The bidirectional relationship between brain structure and physical activity: A longitudinal analysis in the UK Biobank.

Physical activity is a protective factor against brain atrophy, while loss of brain volume could also be a determinant of physical activity. Therefore, we aimed to explore the bidirectional association of physical activity with brain structures in middle-aged and older adults from the UK Biobank. Overall, 3027 participants (62.45 ± 7.27 years old, 51.3% females) had data at two time points. Hippocampal volume was associated with total (ß=0.048, pFDR=0.016) and household (ß=0.075, pFDR<0.001) physical activity. Global fractional anisotropy (ß=0.042, pFDR=0.028) was also associated with household physical activity. In the opposite direction, walking was negatively associated with white matter volume (ß=-0.026, pFDR=0.008). All these associations were confirmed by the linear mixed models. Interestingly, sports at baseline were linked to hippocampal and frontal cortex volumes at follow-up but these associations disappeared after adjusting for multiple comparisons (pall>0.104). In conclusion, we found more consistent evidence that a healthier brain structure predicted higher physical activity levels than for the inverse, more established relationship.

Associations between muscular strength and mental health in cognitively normal older adults: a cross-sectional study from the AGUEDA trial.

Objective: To examine the associations between muscular strength and mental health. Design: We used baseline data of 91 cognitively healthy older adults (71.69 ± 3.91 years old, 57 % women) participating in the AGUEDA randomized controlled trial. Methods: Muscular strength was assessed using both objective (i.e., handgrip strength, biceps curl, squats, and isokinetic test) and perceived (i.e., International Fitness Scale) indicators. Psychological ill-being indicators: anxiety, depression, stress, and loneliness; and psychological well-being indicators: satisfaction with life, self-esteem, and emotional well-being) were assessed using a set of valid and reliable self-reported questionnaires. Linear regression analyses were performed adjusting for sex, age, years of education, body mass index , alcohol, diet, and smoking (model 1), and additionally by cardiorespiratory fitness (model 2). Results: Elbow extension was positively associated with stress in model 1 (ß = 0.252, 95 % Confidence Interval [95 % CI] = 0.007 to 0.497, p = 0.044), and even after further adjustment for cardiorespiratory fitness (ß = 0.282, 95 % CI = 0.032 to 0.532, p = 0.028). Perceived strength was negatively associated with depressive symptoms in model 1 (ß = -0.271, 95 % CI = -0.491 to -0.049, p = 0.017) and model 2 reported associations tending towards significant (ß = -0.220, 95 % CI = -0.445 to 0.005, p = 0.055). Handgrip strength was positively associated with self-esteem in model 1 (ß = 0.558, 95 % CI = 0.168 to 0.949, p = 0.006) and model 2 (ß = 0.546, 95 % CI = 0.135 to 0.956, p = 0.010). No further associations were found among other muscular strength and mental health variables. Conclusion: Handgrip had a moderate association with self-esteem and there was a small association between perceived strength with depressive symptoms and elbow extension with stress. No other associations were observed between muscular strength and mental health outcomes in cognitively normal older adults.

The effects of physical activity on white matter microstructure in children with overweight or obesity: The ActiveBrains randomized clinical trial / Los efectos de la actividad física sobre la microestructura de la sustancia blanca en niños con sobrepeso u obesidad: el ensayo clínico aleatorizado ActiveBrains

Background: Emerging research supports the idea that physical activity benefits brain development. However, the body of evidence focused on understanding the effects of physical activity on white matter microstructure during childhood is still in its infancy, and further well-designed randomized clinical trials are needed. Aim: This study aimed: (i) to investigate the effects of a 20-week physical activity intervention on global white matter microstructure in children with overweight or obesity, and (ii) to explore whether the effect of physical activity on white matter microstructure is global or restricted to a particular set of white matter bundles. Methods: In total, 109 children aged 8 to 11 years with overweight or obesity were randomized and allocated to either the physical activity program or the control group. Data were collected from November 2014 to June 2016, with diffusion tensor imaging (DTI) data processing and analyses conducted between June 2017 and November 2021. Images were pre-processed using the Functional Magnetic Resonance Imaging (MRI) of the Brain´s Software Library (FSL) and white matter properties were explored by probabilistic fiber tractography and tract-based spatial statistics (TBSS). Results: Intention-to-treat analyses were performed for all children who completed the pre-test and post-test DTI assessment, with good quality DTI data (N = 89). Of them, 83 children (10.06±1.11 years, 39 % girls, intervention group=44) met the per-protocol criteria (attended at least 70 % of the recommended sessions). Our probabilistic fiber tractography analysis did not show any effects in terms of global and tract-specific fractional anisotropy (FA) and mean diffusivity (MD) in the per-protocol or intention-to-treat analyses. Additionally, we did not observe any effects on the voxel-wise DTI parameters (i.e., FA and MD) using the most restricted TBSS approach (i.e., per protocol analyses and p-corrected image with a statistical...(AU)

Early morning physical activity is associated with healthier white matter microstructure and happier children: the ActiveBrains project.

