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Background Short sleep duration has been associated with an increased risk of cognitive impairment and dementia. Short sleep is associated with elevated blood pressure, yet the combined insult of short sleep and hypertension on brain health remains unclear. We assessed whether the association of sleep duration with cognition and vascular brain injury was moderated by hypertensive status. Methods and Results A total of 682 dementia‐free participants (mean age, 62±9 years; 53% women) from the Framingham Heart Study completed assessments of cognition, office blood pressure, and self‐reported habitual and polysomnography‐derived sleep duration; 637 underwent brain magnetic resonance imaging. Linear regressions were performed to assess effect modification by hypertensive status on total sleep time (coded in hours) and cognitive and magnetic resonance imaging outcomes. There was a significant interaction between sleep duration and hypertensive status when predicting executive function/processing speed (Trail Making B‐A) and white matter hyperintensities. When results were stratified by hypertensive status, longer sleep duration was associated with better executive functioning/processing speed scores in the hypertensive group (meaning that shorter sleep duration was associated with poorer executive function/processing speed scores) (self‐report sleep: β=0.041 [95% CI, 0.012–0.069], P=0.005; polysomnography sleep: β=0.045 [95% CI, 0.002–0.087], P=0.038), but no association was observed for the normotensive group. Similarly, shorter subjective sleep duration was associated with higher white matter hyperintensity burden in the hypertensive group (β=−0.115 [95% CI, −0.227 to −0.004], P=0.042), but not in the normotensive group. Conclusions In individuals with hypertension, shorter sleep duration was associated with worse cognitive performance and greater brain injury.

Abstract INTRODUCTION Characterizing pathological changes in the brain that underlie cognitive impairment, including Alzheimer's disease and related disorders, is central to clinical concerns of prevention, diagnosis, and treatment. METHODS We describe the properties of a brain gray matter region (“Union Signature”) that is derived from four behavior‐specific, data‐driven signatures in a discovery cohort. RESULTS In a separate validation set, the Union Signature demonstrates clinically relevant properties. Its associations with episodic memory, executive function, and Clinical Dementia Rating Sum of Boxes are stronger than those of several standardly accepted brain measures (e.g., hippocampal volume, cortical gray matter) and other previously developed brain signatures. The ability of the Union Signature to classify clinical syndromes among normal, mild cognitive impairment, and dementia exceeds that of the other measures. DISCUSSION The Union Signature is a powerful, multipurpose correlate of clinically relevant outcomes and a strong classifier of clinical syndromes. Highlights Data‐driven brain signatures are potentially valuable in models of cognitive aging. In previous work, we outlined rigorous validation of signatures for memory. This work demonstrates a signature predicting multiple clinical measures. This could be useful in models of interventions for brain support of cognition.

Abstract The Hispanic/Latino population is one of the largest and most diverse ethnoracial groups in the United States at high risk for dementia. We examined cognitive constructs and associations with subsequent hippocampal volume (HV) and white matter hyperintensity volume (WMHV). Participants were from the Hispanic Community Health Study/Study of Latinos–Magnetic Resonance Imaging Study (n = 2029). We examined confirmatory factor analysis and longitudinal invariance using neurocognitive scores at Visits 1 (2008–2011) and 2 (2014–2018) and path analyses. We obtained a longitudinally invariant two‐factor episodic memory (EM) and working memory (WM) construct. Lower EM profile at both visits was associated with greater WMHV and smaller HV at Visit 2. Lower WM profile at both visits was associated with larger WMHV and smaller HV at Visit 2. Neurocognitive profiles were associated with subsequent neurodegeneration in a sample of Hispanics/Latinos. Identifying neurocognitive risk profiles may lead to early detection and intervention, and significantly impact the course of neurodegeneration. Highlights Cognitive profiles predict brain integrity up to 10 years later. We observed two‐factor latent memory constructs and longitudinal invariance. These findings were observed in a Hispanic/Latino cohort.

