Cognitive Aging and the Promise of Physical Activity.

Is the field of cognitive aging irretrievably concerned with decline and deficits, or is it shifting to emphasize the hope of preservation and enhancement of cognitive function in late life? A fragment of an answer comes from research attempting to understand the reasons for individual variability in the extent and rate of cognitive decline. This body of work has created a sense of optimism based on evidence that there are some health behaviors that amplify cognitive performance or mitigate the rate of age-related cognitive decline. In this context, we discuss the role of physical activity on neurocognitive function in late adulthood and summarize how it can be conceptualized as a constructive approach both for the maintenance of cognitive function and as a therapeutic for enhancing or optimizing cognitive function in late life. In this way, physical activity research can be used to shape perceptions of cognitive aging.

Aerobic exercise, cardiorespiratory fitness, and the human hippocampus.

The hippocampus is particularly susceptible to neurodegeneration. Physical activity, specifically increasing cardiorespiratory fitness via aerobic exercise, shows promise as a potential method for mitigating hippocampal decline in humans. Numerous studies have now investigated associations between the structure and function of the hippocampus and engagement in physical activity. Still, there remains continued debate and confusion about the relationship between physical activity and the human hippocampus. In this review, we describe the current state of the physical activity and exercise literature as it pertains to the structure and function of the human hippocampus, focusing on four magnetic resonance imaging measures: volume, diffusion tensor imaging, resting-state functional connectivity, and perfusion. We conclude that, despite significant heterogeneity in study methods, populations of interest, and scope, there are consistent positive findings, suggesting a promising role for physical activity in promoting hippocampal structure and function throughout the lifespan.

Exercise interventions preserve hippocampal volume: A meta-analysis.

Hippocampal volume is a marker of brain health and is reduced with aging and neurological disease. Exercise may be effective at increasing and preserving hippocampal volume, potentially serving as a treatment for conditions associated with hippocampal atrophy (e.g., dementia). This meta-analysis aimed to identify whether exercise training has a positive effect on hippocampal volume and how population characteristics and exercise parameters moderate this effect. Studies met the following criteria: (a) controlled trials; (b) interventions of physical exercise; (c) included at least one time-point of hippocampal volume data before the intervention and one after; (d) assessed hippocampal volume using either manual or automated segmentation algorithms. Animal studies, voxel-based morphometry analyses, and multi-modal interventions (e.g., cognitive training or meditation) were excluded. The primary analysis in n = 23 interventions from 22 published studies revealed a significant positive effect of exercise on total hippocampal volume. The overall effect was significant in older samples (65 years of age or older) and in interventions that lasted over 24 weeks and had less than 150 min per week of exercise. These findings suggest that moderate amounts of exercise for interventions greater than 6 months have a positive effect on hippocampal volume including in older populations vulnerable to hippocampal atrophy.

Physical fitness, hippocampal functional connectivity and academic performance in children with overweight/obesity: The ActiveBrains project.

OBJECTIVES: Physical fitness is a modifiable factor associated with enhanced brain health during childhood. To our knowledge, the present study is the first to examine: (i) whether physical fitness components (i.e., cardiorespiratory, motor and muscular fitness) are associated with resting state functional connectivity of hippocampal seeds to different cortical regions in children with overweight/obesity, and (ii) whether resting state hippocampal functional connectivity is coupled with better academic performance. PATIENTS AND METHODS: In this cross-sectional study, a total of 99 children with overweight/obesity aged 8-11 years were recruited from Granada, Spain (November 2014 to February 2016). The physical fitness components were assessed following the ALPHA health-related fitness test battery. T1-weighted and resting-state fMRI images were acquired with a 3.0 Tesla Siemens Magnetom Tim Trio system. Academic performance was assessed by the Woodcock-Muñoz standardized test. Hippocampal seed-based procedures with post-hoc regression analyses were performed. RESULTS: In the fully adjusted models, cardiorespiratory fitness was independently associated with greater hippocampal connectivity between anterior hippocampus and frontal regions (ß ranging from 0.423 to 0.424, p < 0.001). Motor fitness was independently associated with diminished hippocampal connectivity between posterior hippocampus and frontal regions (ß ranging from -0.583 to -0.694, p < 0.001). However, muscular fitness was not independently associated with hippocampal functional connectivity. Positive resting state hippocampal functional connectivity was related to better written expression (ß ranging from 0.209 to 0.245; p < 0.05). CONCLUSIONS: Physical fitness components may associate with functional connectivity between hippocampal subregions and frontal regions, independent of hippocampal volume, in children with overweight/obesity. Particularly, cardiorespiratory fitness may enhance anterior hippocampal functional connectivity and motor fitness may diminish posterior hippocampal functional connectivity. In addition, resting state hippocampal functional connectivity may relate to better written expression.

