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1.  Association of Shorter Leukocyte Telomere Repeat Length with Dementia and Mortality 
Archives of neurology  2012;69(10):1332-1339.
Shortening of chromosomal telomeres is a consequence of cell division, and is a biological factor related to cellular aging and potentially to more rapid organismal biological aging. We have hypothesized that shorter telomere length, as measured in human blood samples, is associated with the development of Alzheimer disease, and with mortality.
Using data from a multiethnic community-based study of aging and dementia, we studied 1,983 subjects over age 65 yr, who had available stored leukocyte DNA. Mean age-at-blood-draw was 78.3 ± 6.9 yr. Mean age of death was 86.0 ± 7.4 yr. Median follow-up for mortality was 9.3 yr; 190 (9.6%) developed incident dementia. We used real-time PCR to determine mean telomere length (TL) in a modified telomere-sequence to single-copy-gene-sequence ratio method.
TL was inversely related to age, and shorter in men than women. Persons dying during follow-up had shorter TL compared to survivors (6,218±819 vs. 6,491±881 basepairs, p<0.0001) even after adjustment for age, sex, education, and APOE genotype. Individuals who developed dementia had significantly shorter TL (6,131±798 for prevalent cases, and 6,315±817 for incident cases) compared with those remaining dementia-free (6,431±864). Cox-regression analyses showed that shorter TL was a risk for earlier onset of dementia (p=0.05), but stratified analyses for sex showed that this association of age-at-onset of dementia with shorter TL was significant in women, but not in men.
Our findings suggest that shortened leukocyte TL is associated with risks of dementia and mortality, and may therefore be a marker of biological aging.
PMCID: PMC3622729  PMID: 22825311
biological aging; Alzheimer's disease; apolipoprotein E; leukocyte; DNA
2.  Telephone-based identification of MCI and dementia in a multicultural cohort 
Archives of neurology  2011;68(5):607-614.
Telephone-based interviews can be used for screening and to obtain key study outcomes when participants in longitudinal studies die or cannot be seen in person, but must be validated among ethnically and educationally diverse people.
The sample consisted of 377 (31% non-Hispanic white, 35% non-Hispanic black, and 34% Caribbean Hispanic) older adults. The validation standard was diagnosis of dementia and mild cognitive impairment (MCI) based on in-person evaluation. The Telephone Interview for Cognitive Status (TICS) and the Dementia Questionnaire (DQ) were administered within the same assessment wave.
The sample included 256 (68%) people with normal cognition, 68 (18%) with MCI, and 53 (14%) with dementia. Validity of the TICS was comparable among non-Hispanic whites, non-Hispanic blacks, and Hispanics, but the DQ had better discrimination of dementia from those without dementia and with MCI among Whites than other groups. Telephone measures discriminated best when used to differentiate demented from nondemented participants (sensitivity/specificity for the TICS = 88%/87%; DQ = 66%/89%) and when used to differentiate cognitively normal participants from those with cognitive impairment (i.e., MCI and demented combined; sensitivity/specificity for the TICS = 73%/77%; DQ = 49%/82%). When demographics and prior memory test performance were used to calculate pre-test probability, consideration of the telephone measures significantly improved diagnostic validity.
The TICS has high diagnostic validity for identification of dementia among ethnically diverse older adults, especially when supported by the DQ and prior visit data. However, telephone interview data were unable to reliably distinguish MCI from normal cognition.
PMCID: PMC3102767  PMID: 21555635
3.  Longterm blood pressure fluctuation and cerebrovascular disease in an elderly cohort 
Archives of neurology  2010;67(5):564-569.
To determine the association of blood pressure (BP) level and longterm fluctuation in BP with cerebrovascular disease.
Participants received structural MRI and BP measurements in 3, 24 month intervals prior to scanning. We derived the mean and standard deviation (SD) of the mean BP for each participant over the 3 intervals and divided them into four groups defined as above and below the group median (≤ 96.48 mmHg or >96.48mmHg) and further subdivided by the median standard deviation (below SD ≤ 7.21 mmHg or above SD > 7.21 mmHg). This scheme yielded four groups representing the full range of BP and fluctuations in BP. We examined differences in white matter hyperintensity (WMH) volume and brain infarctions across these groups.
The Washington Heights-Inwood Columbia Aging Project, a community-based epidemiological study of older adults from northern Manhattan.
