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Can plasma metabolomics reveal mechanisms of brain aging? We investigated metabolomic signatures of brain atrophy patterns related to cognitive decline and Alzheimer’s disease(AD) risk. Relationships between metabolomics(Biocrates-p500) and annual rates of change in two neuroimaging-based brain atrophy patterns(SPARE-BA indexing brain aging, SPARE-AD indexing AD-related atrophy) were examined using multivariable linear regression in 477 Baltimore Longitudinal Study of Aging participants aged 60+, adjusted for demographic variables and BMI. Higher concentrations of sarcosine, triglycerides, diglycerides, and ceramides and lower concentrations from phosphatidylcholines and cholesteryl ester were associated with faster rates of SPARE-BA increase longitudinally. Higher concentrations of diglyceride and alpha-amino-butyric acid and lower concentrations of tryptophan, hippuric acid, cholesteryl ester, phosphatidylcholine and sphingomyelin were associated with faster rates of SPARE-AD. Metabolites have differential associations with age-related and AD-related brain atrophy patterns, which may provide new insights into preventive and therapeutic interventions. Future studies should examine whether metabolite changes precede brain atrophy patterns.

Normal and pathologic neurobiological processes influence brain morphology in coordinated ways that give rise to structural covariance patterns across brain regions and individuals. We present a mega-analysis of structural covariance with magnetic resonance imaging of 50,699 healthy and diseased individuals (12 studies, 130 sites, and 12 countries) over their lifespan (ages 5 through 97). Patterns of structural covariance (PSC) were highly heritable (0.05< h2 -log10[p-value] > 8.8): 1245 previously unreported, and 69% of them independently replicated (-log10[p-value] = 4.5). Associations revealed an imaging phenotypic landscape between 2003 PSCs and 49 clinical and cognitive traits at multiple scales. We constructed machine learning-derived individualized imaging signatures for various disease diagnoses using PSC features at multiple scales, suggesting that disease effects on the brain were better manifested in a multi-scale continuum than on any single scale. Experimental results were integrated into the Multi-scale Structural Imaging Covariance (MuSIC) atlas and made publicly accessible through the BRIDGEPORT web portal (https://www.cbica.upenn.edu/bridgeport/). Our results reveal strong associations between brain structural covariance, genetics, and clinical phenotypes, supporting that PSCs can serve as an endophenotypic anatomic dictionary in future research.

Diffusion weighted MRI (DW-MRI) harmonization is necessary for multi-site or multi-acquisition studies. Current statistical methods address the need to harmonize from one site to another, but do not simultaneously consider the use of multiple datasets which are comprised of multiple sites, acquisitions protocols, and age demographics. This work explores deep learning methods which can generalize across these variations through semi-supervised and unsupervised learning while also learning to estimate multi-shell data from single-shell data using the Multi-shell Diffusion MRI Harmonization Challenge (MUSHAC) and Baltimore Longitudinal Study on Aging (BLSA) datasets. We compare disentanglement harmonization models, which seek to encode anatomy and acquisition in separate latent spaces, and a CycleGAN harmonization model, which uses generative adversarial networks (GAN) to perform style transfer between sites, to the baseline preprocessing and to SHORE interpolation. We find that the disentanglement models achieve superior performance in harmonizing all data while at the same transforming the input data to a single target space across several diffusion metrics (fractional anisotropy, mean diffusivity, mean kurtosis, primary eigenvector).

Quantifying the microstructural and macrostructural geometrical features of the human brain’s connections is necessary for understanding normal aging and disease. Here, we examine brain white matter diffusion magnetic resonance imaging data from one cross-sectional and two longitudinal datasets totaling in 1184 subjects and 2236 sessions of people aged 50-97 years. Data was drawn from well-established cohorts, including the Baltimore Longitudinal Study of Aging dataset, Cambridge Centre for Ageing Neuroscience dataset, and the Vanderbilt Memory & Aging Project. Quantifying 4 microstructural features and, for the first time, 11 macrostructure-based features of volume, area, and length across 120 white matter pathways, we apply linear mixed effect modeling to investigate changes in pathway-specific features over time, and document large age associations within white matter. Conventional diffusion tensor microstructure indices are the most age-sensitive measures, with positive age associations for diffusivities and negative age associations with anisotropies, with similar patterns observed across all pathways. Similarly, pathway shape measures also change with age, with negative age associations for most length, surface area, and volume-based features. A particularly novel finding of this study is that while trends were homogeneous throughout the brain for microstructure features, macrostructural features demonstrated heterogeneity across pathways, whereby several projection, thalamic, and commissural tracts exhibited more decline with age compared to association and limbic tracts. The findings from this large-scale study provide a comprehensive overview of the age-related decline in white matter and demonstrate that macrostructural features may be more sensitive to heterogeneous white matter decline. Therefore, leveraging macrostructural features may be useful for studying aging and could have widespread implications for a variety of neurodegenerative disorders.