The background of this study is to examine the associations of individual and combined early morning patterns (i.e., active commuting to school, physical activity before school, having breakfast and good sleep) with white matter microstructure (WMM) and, whether the associated white mater microstructure outcomes were related to mental health outcomes in children with overweight or obesity. 103 children with overweight or obesity (10.0 ± 1.1 years old, 42 girls) from the ActiveBrains project participated in this cross-sectional study. Early morning patterns and mental health indicators (i.e., self-esteem, optimism, positive and negative affect, stress, depression and anxiety) were self-reported by the children using validated questionnaires. WMM was assessed by magnetic resonance imaging using diffusion tensor imaging. When examined independently, early morning patterns were not related with WMM (all P > 0.05). However, the combination of early morning patterns was related with WMM (P < 0.05). Specifically, physically active early morning patterns (i.e., active commuting to school and physical activity before school) were associated with global fractional anisotropy (FA) (ß = 0.298, P = 0.013) and global radial diffusivity (RD) (ß = - 0.272, P = 0.021), as well as with tract-specific FA (ß = 0.314, P = 0.004) and RD (ß = - 0.234, P = 0.032) in the superior longitudinal fasciculus (SLF). Furthermore, combined physically active early morning pattern-associated global (i.e., FA and RD) and tract-specific (i.e., FA and RD in the SLF) WMM indicators were positively associated with happiness (ß absolute value range from 0.252 to 0.298, all P < 0.05). A combination of physically active early morning patterns may positively relate to white matter microstructure in children with overweight or obesity, and, in turn, happiness.

Physical activity and amyloid beta in middle-aged and older adults: A systematic review and meta-analysis.

BACKGROUND: One of the pathological hallmarks distinguishing Alzheimer's disease from other dementias is the accumulation of amyloid beta (Aß). Higher physical activity is associated with decreased dementia risk, and one potential path could be through Aß levels modulation. We aimed to explore the relationship between physical activity and Aß in middle-aged and older adults. METHODS: A systematic search of PubMed, Web of Science, PsycINFO, Cochrane Central Register of Controlled Trials, and SPORTDiscus was performed from inception to April 28, 2022. Studies were eligible if they included physical activity and Aß data in adults aged 45 years or older. Multi-level meta-analyses of intervention and observational studies were performed to examine the role of physical activity in modulating Aß levels. RESULTS: In total, 37 articles were included (8 randomized controlled trials, 3 non-randomized controlled trials, 4 prospective longitudinal studies, and 22 cross-sectional studies). The overall effect size of physical activity interventions on changes in blood Aß was medium (pooled standardized mean difference = -0.69, 95% confidence interval (95%CI): -1.41 to 0.03; I2 = 74.6%). However, these results were not statistically significant, and there were not enough studies to explore the effects of physical activity on cerebrospinal fluid (CSF) and brain Aß. Data from observational studies were examined based on measurements of Aß in the brain using positron emission tomography scans, CSF, and blood. Higher physical activity was positively associated with Aß only in the CSF (Estimate r = 0.12; 95%CI: 0.05-0.18; I2 = 38.00%). CONCLUSION: Physical activity might moderately reduce blood Aß in middle-aged and older adults. However, results were only near statistical significance and might be interpreted with caution given the methodological limitations observed in some of the included studies. In observational studies, higher levels of physical activity were positively associated with Aß only in CSF. Therefore, further research is needed to understand the modulating role of physical activity in the brain, CSF, and blood Aß, as well as its implication for cognitive health.

The effects of an exercise intervention on neuroelectric activity and executive function in children with overweight/obesity: The ActiveBrains randomized controlled trial.

OBJECTIVE: To investigate whether a 20-week aerobic and resistance exercise program induces changes in brain current density underlying working memory and inhibitory control in children with overweight/obesity. METHODS: A total of 67 children (10.00 ± 1.10 years) were randomized into an exercise or control group. Electroencephalography (EEG)-based current density (µA/mm2 ) was estimated using standardized low-resolution brain electromagnetic tomography (sLORETA) during a working memory task (Delayed non-matched-to-sample task, DNMS) and inhibitory control task (Modified flanker task, MFT). In DNMS, participants had to memorize four stimuli (Pokemons) and then select between two of them, one of which had not been previously shown. In MFT, participants had to indicate whether the centered cow (i.e., target) of five faced the right or left. RESULTS: The exercise group had significantly greater increases in brain activation in comparison with the control group during the encoding phase of DNMS, particularly during retention of second stimuli in temporal and frontal areas (peak t = from 3.4 to 3.8, cluster size [k] = from 11 to 39), during the retention of the third stimuli in frontal areas (peak t = from 3.7 to 3.9, k = from 15 to 26), and during the retention of the fourth stimuli in temporal and occipital areas (peak t = from 2.7 to 4.3, k = from 13 to 101). In MFT, the exercise group presented a lower current density change in the middle frontal gyrus (peak t = -4.1, k = 5). No significant change was observed between groups for behavioral performance (p ≥ 0.05). CONCLUSION: A 20-week exercise program modulates brain activity which might provide a positive influence on working memory and inhibitory control in children with overweight/obesity.

