A blood-based marker of mitochondrial DNA damage in Parkinson's disease.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder, and neuroprotective or disease-modifying interventions remain elusive. High-throughput markers aimed at stratifying patients on the basis of shared etiology are required to ensure the success of disease-modifying therapies in clinical trials. Mitochondrial dysfunction plays a prominent role in the pathogenesis of PD. Previously, we found brain region-specific accumulation of mitochondrial DNA (mtDNA) damage in PD neuronal culture and animal models, as well as in human PD postmortem brain tissue. To investigate mtDNA damage as a potential blood-based marker for PD, we describe herein a PCR-based assay (Mito DNADX) that allows for the accurate real-time quantification of mtDNA damage in a scalable platform. We found that mtDNA damage was increased in peripheral blood mononuclear cells derived from patients with idiopathic PD and those harboring the PD-associated leucine-rich repeat kinase 2 (LRRK2) G2019S mutation in comparison with age-matched controls. In addition, mtDNA damage was elevated in non-disease-manifesting LRRK2 mutation carriers, demonstrating that mtDNA damage can occur irrespective of a PD diagnosis. We further established that Lrrk2 G2019S knock-in mice displayed increased mtDNA damage, whereas Lrrk2 knockout mice showed fewer mtDNA lesions in the ventral midbrain, compared with wild-type control mice. Furthermore, a small-molecule kinase inhibitor of LRRK2 mitigated mtDNA damage in a rotenone PD rat midbrain neuron model and in idiopathic PD patient-derived lymphoblastoid cell lines. Quantifying mtDNA damage using the Mito DNADX assay may have utility as a candidate marker of PD and for measuring the pharmacodynamic response to LRRK2 kinase inhibitors.

Novel automaticity index reveals a cognitive ability-related decline in gait automaticity during dual-task walking.

Gait automaticity refers to the ability to walk with minimal recruitment of attentional networks typically mediated through the prefrontal cortex (PFC). Reduced gait automaticity is common with aging, contributing to an increased risk of falls and reduced quality of life. A common assessment of gait automaticity involves examining PFC activation using near-infrared spectroscopy (fNIRS) during dual-task (DT) paradigms, such as walking while performing a cognitive task. However, neither PFC activity nor task performance in isolation measures automaticity accurately. For example, greater PFC activation could be interpreted as worse gait automaticity when accompanied by poorer DT performance, but when accompanied by better DT performance, it could be seen as successful compensation. Thus, there is a need to incorporate behavioral performance and PFC measurements for a more comprehensive evaluation of gait automaticity. To address this need, we propose a novel automaticity index as an analytical approach that combines changes in PFC activity with changes in DT performance to quantify gait automaticity. We validated the index in 173 participants (≥65 y/o) who completed DTs with two levels of difficulty while PFC activation was recorded with fNIRS. The two DTs consisted of reciting every other letter of the alphabet while walking over either an even or uneven surface. We found that as DT difficulty increases, more participants showed the anticipated decrease in automaticity as measured by the novel index compared to PFC activation. Furthermore, when comparing across individuals, lower cognitive function related to worse automaticity index, but not PFC activation or DT performance. In sum, the proposed index better quantified the differences in automaticity between tasks and individuals by providing a unified measure of gait automaticity that includes both brain activation and performance. This new approach opens exciting possibilities to assess participant-specific deficits and compare rehabilitation outcomes from gait automaticity interventions.

Design of the think PHRESH longitudinal cohort study: Neighborhood disadvantage, cognitive aging, and alzheimer's disease risk in disinvested, black neighborhoods.

