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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.  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
3.  Telephone-based identification of MCI and dementia in a multicultural cohort 
Archives of neurology  2011;68(5):607-614.
Objective
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.
Method
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.
Results
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.
Conclusions
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.
doi:10.1001/archneurol.2011.88
PMCID: PMC3102767  PMID: 21555635
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.  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
6.  Linking Hippocampal Structure and Function to Memory Performance in an Aging Population 
Archives of neurology  2009;66(11):1385-1392.
Objective
Hippocampal atrophy and reductions in basal cerebral blood volume (CBV), a hemodynamic correlate of brain function, occur with cognitive impairment in Alzheimer's disease but whether these are early or late changes remains unclear. Magnetic resonance imaging (MRI) assesses structure and function in the hippocampal formation. The objective of the present study was to estimate differences in the associations of hippocampus and entorhinal cortex volumes and CBV with memory function in early and late stages of cognitive impairment by relating these measures with memory function in demented and nondemented persons with detailed brain imaging and neuropsychological assessment.
Design and Setting
Multivariate regression analyses were used to relate entorhinal cortex volume, entorhinal cortex CBV, hippocampus volume and hippocampus-CBV with measures of memory performance in 231 elderly persons from a community-based cohort. The same measures were related with language function as a reference cognitive domain.
Results
There was no association between entorhinal cortex volume or hippocampus-CBV and memory. Decreased hippocampus volume was strongly associated with worse performance in total recall, while lower entorhinal cortex CBV was significantly associated with lower performance in delayed recall. Excluding persons with Alzheimer's disease (AD), the associations of entorhinal cortex CBV with memory measures was stronger, while the association between hippocampus volume and total recall became non-significant.
Conclusions
These finding suggest that in the early stages of AD or in nondemented persons with worse memory ability functional/metabolic hippocampal hypofunction contribute to memory impairment, while in the later stages both functional and structural changes play a role.
doi:10.1001/archneurol.2009.214
PMCID: PMC2778802  PMID: 19901171
entorhinal cortex cerebral blood volume; hippocampus volume; memory performance
7.  Measuring cerebral atrophy and white matter hyperintensity burden to predict the rate of cognitive decline in Alzheimer disease 
Archives of neurology  2008;65(9):1202-1208.
Objective
Although non-specific, cerebral atrophy and white matter hyperintensities (WMH) are features of the neurodegeneration associated with Alzheimer’s disease (AD). The purpose of the current study was to determine if baseline measurements of cerebral atrophy and WMH predict the rate of future cognitive decline in AD.
Design
Data were drawn from the Predictors Study, a longitudinal study that enrolls mild AD patients and re-asseses them every six months with the Columbia modified Mini Mental State Examination (mMMS; 0–57). MR images were analyzed to determine the severity of WMH (Scheltens Scale) and the degree of atrophy (bicaudate ratio). Generalized estimating equations (GEE) were used to determine whether severity of baseline MRI measurements and their interaction predicted the rate of mMMS decline at subsequent visits.
Setting
Three university-based AD centers in the United States (Predictors Study).
Participants
Eighty-four AD patients from the Predictors Study received structural MRI at baseline and were selected for analysis. They had an average of 6 follow-up evaluations.
Main outcome measure
Cognitive (Columbia modified Mini-Mental State Examination).
Results
Generalized estimating equation models demonstrated that degree of baseline atrophy (β = −0.316, p = 0.036), severity of WMH (β = −0.173, p = 0.028), and their interaction (β = − 6.061, p = 0.018) predicted rate of decline in mMMS scores.
Conclusions
Both degree of cerebral atrophy and severity of WMH are associated with the rapidity of cognitive decline in AD. Atrophy and WMH may interact to have a synergistic effect on future decline, such that AD patients with a high degree of both have a particularly precipitous cognitive course. These findings lend further support to the hypothesis that cerebrovascular pathology contributes to the clinical syndrome of Alzheimer’s disease.
doi:10.1001/archneur.65.9.1202
PMCID: PMC2629007  PMID: 18779424
Alzheimer’s disease; MRI; neuropsychological assessment
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.  Quantitative Brain Measures in the Community-Dwelling Elderly with Mild Parkinsonian Signs 
Archives of neurology  2008;65(12):1649-1654.
Background
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.
Objective
To examine white matter hyperintensity (WMH) volume and total hippocampal volume in elderly with vs. without MPS.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1001/archneurol.2008.504
PMCID: PMC2676900  PMID: 19064753
elderly; mild parkinsonian signs; magnetic resonance imaging; hippocampus; Alzheimer's disease; population; epidemiology; white matter hyperintensities

Results 1-9 (9)