Cardiorespiratory fitness is associated with enhanced hippocampal functional connectivity in healthy young adults.

Consistent associations have been found between higher cardiorespiratory fitness (CRF) and indices of enhanced brain health and function, including behavioral measures of cognition as well as neuroimaging indicators such as regional brain volume. Several studies have reported that higher CRF levels are associated with a larger hippocampus, yet associations between volume and memory or functional connectivity metrics remain poorly understood. Using a multi-modal framework, we hierarchically examine the association between CRF and hippocampal volume and resting state functional connectivity (rsFC) in younger adults, as well as their relationship between with memory function. We conducted theoretically-driven analyses with seeds in the anterior and posterior hippocampus, as well as control seeds in the caudate nucleus. We tested whether (1) hippocampal connectivity with prefrontal cortical regions was associated with CRF in an adult sample much younger than traditionally tested, (2) associations between CRF and rsFC remain significant after adjusting for volume, and (3) volume and rsFC are related to memory. We found that higher CRF levels were associated with larger anterior hippocampal volume and more positive rsFC of the anterior hippocampus to several regions including the prefrontal cortex. rsFC also accounted for significant variance in CRF, above and beyond volume. CRF can thus be independently linked to increased anterior hippocampal volume, as well as stronger hippocampal rsFC in a population much younger than those typically tested, suggesitng it is critical to maintainig multiple aspects of brain health.

Task-related functional connectivity of the caudate mediates the association between trait mindfulness and implicit learning in older adults.

Accumulating evidence shows a positive relationship between mindfulness and explicit cognitive functioning, i.e., that which occurs with conscious intent and awareness. However, recent evidence suggests that there may be a negative relationship between mindfulness and implicit types of learning, or those that occur without conscious awareness or intent. Here we examined the neural mechanisms underlying the recently reported negative relationship between dispositional mindfulness and implicit probabilistic sequence learning in both younger and older adults. We tested the hypothesis that the relationship is mediated by communication, or functional connectivity, of brain regions once traditionally considered to be central to dissociable learning systems: the caudate, medial temporal lobe (MTL), and prefrontal cortex (PFC). We first replicated the negative relationship between mindfulness and implicit learning in a sample of healthy older adults (60-90 years old) who completed three event-related runs of an implicit sequence learning task. Then, using a seed-based connectivity approach, we identified task-related connectivity associated with individual differences in both learning and mindfulness. The main finding was that caudate-MTL connectivity (bilaterally) was positively correlated with learning and negatively correlated with mindfulness. Further, the strength of task-related connectivity between these regions mediated the negative relationship between mindfulness and learning. This pattern of results was limited to the older adults. Thus, at least in healthy older adults, the functional communication between two interactive learning-relevant systems can account for the relationship between mindfulness and implicit probabilistic sequence learning.

Dispositional mindfulness is associated with reduced implicit learning.

Behavioral and neuroimaging evidence suggest that mindfulness exerts its salutary effects by disengaging habitual processes supported by subcortical regions and increasing effortful control processes supported by the frontal lobes. Here we investigated whether individual differences in dispositional mindfulness relate to performance on implicit sequence learning tasks in which optimal learning may in fact be impeded by the engagement of effortful control processes. We report results from two studies where participants completed a widely used questionnaire assessing mindfulness and one of two implicit sequence learning tasks. Learning was quantified using two commonly used measures of sequence learning. In both studies we detected a negative relationship between mindfulness and sequence learning, and the relationship was consistent across both learning measures. Our results, the first to show a negative relationship between mindfulness and implicit sequence learning, suggest that the beneficial effects of mindfulness do not extend to all cognitive functions.

