonism) in DLB.
Design
Familial cohort study.
Setting
Academic research.
Patients
We separately compared risks of possible DLB, probable DLB, and clinical core features of DLB (cognitive fluctuations, visual hallucinations, and parkinsonism) between siblings of probands with clinically diagnosed DLB (n=344) and siblings of probands with clinically diagnosed Alzheimer disease (n=280) in 214 Caribbean Hispanic families with extended neurologic and neuropsychological assessment.
Main Outcome Measures
We applied general estimating equations to adjust for clustering within families. In these models, age and proband disease status were independent variables, and disease status of siblings was the measure of disease risk and the dependent variable.
Results
Compared with siblings of probands having clinically diagnosed Alzheimer disease, siblings of probands having clinically diagnosed DLB had higher risks of probable DLB (odds ratio [OR], 2.29; 95% confidence interval [CI], 1.04–5.04) and visual hallucinations (2.32; 1.16–4.64). They also had increased risks of possible DLB (OR, 1.51; 95% CI, 0.97–2.34) and cognitive fluctuations (1.55; 0.95–2.53).
Conclusions
Dementia with Lewy bodies and core features of DLB aggregate in families. Compared with siblings of probands having clinically diagnosed AD, siblings of probands having clinically diagnosed DLB are at increased risks of DLB and visual hallucinations. These findings are an important step in elucidating the genetic risk factors underlying DLB and in delineating DLB from other neurodegenerative diseases, such as Alzheimer disease.
doi:10.1001/archneurol.2010.319
PMCID: PMC3268781  PMID: 21220678
4.  A Summary Risk Score for the Prediction of Alzheimer Disease in Elderly Persons 
Archives of neurology  2010;67(7):835-841.
Objective
To develop a simple summary risk score for the prediction of Alzheimer disease in elderly persons based on their vascular risk profiles.
Design
A longitudinal, community-based study.
Setting
New York, New York.
Patients
One thousand fifty-one Medicare recipients aged 65 years or older and residing in New York who were free of dementia or cognitive impairment at baseline.
Main Outcome Measures
We separately explored the associations of several vascular risk factors with late-onset Alzheimer disease (LOAD) using Cox proportional hazards models to identify factors that would contribute to the risk score. Then we estimated the score values of each factor based on their βcoefficients and created the LOAD vascular risk score by summing these individual scores.
Results
Risk factors contributing to the risk score were age, sex, education, ethnicity, APOE ε4 genotype, history of diabetes, hypertension or smoking, high-density lipoprotein levels, and waist to hip ratio. The resulting risk score predicted dementia well. According to the vascular risk score quintiles, the risk to develop probable LOAD was 1.0 for persons with a score of 0 to 14 and increased 3.7-fold for persons with a score of 15 to 18, 3.6-fold for persons with a score of 19 to 22, 12.6-fold for persons with a score of 23 to 28, and 20.5-fold for persons with a score higher than 28.
Conclusions
While additional studies in other populations are needed to validate and further develop the score, our study suggests that this vascular risk score could be a valuable tool to identify elderly individuals who might be at risk of LOAD. This risk score could be used to identify persons at risk of LOAD, but can also be used to adjust for confounders in epidemiologic studies.
doi:10.1001/archneurol.2010.136
PMCID: PMC3068839  PMID: 20625090
5.  Association of Higher Levels of High-Density Lipoprotein Cholesterol in Elderly Individuals and Lower Risk of Late-Onset Alzheimer Disease 
Archives of neurology  2010;67(12):1491-1497.
Objective
To reexamine the association of lipid levels with Alzheimer disease (AD) using Cox proportional hazards models.
Design
Prospective cohort study.
Setting
Northern Manhattan, New York.
Participants
One thousand one hundred thirty elderly individuals free of cognitive impairment at baseline.
Main Outcome Measure
High-density lipoprotein cholesterol (HDL-C) levels.
Results
Higher levels of HDL-C (>55 mg/dL) were associated with a decreased risk of both probable and possible AD and probable AD compared with lower HDL-C levels (hazard ratio, 0.4; 95% confidence interval, 0.2–0.9; P=.03 and hazard ratio, 0.4; 95% confidence interval, 0.2–0.9; P=.03). In addition, higher levels of total and non–HDL-C were associated with a decreased risk of AD in analyses adjusting for age, sex, education, ethnic group, and APOEe4 genotype.
