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Background: New-onset Alzheimer 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 (WMHs) on magnetic resonance imaging, remains unclear. Objective: To determine whether regional WMHs and hippocampal volume predict incident AD in an epidemiological study. Design: A longitudinal community-based epidemiological study of older adults from northern Manhattan, New York. Setting: The Washington Heights/Inwood Columbia Aging Project. Participants: Between 2005 and 2007, 717 participants without dementia received magnetic resonance imaging scans. A mean (SD) of 40.28 (9.77) months later, 503 returned for follow-up clinical examination and 46 met criteria for incident dementia (45 with AD). Regional WMHs 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 2 measurements. Main Outcome: Measure Incident AD. Results: White matter hyperintensity volume in the parietal lobe predicted time to incident dementia (hazard ratio [HR] = 1.194; P = .03). Relative hippocampal volume did not predict incident dementia when considered alone (HR = 0.419; P = .77) or with the WMH measures included in the model (HR = 0.302; P = .70). Including hippocampal volume in the model did not notably alter the predictive utility of parietal lobe WMHs (HR = 1.197; P = .049). Conclusions: The findings highlight the regional specificity of the association of WMHs with AD. It is not clear whether parietal WMHs solely represent a marker for cerebrovascular burden or point to distinct injury compared with other regions. Future work should elucidate pathogenic mechanisms linking WMHs and AD pathology.

Background The importance of subclinical cerebrovascular disease in the elderly is increasingly recognized, but its determinants have not been fully explicated. Elevated blood pressure (BP) and fluctuation in BP may lead to cerebrovascular disease through ischemic changes and compromised cerebral autoregulation. Objective To determine the association of BP and long-term fluctuation in BP with cerebrovascular disease. Design A community-based epidemiological study of older adults from northern Manhattan. Setting The Washington Heights–Inwood Columbia Aging Project. Participants A total of 686 nondemented older adults who had BP measurements during 3 study visits at 24-month intervals and underwent structural magnetic resonance imaging (corresponding temporally with the third assessment). We derived the mean (SD) of the mean BP for each participant during the 3 intervals and divided the participants into 4 groups defined as below or above the group median (≤96.48 or >96.48 mm Hg) and further subdivided them as below or above the median SD (≤7.21 or >7.21 mm Hg). This scheme yielded 4 groups representing the full range of BPs and fluctuations in BP. Main Outcome Measures Differences in white matter hyperintensity (WMH) volume and presence of brain infarctions across groups. Results White matter hyperintensity volume increased across the 4 groups in a linear manner, with the lowest WMH volume in the lowest mean/lowest SD group and the highest WMH volume in the highest mean/highest SD group ( F 3,610 = 3.52, P = .02). Frequency of infarction also increased monotonically across groups (from 22% to 41%, P for trend = .004). Conclusions Compared with individuals with low BP and low fluctuations in BP, the risk of cerebrovascular disease increased with higher BP and BP fluctuations. Given that cerebrovascular disease is associated with disability, these findings suggest that interventions should focus on long-term fluctuating BP and elevated BP.

Background Hippocampal atrophy and reductions in basal cerebral blood volume (CBV), a hemodynamic correlate of brain function, occur with cognitive impairment in Alzheimer disease, but whether these are early or late changes remains unclear. Magnetic resonance imaging is used to assess structure and function in the hippocampal formation. Objective To estimate differences in the associations of hippocampal and entorhinal cortex volumes and CBV with memory function in the early and late stages of cognitive impairment by relating these measures to memory function in persons with and without dementia who underwent detailed brain imaging and neuropsychological assessment. Design Multivariate regression analyses were used to relate entorhinal cortex volume, entorhinal cortex CBV, hippocampal volume, and hippocampal CBV to measurements of memory performance. The same measures were related to language function as a reference cognitive domain. Setting Community-based cohort. Participants Two hundred thirty-one elderly Medicare recipients (aged ≥65 years) residing in northern Manhattan, New York. Main Outcome Measures Values for entorhinal cortex volume, hippocampal volume, entorhinal cortex CBV, and hippocampal CBV and their relation to memory performance. Results No association was noted between entorhinal cortex volume or hippocampal CBV and memory. Decreased hippocampal volume was strongly associated with worse performance in total recall, and lower entorhinal cortex CBV was associated with lower performance in delayed recall. Excluding persons with Alzheimer disease, the association of entorhinal cortex CBV with memory measures was stronger, whereas the association between hippocampal volume and total recall became nonsignificant. Conclusions In the early stages of Alzheimer disease or in persons without dementia with worse memory ability, functional and metabolic hippocampal hypofunction contributes to memory impairment, whereas in the later stages, functional and structural changes play a role.