BACKGROUND: Black Americans have disproportionately higher rates and earlier onset of Alzheimer's disease and related dementias (ADRD) relative to White Americans. We currently lack a comprehensive understanding of how the lived experience and broader societal factors, including cumulative exposure to structural racism and the mechanisms underlying the risks, may contribute to elevated ADRD risk in Black Americans. METHODS: The Think PHRESH study builds on existing, community-based research infrastructure, from the ongoing Pittsburgh Hill/Homewood Research on Neighborhood Change and Health (PHRESH) studies, to examine the contributions of dynamic neighborhood socioeconomic conditions across the lifecourse to cognitive outcomes in mid- and late-life adults living in two historically disinvested, predominantly Black communities (anticipated n = 1133). This longitudinal, mixed-methods study rests on the premise that neighborhood racial segregation and subsequent disinvestment contributes to poor cognitive outcomes via factors including (a) low access to educational opportunities and (b) high exposure to race- and socioeconomically-relevant stressors, such as discrimination, trauma, and adverse childhood events. In turn, these cumulative exposures foster psychological vigilance in residents, leading to cardiometabolic dysregulation and sleep disruption, which may mediate associations between neighborhood disadvantage and ADRD risk. This premise recognizes the importance of potential protective factors that may promote cognitive health, including neighborhood social cohesion, safety, and satisfaction. The proposed study will leverage our existing longitudinal data on risk/protective factors and biobehavioral mediators and will include: (1) up to three waves of cognitive assessments in participants ages 50 years + and one assessment in participants ages 35-49 years; clinical adjudication of ADRD will be completed in participants who are 50+, (2) extensive surveys of risk and protective factors, (3) two assessments of blood pressure and objectively measured sleep, (4) a comprehensive assessment of life and residential history; and (5) two rounds of in-depth qualitative interviews to reveal lifecourse opportunities and barriers experienced by Black Americans in achieving optimal cognitive health in late life. DISCUSSION: Understanding how structural racism has influenced the lived experience of Black Americans, including dynamic changes in neighborhood conditions over time, is critical to inform multi-level intervention and policy efforts to reduce pervasive racial and socioeconomic disparities in ADRD.

The role of social support on cognitive function among midlife and older adult MSM.

OBJECTIVE: This study examines the association between social support and cognitive function among midlife and older MSM living with or without HIV. DESIGN: We analyzed longitudinal data from participants enrolled from October 2016 to March 2019 in the Patterns of Healthy Aging Study, a substudy of the Multicenter AIDS Cohort Study. METHODS: We conducted a cross-sectional analysis to estimate the association between social support and three measures of cognitive function [Trail Making Test (TMT) Part A, TMT Part B to A ratio, and Symbol Digit Modalities Tasks (SDMT)]. We also used linear mixed-effects models to estimate the association between baseline social support and cognitive function across four subsequent time points. We evaluated a multiplicative interaction term between baseline social support and time, in order to determine whether cognitive trajectories over time vary by baseline social support. RESULTS: Social support was associated with lower TMT Part A scores at baseline and over the subsequent 2 years, indicating better psychomotor ability. Social support was associated with higher SDMT scores at baseline and across 2 years, indicating better information processing. We observed no association between social support and TMT B to A ratio at baseline or across 2 years, indicating no effect on set-shifting ability. Longitudinal cognition outcome trajectories did not vary by the level of baseline social support. CONCLUSION: Social support and cognitive function were associated in this sample over a short time period. Further research should explore causal relationships over the lifespan.

Examining the Cross-sectional Association Between Neighborhood Conditions, Discrimination, and Telomere Length in a Predominantly African American Sample.

Disproportionate exposure to adverse neighborhood conditions and greater discrimination may contribute to health disparities among African Americans (AAs). We examined whether adverse neighborhood conditions, alone or in conjunction with discrimination, associate with shorter leukocyte telomere length among a predominantly AA cohort. The sample included 200 residents from two low-income neighborhoods (96% AA; mean age = 67 years). Perceived neighborhood conditions and discrimination were surveyed in 2018, and objective neighborhood conditions (total crime rate, neighborhood walkability, ambient air pollution (PM2.5, black carbon)) were collected in 2017/2018. Relative telomere length (T/S; ratio of telomeric DNA to a single-gene copy) was assessed from blood samples. Linear regression models estimated the main effects of each neighborhood condition and discrimination and their interactions on the T/S ratio. Less walkable neighborhoods were associated with shorter telomeres. Higher air pollution (PM2.5) was associated with shorter telomeres among those experiencing greater discrimination. Findings highlight the importance of understanding the intersecting influences of historic and contemporary sources of systemic racism and how they contribute to accelerated aging among adults.

