The influence of aerobic fitness on cerebral white matter integrity and cognitive function in older adults: Results of a one-year exercise intervention

Associations between white matter microstructure and cognitive decline in major depressive disorder versus controls in Germany: a prospective case-control cohort study

Aerobic fitness may help maintain cognitive function in older adults. However, little is known about the potential mechanisms by which improvements in aerobic fitness may lead to these changes. One potential mechanism is cerebral white matter integrity (CWMI). Both CWMI and aerobic fitness decline with aging. Hence, different aerobic fitness levels may be related to varying amounts of CWMI, which then could impact cognitive function. PURPOSE: To determine brain regions with significant positive associations between CWMI and aerobic fitness in older adults. METHODS: 15 older adults (66 + 6 yrs) completed peak VO2 treadmill testing (Modified Pepper Protocol; VO2 peak range = 14 to 54 ml/kg/min). Magnetic resonance (MR) imaging was used to analyze multiple brain regions during rest on a separate day. Structural 3D T1 MP-Rage and diffusion tensor imaging (DTI, 21 directions, repeated 4x) was done using a 3.0 Tesla MR imaging unit. 3D fractional anisotropy (FA) maps were computed from the raw DTI data. Previous research has shown age-related FA declines in the frontal regions, therefore the specific regions of interest (ROI) identified for this study were the cingulum, genu of the corpus callosum, and uncinate fasciculus (UNC). All ROIs were outlined using InsightSNAP software on the FA maps (FA Coefficient of Variance = 3.9%). RESULTS: Manova revealed no significant age and gender effects. Bivariate analysis showed an overall positive correlation between FA and VO2 peak for the entire cingulum (r = 0.536: p = 0.032). A multiple regression analysis indicated varying contributions of VO2peak on the FA within specific segments of the cingulum (anterior: R2 = 0.32, p = 0.014; medial: R2 = 0.18, p = 0.056; posterior: R2 = 0.04, p = 0.25). Analyses of specific segments within the left and right cingulum resulted in significant correlations between FA and VO2peak in the left anterior (r = 0.559, p = 0.030) and left medial (r = 0.572, p = 0.026) segments. Multiple regression revealed that the greatest unique contribution of VO2peak to the FA variance resided in the medial segment of the left cingulum (R2 = 0.33, p = 0.026 ). Genu and UNC results: r < 0.48; R2 < 0.23, p > 0.07. CONCLUSIONS: There are segment and side-specific positive associations between CWMI and aerobic fitness in the cingulum. Funding: Biomedical Research Imaging Center, UNC-CH.

Stressful events can have both short- and long-term effects on the brain. Our recent investigation identified short-term white matter integrity (WMI) changes in 30 subjects soon after the Japanese earthquake. Our findings suggested that lower WMI in the right anterior cingulum (Cg) was a pre-existing vulnerability factor and increased WMI in the left anterior Cg and uncinate fasciculus (Uf) after the earthquake was an acquired sign of postearthquake distress. However, the long-term effects on WMI remained unclear. Here, we examined the 1-year WMI changes in 25 subjects to clarify long-term effects on the WMI. We found differential FAs in the right anterior Cg, bilateral Uf, left superior longitudinal fasciculus (SLF), and left thalamus, suggesting that synaptic enhancement and shrinkage were long-term effects. Additionally, the correlation between psychological measures related to postearthquake distress and the degree of WMI alternation in the right anterior Cg and the left Uf led us to speculate that temporal WMI changes in some subjects with emotional distress occurred soon after the disaster. We hypothesized that dynamic WMI changes predict a better prognosis, whereas persistently lower WMI is a marker of cognitive dysfunction, implying the development of anxiety disorders.

