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Background: Guidelines emphasize screening people with elevated BP for the presence of end-organ damage. Methods: We characterized the prevalence, correlates, and prognosis of hypertension-mediated organ damage (HMOD) in the community-based Framingham Study. 7898 participants (mean age 51.6 years, 54% women) underwent assessment for the following HMOD: electrocardiographic and echocardiographic left ventricular hypertrophy, abnormal brain imaging findings consistent with vascular injury, increased carotid intima-media thickness, elevated carotid-femoral pulse wave velocity, reduced kidney function, microalbuminuria, and low ankle-brachial index. We characterized HMOD prevalence according to blood pressure (BP) categories defined by four international BP guidelines. Participants were followed up for incidence of cardiovascular disease. Results: The prevalence of HMOD varied positively with systolic BP and pulse pressure but negatively with diastolic BP; it increased with age, was similar in both sexes, and varied across BP guidelines based on their thresholds defining hypertension. Among participants with hypertension, elevated carotid-femoral pulse wave velocity was the most prevalent HMOD (40%–60%), whereas low ankle-brachial index was the least prevalent ( Conclusions: The prevalence of HMOD varies across international BP guidelines based on their different thresholds for defining hypertension. The presence of HMOD confers incremental prognostic information regarding cardiovascular disease risk at every BP category.

Background Bone mineral density (BMD) is a potential surrogate marker of lifetime estrogen exposure previously linked to increased risk of Alzheimer dementia among elderly women. We examine the association between BMD in the "young old" with imaging biomarkers of brain aging and cognitive performance. Methods Offspring participants (N=1905, mean age 66) of a population-based cohort who had BMD, brain imaging and detailed cognitive assessment were included in the study. Sex-stratified, linear, and logistic regression models were used for analysis. Results Higher femoral neck BMD was associated with lower white matter hyperintensity burden and better performance on Trails B-A in both sexes, even after adjustment for cerebrovascular risk factors. Among women, the positive association with Trails B-A performance was seen only in APOE4 allele carriers. Higher BMD measurements were linked to better visual reproductions test performance in men. Finally, among women, higher femoral trochanter BMD was associated with better logical memory and Hooper visual organization test performance. Conclusion Among the "young old," higher BMD is associated with less white matter hyperintensity burden and better, domain-specific, cognitive performance. This suggests that lifetime estrogen exposure may modulate the degree of cumulative vascular brain injury independent of cerebrovascular risk factors.

ObjectiveTo test the hypothesis that reduced slow-wave sleep, or N3 sleep, which is thought to underlie the restorative functions of sleep, is associated with MRI markers of brain aging, we evaluated this relationship in the community-based Framingham Heart Study Offspring cohort using polysomnography and brain MRI.MethodsWe studied 492 participants (age 58.8 ± 8.8 years, 49.4% male) free of neurological diseases who completed a brain MRI scan and in-home overnight polysomnography to assess slow-wave sleep (absolute duration and percentage of total sleep). Volumes of total brain, total cortical, frontal cortical, subcortical gray matter, hippocampus, and white matter hyperintensities were investigated as a percentage of intracranial volume, and the presence of covert brain infarcts was evaluated. Linear and logistic regression models were adjusted for age, age squared, sex, time interval between polysomnography and MRI (3.3 ± 1.0 years), APOE ε4 carrier status, stroke risk factors, sleeping pill use, body mass index, and depression.ResultsLess slow-wave sleep was associated with lower cortical brain volume (absolute duration, β [standard error] = 0.20 [0.08], p = 0.015; percentage, 0.16 [0.08], p = 0.044), lower subcortical brain volume (percentage, 0.03 [0.02], p = 0.034), and higher white matter hyperintensities volume (absolute duration, −0.12 [0.05], p = 0.010; percentage, −0.10 [0.04], p = 0.033). Slow-wave sleep duration was not associated with hippocampal volume or the presence of covert brain infarcts.ConclusionLoss of slow-wave sleep might facilitate accelerated brain aging, as evidence by its association with MRI markers suggestive of brain atrophy and injury. Alternatively, subtle injuries and accelerated aging might reduce the ability of the brain to produce slow-wave sleep.

ObjectiveRecent studies suggest that white matter hyperintensities (WMH) on MRI, which primarily reflect small vessel cerebrovascular disease, may play a role in the evolution of Alzheimer disease (AD). In a longitudinal study, we investigated whether WMH promote the progression of AD pathology, or alter the association between AD pathology and risk of progression from normal cognition to mild cognitive impairment (MCI).MethodsTwo sets of analyses were conducted. The relationship between whole brain WMH load, based on fluid-attenuated inversion recovery MRI, obtained in initially cognitively normal participants (n = 274) and time to onset of symptoms of MCI (n = 60) was examined using Cox regression models. In a subset of the participants with both MRI and CSF data (n = 204), the interaction of WMH load and CSF AD biomarkers was also evaluated.ResultsBaseline WMH load interacted with CSF total tau (t-tau) with respect to symptom onset, but not with CSF β-amyloid 1–42 or phosphorylated tau (p-tau) 181. WMH volume was associated with time to symptom onset of MCI among individuals with low t-tau (hazard ratio [HR] 1.35, confidence interval [CI] 1.06–1.73, p = 0.013), but not those with high t-tau (HR 0.86, CI 0.56–1.32, p = 0.47). The rate of change in the CSF biomarkers over time was not associated with the rate of change in WMH volumes.ConclusionThese results suggest that WMH primarily affect the risk of progression when CSF measures of neurodegeneration or neuronal injury (as reflected by t-tau) are low. However, CSF biomarkers of amyloid and p-tau and WMH appear to have largely independent and nonsynergistic effects on the risk of progression to MCI.

OBJECTIVE: A rare variant in TREM2 (p.R47H, rs75932628) has been consistently reported to increase the risk for Alzheimer’s disease, while mixed evidence has been reported for association of the variant with other neurodegenerative diseases. Here, we investigated the frequency of the R47H variant in a diverse and well-characterized multicenter neurodegenerative disease cohort. METHODS: We examined the frequency of the R47H variant in a diverse neurodegenerative disease cohort, including a total of 3,058 patients clinically diagnosed with Alzheimer’s disease, frontotemporal dementia spectrum syndromes, mild cognitive impairment, progressive supranuclear palsy syndrome, corticobasal syndrome, or amyotrophic lateral sclerosis and 5,089 control subjects. RESULTS: We observed a significant association between the R47H variant and Alzheimer’s disease, while no association was observed with any other neurodegenerative disease included in this study. CONCLUSIONS: Our results support the consensus that the R47H variant is significantly associated with Alzheimer’s disease. However, we did not find evidence for association of the R47H variant with other neurodegenerative diseases.

ObjectiveTo examine associations between measures of obesity in middle to early-old age with later-life MRI markers of brain aging.MethodsWe analyzed data from the Northern Manhattan MRI Sub-Study (n = 1,289). Our exposures of interest were body mass index (BMI), waist circumference (WC), waist-to-hip ratio, and plasma adiponectin levels. Our outcomes of interest were total cerebral volume (TCV), cortical thickness, white matter hyperintensity volume (WMHV), and subclinical brain infarcts (SBI). Using multivariable linear and logistic regression models adjusted for sociodemographics, health behaviors, and vascular risk factors, we estimated β coefficients (or odds ratios) and 95% confidence intervals (CIs) and tested interactions with age, sex, and race/ethnicity.ResultsOn average at baseline, participants were aged 64 years and had 10 years of education; 60% were women and 66% were Caribbean Hispanic. The mean (SD) time lag between baseline and MRI was 6 (3) years. Greater BMI and WC were significantly associated with thinner cortices (BMI β [95% CI] −0.089 [−0.153, −0.025], WC β [95% CI] −0.103 [−0.169, −0.037]) in fully adjusted models. Similarly, compared to those with BMI ConclusionsAdiposity in early-old age is related to reduced global gray matter later in life in this diverse sample. Future studies are warranted to elucidate causal relationships and explore region-specific associations.

Background GDF15 (growth differentiation factor 15) and NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) may offer promise as biomarkers for cognitive outcomes, including dementia. We determined the association of these biomarkers with cognitive outcomes in a community‐based cohort. Methods and Results Plasma GDF15 (n=1603) and NT‐proBNP levels (n=1590) (53% women; mean age, 68.7 years) were measured in dementia‐free Framingham Offspring cohort participants at examination 7 (1998–2001). Participants were followed up for incident dementia. Secondary outcomes included Alzheimer disease dementia, magnetic resonance imaging structural brain measures, and neurocognitive performance. During a median 11.8‐year follow‐up, 131 participants developed dementia. On multivariable Cox proportional‐hazards analysis, higher circulating GDF15 was associated with an increased risk of incident all‐cause and Alzheimer disease dementia (hazard ratio [HR] per SD increment in natural log‐transformed biomarker value, 1.54 [95% CI, 1.22–1.95] and 1.37 [95% CI, 1.03–1.81], respectively), whereas higher plasma NT‐proBNP was also associated with an increased risk of all‐cause dementia (HR, 1.32; 95% CI, 1.05–1.65). Elevated GDF15 was associated with lower total brain and hippocampal volumes, greater white matter hyperintensity volume, and poorer cognitive performance. Elevated NT‐proBNP was associated with greater white matter hyperintensity volume and poorer cognitive performance. Addition of both biomarkers to a conventional risk factor model improved dementia risk classification (net reclassification improvement index, 0.25; 95% CI, 0.05–0.45). Conclusions Elevated plasma GDF15 and NT‐proBNP were associated with vascular brain injury on magnetic resonance imaging, poorer neurocognitive performance, and increased risk of incident dementia in individuals aged >60 years. Both biomarkers improved dementia risk classification beyond that of traditional clinical risk factors, indicating their potential value in predicting incident dementia.