The effects of healthy aging on the mnemonic benefit of survival processing.

A number of studies have shown that information is remembered better when it is processed for its survival relevance than when it is processed for relevance to other, non-survival-related contexts. Here we conducted three experiments to investigate whether the survival advantage also occurs for healthy older adults. In Experiment 1, older and younger adults rated words for their relevance to a grassland survival or moving scenario and then completed an unexpected free recall test on the words. We replicated the survival advantage in two separate groups of younger adults, one of which was placed under divided-attention conditions, but we did not find a survival advantage in the older adults. We then tested two additional samples of older adults using a between- (Exp. 2) or within- (Exp. 3) subjects design, but still found no evidence of the survival advantage in this age group. These results suggest that, although survival processing is an effective encoding strategy for younger adults, it does not provide the same mnemonic benefit to healthy elders.

Changes in stress pathways as a possible mechanism of aerobic exercise training on brain health: a scoping review of existing studies.

Physical activity (PA) in the form of aerobic exercise (AE) preserves and improves neurocognitive function across the lifespan. However, a mechanistic understanding of the pathways by which aerobic exercise impacts brain health is still lacking, particularly with respect to stress-related pathways. One mechanistic hypothesis is that AE improves neurocognitive health in part by modifying circulating levels of stress-related hormones and signaling factors associated with the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS), as commonly measured by the biomarkers cortisol (CORT) and salivary α-amylase (sAA). Thus, this hypothesis predicts that changes in stress biomarkers, such as CORT and sAA, are possible explanatory pathways mediating the positive effects of AE on neurocognitive health. In the present review article, we provide a summary of available studies examining the possibility that exercise-induced changes to stress biomarkers could partly account for exercise-related improvements in neurocognitive health. Our review indicates that despite the intuitive appeal of this hypothesis, there is insufficient evidence available to conclude that chronic and habitual AE affects neurocognitive health by altering stress biomarker pathways. The cross-sectional nature of the majority of reviewed studies highlights the need for well-controlled studies to adequately test this hypothesis.

The intergenerational effects of parental physical activity on offspring brain and neurocognition in humans: A scoping review.

Animal models suggest physical activity (PA) has intergenerational effects on brain health and neurocognition. This scoping review compiles the human literature in this area, identifies knowledge gaps, and makes recommendations for future research. We systematically searched for experimental or observational studies conducted in humans, published in English, and reporting parental PA exposure (preconception or prenatal) and subsequent offspring brain and neurocognition. Two reviewers independently screened studies according to predetermined inclusion criteria. Fourteen studies were included (four experimental and 10 observational) reporting on 93,486 parent-child dyads (100% maternal, 0% paternal). Prenatal maternal PA exposure was examined in 10 (71%) studies, while preconception and prenatal PA exposure was examined in four (29%) studies. Maternal PA exposure was positively related to offspring (0-20y) brain and neurocognitive development in 25% of experimental studies and 100% of observational studies. Little is known about the intergenerational effects of parental PA on offspring brain and neurocognition in humans, particularly paternal preconception PA. More experimental studies with longer offspring follow-up and more objective and/or mechanistic assessments are required.

The relationship between fat mass and obesity associated gene polymorphism rs9939609 and resting cerebral blood flow in a midlife sample with overweight and obesity.