The effects of physical activity on white matter microstructure in children with overweight or obesity: The ActiveBrains randomized clinical trial.

Background: Emerging research supports the idea that physical activity benefits brain development. However, the body of evidence focused on understanding the effects of physical activity on white matter microstructure during childhood is still in its infancy, and further well-designed randomized clinical trials are needed. Aim: This study aimed: (i) to investigate the effects of a 20-week physical activity intervention on global white matter microstructure in children with overweight or obesity, and (ii) to explore whether the effect of physical activity on white matter microstructure is global or restricted to a particular set of white matter bundles. Methods: In total, 109 children aged 8 to 11 years with overweight or obesity were randomized and allocated to either the physical activity program or the control group. Data were collected from November 2014 to June 2016, with diffusion tensor imaging (DTI) data processing and analyses conducted between June 2017 and November 2021. Images were pre-processed using the Functional Magnetic Resonance Imaging (MRI) of the Brain´s Software Library (FSL) and white matter properties were explored by probabilistic fiber tractography and tract-based spatial statistics (TBSS). Results: Intention-to-treat analyses were performed for all children who completed the pre-test and post-test DTI assessment, with good quality DTI data (N = 89). Of them, 83 children (10.06±1.11 years, 39 % girls, intervention group=44) met the per-protocol criteria (attended at least 70 % of the recommended sessions). Our probabilistic fiber tractography analysis did not show any effects in terms of global and tract-specific fractional anisotropy (FA) and mean diffusivity (MD) in the per-protocol or intention-to-treat analyses. Additionally, we did not observe any effects on the voxel-wise DTI parameters (i.e., FA and MD) using the most restricted TBSS approach (i.e., per protocol analyses and p-corrected image with a statistical threshold of p < 0.05). In the intention-to-treat analysis, we found that our physical activity program had a borderline effect (p-corrected image with a statistical threshold of p < 0.1) on 7 different clusters, including a cluster in the corpus callosum. Conclusion: We conclude that a 20-week physical activity intervention was not enough to induce changes in global and tract-specific white matter during childhood. The effects of physical activity on white matter microstructure could be restricted to local changes in several white matter tracts (e.g., the body of the corpus callosum). However, our results were not significant, and more interventions are needed to determine whether and how physical activity affects white matter microstructure during childhood.

Early life factors and structural brain network in children with overweight/obesity: The ActiveBrains project.

BACKGROUND: The aims of this study were to investigate the association of early life factors, including birth weight, birth length, and breastfeeding practices, with structural brain networks; and to test whether structural brain networks associated with early life factors were also associated with academic performance in children with overweight/obesity (OW/OB). METHOD: 96 children with OW/OB aged 8-11 years (10.03 ± 1.16) from the ActiveBrains project were included. Early life factors were collected from birth records and reported by parents as weight, height, and months of breastfeeding. T1-weighted images were used to identify structural networks using a non-negative matrix factorization (NNMF) approach. Academic performance was evaluated by the Woodcock-Muñoz standardized test battery. RESULTS: Birth weight and birth length were associated with seven networks involving the cerebellum, cingulate gyrus, occipital pole, and subcortical structures including hippocampus, caudate nucleus, putamen, pallidum, nucleus accumbens, and amygdala. No associations were found for breastfeeding practices. None of the networks linked to birth weight and birth length were linked to academic performance. CONCLUSIONS: Birth weight and birth length, but not breastfeeding, were associated with brain structural networks in children with OW/OB. Thus, early life factors are related to brain networks, yet a link with academic performance was not observed. IMPACT: Birth weight and birth length, but not breastfeeding, were associated with several structural brain networks involving the cerebellum, cingulate gyrus, occipital pole, and subcortical structures including hippocampus, caudate, putamen, pallidum, accumbens and amygdala in children with overweight/obesity, playing a role for a normal brain development. Despite no academic consequences, other behavioral consequences should be investigated. Interventions aimed at improving optimal intrauterine growth and development may be of importance to achieve a healthy brain later in life.