ObjectiveWe investigated differences in the anatomical distribution of cerebral microbleeds (CMBs) on MRI, hypothesized to indicate the type of underlying cerebral small vessel disease (SVD), between Eastern and Western general populations.MethodsWe analyzed data from 11 studies identified by a PubMed search between 1996 and April 2014 according to the Preferred Reporting Items for a Systematic Review and Meta-analysis of Individual Participant Data. Study quality measures indicated low or medium risk of bias. We included stroke-free participants from populations aged between 55 and 75 years, categorized by geographic location (Eastern or Western). We categorized CMB distribution (strictly lobar, deep and/or infratentorial [D/I], or mixed [i.e., CMBs located in both lobar and D/I regions]). We tested the hypothesis that Eastern and Western populations have different anatomical distributions of CMBs using multivariable mixed effects logistic regression analyses adjusted for age, sex, and hypertension and clustering by institution.ResultsAmong 8,595 stroke-free individuals (mean age [SD] 66.7 [5.6] years; 48% male; 42% from a Western population), 624 (7.3%) had CMBs (strictly lobar in 3.1%; D/I or mixed in 4.2%). In multivariable mixed effects models, Eastern populations had higher odds of D/I or mixed CMBs (adjusted odds ratio 2.78, 95% confidence interval [CI] 1.77–4.35) compared to Western populations. Eastern populations had a higher number of D/I or mixed CMBs (adjusted prevalence ratio 2.83, 95% CI 1.27–6.31).ConclusionsEastern and Western general populations have different anatomical distributions of CMBs, suggesting differences in the spectrum of predominant underlying SVDs, with potential implications for SVD diagnosis and treatment.

Importance Birth in areas with high infant mortality rates (IMRs) has been linked to worse long-term health outcomes, yet it is completely unknown if it impacts dementia risk. Methods In total 6268 health care members were followed for dementia diagnosis from 1996 to 2015. Birth state IMRs from 1928 were ranked into quartile (worst IMRs quartile range, whites: 69 to 129 deaths/1000 live births, Non-whites: 129 to 277 deaths/1000 live births). Cox proportional hazard models estimated the dementia risk associated with birth state IMR quartile adjusting for demographics and lifecourse health indicators. Results Compared with whites born outside of states in the worst IMR quartile, African Americans born in states in the worst IMR quartile had 92% increased dementia risk (HR=1.92; 95% CI: 1.42, 2.59), and African Americans born outside those states had 36% increased risk (HR=1.36; 95% CI: 1.20, 1.53). There was no association between birth state IMR and dementia risk among whites. Conclusions Birth in states with the highest rates of infant mortality was associated with elevated dementia risk among African Americans but not whites. The large absolute difference in IMRs likely reflects harsher early childhood conditions experienced by African Americans. These findings suggest that childhood conditions may play a role in racial disparities in dementia rates.

ObjectiveWe examined whether greater depressive symptoms were associated with domain-specific cognitive performance, change in cognition, and MRI markers of brain atrophy and subclinical cerebrovascular disease in a diverse sample of older adults from the Northern Manhattan Study.MethodsData were analyzed from the Northern Manhattan Study, a prospective cohort study of mostly Caribbean Hispanic, stroke-free, older adults. A total of 1,111 participants had baseline measures of depressive symptoms, measured as the Center of Epidemiological Studies–Depression Scale, MRI markers, and cognitive function. A Center of Epidemiological Studies–Depression score ≥16 was considered indicative of greater depressive symptoms. Multivariable linear and logistic regression models were used to examine the associations of interest.ResultsAt baseline, 22% of participants had greater depressive symptoms. Greater depressive symptoms were significantly associated with worse baseline episodic memory in models adjusted for sociodemographic, vascular risk factor, behavioral, and antidepressive medication variables (β [95% confidence interval] = −0.21 [−0.33 to −0.10],p= 0.0003). Greater depressive symptoms were also associated with smaller cerebral parenchymal fraction (β [95% confidence interval] = −0.56 [−1.05 to −0.07],p= 0.02) and increased odds of subclinical brain infarcts (odds ratio [95% confidence interval] = 1.55 [1.00–2.42],p= 0.05), after adjustment for sociodemographic, behavioral, and vascular risk factor variables. Greater depressive symptoms were not significantly associated with white matter hyperintensity volume, hippocampal volume, or change in cognition over an average of 5 years. Results were unchanged when stabilized inverse probability weights were applied to address selective attrition during the study period.ConclusionsIn this sample of mostly Caribbean Hispanic, stroke-free, older adults, greater depressive symptoms were associated with worse episodic memory, smaller cerebral volume, and silent infarcts.

Introduction We examined associations between magnetic resonance imaging (MRI) markers of cerebrovascular disease and neurodegeneration with mild cognitive impairment (MCI) diagnosis at baseline and conversion from normal cognition to MCI at follow-up. Methods Framingham Offspring participants underwent brain MRI and neuropsychological assessment at baseline (n=1049) and follow-up (n=561). Participants were classified at baseline and at follow-up as cognitively normal or MCI using sensitive neuropsychological criteria. White matter hyperintensity (WMH) volume, covert brain infarcts, hippocampal volume, and total cerebral brain volume were quantified. Results Baseline measures of WMH and hippocampal volume were associated with MCI status cross-sectionally and also with conversion from normal cognition to MCI at 6.5-year follow-up. Annualized change rates in total cerebral brain volume and hippocampal volume were associated with conversion from normal cognition to MCI to follow-up. Discussion Baseline WMH and hippocampal volume are markers that are both associated with conversion from normal cognition to MCI, highlighting the role of both vascular lesions and neurodegeneration in MCI.

Objective:To determine the association between blood pressure during midlife (40–64 years) to late life (≥65 years) and risk of incident dementia.Methods:This study included 1,440 (758 women, mean age 69 ± 6 years) Framingham Offspring participants who were free of dementia and attended 5 consecutive examinations at 4-year intervals starting at midlife (1983–1987, mean age 55 years) until late life (1998–2001, mean 69 years) and subsequently were followed up for incident dementia (mean 8 years). We determined the effect of midlife hypertension (≥140/90 mm Hg), late life hypertension, lower late life blood pressure (Results:During the follow-up period, 107 participants (71 women) developed dementia. Using multivariable Cox proportional hazards models, we found that midlife systolic hypertension (hazard ratio [HR] 1.57, 95% confidence interval [CI] 1.05–2.35) and persistence of systolic hypertension into late life (HR 1.96, 95% CI 1.25–3.09) were associated with an elevated risk of incident dementia. However, in individuals with low to normal blood pressure (≤140/90 mm Hg) at midlife, a steep decline in systolic blood pressure during mid- to late life was also associated with a >2-fold increase in dementia risk (HR 2.40, 95% CI 1.39–4.15).Conclusions:Elevated blood pressure during midlife, persistence of elevated blood pressure into late life, and, among nonhypertensives, a steep decline in blood pressure during mid- to late life were associated with an increased dementia risk in a community-based cohort. Our data highlight the potential sustained cognitive benefits of lower blood pressures in midlife but also suggest that declining blood pressure in older adults with prehypertension or normotension, but not in those with hypertension, may be a risk marker for dementia.

Objective:To evaluate the association of early-adulthood and mid-adulthood hypertension with dementia in men and women.Methods:We evaluated 5,646 members of a diverse integrated health care delivery system who had clinical examinations and health survey data from 1964 to 1973 (mean age 32.7 years; early adulthood) and 1978–1985 (mean age 44.3 years; mid-adulthood) and were members as of January 1, 1996 (mean age 59.8 years). Hypertension categories based on measurements of blood pressure (BP) and change in hypertension categories between the 2 examinations (e.g., onset hypertension) were used to predict dementia incidence from January 1, 1996, to September 30, 2015. Cox proportional hazard models were adjusted for demographics, vascular comorbidities, and hypertension treatment; inverse probability weighting accounted for differential attrition between first BP measurement and start of follow-up.Results:A total of 532 individuals (9.4%) were diagnosed with dementia. Early adulthood hypertension was not associated with dementia, though effect estimates were elevated among women. Mid-adulthood hypertension was associated with 65% (95% confidence interval [CI] 1.25–2.18) increased dementia risk among women but not men. Onset of hypertension in mid-adulthood predicted 73% higher dementia risk in women (95% CI 1.24–2.40) compared to stable normotensive. There was no evidence that hypertension or changes in hypertension increased dementia risk among men.Conclusions:Though midlife hypertension was more common in men, it was only associated with dementia risk in women. Sex differences in the timing of dementia risk factors have important implications for brain health and hypertension management.

