Comparison of approaches to control for intracranial volume in research on the association of brain volumes with cognitive outcomes.

Most neuroimaging studies linking regional brain volumes with cognition correct for total intracranial volume (ICV), but methods used for this correction differ across studies. It is unknown whether different ICV correction methods yield consistent results. Using a brain-wide association approach in the MRI substudy of UK Biobank (N = 41,964; mean age = 64.5 years), we used regression models to estimate the associations of 58 regional brain volumetric measures with eight cognitive outcomes, comparing no correction and four ICV correction approaches. Approaches evaluated included: no correction; dividing regional volumes by ICV (proportional approach); including ICV as a covariate in the regression (adjustment approach); and regressing the regional volumes against ICV in different normative samples and using calculated residuals to determine associations (residual approach). We used Spearman-rank correlations and two consistency measures to quantify the extent to which associations were inconsistent across ICV correction approaches for each possible brain region and cognitive outcome pair across 2320 regression models. When the association between brain volume and cognitive performance was close to null, all approaches produced similar estimates close to the null. When associations between a regional volume and cognitive test were not null, the adjustment and residual approaches typically produced similar estimates, but these estimates were inconsistent with results from the crude and proportional approaches. For example, when using the crude approach, an increase of 0.114 (95% confidence interval [CI]: 0.103-0.125) in fluid intelligence was associated with each unit increase in hippocampal volume. However, when using the adjustment approach, the increase was 0.055 (95% CI: 0.043-0.068), while the proportional approach showed a decrease of -0.025 (95% CI: -0.035 to -0.014). Different commonly used methods to correct for ICV yielded inconsistent results. The proportional method diverges notably from other methods and results were sometimes biologically implausible. A simple regression adjustment for ICV produced biologically plausible associations.

Racial Residential Segregation in Young Adulthood and Brain Integrity in Middle Age: Can We Learn From Small Samples?

Racial residential segregation is associated with multiple adverse health outcomes in Black individuals. Yet, the influence of structural racism and racial residential segregation on brain aging is less understood. In this study, we investigated the association between cumulative exposure to racial residential segregation over 25 years (1985-2010) in young adulthood, as measured by the Getis-Ord Gi* statistic, and year 25 measures of brain volume (cerebral, gray matter, white matter, and hippocampal volumes) in midlife. We studied 290 Black participants with available brain imaging data who were enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) Study, a prospective cohort study. CARDIA investigators originally recruited 2,637 Black participants aged 18-30 years from 4 field centers across the United States. We conducted analyses using marginal structural models, incorporating inverse probability of treatment weighting and inverse probability of censoring weighting. We found that compared with low/medium segregation, greater cumulative exposure to a high level of racial residential segregation throughout young adulthood was associated with smaller brain volumes in general (e.g., for cerebral volume, ß = -0.08, 95% confidence interval: -0.15, -0.02) and with a more pronounced reduction in hippocampal volume, though results were not statistically significant. Our findings suggest that exposure to segregated neighborhoods may be associated with worse brain aging.

Internal Carotid Artery Angle Variations are Poorly Explained by Vascular Risk Factors: The Northern Manhattan Study.

OBJECTIVES: The internal carotid artery (ICA) angle of origin may contribute to atherogenesis by altered hemodynamics. We aim to determine the contribution of vascular risk factors and arterial wall changes to ICA angle variations. METHODS: We analyzed 1,065 stroke-free participants from the population-based Northern Manhattan Study who underwent B-mode ultrasound (mean age 68.7±8.9 years; 59% women). ICA angle was estimated at the intersection between the common carotid artery and the ICA center line projections. Narrower external angles translating into greater carotid bifurcation bending were considered unfavorable. Linear regression models were fitted to assess the relationship between ICA angle and demographics, vascular risk factors, and arterial wall changes including carotid intima-media thickness (cIMT) and plaque presence. RESULTS: ICA angles were narrower on the left compared to the right side (153±15.4 degrees versus 161.4±12.7 degrees, p<0.01). Mean cIMT was 0.9±0.1 mm and 54.3% had at least one plaque. ICA angle was not associated with cIMT or plaque presence. Unfavorable left and right ICA angles were associated with advanced age (per 10-year increase ß=-1.6; p=0.01, and -1.3; p=0.03, respectively) and being Black participant (ß=-4.6; p<0.01 and -2.9; p=0.04, respectively), while unfavorable left ICA angle was associated with being female (ß=-2.8; p=0.03) and increased diastolic blood pressure (per 10 mmHg increase ß=-2.1; p<0.01). Overall, studied factors explained less than 10% of the variance in ICA angle (left R2=0.07; right R2=0.05). CONCLUSION: Only a small portion of ICA angle variation were explained by demographics, vascular risk factors and arterial wall changes. Whether ICA angle is determined by other environmental or genetic factors, and is an independent risk factor for atherogenesis, requires further investigation.