Conclusion
High HDL-C levels in elderly individuals may be associated with a decreased risk of AD.
doi:10.1001/archneurol.2010.297
PMCID: PMC3065942  PMID: 21149810
6.  Importance of Symptomatic Cerebral Infarcts on Cognitive Performance in Patients with Alzheimer's Disease 
Journal of Korean Medical Science  2011;26(3):412-416.
The coexistence of cerebral infarcts and Alzheimer's disease (AD) is common, but the influence of symptomatic cerebral infarcts on cognition is uncertain in AD. We hypothesize that symptomatic cerebral infarcts may provide an additive cognitive factor contributing to dementia in the AD population. We studied 1,001 clinically probable or possible AD patients in the Alzheimer Disease Research Center (ADRC) database. Linear regression was used to evaluate for an association between symptomatic cerebral infarcts and memory, language, executive function, abstract reasoning, and visuospatial performance, separately. Models were adjusted for covariates including age, gender, education, ethnicity, hypertension, diabetes mellitus, heart disease, clinical dementia rating, the presence of silent cerebral infarcts, and multiplicity or location of infarcts. Clinical history of stroke was present in 107 patients, radiological infarcts in 308 patients, and 68 patients with both were considered to have symptomatic infarcts. Adjusting for all covariates, AD patients with symptomatic infarcts had more impairment of executive function (P < 0.05). The influence of cerebral infarcts is neither general nor diffuse, and the presence of clinical history may have a more important influence on executive performance in AD.
doi:10.3346/jkms.2011.26.3.412
PMCID: PMC3051090  PMID: 21394311
Alzheimer Disease; Cerebral Infarction; Cognitive; Executive Function; Neuroimaging
7.  Mediterranean Diet and Risk for Alzheimer’s Disease 
Annals of neurology  2006;59(6):912-921.
Objective
Previous research in Alzheimer’s disease (AD) has focused on individual dietary components. There is converging evidence that composite dietary patterns such as the Mediterranean diet (MeDi) is related to lower risk for cardiovascular disease, several forms of cancer, and overall mortality. We sought to investigate the association between MeDi and risk for AD.
Methods
A total of 2,258 community-based nondemented individuals in New York were prospectively evaluated every 1.5 years. Adherence to the MeDi (zero- to nine-point scale with higher scores indicating higher adherence) was the main predictor in models that were adjusted for cohort, age, sex, ethnicity, education, apolipoprotein E genotype, caloric intake, smoking, medical comorbidity index, and body mass index.
Results
There were 262 incident AD cases during the course of 4 (±3.0; range, 0.2–13.9) years of follow-up. Higher adherence to the MeDi was associated with lower risk for AD (hazard ratio, 0.91; 95% confidence interval, 0.83–0.98; p = 0.015). Compared with subjects in the lowest MeDi tertile, subjects in the middle MeDi tertile had a hazard ratio of 0.85 (95% confidence interval, 0.63–1.16) and those at the highest tertile had a hazard ratio of 0.60 (95% confidence interval, 0.42–0.87) for AD (p for trend = 0.007).
Interpretation
We conclude that higher adherence to the MeDi is associated with a reduction in risk for AD.
doi:10.1002/ana.20854
PMCID: PMC3024594  PMID: 16622828
8.  Memory Performance is Related to Amyloid and Tau Pathology in the Hippocampus 
Objective
To determine the relation of amyloid and tau pathology in the hippocampal formation to decline in memory and other cognitive functions in Alzheimer’s disease (AD).
Methods
Regression models were used to relate semiquantitative measurements of amyloid plaques, neurofibrillary tangles (NFTs) and neuropil threads (NTs) at autopsy with antemortem performance in memory, abstract/visuospatial and language domains in two independent samples (n=41, n=66) that had repeated neuropsychological measurements before death.
