Microglial Correlates of Late Life Physical Activity: Relationship with Synaptic and Cognitive Aging in Older Adults.

Physical activity relates to reduced dementia risk, but the cellular and molecular mechanisms are unknown. We translated animal and in vitro studies demonstrating a causal link between physical activity and microglial homeostasis into humans. Decedents from Rush Memory and Aging Project completed actigraphy monitoring (average daily activity) and cognitive evaluation in life, and neuropathological examination at autopsy. Brain tissue was analyzed for microglial activation via immunohistochemistry (anti-human HLA-DP-DQ-DR) and morphology (% Stage I, II, or III), and synaptic protein levels (SNAP-25, synaptophysin, complexin-I, VAMP, syntaxin, synaptotagmin-1). Proportion of morphologically activated microglia (PAM) was estimated in ventromedial caudate, posterior putamen, inferior temporal (IT), and middle frontal gyrus. The 167 decedents averaged 90 years at death, two-thirds were nondemented, and 60% evidenced pathologic Alzheimer's disease (AD). Adjusting for age, sex, education, and motor performances, greater physical activity associated with lower PAM in the ventromedial caudate and IT. Relationships between physical activity and PAM in the ventromedial caudate or IT were particularly prominent in adults evidencing microinfarcts or AD pathology, respectively. Mediational analyses indicated that PAM IT mediated ∼30% of the relationships between (1) physical activity and synaptic protein in IT, and (2) physical activity and global cognition, in separate models. However, the size of the mediation depended on AD pathology ranging from >40% in adults with high AD burden, but <10% in adults with low AD burden. Lower microglial activation may be a pathway linking physical activity to age-related brain health in humans. Physical activity may promote AD-related synaptic and cognitive resilience through reduction of pro-inflammatory microglial states.SIGNIFICANCE STATEMENT Physical activity relates to better cognitive aging and reduced risk of neurodegenerative disease, yet the cellular and molecular pathways linking behavior-to-brain in humans are unknown. Animal studies indicate that increasing physical activity leads to decreased microglial activation and corresponding increases in synaptogenesis and neurogenesis. We objectively monitored physical activity (accelerometer-based actigraphy) and cognitive performances in life, and quantified microglial activation and synaptic markers in brain tissue at death in older adults. These are the first data supporting microglial activation as a physiological pathway by which physical activity relates to brain heath in humans. Although more interventional work is needed, we suggest that physical activity may be a modifiable behavior leveraged to reduce pro-inflammatory microglial states in humans.

Regional Vulnerability of the Corpus Callosum in the Context of Cardiovascular Risk.

Many factors outside of cardiovascular health can impact the structure of white matter. Identification of reliable and clinically meaningful biomarkers of the neural effects of systemic and cardiovascular health are needed to refine etiologic predictions. We examined whether the corpus callosum demonstrates regional vulnerability to systemic cardiovascular risk factors. Three hundred and ninety-four older adults without dementia completed brain MRI, neurobehavioral evaluations, and blood draws. A subset (n = 126, n = 128) of individuals had blood plasma analyzed for inflammatory markers of interest (IL-6 and TNF-alpha). Considering diffusion tensor imaging (DTI) is a particularly reliable measure of white matter integrity, we utilized DTI to examine fractional anisotropy (FA) of anterior and posterior regions of the corpus callosum. Using multiple linear regression models, we simultaneously examined FA of the genu and the splenium to compare their associations with systemic and cardiovascular risk factors. Lower FA of the genu but not splenium was associated with greater systemic and cardiovascular risk, including higher systolic blood pressure (ß = -0.17, p = .020), hemoglobin A1C (ß = -0.21, p = .016) and IL-6 (ß = -0.34, p = .005). FA of the genu was uniquely associated with cognitive processing speed (ß = 0.20, p = .0015) and executive functioning (ß = 0.15, p = .012), but not memory performances (ß = 0.05, p = .357). Our results demonstrated differential vulnerability of the corpus callosum, such that frontal regions showed stronger, independent associations with biomarkers of systemic and cardiovascular health in comparison to posterior regions. Posterior white matter integrity may not reflect cardiovascular health. Clinically, these findings support the utility of examining the anterior corpus callosum as an indicator of cerebrovascular health.

Late-life physical activity relates to brain tissue synaptic integrity markers in older adults.