Bidirectional longitudinal associations of mental health with academic performance in adolescents: DADOS study.

BACKGROUND: The dual-factor model of mental health (i.e., the presence of psychological well-being along with the absence of distress) and its association with academic performance over time has been barely studied in the adolescent population, as most of the prior research focuses on psychological well-being or distress indicators in isolation. The current study analyzed the bidirectional longitudinal association between the dual-factor model of mental health and academic performance in adolescents, comprising a longitudinal assessment 2 years apart. METHODS: A total of 266 secondary school students (13.9 ± 0.3 years at baseline) from Deporte, ADOlescencia y Salud study were assessed. Mental health was assessed through the Behavior Assessment System for Children and Adolescents. Academic performance was assessed through academic grades and the Test of Educational Abilities. A cross-lagged modeling approach was used to examine the bidirectional longitudinal association between mental health and academic performance. RESULTS: Higher academic performance at baseline was associated with better mental health over time, but not vice versa, since this association was not bidirectional. CONCLUSION: Results suggest that academic performance is an important target for developing educational interventions, as it shapes adolescents' mental health at 2 years of follow-up. IMPACT: The overall picture of students' mental health and academic performance was analyzed. Academic performance may be a predictor of adolescents' mental health status. Mental health may not be a predictor of adolescents' academic performance. Good mental health should be promoted among youth with low academic performance.

Physical Performance and Amyloid-ß in Humans: A Systematic Review and Meta-Analysis of Observational Studies.

BACKGROUND: Accumulation of amyloid-ß (Aß) plaques is one of the main features of Alzheimer's disease (AD). Physical performance has been related to dementia risk and Aß, and it has been hypothesized as one of the mechanisms leading to greater accumulation of Aß. Yet, no evidence synthesis has been performed in humans. OBJECTIVE: To investigate the association of physical performance with Aß in humans, including Aß accumulation on brain, and Aß abnormalities measured in cerebrospinal fluid (CSF) and blood. METHODS: A systematic review with multilevel meta-analysis was performed from inception to June 16th, 2022. Studies were eligible if they examined the association of physical performance with Aß levels, including the measure of physical performance as a predictor and the measure of Aß as an outcome in humans. RESULTS: 7 articles including 2,619 participants were included in the meta-analysis. The results showed that physical performance was not associated with accumulation of Aß in the brain (ES = 0.01; 95% CI -0.21 to 0.24; I2 = 69.9%), in the CSF (ES = -0.28; 95% CI -0.98 to 0.41; I2 = 91.0%) or in the blood (ES = -0.19; 95% CI -0.61 to 0.24; I2 = 99.75%). Significant heterogeneity was found across the results , which posed challenges in arriving at consistent conclusions; and the limited number of studies hindered the opportunity to conduct a moderation analysis. CONCLUSIONS: The association between physical performance and Aß is inconclusive. This uncertainly arises from the limited number of studies, study design limitations, and heterogeneity of measurement approaches. More studies are needed to determine whether physical performance is related to Aß levels in humans.

Levels of Physical Activity at Age 10 Years and Brain Morphology Changes From Ages 10 to 14 Years.

Importance: Physical activity may promote healthy brain development in children, but previous research was predominantly cross-sectional and included small samples, providing limited knowledge. Objective: To investigate the longitudinal associations of physical activity with brain morphology changes. Design, Setting, and Participants: A 4-year longitudinal population-based cohort study in Rotterdam, the Netherlands, embedded in Generation R, a cohort from fetal life onward. From the women enrolled during pregnancy, children who had repeated measures of brain structure at ages 10 (range 8 to 12) years and 14 (range 13 to 15) years were included. Data were collected from March 2013 to November 2015 (baseline) and from October 2016 to January 2020 (follow-up). Data were analyzed from April to December 2022. Exposure: At age 10 years, both the child and their primary caregiver reported the child's levels of physical activity with regard to sport participation, outdoor play, and total physical activity. Primary analyses were based on an average multi-informant report. Main outcomes and measures: Brain morphology was quantified by magnetic resonance imaging. Hypothesized regions of interest were the bilateral amygdala and hippocampal volumes. Global brain measures were studied to test the specificity of the hypothesis. Results: Data were available for 1088 children (566 girls [52%]; 693 [64%] Dutch). Their mean (SD) age at baseline was 10.1 (0.6) years. For amygdala volume change, positive associations with multi-informant reports of total physical activity (ß = 2.6; 95% CI, 0.3-4.9) were found. Total physical activity was associated with hippocampal volume increases only when reported by the child (ß = 3.1; 95% CI, 0.4-5.8). No robust associations with global brain measures were found. Conclusions and relevance: In this cohort study of 1088 children, more physical activity at 10 years was consistently associated with an increase in amygdala volume in children aged 10 to 14 years. Physical activity and increases in hippocampal volume were found using child reports of physical activity only. These findings suggest physical activity in late childhood was prospectively associated with volumetric changes in specific subcortical structures, but not to global brain development, from late childhood to early adolescence. These findings may inform the design of future public health interventions to best facilitate neurodevelopment with physical activity.