&lt;p&gt;Older age is a primary risk factor for the development of cardiovascular disease in part through the stiffening of the large cardiothoracic elastic arteries (e.g., aorta, carotid arteries). Aging is also associated with reduced cognitive function, cerebrovascular reactivity and brain white matter integrity, but whether these changes in brain structure and function are associated with age-related large artery stiffness remains unclear. In contrast, older adults who have high aerobic fitness demonstrate attenuated large artery stiffness and better cognitive performance compared to their sedentary counterparts, but the effects of aerobic fitness on white matter integrity and cerebrovascular reactivity with aging are conflicting and limited. Moreover, whether high aerobic fitness-associated lower large artery stiffness in older adults is associated with, and perhaps mediates, the beneficial changes in cognitive function and white matter structure remains unknown. The purpose of this study was to investigate the extent to which high aerobic fitness is associated with preserved white matter structure, cerebrovascular reactivity, and cognitive performance in aged individuals, and if these changes in brain structure and function are associated with attenuated large artery stiffness. In young (n=19, 23.6 ± 2.5 years) and old (n=22, 64.4 ± 4.2 years) healthy adults, large elastic artery stiffness was measured by carotid-femoral pulse wave velocity (cfPWV, aortic stiffness) via non-invasive applanation tonometry of carotid and femoral pulse waveforms and carotid artery beta-stiffness index (β-stiffness index) and compliance using high-resolution ultrasound and carotid blood pressure via applanation tonometry. Aerobic fitness was measured as maximal exercise oxygen uptake (VO2max) using respiratory gas analysis on an upright cycle ergometer. Older subjects were stratified as high or low fit based on gender and age VO2max classification. Letter, pattern and N-Back cognitive tests were used to assess processing speed and working memory respectively. Fractional anisotropy (FA) from diffusion tensor images and Blood Oxygenation Level Dependent (BOLD) imaging was used to assess cerebrovascular reactivity (CVR) response to a breath hold and brain activation during a working memory task. The association between large artery stiffness and FA was then assessed using a voxel-wise general linear model approach and a region-of-interest analysis.&lt;/p&gt; &lt;p&gt;Our results confirmed age-related increases in cfPWV, carotid β-stiffness index and central (carotid) but not brachial systolic blood pressure, and expected reductions in carotid compliance, VO2max, working memory and processing speed, and in white matter integrity in select brain regions (bilateral cingulate, frontal, occipital, temporal). In contrast, we found no age-associated differences in CVR to breath hold stimulus or change in BOLD response to the N-Back. In our cohort of health adults, we found that the age-related changes in large artery stiffness were not attenuated by high compared with low VO2max. Among older adults, large elastic artery stiffness was not associated with regional white matter integrity or cerebrovascular reactivity in any regions-of-interest. Greater carotid artery compliance and lower β-stiffness index was associated with higher processing speed, while compliance was related to higher d'Prime scores and lower reaction time on the 2-Back task among the older adults. CVR to a breath hold stimulus was not related to any measure of cognitive performance. VO2max was not associated with any measures of vascular function, brain structure, function or cognition, indicating relations between large artery stiffness and cognition were independent of aerobic fitness capacity. Taken together, these data suggest that select measures of cognitive performance, but not white matter structure or CVR, may be susceptible to age-related changes in carotid stiffness/compliance and that are unaffected by aerobic fitness. More work is needed to understand the mechanisms by which age-related declines in carotid artery compliance and increased carotid stiffness are associated with reductions in cognitive function in older adults.&lt;/p&gt;