INTRODUCTION: Physical activity (PA) is widely recommended for age-related brain health, yet its neurobiology is not well understood. Animal models indicate PA is synaptogenic. We examined the relationship between PA and synaptic integrity markers in older adults. METHODS: Four hundred four decedents from the Rush Memory and Aging Project completed annual actigraphy monitoring (Mean visits = 3.5±2.4) and post mortem evaluation. Brain tissue was analyzed for presynaptic proteins (synaptophysin, synaptotagmin-1, vesicle-associated membrane proteins, syntaxin, complexin-I, and complexin-II), and neuropathology. Models examined relationships between late-life PA (averaged across visits), and timing-specific PA (time to autopsy) with synaptic proteins. RESULTS: Greater late-life PA associated with higher presynaptic protein levels (0.14 < ß < 0.20), except complexin-II (ß = 0.08). Relationships were independent of pathology but timing specific; participants who completed actigraphy within 2 years of brain tissue measurements showed largest PA-to-synaptic protein associations (0.32 < ß < 0.38). Relationships between PA and presynaptic proteins were comparable across brain regions sampled. DISCUSSION: PA associates with synaptic integrity in a regionally global, but time-linked nature in older adults.

Multimodal lifestyle engagement patterns support cognitive stability beyond neuropathological burden.

BACKGROUND: Modifiable lifestyle behaviors account for a large proportion of dementia risk. However, the combined contributions of multidomain lifestyle patterns to cognitive aging are poorly understood, as most studies have examined individual lifestyle behaviors in isolation and without neuropathological characterization. This study examined data-driven patterns of lifestyle behaviors across multiple domains among older adults and tested their associations with disease-specific neuropathological burden and cognitive decline. METHODS: Participants included 2059 older adults enrolled in the longitudinal Memory and Aging Project (MAP) at the Rush Alzheimer's Disease Center; none of whom had dementia at baseline (73% no cognitive impairment (NCI), 27% mild cognitive impairment [MCI]). All participants completed cognitive testing annually. Lifestyle factors were measured during at least one visit and included (1) actigraphy-measured physical activity, as well as self-reported (2) sleep quality, (3) life space, (4) cognitive activities, (5) social activities, and (6) social network. A subset of participants (n = 791) had autopsy data for which burden of Alzheimer's disease (AD), cerebrovascular disease (CVD), Lewy body disease, and hippocampal sclerosis/TDP-43 was measured. Latent profile analysis across all 2059 participants identified distinct subgroups (i.e., classes) of lifestyle patterns. Linear mixed-effects models examined relationships between lifestyle classes and global cognitive trajectories, with and without covarying for all neuropathologies. Classes were also compared on rates of incident MCI/dementia. RESULTS: Five classes were identified: Class 1Low Life Space (lowest lifestyle engagement), Class 2PA (high physical activity), Class 3Low Avg (low to average lifestyle engagement), Class 4Balanced (high average lifestyle engagement), and Class 5Social (large social network). Classes 4Balanced and 5Social had the lowest AD burden, and Class 2PA had the lowest CVD burden. Classes 2-5 had significantly less steep global cognitive decline compared to Class 1Low Life Space, with comparable effect sizes before and after covarying for neuropathological burden. Classes 4Balanced and 5Social exhibited the lowest rates of incident MCI/dementia. CONCLUSIONS: Lifestyle behavior patterns among older adults account for differential rates of cognitive decline and clinical progression. Those with at least average engagement across all lifestyle domains exhibit greater cognitive stability after adjustment for neuropathology, highlighting the importance of engagement in multiple healthy lifestyle behaviors for later life cognitive health.

Roles of physical activity and diet in cognitive aging: is more better?

Objective: To determine the synergistic effects of nutrition, specifically adherence to the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet, and physical activity on cognition and brain outcomes in a cross-sectional healthy aging cohort. Methods: A total of 132 adults (age range 52-91; Clinical Dementia Rating = 0) from the UCSF Brain Aging Project completed a 15-item MIND diet food frequency questionnaire and an 11-item self-report measure of weekly physical activity (Physical Activity Scale [PASE]). Cognitive outcomes included executive functioning, episodic memory, and language. Neuroimaging outcomes consisted of total grey matter volume and total white matter volume, adjusted for total intracranial volumes. All regression interaction models adjusted for age, sex, education, and a composite vascular burden score. Results: There was a significant interaction between PASE and MIND on executive functioning and total grey matter volume. Low levels of both related to disproportionately poorer cognitive and brain structural outcomes. Increasing levels of either, but not both, PASE or MIND related to better executive functioning and gray matter outcomes. For memory, language, and total white matter volume, the interaction between PASE and MIND showed the same directionality but did not reach statistical significance. Conclusions: Higher levels of physical activity associated with better executive functioning and gray matter volume, particularly when diet was poor. Similarly, higher levels of MIND diet adherence were associated with better brain and cognitive outcomes when physical activity was low. However, highest levels of physical activity and MIND diet together did not necessarily lead to disproportionately better cognitive and brain volume outcomes.