Physical activity, screen time and body composition in 13-year-old adolescents: The Generation R Study.

BACKGROUND: Body composition between prepubertal children and adolescents varies, and it is unclear how physical activity and sedentary behaviour affect adolescent body composition. OBJECTIVES: This study aimed to examine the associations of physical activity and screen time with overall and specific fat depots in the general adolescent population. METHODS: In a population-based prospective cohort study, among 3258 adolescents aged 13 years, physical activity and screen time were assessed via self-report questionnaires. Body mass index, dual-energy X-ray absorptiometry-based measures (i.e. fat mass and lean body mass) and magnetic resonance imaging-based measures (i.e. abdominal subcutaneous and visceral fat mass) were obtained. RESULTS: After adjusting for social-demographic and growth-related factors, each additional hour of daily physical activity was associated with lower fat mass, abdominal visceral fat mass and higher lean body mass (all p < 0.05). However, these associations were not observed in the longitudinal analyses. Each additional hour of daily screen time was associated with higher body mass index, fat mass, abdominal subcutaneous and visceral fat mass (all p < 0.05), which were consistent with the longitudinal analyses. CONCLUSION: Adolescents with higher physical activity and lower screen time had lower levels of adiposity both at the general and visceral levels.

Mechanisms Linking Physical Activity with Psychiatric Symptoms Across the Lifespan: A Systematic Review.

BACKGROUND: Physical activity has been suggested as a protective factor against psychiatric symptoms. While numerous studies have focused on the magnitude of physical activity's effect on psychiatric symptoms, few have examined the potential mechanisms. OBJECTIVE: The current review aimed to synthesize scientific evidence of the mechanisms through which physical activity might reduce psychiatric symptoms across the lifespan. METHODS: We included articles that were published before March 2022 from five electronic databases (MEDLINE, Web of Science, PsycINFO, Embase, and Cochrane). A qualitative synthesis of studies was conducted. The risk of bias assessment was performed using The Joanna Briggs Institute Critical Appraisal Tool for Systematic Reviews. Studies were included if they explored the possible mechanisms through which physical activity influences psychiatric symptoms (i.e., internalizing and externalizing symptoms) across the lifespan. RESULTS: A total of 22 articles were included (three randomized controlled trials, four non-randomized controlled trials, three prospective longitudinal studies, and 12 cross-sectional studies). Overall, most of the studies focused on children, adolescents, and young adults. Our findings showed that self-esteem, self-concept, and self-efficacy were the only consistent paths through which physical activity influences psychiatric symptoms (specifically depressive and anxiety symptoms) across the lifespan. There were insufficient studies to determine the role of neurobiological mechanisms. CONCLUSIONS: Overall, future physical activity interventions with the purpose of improving mental health should consider these mechanisms (self-esteem, self-concept, self-efficacy) to develop more effective interventions. CLINICAL TRIAL REGISTRATION: The protocol of this study was registered in the PROSPERO database (registration number CRD42021239440) and published in April 2022.