Introduction: Higher central elastic artery stiffness is associated with greater brain white matter hyperintensity volume and lower cognitive performance in older adults. However, it is unknown if higher central artery stiffness is related to regional decreases in brain white matter integrity (WMI) and reductions in working memory or processing speed. We hypothesized that greater large elastic artery stiffness would be associated with lower working memory and slower processing speed as well as lower regional WMI in older adults. Methods: In young (n=19; 23.8 ± 0.7 yrs) and older (n=22; 64.4 ± 4.2 yrs; range 60-71 yrs) healthy adults, aortic stiffness (carotid-femoral pulse wave velocity, cfPWV, via tonometry) and carotid artery compliance and β-stiffness index (carotid artery ultrasound and tonometry) were determined non-invasively. WMI was assessed by fractional anisotrophy (FA) (3T MRI) from diffusion tensor images. An N-Back task and letter and pattern comparison tests were performed as measures of working memory and processing speed, respectively. d’Prime, a measure of signal detection, was calculated on the N-Back task as a ratio of positive ‘hits’ to ‘false alarm’ responses. Results: cfPWV (8.4 ± 0.5 vs. 5.2 ± 0.2 m/sec, P&lt;0.01) and carotid β-stiffness (11.3 ± 0.9 vs. 6.1 ± 0.7 U, P&lt;0.01) were greater and carotid compliance (0.16 ± 0.02 vs. 0.07 ± 0.01 mm/mmHg, P&lt;0.01) was lower in older vs. young adults. Carotid β, but not aortic, stiffness was associated with slower processing speed on letter (10.7 ± 0.5 vs. 13.5 ± 0.6 units/ 30 sec, p&lt;0.01) and pattern (16.6 ± 0.6 vs. 22.0 ± 0.7 units/30 sec, p&lt;0.01) comparison tasks and reduced working memory (1.8 ± 0.2 vs. 3.1± 0.2, P&lt;0.01) in older vs. young adults. Lower carotid compliance was associated with slower performance on the letter (r=0.55, P&lt;0.01) and pattern (r=0.54, P&lt;0.01) tests and lower d’Prime (r=0.48, P&lt;0.05). Greater β-stiffness was related to pattern comparison scores only (r=-0.54, P&lt;0.01). Aortic stiffness, carotid compliance and β-stiffness were not related to WMI in any brain region. Conclusions: Our results suggest that lower carotid artery compliance and greater β-stiffness are associated with reduced working memory performance and slower processing speed but not regional WMI in older adults.

Cognitive and physical activities can benefit cognition. However, knowledge about the neurobiological mechanisms underlying these activity-induced cognitive benefits is still limited, especially with regard to the role of white matter integrity (WMI), which is affected in cognitive aging and Alzheimer’s disease. To address this knowledge gap, we investigated the immediate and long-term effects of cognitive or physical training on WMI, as well as the association between cognitive and physical lifestyles and changes in WMI over a 6-month period. Additionally, we explored whether changes in WMI underlie activity-related cognitive changes, and estimated the potential of both trainings to improve WMI by correlating training outcomes with WMI. In an observational and interventional pretest, posttest, 3-month follow-up design, we assigned 47 community-dwelling older adults at risk of dementia to 50 sessions of auditory processing and working memory training (n = 13), 50 sessions of cardiovascular, strength, coordination, balance and flexibility exercises (n = 14), or a control group (n = 20). We measured lifestyles trough self-reports, cognitive training skills through training performance, functional physical fitness through the Senior Fitness Test, and global cognition through a cognitive test battery. WMI was assessed via a composite score of diffusion tensor imaging-based fractional anisotropy (FA) of three regions of interest shown to be affected in aging and Alzheimer’s disease: the genu of corpus callosum, the fornix, and the hippocampal cingulum. Effects for training interventions on FA outcomes, as well as associations between lifestyles and changes in FA outcomes were not significant. Additional analyses did show associations between cognitive lifestyle and global cognitive changes at the posttest and the 3-month follow-up (β ≥ 0.40, p ≤ 0.02) and accounting for changes in WMI did not affect these relationships. The targeted training outcomes were related to FA scores at baseline (cognitive training skills and FA composite score, rs = 0.68, p = 0.05; functional physical fitness and fornix FA, r = 0.35, p = 0.03). Overall, we found no evidence of a link between short-term physical or cognitive activities and WMI changes, despite activity-related cognitive changes in older adults at risk of dementia. However, we found positive associations between the two targeted training outcomes and WMI, hinting at a potential of long-term activities to affect WMI.