Diastolic Blood Pressure Is Associated With Regional White Matter Lesion Load: The Northern Manhattan Study.

Background and Purpose- Few studies have examined the separate contributions of systolic blood pressure and diastolic blood pressures (DBP) on subclinical cerebrovascular disease, especially using the 2017 American College of Cardiology/American Heart Association Blood Pressure Guidelines. Furthermore, associations with region-specific white matter hyperintensity volume (WMHV) are underexplored. Methods- Using data from the NOMAS (Northern Manhattan Study), a prospective cohort study of stroke risk and cognitive aging, we examined associations between systolic blood pressure and DBP, defined by the 2017 American College of Cardiology/American Heart Association guidelines, with regional WMHV. We used a linear mixed model approach to account for the correlated nature of regional brain measures. Results- The analytic sample (N=1205; mean age 64±8 years) consisted of 61% women and 66% Hispanics/Latinos. DBP levels were significantly related to WMHV differentially across regions (P for interaction<0.05). Relative to those with DBP 90+ mm Hg, participants with DBP <80 mm Hg had 13% lower WMHV in the frontal lobe (95% CI, -21% to -3%), 11% lower WMHV in the parietal lobe (95% CI, -19% to -1%), 22% lower WMHV in the anterior periventricular region (95% CI, -30% to -14%), and 16% lower WMHV in the posterior periventricular region (95% CI, -24% to -6%). Participants with DBP 80 to 89 mm Hg also exhibited about 12% (95% CI, -20% to -3%) lower WMHV in the anterior periventricular region and 9% (95% CI, -18% to -0.4%) lower WMHV in the posterior periventricular region, relative to participants with DBP 90≥ mm Hg. Post hoc pairwise t tests showed that estimates for periventricular WMHV were significantly different from estimates for temporal WMHV (Holms stepdown-adjusted P<0.05). Systolic blood pressure was not strongly related to regional WMHV. Conclusions- Lower DBP levels, defined by the 2017 American College of Cardiology/American Heart Association guidelines, were related to lower white matter lesion load, especially in the periventricular regions relative to the temporal region.

Ultrasound Markers of Carotid Atherosclerosis and Cognition: The Northern Manhattan Study.

BACKGROUND AND PURPOSE: Ultrasound markers of carotid atherosclerosis may be related to cognitive status. We hypothesized that individuals with greater carotid intima-media thickness (cIMT) and carotid plaque burden would exhibit worse cognition. METHODS: One thousand one hundred sixty-six stroke-free participants from the NOMAS (Northern Manhattan Study) underwent carotid ultrasound and neuropsychological examination. Among them, 826 underwent a second neuropsychological examination an average of 5 years later. cIMT and plaque were assessed by a standardized B-mode ultrasound imaging and reading protocol. We used multivariable linear regression to examine cIMT, carotid plaque presence, and carotid plaque area as correlates of domain-specific neuropsychological Z scores cross-sectionally and over time. We also investigated possible effect modification by APOE ε4 allele, age, and race/ethnicity. RESULTS: Participants had a mean (SD) age of 70 (9) years and were 60% women, 66% Hispanic, 15% white, and 18% black. Those with greater cIMT exhibited worse episodic memory after adjustment for demographics and vascular risk factors (ß=-0.60; P=0.04). APOE ε4 carriers with greater cIMT exhibited worse episodic memory (ß=-1.31; P=0.04), semantic memory (ß=-1.45; P=0.01), and processing speed (ß=-1.21; P=0.03). Participants with greater cIMT at baseline did not exhibit significantly greater cognitive decline after adjustment. APOE ε4noncarriers with greater cIMT exhibited greater declines in executive function (ß=-0.98; P=0.06). Carotid plaque burden was not significantly associated with cognition at baseline or over time. CONCLUSIONS: Subclinical carotid atherosclerosis was associated with worse cognition among those at higher risk for Alzheimer disease. Interventions targeting early stages of atherosclerosis may modify cognitive aging.