Results
In both groups, the number of NFTs in entorhinal cortex, subiculum and CA1-region was inversely associated with memory performance at last visit before death. However, the number of amyloid plaques and NTs in the entorhinal cortex was also inversely related to poor memory function. Moreover, as the number of plaques or NTs increased in any region of the hippocampal formation there was a more rapid decline in memory performance over time, a similar decline was associated with increasing numbers of NFTs in the CA1 or subiculum. In contrast, there was no association between amyloid plaques, NFTs or NTs in the frontal or parietal lobe and performance in memory, nor was there an association between plaques, NFTs or NTs in the hippocampal formation and cognitive functions unrelated to memory.
Interpretation
This study implicates both amyloid deposition and tau pathology in the hippocampus as an early and late cause of decline in memory function over time in AD. Memory performance appears to be specifically related with amount of amyloid plaques, NFTs and NTs in the entorhinal cortex and hippocampus.
doi:10.1136/jnnp.2008.154146
PMCID: PMC2785022  PMID: 19258354
amyloid; neurofibrillary tangles; memory performance; hippocampus
9.  Impact of Plasma Lipids and Time on Memory Performance in Healthy Elderly without Dementia 
Neurology  2005;64(8):1378-1383.
Objective
To examine the association of plasma lipid levels to changes in cognitive function in the elderly without dementia.
Methods
We examined changes in performance in tests of memory, visuospatial/cognitive and language abilities in 1147 elderly individuals without dementia or cognitive impairment at baseline followed for seven years using generalized estimating equations.
Results
Performance in all cognitive domains declined significantly over time, while there was no association between levels of any plasma lipid or lipid lowering treatment and memory, cognitive/visuospatial or language performance at any interval. Higher age at baseline was related to lower scores in all three domains at each interval, while higher education and Caucasian ethnicity were associated with higher scores in all domains. Analyses relating plasma lipids to performance in color trails tests using proportional hazards regression showed no association.
In subsequent analyses excluding subjects with incident dementia, memory performance declined over time, while cognitive/visuospatial and language performance did not. Higher plasma HDL and total cholesterol were associated with higher scores in language performance at baseline; this domain declined faster among individuals with higher total cholesterol, but this result was not significant after taking multiple comparisons into account. Plasma triglycerides, LDL, or treatment with lipid lowering agents were not associated to changes in cognitive performance.
Conclusions
Plasma lipid levels or treatment with lipid lowering agents in the elderly were not associated with changes in cognitive function.
doi:10.1212/01.WNL.0000158274.31318.3C
PMCID: PMC2737324  PMID: 15851727
plasma lipids; memory performance; cognitive performance
10.  Plasma Lipid Levels in the Elderly Are Not Associated with the Risk of Mild Cognitive Impairment 
Background
There are conflicting data relating plasma lipids to the risk of Alzheimer's disease (AD). We explored the association of plasma lipids to mild cognitive impairment (MCI), a transitional stage between normal cognition and dementia, in a prospective community-based cohort study among randomly sampled Medicare recipients ≥65 years. Baseline data were collected from 1992 to 1994, follow-up data were collected at 18-month intervals.
Methods
Multivariate proportional hazards regression was used to relate plasma lipid levels to incident total MCI, amnestic MCI and nonamnestic MCI in 854 persons without MCI or dementia at baseline.
Results
There were 324 cases of incident MCI, 153 cases of amnestic MCI and 171 cases of nonamnestic MCI during 4,189 person-years of follow-up. Higher levels of total cholesterol and LDL were associated with a decreased risk of total MCI in models adjusting for age and sex. However, these associations were attenuated after adjusting for ethnicity, education, APOEε4 and vascular risk factors. There was no association between lipids and the risk of amnestic or nonamnestic MCI, and there was no effect of lipid-lowering treatment on MCI risk.
Conclusions
Plasma lipid levels or lipid-lowering treatment in the elderly are not associated with the risk of MCI.
doi:10.1159/000115847
PMCID: PMC2725016  PMID: 18264008
Plasma lipid levels; Mild cognitive impairment
11.  Body Mass Index, Dementia, and Mortality in the Elderly 
Objectives
To explore the association between body mass index and mortality in the elderly taking the diagnosis of dementia into account.