Background and Purpose— Chronic infections and cardiac dysfunction are risk factors for stroke. We hypothesized that blood biomarkers of infection (procalcitonin) and cardiac dysfunction (midregional proatrial natriuretic peptide [MR-proANP]), previously associated with small vessel stroke and cardioembolic stroke are also associated with subclinical cerebrovascular damage, including silent brain infarcts and white matter hyperintensity volume. Methods— The NOMAS (Northern Manhattan Study) was designed to assess risk factors for incident vascular disease in a multiethnic cohort. A subsample underwent brain magnetic resonance imaging and had blood samples available for biomarker measurement (n=1178). We used logistic regression models to estimate the odds ratios and 95% confidence intervals (95% CIs) for the association of these biomarkers with silent brain infarcts after adjusting for demographic, behavioral, and medical risk factors. We used linear regression to assess associations with log-white matter hyperintensity volume. Results— Mean age was 70±9 years; 60% were women, 66% Hispanic, 17% black, and 15% were white. After adjusting for risk factors, subjects with procalcitonin or MR-proANP in the top quartile, compared with the lowest quartile were more likely to have silent brain infarcts (adjusted odds ratio for procalcitonin, 2.2; 95% CI, 1.3–3.7 and for MR-proANP, 3.3; 95% CI, 1.7–6.3) and increased white matter hyperintensity volume (adjusted mean change in log-white matter hyperintensity volume for procalcitonin, 0.29; 95% CI, 0.13–0.44 and for MR-proANP, 0.18; 95% CI, 0.004–0.36). Conclusions— Higher concentrations of procalcitonin, a marker of infection, and MR-proANP, a marker of cardiac dysfunction, are independently associated with subclinical cerebrovascular damage. If further studies demonstrate an incremental value for risk stratification, biomarker-guided primary prevention studies may lead to new approaches to prevent cerebrovascular disease.

Background and Purpose— Little is known about associations between vascular growth factors and magnetic resonance imaging (MRI) markers in midlife. We investigated the association of serum VEGF (vascular endothelial growth factor), Ang2 (angiopoietin 2), sTie2 (soluble tyrosine kinase with immunoglobulin-like and EGF-like domains 2), and HGF (hepatocyte growth factor) concentrations with MRI markers of brain aging in middle-aged adults. Methods— We evaluated 1853 participants (mean age, 46±9 years; 46% men) from the Framingham Heart Study. Serum growth factor concentrations were measured using standardized immunoassays. Outcomes included total brain, cortical and subcortical gray matter, white matter, cerebrospinal fluid, and white matter hyperintensity volumes derived from MRI; as well as fractional anisotropy in white matter tracts from diffusion tensor imaging. We related VEGF, Ang2, sTie2, and HGF to MRI measures using multivariable regression models adjusting for vascular risk factors. We tested for interactions with APOE (apolipoprotein E) genotype and CRP (C-reactive protein). Results were corrected for multiple comparisons. Results— Higher sTie2 was associated with smaller total brain (estimate by SD unit±SE=−0.08±0.02, P =0.002) and larger white matter hyperintensity (0.08±0.02, P =0.002) volumes. Furthermore, higher Ang2 (0.06±0.02, P =0.049) and HGF (0.09±0.02, P =0.001) were associated with larger cerebrospinal fluid volumes. Finally, higher Ang2 was associated with decreased fractional anisotropy, in APOE-ε4 carriers only. Conclusions— Vascular growth factors are associated with early MRI markers of small vessel disease and neurodegeneration in middle-aged adults.

Background Excess transmission of pressure pulsatility caused by increased arterial stiffness may incur microcirculatory damage in end organs (target organ damage [TOD] ) and, in turn, elevate risk for cardiovascular disease ( CVD ) events. Methods and Results We related arterial stiffness measures (carotid‐femoral pulse wave velocity, mean arterial pressure, central pulse pressure) to the prevalence and incidence of TOD (defined as albuminuria and/or echocardiographic left ventricular hypertrophy) in up to 6203 Framingham Study participants (mean age 50±15 years, 54% women). We then related presence of TOD to incident CVD in multivariable Cox regression models without and with adjustment for arterial stiffness measures. Cross‐sectionally, greater arterial stiffness was associated with a higher prevalence of TOD (adjusted odds ratios ranging from 1.23 to 1.54 per SD increment in arterial stiffness measure, P SD 1.28, 95% CI, 1.02–1.61; P SD 1.37 and 1.45, respectively; P CVD event. Presence of TOD was associated with a 33% greater hazard of incident CVD (95% CI , 0–77%; P Conclusions Elevated arterial stiffness is associated with presence of TOD and may partially mediate the relations of TOD with incident CVD . Our observations in a large community‐based sample suggest that mitigating arterial stiffness may lower the burden of TOD and, in turn, clinical CVD .

Objective: Adherence to the Mediterranean- DASH for Neurodegenerative Delay (MIND) diet has previously been associated with cognitive decline and dementia. To our knowledge, no prior study has investigated the association between the MIND diet and measures of brain volume, silent brain infarcts (SBIs) or brain atrophy. Methods: We aimed to evaluate, cross-sectionally and longitudinally, whether consumption of a diet consist with the MIND diet was associated with larger brain volumes, fewer SBIs and fewer atrophy in the community-based Framinham Heart Study. We included 1,904 participants (mean age 69 (SD, 9)) who completed a brain MRI and a validated food frequency questionnaire (FFQ). The MIND diet consists of 10 healthy and five unhealthy components (range: 0-15). A cumulative MIND diet score was calculated by averaging across three FFQs (exams 5 (1991-1995), 6 (1995-1998), and 7 (1998-2001)). From the total study population, 86 % completed all three FFQs. Brain MRI was performed proximal to exam 7 and again after a mean of 7 years (SD, 1.1) (n=1,317). Total brain volume (TBV), hippocampal volume (HPV), white matter hyperintensity volume (WMHV), expressed as a percentage of total cranial volume, and presence of SBIs were assessed from MRI scans. We used multivariable linear (TBV, HPV and WMHV) and logistic (SBIs) regressions for the cross-sectional analyses, and we analyzed the annualized change of TBV and HPV as atrophy measures using multivariable linear regression. Results: In cross-sectional analyses, higher MIND diet scores were significantly associated with larger TBV (β±SE, +0.09±0.04; p=0.03) after adjustment for basic demographic factors, total daily energy intake, and APOE e4 allele status, but was not associated with HPV (+0.001±0.001; p=0.09), WMHV (-0.01±0.01; p=0.27), SBIs (OR (95%CI), +1.01, 0.92:1.10; p=0.61) or atrophy (TBV, -0.001±0.01; p=0.88; HPV, -0.0003±0.001; p=0.62). After additional adjustments for cardiovascular risk factors the association with TBV was attenuated (+0.05±0.04; p=0.17). Significant interactions were observed for HPV by APOE ε4 status and BMI in the basic model. After stratification by APOE ε4 status, higher MIND diet scores were significantly associated with higher HPV among APOE ε4 non-carriers (+0.002±0.001; p=0.01) but not carriers (n=412). After stratification by BMI, higher adherence to the MIND diet was associated with larger HPV among participants with a BMI above 25 (+0.002±0.001; p=0.01), but not among participants with a BMI below 25. Conclusions: Higher adherence to the MIND diet was not independently associated with brain volume measures, SBIs or brain atrophy in our community cohort as the associations appeared to be mediated by cardiovascular risk factors. In addition, we observed that adherence to the diet was associated with larger brain volume measures in sub groups. Replication is needed to confirm our findings.

Background and Purpose— Elevated fibroblast growth factor 23 (FGF23) regulates phosphate homeostasis and is linked with mortality, cardiovascular events, and stroke. However, the role of FGF23 as a risk factor for subclinical cerebrovascular damage is unclear. Methods— We used multivariable linear and logistic regression to evaluate associations between FGF23, continuously and by quartiles, with white matter hyperintensity volume, expressed as percent intracranial volume (%ICV), and subclinical brain infarction (SBI) in a community-based stroke-free sample. Results— There were 1170 stroke-free Northern Manhattan Study (NOMAS) participants with FGF23 levels and quantitative magnetic resonance imaging data on white matter hyperintensity volume and SBI. Participants with FGF23 levels in the top quartile (range=85–1425 RU/mL) had greater white matter hyperintensity volume (β=0.19 %ICV; 95% CI, 0.04–0.33 %ICV; P =0.01) compared with those in the lowest quartile (range=15–49 RU/mL), adjusted for demographics, vascular risk factors, and estimated glomerular filtration rate. These findings remained significant in those without evidence of chronic kidney disease (estimated glomerular filtration rate 2 ). Elevated FGF23 was not associated with SBI overall after adjusting for demographic factors and estimated glomerular filtration rate, but sex modified the effect of FGF23 on odds of SBI ( P for interaction=0.03). FGF23 was associated with significantly greater odds of SBI only in men (odds ratio, 1.7; 95% CI, 1.1–2.7; P =0.03) after full adjustment. Conclusions— These cross-sectional community-based data from a diverse urban sample show an association between elevated FGF23 and small vessel disease and magnetic resonance imaging–defined brain infarction in men, independent of chronic kidney disease. Data on elevated FGF23 and subclinical cerebrovascular damage progression are needed.