Novel attentional gait index reveals a cognitive ability-related decline in gait automaticity during dual-task walking.

Introduction: Gait automaticity refers to the ability to walk with minimal recruitment of attentional networks typically mediated through the prefrontal cortex (PFC). Reduced gait automaticity (i.e., greater use of attentional resources during walking) is common with aging, contributing to an increased risk of falls and reduced quality of life. A common assessment of gait automaticity involves examining PFC activation using near-infrared spectroscopy (fNIRS) during dual-task (DT) paradigms, such as walking while performing a cognitive task. However, neither PFC activity nor task performance in isolation measures automaticity accurately. For example, greater PFC activation could be interpreted as worse gait automaticity when accompanied by poorer DT performance, but when accompanied by better DT performance, it could be seen as successful compensation. Thus, there is a need to incorporate behavioral performance and PFC measurements for a more comprehensive evaluation of gait automaticity. To address this need, we propose a novel attentional gait index as an analytical approach that combines changes in PFC activity with changes in DT performance to quantify automaticity, where a reduction in automaticity will be reflected as an increased need for attentional gait control (i.e., larger index). Methods: The index was validated in 173 participants (≥65 y/o) who completed DTs with two levels of difficulty while PFC activation was recorded with fNIRS. The two DTs consisted of reciting every other letter of the alphabet while walking over either an even or uneven surface. Results: As DT difficulty increases, more participants showed the anticipated increase in the attentional control of gait (i.e., less automaticity) as measured by the novel index compared to PFC activation. Furthermore, when comparing across individuals, lower cognitive function was related to higher attentional gait index, but not PFC activation or DT performance. Conclusion: The proposed index better quantified the differences in attentional control of gait between tasks and individuals by providing a unified measure that includes both brain activation and performance. This new approach opens exciting possibilities to assess participant-specific deficits and compare rehabilitation outcomes from gait automaticity interventions.

Higher Soluble CD163 in Blood Is Associated With Significant Depression Symptoms in Men With HIV.

BACKGROUND: People with HIV (PWH) are more likely to experience depression, a highly morbid disease. More evidence is needed to better understand mechanisms of depression in PWH. We evaluated a panel of blood biomarkers in relation to depression symptoms in the Multicenter AIDS Cohort Study (MACS). SETTING: Four sites in the United States. METHODS: A cross-sectional analysis was performed within the MACS, a prospective study of cisgender men with and without HIV. Depression was assessed with the Center for Epidemiological Studies-Depression Scale, and six blood biomarkers were measured: GlycA, high sensitivity C-reactive protein (CRP), interleukin-6, CCL2, soluble CD14 (sCD14), and soluble CD163 (sCD163). Using univariable and multivariable logistic regression, the biomarkers and other factors were evaluated in relation to significant depression symptoms (SDS) by Center for Epidemiological Studies-Depression score ≥16. RESULTS: 784 men were analyzed; most of whom (63%) were PWH. PWH were more likely to have SDS (32% vs. 21%). In univariable analysis, higher GlycA, CRP, and sCD163 concentrations were associated with SDS. In multivariable analysis, however, only higher sCD163 concentration was associated with SDS (odds ratio = 2.30, 95% CI = 1.11 to 4.76). This relationship was driven by the PWH group (odds ratio = 2.72, 95% CI = 1.12 to 6.58) and remained significant when controlling for antidepressant use. Lack of college education was also associated with SDS. CONCLUSIONS: Higher sCD163, a marker of macrophage activation, was significantly associated with significant depression symptoms in the MACS. Further research on this biomarker and macrophage activation in general is warranted to better understand and treat depression in PWH.