Background: The single nucleotide polymorphism (SNP) rs9939609 in the fat mass and obesity associated fat mass and obesity associated gene (FTO) gene has been linked with increased BMI in adults. Higher BMI has been associated with poor brain health and may exert deleterious effects on neurocognitive health through cerebral hypoperfusion. However, it is unclear if there is a relationship between the FTO genotype and cerebral perfusion, or whether FTO genotype moderates the effects of weight loss on cerebral perfusion. Using data from a randomized controlled behavioral weight loss trial in adults with overweight and obesity, we tested (1) whether carriers of the A allele for FTO rs9939609 demonstrate different patterns of resting cerebral blood flow (rCBF) compared to T carriers, and (2) whether the FTO genotype moderates the effects of weight loss on rCBF. We hypothesized that carriers of the A allele would exhibit lower resting CBF in frontal brain areas compared to T/T homozygotes at baseline, and that intervention-induced weight loss may partially remediate these differences. Methods and results: One hundred and five adults (75.2% female, mean age 44.9 years) with overweight or obesity were included in the analyses. These participants represent a subsample of participants in a larger randomized controlled trial (NCT01500356). A resting pseudo-continuous arterial spin labeling (pCASL) scan was acquired to examine rCBF. Age, sex, and BMI were included as covariates. At baseline, A carriers had greater rCBF in a diffuse cluster extending into the brainstem, motor cortex, and occipital lobe, but lower perfusion in the temporal lobe. We found no evidence that FTO moderated the effect of the intervention group assignment on rCBF changes. Conclusion: Overall, these results indicate that (a) individual variation in rCBF within a sample with overweight and obesity may be attributed to a common FTO variant, but (b) a weight loss intervention is effective at increasing rCBF, regardless of FTO genotype.

Aerobic exercise improves episodic memory in late adulthood: a systematic review and meta-analysis.

Background: Aerobic exercise remains one of the most promising approaches for enhancing cognitive function in late adulthood, yet its potential positive effects on episodic memory remain poorly understood and a matter of intense debate. Prior meta-analyses have reported minimal improvements in episodic memory following aerobic exercise but have been limited by restrictive inclusion criteria and infrequent examination of exercise parameters. Methods: We conducted a meta-analysis of randomized controlled trials to determine if aerobic exercise influences episodic memory in late adulthood (M = 70.82 years) and examine possible moderators. Thirty-six studies met inclusion criteria, representing data from 2750 participants. Results: Here we show that aerobic exercise interventions are effective at improving episodic memory (Hedges'g = 0.28; p = 0.002). Subgroup analyses revealed a moderating effect of age (p = 0.027), with a significant effect for studies with a mean age between 55-68 but not 69-85. Mixed-effects analyses demonstrated a positive effect on episodic memory among studies with a high percentage of females (65-100%), participants with normal cognition, studies reporting intensity, studies with a no-contact or nonaerobic physical activity control group, and studies prescribing >3900 total minutes of activity (range 540-8190 min). Conclusions: Aerobic exercise positively influences episodic memory among adults ≥55 years without dementia, with larger effects observed among various sample and intervention characteristics-the clearest moderator being age. These results could have far-reaching clinical and public health relevance, highlighting aerobic exercise as an accessible, non-pharmaceutical intervention to improve episodic memory in late adulthood.

Reduced brain activity during a working memory task in middle-aged apolipoprotein E ε4 carriers with overweight/obesity.

Objective: The apolipoprotein E ε4 (APOE ε4) allele and midlife obesity are independent risk factors for Alzheimer's disease (AD). Both of these risk factors are also associated with differences in brain activation, as measured by blood oxygenation level-dependent (BOLD) responses, in the absence of detectable cognitive deficits. Although the presence of these risk factors may influence brain activity during working memory tasks, no study to date has examined whether the presence of the ε4 allele explains variation in working memory brain activity while matching for levels of overweight/obesity. The primary aim of this study was to determine whether the presence of the ε4 allele is associated with differences in task-functional magnetic resonance imaging (fMRI) brain activation in adults with overweight/obesity. We predicted that ε4 carriers would have greater brain activation in regions that support working memory. Methods: This ancillary study included 48 (n = 24 APOE ε4 carriers; n = 24 APOE ε4 non-carriers), sedentary middle-aged adults (Mean age = 44.63 ± 8.36 years) with overweight/obesity (Mean BMI = 32.43 ± 4.12 kg/m2) who were matched on demographic characteristics. Participants were a subsample enrolled in 12-month randomized clinical trial examining the impact of energy-restricted diet and exercise on cardiovascular health outcomes. Participants completed a n-back working memory task with fMRI, which were completed within one month of the start of the intervention. Participants also underwent pseudo-continuous arterial spin labeling scans, a MRI measure of cerebral blood flow (CBF). Results: Compared to non-ε4 carriers with overweight/obesity, ε4 carriers with overweight/obesity had lower fMRI brain activity in the middle frontal gyrus, pre and post central gyrus, supramarginal gyrus, superior temporal gyrus, lateral occipital cortex, and angular gyrus (z range = 2.52-3.56) during the n-back working memory task. Differences persisted even when controlling for CBF in these brain regions. Conclusion: These results indicate that presence of the APOE ε4 allele in middle-aged adults with overweight/obesity is related to altered brain activity during a working memory paradigm, which may confer risk for accelerated neurocognitive decline in late adulthood. Future research is needed to clarify the clinical implications of these findings in the context of risk for AD.