MRI Markers Predict Cognitive Decline Assessed by Telephone Interview: The Northern Manhattan Study.

BACKGROUND: Brain magnetic resonance imaging (MRI) allows researchers to observe structural pathology that may predict cognitive decline. Some populations are less accessible through traditional in-person visits, and may be under-represented in the literature. METHODS: We examined white matter hyperintensity volume (WMHV) and cerebral parenchymal fraction (CPF) as predictors of cognitive decline measured by a modified Telephone Interview for Cognitive Status (TICS-m) in the Northern Manhattan Stroke Study, a racially and ethnically diverse cohort study. Participants were stroke-free, above 50 years old, and had no contraindications to MRI. A total of 1143 participants had MRI and TICS-m data available [mean age 70 (SD=9), 61% women, 66% Hispanic, 17% Black, 15% white]. RESULTS: Those in the third and fourth quartiles of WMHV had significantly greater decline in TICS-m over time as compared with those in the first quartile (Q3: -0.17 points/year, Q4: -0.30 points/year). Those in the bottom 2 quartiles of CPF had significantly greater decline in TICS-m than those in the top quartile (Q1: -0.3 points/year, Q2: -0.2 points/year). Apolipoprotein E (APOE) e4 allele carriers had greater cognitive decline per unit of CPF. Those with greater CPF preserve TICS-m performance better despite greater WMHV. CONCLUSIONS: Telephone cognitive assessments can detect decline due to white matter lesions and smaller brain volumes.

Associations Between Handgrip Strength and Dementia Risk, Cognition, and Neuroimaging Outcomes in the UK Biobank Cohort Study.

Importance: The associations between muscle strength and cognitive outcomes have sparked interest in interventions that increase muscle strength for prevention of dementia, but the associations between muscle strength and cognitive aging are unclear, particularly among middle-aged adults. Objective: To evaluate the association between handgrip strength (HGS) and dementia, reduced cognition, and poorer neuroimaging outcomes in a UK population of middle-aged adults. Design, Setting, and Participants: This cohort study evaluated UK Biobank participants aged 39 to 73 years enrolled from 2006 to 2010 with measured HGS and prospectively followed up for dementia diagnosis. Data were analyzed from October 2021 to April 2022. Exposures: HGS assessed in both hands via dynamometer. Main Outcomes and Measures: Outcomes included cognitive test scores (fluid intelligence and prospective memory), brain magnetic resonance imaging measures (total brain volume, white matter hyperintensity, and hippocampal volume), and incident dementia (all-cause, vascular, and Alzheimer disease [AD] from primary care, hospital, or death records) over a median (IQR) of 11.7 (11.0-12.4) years of follow-up. Mixed-effects linear and logistic regressions and Cox proportional-hazard models were used to estimate associations, stratified by gender and adjusted for covariates. Estimates are presented per 5-kg decrement in HGS. To evaluate reverse causation, we assessed whether a polygenic risk score for AD is associated with HGS. Results: A subsample of 190 406 adult participants in the UK Biobank (mean [SD] age, 56.5 [8.1] years; 102 735 women [54%]) were evaluated. A 5-kg decrement in HGS was associated with lower fluid intelligence scores in men (ß, -0.007; 95% CI, -0.010 to -0.003) and women (ß, -0.04; 95% CI, -0.05 to -0.04. A 5-kg decrement in HGS was associated with worse odds of correctly responding to a prospective memory task for men (odds ratio, 0.91; 95% CI, 0.90 to 0.92) and women (odds ratio, 0.88; 95% CI, 0.87 to 0.90). A 5-kg decrement in HGS was associated with greater white matter hyperintensity volume in men (ß, 92.22; 95% CI, 31.09 to 153.35) and women (ß, 83.56; 95% CI, 13.54 to 153.58). A 5-kg decrement in HGS was associated with incident dementia for men (hazard ratio, 1.20; 95% CI, 1.12 to 1.28) and women (hazard ratio, 1.12; 95% CI, 1.00 to 1.26). The AD genetic risk score was not significantly associated with HGS. Conclusions and Relevance: These findings suggest that HGS is associated with measures of neurocognitive brain health among men and women and they add to a growing body of research indicating that interventions designed to increase muscle strength, particularly among middle-aged adults, may hold promise for the maintenance of neurocognitive brain health.