686 non-demented older adults who received structural MRI and had BP measurements over three study visits.
WMH volume increased across the four groups in a linear fashion with the lowest WMH volume in the lowest mean/lowest SD group and the highest in the highest mean/highest SD group (F(3,610)=27.43, p=0.0017). Frequency of infarction also increased monotonically across groups (from 22% to 41%; p-for-trend=0.004).
Compared to individuals with low BP with low fluctuations in BP, the risk of cerebrovascular disease increases with increasing BP and BP fluctuation. Given that cerebrovascular disease is associated with disability, findings suggest that interventions should focus on longterm fluctuating BP as well as elevated BP.
PMCID: PMC2917204  PMID: 20457955
blood pressure; cerebrovascular disease; white matter hyperintensities
4.  A Summary Risk Score for the Prediction of Alzheimer Disease in Elderly Persons 
Archives of neurology  2010;67(7):835-841.
To develop a simple summary risk score for the prediction of Alzheimer disease in elderly persons based on their vascular risk profiles.
A longitudinal, community-based study.
New York, New York.
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.
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.
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.
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.
To reexamine the association of lipid levels with Alzheimer disease (AD) using Cox proportional hazards models.
Prospective cohort study.
Northern Manhattan, New York.
One thousand one hundred thirty elderly individuals free of cognitive impairment at baseline.
Main Outcome Measure
High-density lipoprotein cholesterol (HDL-C) levels.
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.
High HDL-C levels in elderly individuals may be associated with a decreased risk of AD.
PMCID: PMC3065942  PMID: 21149810
6.  Validity of self-reported Stroke in elderly African Americans, Caribbean Hispanics and Caucasians 
Archives of neurology  2009;66(7):834-840.
Background and Objective
The validity of a self-reported stroke remains inconclusive. The objective of the present study was to validate the diagnosis of self-reported stroke using stroke identified by magnetic resonance imaging (MRI) as the standard.
Design and Setting
Community-based cohort study of non-demented, ethnically diverse elderly in northern Manhattan.
High-resolution quantitative MRI was acquired on 717 participants without dementia. Sensitivity and specificity of stroke by self-report were examined using cross-sectional analyses and the χ2-test. Putative relations between factors potentially influencing the reporting of stroke, including memory performance, cognitive function and vascular risk factors were assessed using logistic regression models. Subsequently all analyses were repeated stratified by age, sex, ethnic group and level of education.
In analyses for the whole sample, sensitivity of stroke self-report for a diagnosis of stroke on MRI was 32.4% and specificity was 78.9%. In analyses stratified by median of age (80.1 years), the validity between reported stroke and detection of stroke on MRI was significantly better in the younger than the older age group (for all vascular territories: sensitivity: 36.7% (specificity 81.3%) vs. sensitivity 27.6% (specificity: 26.2%), p=0.02). Impaired memory, cognitive or language ability, and the presence of hypertension or myocardial infarction were associated with higher false-negatives.
Using brain MRI as the standard, specificity and sensitivity of stroke self-report are low. Accuracy of self-report is influenced by age, presence of vascular disease and cognitive function. In stroke research, sensitive neuroimaging techniques rather than stroke self-report should be used to determine stroke history.
PMCID: PMC2881576  PMID: 19433651
7.  Brain morphology in elderly African Americans, Caribbean Hispanics, and Caucasians from Northern Manhattan 
Archives of neurology  2008;65(8):1053-1061.
To examine the impact of age, sex, ethnicity, and vascular disease on measures of brain morphology, including relative brain volume, ventricle volume, hippocampus and entorhinal cortex volume, and white matter hyperintensity (WMH) burden in a large community-based cohort of non-demented, ethnically diverse older adults.
Beginning in 2003, high-resolution quantitative magnetic resonance imaging (MRI) was acquired on 769 participants without dementia. The relations of age, sex, self reported vascular disease history, and ethnicity, with brain morphology was examined in a cross-sectional study using multiple linear regression analyses. Sex and ethnicity interactions were also considered.
The Washington Heights/Hamilton Heights Aging Project (WHICAP), a community-based epidemiological study of older adults from three ethnic groups (i.e., Caucasian, Hispanic, African American) from northern Manhattan.
Main outcome measures
Relative brain volume (absolute brain volume/cranial volume), ventricular volume, hippocampus and entorhinal cortex volumes were derived manually on high-resolution MRI scans. White matter hyperintensities were quantified semi-automatically on FLAIR-weighted MRI.