Aortic stiffness is associated with cognitive decline and cerebrovascular disease late in life, although these associations have not been examined in young adults. Understanding the effects of aortic stiffness on the brain at a young age is important both from a pathophysiological and public health perspective. The aim of this study was to examine the cross-sectional associations of aortic stiffness with cognitive function and brain aging in the Framingham Heart Study Third Generation cohort (47% men; mean age, 46 years). Participants completed the assessment of aortic stiffness (carotid–femoral pulse wave velocity), a neuropsychological test battery assessing multiple domains of cognitive performance and magnetic resonance imaging to examine subclinical markers of brain injury. In adjusted regression models, higher aortic stiffness was associated with poorer processing speed and executive function (Trail Making B–A; β±SE, −0.08±0.03; P P P

Background and Purpose— Cerebral microbleeds (CMB) represent a common magnetic resonance imaging marker of cerebral small vessel disease, increasingly recognized as a subclinical marker of stroke and dementia risk. CMB detection may reflect the cumulative effect of vascular risk burden and be a marker of higher mortality. We investigated the relation of CMB to risk of death in community dwelling participants free of stroke and dementia. Methods— We evaluated 1963 Framingham Original and Offspring Cohort participants (mean age 67 years; 54% women) with available brain magnetic resonance imaging and mortality data. Using Cox proportional hazards models, we related CMB to all-cause, cardiovascular, and stroke-related mortality. Results— Participants with CMB (8.9%) had higher prevalence of cardiovascular risk factors and use of preventive medications. During a mean follow-up of 7.2±2.6 years, we observed 296 deaths. In age- and sex-adjusted analysis, CMB were associated with increased all-cause mortality (hazards ratio, 1.39; 95% confidence interval 1.03–1.88), a relation that was no longer significant after adjustment for cardiovascular risk and preventive medication use (hazards ratio, 1.15; 95% confidence interval, 0.82–1.63). Conclusions— CMBs may represent the deleterious effect of cardiovascular risk factors in the cerebral vasculature. Although their presence was associated with increased all-cause mortality, the effect was no longer present after accounting for vascular risk factors and preventive treatment use. Further studies are required to clarify the role of cardiovascular preventive therapies for prevention of mortality in persons with incidental detection of CMB.

Introduction: Plasma β-amyloid (Aβ), Tau and Clusterin have been considered biomarkers of vascular and dementia pathology, and as candidate biomarkers to identify persons at high risk of dementia. Cerebral microbleeds (CMBs) are subclinical MRI markers representing the most common forms of cerebral small vessel disease: hypertensive for deep CMB and cerebral amyloid angiopathy for lobar CMB. CMB are associated with higher risk of stroke and dementia, predating clinical diagnosis by several years. We studied the association of circulating Aβ, Tau and Clusterin levels with CMB to elucidate their role as biomarkers for the angiopathies represented by CMB, and further understand the early pathophysiology of cerebrovascular disease predating diagnosis of clinical dementia and stroke. Methods: We included dementia and stroke-free Framingham Heart Study participants (mean age 57years, 54% women) with available brain MRI T2*gradient-echo sequences and Aβ (N=1711), Tau (N=3680) and Clusterin (N=3129) measurements. We used multivariable logistic regression analyses to relate circulating biomarker levels to CMB presence overall and stratified by brain topography (OR per SD increase in biomarker level). Models were adjusted for age, sex, time between biomarker measurement and MRI, APOE-e4 genotype, hypertension, statin and antiplatelet use, and C-reactive protein levels. Results: CMB were observed in 208 (5.7%) participants (any lobar 174 (4.7%), any deep (56, 1.5%). After multivariable adjustment we observed a borderline association of Aβ-40 with any CMB (OR (95%CI) 1.21(0.99, 1.46) p-value=0.058), a strong association with lobar CMB (OR (95%CI) 1.37 (1.10, 1.71) p-value=0.005), and no significant association with deep CMB. Tau levels were associated with any CMB (OR (95%CI) 1.22 (1.06, 1.40) p-value=0.006), lobar CMB (OR (95%CI) 1.17 (1.01, 1.36) p-value=0.036), and no significant association with deep CMB. No significant association of CMB with clusterin or Aβ-42 levels was found. Conclusions: Our results suggest that Plasma Aβ-40 and Tau may serve as biomarkers of cerebral amyloid angiopathy (represented by lobar CMB) and support the role of CMB as markers of neuronal injury.

Background: Carotid atherosclerosis is a known risk factor for stroke and dementia. Carotid atherosclerosis may play a role in neurodegeneration and be a potential target for treatment and preventive efforts for stroke and dementia in asymptomatic individuals. We studied the association of carotid intima media thickness (CIMT) with hippocampal volume (HV) in community-dwelling individuals, and hypothesize that persons with carotid atherosclerosis progression would have a lower HV. Methods: We studied 1,376 Framingham Offspring participants (age 67±8.7 years; 53% women) with two carotid ultrasound measurements (1995-1998 and 2005-2008) and brain MRI scans at or near the second ultrasound, who were stroke, dementia, or other neurological illnesses-free at MRI. We used multivariable linear regression analyses to relate annualized carotid IMT change at internal [ICA] and common carotid [CCA] to HV volume (as a percentage of total cranial volume). Models were adjusted for age, sex, time interval between second carotid duplex and MRI, systolic blood pressure, hypertension treatment (HRx), diabetes, total cholesterol level, smoking, cardiovascular disease and baseline CIMT. We additionally assessed effect modification by HRx and statin use. Results: Mean (±SD) carotid IMT change per year was 0.064±0.082mm in ICA and 0.008±0.008 mm in CCA. Participants with higher ICA IMT progression had significantly lower HV after adjustment for vascular risk factors and baseline IMT (β±SE [standardized beta±standard error]: -0.067±0.027, p= 0.01), but not CCA IMT progression (β±SE: 0.01± 0.0276 p= 0.72). In subgroup analyses, we observed weaker association between ICA IMT change and HV among subjects with HRx (β = -0.047, p=0.19 vs. β =-0.096, p=0.026 in untreated individuals), but HRx by IMT change interaction was not statistically significant (p-interaction=0.39). Effects were similar in statin subgroups and statistically non-significant for CCA IMT progression. Conclusions: Cumulative vascular risk factor exposure, as reflected by ICA IMT progression, are associated with neurodegeneration represented by lower hippocampal volumes. Such changes occur prior to onset of clinical dementia, suggesting that carotid IMT may be a target for preventive efforts.

Introduction: Chronic stress and related changes in serum cortisol have adverse effects on brain structure and cognition in animal models. However, evidence from population-based studies is scant. We assessed the association of early morning serum cortisol with cognition and brain structural integrity in middle-aged adults without dementia. Hypotheses: High or low levels of serum cortisol are associated with lower cognitive performance and brain volumes. Methods: We evaluated dementia-free Framingham Study (Generation 3) participants (mean age 48.5 years; 46.8% men), who underwent cognitive testing of memory, abstract reasoning, visual perception, attention, and executive function (n= 2231), and brain MRI (n=2018) to assess total white matter, lobar gray matter, and white matter hyperintensity volumes and fractional anisotropy (FA) measures. We used linear or logistic (cortisol categorized in tertiles, middle tertile as the reference) regression to assess the relations of cortisol with cognition, MRI volumes and voxel-based microstructural white matter integrity and gray matter density, adjusting for age, sex, APOE and vascular risk factors. Results: Higher cortisol (highest tertile vs. middle tertile) was associated with worse memory and visual perception, as well as lower total cerebral brain, occipital and frontal lobar gray matter volumes (Table ) . Higher cortisol was associated with multiple areas of microstructural changes on voxel-based analyses (gray matter density and FA). The association of cortisol with total cerebral brain volume varied by sex ( Pinteraction =0.048 , highest cortisol tertile inversely associated with cerebral brain volume in women [ P= 0.001] but not in men [ P =0.717]). There was no effect modification by the apoE4 genotype of the relations of cortisol and cognition or imaging traits. Conclusions: Higher serum cortisol was associated with lower brain volumes and impaired memory in asymptomatic young adults in their forties; women may be particularly susceptible to this influence.

To determine whether poor cardiovascular (CV) fitness and exaggerated exercise blood pressure (BP) and heart rate (HR) were associated with worse brain morphology in later life.Framingham Offspring participants (n = 1,094, 53.9% female) free from dementia and CV disease (CVD) underwent an exercise treadmill test at a mean age of 40 ± 9 years. A second treadmill test and MRI scans of the brain were administered 2 decades later at mean age of 58 ± 8 years.Poor CV fitness and greater diastolic BP and HR response to exercise at baseline were associated with a smaller total cerebral brain volume (TCBV) almost 2 decades later (all p0.05) in multivariable adjusted models; the effect of 1 SD lower fitness was equivalent to approximately 1 additional year of brain aging in individuals free of CVD. In participants with prehypertension or hypertension at baseline, exercise systolic BP was also associated with smaller TCBV (p0.05).Our results suggest that lower CV fitness and exaggerated exercise BP and HR responses in middle-aged adults are associated with smaller brain volume nearly 2 decades later. Promotion of midlife CV fitness may be an important step towards ensuring healthy brain aging.

Background and Purpose— Growth differentiation factor-15 (GDF-15) and soluble (s)ST2 are markers of cardiac and vascular stress. We investigated the associations between circulating concentrations of these biomarkers and incident stroke and subclinical vascular brain injury in a sample from the Framingham Offspring cohort. Methods— We followed 3374 stroke- and dementia-free individuals (mean age, 59.0±9.7 years; 53% women) attending the Framingham Offspring sixth examination cycle 11.8±3.0 years for incident stroke. A subsample of 2463 individuals underwent brain magnetic resonance imaging and neuropsychological testing ≈4.0±1.7 years after the sixth examination. Results— After adjustment for traditional cardiovascular risk factors, B-type natriuretic peptide, high-sensitivity C-reactive protein, and urine albumin levels, higher stress biomarker levels were associated cross-sectionally with lower brain volumes ( β coefficients for intracranial volume comparing fourth [Q4] versus first biomarker [Q1] quartiles: −0.71% for GDF-15; P =0.002 and 0.47% for sST2; P =0.02) and worse performance on the visual reproduction test ( β coefficients for Q4 versus Q1: −0.62 for GDF-15; P =0.009 and −0.40 for sST2; P =0.04). Higher GDF-15 concentrations were also associated with greater log-transformed white-matter hyperintensity volumes ( β for Q4 versus Q1=0.19; P =0.01). Prospectively, a total of 203 (6%) individuals developed incident stroke/transient ischemic attack during follow-up. After multivariable adjustment, sST2 remained significantly associated with stroke/transient ischemic attack, hazard ratio for Q4 versus Q1 of 1.76, 95% confidence interval of 1.06 to 2.92, and P =0.03. Conclusions— Circulating GDF-15 and sST2 are associated with subclinical brain injury and cognitive impairment. Higher sST2 concentrations are also associated with incident stroke, suggesting potential links between cardiac stress biomarkers and brain injury.