Changes in cerebral perfusion following a 12-month exercise and diet intervention.

Overweight and obesity may damage the cerebrovascular architecture, resulting in a significant reduction in cerebral blood flow. To date, there have been few randomized clinical trials (RCT) examining whether obesity-related reductions in cerebral blood flow could be modified by weight loss. Further, it is unknown whether the behavioral intervention strategy for weight loss (i.e., diet alone or diet combined with exercise) differentially influences cerebral blood flow in adults with overweight or obesity. The primary aim of this study was to determine whether a 12-month RCT of exercise and diet increases cerebral blood flow in 125 midlife (Mean age ± SD = 44.63 ± 8.36 years) adults with overweight and obesity. Further, we evaluated whether weight loss via diet combined with aerobic exercise has an added effect on changes in cerebral blood flow compared to weight loss via diet alone and whether there were regionally specific effects of the type of behavioral intervention on cerebral blood flow patterns. Consistent with our predictions, a 12-month diet and exercise program resulting in 10% weight loss increased cerebral blood flow. These effects were widespread and extended throughout frontal, parietal, and subcortical regions. Further, there was some regional specificity of effects for both diet-only and diet combined with exercise. Our results demonstrate that weight-related reductions in cerebral blood flow can be modified by 10% weight loss over the course of 12 months and that interventions involving exercise exposure may provide unique effects on cerebral blood flow compared to interventions involving only diet.

Promoting brain health through physical activity among adults exposed to early life adversity: Potential mechanisms and theoretical framework.

Adverse childhood experiences such as abuse, neglect, and poverty, profoundly alter neurobehavioral development in a manner that negatively impacts health across the lifespan. Adults who have been exposed to such adversities exhibit premature and more severe age-related declines in brain health. Unfortunately, it remains unclear whether the negative effects of early life adversity (ELA) on brain health can be remediated through intervention in adulthood. Physical activity may represent a low-cost behavioral approach to address the long-term consequences of ELA on brain health. However, there has been limited research examining the impact of physical activity on brain health among adults with a history of ELA. Accordingly, the purpose of this review is to (1) review the influence of ELA on brain health in adulthood and (2) highlight evidence for the role of neurotrophic factors, hypothalamic-adrenal-pituitary axis regulation, inflammatory processes, and epigenetic modifications in mediating the effects of both ELA and physical activity on brain health outcomes in adulthood. We then propose a theoretical framework to guide future research in this area.

The fitness versus body fat hypothesis in relation to hippocampal structure.

