Showing papers by "Charles DeCarli published in 2017"

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

Abstract: We identified rare coding variants associated with Alzheimer's disease in a three-stage case–control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10−4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10−8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10−10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10−10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10−14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein–protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

Impact of multiple pathologies on the threshold for clinically overt dementia

Abstract: Longitudinal clinical–pathological studies have increasingly recognized the importance of mixed pathologies (the coexistence of one or more neurodegenerative and cerebrovascular disease pathologies) as important factors in the development of Alzheimer’s disease (AD) and other forms of dementia. Older persons with AD pathology, often have concomitant cerebrovascular disease pathologies (macroinfarcts, microinfarcts, atherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy) as well as other concomitant neurodegenerative disease pathologies (Lewy bodies, TDP-43, hippocampal sclerosis). These additional pathologies lower the threshold for clinical diagnosis of AD. Many of these findings from pathologic studies, especially for CVD, have been confirmed using sophisticated neuroimaging technologies. In vivo biomarker studies are necessary to provide an understanding of specific pathologic contributions and time course relationships along the spectrum of accumulating pathologies. In this review, we provide a clinical–pathological perspective on the role of multiple brain pathologies in dementia followed by a review of the available clinical and biomarker data on some of the mixed pathologies.

Transethnic genome-wide scan identifies novel Alzheimer's disease loci

Abstract: Introduction Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. Methods We conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset. Results Genome-wide significant (GWS) associations in single-nucleotide polymorphism (SNP)–based tests ( P −8 ) were identified for SNPs in PFDN1/HBEGF , USP6NL/ECHDC3 , and BZRAP1-AS1 and for the interaction of the (apolipoprotein E) APOE e4 allele with NFIC SNP. We also obtained GWS evidence ( P −6 ) for gene-based association in the total sample with a novel locus, TPBG ( P = 1.8 × 10 −6 ). Discussion Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci.

Blood pressure from mid- to late life and risk of incident dementia

Abstract: 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.

The Vascular Impairment of Cognition Classification Consensus Study

Abstract: Introduction Numerous diagnostic criteria have tried to tackle the variability in clinical manifestations and problematic diagnosis of vascular cognitive impairment (VCI) but none have been universally accepted. These criteria have not been readily comparable, impacting on clinical diagnosis rates and in turn prevalence estimates, research, and treatment. Methods The Vascular Impairment of Cognition Classification Consensus Study (VICCCS) involved participants (81% academic researchers) from 27 countries in an online Delphi consensus study. Participants reviewed previously proposed concepts to develop new guidelines. Results VICCCS had a mean of 122 (98–153) respondents across the study and a 67% threshold to represent consensus. VICCCS redefined VCI including classification of mild and major forms of VCI and subtypes. It proposes new standardized VCI-associated terminology and future research priorities to address gaps in current knowledge. Discussion VICCCS proposes a consensus-based updated conceptualization of VCI intended to facilitate standardization in research.

Female sex, early-onset hypertension, and risk of dementia.

Abstract: 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.

Prolonged sleep duration as a marker of early neurodegeneration predicting incident dementia

Abstract: Objective: To evaluate the association between sleep duration and the risk of incident dementia and brain aging. Methods: Self-reported total hours of sleep were examined in the Framingham Heart Study (n = 2,457, mean age 72 ± 6 years, 57% women) as a 3-level variable: 9 hours (long), and was related to the risk of incident dementia over 10 years, and cross-sectionally to total cerebral brain volume (TCBV) and cognitive performance. Results: We observed 234 cases of all-cause dementia over 10 years of follow-up. In multivariable analyses, prolonged sleep duration was associated with an increased risk of incident dementia (hazard ratio [HR] 2.01; 95% confidence interval [CI] 1.24–3.26). These findings were driven by persons with baseline mild cognitive impairment (HR 2.83; 95% CI 1.06–7.55) and persons without a high school degree (HR 6.05; 95% CI 3.00–12.18). Transitioning to sleeping >9 hours over a mean period of 13 years before baseline was associated with an increased risk of all-cause dementia (HR 2.43; 95% CI 1.44–4.11) and clinical Alzheimer disease (HR 2.20; 95% CI 1.17–4.13). Relative to sleeping 6–9 hours, long sleep duration was also associated cross-sectionally with smaller TCBV (β ± SE, −1.08 ± 0.41 mean units of TCBV difference) and poorer executive function (β ± SE, −0.41 ± 0.13 SD units of Trail Making Test B minus A score difference). Conclusions: Prolonged sleep duration may be a marker of early neurodegeneration and hence a useful clinical tool to identify those at a higher risk of progressing to clinical dementia within 10 years.