Abstract Objective We aimed to determine whether combining white matter hyperintensity (WMH) with neurofilament light chain (NfL) could provide additional information for cognition in older adults. Methods Utilizing data from the population‐based Chicago Health and Aging Project, we studied 701 individuals with both biomarkers and cognitive data during the follow‐up period. NfL was measured using an ultrasensitive immunoassay, single‐molecule array technology. MRI scans of the brain were acquired using 1.5‐T systems. Global cognitive function was created as a composite measure of four neuropsychological tests, standardized and averaged to z‐scores. Multivariable linear mixed‐effects models were used to evaluate the association of WMH and NfL with the rate of cognitive decline. Results Higher WMH and NfL were associated with a faster rate of cognitive decline during the follow‐up; β‐coefficients (95%CIs) were −0.011 (−0.02, −0.001) and −0.010 (−0.017, −0.003), respectively. In individuals with lower concentration of NfL (i.e., bottom tertile), a higher WMH volume was associated with a faster cognitive decline (β: −0.030; 95%CI −0.046, −0.014). Similarly, in individuals with lower volumes of WMH (i.e., bottom tertile), a higher concentrations of NfL was associated with a faster cognitive decline (β: −0.023; 95%CI −0.042, −0.005). When we combined WMH with NfL, we noted a graded association with increasing volumes of WMH, particularly in people with lower NfL values. Interpretation While both biomarkers, WMH and NfL, were similarly associated with the annual rate of cognitive decline, our study suggests that they provide different underlying mechanisms affecting cognition.

Abstract Objective Examine whether cognitive reserve moderates the association of 1) vascular risk factors and 2) white matter hyperintensity burden with risk of clinical progression and longitudinal cognitive decline. Methods BIOCARD Study participants were cognitively normal and primarily middle‐aged (M = 57 years) at baseline and have been followed with annual cognitive and clinical assessments (M = 13 years). Baseline cognitive reserve was indexed with a composite score combining education with reading and vocabulary scores. Baseline vascular risk (N = 229) was assessed with a composite risk score reflecting five vascular risk factors. Baseline white matter hyperintensity load (N = 271) was measured with FLAIR magnetic resonance imaging. Cox regression models assessed risk of progression from normal cognition to onset of clinical symptoms of Mild Cognitive Impairment. Longitudinal mixed effects models measured the relationship of these variables to cognitive decline, using a global composite score, and executive function and episodic memory sub‐scores. Results Both vascular risk and white matter hyperintensities were associated with cognitive decline, particularly in executive function. Higher vascular risk, but not white matter hyperintensity burden, was associated with an increased risk of progression to Mild Cognitive Impairment. Higher cognitive reserve was associated with a reduced risk of symptom onset and higher levels of baseline cognition but did not modify the associations between the vascular risk score and white matter hyperintensities with clinical progression or cognitive decline. Interpretation Although cognitive reserve has protective effects on clinical and cognitive outcomes, it does not mitigate the negative impact of vascular risk and small vessel cerebrovascular disease on these same outcomes.

Abstract Objective Cerebral microbleeds (CMBs) are associated with higher risk of stroke and dementia, predating clinical diagnosis by several years. CMB are considered markers of cerebral small vessel disease (CSVD): hypertensive (deep CMB) and cerebral amyloid angiopathy (lobar CMB). We related plasma β‐Amyloid (40, 42 and their ratio), clusterin, and tau levels to CMB to elucidate their role as biomarkers for the angiopathies represented by CMB. Methods Dementia, stroke, and other neurological disease‐free Framingham Heart Study participants with available CMB and biomarker measurements were included. We related biomarker levels (standardized for analyses) to CMB presence overall and stratified by brain topography (any, lobar, deep), using multivariable logistic regression analyses. Results CMB were observed in 208 (5.7%) participants (mean age 57 years, 54% women). After multivariable adjustment, Aβ1‐40 was associated with any CMB (OR (95%CI) 1.20 (0.99, 1.45) P = 0.062)) and lobar CMB (OR (95%CI) 1.33 (1.05, 1.68) P = 0.019), but not with deep CMB. Log‐Aβ1‐42 levels were not associated with CMB overall. Clusterin was related to mixed CMB (1.70 [1.05, 2.74], P = 0.031). Tau levels were associated with any CMB (OR (95%CI) 1.26 (1.07, 1.49) P = 0.006), lobar CMB (OR (95%CI) 1.26 (1.05, 1.52) P = 0.013), and with deep CMB (OR (95% CI) 1.46 (1.13, 1.89) P = 0.004). Interpretation We found that plasma Aβ1‐40 and Tau are associated with CMB but further studies are needed to confirm their role in hemorrhage prone CSVD represented by CMB and as indicators of ongoing subclinical neuronal injury.