Design
Cohort study.
Setting
cohort study of aging in Medicare recipients in New York City.
Participants
1,452 elderly individuals 65 years and older of both genders.
Measurements
We used proportional hazards regression for longitudinal multivariate analyses relating body mass index (BMI) and weight change to all-cause mortality.
Results
There were 479 deaths during 9,974 person-years of follow-up. There were 210 cases of prevalent dementia at baseline, and 209 cases of incident dementia during follow-up. Among 1,372 persons with BMI information, the lowest quartile of BMI was associated with a higher mortality risk compared to the second quartile (HR = 1.5; 95% CI: 1.1,2.0) after adjustment for age, gender, education, ethnic group, smoking, cancer, and dementia. When persons with dementia were excluded, both the lowest (HR = 1.9; 95% CI =1.3,2.6) and highest (HR = 1.6; 95% CI : 1.1,2.3) quartiles of BMI were related to higher mortality. Weight loss was related to a higher mortality risk (HR = 1.5; 95% CI: 1.2,1.9) but this association was attenuated when persons with short follow-up or persons with dementia were excluded.
Conclusion
The presence of dementia does not explain the association between low BMI and higher mortality in the elderly. However, dementia may explain the association between weight loss and higher mortality.
PMCID: PMC2716999  PMID: 18264640
mortality; dementia; body mass index; weight change
12.  Relation of plasma lipids to all-cause mortality in Caucasian, African-American and Hispanic elders 
Age and ageing  2008;37(2):207-213.
Objectives
to investigate the relation of plasma lipids to all-cause mortality in a multi-ethnic cohort of non-demented elderly.
Setting
community-based sample of Medicare recipients, 65 years and older, residing in Northern Manhattan.
Participants
about two thousand five hundred and fifty-six non-demented elderly, 65–103 years. Among participants, 66.1% were women, 27.6% were White/non-Hispanic, 31.2% were African-American and 41.2% were Hispanic.
Methods
a standardised assessment, including functional ability, medical history, physical and neurological examination and a neuropsychological battery was conducted. Vital status was ascertained through the National Death Index (NDI). We used survival analyses stratified by race and ethnicity to examine the relation of plasma lipids to subsequent all-cause mortality.
Results
hispanics had the best overall survival, followed by African-Americans and Whites. Whites and African-Americans in the lowest quartiles of total cholesterol, non-HDL cholesterol and low-density lipoprotein cholesterol (LDL cholesterol) were approximately twice as likely to die as those in the highest quartile (White HR: 2.2, for lowest total cholesterol quartile; HR: 2.3, for lowest non-HDL cholesterol quartile; and HR: 1.8, for lowest LDL cholesterol quartile. African-American HR: 1.9, for lowest total cholesterol, HR: 2.0, for lowest non-HDL cholesterol and HR: 1.9, for lowest LDL cholesterol). In contrast, plasma lipid levels were not related to mortality risk among Hispanics.
Conclusions
hispanic ethnicity modifies the associations between lipid levels and all-cause mortality in the elderly.
doi:10.1093/ageing/afn017
PMCID: PMC2715146  PMID: 18349015
plasma lipids; all-cause mortality; race/ethnicity; ageing; elderly
13.  Plasma Homocysteine and Risk of Mild Cognitive Impairment 
Background and Objective
There are conflicting data relating homocysteine levels to the risk of Alzheimer´s disease (AD). We sought to explore whether fasting plasma homocysteine is associated with the risk of mild cognitive impairment (MCI), an intermediate stage to dementia.
Methods
Fasting levels of plasma homocysteine were obtained from 678 elderly subjects chosen at random from a cohort of Medicare recipients. There was longitudinal data in 516 subjects without MCI or dementia at baseline who were followed for 2,705 person-years. The relation of plasma homocysteine with prevalent and incident all-cause MCI, amnestic MCI and non-amnestic MCI was assessed using logistic and Cox proportional hazards regression analyses.