Diminished white matter integrity in patients with systemic lupus erythematosus.

Tobacco smoking is an addictive behavior that supports nicotine dependence and is an independent risk factor for cancer and other illnesses. Its neurogenetic mechanisms are not fully understood but may act through alterations in the cerebral white matter (WM). We hypothesized that the vertical pleiotropic pathways, where genetic variants influence a trait that in turn influences another trait, link genetic factors, integrity of cerebral WM, and nicotine addiction. We tested this hypothesis using individual genetic factors, WM integrity measured by fractional anisotropy (FA), and nicotine dependence-related smoking phenotypes, including smoking status (SS) and cigarettes per day (CPDs), in a large epidemiological sample collected by the UK Biobank. We performed a genome-wide association study (GWAS) to identify previously reported loci associated with smoking behavior. Smoking was found to be associated with reduced WM integrity in multiple brain regions. We then evaluated two competing vertical pathways: Genes → WM integrity → Smoking versus Genes → Smoking → WM integrity and a horizontal pleiotropy pathway where genetic factors independently affect both smoking and WM integrity. The causal pathway analysis identified 272 pleiotropic single-nucleotide polymorphisms (SNPs) whose effects on SS were mediated by FA, as well as 22 pleiotropic SNPs whose effects on FA were mediated by CPD. These SNPs were mainly located in important susceptibility genes for smoking-induced diseases NCAM1 and IREB2. Our findings revealed the role of cerebral WM in the maintenance of the complex addiction and provided potential genetic targets for future research in examining how changes in WM integrity contribute to the nicotine effects on the brain.

Advanced aging is associated with cognitive decline. To decrease the healthcare system and socio-economic burdens as well as to promote better quality of life, is important to uncover the factors that may be related to the delay of cognitive impairments in older adults. This study investigated the relationship between physical activity levels, sedentary behavior and cardiorespiratory fitness with cognitive functioning in healthy older adults. Furthermore, it examined the mediating role of processing speed on the association between physical activity and executive functions and long-term memory. Thirty-two individuals aged between 63 and 77 years (M = 68.16, SD = 3.73) underwent measurements of maximal oxygen uptake (VO2peak), 1-week of PA accelerometer measurement and a comprehensive cognitive assessment. Significant associations were observed between MVPA and cognitive processing speed. Equally, a significant positive indirect effect of MVPA on executive functioning and long-term memory was mediated by processing speed. Also, MVPA levels differentiated cognitive functioning in older adults – the physical active group outperformed the physical inactive group in processing speed, executive functions, and language abilities. Our results contribute to the literature on the MVPA levels as an important tool to promote healthier cognitive aging.

Neuroimaging research suggests that cerebral white matter (WM) integrity, as reflected in fractional anisotropy (FA) via diffusion tensor imaging (DTI), is decreased in older adults, especially in the prefrontal regions of the brain. Behavioral investigations of cognitive functioning suggest that some aspects of cognition may be better preserved in older adults who possess higher levels of aerobic fitness. There are only a few studies, however, investigating potential mechanisms for the improvements in aerobic fitness. Our study suggests that greater aerobic fitness may be related to greater WM integrity in select brain regions.

In the context of a globally aging population, exploring interventions that counteract age-related cognitive decline and cerebral structural alterations is paramount. Among various strategies, physical exercise (PE) emerges as a prevalent activity routinely incorporated in many individuals' lives. This systematic review and meta-analysis aims to elucidate the impact of PE on white matter (WM) integrity and cognitive function in older adults. Data from 581 participants, 312 in the PE intervention group, and 269 in the control group were extracted from nine randomized controlled trials (RCTs) retrieved from databases including PubMed, Embase, Web of Science, and the Cochrane Library. The results indicated a significant improvement in white matter (WM) integrity in individuals engaged in PE, as evidenced by enhanced fractional anisotropy (FA) scores (SMD = 0.4, 95% confidence interval (CI) [0.05, 0.75], P = 0.024). The GRADE assessment revealed a moderate risk. However, no significant associations were found between PE and other metrics such as radial diffusivity (RD), mean diffusivity (MD), white matter volume (WMV), hippocampal volume (HV), and cognitive functions (executive function [EF], memory, processing speed). In conclusion, our study emphasizes the potential neurostructural and cognitive functional benefits of physical exercise for the brain health of older adults.