Effects of an Exercise Program on Cardiometabolic and Mental Health in Children With Overweight or Obesity: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Childhood obesity is a risk factor associated with type 2 diabetes, cardiovascular disease, and mental disorders later in life. Investigation of the parallel effects of a defined exercise program on cardiometabolic and mental health in children with overweight or obesity may provide new insights on the potential benefits of exercise on overall health. Objective: To investigate the effects of a 20-week exercise program on cardiometabolic and mental health in children with overweight or obesity. Design, Setting, and Participants: This secondary analysis of a parallel-group randomized clinical trial was conducted in Granada, Spain, from November 1, 2014, to June 30, 2016. Data analyses were performed between February 1, 2020, and July 14, 2022. Children with overweight or obesity aged 8 to 11 years were eligible, and the study was performed in an out-of-school context. Intervention: The exercise program included 3 to 5 sessions/wk (90 min/session) of aerobic plus resistance training for 20 weeks. The wait-list control group continued with their usual routines. Main Outcomes and Measures: Cardiometabolic outcomes as specified in the trial protocol included body composition (fat mass, fat-free mass, and visceral adipose tissue), physical fitness (cardiorespiratory, speed-agility, and muscular), and traditional risk factors (waist circumference, blood lipid levels, glucose levels, insulin levels, and blood pressure). Cardiometabolic risk score (z score) was calculated based on age and sex reference values for levels of triglycerides, inverted high-density lipoprotein cholesterol, and glucose, the mean of systolic and diastolic blood pressure, and waist circumference. An additional cardiometabolic risk score also included cardiorespiratory fitness. Mental health outcomes included an array of psychological well-being and ill-being indicators. Results: The 92 participants included in the per-protocol analyses (36 girls [39%] and 56 boys [61%]) had a mean (SD) age of 10.0 (1.1) years. The exercise program reduced the cardiometabolic risk score by approximately 0.38 (95% CI, -0.74 to -0.02) SDs; decreased low-density lipoprotein cholesterol level by -7.00 (95% CI, -14.27 to 0.37) mg/dL (to convert to mmol/L, multiply by 0.0259), body mass index (calculated as weight in kilograms divided by height in meters squared) by -0.59 (95% CI, -1.06 to -0.12), fat mass index by -0.67 (95% CI, -1.01 to -0.33), and visceral adipose tissue by -31.44 (95% CI, -58.99 to -3.90) g; and improved cardiorespiratory fitness by 2.75 (95% CI, 0.22-5.28) laps in the exercise group compared with the control group. No effects were observed on mental health outcomes. Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, an aerobic plus resistance exercise program improved cardiometabolic health in children with overweight or obesity but had no effect on mental health. Trial Registration: ClinicalTrials.gov Identifier: NCT02295072.

Association of muscular strength and targeted proteomics involved in brain health in children with overweight/obesity.

Muscular strength has been positively associated with better brain health indicators during childhood obesity. However, the molecular mechanisms underlying the positive impact of muscular strength in brain health are poorly understood. We aimed to study the association of muscular strength with neurology-related circulating proteins in plasma in children with overweight/obesity and to explore the role of cardiorespiratory fitness (CRF) as a confounder. The participants were 86 Caucasian children (10.1 ± 1.1 years old; 41% girls) from the ActiveBrains project. Muscular strength was measured by field and laboratory tests. CRF was assessed with an incremental treadmill test. Olink's technology was used to quantify 92 neurology-related proteins in plasma. Protein-protein interactions were computed using the STRING website. Muscular strength was positively associated with 12 proteins (BetaNGF, CDH6, CLEC10A, CLM1, FcRL2, HAGH, IL12, LAIR2, MSR1, SCARB2, SMOC2, and TNFRSF12A), and negatively associated with 12 proteins (CLEC1B, CTSC, CTSS, gal-8, GCP5, NAAA, NrCAM, NTRK2, PLXNB3, RSPO1, sFRP3, and THY1). After adjustment for CRF, muscular strength was positively associated with eight proteins (BetaNGF, CDH6, CLEC10A, FcRL2, LAIR2, MSR1, SCARB2, and TNFRSF12A) and negatively associated with two proteins (gal-8 and NrCAM). After applying FDR correction, only CLEC10A remained statistically significant. In conclusion, muscular strength was associated with blood circulating proteins involved in several biological processes, particularly anti-inflammatory response, lipid metabolism, beta amyloid clearance, and neuronal action potential propagation. More powered studies are warranted in pediatric populations to contrast or confirm our findings.

Neurobiological, Psychosocial, and Behavioral Mechanisms Mediating Associations Between Physical Activity and Psychiatric Symptoms in Youth in the Netherlands.