Results
There were 162 cases of prevalent MCI and 132 cases of incident MCI in 5,2 years of follow-up. There was no association between plasma homocysteine and prevalence of MCI or amnestic or non-amnestic MCI in the cross-sectional analyses. There was no association between higher homocysteine levels and a lower risk of all-cause MCI. Consistent with the cross-sectional analyses, there was no specific association with the amnestic or non-amnestic subtype of MCI in crude or adjusted models.
Conclusion
Plasma homocysteine levels measured at baseline were not related to MCI or its subtypes in an elderly multiethnic cohort.
doi:10.1159/000182421
PMCID: PMC2698462  PMID: 19088473
homocysteine; dementia; mild cognitive impairment
14.  Relation of Plasma Lipids to Alzheimer Disease and Vascular Dementia 
Archives of neurology  2004;61(5):705-714.
Background
The relation between plasma lipid levels and Alzheimer disease (AD) and vascular dementia (VaD), and the impact of drugs to lower lipid levels remains unclear.
Objective
To investigate the relation between plasma lipid levels and the risk of AD and VaD and the impact of drugs to lower lipid levels on this relationship.
Design and Setting
Cross-sectional and prospective community-based cohort studies.
Participants
Random sample of 4316 Medicare recipients, 65 years and older, residing in northern Manhattan, NY.
Main Outcome Measures
Vascular dementia and AD according to standard criteria.
Results
Elevated levels of non–high-density lipoprotein (HDL-C) and low-density lipoprotein cholesterol (LDL-C) and decreased levels of HDL-C were weak risk factors for VaD in either cross-sectional or prospective analyses. Higher levels of total cholesterol were associated with a decreased risk of incident AD after adjustment for demographics, apolipoprotein E genotype, and cardiovascular risk factors. Treatment with drugs to lower lipid levels did not change the disease risk of either disorder.
Conclusions
We found a weak relation between non–HDL-C, LDL-C, and HDL-C levels and the risk of VaD. Lipid levels and the use of agents to lower them do not seem to be associated with the risk of AD.
doi:10.1001/archneur.61.5.705
PMCID: PMC2696387  PMID: 15148148
15.  Hypertension and the Risk of Mild Cognitive Impairment 
Archives of neurology  2007;64(12):1734-1740.
Background and Objective
There are conflicting data relating hypertension to the risk of Alzheime's disease (AD). We sought to explore whether hypertension is associated with the risk of mild cognitive impairment (MCI), an intermediate stage to dementia.
Design and Setting
Prospective community-based cohort study conducted in northern Manhattan.
Methods
Multivariate proportional hazards regression analyses, relating hypertension to incident all-cause MCI, amnestic MCI, and non-amnestic MCI in 918 persons without prevalent MCI at baseline followed for a mean of 4.7 years.
Results
There were 334 cases of incident MCI, 160 cases of amnestic MCI and 174 cases of non-amnestic MCI during 4337 person years of follow-up. Hypertension was associated with an increased risk of all-cause MCI (HR 1.4, 95% CI 1.06-1.77, p=0.02) and non-amnestic MCI (HR 1.7, 95% CI 1.13-2.42, p=0.009) after adjusting for age and gender. Both associations were slightly attenuated in models additionally adjusting for stroke and other vascular risk factors. There was no association between hypertension and the risk of amnestic MCI (HR 1.1, 95% CI 0.79-1.63, p=0.49). Consistent with this association, hypertension was related with the slope of change in an executive ability score, but not with memory or language scores. There was no effect modification of the association between hypertension and MCI by APOEε4 genotype or use of antihypertensive medication.
Conclusion
A history of hypertension is related to a higher risk of MCI. The association seems to be stronger with the non-amnestic than the amnestic component of MCI. These findings suggest that prevention and treatment of hypertension may have an important impact in lowering the risk of cognitive impairment.
doi:10.1001/archneur.64.12.1734
PMCID: PMC2672564  PMID: 18071036
blood pressure; hypertension; mild cognitive impairment
16.  Frequency of Subclinical Heart Disease in Elderly Persons with Dementia 
We compared the frequency of structural and functional heart abnormalities, assessed using transthoracic echocardiography, among persons with Alzheimer's disease (AD), vascular dementia (VaD), stroke and healthy control subjects. Compared with controls, patients with AD were more likely to have aortic valve thickening, aortic valve regurgitation, left ventricular wall motion abnormalities, left ventricular hypertrophy and a reduced ejection fraction. Persons with VaD were more likely to have aortic valve regurgitation, but mitral valve thickening and triscuspid valve regurgitation were also more frequent. In the absence of dementia, persons with stroke differed from controls by more frequent mitral valve calcifications. With the increasing prevalence of AD and VaD, clinicians have to be more attentive to the presence of structural heart disease and its complications in persons with these conditions.