A case study and proposal for publishing directed acyclic graphs: The effectiveness of the quadrivalent human papillomavirus vaccine in perinatally HIV Infected girls.

BACKGROUND: Developing a causal graph is an important step in etiologic research planning and can be used to highlight data flaws and irreparable bias and confounding. As a case study, we consider recent findings that suggest human papillomavirus (HPV) vaccine is less effective against HPV-associated disease among girls living with HIV compared to girls without HIV. OBJECTIVES: To understand the relationship between HIV status and HPV vaccine effectiveness, it is important to outline the key assumptions of the causal mechanisms before designing a study to investigate the effect of the HPV vaccine in girls living with HIV infection. METHODS: We present a causal graph to describe our assumptions and proposed approach to explore this relationship. We hope to obtain feedback on our assumptions before data analysis and exemplify the process for designing causal graphs to inform an etiologic study. CONCLUSION: The approach we lay out in this paper may be useful for other researchers who have an interest in using causal graphs to describe and assess assumptions in their own research before undergoing data collection and/or analysis.

Associations Between Cognitive Functioning and Mortality in a Population-Based Sample of Older United States Adults: Differences by Sex and Education.

Objective: To determine whether cognition is associated with mortality among older US adults. Methods: We studied 5,989 National Health and Nutrition Examination Survey participants age 60+ in years 1999-2014 with mortality follow-up through 2015. Cognitive function was measured in one standard deviation decrements using the Digit Symbol Substitution Test (DSST), Animal Fluency (AnFl), and two Consortium to Establish a Registry for Alzheimer's Disease (CERAD) tests. Results: Each decrement in cognitive function was associated with increased risk of mortality overall (DSST HR: 1.36, 95% CI: 1.25, 1.48), among women only (AnFl: 1.51, 95% CI: 1.02, 2.24), and among those with less than a high school education only (AnFl HR: 1.46, 95% CI: 1.09, 1.97; CERAD-WL HR: 1.34, 95% CI: 1.07, 1.67; and CERAD-DR HR: 1.38, 95% CI: 1.05, 1.82). Discussion: Among US adults, lower cognitive functioning was associated with mortality; associations were stronger among women and those with less education.

Associations Between 20-Year Lipid Variability Throughout Young Adulthood and Midlife Cognitive Function and Brain Integrity.

BACKGROUND: Little is known about long-term lipid variability in young adulthood in relation to cognitive function and brain integrity in midlife. METHOD: We studied 3 328 adults from the Coronary Artery Risk Development in Young Adults. We defined low- and high-density lipoprotein (LDL and HDL) variability as the intraindividual standard deviation of lipid measurements over 20 years of young adulthood (1985-2005). Cognitive tests were administered in 2010. Brain scans were performed in 2010 on 714 participants. To facilitate comparison, cognitive tests and brain metrics were z-scored. RESULTS: Mean age at baseline was 25.4 years. Higher 20-year LDL variability was associated with worse verbal memory in midlife (ß = -0.25, 95% CI: -0.42, -0.08), adjusted for important covariates. Higher 20-year HDL variability was associated with worse processing speed in midlife (ß = -0.80, 95% CI: -1.18, -0.41) and brain integrity, for example, smaller total brain volume (ß = -0.58, 95% CI: -0.82, -0.34) and worse total brain fractional anisotropy (ß = -1.13, 95% CI: -1.87, -0.39). CONCLUSIONS: Higher long-term lipid variability in adulthood was associated with worse cognition and brain integrity in midlife, in a relatively young cohort.