β-amyloid is a hallmark of Alzheimer’s disease and can be measured in vivo by PET imaging. Whether PiB+ (elevated β-amyloid) individuals exhibit distinct physical activity patterns throughout the day (i.e., activity amount or fragmentation) is unknown. Using data from 125 BLSA participants (56-95 years) with PET imaging and ≥3 days of wrist accelerometry, we examined associations between PiB status and activity patterns daily and during 6-hour time blocks using multivariable linear regression models. Modification by age was also examined. Daily total activity counts and activity fragmentation did not differ by PiB status (p=0.34 and p=0.70, respectively). Yet, per each additional year of age, PiB+ individuals were more active during early morning (p=0.04) and evening (p=0.029) but trended towards less active in mid-morning (p=0.069) than PiB- individuals. Though replication of findings is needed, older PiB+ participants appeared more active in the late evening/early morning, possibly reflecting altered sleep-time, agitation, or restlessness.

Understanding how trajectories of positive and negative affect relate to dementia risk and underlying structural brain variables is important for dementia prevention. We examined associations between annually assessed Positive and Negative Affect Scale subscales and dementia risk (2000-18) among cognitively-intact community-dwelling women (N=948; aged 72.9±3.7) from the Women’s Health Initiative Study of Cognitive Aging (years 2000-2010) and Magnetic Resonance Imaging Study (2005-2006). Joint latent class mixture models were constructed to identify latent classes of women with similar trajectories of affect and dementia risk over time. Multinomial and logistic regressions examined whether structural MRI measures predicted latent class membership (adjusted for sociodemographic, lifestyle, clinical characteristics, and intracranial volume). Two latent classes of positive affect (high stable:88% and decreasing:12%) and four classes of negative affect (Minimal stable:75%; high stable:4%; emerging:12%; moderate decreasing:9%) were identified. With the high stable trajectory as referent, women with decreasing positive affect were more likely to develop dementia (HR=4.33;p

The Apolipoprotein-ε4 (APOE-ε4) genotype is associated with earlier onset and greater risk of β-amyloid deposition, but whether APOE-ε4 status is associated with physical activity amount or fragmentation remains unclear. In 563 BLSA participants aged 55-97 years with APOE-ε4 and ≥3 days of wrist accelerometry data, multivariable linear regression models were fitted to estimate differences in activity amount (daily or by 6-hour time blocks) or fragmentation by APOE-ε4 status and to test whether age modifies these effects. Overall, daily activity amount and fragmentation did not differ by APOE-ε4 status (p=0.28 and p=0.93, respectively). Yet, age significantly modified the APOE-ε4 effect. Per each additional year of age, APOE-ε4 carriers had less activity during early morning (12:00-6:00AM) than non-carriers (p=0.035). This association was non-significant among the oldest-old (p=0.697 at age 80 years, p=0.347 at age 90 years), suggesting possible decreases in the predictive power of APOE-ε4 with increasing age.

Motor impairment is one early feature of preclinical Alzheimer’s disease and strongly predicts future dementia. Whether older persons with dementia who had prior motor impairment present specific characteristics is less clear. In the Baltimore Longitudinal Study of Aging, we compared characteristics of participants with cognitive impairment or dementia who had slow gait on average 6 years before symptom onset (

Alterations in 24-hour movement patterns, or circadian rest/activity rhythms (RARs), commonly occur with aging. Using linear mixed effects (LME) modeling, we examined associations of baseline RARs with longitudinal change in cognition. Participants (N=424; 47% male, baseline age 72.8±10.1 years) were from the Baltimore Longitudinal Study of Aging and completed 5.6±0.8 nights of wrist actigraphy at baseline. Tests of memory, executive function, attention, language, and visuospatial ability were administered at baseline and subsequent visits (3.7±1.7 years of follow-up in those with >1 visit (n=295)). In unadjusted random intercept and slope LME models, greater RAR stability predicted slower memory decline, and higher activity during participants’ least active 5 hours (L5) predicted slower decline in visuospatial ability. After covariate adjustment, higher activity in participants’ most active 10 hours (M10) and higher L5 predicted slower decline in visuospatial ability (p