Validation of a Regression Technique for Segmentation of White Matter Hyperintensities in Alzheimer’s Disease

Abstract: Segmentation and volumetric quantification of white matter hyperintensities (WMHs) is essential in assessment and monitoring of the vascular burden in aging and Alzheimer’s disease (AD), especially when considering their effect on cognition. Manually segmenting WMHs in large cohorts is technically unfeasible due to time and accuracy concerns. Automated tools that can detect WMHs robustly and with high accuracy are needed. Here, we present and validate a fully automatic technique for segmentation and volumetric quantification of WMHs in aging and AD. The proposed technique combines intensity and location features frommultiplemagnetic resonance imaging contrasts and manually labeled training data with a linear classifier to perform fast and robust segmentations. It provides both a continuous subject specific WMH map reflecting different levels of tissue damage and binary segmentations. Themethodwas used to detectWMHs in 80 elderly/AD brains (ADC data set) as well as 40 healthy subjects at risk of AD (PREVENT-AD data set). Robustness across different scanners was validated using ten subjects from ADNI2/GO study. Voxel-wise and volumetric agreements were evaluated using Dice similarity index (SI) and intra-class correlation (ICC), yielding ${\mathrm{ ICC}}=0.96$ , ${\mathrm{ SI}}= 0.62\pm 0.16$ for ADC data set and ${\mathrm{ ICC}}=0.78$ , ${\mathrm{ SI}}=0.51\pm 0.15$ for PREVENT-AD data set. The proposed method was robust in the independent sample yielding ${\mathrm{ SI}}=0.64\pm 0.17$ with ${\mathrm{ ICC}}=0.93$ for ADNI2/GO subjects. The proposed method provides fast, accurate, and robust segmentations on previously unseen data from different models of scanners, making it ideal to study WMHs in large scale multi-site studies.

Aortic Stiffness, Increased White Matter Free Water, and Altered Microstructural Integrity: A Continuum of Injury.

Abstract: Background and Purpose— Previous reports from the Framingham Heart Study have identified cross-sectional associations of arterial stiffness, as reflected by carotid–femoral pulse wave velocity (CFPWV) and systolic blood pressure with vascular brain injury. The purpose of this study is to examine free water (FW), fractional anisotropy (FA), and white matter hyperintensities (WMH) in relation to arterial stiffness among subjects of the Framingham Offspring and Third-Generation cohorts. Methods— In 2422 participants aged 51.3±11.6 years, FA, FW, and WMH were related to CFPWV using voxel-based linear and generalized linear regressions, adjusting for relevant covariables. Mean FW, mean FA, and WMH burden (log transformed) were computed within white matter (WM) region and related to systolic blood pressure and CFPWV using multiple mediation analyses. Results— CFPWV was found to be associated with higher FW, lower FA, and higher WMH incidence in WM areas covering, respectively, 356.1, 211.8, and 10.9 mL of the WM mask. Mediation analyses revealed that the effect of systolic blood pressure on FW was mediated by CFPWV (direct and indirect effects: a=0.040; P 0.05). Moreover, the effect of CFPWV on FA was mediated by FW (direct and indirect effects: b=−0.092; P 0.05), whose effect on WMH was, in turn, mediated by FA (direct and indirect effects: c=0.246; P 0.05). Conclusions— From these data, we propose a biomechanical hypothesis designed for future research experiments to explain how hemodynamic alteration may lead to WM injury by impacting cerebral water content and more subtly WM integrity, to finally lead to WMH development.

Progression from normal cognition to mild cognitive impairment in a diverse clinic-based and community-based elderly cohort.