Clinical Progression of Baseline Risk States for Mild Cognitive Impairment.

BACKGROUND: This memory-clinic study joins efforts to study earliest clinical signs and symptoms of Alzheimer's disease and related dementias: subjective reports and objective neuropsychological test performance. OBJECTIVE: The memory-clinic denoted two clinical "grey zones": 1) subjective cognitive decline (SCD; n = 107) with normal objective test scores, and 2) isolated low test scores (ILTS; n = 74) without subjective complaints to observe risk for future decline. METHODS: Initial and annual follow-up clinical research evaluations and consensus diagnosis were used to evaluate baseline characteristics and clinical progression over 2.7 years, compared to normal controls (NC; n = 117). RESULTS: The ILTS group was on average older than the NC and SCD groups. They had a higher proportion of people identifying as belonging to a minoritized racial group. The SCD group had significantly more years of education than the ILTS group. Both ILTS and SCD groups had increased risk of progression to mild cognitive impairment. Older age, minoritized racial identity, and baseline cognitive classification were risk factors for progression. CONCLUSION: The two baseline risk groups look different from each other, especially with respect to demographic correlates, but both groups predict faster progression than controls, over and above demographic differences. Varied presentations of early risk are important to recognize and may advance cognitive health equity in aging.

Sleep Disturbances, Changes in Sleep, and Cognitive Function in Low-Income African Americans.

BACKGROUND: Sleep problems may contribute to the disproportionate burden of Alzheimer's disease and related dementias (ADRD) among African Americans (AAs). OBJECTIVE: To examine the role of sleep problems in contributing to cognitive function and clinically adjudicated cognitive impairment in a predominantly AA sample. METHODS: This study (n = 216, 78.8% female; mean age = 67.7 years) examined associations between 1) the level (i.e., measured in 2018) and 2) change over time (from 2013 to 2018; n = 168) in actigraphy-assessed sleep with domain-specific cognitive function and clinically adjudicated cognitive impairment (2018) in a community-dwelling, predominantly AA (96.9%) sample. A comprehensive cognitive battery assessed global cognitive function (3MS) and domain-specific cognitive function (attention, visuo-spatial ability, language, delayed recall, immediate recall, and executive function) in 2018. Sleep was measured in 2013 and 2018 via actigraphy. RESULTS: Higher sleep efficiency and less wakefulness after sleep onset (WASO; measured in 2018) were associated with greater attention, executive function, and visuospatial ability. Increases in sleep efficiency between 2013 and 2018 were associated with better executive function, language, immediate recall, and visuospatial ability, whereas increases in WASO (2013-2018) were associated with poorer attention, executive function, and visuospatial ability. Level or change in sleep duration were not associated with domain-specific cognitive function, nor were any sleep measures associated with clinically adjudicated cognitive impairment. CONCLUSION: In a predominantly AA sample of older adults, both the level and change (i.e., worsening) of sleep efficiency and WASO were associated with poorer cognitive function. Improving sleep health may support ADRD prevention and reduce health disparities.

Diagnostic Precision in the Detection of Mild Cognitive Impairment: A Comparison of Two Approaches.