Objective: To evaluate the possible early consequences of impaired glucose metabolism on the brain by assessing the relationship of diabetes, fasting blood glucose (FBG) levels, and insulin resistance with cognitive performance and brain integrity in healthy young and middle-aged adults. Methods: The sample included dementia-free participants (mean age 40 ± 9 years; 53% women) of the Framingham Heart Study third-generation cohort with cognitive testing of memory, abstract reasoning, visual perception, attention, and executive function (n = 2,126). In addition, brain MRI examination (n = 1,597) was used to determine white matter, gray matter, and white matter hyperintensity (WMH) volumes and fractional anisotropy measures. We used linear regression models to assess relationships between diabetes, FBG, and insulin resistance with cognition, lobar gray matter, and WMH volumes as well as voxel-based microstructural white matter integrity and gray matter density, adjusting for potential confounders. Mediating effect of brain lesions on the association of diabetes with cognitive performance was also tested. Results: Diabetes was associated with worse memory, visual perception, and attention performance; increased WMH; and decreased total cerebral brain and occipital lobar gray matter volumes. The link of diabetes with attention and memory was mediated through occipital and frontal atrophy, and the latter also through hippocampal atrophy. Both diabetes and increased FBG were associated with large areas of reductions in gray matter density and fractional anisotropy on voxel-based analyses. Conclusions: We found that hyperglycemia is associated with subtle brain injury and impaired attention and memory even in young adults, indicating that brain injury is an early manifestation of impaired glucose metabolism.

Background and Purpose— Long-term exposure to ambient air pollution is associated with cerebrovascular disease and cognitive impairment, but whether it is related to structural changes in the brain is not clear. We examined the associations between residential long-term exposure to ambient air pollution and markers of brain aging using magnetic resonance imaging. Methods— Framingham Offspring Study participants who attended the seventh examination were at least 60 years old and free of dementia and stroke were included. We evaluated associations between exposures (fine particulate matter [PM 2.5 ] and residential proximity to major roadways) and measures of total cerebral brain volume, hippocampal volume, white matter hyperintensity volume (log-transformed and extensive white matter hyperintensity volume for age), and covert brain infarcts. Models were adjusted for age, clinical covariates, indicators of socioeconomic position, and temporal trends. Results— A 2-μg/m 3 increase in PM 2.5 was associated with −0.32% (95% confidence interval, −0.59 to −0.05) smaller total cerebral brain volume and 1.46 (95% confidence interval, 1.10 to 1.94) higher odds of covert brain infarcts. Living further away from a major roadway was associated with 0.10 (95% confidence interval, 0.01 to 0.19) greater log-transformed white matter hyperintensity volume for an interquartile range difference in distance, but no clear pattern of association was observed for extensive white matter. Conclusions— Exposure to elevated levels of PM 2.5 was associated with smaller total cerebral brain volume, a marker of age-associated brain atrophy, and with higher odds of covert brain infarcts. These findings suggest that air pollution is associated with insidious effects on structural brain aging even in dementia- and stroke-free persons.

Introduction: Endothelial microparticles (EMP) are membrane vesicles, with a characteristic diameter of 0.1-1.0μ, shed by endothelial cells during cellular activation or apoptosis. EMP are associated with cardiovascular disease and risk factors, but data are lacking on the relations of EMP with subclinical vascular brain injury. Methods: We studied 487 individuals (mean age 66.9±8.8 years, 55% women) from the Framingham Offspring Cohort, who were free from clinical stroke. CD31+/CD41- EMP were identified and quantified using flow cytometry. Silent cerebral infarcts (SCI) were quantified as parenchymal lesions on brain MRI >3mm in size with characteristics of previous infarcts. Logistic regression models were used to investigate cross-sectional associations of EMP levels with prevalent SCI. We tested for interaction between EMP levels and statin use in their relationship with SCI. Results: SCI was observed in 49 (10%) participants. Figure 1 displays results of the logistic regression analysis. Circulating CD31+/CD41- EMP levels were inversely associated with SCI, adjusting for age, sex, and time interval between blood draw and brain MRI (OR 0.90 [0.82-0.98], p=0.016). Similar results were observed when adjusting for additional vascular risk factors. We observed an interaction between statin use and EMP levels in their association with SCI. There was an inverse association (OR 0.76 [0.64-0.89], p=0.001) among statin users and no association among non-statin users. Conclusions: In our analysis of the relationship of CD31+/CD41- EMP with SCI, in a well-defined community cohort, we observed an inverse association of higher EMP levels, primarily in participants on statins. Our data question whether constitutive or induced release of EMP, associated with a pleiotropic effect of statin medication, might mitigate vascular risk factor exposure and reduce risk of SCI. Further studies are needed to determine the associations of EMP with SCI and clinical stroke.

Objective: We investigated the association between circulating biomarkers of inflammation and MRI markers of small vessel disease. Methods: We performed a cross-sectional study relating a panel of 15 biomarkers, representing systemic inflammation (high-sensitivity C-reactive protein, interleukin-6, monocyte chemotactic protein-1, tumor necrosis factor α, tumor necrosis factor receptor 2, osteoprotegerin, and fibrinogen), vascular inflammation (intercellular adhesion molecule 1, CD40 ligand, P-selectin, lipoprotein-associated phospholipase A 2 mass and activity, total homocysteine, and vascular endothelial growth factor), and oxidative stress (myeloperoxidase) to ischemic (white matter hyperintensities/silent cerebral infarcts) and hemorrhagic (cerebral microbleeds) markers of cerebral small vessel disease (CSVD) on MRI in 1,763 stroke-free Framingham offspring (mean age 60.2 ± 9.1 years, 53.7% women). Results: We observed higher levels of circulating tumor necrosis factor receptor 2 and myeloperoxidase in the presence of cerebral microbleed (odds ratio [OR] 2.2, 95% confidence interval [CI] 1.1–4.1 and OR 1.5, 95% CI 1.1–2.0, respectively), higher levels of osteoprotegerin (OR 1.1, 95% CI 1.0–1.2), intercellular adhesion molecule 1 (OR 1.7, 95% CI 1.1–2.5), and lipoprotein-associated phospholipase A 2 mass (OR 1.5, 95% CI 1.1–2.1), and lower myeloperoxidase (OR 0.8, 95% CI 0.7–1.0) in participants with greater white matter hyperintensity volumes and silent cerebral infarcts. Conclusions: Our study supports a possible role for inflammation in the pathogenesis of CSVD, but suggests that differing inflammatory pathways may underlie ischemic and hemorrhagic subtypes. If validated in other samples, these biomarkers may improve stroke risk prognostication and point to novel therapeutic targets to combat CSVD.

Background Relations of orthostatic change in blood pressure with brain structure and function have not been studied thoroughly, particularly in younger, healthier individuals. Elucidation of factors that contribute to early changes in brain integrity may lead to development of interventions that delay or prevent cognitive impairment. Methods and Results In a sample of the Framingham Heart Study Third Generation (N=2119; 53% women; mean age±SD, 47±8 years), we assessed orthostatic change in mean arterial pressure ( MAP ), aortic stiffness (carotid‐femoral pulse wave velocity), neuropsychological function, and markers of subclinical brain injury on magnetic resonance imaging. Multivariable regression analyses were used to assess relations between orthostatic change in MAP and brain structural and neuropsychological outcomes. Greater orthostatic increase in MAP on standing was related to better Trails B‐A performance among participants aged SE , 0.062±0.029; P =0.031) and among participants with carotid‐femoral pulse wave velocity SE , 0.063±0.026; P =0.016). This relation was not significant among participants who were older or had stiffer aortas. Conversely, greater orthostatic increase in MAP was related to larger total brain volume among older participants (β± SE , 0.065±0.029; P =0.023) and among participants with carotid‐femoral pulse wave velocity ≥6.9 m/s (β± SE , 0.078±0.031; P =0.011). Conclusions Blunted orthostatic increase in MAP was associated with smaller brain volume among participants who were older or had stiffer aortas and with poorer executive function among persons who were younger or who had more‐elastic aortas. Our findings suggest that the brain is sensitive to orthostatic change in MAP , with results dependent on age and aortic stiffness.