Moderating role of physical activity on hippocampal iron deposition and memory outcomes in typically aging older adults.

Physical activity (PA) is linked to better cognitive and brain health, though its mechanisms are unknown. While brain iron is essential for normal function, levels increase with age and, when excessive, can cause detrimental neural effects. We examined how objectively measured PA relates to cerebral iron deposition and memory functioning in normal older adults. Sixty-eight cognitively unimpaired older adults from the UCSF Memory and Aging Center completed neuropsychological testing and brain magnetic resonance imaging, followed by 30-day Fitbit monitoring. Magnetic resonance imaging quantitative susceptibility mapping (QSM) quantified iron deposition. PA was operationalized as average daily steps. Linear regression models examined memory as a function of hippocampal QSM, PA, and their interaction. Higher bilateral hippocampal iron deposition correlated with worse memory but was not strongly related to PA. Covarying for demographics, PA moderated the relationship between bilateral hippocampal iron deposition and memory such that the negative effect of hippocampal QSM on memory performances was no longer significant above 9120 daily steps. PA may mitigate adverse iron-related pathways for memory health.

Data-driven physical actigraphy patterns relate to cognitive and vascular health in older adults.

Health benefits of physical activity (PA) are well known; however, specific PA patterns that relate most strongly to cognitive aging outcomes are poorly understood. We characterized latent profiles of PA among older adults and examined associations with cognition and vascular burden. 124 functionally normal older adults wore a Fitbit™ for 30 days. Daily average step count, sedentary time (0 steps/min), and high-intensity time (≥120 steps/min) were calculated. Participants completed neurocognitive testing assessing cognitive domains of executive functioning and memory; medical history, from which vascular burden (i.e., a count of cardiovascular conditions) was calculated; and brain MRI (n = 44). Subgroups with similar PA patterns were identified via latent profile analysis. Three latent PA classes emerged: Class 1Low PA (n = 49), Class 2Average PA (n = 59), and Class 3High-intensity PA (n = 16). PA class related to executive functioning and vascular burden, driven by better outcomes in Class 3 than Class 1. Sex-stratified analyses revealed these associations were strongest in males. Post hoc analyses showed a positive association between high-intensity PA and white matter integrity among males. High-intensity PA related to better cognitive and vascular health, particularly among males. Findings inform physical activity-specific and person-specific recommendations for optimal cognitive aging.

Association of Physical Activity With Neurofilament Light Chain Trajectories in Autosomal Dominant Frontotemporal Lobar Degeneration Variant Carriers.

Importance: Physical activity is associated with cognitive health, even in autosomal dominant forms of dementia. Higher physical activity is associated with slowed cognitive and functional declines over time in adults carrying autosomal dominant variants for frontotemporal lobar degeneration (FTLD), but whether axonal degeneration is a potential neuroprotective target of physical activity in individuals with FTLD is unknown. Objective: To examine the association between physical activity and longitudinal neurofilament light chain (NfL) trajectories in individuals with autosomal dominant forms of FTLD. Design, Setting, and Participants: This cohort study included individuals from the ALLFTD Consortium, which recruited patients from sites in the US and Canada. Symptomatic and asymptomatic adults with pathogenic variants in one of 3 common genes associated with FTLD (GRN, C9orf72, or MAPT) who reported baseline physical activity levels and completed annual blood draws were assessed annually for up to 4 years. Genotype, clinical measures, and blood draws were collected between December 2014 and June 2019; data were analyzed from August 2021 to January 2022. Associations between reported baseline physical activity and longitudinal plasma NfL changes were assessed using generalized linear mixed-effects models adjusting for baseline age, sex, education, functional severity, and motor symptoms. Exposures: Baseline physical activity levels reported via the Physical Activity Scale for the Elderly. To estimate effect sizes, marginal means were calculated at 3 levels of physical activity: 1 SD above the mean represented high physical activity, 0 SD represented average physical activity, and 1 SD below the mean represented low physical activity. Main Outcomes and Measures: Annual plasma NfL concentrations were measured with single-molecule array technology. Results: Of 160 included FTLD variant carriers, 84 (52.5%) were female, and the mean (SD) age was 50.7 (14.7) years. A total of 51 (31.8%) were symptomatic, and 77 carried the C9orf72 variant; 39, GRN variant; and 44, MAPT variant. Higher baseline physical activity was associated with slower NfL trajectories over time. On average, NfL increased 45.8% (95% CI, 22.5 to 73.7) over 4 years in variant carriers. Variant carriers with high physical activity demonstrated 14.0% (95% CI, -22.7 to -4.3) slower NfL increases compared with those with average physical activity and 30% (95% CI, -52.2 to -8.8) slower NfL increases compared with those with low physical activity. Within genotype, C9orf72 and MAPT carriers with high physical activity evidenced 18% to 21% (95% CI, -43.4 to -7.2) attenuation in NfL, while the association between physical activity and NfL trajectory was not statistically significant in GRN carriers. Activities associated with higher cardiorespiratory and cognitive demands (sports, housework, and yardwork) were most strongly correlated with slower NfL trajectories (vs walking and strength training). Conclusions and Relevance: In this study, higher reported physical activity was associated with slower progression of an axonal degeneration marker in individuals with autosomal dominant FTLD. Physical activity may serve as a primary prevention target in FTLD.