The Fitness Versus Body Fat Hypothesis argues that cardiorespiratory fitness (CRF) plays a more important role in cardiovascular health than adiposity. It remains poorly understood whether CRF or adiposity accounts for a greater amount of variation in measures of brain health. We examined the contribution of CRF, adiposity, and their interaction with hippocampal structure. This study included 124 sedentary adults (M = 44.34) with overweight/obesity (Body Mass Index mean = 32.43). FMRIB's Integrated Registration and Segmentation Tool was used to segment the hippocampus. Using hierarchical regression, we examined whether CRF, assessed via a submaximal graded exercise test, or adiposity, assessed as percent body fat using dual-energy x-ray absorptiometry (DXA) was associated with left and right hippocampal volume. Vertex-wise shape analysis was performed to examine regional shape differences associated with CRF and adiposity. Higher CRF was significantly associated with greater left hippocampal volume (p = .031), with outward shape differences along the surface of the subiculum and CA1 regions. Adiposity was not associated with left or right hippocampal volume or shape. The interaction between adiposity and CRF was not significant. Neither CRF nor adiposity were associated with thalamus or caudate nucleus volumes or shapes, two control regions. Higher CRF, but not adiposity, was related to greater left hippocampal volume, with outward shape differences along the surface of the subiculum and CA1 regions in a midlife sample with overweight/obesity. These findings indicate that, within the context of obesity, CRF is an important contributor to hippocampal structure, highlighting the importance of interventions targeting CRF.

Differences in adolescent cerebral perfusion as a function of obesity: Results from the FLEX-Brain study.

OBJECTIVE: Children and adolescents have greater resting cerebral blood flow (rCBF) during periods of rapid brain growth. Overweight and obesity have a global impact on brain cerebrovascular health in adults, but whether these effects are discernable in adolescents with overweight and obesity remains unknown. This study examined differences in rCBF between adolescents with a healthy weight (HW) and adolescents with overweight or obesity (OW). METHODS: The current study focused on analyzing data from 58 participants (mean age = 15.43 [SD 1.37] years). Participants were classified into OW (n = 38) and HW groups (n = 20) according to the Centers for Disease Control and Prevention's guidelines for children. Voxelwise t tests between the HW and OW groups were conducted to test for regional group differences in rCBF, controlling for age and sex. Mean rCBF was extracted from a gray matter mask to compare global rCBF between the HW and OW groups. RESULTS: The HW group had greater rCBF compared with the OW group in five clusters, with peaks in the cerebellum, precentral gyrus, and supplementary motor area. No clusters survived correction for the OW > HW contrast. Global rCBF did not significantly differ between the groups (p = 0.09). CONCLUSIONS: These results suggest that overweight and obesity in adolescence are associated with discernable reductions in blood flow to specific brain regions rather than having a global impact on rCBF.

A review of the relationship between eating behavior, obesity and functional brain network organization.

Obesity is a major public health issue affecting nearly 40% of American adults and is associated with increased mortality and elevated risk for a number of physical and psychological illnesses. Obesity is associated with impairments in executive functions such as decision making and inhibitory control, as well as in reward valuation, which is thought to contribute to difficulty sustaining healthy lifestyle behaviors, including adhering to a healthy diet. Growing evidence indicates that these impairments are accompanied by disruptions in functional brain networks, particularly those that support self-regulation, reward valuation, self-directed thinking and homeostatic control. Weight-related differences in task-evoked and resting-state connectivity have most frequently been noted in the executive control network (ECN), salience network (SN) and default mode network (DMN), with obesity generally being associated with weakened connectivity in the ECN and enhanced connectivity in the SN and DMN. Similar disruptions have been observed in the much smaller literature examining the relationship between diet and disordered eating behaviors on functional network organization. The purpose of this narrative review was to summarize what is currently known about how obesity and eating behavior relate to functional brain networks, describe common patterns and provide recommendations for future research based on the identified gaps in knowledge.

Effects of Exercise on Brain and Cognition Across Age Groups and Health States.

Exercise has been shown to benefit brain structure and function, particularly in aging populations. However, the mechanisms by which exercise exerts its effects, especially in humans, are not fully understood. This review argues that one reason for this knowledge gap is that exercise likely operates through multiple levels of mechanisms. Furthermore, the mechanisms of exercise may vary depending on factors such as age and health state. We discuss the state of evidence at each of three levels of analysis (molecular/cellular, brain structure/function, and mental states and higher-order behaviors) and highlight consistencies across these levels, inconsistencies within them, and knowledge gaps. Lastly, based on these, we speculate about which mechanisms of exercise may be universal across age groups and populations versus those that might be distinct to specific age ranges or populations.