Background: Recent evidence suggests that dementia appears linked to subclinical vascular changes, which may be attenuated by physical activity. The Physical Activity Guidelines for Americans (PA-Guidelines) are currently set at 150 min of moderate-to-vigorous physical activity (MVPA) per week, as a target for adults to achieve favorable health outcomes, but make no specific recommendations for prevention of dementia. Many Americans fall well below the PA-Guidelines. The aim of this investigation was to determine whether there is a continuum of lower intensities and volumes of physical activity associated with healthy brain aging even in individuals not meeting the PA-Guidelines. Methods: We included Framingham Heart Study (FHS) participants who wore an Actical accelerometer for ≥3 valid days (>10 h wear time per day) on their right hip during the most recent cohort examinations and completed brain magnetic resonance imaging (MRI) an average of 1.7 (±0.9) years later (n=2534): Offspring exam 9, Third Generation exam 2, and corresponding examinations of the Omni cohorts. Participants were excluded from this analysis if they had prevalent stroke or dementia (n=63) or met the 150 min MVPA per week PA-Guidelines (n=1158). Non-wear time (defined as 60 min of zero-counts, with two interruptions allowed) was removed. Sedentary time (1486 counts/min, ≥3 METs) and steps were accumulated at any time of day. The relations of physical activity measures to brain MRI measures were assessed using multivariable linear regression. Results: More than 53% of FHS participants did not meet the PA-Guidelines for MVPA during their last exam, and were thus included in this investigation (n=1313, 56 [±14] years old, 60% women). These participants took an average of 6149 [±3079] steps, spent 10.5 [±6.1] min MVPA, 13 h 36 min [±48 min] sedentary and 2 h 14 min [±48 min] in light activities per day. Each additional 40 min of light activity (spent in 1.5-3 METs) or 42 min less time spent sedentary was associated with 0.22% [±0.07%] greater total cerebral brain volume (TCBV), after adjusting for age, sex, body mass index, smoking, diabetes mellitus, and cardiovascular disease (p=0.001), equivalent to approximately 1.1 years less brain aging. Greater light activity and lower sedentary time were also associated with greater hippocampal volume (p Conclusions: Our investigation demonstrates, in a community setting, that there may be a negative association of light physical activity with brain aging even among individuals not meeting the PA-Guidelines for MVPA.

Background Defining the RNA transcriptome in Alzheimer Disease (AD) will help understand the disease mechanisms and provide biomarkers. Though the AD blood transcriptome has been studied, effects of white matter hyperintensities (WMH) were not considered. This study investigated the AD blood transcriptome and accounted for WMH. Methods RNA from whole blood was processed on whole-genome microarrays. Results A total of 293 probe sets were differentially expressed in AD versus controls, 5 of which were significant for WMH status. The 288 AD-specific probe sets classified subjects with 87.5% sensitivity and 90.5% specificity. They represented 188 genes of which 29 have been reported in prior AD blood and 89 in AD brain studies. Regulated blood genes included MMP9, MME (Neprilysin), TGFβ1, CA4, OCLN, ATM, TGM3, IGFR2, NOV, RNF213, BMX, LRRN1, CAMK2G, INSR, CTSD, SORCS1, SORL1, and TANC2. Conclusions RNA expression is altered in AD blood irrespective of WMH status. Some genes are shared with AD brain.

Studies of clinical and community cohorts have shown that antemortem imaging measures of hippocampal volume have correlated with postmortem Alzheimer's pathology. Fewer studies have examined the relationship between both Alzheimer's and cerebrovascular pathology, and antemortem brain imaging. The aim of this study was to correlate antemortem brain magnetic resonance imaging (MRI) volumes with postmortem brain pathology (both Alzheimer-related and cerebrovascular) in a community-derived cohort from the Framingham Heart Study (FHS). Participants (n=59) from the FHS were included if they were enrolled in the brain autopsy program and underwent antemortem clinical evaluation, neuropsychological testing and brain MRI. Cortical neurofibrillary tangle pathology correlated with lower total cerebral brain (beta±SE=−0.04±0.01, p=0.004) and hippocampal volumes (beta±SE=−0.03±0.02, p=0.044) and larger temporal horns (log-transformed, beta±SE=0.05±0.01, p=0.001). Similar findings were seen between total/cortical neuritic plaques and total cerebral brain and temporal horn volume. White matter hyperintensities (also log-transformed) were best predicted by the presence of deep nuclei microinfarcts (beta±SE=0.53±0.21, p=0.016), whereas hippocampal volume was significantly decreased in the presence of hippocampal sclerosis (beta±SE =−1.23±0.30, p

Background and Purpose— Aging is accompanied by clinically silent cerebral white matter injury identified through white matter hyperintensities (WMHs) on fluid-attenuated inversion recovery (FLAIR)– and diffusion tensor imaging–based measures of white matter integrity. The temporal course of FLAIR and diffusion tensor imaging changes within WMHs and their less-injured periphery (ie, their penumbra), however, has not been fully studied. We used longitudinal diffusion tensor imaging and FLAIR to explore these changes. Methods— One hundred fifteen participants, aged 73.7±6.7 years, received clinical evaluations and MRIs on 2 dates. WMHs and fractional anisotropy (FA) maps were produced from FLAIR and diffusion tensor imaging and coregistered to a standardized space. Each distinct WMH was categorized as growing, stagnant, or noncontiguous incident. The penumbra of each WMH was similarly categorized as corresponding to a stagnant, growing, or noncontiguous incident WMH. Linear mixed-effect models were used to assess whether FA and FLAIR measurements changed between baseline and follow-up and differed between tissue categories. Results— Baseline FA differed significantly by tissue category, with the following ordering of categories from highest to lowest FA: penumbra of noncontiguous incident, then stagnant, then growing WMHs; noncontiguous incident, then stagnant, then growing WMHs. Despite differences in baseline values, all tissue categories experienced declines in FA over time. Only noncontiguous incident WMHs showed significant FLAIR signal increases over time, and FLAIR signal significantly decreased in stagnant WMHs. Conclusions— WMHs and their penumbra vary in severity and together span a continuous spectrum of white matter injury that worsens with time. FLAIR fails to capture this continuous injury process fully but does identify a subclass of lesions that seem to improve over time.

Background and Purpose— Brain-derived neurotrophic factor (BDNF), a major neurotrophin and vascular endothelial growth factor (VEGF) have a documented role in neurogenesis, angiogenesis, and neuronal survival. In animal experiments, they impact infarct size and functional motor recovery after an ischemic brain lesion. We sought to examine the association of serum BDNF and VEGF with the risk of clinical stroke or subclinical vascular brain injury in a community-based sample. Methods— In 3440 Framingham Study participants (mean age, 65±11 years; 56% women) who were free of stroke/transient ischemic attack (TIA), we related baseline BDNF and logVEGF to risk of incident stroke/TIA. In a subsample with brain MRI and with neuropsychological tests available (n=1863 and 2104, respectively; mean age, 61±9 years, 55% women, in each), we related baseline BDNF and logVEGF to log-white matter hyperintensity volume on brain MRI, and to visuospatial memory and executive function tests. Results— During a median follow-up of 10 years, 193 participants experienced incident stroke/TIA. In multivariable analyses adjusted for age, sex, and traditional stroke risk factors, lower BDNF and higher logVEGF levels were associated with an increased risk of incident stroke/TIA (hazard ratio comparing BDNF Q1 versus Q2–Q4, 1.47; 95% confidence interval, 1.09–2.00; P =0.012 and hazard ratio/SD increase in logVEGF, 1.21; 95% confidence interval, 1.04–1.40; P =0.012). Persons with higher BDNF levels had less log-white matter hyperintensity volume (β±SE=−0.05±0.02; P =0.025), and better visual memory (β±SE=0.18±0.07; P =0.005). Conclusions— Lower serum BDNF and higher VEGF concentrations were associated with increased risk of incident stroke/TIA. Higher levels of BDNF were also associated with less white matter hyperintensity and better visual memory. Our findings suggest that circulating BDNF and VEGF levels modify risk of clinical and subclinical vascular brain injury.

Background— Silent brain infarcts (SBIs) and white matter hyperintensities are subclinical cerebrovascular lesions associated with incident stroke and cognitive decline. Left ventricular ejection fraction (LVEF) is a predictor of stroke in patients with heart failure, but its association with subclinical brain disease in the general population is unknown. Left ventricular global longitudinal strain (GLS) can detect subclinical cardiac dysfunction even when LVEF is normal. We investigated the relationship of LVEF and GLS with subclinical brain disease in a community-based cohort. Methods and Results— LVEF and GLS were assessed by 2-dimensional and speckle-tracking echocardiography in 439 participants free of stroke and cardiac disease from the Cardiovascular Abnormalities and Brain Lesions (CABL) study. SBIs and white matter hyperintensities were assessed by brain MRI. Mean age of the study population was 69±10 years, 61% were women, LVEF was 63.8±6.4%, GLS was −17.1±3.0%. SBIs were detected in 53 participants (12%), white matter hyperintensity volume was 0.63±0.86%. GLS was significantly lower in participants with SBI versus those without (−15.7±3.5% versus −17.3±2.9%, P P =0.60). In multivariate analysis, lower GLS was associated with SBI (odds ratio/unit decrease=1.18; 95% confidence interval, 1.05–1.33; P P =0.98). Lower GLS was associated with greater white matter hyperintensity volume (adjusted β=0.11, P P =0.42). Conclusions— Lower GLS was independently associated with subclinical brain disease in a community-based cohort without overt cardiac disease. GLS can provide additional information on cerebrovascular risk burden beyond LVEF assessment.

To determine the association of arterial stiffness and pressure pulsatility, which can damage small vessels in the brain, with vascular and Alzheimer-type brain aging.Stroke- and dementia-free Framingham Offspring Study participants (n = 1,587, 61 ± 9 years, 45% male) underwent study of tonometric arterial stiffness and endothelial function (1998-2001) and brain MRI and cognition (1999-2002). We related carotid-femoral pulse wave velocity (CFPWV), mean arterial and central pulse pressure, and endothelial function to vascular brain aging by MRI (total cerebral brain volume [TCBV], white matter hyperintensity volume, silent cerebral infarcts) and vascular and Alzheimer-type cognitive aging (Trails B minus Trails A and logical memory-delayed recall, respectively).Higher CFPWV was associated with lower TCBV, greater white matter hyperintensity volume, and greater prevalence of silent cerebral infarcts (all p0.05). Each SD greater CFPWV was associated with lower TCBV equivalent to 1.2 years of brain aging. Mean arterial and central pulse pressure were associated with greater white matter hyperintensity volume (p = 0.005) and lower TCBV (p = 0.02), respectively, and worse verbal memory (both p0.05). Associations of tonometry variables with TCBV and white matter hyperintensity volume were stronger among those aged 65 years and older vs those younger than 65 years (p0.10 for interaction). Brachial artery endothelial function was unrelated to MRI measures (all p0.05).Greater arterial stiffness and pressure pulsatility are associated with brain aging, MRI vascular insults, and memory deficits typically seen in Alzheimer dementia. Future investigations are warranted to evaluate the potential impact of prevention and treatment of unfavorable arterial hemodynamics on neurocognitive outcomes.