Studies have demonstrated a link between sensory impairment and dementia risk, but little is known about the presence of beta-amyloid plaques in individuals with single and multisensory impairments. Sensory function (combinations of vision, hearing, vestibular function, and proprioception) and amyloid PET imaging were measured in 170 BLSA participants (age=78± 9 years; 53% women; 77% white; 28% amyloid positive) from 2012 to 2019. Log-binomial regression models were used to examine the prevalence ratios (PR) of amyloid positivity for individual sensory impairments and across categories of impairments. While crude associations indicate associations of vision impairment (PR=1.72, p=0.04) and impairments in all four senses (PR=2.38, p=0.03) with amyloid positivity, these associations were insignificant after adjusting for age, sex, race, and education. There were no other crude and adjusted associations. These results suggest sensory impairments may be related to dementia independent of AD pathology. Future studies with larger sample sizes are warranted.

Motor and sensory impairments are linked with dementia risk, but whether there is a joint effect of deficits in motor and sensory function is unknown. We analyzed 649 BLSA participants (aged 72±11 years; 55% women; 68% white) who had concurrent baseline 6-meter usual gait speed and sensory function (vision, hearing) between 2012-2019. Mild cognitive impairment (MCI) and dementia were adjudicated during an average follow-up of 3 years. We examined the association between baseline gait speed, z-scored sensory function, and a gait*sensory interaction with risk of MCI/dementia using Cox proportional hazard models, adjusted for demographics and chronic conditions. Each .01 m/s faster baseline gait was associated with a reduced risk (HR:0.98 (0.96-0.99)) of MCI/dementia, and each 1 SD higher in hearing and vision z-score was associated with an increased risk (HR:1.84 (1.1-3.1)) increased risk. The was no significant interaction, suggesting motor and sensory impairments may be independently associated with MCI/dementia risk.

Perceived fatigability is linked to declining physical and cognitive performance, yet whether fatigability reflects early subclinical change in brain structure is unknown. Using mixed effects models, we assessed the longitudinal association of 3T MRI-derived brain volumes with perceived fatigability after a 5-min treadmill walk (0.67 m/s, 0% grade) using the Borg Rating of Perceived Exertion scale (range 6-20) in 802 BLSA participants (age 68.2+/-12.4 years, 45% men 66% White). In models adjusted for intracranial volume, demographics, chronic conditions, and CESD score, declining gray matter volumes in the frontal (β=-0.01) and temporal (β=-0.02) lobes, as well as the hippocampus (β=-0.25), precuneus (β=-0.10) and thalamus (β=-0.19) were associated with higher fatigability. Larger ventricular volumes were also associated with higher fatigability (β=0.02). Brain atrophy, particularly in gray matter and the hippocampal region, is longitudinally associated with increased fatigability in cognitively normal older adults, making it a potential marker of brain atrophy.

Physical activity especially at moderate-to-vigorous intensity may preserve brain structure in old age. However, current findings are cross-sectional and rely on absolute intensity. This study aimed to examine whether relative or absolute vigorous-intensity physical activity (VPA) predicts brain microstructural changes. We analyzed 260 initially cognitively normal and well-functioning participants(age=70.5yrs) who had VPA data via ActiHeart and longitudinal brain microstructure by DTI(follow-up=3.7yrs). Associations of VPA with microstructural changes were examined using linear mixed-effects models, adjusted for demographics. Each SD higher relative VPA defined by heart rate reserve (i.e. 21 min/day) was significantly associated with less decline in memory-related microstructural integrity, including mean diffusivity of entorhinal cortex and parahippocampal gyrus and fractional anisotropy of uncinate fasciculus and cingulum-hippocampal part, and not executive/motor-related microstructure. Absolute VPA was not associated with microstructural markers. Among well-functioning older adults, participating in VPA defined by heart rate reserve may predict less brain microstructural decline in memory-related areas.