Physical activity measurement in older adults: Wearables versus self-report.

Physical activity (PA) is associated with preserved age-related body and brain health. However, PA quantification can vary. Commercial-grade wearable monitors are objective, low burden tools to capture PA but are less well validated in older adults. Self-report PA questionnaires are widely accepted and more frequently used but carry inherent limitations. We aimed to compare these commonly used PA measures against one another and examine their convergent validity with a host of relevant outcomes. We also examined the factors that drive differences in PA self-reporting styles in older adults. 179 older adults completed 30-day Fitbit Flex2™ monitoring and reported PA levels via two widely used PA questionnaires: PASE and CHAMPS-METs (metabolic expenditure calories burned). Participants also completed measures of cardiometabolic (hypertension diagnosis, resting heart rate, A1C levels), cognitive (memory, processing speed, executive functioning), and brain MRI (medial temporal lobe volume) outcomes. The discrepancy between objective Fitbit monitoring and self-reported PA was evaluated using a sample-based z difference score. There were only modest relationships across all PA metrics. Fitbit step count demonstrated a stronger association with the PASE, whereas Fitbit calories burned was more strongly associated with CHAMPS-MET. Fitbit outcomes had more consistent convergence with relevant outcomes of interest (e.g., cardiometabolic and brain health indices) when compared to subjective measures; however, considerable heterogeneity within these associations was observed. A higher degree of overreporting was associated with worse memory and executive performances, as well as hypertension diagnoses. We build on prior findings that wearable, digital health indicators of PA demonstrate greater construct validity than self-report in older adults. We further show important clinical features (e.g., poorer cognitive status) of older adults that could contribute to a higher level of overreporting on self-report measures. Characterization of what PA measures truly operationalize will help elucidate relationships between most relevant facets of PA and outcomes of interest.

Wearable Use in an Observational Study Among Older Adults: Adherence, Feasibility, and Effects of Clinicodemographic Factors.

Introduction: Wearables have great potential to improve monitoring and delivery of physical activity interventions to older adults with downstream benefits to multisystem health and longevity; however, benefits obtained from wearables depend on their uptake and usage. Few studies have examined person-specific factors that relate to wearable adherence. We characterized adherence to using a wearable activity tracker for 30 days and examined associations between adherence and demographics, cognitive functioning, brain volumes, and technology familiarity among community-dwelling older adults. Methods: Participants were 175 older adults enrolled in the UCSF Longitudinal Brain Aging Study who were asked to wear a FitbitTM Flex 2 during waking hours for 30 days. Sixty two of these participants were also asked to sync their devices to the Fitbit smartphone app daily to collect minute-level data. We calculated adherence to wearing the Fitbit daily (i.e., proportion of days with valid activity data) and adherence to daily device syncing (i.e., proportion of days with minute-level activity data). Participants also completed a brain MRI and in-person cognitive testing measuring memory, executive functioning, and processing speed. Spearman correlations, Wilcoxon rank sum tests, and logistic regression tested relationships between wearable adherence and clinicodemographic factors. Results: Participants wore the Fitbits for an average of 95% of study days and were 85% adherent to the daily syncing protocol. Greater adherence to wearing the device was related to female sex. Greater adherence to daily device syncing was related to better memory, independent of demographic factors. Wearable adherence was not significantly related to age, education, executive functioning, processing speed, brain gray matter volumes, or self-reported familiarity with technology. Participants reported little-to-no difficulty using the wearable and all reported willingness to participate in another wearable study in the future. Conclusions: Older adults have overall high adherence to wearable use in the current study protocol. Person-specific factors, however, may represent potential barriers to equitable uptake of wearables for physical activity among older adults, including demographics and cognitive functioning. Future studies and clinical providers utilizing wearable activity trackers with older adults may benefit from implementation of reminders (e.g., texts, calls) for device use, particularly among men and individuals with memory impairment.