Machine learning-based estimation of cognitive performance using regional brain MRI markers: the Northern Manhattan Study.

High dimensional neuroimaging datasets and machine learning have been used to estimate and predict domain-specific cognition, but comparisons with simpler models composed of easy-to-measure variables are limited. Regularization methods in particular may help identify regions-of-interest related to domain-specific cognition. Using data from the Northern Manhattan Study, a cohort study of mostly Hispanic older adults, we compared three models estimating domain-specific cognitive performance: sociodemographics and APOE ε4 allele status (basic model), the basic model and MRI markers, and a model with only MRI markers. We used several machine learning methods to fit our regression models: elastic net, support vector regression, random forest, and principal components regression. Model performance was assessed with the RMSE, MAE, and R2 statistics using 5-fold cross-validation. To assess whether prediction models with imaging biomarkers were more predictive than prediction models built with randomly generated biomarkers, we refit the elastic net models using 1000 datasets with random biomarkers and compared the distribution of the RMSE and R2 in models using these random biomarkers to the RMSE and R2 from observed models. Basic models explained ~ 31-38% of the variance in domain-specific cognition. Addition of MRI markers did not improve estimation. However, elastic net models with only MRI markers performed significantly better than random MRI markers (one-sided P < .05) and yielded regions-of-interest consistent with previous literature and others not previously explored. Therefore, structural brain MRI markers may be more useful for etiological than predictive modeling.

Design and Usability Testing of the Stroke Caregiver Support System: A Mobile-Friendly Website to Reduce Stroke Caregiver Burden.

PURPOSE: The purpose of this study was to design a mobile-friendly, Internet-based website, modeled on previously described websites for Alzheimer caregivers, to equip stroke caregivers and potentially reduce caregiver burden. DESIGN: A mixed-methods study was performed to design and test the usability of the Stroke Caregiver Support System (SCSS). METHODS: An iterative, user-centered design approach was employed in three phases: (I) Focus Groups, (II) Structured Interviews, and (III) Usability Testing. Phase I and Phase II provided information for the development of the SCSS website, whereas Phase III helped in gathering data regarding the usability and efficacy of the newly implemented SCSS website. FINDINGS: Qualitative data on caregiving and the content and design of the SCSS were obtained from focus groups and interviews. In the usability test, the nine caregivers who completed Phase III (78% women, mean age = 46, SD = 17) exhibited a high level of burden and depressive symptoms (median [Q1, Q3] Zarit burden score = 18 [16, 23], Center of Epidemiologic Studies-Depression Scale = 15 [8, 17]). Caregivers conveyed the usability of the SCSS but also expressed several needed improvements. CONCLUSIONS: Participants reported the value of the SCSS, but further refinements are needed to maximize its usability and potential efficacy. CLINICAL RELEVANCE: The SCSS has potential to reduce caregiver burden in stroke.

Cholinergic White Matter Lesions, AD-Signature Cortical Thickness, and Change in Cognition: The Northern Manhattan Study.

BACKGROUND: How cerebrovascular disease and neurodegeneration affect each other to impact cognition is not yet known. We aimed to test whether Alzheimer's disease-signature (AD) cortical thickness mediates the association between cholinergic white matter lesion load and change in domain-specific cognition. METHODS: Clinically stroke-free participants from the Northern Manhattan Study with both regional white matter hyperintensity volume (WMHV) and gray matter measurements were included (N = 894). Tract-specific WMHVs were quantified through FSL using the Johns Hopkins University white matter tract atlas. We used Freesurfer 5.1 to estimate regional cortical thickness. We fit structural equation models, including multiple indicator latent change score models, to examine associations between white matter hyperintensity volume (WMHV) in cholinergic tracts, AD-signature region cortical thickness (CT), and domain-specific cognition. RESULTS: Our sample (N = 894) had a mean (SD) age = 70 (9) years, years of education = 10 (5), 63% women, and 67% Hispanics/Latinos. Greater cholinergic WMHV was significantly related to worse processing speed at baseline (standardized ß = -0.17, SE = 0.05, p = .001) and over time (standardized ß = -0.28, SE = 0.09, p = .003), with a significant indirect effect of AD-signature region CT (baseline: standardized ß = -0.02, SE = 0.01, p = .023; change: standardized ß = -0.03, SE = 0.02, p = .040). CONCLUSIONS: Cholinergic tract WMHV is associated with worse processing speed, both directly and indirectly through its effect on AD-signature region CT.