Sensory function has been linked to cognitive impairment and dementia, but the link between multiple sensory impairments and early cognitive impairment (ECI) is unclear. Sensory function (vision, hearing, vestibular, proprioception, and olfaction) was measured in 390 BLSA participants (age=75±8 years; 57% women; 69% white) from 2012 to 2018 over a mean 3.6 years. ECI was defined based on 1 standard deviation below age-and race-specific means in Card Rotations or California Verbal Learning Test immediate recall. Cox proportional hazard models examined the risk of ECI for each sensory impairment and across categories of impairments. Vision impairment (vs. no vision impairment) was associated with a 70% greater risk of ECI (HR=1.70, p=0.05). Participants with 1 or ≥2 sensory impairments had triple the risk of ECI (HR=3.74 and 3.44, p=0.008 and 0.02, respectively) compared to those without impairment. Future studies are needed to examine whether treatment for sensory impairments can modify these risks.

Anemia has been associated with elevated cerebral blood flow (CBF) in animal models and certain clinical conditions (eg, renal disease), but whether hemoglobin level variations across a relatively normal range are associated with local or diffuse CBF changes is unclear. We investigated whether lower hemoglobin is associated with regional increases in relative CBF in older individuals, and if these increases occur in watershed regions.Seventy-four older nondemented adults underwent serial (15)O water positron emission tomography scans. Voxel-based analysis was used to investigate regional relative CBF patterns in association with hemoglobin level and in individuals with and without anemia. Analyses of cross-sectional relations between regional CBF and anemia were performed separately at two time points, 2 years apart, to identify replicable patterns of associations.Restricting results to associations replicated across two cross-sectional analyses, lower hemoglobin was associated with higher relative CBF within the middle/inferior frontal, occipital, precuneus, and cerebellar regions. In addition, individuals with anemia (n = 15) showed higher relative CBF in superior frontal, middle temporal, hippocampal, and gyrus rectus regions than those without anemia. In some regions (right superior temporal gyrus, left inferior frontal gyrus, midline cuneus, and right precuneus); however, lower hemoglobin was associated with lower relative CBF.In nondemented individuals, lower hemoglobin is associated with elevated relative CBF in specific cortical areas but reduced CBF in other areas. Whether this association between anemia and CBF in the absence of chronic diseases and in a normal physiologic range is related to clinical endpoints warrants further study.

Objective The role of neighborhood physical activity resources on childhood physical activity level is increasingly examined in pediatric obesity research. We describe how availability of physical activity resources varies by individual and block characteristics and then examine its associations with physical activity levels of Latino and black children in East Harlem, New York City. Methods Physical activity resource availability by individual and block characteristics were assessed in 324 children. Availability was measured against 4 physical activity measures: average weekly hours of outdoor unscheduled physical activity, average weekly metabolic hours of scheduled physical activity, daily hours of sedentary behavior, and daily steps. Results Physical activity resource availability differed by race/ethnicity, caregiver education, and income. Presence of one or more playgrounds on a child's block was positively associated with outdoor unscheduled physical activity (odds ratio [OR] = 1.95, 95% confidence interval [CI] 1.11–3.43). Presence of an after-school program on a child's block was associated with increased hours of scheduled physical activity (OR = 3.25, 95% CI 1.41–7.50) and decreased sedentary behavior (OR = 3.24, 95% CI 1.30–8.07). The more resources a child had available, the greater the level of outdoor unscheduled physical activity ( P for linear trend = .026). Conclusions Neighborhood physical activity resource availability differs by demographic factors, potentially placing certain groups at risk for low physical activity level. Availability of select physical activity resources was associated with reported physical activity levels of East Harlem children but not with objective measures of physical activity.

The current study investigated executive function measures emphasizing Alpha Span (ASp) to understand relationships among executive and nonexecutive tasks. Nondemented older participants (N = 417) received a comprehensive cognitive battery. Age and vocabulary adjusted correlations revealed associations among ASp, Wechsler Adult Intelligence Scale--Revised (D. Wechsler, 1981) Digit Span subtests, and fluency tasks. Principal-components analysis with varimax rotation revealed a 4 component solution (86.4% of the variance) with executive variables contributing to all loadings. Calculated component indices were submitted to a regression analysis predicting ASp performance. After accounting for age (6.3% of the variance), Component 3 reflecting brief attention-mental manipulation accounted for 13.4% of ASp variance; Component 1, verbal language ability, 11.5%; Component 2, sustained attention-mental tracking, 1.9%; and Component 4, visuoperceptual spatial organization-planning, 0.9%. Results stress the importance of considering executive and nonexecutive aspects of cognition when conceptualizing executive functioning.