Importance: Understanding the mechanisms by which physical activity is associated with a lower risk of psychiatric symptoms may stimulate the identification of cost-efficient strategies for preventing and treating mental illness at early life stages. Objective: To examine neurobiological, psychosocial, and behavioral mechanisms that mediate associations of physical activity with psychiatric symptoms in youth by testing an integrated model. Design, setting, and participants: Generation R is an ongoing prospective population-based cohort study collecting data from fetal life until young adulthood in a multiethnic urban population in the Netherlands. Pregnant women living in Rotterdam with an expected delivery date between April 2002 and January 2006 were eligible for participation along with their children born during this time. Data were collected at a single research center in the Erasmus Medical Center Sophia Children's Hospital. For the current study, data were analyzed from 4216 children with complete data on both exposure and outcome at ages 6, 10, and 13 years. Data were analyzed from January 2021 to November 2022. Exposures: Physical activity was ascertained at age 6 years (visit 1) via parent report and included weekly frequency and duration of walking or cycling to or from school, physical education at school, outdoor play, swimming, and sports participation. Main Outcomes and Measures: Psychiatric symptoms (internalizing and externalizing symptoms) were assessed at age 6 years (visit 1) and at age 13 years (visit 3) using the Child Behavior Checklist. Several mechanisms were explored as mediators, measured at age 10 years (visit 2). Neurobiological mechanisms included total brain volume, white matter microstructure, and resting-state connectivity assessed using a 3-T magnetic resonance imaging scanner. Psychosocial mechanisms included self-esteem, body image, and friendship. Behavioral mechanisms included sleep quality, diet quality, and recreational screen time. Pearson correlations between physical activity measures and psychiatric symptoms were calculated, with false discovery rate correction applied to account for the number of tests performed. Mediation analyses were performed when a correlation (defined as false discovery rate P < .05) between exposure and outcome was observed and were adjusted for confounders. Results: Among the 4216 children included in this study, the mean (SD) age was 6.0 (0.4) years at visit 1, and 2115 participants (50.2%) were girls. More sports participation was associated with fewer internalizing symptoms (ß for direct effect, -0.025; SE, 0.078; P = .03) but not externalizing symptoms. Self-esteem mediated the association between sports participation and internalizing symptoms (ß for indirect effect, -0.009; SE, 0.018; P = .002). No evidence was found for associations between any other neurobiological, psychosocial, or behavioral variables. No association was found between other types of physical activity and psychiatric symptoms at these ages. Conclusions and Relevance: The integrated model presented in this cohort study evaluated potential mechanisms mediating associations between physical activity and psychiatric symptoms in youth. Self-esteem mediated an association between sports participation in childhood and internalizing symptoms in adolescence; other significant mediations were not observed. Further studies might explore whether larger effects are present in certain subgroups (eg, children at high risk of developing psychiatric symptoms), different ages, or structured sport-based physical activity interventions.

Cardiorespiratory fitness and targeted proteomics involved in brain and cardiovascular health in children with overweight/obesity.

Cardiorespiratory fitness (CRF) is inversely associated with cardiovascular disease (CVD) risk factors and brain health impairments. However, the molecular mechanisms linking CRF to health in children are poorly understood. We aimed to examine protein levels related to brain health and CVD in plasma of fit compared to unfit children with overweight/obesity (OW/OB). Eighty-seven children with OW/OB (10.08 ± 1.1 years, 59% boys) from the ActiveBrains project were included. CRF was measured by performing a treadmill test, and children were categorized into fit or unfit. Targeted proteomics in plasma was performed using Olink's proximity extension assay technology of Neurology panel in the whole sample and of Cardiovascular panel in a subsample. Sixteen proteins (PLXNB3, sFRP3, CLEC1B, RSPO1, Gal8, CLEC10A, GCP5, MDGA1, CTSC, LAT, IL4RA, PRSS27, CXCL1, Gal9, MERTK, and GT) were differentially expressed between fit and unfit children with OW/OB after adjusting for sex, maturational status, and body mass index. However, statistically significant differences disappeared after applying FDR correction. Potential candidate proteins related to CRF levels in children with OW/OB were detected, being involved in several biological processes such as neurogenesis, immune/inflammatory response, signal transduction, platelet activation. Nevertheless, these preliminary findings should be confirmed or contrasted in future studies using larger sample sizes, longitudinal and experimental designs.HighlightsThe molecular mechanisms underlying the link of cardiorespiratory fitness (CRF) with cardiovascular and brain health in children with overweight/obesity (OW/OB) are poorly understood.Targeted proteomic analysis revealed differentially expressed proteins (PLXNB3, sFRP3, CLEC1B, RSPO1, Gal8, CLEC10A, GCP5, MDGA1, CTSC, LAT, IL4RA, PRSS27, CXCL1, Gal9, MERTK, and GT) in plasma of "Fit" compared to "Unfit" children with OW/OB. These proteins are involved in several biological processes such as immune/inflammatory response, neurogenesis, signal transduction, and cellular metabolic process.Longitudinal and experimental studies are warranted to reveal how improvements in CRF are related to changes in circulating levels of the abovementioned proteins and how they might reduce cardiovascular diseases risk factors and brain health impairments later in life.

Neurotrophic factors and brain health in children with overweight and obesity: The role of cardiorespiratory fitness.