Association of Racial Residential Segregation Throughout Young Adulthood and Cognitive Performance in Middle-aged Participants in the CARDIA Study.

Importance: Neighborhood-level residential segregation is implicated as a determinant for poor health outcomes in black individuals, but it is unclear whether this association extends to cognitive aging, especially in midlife. Objective: To examine the association between cumulative exposure to residential segregation during 25 years of young adulthood among black individuals and cognitive performance in midlife. Design, Setting, and Participants: The ongoing prospective cohort Coronary Artery Risk Development in Young Adults (CARDIA) Study recruited 5115 black and white participants aged 18 to 30 years from 4 field centers at the University of Alabama, Birmingham; University of Minnesota, Minneapolis; Northwestern University, Chicago, Illinois; and Kaiser Permanente, Oakland, California. Data were acquired from February 1985 to May 2011. Among the surviving CARDIA cohort, 3671 (71.8%) attended examination year 25 of the study in 2010, when cognition was measured, and 3008 (81.9%) of those completed the cognitive assessments. To account for time-varying confounding and differential censoring, marginal structural models using inverse probability weighting were applied. Data were analyzed from April 16 to July 20, 2019. Main Outcomes and Measures: Racial residential segregation was measured using the Getis-Ord Gi* statistic, and the mean cumulative exposure to segregation was calculated across 6 follow-up visits from baseline to year 25 of the study, then categorized into high, medium, and low segregation. Cognitive function was measured at year 25 of the study, using the Digit Symbol Substitution Test (DSST), Stroop color test (reverse coded), and Rey Auditory Verbal Learning Test. To facilitate comparison of estimates, z scores were calculated for all cognitive tests. Results: A total of 1568 black participants with available cognition data were included in the analysis. At baseline, participants had a mean (SD) age of 25 (4) years and consisted of 936 women (59.7%). Greater cumulative exposure to segregated neighborhoods was associated with a worse DSST z score (for high segregation, ß = -0.37 [95% CI, -0.61 to -0.13]; for medium segregation, ß = -0.25 [95% CI, -0.51 to 0.0002]) relative to exposure to low segregation. Conclusions and Relevance: In this cohort study, exposure to residential segregation throughout young adulthood was associated with worse processing speed among black participants as early as in midlife. This association may potentially explain black-white disparities in dementia risk at older age.

Association of High-Density Lipoprotein Cholesterol With Cognitive Function: Findings From the PROspective Study of Pravastatin in the Elderly at Risk.

Objective: We aimed to examine whether variability in high-density lipoprotein cholesterol (HDL-c) over time was associated with cognitive function. Method: We conducted a post hoc analysis of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial. Our sample included 4,428 participants with at least two repeated HDL-c measures between Months 3 and 24 postbaseline and with cognitive assessments at Month 30. HDL-c variability was defined as the intraindividual standard deviation over each person's repeated measurements. Results: Higher HDL-c variability was associated with worse performance on the Letter-Digit Coding Test (ß [95% confidence interval] [CI] = -4.39 [-7.36, -1.43], p = .004), immediate recall on the 15-Picture Learning Test (ß [95% CI] = -0.98 [-1.86, -0.11], p = .027), and delayed recall on the 15-Picture Learning Test (ß [95% CI] = -1.90 [-3.14, -0.67], p = .002). The associations did not vary by treatment group. Discussion: Our findings suggest that variability in HDL-c may be associated with poor cognitive function among older adults.

Neuroimaging of Cerebral Small Vessel Disease and Age-Related Cognitive Changes.