Increased age was associated with decreased relative brain volume and increased ventricular and WMH volume. Hispanic and African American participants had larger relative brain volumes and more severe WMH burden than Caucasians, but their associations with age were similar across ethnic groups. Compared with men, women had larger relative brain volumes. Vascular disease was associated with smaller relative brain volume and higher WMH burden, particularly among African Americans.
Increased age and vascular disease particularly among African Americans are associated with increased brain atrophy and WMH burden. African American and Hispanic participants have larger relative brain volumes and more WMH than Caucasians. Ethnic group differences in WMH severity appear to be partially attributable to differences in vascular disease. Future work will focus on the determinants and cognitive correlates of these differences.
PMCID: PMC2692286  PMID: 18695055
8.  Quantitative Brain Measures in the Community-Dwelling Elderly with Mild Parkinsonian Signs 
Archives of neurology  2008;65(12):1649-1654.
Mild Parkinsonian signs (MPS) are a marker for incident dementia. MPS have been linked with cerebrovascular disease, which can be evaluated using magnetic resonance imaging (MRI). Also, if MPS are a marker for developing Alzheimer's type changes, hippocampal volume on MRI might be diminished among individuals with MPS.
To examine white matter hyperintensity (WMH) volume and total hippocampal volume in elderly with vs. without MPS.
Community-dwelling elderly in northern Manhattan had a neurological examination and brain MRI. WMH volume (derived on FLAIR-weighted MRI scans using a semi-automated thresholding approach) and total hippocampal volume (manually-derived) were expressed relative to total cranial volume.
MPS were present in 111/666 (16.7%) participants. Relative WMH volume was larger in participants with vs. without MPS (1.70 ± 1.28 vs. 1.17 ± 1.18, p < 0.001) and, in a multivariate logistic regression analysis adjusting for age, gender, years of education, ethnicity, and depression, relative WMH volume was associated with MPS (OR = 1.26, 95% CI = 1.08 − 1.47, p = 0.004). In both unadjusted and adjusted analyses, total relative hippocampal volume was similar in participants with vs. without MPS, regardless of cognitive status.
In this MRI study of the community-dwelling elderly, WMH volume was associated with MPS and total relative hippocampal volume was not. These data raise the possibility that vascular disease could play a role in the development of MPS.
PMCID: PMC2676900  PMID: 19064753
elderly; mild parkinsonian signs; magnetic resonance imaging; hippocampus; Alzheimer's disease; population; epidemiology; white matter hyperintensities
9.  Mediterranean Diet and Mild Cognitive Impairment 
Archives of neurology  2009;66(2):216-225.
Higher adherence to the Mediterranean diet (MeDi) may protect from Alzheimer’s disease (AD) but its association with Mild Cognitive Impairment (MCI) has not been explored.
To investigate the association between MeDi and MCI.
Design, Setting, Patients, Outcomes
In a multiethnic community study in New York, we used Cox proportional hazards to investigate the association between adherence to the MeDi (0 – 9 scale; higher scores higher adherence) and (1) incidence of MCI and (2) progression from MCI to AD. All models were adjusted for cohort, age, gender, ethnicity, education, APOE genotype, caloric intake, body mass index and time duration between baseline dietary assessment and baseline diagnosis.
There were 1393 cognitively normal participants, 275 of whom developed MCI during 4.5 (± 2.7, 0.9–16.4) years of follow-up. Compared to subjects in the lowest MeDi adherence tertile, subjects in the middle MeDi tertile had 17 % (HR, 0.83; 95% CI, 0.62 – 1.12; p=0.24) less risk of developing MCI, while those at the highest MeDi adherence tertile had 28 % (HR, 0.72; 95% CI, 0.52 – 1.00; p=0.05) less risk of developing MCI (trend HR, 0.85; 95% CI, 0.72 – 1.00; p for trend= 0.05). There were 482 subjects with MCI, 106 of whom developed AD during 4.3 (± 2.7, 1.0 – 13.8) years of follow-up. Compared to subjects in the lowest MeDi adherence tertile, subjects in the middle MeDi adherence tertile had 45 % (HR, 0.55; 95% CI, 0.34 – 0.90; p=0.01) less risk of developing AD, while those at the highest MeDi adherence tertile had 48 % (HR, 0.52; 95% CI, 0.30 – 0.91; p=0.02) less risk of developing AD (trend HR, 0.71; 95% CI, 0.53 – 0.95; p for trend= 0.02).
