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1.  Regional white matter hyperintensity volume, not hippocampal atrophy, predicts incident Alzheimer’s disease in the community 
Archives of neurology  2012;69(12):1621-1627.
Background
New onset Alzheimer’s disease (AD) is often attributed to degenerative changes in the hippocampus. However, the contribution of regionally distributed small vessel cerebrovascular disease, visualized as white matter hyperintensities (WMH) on MRI, remains unclear.
Objective
To determine whether regional WMH and hippocampal volume predict incident AD in an epidemiological study.
Design
A longitudinal community-based epidemiological study of older adults from northern Manhattan.
Setting
The Washington Heights/Inwood Columbia Aging Project
Participants
Between 2005 and 2007, 717 non-demented participants received MRI scans. An average of 40.28 (SD=9.77) months later, 503 returned for follow-up clinical examination and 46 met criteria for incident dementia (45 with AD). Regional WMH and relative hippocampal volumes were derived. Three Cox proportional hazards models were run to predict incident dementia, controlling for relevant variables. The first included all WMH measurements; the second included relative hippocampal volume; and the third combined the two measurements.
Main outcome measures
Incident Alzheimer’s disease.
Results
White matter hyperintensity volume in the parietal lobe predicted time to incident dementia (HR=1.194, p=0.031). Relative hippocampal volume did not predict incident dementia when considered alone (HR=0.419, p=0.768) or with the WMH measures included in the model (HR=0.302, p=0.701). Including hippocampal volume in the model did not notably alter the predictive utility of parietal lobe WMH (HR=1.197, p=0.049).
Conclusion
The findings highlight the regional specificity of the association of WMH with AD. It is not clear whether parietal WMH solely represent a marker for cerebrovascular burden or point to distinct injury compared to other regions. Future work should elucidate pathogenic mechanisms linking WMH and AD pathology.
doi:10.1001/archneurol.2012.1527
PMCID: PMC3597387  PMID: 22945686
Alzheimer’s disease; MRI; cerebrovascular disease; hippocampus
2.  Mid- and Late-Life Obesity: Risk of Dementia in the Cardiovascular Health Cognition Study 
Archives of neurology  2009;66(3):336-342.
Objectives
To evaluate associations between mid- and late-life obesity and risk of dementia.
Design
Prospective cohort followed 5.4 years from 1992/4 through 1999.
Setting
Community-dwelling sample in four US sites recruited from Medicare eligibility files.
Participants
2,798 adults without dementia, mean age 74.7 years, 59.1% women, participating in the Cardiovascular Health Cognition Study completing a magnetic resonance image, measured for height and weight at baseline (late-life) and self-reporting weight at age 50 (mid-life). Body mass index (BMI) was calculated at both times.
Main Outcome Measures
Dementia, Alzheimer’s disease (AD) and vascular dementia (VaD) classified by a multidisciplinary committee using standardized criteria.
Results
Classification resulted in 480 persons with incident dementia, 245 with AD (no VaD) and 213 with VaD (with or without AD). In evaluations of mid-life obesity, an increased risk of dementia was found for obese (BMI >30) compared to normal (BMI 20-25) persons adjusted for demographics (HR: 1.39, 95% CI: 1.03-1.87) and for caradiovascularl risk factors (HR: 1.36, 95% CI: 0.94-1.95). The risk estimates reversed in assessments of late-life BMI. Underweight persons (BMI < 20) had an increased risk of dementia (HR: 1.62, 95% CI: 1.02-2.64) while being overweight (BMI 25-30) was not associated (HR: 0.92, 95% CI: 0.72-1.18) and being obese reduced the risk of dementia (HR: 0.63, 95% CI: 0.44-0.91) compared to those with normal BMI.
Conclusions
These results help explain the “obesity paradox” as differences in dementia risk over time are consistent with physical changes in the trajectory toward disability.
doi:10.1001/archneurol.2008.582
PMCID: PMC3513375  PMID: 19273752
3.  Contribution of vascular risk factors to disease progression in Alzheimer’s Disease 
Archives of neurology  2009;66(3):343-348.
Objective
To determine whether pre-diagnosis vascular risk factors are associated with Alzheimer’s disease progression.
Design
Inception cohort followed longitudinally for a mean of 3.5 (up to 10.2) years.
Setting
Washington Heights Inwood Columbia Aging Project, New York City
Participants
156 incident AD patients (mean age 83 years at diagnosis)
Predictor variables
Vascular factors including medical history (heart disease, stroke, diabetes, hypertension), smoking, and pre-diagnosis blood lipid measurements (total cholesterol, High density lipoproteins (HDL-C), Low density lipoproteins (LDL-C) and triglycerides).
Main Outcome Measure
Change in a composite score of cognitive ability from diagnosis on.
Results
In Generalized Estimating Equation (GEE) models (adjusted for age, race/ethnicity and education), higher cholesterol (total and LDL-C), and diabetes history were associated with faster cognitive decline. Each 10-unit increase in cholesterol and LDL-C was associated with a 10% of a standard deviation decrease in cognitive score per year of follow-up (p<0.001 for total cholesterol, p=0.001 for LDL-C). HDL and triglycerides were not associated with rate of decline. Diabetes history was associated with an additional 50% of a standard deviation decrease in cognitive score per year (p=0.05). History of heart disease and stroke were associated with cognitive decline among APOE-ε4 carriers only. In a final GEE model that included HDL-C, LDL-C and diabetes, only higher LDL-C was independently associated with faster cognitive decline.
Conclusions
Higher pre-diagnosis total cholesterol, LDL-C, and diabetes were associated with faster cognitive decline among incident AD patients, providing further evidence for the role of vascular risk factors in Alzheimer’s disease course.
doi:10.1001/archneur.66.3.343
PMCID: PMC3105324  PMID: 19273753
Alzheimer’s Disease; Natural History; Epidemiology; Cholesterol; Vascular factors
4.  Longterm blood pressure fluctuation and cerebrovascular disease in an elderly cohort 
Archives of neurology  2010;67(5):564-569.
Objective
To determine the association of blood pressure (BP) level and longterm fluctuation in BP with cerebrovascular disease.
Design
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.
Setting
The Washington Heights-Inwood Columbia Aging Project, a community-based epidemiological study of older adults from northern Manhattan.
Participants
686 non-demented older adults who received structural MRI and had BP measurements over three study visits.
Results
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).
Conclusions
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.
doi:10.1001/archneurol.2010.70
PMCID: PMC2917204  PMID: 20457955
blood pressure; cerebrovascular disease; white matter hyperintensities
5.  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
6.  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
7.  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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1001/archneurol.2009.83
PMCID: PMC2881576  PMID: 19433651
8.  Brain morphology in elderly African Americans, Caribbean Hispanics, and Caucasians from Northern Manhattan 
Archives of neurology  2008;65(8):1053-1061.
Objective
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.
Design
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.
Setting
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.
Results
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.
Conclusions
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.
doi:10.1001/archneur.65.8.1053
PMCID: PMC2692286  PMID: 18695055
9.  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

Results 1-9 (9)