To investigate the association between cognitive function and body composition in older adults. We collected data on 2080 older adults (>60 years of age) from the National Health and Nutrition Examination Survey (NHANES) for the years 1999-2000 and 2001-2002. Candidate variables included: demographic data (sex, age, race, education level, marital status, poverty-to-income ratio), alcohol consumption, cardiovascular disease, diabetes, osteoporosis, total bone mineral density, and total fat mass. A logistic regression model was established to analyze the association between cognitive function and body composition in older adults. In addition, stratified logics regression analysis was performed by sex and age. Bone mineral density significantly affects cognitive function in older adults (p<0.01). When examining the data according to sex, this correlation is present for women (p < 0.01). For men, though, it is not significant (p = 0.081). Stratified by age, total bone mineral density was significantly correlated with cognitive function in 60-70 and 70-80 years old people, but not in older adults older than 80 years(for 60-70 years old, p = 0.019; for 70-80 years old, p = 0.022). There was no significant correlation between total bone mineral density and cognitive function (p = 0.575). The decrease of total bone mineral density was significantly correlated with cognitive decline in the older adults, especially among women and older people in the 60 to 80 age group. There was no connection between total fat mass, total percent fat, total lean mass, appendicular lean mass, appendicular lean mass /BMI and cognitive function in the older adults.

Chronic obstructive pulmonary disease (COPD) is considered to be a multi-systemic disease involving pathological changes in the brain. This study investigated how diffusion tensor imaging (DTI) parameters in patients with non-hypoxemic COPD differ from those in controls. Moreover, we tried to examine whether the mode of anisotropy (MO) reflects early changes in white matter (WM) integrity in COPD. DT images were obtained from 13 male COPD patients and 13 age- and sex-matched healthy controls. Raw DT images were processed using an automated tract-based spatial statistics (TBSS) pipeline. DTI scalars of fractional anisotropy (FA); axial, radial, and mean diffusivities (AD, RD, and MD, respectively); MO; and raw T2 signal (S0) were statistically compared between COPD patients and controls. TBSS methods were used for analysis. In patients with COPD, decreased AD was observed in the temporal stem (TS), corticospinal tract (CST), thalamus, subiculum, crus cerebri, and midbrain. Increased MO values were found in the corpus callosum, CST, internal capsule, cerebellar peduncle (CP), and medial lemniscus (ML). Additionally, increased S0 was found in the TS, CP, pons, and cerebellar tonsil (threshold-free cluster enhancement to a family-wise error rate of p < 0.05). The results revealed decreased AD and increased MO scalars in COPD patients compared with the controls, although there were no differences in FA, RD, and MD scalars. Decreased AD and increased MO scalars may reflect early changes in WM integrity in COPD patients.

Human imitation is supported by an underlying "mirror system" principally composed of inferior frontal, inferior parietal, and superior temporal cortical regions. Across primate species, differences in frontoparietotemporal connectivity have been hypothesized to explain phylogenetic variation in imitative abilities. However, if and to what extent these regions are involved in imitation in nonhuman primates is unknown. We hypothesized that "Do As I Do" (DAID) imitation training would enhance white matter integrity within and between frontoparietotemporal regions. To this end, four captive chimpanzees ( Pan troglodytes) were trained to reproduce 23 demonstrated actions, and four age-/sex-matched controls were trained to produce basic husbandry behaviors in response to manual cues. Diffusion tensor images were acquired before and after 600 min of training over an average of 112 days. Bilateral and asymmetrical changes in frontoparietotemporal white matter integrity were compared between DAID trained subjects and controls. We found that imitation trained subjects exhibited leftward shifts in both mean fractional anisotropy and tract strength asymmetry measures in brain regions within the mirror system. This is the first report of training-induced changes in white matter integrity in chimpanzees and suggests that frontoparietotemporal connectivity, particularly in the left hemisphere, may have facilitated the emergence of increasingly complex imitation learning abilities.