Abstract: Introduction Investigation of the conversion rates from normal cognition (NC) to mild cognitive impairment (MCI) is important, as effective early intervention could potentially prevent or substantially delay the onset of dementia. However, reported conversion rates differ across studies and recruitment source. Our study examined predictors of conversion from NC to MCI in a racially and ethnically diverse sample drawn both from community and clinic recruitment sources. Methods Rates and predictors of conversion were assessed in an ongoing prospective longitudinal study at University of California, Davis, Alzheimer's Disease Center from 2000 to 2015. Participants (n = 254) were recruited through a clinic (5%) and community sample (95%). They were clinically confirmed as cognitively normal at baseline and followed up to seven years. Recruitment source, demographic factors (age, gender, race/ethnicity, year of education, APOE e4 positive), cognitive measures (SENAS test scores), functional assessments (CDR sum of boxes), and neuroimaging measures (total brain volume, total hippocampal volume, white hyperintensity volume) were assessed as predictors of conversion from cognitively normal to mild cognitive impairment using proportional hazards models. Results Of 254 participants, 62 (11 clinic, 51 community) progressed to MCI. The clinic-based sample showed an annual conversion rate of 30% (95% CI 17%–54%) per person-year, whereas the community-based sample showed a conversion rate of 5% (95% CI 3%–6%) per person-year. Risk factors for conversion include clinic-based recruitment, being older, lower executive function and worse functional assessment at baseline, and smaller total brain volume. Discussion Older adults who sought out a clinical evaluation, even when they are found to have normal cognition, have increased risk of subsequent development of MCI. Results are consistent with other studies showing subjective cognitive complaints are a risk for future cognitive impairment, but extend such findings to show that those who seek evaluation for their complaints are at particularly high risk. Moreover, these individuals have subtle, but significant differences in functional and cognitive abilities that, in the presence of concerns and evidence of atrophy on by brain imaging, warrant continued clinical follow-up. These risk factors could also be used as stratification variables for dementia prevention clinical trial design.

Longitudinal measurement and hierarchical classification framework for the prediction of Alzheimer's disease.

Abstract: Accurate prediction of Alzheimer's disease (AD) is important for the early diagnosis and treatment of this condition. Mild cognitive impairment (MCI) is an early stage of AD. Therefore, patients with MCI who are at high risk of fully developing AD should be identified to accurately predict AD. However, the relationship between brain images and AD is difficult to construct because of the complex characteristics of neuroimaging data. To address this problem, we present a longitudinal measurement of MCI brain images and a hierarchical classification method for AD prediction. Longitudinal images obtained from individuals with MCI were investigated to acquire important information on the longitudinal changes, which can be used to classify MCI subjects as either MCI conversion (MCIc) or MCI non-conversion (MCInc) individuals. Moreover, a hierarchical framework was introduced to the classifier to manage high feature dimensionality issues and incorporate spatial information for improving the prediction accuracy. The proposed method was evaluated using 131 patients with MCI (70 MCIc and 61 MCInc) based on MRI scans taken at different time points. Results showed that the proposed method achieved 79.4% accuracy for the classification of MCIc versus MCInc, thereby demonstrating very promising performance for AD prediction.

Baseline White Matter Hyperintensities and Hippocampal Volume are Associated With Conversion From Normal Cognition to Mild Cognitive Impairment in the Framingham Offspring Study.

Abstract: 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.

Sugary beverage intake and preclinical Alzheimer's disease in the community

Abstract: Introduction Excess sugar consumption has been linked with Alzheimer's disease (AD) pathology in animal models. Methods We examined the cross-sectional association of sugary beverage consumption with neuropsychological ( N = 4276) and magnetic resonance imaging ( N = 3846) markers of preclinical Alzheimer's disease and vascular brain injury (VBI) in the community-based Framingham Heart Study. Intake of sugary beverages was estimated using a food frequency questionnaire. Results Relative to consuming less than one sugary beverage per day, higher intake of sugary beverages was associated with lower total brain volume (1–2/day, β ± standard error [SE] = −0.55 ± 0.14 mean percent difference, P = .0002; >2/day, β ± SE = −0.68 ± 0.18, P P P Discussion Higher intake of sugary beverages was associated cross-sectionally with markers of preclinical AD.