OBJECTIVE: This study compared diagnostic rates and clinical predictors of discrepancies between diagnoses conferred via: 1) a comprehensive neuropsychological evaluation and National Institute on Aging-Alzheimer's Association (NIA-AA) criteria versus 2) a cognitive screener and Diagnostic Statistical Manual of Mental Disorders (DSM-5) criteria. DESIGN: Cross-sectional examination of baseline data from the Prevention of Alzheimer's dementia (AD) using Cognitive remediation and transcranial direct current stimulation in Mild Cognitive Impairment (MCI) and Depression (PACt-MD; ClinicalTrials.gov Identifier: NCT02386670) trial. SETTING: Five geriatric psychiatry and memory clinics located at academic hospitals affiliated with the Department of Psychiatry, University of Toronto. PARTICIPANTS: Older adults (N = 431) with a history of major depressive disorder (MDD) in remission, MCI, or both. MEASUREMENTS: Main outcome was a comparison of NIA-AA diagnostic rates of MCI or dementia versus DSM-5 rates of mild or major neurocognitive disorder. Secondary analyses examined demographic, race, gender, premorbid intellectual ability, psychosocial, health-related, and genetic predictors of discrepancy between DSM-5 and NIA-AA diagnoses. RESULTS: There were 103 (23.8%) discrepant cases, with most (91; 88.3%) of these discrepant cases reflecting more impairment with the detailed neuropsychological testing and NIA-AA criteria. Discrepancies were more likely in individuals with a history of MDD or who had at least one ApoE4 allele. CONCLUSION: The NIA-AA criteria, in conjunction with comprehensive neuropsychological testing, identified a greater prevalence of cognitive impairment than DSM-5 criteria, in conjunction with the Montreal Cognitive Assessment. Detailed neuropsychological evaluations are recommended for older adults who have a history of MDD or a genetic vulnerability to dementia.

Sedentary Time is Associated with Worse Attention in Parkinson's Disease: A Pilot Study.

OBJECTIVE: Cognitive symptoms of Parkinson's disease (PD) may be alleviated by moderate-to-vigorous physical activity (MVPA), but no published research has characterized the relationship between objectively measured sedentary behavior and cognitive symptoms of PD. Therefore, the objective of this study was to assess the cross-sectional relationship between sedentary time and cognitive performance in a small pilot sample of individuals with mild-to-moderate PD. METHODS: Objective measures of sedentary time were obtained using an armband accelerometer. Cognition was assessed with the Parkinson's Disease Cognitive Rating Scale and a computerized task-switching paradigm. RESULTS: The percentage of awake time spent in sedentary activities was negatively correlated with attention (ß = -14.20, t(12) = -2.47, p = 0.03) but not other cognitive domains (p > 0.05) after controlling for MVPA and medication dosage. CONCLUSION: Sedentary activity may have unique associations with cognition, particularly attention, over and above MVPA in individuals with PD.

Investigating Gains in Neurocognition in an Intervention Trial of Exercise (IGNITE): Protocol.

Despite the ubiquity of normal age-related cognitive decline there is an absence of effective approaches for improving neurocognitive health. Fortunately, moderate intensity exercise is a promising method for improving brain and cognitive health in late life, but its effectiveness remains a matter of skepticism and debate because of the absence of large, comprehensive, Phase III clinical trials. Here we describe the protocol for such a randomized clinical trial called IGNITE (Investigating Gains in Neurocognition in an Intervention Trial of Exercise), a study capable of more definitively addressing whether exercise influences cognitive and brain health in cognitively normal older adults. We are conducting a 12-month, multi-site, randomized dose-response exercise trial in 639 cognitively normal adults between 65 and 80 years of age. Participants are randomized to (1) a moderate intensity aerobic exercise condition of 150 min/week (N = 213), (2) a moderate intensity aerobic exercise condition at 225 min/week (N = 213), or (3) a light intensity stretching-and-toning control condition for 150 min/week (N = 213). Participants are engaging in 3 days/week of supervised exercise and two more days per week of unsupervised exercise for 12 months. A comprehensive cognitive battery, blood biomarkers and battery of psychosocial questionnaires is assessed at baseline, 6 and 12-months. In addition, brain magnetic resonance imaging, physiological biomarkers, cardiorespiratory fitness, physical function, and positron emission tomography of amyloid deposition are assessed at baseline and at the 12-month follow-up. The results from this trial could transform scientific-based policy and health care recommendations for approaches to improve cognitive function in cognitively normal older adults.