PMCID: PMC2669795  PMID: 17483671
Heart disease; echocardiography; dementia; Alzheimer's disease; vascular dementia
17.  Stroke and Memory Performance in Elderly without Dementia 
Archives of neurology  2006;63(4):571-576.
Background
There is conflicting data showing that stroke is associated with a higher risk of dementia and a more severe decline in persons with cognitive impairment. However, if cerebrovascular disease is directly related to cognitive decline in the absence of cognitive impairment or dementia remains unclear.
Objective
To examine the association between stroke and changes in cognitive function over time in elderly persons without dementia at baseline.
Design
The results of neuropsychological tests from several intervals over a five-year-period were clustered into domains of memory, abstract/visuospatial and language in 1271 elderly without dementia or cognitive decline. Stroke was related to the slope of performance in each cognitive domain using generalized estimating equations.
Results
Memory performance declined over time while abstract/visuospatial and language performance remained stable over the study period. Stroke was associated with a more rapid decline in memory performance, while there was no association between stroke and decline in abstract/visuospatial or language performance. The association between stroke and decline in memory performance was strongest for men and for persons without an APOE4 allele. A significant association between stroke and decline in abstract/visuospatial performance was also observed for persons without the APOE-e4 allele.
Conclusion
A history of stroke is related to a progressive decline in memory and abstract/visuospatial performance especially among men and those without an APOE-e4 allele.
doi:10.1001/archneur.63.4.571
PMCID: PMC2669794  PMID: 16606771
stroke; memory performance; cognitive performance
18.  Familial Alzheimer Disease in Latinos: Interaction Between APOE, Stroke and Estrogen Replacement 
Neurology  2006;66(1):35-40.
Background
Factors that modify risk related to APOE variants have been examined primarily in unrelated patients and controls, but seldom in family-based studies. Stroke, vascular risk factors, estrogen replacement therapy (ERT), head injury (HI) and smoking have been reported to influence risk of sporadic but not familial AD.
Objectives
To examine the potential relationship between these risk factors and APOE, we used a family study design in a population in which the APOE-ε4 variant is strongly associated with risk of AD.
Methods
Latino families primarily from the Caribbean Islands in which two or more living relatives had dementia were identified in the New York City metropolitan area, the Dominican Republic and Puerto Rico. 1,498 participants from 350 families underwent a clinical interview, medical and neurological examinations, neuropsychological testing and APOE genotyping. Diagnosis was made by consensus using research criteria for AD.
Results
APOE-ε4 was associated with a nearly two-fold increased risk of AD. A history of stroke was also associated with a four-fold increased risk. A statistical interaction between APOE-ε4 and stroke was observed. Women with an APOE-ε4 who took ERT did not have an increased risk of AD, but in women with a history of stroke ERT was a deleterious effect modifier.
Conclusions
APOE-ε4 and stroke independently increase risk of familial AD among Latinos, and may interact to further increase AD risk. Among women, the risk of AD associated with APOE-ε4 may be attenuated by a history of ERT.
doi:10.1212/01.wnl.0000191300.38571.3e
PMCID: PMC2639210  PMID: 16401842
Alzheimer disease; estrogen; stroke; APOE
19.  Comparison of Clinical Manifestation in Familial Alzheimer's disease and Dementia with Lewy Bodies 
Archives of neurology  2008;65(12):1634-1639.
Background
The clinical delineation of Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) remains unclear.
Objective
To compare the neuropsychological profiles of patients with clinically diagnosed Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD).