Subclinical cerebrovascular disease is frequently identified in neuroimaging studies and is thought to play a role in the pathogenesis of cognitive disorders. Identifying the etiologies of different types of lesions may help investigators differentiate between age-related and pathological cerebrovascular damage in cognitive aging. In this review article, we aim to describe the epidemiology and etiology of various brain magnetic resonance imaging (MRI) measures of vascular damage in cognitively normal, older adult populations. We focus here on population-based prospective cohort studies of cognitively unimpaired older adults, as well as discuss the heterogeneity of MRI findings and their relationships with cognition. This review article emphasizes the need for a better understanding of subclinical cerebrovascular disease in cognitively normal populations, in order to more effectively identify and prevent cognitive decline in our rapidly aging population.

Measures of Adiposity and Alzheimer's Disease-Related MRI Markers: The Northern Manhattan Study.

BACKGROUND: Adiposity may increase risk for dementia and Alzheimer's disease (AD), but mechanisms are unclear. OBJECTIVE: To examine associations between measures of adiposity with AD-signature region cortical thickness and hippocampal volume. METHODS: We used data from the Northern Manhattan Study, a clinically stroke-free cohort of mostly Hispanic participants. Exposures of interest included body mass index (BMI), waist-hip-ratio (WHR), waist circumference (WC), and adiponectin concentration, measured at study entry. AD-signature region cortical thickness and hippocampal volume were obtained using Freesurfer. We estimated associations using multivariable linear regression, adjusting for sociodemographics and health behaviors. We re-examined estimates after adjustment for APOEɛ4 allele status or carotid intima-media thickness (cIMT), among those cognitively unimpaired, and after weighting for the inverse probability of selection into the MRI sub-study. We also repeated analyses for cortical thickness in non-AD signature regions. RESULTS: The sample (N = 947, 63% women, 66% Hispanic/Latino, 26% obese) had a mean (SD) age = 63 (8) years. Greater BMI and WC (both z-scored) were associated with thinner AD-signature region cortex (also z-scored) (BMI: ß [95% CI] = -0.09 [-0.18, -0.01], WC: ß [95% CI] = -0.11 [-0.20, -0.02]). We did not find evidence that adiposity was related to hippocampal volume. Results were consistent after adjustment for APOEɛ4 allele status or cIMT, after weighting for selection, among those cognitively unimpaired, and for non-AD signature region cortical thickness. CONCLUSION: Greater BMI and WC were related to cortical thinning within and outside the AD-signature region, suggesting a global effect not specific to AD.

Measures of obesity are associated with MRI markers of brain aging: The Northern Manhattan Study.

OBJECTIVE: To examine associations between measures of obesity in middle to early-old age with later-life MRI markers of brain aging. METHODS: We 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 ß coefficients (or odds ratios) and 95% confidence intervals (CIs) and tested interactions with age, sex, and race/ethnicity. RESULTS: On 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 ß [95% CI] -0.089 [-0.153, -0.025], WC ß [95% CI] -0.103 [-0.169, -0.037]) in fully adjusted models. Similarly, compared to those with BMI <25, obese participants (BMI ≥30) exhibited smaller cortical thickness (ß [95% CI] -0.207 [-0.374, -0.041]). These associations were particularly evident for those aged <65 years. Similar but weaker associations were observed for TCV. Most associations with WMHV and SBI did not reach statistical significance. CONCLUSIONS: Adiposity 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.

Mediterranean Diet in Preventing Neurodegenerative Diseases.

PURPOSE OF REVIEW: We reviewed the most recent literature examining the associations between the Mediterranean-style diet (MD), neurodegenerative diseases, and markers and mechanisms of neurodegeneration. RECENT FINDINGS: Most, but not all, epidemiologic studies report a protective association between MD adherence, cognitive impairment, and brain health. Data from clinical trials supporting these observational findings are also emerging. Limited evidence suggests that MD adherence may be protective for Parkinson's disease risk. Mechanistically, plant polyphenols may activate similar molecular pathways as caloric restriction diets, which helps explain the neuroprotective properties of the MD. Evidence for cognitive disorders is abundant, but there is a dearth of literature for other neurodegenerative disorders and for markers of neurodegeneration. Further research is needed to elucidate the protective role of MD on neurodegeneration, the most salient components of the MD, and the most sensitive time periods over the lifecourse at which the MD may exert its effects.