Body-Brain Connections: The Effects of Obesity and Behavioral Interventions on Neurocognitive Aging.

Obesity is a growing public health problem in the United States, particularly in middle-aged and older adults. Although the key factors leading to a population increase in body weight are still under investigation, there is evidence that certain behavioral interventions can mitigate the negative cognitive and brain ("neurocognitive") health consequences of obesity. The two primary behaviors most often targeted for weight loss are caloric intake and physical activity. These behaviors might have independent, as well as overlapping/synergistic effects on neurocognitive health. To date obesity is often described independently from behavioral interventions in regards to neurocognitive outcomes, yet there is conceptual and mechanistic overlap between these constructs. This review summarizes evidence linking obesity and modifiable behaviors, such as physical activity and diet, with brain morphology (e.g., gray and white matter volume and integrity), brain function (e.g., functional activation and connectivity), and cognitive function across the adult lifespan. In particular, we review evidence bearing on the following question: Are associations between obesity and brain health in aging adults modifiable by behavioral interventions?

Exercise Mode Moderates the Relationship Between Mobility and Basal Ganglia Volume in Healthy Older Adults.

OBJECTIVES: To examine whether 12 months of aerobic training (AT) moderated the relationship between change in mobility and change in basal ganglia volume than balance and toning (BAT) exercises in older adults. DESIGN: Secondary analysis of a randomized controlled trial. SETTING: Champaign-Urbana, Illinois. PARTICIPANTS: Community-dwelling older adults (N=101; mean age 66.4). INTERVENTION: Twelve-month exercise trial with two groups: AT and BAT. MEASUREMENTS: Mobility was assessed using the Timed Up and Go test. Basal ganglia (putamen, caudate nucleus, pallidum) was segmented from T1-weighted magnetic resonance images using the Oxford Centre for Functional Magnetic Resonance Imaging of the Brain Software Library Integrated Registration and Segmentation Tool. Measurements were obtained at baseline and trial completion. Hierarchical multiple regression was conducted to examine whether exercise mode moderates the relationship between change in mobility and change in basal ganglia volume over 12 months. Age, sex, and education were included as covariates. RESULTS: Exercise significantly moderated the relationship between change in mobility and change in left putamen volume. Specifically, for the AT group, volume of the left putamen did not change, regardless of change in mobility. Similarly, in the BAT group, those who improved their mobility most over 12 months had no change in left putamen volume, although left putamen volume of those who declined in mobility levels decreased significantly. CONCLUSION: The primary finding that older adults who engaged in 12 months of BAT training and improved mobility exhibited maintenance of brain volume in an important region responsible for motor control provides compelling evidence that such exercises can contribute to the promotion of functional independence and healthy aging.

Genetic Risk Score Predicts Late-Life Cognitive Impairment.

Introduction. A family history of Alzheimer's disease is a significant risk factor for its onset, but the genetic risk associated with possessing multiple risk alleles is still poorly understood. Methods. In a sample of 95 older adults (Mean age = 75.1, 64.2% female), we constructed a genetic risk score based on the accumulation of risk alleles in BDNF, COMT, and APOE. A neuropsychological evaluation and consensus determined cognitive status (44 nonimpaired, 51 impaired). Logistic regression was performed to determine whether the genetic risk score predicted cognitive impairment above and beyond that associated with each gene. Results. An increased genetic risk score was associated with a nearly 4-fold increased risk of cognitive impairment (OR = 3.824, P = .013) when including the individual gene polymorphisms as covariates in the model. Discussion. A risk score combining multiple genetic influences may be more useful in predicting late-life cognitive impairment than individual polymorphisms.

Education mitigates age-related decline in N-Acetylaspartate levels.