Methods
We first compared measures of memory, orientation, language, executive, visual perception and visual construction function between persons with DLB and AD in two Caribbean Hispanic cohorts, including a family dataset (DLB =89; AD: n=118) and an epidemiologic dataset (DLB: n=70; AD: n=157). DLB in the family sample was further divided into i) families with two or more affected family members (DLB), or ii) one affected family member (DLB). To determine whether observed differences in cognitive profiles were driven by heritable factors, we then repeated the analyses in the epidemiologic cohort excluding all familial cases. We applied general linear models adjusting for age, sex, education, disease duration, and APOE-ε4 genotype.
Results
Persons with DLB were in both cohorts more severely impaired in orientation, visual construction and non verbal reasoning after controlling for potential confounders. Persons with 2 or more DLB cases per family had the most severe impairment in episodic and semantic memory, followed by those with one DLB case per family, then by those with AD. When familial AD and DLB cases were excluded from the analysis in the epidemiologic cohort, the differences between the AD and DLB groups persisted but were attenuated.
Conclusions
Compared to persons with AD, persons with DLB are more severely impaired in various cognitive domains, particularly orientation, visual perception and visual construction. The difference appears strong in familial rather than sporadic DLB. Whether this divergence in cognitive functions is caused by gene-gene or gene-environmental interactions remains unclear.
doi:10.1001/archneur.65.12.1634
PMCID: PMC2633487  PMID: 19064751
20.  Plasma Homocysteine and Risk of Mild Cognitive Impairment 
Background and Objective
There are conflicting data relating homocysteine levels to the risk of Alzheimer's disease (AD). We sought to explore whether fasting plasma homocysteine is associated with the risk of mild cognitive impairment (MCI), an intermediate stage to dementia.
Methods
Fasting levels of plasma homocysteine were obtained from 678 elderly subjects chosen at random from a cohort of Medicare recipients. There were longitudinal data in 516 subjects without MCI or dementia at baseline who were followed for 2,705 person-years. The relation of plasma homocysteine with prevalent and incident all-cause MCI, amnestic MCI and non-amnestic MCI was assessed using logistic and Cox proportional hazards regression analyses.
Results
There were 162 cases of prevalent MCI and 132 cases of incident MCI in 5.2 years of follow-up. There was no association between plasma homocysteine and prevalence of MCI or amnestic or non-amnestic MCI in the cross-sectional analyses. There was no association between higher homocysteine levels and a lower risk of all-cause MCI. Consistent with the cross-sectional analyses, there was no specific association with the amnestic or non-amnestic subtype of MCI in crude or adjusted models.
Conclusion
Plasma homocysteine levels measured at baseline were not related to MCI or its subtypes in an elderly multiethnic cohort.
doi:10.1159/000182421
PMCID: PMC2698462  PMID: 19088473
Homocysteine; Dementia; Mild cognitive impairment
21.  Depressive symptoms, vascular risk factors, and Alzheimer’s disease 
Background
Depressive symptoms in the elderly are associated with an increased Alzheimer’s disease (AD) risk. We sought to determine whether the association between depressive symptoms and AD is explained by a history of vascular risk factors and stroke.
Methods
526 elderly persons from New York City without dementia at baseline were followed for a mean of 5 years. Depressive symptoms were assessed using the 17-item Hamilton Depression Rating Scale (HAM). Incident AD was ascertained using standard criteria. Diabetes, hypertension, heart disease, current smoking and stroke were ascertained by self-report. Proportional hazards regression was used to relate HAM scores to incident AD.
Results
HAM scores were higher in persons with hypertension, heart disease, and stroke, which in turn were related to higher AD risk. AD risk increased with increasing HAM scores as a continuous logarithmically transformed variable (HR for one point increase = 1.4; 95% CI: 1.1,1.8) and as a categorical variable (HR for HAM ≥ 10 = 3.4; 95% CI=1.5,8.1; p for trend = 0.004 with HAM =0 as the reference). These results were virtually unchanged after adjustment for vascular risk factors and stroke, individually (HR for HAM ≥ 10 = 3.4; 95% CI=1.5,8.1; p for trend = 0.004), and in a composite measure (HR for HAM ≥ 10 = 3.0; 95% CI: 1.2,7.8; p for trend = 0.02).