Relation of Dysglycemia to Structural Brain Changes in a Multiethnic Elderly Cohort.

Abstract: Objectives Abnormally high glucose levels (dysglycemia) increase with age. Epidemiological studies suggest that dysglycemia is a risk factor for cognitive impairment but the underlying pathophysiological mechanisms remain unclear. The objective of this study was to examine the relation of dysglycemia clinical categories (normal glucose tolerance (NGT), pre-diabetes, undiagnosed diabetes, known diabetes) with brain structure in older adults. We also assessed the relation between dysglycemia and cognitive performance. Design Cross-sectional and longitudinal cohort study. Setting Northern Manhattan (Washington Heights, Hamilton Heights, and Inwood). Participants Medicare recipients 65 years and older. Measurements Dysglycemia categories were based on HBA1c or history of type 2 diabetes (diabetes). Brain structure (brain infarcts, white matter hyperintensities (WMH) volume, total gray matter volume, total white matter volume, total hippocampus volume) was assessed with brain magnetic resonance imaging; cognitive function (memory, language and visuospatial function, speed) was assessed with a validated neuropsychological battery. Results Dysglycemia, defined with HbA1c as a continuous variable or categorically as pre-diabetes and diabetes, was associated with a higher number of brain infarcts, WMH volume and decreased total white matter, gray matter and hippocampus volumes cross-sectionally, and a significant decline in gray matter volume longitudinally. Dysglycemia was also associated with lower performance in language, speed and visuospatial function although these associations were attenuated when adjusted for education, APOE-e4, ethnic group and vascular risk factors. Conclusion Our results suggest that dysglycemia affects brain structure and cognition even in elderly survivors, evidenced by higher cerebrovascular disease, lower white and gray matter volume, and worse language and visuospatial function and cognitive speed.

Subclinical cerebrovascular disease increases the risk of incident stroke and mortality: The Northern Manhattan study

Abstract: Background The 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 Results Stroke‐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 P =0.040 for heterogeneity). Subclinical brain infarct was associated with increased vascular mortality among Hispanic participants only (HR: 2.9; 95% CI, 1.4–5.8). Conclusions In this urban US sample, subclinical cerebrovascular lesions increased the risk of clinical stroke and vascular mortality and varied by race/ethnicity and lesion type.

Triglycerides are negatively correlated with cognitive function in nondemented aging adults.

Abstract: Objective Vascular risk factors like hyperlipidemia may adversely affect brain function. We hypothesized that increased serum triglycerides are associated with decreased executive function and memory in nondemented elderly subjects. We also researched possible vascular mediators and white matter microstructure as assessed with diffusion tensor imaging (DTI). Design/method Participants were 251 nondemented elderly adults (54% male) with a mean age of 78 (SD = 6.4; range: 62-94) years and a mean education of 15.6 (SD = 2.9; range: 8-23) years. Fasting blood samples were used to detect serum triglyceride and low-density lipoprotein (LDL) levels along with ApoE4 status. DTI was used to determine whole brain fractional anisotropy (FA). Composite executive and memory scores were derived from item response theory. Clinical Dementia Rating (CDR) scores provided informant-based measures of daily functioning. Results Triglyceride levels were inversely correlated with executive function, but there was no relationship with memory. Controlling for age, gender, and education did not affect this correlation. This relationship persisted after controlling for vascular risk factors like LDL, total cholesterol, CDR and ApoE4 status. Lastly, adding whole-brain FA to the model did not affect the correlation between triglycerides and executive function. Conclusion Triglyceride levels are inversely correlated with executive function in nondemented elderly adults after controlling for age, education, gender, total cholesterol, LDL, ApoE4 status, CDR, and white-matter microstructure. The fact that the effect of triglycerides on cognition was not clearly mediated by vascular risks or cerebrovascular injury raises questions about widely held assumptions of how triglycerides might impact cognition function. (PsycINFO Database Record

Relationship between carotid arterial properties and cerebral white matter hyperintensities.