Studies suggest that regular physical activity can help maintain and enhance brain functions in older adults. However, we still do not understand how physical activity impacts the rate of cognitive decline. One major issue is whether physical activity broadly defined (i.e., activity that is part of one's daily life involving bodily movements and the use of skeletal muscles) or structured exercise (i.e., physical activity that is planned, structured, and purposive to improve physical fitness) leads to the same benefits in preventing age-related cognitive decline. More studies are needed to appreciate the level of change or protection provided by physical activity, the basic mechanisms by which this change occurs, and whether physical activity can be beneficial despite chronic medical conditions and neurological or geriatric syndromes. This special issue presents original research results that bring additional support to the notion that physical exercise is an efficient nonpharmaceutical approach that can be used to enhance and maintain cognitive functions in healthy older adults and patients suffering from mild cognitive impairment. In a paper, we propose a brief review of the main impacts of exercise on cognition in older adults, frail patients, and those with mild cognitive impairment and dementia. Another paper of this special issue brings important knowledge in this regard. L. S. Nagamatsu et al. showed that physical activity helps improve verbal and spatial memory in older adults with probable mild cognitive impairment. In this study, eighty-six women aged 70–80 years with subjective memory complaints completed one of three interventions for 6 months: resistance training, aerobic training, or balance and tone (control). Both exercise groups showed significant improvements in memory performance, which was not observed in controls. An original study of this special issue explored the benefits of swimming on cognition in older adults. A. Abou-Dest et al. compared three groups of sixteen volunteer participants (young adults, sedentary older adults, and older adults who regularly practice swimming) on a battery of cognitive tasks. They reported that in older adults, regular swimming was related to better performance on executive functions but not on information processing speed. The selective benefit of exercise on executive control tasks was also reported after only 3 months of exercise intervention in a study of this special issue by D. Predovan et al. compared to controls, the training group showed significant improvements in physical capacity and enhanced Stroop performance, but only in the inhibition/switching condition, and the increase in aerobic capacity induced by the training regimen correlated negatively with reaction time in the inhibition/switching condition of the Stroop task at posttest. Importantly, the reported gains in cognitive performance were observed after only three months of physical training. The complex interaction between bodily exercise and cognition also calls into question the impact that mobility and gait might have on cognition in older adults. P. Plummer-D'Amato et al. addressed this issue in a contribution to this special issue. Studying how gait difficulty and cognitive task difficulty impact cognitive-motor interference in aging, they showed that gait task difficulty influences dual-task effects on gait speed, especially in older adults, and that this effect is influenced by the difficulty of the cognitive task. Another paper of the special issue brings up important issues on the potential moderators of physical activity on brain functions. R. L. Leckie et al. demonstrated how genes (APOE, BDNF, and COMT) along with dietary omega-3 fatty acid and docosahexaenoic acid (DHA) are potential moderators of the effect of physical activity on brain health. R. L. Leckie et al.'s proposal calls for further studies on the role of genes and dietary factors in the relationship between physical exercise and cognitive functions in older adults populations. All together, the studies published in this special issue bring additional scientific support to the notion that physical activity and exercise are a promising approach to alleviate the age-related impact on the body and mind. By doing so, they also support the promotion of health policies that should target inactivity in individuals of all ages and with any medical condition who are able to safely participate in physical activity.