Conclusion
The prospective relation between depressive symptoms and AD is not explained by the a history of vascular risk factors and stroke, suggesting that other mechanisms may account for this association.
doi:10.1002/gps.2006
PMCID: PMC2562891  PMID: 18327871
depressive symptoms; vascular risk factors; stroke; Alzheimer’s disease
22.  Measures of adiposity and dementia risk in the elderly 
Archives of neurology  2007;64(3):392-398.
Background
Studies relating adiposity to dementia are conflicting. We explored the associations of body mass index (BMI) waist circumference (WC), and weight change to dementia, probable Alzheimer’s disease (AD), and dementia associated with stroke (DAS).
Methods
Persons without dementia were followed for 5 years; 893 persons had BMI, 907 persons had WC, and 709 persons had a second weight measurement. Dementia was ascertained using standard methods. Cox regression was used for analyses using follow-up as time-to-event, adjusting for demographics, and APOE-ɛ4.
Results
Compared to persons in the first quartile of BMI, persons in the third quartile had a lower dementia and AD risk, and persons in the second quartile had a lower DAS risk. The association between BMI and dementia resembled a U-shape in those < 76 years, while dementia risk decreased with higher BMI in those ≥ 76 years. The 4th quartile of WC was related to a higher DAS risk in the whole sample, and to dementia and AD in persons < 76 years. Weight loss was related to a higher dementia and DAS risk, and weight gain was related to a higher DAS risk only.
Conclusions
The prospective association between adiposity and dementia differs depending on the anthropometric measure used and is modified by age. This may explain previous conflicting reports.
doi:10.1001/archneur.64.3.392
PMCID: PMC1821350  PMID: 17353383
23.  Aggregation of Vascular Risk Factors and Risk of Incident Alzheimer’s Disease 
Neurology  2005;65(4):545-551.
Background
The prevalence of Alzheimer disease (AD) is increasing in the elderly and vascular risk factors may increase its risk. We explored the association of the aggregation of vascular risk factors to AD.
Methods
we followed 1,138 individuals without dementia at baseline (mean age = 76.2 years) for a mean of 5.5 years. The presence of vascular risk factors was related to incident possible and probable AD.
Results
Four risk factors, diabetes, hypertension, heart disease, and current smoking, were associated with a higher risk of AD (p < 0.10) when analyzed individually. The risk of AD increased with the number of risk factors (diabetes + hypertension + heart disease + current smoking). The adjusted HR of probable AD for the presence of 3 or more risk factors was 3.4 (95% CI: 1.8,6.3; p for trend < 0.0001) compared to no risk factors. Diabetes and current smoking were the strongest risk factors in isolation or in clusters, but hypertension and heart disease were also related to a higher risk of AD when clustered with diabetes, smoking, or each other.
Conclusions
The risk of AD increased with the number of vascular risk factors. Diabetes and current smoking were the strongest risk factors, but clusters including hypertension and heart disease also increased the risk of AD. These associations are unlikely to be explained by misclassification of the outcome given strong associations when only probable AD is considered.
doi:10.1212/01.wnl.0000172914.08967.dc
PMCID: PMC1619350  PMID: 16116114
24.  Lower cognitive performance in healthy G2019S LRRK2 mutation carriers 
Neurology  2012;79(10):1027-1032.
Objective:
To assess cognitive abilities of healthy first-degree relatives of Ashkenazi patients with Parkinson disease (PD), carriers of the G2019S mutation in the LRRK2 gene.
Methods:
In this observational study, 60 consecutive healthy first-degree relatives (aged 50.9 ± 6.2 years; 48% male; 30 G2019S carriers) were assessed using a computerized cognitive program, the Montreal Cognitive Assessment questionnaire, the Unified Parkinson's Disease Rating Scale Part III, and the Geriatric Depression Scale.
Results:
G2019S carriers scored significantly lower on the computerized executive function index (p = 0.04) and on specific executive function tasks (Stroop test, p = 0.007).
Conclusion:
Carrying the LRRK2 G2019S mutation was associated with lower executive performance in a population at risk for PD.
doi:10.1212/WNL.0b013e3182684646
PMCID: PMC3430708  PMID: 22914834

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