ABSTRACTNeurotrophic factors and cardiorespiratory fitness are both considered important in developmental trajectories but their link to brain health remains poorly understood. The aims of the study were to examine whether levels of plasma-derived neurotrophic factors were associated with brain health indicators in children with overweight or obesity; and to test whether these associations were moderated by cardiorespiratory fitness. 100 children (41% girls) were included in this analysis. Plasma levels of brain-derived neurotrophic factor, insulin-like growth factor-1, vascular endothelial growth factor A, and epidermal growth factor were determined by XMap technology. Academic performance and executive function were assessed using validated neuropsychological tests. Hippocampal volume was measured using magnetic resonance imaging. Cardiorespiratory fitness was assessed using the 20-m Shuttle Run Test. Insulin-like growth factor-1 was positively associated with cognitive flexibility. Stratified analyses by fitness categories (i.e. unfit vs. fit) showed that brain-derived neurotrophic factor was positively associated with right posterior hippocampal volume in fit children, and epidermal growth factor was negatively associated with right hippocampal, and right anterior hippocampal volumes in their unfit peers, with a moderating role of cardiorespiratory fitness in these associations. However, all these significant associations disappeared after correction for multiple comparisons. The association between neurotrophic factors and brain health indicators in children with overweight/obesity was neither strong nor consistent. These results could help enhance our understanding of determinants of brain health in children with overweight/obesity.HighlightsThis study provides novel findings on the associations between neurotrophic factors and a wide range of brain health indicators in children.This study additionally explored the role of cardiorespiratory fitness in these associations.The association between neurotrophic factors and brain health in children with overweight/obesity was neither strong nor consistent.Cardiorespiratory fitness moderated the associations of brain-derived neurotrophic factor and epidermal growth factor with right hippocampal volume.

The effects of a 20-week exercise program on blood-circulating biomarkers related to brain health in overweight or obese children: The ActiveBrains project.

BACKGROUND: Emerging research supports the idea that exercise positively affects neurodevelopment. However, the mechanisms linking exercise with brain health are largely unknown. We aimed to investigate the effect of exercise on (a) blood biomarkers selected based on previous evidence (brain-derived neurotrophic factor, ß-hydroxybutyrate (BHB), cathepsin B (CTSB), kynurenine, fibroblast growth factor 21 (FGF21), soluble vascular cell adhesion molecule-1 (sVCAM-1)); and (b) a panel of 92 neurology-related proteins (discovery analysis). We also investigated whether changes in these biomarkers mediate the effects of exercise on brain health (hippocampal structure and function, cognitive performance, and mental health). METHODS: We randomized 81 overweight/obese children (10.1 ± 1.1 years, 41% girls) into 2 groups: either 20 weeks of aerobic plus resistance exercise or control. Candidate biomarkers were assessed using enzyme-linked immunosorbent assay (ELISA) for kynurenine, FGF21, and CTSB; colorimetry for ß-hydroxybutyrate; and XMap for brain-derived neurotrophic factor and soluble vascular cell adhesion molecule-1. The 92 neurology-related proteins were analyzed by an antibody-based proteomic analysis. RESULTS: Our intervention had no significant effect on candidate biomarkers (all p > 0.05). In the discovery analysis, a reduction in circulating macrophage scavenger receptor type-I was observed (standardized differences between groups = -0.3, p = 0.001). This effect was validated using ELISA methods (standardized difference = -0.3, p = 0.01). None of the biomarkers mediated the effects of exercise on brain health. CONCLUSIONS: Our study does not support a chronic effect of exercise on candidate biomarkers. We observed that while chronic exercise reduced the levels of macrophage scavenger receptor type-I, it did not mediate the effects of exercise on brain health. Future studies should explore the implications of this novel biomarker for overall health.

Physical activity levels and brain structure in middle-aged and older adults: a bidirectional longitudinal population-based study.

Physical activity has been suggested as modifiable factor that might contribute to improving cognitive and brain function during aging. However, previous studies were mainly of cross-sectional design and did not consider effects of time or potential reverse causality. We aimed to investigate the bidirectional associations of physical activity with brain structure in middle-aged and older adults. Overall, 4365 participants (64.01 ± 10.82 years; 56% women) from the Rotterdam Study had physical activity and brain structure assessed on at least one of 2 timepoints ('baseline': 2006-2012 or 'follow-up': 2012-2017, median duration between visits: 5 years). Physical activity was assessed through the LASA Physical Activity Questionnaire. T1-weighted MRI and diffusion tensor imaging were used to quantify brain volumes and white matter microstructure, respectively. Cross-lagged panel models were performed to estimate bidirectional associations, and linear mixed-effects models to investigate the consistency of findings. Larger total brain volume (ß = 0.067, 95%-confidence interval 0.035;0.099, pFDR = 0.001), gray matter volume (ß = 0.063, 0.031;0.096, pFDR = 0.002), and white matter volume (ß = 0.051, 0.020;0.083, pFDR = 0.013) at baseline were associated with higher levels of sports at follow-up. Lower global mean diffusivity at baseline was associated with higher levels of walking at follow-up (ß = -0.074, -0.111;-0.037, pFDR = 0.001). No associations were found between physical activity levels at baseline and brain metrics at follow-up. In conclusion, larger brain volumes and white matter microstructure at baseline were associated with individuals remaining more physically active at follow-up. Overall, this study identified older adults with potentially advanced brain aging status as being at higher risk of physical inactivity over time, and therefore as potential target group for prevention and novel intervention strategies.