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.

Intrinsic functional brain connectivity changes following aerobic exercise, computerized cognitive training, and their combination in physically inactive healthy late-middle-aged adults: the Projecte Moviment.

Lifestyle interventions have positive neuroprotective effects in aging. However, there are still open questions about how changes in resting-state functional connectivity (rsFC) contribute to cognitive improvements. The Projecte Moviment is a 12-week randomized controlled trial of a multimodal data acquisition protocol that investigated the effects of aerobic exercise (AE), computerized cognitive training (CCT), and their combination (COMB). An initial list of 109 participants was recruited from which a total of 82 participants (62% female; age = 58.38 ± 5.47) finished the intervention with a level of adherence > 80%. Only in the COMB group, we revealed an extended network of 33 connections that involved an increased and decreased rsFC within and between the aDMN/pDMN and a reduced rsFC between the bilateral supplementary motor areas and the right thalamus. No global and especially local rsFC changes due to any intervention mediated the cognitive benefits detected in the AE and COMB groups. Projecte Moviment provides evidence of the clinical relevance of lifestyle interventions and the potential benefits when combining them.

Early life factors and hippocampal functional connectivity in children with overweight/obesity.

OBJECTIVE: We investigated the association of anthropometric neonatal data (birth length and birth weight) and breastfeeding practices (exclusive and any breastfeeding) with hippocampal functional connectivity and its academic implication in children with overweight/obesity. METHODS: Ninety six children with overweight/obesity aged 8-11 years (10.01 ± 1.14), from the ActiveBrains project were included in this cross-sectional study. Anthropometric neonatal data were collected from birth records, whereas breastfeeding practices were reported by parents. A 3.0 Tesla Siemens Magnetom Tim Trio system was used to acquire T1-weighted and resting-state functional magnetic resonance images. Academic performance was assessed by the Woodcock-Muñoz standardized test. Hippocampal seed-based methods with post-hoc regression analyses were performed. Analyses were considered significant when surpassing Family-Wise Error corrections. RESULTS: Birth weight showed a positive association with the connectivity between the hippocampus and the pre- and postcentral gyri, and the cerebellum. In addition, breastfeeding was negatively associated with the connectivity between the hippocampus and the primary motor cortex and the angular gyrus. Any breastfeeding, in turn, showed a positive association with the connectivity between the hippocampus and the middle temporal gyrus. None of the connectivity outcomes related to early life factors was coupled with better academic abilities (all p > 0.05). CONCLUSIONS: Our findings suggest that birth weight at birth and breastfeeding are associated with hippocampal connectivity in children with overweight/obesity. Despite this, how the results relate to academic performance remains a matter of speculation. Our findings suggest that clinicians should recognize the importance early life factors for potentially avoiding consequences on offspring's brain development.

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.

The Relationship between Physical Activity, Self-Perceived Health, and Cognitive Function in Older Adults.

There are consistent associations between physical activity and self-perceived health. However, it is not clear whether associations between self-perceived health and participation in physical activity could be accounted for by associations with cognitive function. In the present study, we examined whether associations between physical activity and cognitive functioning could explain the variability between physical activity and self-perceived health. A sample of 204 older adults performed three cognitive tests selected from the Vienna test system battery: The Determination, Cognitrone, and Visual Memory tests. These tests measure general processing speed, attention, and visual memory, respectively. Participants also completed the 12-item Short Form Health Questionnaire SF-12 to measure perceived health, and the Physical Activity Survey for the Elderly to measure physical activity. Linear regressions and the PROCESS macro for SPSS were used to test our hypotheses. Consistent with our hypotheses, processing speed accounted for significant variance in the relationship between physical activity and self-perceived health. This suggests that cognitive processing speed might be an indirect path by which physical activity relates to enhanced health perceptions. The results demonstrate that associations between physical activity and self-perceptions of health are related to a fundamental cognitive process.

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.

Estimating the financial costs associated with a phase III, multi-site exercise intervention trial: Investigating Gains in Neurocognition in an Intervention Trial of Exercise (IGNITE).

INTRODUCTION: Supervised exercise interventions are expensive and time intensive. However, there are financial costs to consider in addition to the intervention itself, namely: advertising and recruitment, outcome assessments, and other trial-related costs. OBJECTIVES: In this analysis, we examine the financial costs associated with the administration of Investigating Gains in Neurocognition in an Intervention Trial of Exercise (IGNITE) to quantify the costs associated with large exercise intervention trials and to provide future investigators with financial estimates if they wish to pursue studies of a similar design. METHODS: Cost per randomized participant were calculated in four areas: (1) advertising and recruitment, (2) outcome assessments, (3) delivery of the intervention, and (4) other trial-related expenses. Overall trial costs associated with data analysis, faculty salaries, and indirect costs were estimated as well. RESULTS: The total cost per randomized participant was estimated to be $16,494. Outcome assessments accounted for the highest proportion of per-participant (75%) and total trial (38%) costs. Neuroimaging assessments (MRI & PET) cost $8247 per randomized participant, accounting for two-thirds (67%) of outcome assessment costs and half (50%) of per-participant costs. CONCLUSION: Large clinical trials of exercise are expensive (~$21 million), particularly when administering several visits to assess study aims. Outcome assessments, specifically those involving neuroimaging, accounted for a significant proportion of total costs in this analysis. Future investigators must budget accordingly if they wish to conduct a comprehensive, multi-site exercise intervention trial that examines numerous physiological and psychological outcomes.