Revised diagnostic criteria for Alzheimer disease (AD) acknowledge a key role of imaging biomarkers for early diagnosis. Diagnostic accuracy depends on which marker (i.e., amyloid imaging, ¹⁸F-fluorodeoxyglucose [FDG]-PET, SPECT, MRI) as well as how it is measured ("metric": visual, manual, semiautomated, or automated segmentation/computation). We evaluated diagnostic accuracy of marker vs metric in separating AD from healthy and prognostic accuracy to predict progression in mild cognitive impairment. The outcome measure was positive (negative) likelihood ratio, LR+ (LR-), defined as the ratio between the probability of positive (negative) test outcome in patients and the probability of positive (negative) test outcome in healthy controls. Diagnostic LR+ of markers was between 4.4 and 9.4 and LR- between 0.25 and 0.08, whereas prognostic LR+ and LR- were between 1.7 and 7.5, and 0.50 and 0.11, respectively. Within metrics, LRs varied up to 100-fold: LR+ from approximately 1 to 100; LR- from approximately 1.00 to 0.01. Markers accounted for 11% and 18% of diagnostic and prognostic variance of LR+ and 16% and 24% of LR-. Across all markers, metrics accounted for an equal or larger amount of variance than markers: 13% and 62% of diagnostic and prognostic variance of LR+, and 29% and 18% of LR-. Within markers, the largest proportion of diagnostic LR+ and LR- variability was within ¹⁸F-FDG-PET and MRI metrics, respectively. Diagnostic and prognostic accuracy of imaging AD biomarkers is at least as dependent on how the biomarker is measured as on the biomarker itself. Standard operating procedures are key to biomarker use in the clinical routine and drug trials.

We analyzed the baseline and 3-year T1-weighted magnetic resonance imaging data of 110 amnestic mild cognitive impairment (MCI) participants with minimal hippocampal atrophy at baseline from the Alzheimer's Disease Cooperative Study group MCI Donepezil/Vitamin E trial. Forty-six subjects converted to Alzheimer disease (AD) (MCIc), whereas 64 remained stable (MCInc). We used the radial distance technique to examine the differences in lateral ventricle shape and size between MCIc and MCInc and the associations between ventricular enlargement and cognitive decline. MCIc group had significantly larger frontal and right body/occipital horns relative to MCInc at baseline and significantly larger bilateral frontal, body/occipital, and left temporal horns at follow-up. Global cognitive decline measured with AD Assessment scale cognitive subscale and Mini-Mental State Examination and decline in activities of daily living (ADL) were associated with posterior lateral ventricle enlargement. Decline in AD Assessment scale cognitive subscale and ADL were associated with left temporal and decline in Mini-Mental State Examination with right temporal horn enlargement. After correction for baseline hippocampal volume, decline in ADL showed a significant association with right frontal horn enlargement. Executive decline was associated with right frontal and left temporal horn enlargement.

Background— Several biomarkers have been individually associated with vascular brain injury, but no prior study has explored the simultaneous association of a biologically plausible panel of biomarkers with the incidence of stroke/transient ischemic attack and the prevalence of subclinical brain injury. Methods and Results— In 3127 stroke-free Framingham offspring (age, 59±10 years; 54% female), we related a panel of 8 biomarkers assessing inflammation (C-reactive protein), hemostasis (D-dimer and plasminogen activator inhibitor-1), neurohormonal activity (aldosterone-to-renin ratio, B-type natriuretic peptide, and N-terminal proatrial natriuretic peptides), and endothelial function ( homocysteine and urinary albumin/creatinine ratio) measured at the sixth examination (1995–1998) to risk of incident stroke/transient ischemic attack. In a subset of 1901 participants with available brain magnetic resonance imaging (1999–2005), we further related these biomarkers to total cerebral brain volume, covert brain infarcts, and large white-matter hyperintensity volume. During a median follow-up of 9.2 years, 130 participants experienced incident stroke/transient ischemic attack. In multivariable analyses adjusted for stroke risk factors, the biomarker panel was associated with incident stroke/transient ischemic attack and with total cerebral brain volume ( P P >0.05). In backward elimination analyses, higher log–B-type natriuretic peptide (hazard ratio, 1.39 per 1-SD increment; P =0.002) and log–urinary albumin/creatinine ratio (hazard ratio, 1.31 per 1-SD increment; P =0.004) were associated with increased risk of stroke/transient ischemic attack and improved risk prediction compared with the Framingham Stroke Risk Profile alone; when the 15% 10-year risk category was used, the net reclassification index was 0.109 ( P =0.037). Higher C-reactive protein (β=−0.21 per 1-SD increment; P =0.008), D-dimer (β=−0.18 per 1-SD increment; P =0.041), total homocysteine (β=−0.21 per 1-SD increment; P =0.005), and urinary albumin/creatinine ratio (β=−0.15 per 1-SD increment; P =0.042) were associated with lower total cerebral brain volume. Conclusion— In a middle-aged community sample, we identified multiple biomarkers that were associated with clinical and subclinical vascular brain injury and could improve risk stratification.

Background and Purpose— White matter hyperintensities (WMHs) are associated with progressive age-related cognitive decline and cardiovascular risk factors, but their biological relevance as indicators of generalized white matter injury is unclear. Diffusion tensor imaging provides more sensitive indications of subtle white matter disruption and can therefore clarify whether WMHs represent foci of generalized white matter damage that extends over a broader neighborhood. Methods— Two hundred eight participants from the University of California, Davis Alzheimer's Disease Center received a comprehensive clinical evaluation and brain MRI including fluid-attenuated inversion recovery and diffusion tensor imaging sequences. Voxelwise maps of WMHs were produced from fluid-attenuated inversion recovery using a standardized WMH detection protocol. Fractional anisotropy maps were calculated from diffusion tensor imaging. All WMH and fractional anisotropy maps were coregistered to a standardized space. For each normal-appearing white matter voxel in each subject fluid-attenuated inversion recovery scan, a neighborhood white matter injury score was calculated that increased with increasing number and proximity of WMH in the vicinity of the normal-appearing white matter voxel. Fractional anisotropy was related to neighborhood white matter injury using a nonlinear mixed effect model controlling for relevant confounding factors. Results— Fractional anisotropy was found to decrease as neighborhood white matter injury increased (β=−0.0017/%, P P 0.4. An increase of 1% in neighborhood white matter injury score was associated with a decrease in mean fractional anisotropy of 0.012 ( P Conclusions— WMH may represent foci of more widespread and subtle white matter changes rather than distinct, sharply delineated anatomic abnormalities. We use the term white matter hyperintensities penumbra to explain this phenomenon.

Objective: To examine the independent association between physical activity and subclinical cerebrovascular disease as measured by silent brain infarcts (SBI) and white matter hyperintensity volume (WMHV). Methods: The Northern Manhattan Study (NOMAS) is a population-based prospective cohort examining risk factors for incident vascular disease, and a subsample underwent brain MRI. Our primary outcomes were SBI and WMHV. Baseline measures of leisure-time physical activity were collected in person. Physical activity was categorized by quartiles of the metabolic equivalent (MET) score. We used logistic regression models to examine the associations between physical activity and SBI, and linear regression to examine the association with WMHV. Results: There were 1,238 clinically stroke-free participants (mean age 70 ± 9 years) of whom 60% were women, 65% were Hispanic, and 43% reported no physical activity. A total of 197 (16%) participants had SBI. In fully adjusted models, compared to those who did not engage in physical activity, those in the upper quartile of MET scores were almost half as likely to have SBI (adjusted odds ratio 0.6, 95% confidence interval 0.4–0.9). Physical activity was not associated with WMHV. Conclusions: Increased levels of physical activity were associated with a lower risk of SBI but not WMHV. Engaging in moderate to heavy physical activities may be an important component of prevention strategies aimed at reducing subclinical brain infarcts.

Background and Purpose— Cerebral microbleeds (CMBs) are associated with increased risk of stroke and poor cognition. Vascular risk factors and medications used for stroke prevention may increase the risk of CMB. We examined the prevalence of CMB and the association of these risk factors with CMB, postulating that risk factors for cerebral amyloid angiopathy would be associated with lobar CMB and markers of hypertensive vasculopathy with deep CMB. Methods — We include 1965 Framingham Original and Offspring participants (age, 66.5±11.0 years; 54% women) and evaluated the age- and sex-specific prevalence of CMB. We related various vascular and genetic (apolipoprotein E [ APOE ]) risk factors and medication use to the presence of CMB overall and stratified by brain location (deep, lobar, or mixed). Results — CMBs were observed in 8.8% of participants, being mostly lobar (63%). CMB prevalence increased with age ( P P P APOE ε4 increased risk of lobar CMB ( P P Conclusions — We observed the expected association of hypertension with deep CMB and low cholesterol and APOE ε4 with lobar CMB. In addition, statin use was independently associated with CMB risk. This potential adverse effect of statin use needs to be examined in other cohorts.