Abstract: Objective: Since arterial stiffness is a functional measure of arterial compliance and may be an important marker of cerebrovascular disease, we examined the association of carotid artery stiffness with white matter hyperintensity volume (WMHV) in a cross-sectional study of 1,166 stroke-free participants. Methods: Carotid beta stiffness index (STIFF) was assessed by M-mode ultrasound of the common carotid artery and calculated as the ratio of natural log of the difference between systolic and diastolic blood pressure over STRAIN, a ratio of the difference between carotid systolic and diastolic diameter (DD) divided by DD. WMHV was measured by fluid-attenuated inversion recovery MRI. The associations of STIFF, DD, and STRAIN with WMHV were examined using linear regression after adjusting for sociodemographic, lifestyle, and vascular risk factors. Results: In a fully adjusted model, larger carotid DD was significantly associated with greater log-WMHV (β = 0.09, p = 0.001). STIFF and STRAIN were not significantly associated with WMHV. In adjusted analyses stratified by race–ethnicity, STRAIN (β = −1.78, p = 0.002) and DD (β = 0.11, p = 0.001) were both associated with greater log-WMHV among Hispanic participants, but not among black or white participants. Conclusions: Large carotid artery diameters are associated with greater burden of white matter hyperintensity (WMH) in this multiethnic population. The association between increased diameters, decreased STRAIN, and greater WMH burden is more pronounced among Hispanics. These associations suggest a potential important pathophysiologic role of extracranial large artery remodeling in the burden of WMH.

Blood Pressure Control in Aging Predicts Cerebral Atrophy Related to Small-Vessel White Matter Lesions

Abstract: Cerebral small-vessel damage manifests as white matter hyperintensities and cerebral atrophy on brain MRI and is associated with aging, cognitive decline and dementia. We sought to examine the interrelationship of these imaging biomarkers and the influence of hypertension in older individuals. We used a multivariate spatial covariance neuroimaging technique to localize the effects of white matter lesion load on regional gray matter volume and assessed the role of blood pressure control, age and education on this relationship. Using a case-control design matching for age, gender, and educational attainment we selected 64 participants with normal blood pressure, controlled hypertension or uncontrolled hypertension from the Northern Manhattan Study cohort. We applied gray matter voxel-based morphometry with the scaled subprofile model to 1) identify regional covariance patterns of gray matter volume differences associated with white matter lesion load, 2) compare this relationship across blood pressure groups, and 3) relate it to cognitive performance. In this group of participants aged 60 to 86 years, we identified a pattern of reduced gray matter volume associated with white matter lesion load in bilateral temporal-parietal regions with relative preservation of volume in the basal forebrain, thalami and cingulate cortex. This pattern was expressed most in the uncontrolled hypertension group and least in the normotensives, but was also more evident in older and more educated individuals. Expression of this pattern was associated with worse performance in executive function and memory. In summary, white matter lesions from small-vessel disease are associated with a regional pattern of gray matter atrophy that is mitigated by blood pressure control, exacerbated by aging, and associated with cognitive performance.

Inter-Relations of Orthostatic Blood Pressure Change, Aortic Stiffness, and Brain Structure and Function in Young Adults.

Abstract: BackgroundRelations of orthostatic change in blood pressure with brain structure and function have not been studied thoroughly, particularly in younger, healthier individuals. Elucidation of factor...

Cascaded Multi-view Canonical Correlation (CaMCCo) for Early Diagnosis of Alzheimer's Disease via Fusion of Clinical, Imaging and Omic Features.