Higher adherence to the MeDi is associated with a trend for reduced risk for developing MCI and with reduced risk for MCI conversion to AD.
PMCID: PMC2653223  PMID: 19204158
10.  The Association Between Genetic Variants in SORL1 and Alzheimer’s Disease in an Urban, Multiethnic, Community-Based Cohort 
Archives of neurology  2007;64(4):501-506.
Variants in 3′ and 5′ regions of SORL1, the neuronal sorting protein-related receptor, were recently found to be associated with late onset familial and sporadic Alzheimer’s disease in several datasets that were selected for familial aggregation or were ethnically diverse or clinic-based selected series.
To investigate the association between Alzheimer’s disease and variant alleles in SORL1 using a series of single nucleotide polymorphisms (SNPs) in an urban, multiethnic community-based population.
Design & Setting
We used a nested case-control analysis in a population-based, prospective study of aging and dementia in Medicare recipients, 65 years and older, residing in northern Manhattan.
There were 296 patients with probable Alzheimer’s disease and 428 healthy elderly controls. The participants were of African American (34%), Caribbean Hispanic (51%) or non-Hispanic whites (15%).
Main Outcome Measures
We genotyped all 29 SNPs in SORL1 that were examined in the earlier report. We assessed allelic association with AD using standard case-control methods which included APOE genotype as a covariate.
Several individual SNPs and SNP haplotypes were significantly associated with AD in this prospectively collected community-based cohort, confirming the previously reported positive association of SORL1 with Alzheimer’s disease. SNP 12 near the 5′ region was associated with AD in African-Americans and Hispanics. Two SNPs in the 3′ region were also associated with AD in African-Americans (SNP 26) and Whites (SNP 20). A single haplotype in the 3′ region was associated with AD in Hispanics. However, several different haplotypes were associated with AD in the African-Americans and Whites, including the “TTC” haplotypes at SNPs 23–25 (p=0.035) that was significantly associated with AD in the North European Whites in the previous report.
This study confirms the association between genetic variants in SORL1 and AD. While the associations observed in these datasets overlap with those previously reported, the finding of novel SNP and haplotype associations suggest that there may be extensive allelic heterogeneity in SORL1. Broad regions of the SORL1 gene will therefore need to be scrutinized for functional pathogenic variants.
PMCID: PMC2639214  PMID: 17420311
SORL1; Alzheimer’s disease; sporadic; African American; Caribbean Hispanic
11.  Elevated plasma amyloid β-peptide Aβ42, incident dementia and mortality in Down syndrome 
Archives of neurology  2007;64(7):1007-1013.
Deposition of the amyloid beta peptide, Aβ42, is thought to be an important initial step in the pathogenesis of Alzheimer’s disease. Individuals with Down syndrome have both increased levels of Aβ peptides and increased risk for Alzheimer’s disease.
To examine the relation of plasma levels of Aβ42 and Aβ40 to risk of dementia in nondemented participants and to all-cause mortality in adults with Down syndrome.
Prospective, community-based longitudinal cohort study.
State and voluntary service providers in New York State
Adults with Down syndrome (N=204).
Plasma Aβ42 and Aβ40 levels were measured at initial examination. Participants were assessed for cognitive and functional abilities, behavioral/psychiatric conditions, health and vital status at 14–18 month intervals over four cycles of data collection.
Among participants who were nondemented at baseline, those in the middle and highest tertiles of plasma Aβ42 levels were over 2 times as likely to develop AD as those in the lowest tertile. Compared with participants without AD, participants with prevalent AD had higher levels of plasma Aβ42 but not Aβ40. Among all participants, those in the highest tertile of plasma Aβ42 level at baseline were over twice as likely to die over the study period as those in the lowest tertile, while there was no difference in risk of death between those in the middle and lowest tertile of plasma Aβ42 level.
Elevations in plasma Aβ42 peptide are associated with earlier onset of AD and increased risk of death.
PMCID: PMC2587094  PMID: 17620492
Beta amyloid 1–42; Down syndrome; Alzheimer’s disease; blood plasma
12.  Measures of adiposity and dementia risk in the elderly 
Archives of neurology  2007;64(3):392-398.
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).
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.
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.
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.
PMCID: PMC1821350  PMID: 17353383

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