Abstract Background We determined the association between ratios of plasma ceramide species of differing fatty‐acyl chain lengths and incident dementia and Alzheimer’s disease (AD) dementia in a large, community‐based sample. Methods We measured plasma ceramide levels in 1892 [54% women, mean age 70.1 (SD 6.9) yr.] dementia‐free Framingham Offspring Study cohort participants between 2005 and 2008. We related ratios of very long‐chain (C24:0, C22:0) to long‐chain (C16:0) ceramides to subsequent risk of incident dementia and AD dementia. Structural MRI brain measures were included as secondary outcomes. Results During a median 6.5 year follow‐up, 81 participants developed dementia, of whom 60 were diagnosed with AD dementia. In multivariable Cox‐proportional hazards analyses, each standard deviation (SD) increment in the ratio of ceramides C24:0/C16:0 was associated with a 27% reduction in the risk of dementia (HR 0.73, 95% CI 0.56–0.96) and AD dementia (HR 0.73, 95% CI 0.53–1.00). The ratio of ceramides C22:0/C16:0 was also inversely associated with incident dementia (HR per SD 0.75, 95% CI 0.57–0.98), and approached statistical significance for AD (HR 0.73, 95% CI 0.53–1.01, P = 0.056). Higher ratios of ceramides C24:0/C16:0 and C22:0/C16:0 were also cross‐sectionally associated with lower white matter hyperintensity burden on MRI (−0.05 ± 0.02, P = 0.02; −0.06 ± 0.02, P = 0.003; respectively per SD increase), but not with other MRI brain measures. Conclusions Higher plasma ratios of very long‐chain to long‐chain ceramides are associated with a reduced risk of incident dementia and AD dementia in our community‐based sample. Circulating ceramide ratios may serve as potential biomarkers for predicting dementia risk in cognitively healthy adults.

Abstract Advances in technology enable increasing amounts of data collection from individuals for biomedical research. Such technologies, for example, in genetics and medical imaging, have also led to important scientific discoveries about health and disease. The combination of multiple types of high‐throughput data for complex analyses, however, has been limited by analytical and logistic resources to handle high‐dimensional data sets. In our previous EU Joint Programme–Neurodegenerative Disease Research (JPND) Working Group, called HD‐READY, we developed methods that allowed successful combination of omics data with neuroimaging. Still, several issues remained to fully leverage high‐dimensional multimodality data. For instance, high‐dimensional features, such as voxels and vertices, which are common in neuroimaging, remain difficult to harmonize. In this Full‐HD Working Group, we focused on such harmonization of high‐dimensional neuroimaging phenotypes in combination with other omics data and how to make the resulting ultra‐high‐dimensional data easily accessible in neurodegeneration research.

Abstract Introduction Many consequences of cerebrovascular disease are identifiable by magnetic resonance imaging (MRI), but variation in methods limits multicenter studies and pooling of data. The European Union Joint Program on Neurodegenerative Diseases (EU JPND) funded the HARmoNizing Brain Imaging MEthodS for VaScular Contributions to Neurodegeneration (HARNESS) initiative, with a focus on cerebral small vessel disease. Methods Surveys, teleconferences, and an in‐person workshop were used to identify gaps in knowledge and to develop tools for harmonizing imaging and analysis. Results A framework for neuroimaging biomarker development was developed based on validating repeatability and reproducibility, biological principles, and feasibility of implementation. The status of current MRI biomarkers was reviewed. A website was created at www.harness‐neuroimaging.org with acquisition protocols, a software database, rating scales and case report forms, and a deidentified MRI repository. Conclusions The HARNESS initiative provides resources to reduce variability in measurement in MRI studies of cerebral small vessel disease.

Abstract Introduction The Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) study enrolled Asian, Black, Latino, and White adults ages 65+ without prior dementia diagnosis (N = 1709). We evaluated the prevalence of cognitive impairment (mild cognitive impairment or dementia) accounting for potential biases. Methods A random subgroup (N = 541) received clinical evaluation and others were evaluated if they failed a cognitive screen. Diagnoses were made under two conditions: (1) demographics‐blind, based on clinical exam and demographically adjusted neuropsychological test scores; and (2) all available information (clinical exam, demographics, and adjusted and unadjusted test scores). Results Cognitive impairment prevalence was 28% for blinded‐adjusted diagnosis and 25% using all available information. Black participants had higher impairment rates than White (both conditions) and Latino (blinded‐adjusted diagnosis) participants. Incomplete assessments negatively biased prevalence estimates for White participants. Discussion Racial/ethnic disparities in cognitive impairment were amplified by attrition bias in White participants but were unaffected by type of test norms and diagnosticians’ knowledge of demographics.

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.