BACKGROUND: Greater educational attainment is associated with better neurocognitive health in older adults and is thought to reflect a measure of cognitive reserve. In vivo neuroimaging tools have begun to identify the brain systems and networks potentially responsible for reserve. METHODS: We examined the relationship between education, a commonly used proxy for cognitive reserve, and N-acetylaspartate (NAA) in neurologically healthy older adults (N=135; mean age=66 years). Using single voxel MR spectroscopy, we predicted that higher levels of education would moderate an age-related decline in NAA in the frontal cortex. RESULTS: After controlling for the variance associated with cardiorespiratory fitness, sex, annual income, and creatine levels, there were no significant main effects of education (B=0.016, P=0.787) or age (B=-0.058, P=0.204) on NAA levels. However, consistent with our predictions, there was a significant education X age interaction such that more years of education offset an age-related decline in NAA (B=0.025, P=0.031). When examining working memory via the backwards digit span task, longer span length was associated with greater education (P<0.01) and showed a trend with greater NAA concentrations (P<0.06); however, there was no age X education interaction on digit span performance nor a significant moderated mediation effect between age, education, and NAA on digit span performance. CONCLUSIONS: Taken together, these results suggest that higher levels of education may attenuate an age-related reduction in neuronal viability in the frontal cortex.

Physical activity, fitness, and gray matter volume.

In this review, we explore the association among physical activity, cardiorespiratory fitness, and exercise on gray matter volume in older adults. We conclude that higher cardiorespiratory fitness levels are routinely associated with greater gray matter volume in the prefrontal cortex and hippocampus and less consistently in other regions. We also conclude that physical activity is associated with greater gray matter volume in the same regions that are associated with cardiorespiratory fitness including the prefrontal cortex and hippocampus. Some heterogeneity in the literature may be explained by effect moderation by age, stress, or other factors. Finally, we report promising results from randomized exercise interventions that suggest that the volume of the hippocampus and prefrontal cortex remain pliable and responsive to moderate intensity exercise for 6 months-1 year. Physical activity appears to be a propitious method for influencing gray matter volume in late adulthood, but additional well-controlled studies are necessary to inform public policies about the potential protective or therapeutic effects of exercise on brain volume.

The brain-derived neurotrophic factor Val66Met polymorphism moderates an effect of physical activity on working memory performance.

Physical activity enhances cognitive performance, yet individual variability in its effectiveness limits its widespread therapeutic application. Genetic differences might be one source of this variation. For example, carriers of the methionine-specifying (Met) allele of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism have reduced secretion of BDNF and poorer memory, yet physical activity increases BDNF levels. To determine whether the BDNF polymorphism moderated an association of physical activity with cognitive functioning among 1,032 midlife volunteers (mean age = 44.59 years), we evaluated participants' performance on a battery of tests assessing memory, learning, and executive processes, and evaluated their physical activity with the Paffenbarger Physical Activity Questionnaire. BDNF genotype interacted robustly with physical activity to affect working memory, but not other areas of cognitive functioning. In particular, greater levels of physical activity offset a deleterious effect of the Met allele on working memory performance. These findings suggest that physical activity can modulate domain-specific genetic (BDNF) effects on cognition.

Physical activity, brain plasticity, and Alzheimer's disease.

In this review we summarize the epidemiological, cross-sectional, and interventional studies examining the association between physical activity and brain volume, function, and risk for Alzheimer's disease. The epidemiological literature provides compelling evidence that greater amounts of physical activity are associated with a reduced risk of dementia in late life. In addition, randomized interventions using neuroimaging tools have reported that participation in physical activity increases the size of prefrontal and hippocampal brain areas, which may lead to a reduction in memory impairments. Consistent with these findings, longitudinal studies using neuroimaging tools also find that the volume of prefrontal and hippocampal brain areas are larger in individuals who engaged in more physical activity earlier in life. We conclude from this review that there is convincing evidence that physical activity has a consistent and robust association with brain regions implicated in age-related cognitive decline and Alzheimer's disease. In addition to summarizing this literature we provide recommendations for future research on physical activity and brain health.