Background and Purpose— White matter hyperintensities (WMH) are areas of high signal detected by T2 and fluid-attenuated inversion recovery sequences on brain MRI. Although associated with aging, cerebrovascular risk factors, and cognitive impairment, the pathogenesis of WMH remains unclear. Thus, RNA expression was assessed in the blood of individuals with and without extensive WMH to search for evidence of oxidative stress, inflammation, and other abnormalities described in WMH lesions in brain. Methods— Subjects included 20 with extensive WMH (WMH+), 45% of whom had Alzheimer disease, and 18 with minimal WMH (WMH−), 44% of whom had Alzheimer disease. All subjects were clinically evaluated and underwent quantitative MRI. Total RNA from whole blood was processed on human whole genome Affymetrix HU133 Plus 2.0 microarrays. RNA expression was analyzed using an analysis of covariance. Results— Two hundred forty-one genes were differentially regulated at ±1.2-fold difference ( P P Conclusions— The unique RNA expression profile in blood associated with WMH is consistent with roles of systemic oxidative stress and inflammation, as well as other potential processes in the pathogenesis or consequences of WMH.

Background: Clinical and epidemiologic studies suggest that patients with Alzheimer disease (AD) with larger head circumference have better cognitive performance at the same level of brain pathology than subjects with smaller head circumference.Methods: A total of 270 patients with AD participating in the Multi-Institutional Research in Alzheimer's Genetic Epidemiology (MIRAGE) study underwent cognitive testing, APOE genotyping, and MRI of the brain in a cross-sectional study. Linear regression analysis was used to examine the association between cerebral atrophy, as a proxy for AD pathology, and level of cognitive function, adjusting for age, duration of AD symptoms, gender, head circumference, APOE genotype, diabetes mellitus, hypertension, major depression, and ethnicity. An interaction term between atrophy and head circumference was introduced to explore if head circumference modified the association between cerebral atrophy and cognition.Results: There was a significant inverse association between atrophy and cognitive function, and a significant interaction between atrophy and head circumference. With greater levels of atrophy, cognition was higher for individuals with greater head circumference.Conclusion: This study suggests that larger head circumference is associated with less cognitive impairment in the face of cerebral atrophy. This finding supports the notion that head circumference (and presumably brain size) offers protection against AD symptoms through enhanced brain reserve.

Background and Purpose— We sought to assess the efficacy and safety of donepezil in patients with vascular dementia (VaD) fulfilling National Institute of Neurological Disorders and Stroke–Association Internationale pour la Recherche et l’Enseignement en Neurosciences criteria. Methods— This international, multicenter, 24-week trial was conducted from March 2003 to August 2005. Patients (N=974; mean age, 73.0 years) with probable or possible VaD were randomized 2:1 to receive donepezil 5 mg/d or placebo. Coprimary outcome measures were scores on the Vascular-Alzheimer Disease Assessment Scale–Cognitive Subscale and Clinician’s Interview–Based Impression of Change, plus carer interview. Analyses were performed for the intent-to-treat population with the last-observation-carried-forward method. Results— Compared with placebo, donepezil-treated patients showed significant improvement from baseline to end point on the Vascular-Alzheimer Disease Assessment Scale–Cognitive Subscale (least-squares mean difference, −1.156; 95% CI, −1.98 to −0.33; P Conclusions— Patients treated with donepezil 5 mg/d demonstrated significant improvement in cognitive, but not global, function. Donepezil was relatively well tolerated; adverse events were consistent with current labeling. Mortality in the placebo group was unexpectedly low. The differential treatment response of VaD patients by hippocampal size suggests that hippocampal imaging warrants further investigation for understanding VaD.

Objective: To examine whether there are sex-specific associations between brain magnetic resonance imaging (MRI) measures and neuropsychologic (NP) test performance. Background: Differences in cardiovascular risk factors have been linked to decreased total cerebral brain volume and white matter hyperintensities (WMHs). Although brain morphology has been related to cognitive performance, few studies have addressed sex-specific effects in this relationship. Methods: Framingham Offspring who were stroke and dementia-free underwent a brain MRI scan and NP testing (n = 2085; 978 men). Factor analysis identified 4 domain-specific NP factors. MRI participants were divided into 4 MRI subgroups based on measures of total cerebral brain volume and combinations of the presence of WMH and silent cerebral infarcts (≥ 3 mm). Results: Overall, the relationship between MRI and NP measures was similar between the sexes. The exception was that only men showed a positive relationship between executive function and cerebrovascular disease defined as large WMH volume plus silent cerebral infarct. This finding was attributed only among men with Framingham Stroke Risk Profile scores > 90th percentile range (P = 0.0019). Conclusions: Measures of brain atrophy and subclinical markers of vascular disease showed that sex does not significantly alter the relationship between MRI and NP, except among men and women who are at high risk for stroke; these men show poorer performance on executive function, whereas the women do not.

Objective: To cross-sectionally compare the regional white matter fractional anisotropy (FA) of cognitively normal (CN) older individuals and patients with mild cognitive impairment (MCI) and Alzheimer disease (AD), separately focusing on the normal-appearing white matter (NAWM) and white matter hyperintensities (WMH), and to test the independent effects of presumed degenerative and vascular process on FA differences. Methods: Forty-seven patients with AD, 73 patients with MCI, and 95 CN subjects received diffusion tensor imaging and vascular risk evaluation. To properly control normal regional variability of FA, we divided cerebral white matter into 4 strata as measured from a series of young healthy individuals (H1 = highest; H2 = intermediate high; H3 = intermediate low; H4 = lowest anisotropy stratum). Results: For overall cerebral white matter, patients with AD had significantly lower FA than CN individuals or patients with MCI in the regions with higher baseline anisotropy (H1, H2, and H3), corresponding to long corticocortical association fibers, but not in H4, which mostly includes heterogeneously oriented fibers. Vascular risk showed significant independent effects on FA in all strata except H1, which corresponds to the genu and splenium of the corpus callosum. Similar results were found within NAWM. FA in WMH was significantly lower than NAWM across all strata but was not associated with diagnosis or vascular risk. Conclusions: Both vascular and Alzheimer disease degenerative process contribute to microstructural injury of cerebral white matter across the spectrum of cognitive ability and have different region-specific injury patterns.

Background and Purpose— Carotid atherosclerosis has been associated with increased risk of stroke and poorer cognitive performance in older adults. The relation of carotid atherosclerosis to cognitive impairment and MRI indices of ischemia and aging in midlife is less clear. Methods— We studied 1975 Framingham Offspring Study participants free of stroke and dementia with available carotid ultrasound, brain MRI, and neuropsychological testing. We related common and internal carotid artery intima-media thickness and internal carotid stenosis to large white matter hyperintensity (>1 SD above age-specific mean), total brain volume, hippocampal volume, silent cerebral infarcts, and neuropsychological measures of verbal memory, executive function, and nonverbal memory measures. Results— We observed that internal carotid artery intima-media thickness, but not common carotid artery intima-media thickness, was associated with higher prevalence of silent cerebral infarcts (OR, 1.21; 95% CI, 1.03–1.43; P P P P P P =0.042) but not with silent cerebral infarcts or hippocampal volume. Internal carotid stenosis ≥50% was associated with higher prevalence of silent cerebral infarcts (OR, 2.53; 95% CI, 1.17–5.44), large white matter hyperintensity (OR, 2.35; 95% CI, 1.08–5.13), and poorer performance on executive function (−0.39 per SD; P Conclusions— Carotid atherosclerosis markers were associated with MRI indices of brain ischemia and aging and with cognitive impairment in a community-based sample of middle-aged adults. Our data suggest that internal carotid artery intima-media thickness may be a better marker for cognitive impairment than common carotid artery intima-media thickness.

There is an increasing racial and ethnic diversity within the elderly population of the United States. Although increased diversity offers unique opportunities to study novel influences on aging and dementia, some aspects of racial and ethnic research have been hampered by the lack of culturally and linguistically consistent testing protocols. Structural brain imaging is commonly used to study the biology of normal aging and cognitive impairment and may therefore serve to explore potential biologic differences of cognitive impairment among racially and ethnically diverse individuals. To test this hypothesis, we recruited a cohort of approximately 400 African American, white, and Hispanic subjects with various degrees of cognitive ability. Each subject was carefully evaluated using standardized diagnostic protocols that included clinical review of brain magnetic resonance image (MRI) to arrive at a clinical diagnosis of normal cognition, mild cognitive impairment or dementia. Each MRI was then independently quantified for measures of brain, white matter hyperintensities, and hippocampal volumes by a technician blind to subject age, sex, ethnicity, race, and diagnostic category. The appearance of infarction on MRI was also rated by examining neurologists. Regression analyses were used to assess associations with various MRI measures across clinical diagnostic categories in relation to racial and ethnic differences. Hispanic subjects were, on average, significantly younger and had less years of education than African Americans or whites. Whites with dementia were significantly older than both African American and Hispanic dementia patients. Highly significant differences in MRI measures were associated with clinical diagnoses for the group as a whole after adjusting for the effects of age, sex, education, race, and ethnicity. Subsequent independent analyses by racial and ethnic status revealed consistent relationships between diagnostic category and MRI measures. Clinical diagnoses were associated with consistent differences in brain structure among a group of racially and ethnically diverse individuals. We believe these results help to validate current diagnostic assessment of individuals across a broad range of racial, ethnic, linguistic, and educational backgrounds. Moreover, interesting and potentially biologically relevant differences were found that might stimulate further research related to the understanding of dementia etiology within an increasingly racially and ethnically diverse population.