Abstract Introduction Current models posit a sequence of amyloid β (Aβ), tau, atrophy, and cognitive change leading to Alzheimer's disease, but ambiguities remain. We examined these sequences via serial mediations. Methods We studied normal controls, early mild cognitive impairment, and late mild cognitive impairment individuals from the Alzheimer's Disease Neuroimaging Initiative 2 database for the mediation of baseline cerebrospinal fluid Aβ effects on 2‐year cognitive change via regional longitudinal atrophy rate (AR) alone or AR and tau. Results In normal controls, Aβ correlated directly with regional ARs and memory loss, with no mediations. In early mild cognitive impairment, tau and lateral temporal ARs serially mediated the influence of Aβ on memory while Aβ affected memory via hippocampal AR. Late mild cognitive impairment consistently showed serial mediations of tau followed by atrophy. However, Aβ effects on memory also continued to be specifically mediated by medial temporal ARs without intermediate tau. Discussion Biomarker sequences vary by region and disease state, suggesting the need to refine current cascade models.

Abstract Introduction We studied the association of carotid intima‐media thickness (CIMT) with hippocampal volume (HV) in community dwelling individuals, testing the hypothesis that persons with carotid atherosclerosis progression would have lower HV. Methods We studied 1376 Framingham Offspring participants with two carotid ultrasounds and brain magnetic resonance imaging (MRIs). We used multivariable linear regression analyses to relate CIMT progression and HV and total brain volume. Regression models were adjusted for demographics and vascular risk factors, time interval between imaging examinations, and baseline CIMT. We assessed effect modification by hypertension treatment (HRx). Results Participants with higher ICA IMT progression had significantly lower HV after adjustment for vascular risk factors and baseline IMT (standardized beta ± standard error: −0.067 ± 0.027, P = .01). We observed weaker association between ICA IMT change and HV among subjects treated for hypertension (β = −0.047, P = .19 vs β = −0.096, P = .026). Discussion Cumulative vascular risk factor exposure, reflected by CIMT progression, may increase the risk of neurodegeneration.

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

BackgroundThe effects of white matter hyperintensity volume and subclinical brain infarcts on the risk of incident stroke, its ischemic subtypes, and mortality require further study in diverse samples. Methods and ResultsStroke‐free participants in the Northern Manhattan Study underwent magnetic resonance imaging (N=1287; mean age 71±9 years, 60% women, 15% non‐Hispanic white, 17% non‐Hispanic black, 68% Hispanic) and were followed for a median of 8 years (interquartile range: 6–9 years). Cox models estimated proportional hazards of incident stroke of all types, ischemic stroke (and its subtypes), and mortality and stratified by race/ethnicity. In total 72 participants (6%) had incident strokes and 244 died (19%). In fully adjusted models, those with larger white matter hyperintensity volume had greater risk of all stroke types (hazard ratio [HR]: 1.4; 95% CI, 1.1–1.9), ischemic stroke (HR: 1.3; 95% CI, 1.0–1.8), and cryptogenic stroke (HR: 2.2; 95% CI, 1.1–4.4). White and black but not Hispanic participants had increased stroke risk (P

BackgroundRelations 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 ResultsIn 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

BackgroundCarotid atherosclerosis is associated with subclinical ischemic cerebrovascular disease, but its role in hemorrhage‐prone small vessel disease—represented by cerebral microbleed (CMB)—is unclear, although vascular risk factors underlie both conditions. We hypothesized that persons with carotid atherosclerosis would have higher risk of CMB, particularly in deep regions. Methods and ResultsWe studied 1243 participants in the Framingham Offspring Study (aged 56.9±8.8 years; 53% women) with carotid ultrasound available on 2 occasions (1995–1998 and 2005–2008) prior to brain magnetic resonance imaging. Using multivariable logistic regression, we related baseline carotid stenosis, baseline intima–media thickness, and site‐specific carotid intima–media thickness progression (at internal and common carotid locations) to the prevalence and location (lobar or deep plus mixed) of CMB. In addition, we assessed effect modification by lipid levels and use of statin and antithrombotic medications. Carotid stenosis ≥25% (a marker of cerebrovascular atherosclerosis) was associated with presence of CMB overall (Odds Ratio 2.20, 95% CI 1.10–4.40) and at deep and mixed locations (odds ratio 3.60, 95% CI 1.23–10.5). Baseline carotid intima–media thickness was not associated with CMB. Progression of common carotid artery intima–media thickness among persons on hypertension treatment was associated with lower risk of deep and mixed CMB (odds ratio per SD 0.41, 95% CI 0.18–0.96). ConclusionsCumulative vascular risk factor exposure may increase the risk of CMB, especially in deep regions. The apparent paradoxical association of carotid intima–media thickness progression with lower risk of CMB may reflect benefits of intensive vascular risk factor treatment among persons with higher cardiovascular risk and deserves further investigation. If replicated, the results may have potential implications for assessment of preventive and therapeutic interventions for subclinical cerebral hemorrhage.