Abstract: The introduction of mild cognitive impairment (MCI) as a diagnostic category adds to the challenges of diagnosing Alzheimer’s Disease (AD). No single marker has been proven to accurately categorize patients into their respective diagnostic groups. Thus, previous studies have attempted to develop fused predictors of AD and MCI. These studies have two main limitations. Most do not simultaneously consider all diagnostic categories and provide suboptimal fused representations using the same set of modalities for prediction of all classes. In this work, we present a combined framework, cascaded multiview canonical correlation (CaMCCo), for fusion and cascaded classification that incorporates all diagnostic categories and optimizes classification by selectively combining a subset of modalities at each level of the cascade. CaMCCo is evaluated on a data cohort comprising 149 patients for whom neurophysiological, neuroimaging, proteomic and genomic data were available. Results suggest that fusion of select modalities for each classification task outperforms (mean AUC = 0.92) fusion of all modalities (mean AUC = 0.54) and individual modalities (mean AUC = 0.90, 0.53, 0.71, 0.73, 0.62, 0.68). In addition, CaMCCo outperforms all other multi-class classification methods for MCI prediction (PPV: 0.80 vs. 0.67, 0.63).

Association Between Heart Rate and Subclinical Cerebrovascular Disease in the Elderly.

Abstract: Background and Purpose— Although increased heart rate (HR) is a predictor of cardiovascular events and mortality, its possible association with subclinical cerebrovascular disease, which is prevalent in the elderly, has not been evaluated. This study aimed to investigate the association of daytime, nighttime, 24-hour HR, and HR variability with subclinical cerebrovascular disease in an elderly cohort without history of stroke. Methods— The study cohort consisted of 680 participants (mean age, 73±7 years; 42% men) in sinus rhythm who underwent 24-hour ambulatory blood pressure and HR monitoring, 2-dimensional echocardiography, and brain magnetic resonance imaging as part of the CABL study (Cardiac Abnormalities and Brain Lesion). Subclinical cerebrovascular disease was defined as silent brain infarcts and white matter hyperintensity volume (WMHV). The relationship of HR measures with the presence of silent brain infarct and upper quartile of log WMHV (log WMHV4) was analyzed. Results— Presence of silent brain infarct was detected in 93 participants (13.7%); mean log WMHV was −0.92±0.93 (median, −1.05; min, −5.88; max, 1.74). Multivariate analysis showed that only nighttime HR (adjusted odds ratio, 1.29 per 10 bpm; 95% confidence interval, 1.03–1.61; P =0.026) was significantly associated with log WMHV4, independent of traditional cardiovascular risk factors, ambulatory systolic blood pressure, and echocardiographic parameters. No similar association was observed for daytime HR and HR variability. There was no significant association between all HR measures and silent brain infarct. Conclusions— In a predominantly elderly cohort, elevated nighttime HR was associated with WMHV, suggesting an independent role of HR in subclinical cerebrovascular disease.

Lacunar Infarcts and Intracerebral Hemorrhage Differences: A Nested Case-Control Analysis in the FHS (Framingham Heart Study)

Abstract: Background and Purpose—Lacunar stroke (LS) and intracerebral hemorrhage (ICH) are 2 diverse manifestations of small vessel disease. What predisposes some patients to ischemic stroke and others to h...

Cerebral Microbleeds as Predictors of Mortality: The Framingham Heart Study.

Abstract: 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.

Strategies for enhancing research in aging health disparities by mentoring diverse investigators

Abstract: Author(s): Harawa, Nina T; Manson, Spero M; Mangione, Carol M; Penner, Louis A; Norris, Keith C; DeCarli, Charles; Scarinci, Isabel C; Zissimopoulos, Julie; Buchwald, Dedra S; Hinton, Ladson; Perez-Stable, Eliseo J | Abstract: IntroductionThe Resource Centers for Minority Aging Research (RCMAR) program was launched in 1997. Its goal is to build infrastructure to improve the well-being of older racial/ethnic minorities by identifying mechanisms to reduce health disparities.MethodsIts primary objectives are to mentor faculty in research addressing the health of minority elders and to enhance the diversity of the workforce that conducts elder health research by prioritizing the mentorship of underrepresented diverse scholars.ResultsThrough 2015, 12 centers received RCMAR awards and provided pilot research funding and mentorship to 361 scholars, 70% of whom were from underrepresented racial/ethnic groups. A large majority (85%) of RCMAR scholars from longstanding centers continue in academic research. Another 5% address aging and other health disparities through nonacademic research and leadership roles in public health agencies.ConclusionsLongitudinal, team-based mentoring, cross-center scholar engagement, and community involvement in scholar development are important contributors to RCMAR's success.