Background Aging is accompanied by a decrease in brain volume and by an increase in cerebrovascular disease. Objective To examine the effects of age, sex, race/ethnicity, and vascular disease history on measures of brain morphology, including relative brain volume, ventricular volume, hippocampus and entorhinal cortex volumes, and white matter hyperintensity (WMH) burden, in a large community-based cohort of racially/ethnically diverse older adults without dementia. Design The associations of age, sex, race/ethnicity, and self-reported vascular disease history with brain morphology were examined in a cross-sectional study using multiple linear regression analyses. Sex × race/ethnicity interactions were also considered. Setting The Washington Heights–Inwood Columbia Aging Project, a community-based epidemiological study of older adults from 3 racial/ethnic groups (white, Hispanic, and African American) from northern Manhattan. Participants Beginning in 2003, high-resolution quantitative magnetic resonance (MR) images were acquired in 769 participants without dementia. Main Outcome Measures Relative brain volume (total brain volume/intracranial volume), ventricular volume, and hippocampus and entorhinal cortex volumes were derived manually on high-resolution MR images. White matter hyperintensities were quantified semiautomatically on fluid-attenuated inversion recovery–T2-weighted MR images. Results Older age was associated with decreased relative brain volume and with increased ventricular and WMH volumes. Hispanic and African American participants had larger relative brain volumes and more severe WMH burden than white participants, but the associations of these variables with age were similar across racial/ethnic groups. Compared with men, women had larger relative brain volumes. Vascular disease was associated with smaller relative brain volume and with higher WMH burden, particularly among African Americans. Conclusions Older age and vascular disease, particularly among African Americans, are associated with increased brain atrophy and WMH burden. African American and Hispanic subjects have larger relative brain volumes and more WMH than white subjects. Racial/ethnic group differences in WMH severity seem to be partially attributable to differences in vascular disease. Future work will focus on the determinants and cognitive correlates of these differences.

Background Neurotoxicity related to the Aβ peptide is thought to be a primary mechanism of dysfunction in Alzheimer disease (AD). Although numerous imaging studies have observed brain dysfunction in AD, whether these imaged defects reflect Aβ-related neurotoxicity remains unknown. Objective To study Aβ-related neurotoxicity by means of functional imaging maps of the hippocampal formation in human patients and mouse models. Design Cross-sectional study comparing humans with AD and control subjects, cross-sectional study of J20 mice, a transgenic mouse model of AD, and a longitudinal study of flurbiprofen administration to transgenic mice. Setting Alzheimer disease research center. Subjects Eleven subjects with probable Alzheimer disease and 11 age-matched controls, plus J20 mice and wild-type littermates. Interventions In the first study, human subjects and controls underwent magnetic resonance imaging. In the second study, mice underwent imaging at 3, 6, 12, 15, and 21 months of age, for a total of 57 imaging experiments. In the third study, 12 J20 mice underwent imaging repeatedly over time; 6 received flurbiprofen to ameliorate Aβ-related neurotoxicity and 6 received vehicle control. Main Outcome Measures Comparison of hippocampal functional maps. Results Among all hippocampal subregions, the entorhinal cortex was the dominant site of dysfunction observed in both human patients and J20 mice. Long-term administration of flurbiprofen rescued entorhinal cortex dysfunction in transgenic mice. Conclusion Our results establish that the neurotoxicity related to the Aβ peptide can be captured in vivo by functional imaging and suggest hippocampal subregions most vulnerable to its toxic effects.