Inflammatory biomarkers and brain health indicators in children with overweight and obesity: The ActiveBrains project

INTRODUCTION: Chronic inflammation plays an important role on the pathogenesis of several cardiovascular and metabolic diseases, as well as on brain function and behaviour. The aim of the present study was to examine the associations between inflammatory biomarkers and a wide range of brain health indicators (i.e., academic performance, executive function, behavioural and emotional functioning, and brain volume) in children with overweight/obesity. METHODS: A total of 107 children (10.0 ± 1.1 years, 41% girls) from the ActiveBrains project were included in the analysis. Five inflammatory biomarkers were analysed in plasma: white blood cell (WBC) count, interleukin-6 (IL-6), interleukin-1beta, tumor necrosis factor-alpha (TNF-alpha), and C-reactive protein (CRP). Academic performance was assessed by Woodcock-Munoz Tests of Achievement. Executive function was assessed through the Design Fluency Test for cognitive flexibility, the Stroop test for cognitive inhibition, and the Delayed Non-Match-to-Sample task for working memory. Behavioural and emotional functioning was evaluated through the Behavior Assessment System for Children (BASC) questionnaire. Total and regional brain volume was assessed by magnetic resonance imaging. RESULTS: IL-6 was inversely associated with adaptive skills (beta = -0.228; p = 0.030), while TNF-alpha was related to mathematics (beta = -0.198; p = 0.034). In addition, CRP was positively associated with externalizing (beta = 0.246; p = 0.046) and internalizing problems (beta = 0.234; p = 0.039), as well as the behavioural symptoms index (beta = 0.236; p = 0.047). However, these significant associations disappeared after multiple comparisons correction. Inflammatory biomarkers were not associated with executive function and total brain volumes. Regarding regional brain analyses, WBC was positively associated with gray matter volume in the left middle temporal gyrus (beta = 0.387; p < 0.001, k = 44), and CRP was positively associated with gray matter volume in the right superior temporal gyrus (beta = 0.439; p < 0.001, k = 29). Additionally, when adjusting by total brain volume, CRP was positively associated with gray matter volume in the right supplementary motor cortex (beta = 0.453; p < 0.001, k = 51). Moreover, both, IL-6 (beta = 0.366; p < 0.001, k = 81) and TNF-alpha (beta = 0.368; p < 0.001, k = 62) were positively associated with white matter volume around the right inferior frontal gyrus pars opercularis, while CRP was inversely associated with white matter volume around the left superior frontal gyrus (beta = -0.482; p < 0.001, k = 82). After adjusting by total brain volume, CRP was also inversely associated with white matter volume in 3 additional clusters (beta ranging from -0.473 to -0.404; p < 0.001, k = 87). CONCLUSIONS: Inflammation was slightly associated with brain health (i.e., academic performance, behavioural and emotional functioning and regional brain volume) in children with overweight or obesity. Further larger longitudinal and interventional studies are warranted to elucidate the short-term and long-term effect of systemic low-grade inflammation on children's brain health

Physical fitness and white matter microstructure in children with overweight or obesity: the ActiveBrains project

Recent studies investigated the association of cardiorespiratory fitness with white matter microstructure in children, yet little work has explored to what extent other components of physical fitness (i.e., muscular or motor fitness) are associated with white matter microstructure. Indeed, this association has not been previously explored in children with overweight/obesity who present a different white matter development. Therefore, we aimed to examine associations between physical fitness components and white matter microstructure in children with overweight/obesity. In total, 104 (10.04 +/- 1.15 years old; 43 girls) children were included in this cross-sectional study. Physical fitness was assessed using the ALPHA-fitness test battery. Fractional anisotropy (FA) and mean diffusivity were derived from diffusion tensor imaging (DTI). No association was found between physical fitness and global DTI metrics (all P>0.082). Within individual tracts, all associations became non-significant when analyses were adjusted for multiple comparisons. Using the voxel-wise approach, we identified a small cluster in the left lateral frontal lobe where children with greater upper-body muscular fitness showed higher FA (PFWE-corrected=0.042). Although our results cannot conclude physical fitness is related to white matter microstructure in children with overweight/obesity; those findings indicate that the association of muscular fitness with white matter microstructure might be more focal on frontal areas of the brain, as opposed to global differences

Effects of Maternal Fish Oil and/or 5-MethylTetrahydrofolate Supplementation during Pregnancy on Offspring Brain Resting-State at 10 Years Old: A Follow-Up Study from the NUHEAL Randomized Controlled Trial

Recent studies have shown that maternal supplementation with folate and long-chain polyunsaturated fatty acids (LC-PUFAs) during pregnancy may affect children’s brain development. We aimed at examining the potential long-term effect of maternal supplementation with fish oil (FO) and/or 5-methyl-tetrahydrofolate (5-MTHF) on the brain functionality of offspring at the age of 9.5–10 years. The current study was conducted as a follow-up of the Spanish participants belonging to the Nutraceuticals for a Healthier Life (NUHEAL) project; 57 children were divided into groups according to mother’s supplementation and assessed through functional magnetic resonance imaging (fMRI) scanning and neurodevelopment testing. Independent component analysis and double regression methods were implemented to investigate plausible associations. Children born to mothers supplemented with FO (FO and FO + 5-MTHF groups, n = 33) showed weaker functional connectivity in the default mode (DM) (angular gyrus), the sensorimotor (SM) (motor and somatosensory cortices) and the fronto-parietal (FP) (angular gyrus) networks compared to the No-FO group (placebo and 5-MTHF groups, n = 24) (PFWE < 0.05). Furthermore, no differences were found regarding the neuropsychological tests, except for a trend of better results in an object recall (memory) test. Considering the No-FO group, the aforementioned networks were associated negatively with attention and speed-processing functions. Mother’s FO supplementation during pregnancy seems to be able to shape resting-state network functioning in their children at school age and appears to produce long-term effects on children´s cognitive processing.European Union (EU) 212652 007036Commission of the European Community within the 5th Framework Program QLK1-CT-1999-00888European Research Council (ERC) 322605 META-GROWTHSpanish Ministry of Science, Innovation and Universities FJCI-2017-3339

Effects of an exercise program on brain health outcomes for children with overweight or obesity

Importance Pediatric overweight and obesity are highly prevalent across the world, with implications for poorer cognitive and brain health. Exercise might potentially attenuate these adverse consequences. Objectives To investigate the effects of an exercise program on brain health indicators, including intelligence, executive function, academic performance, and brain outcomes, among children with overweight or obesity and to explore potential mediators and moderators of the main effects of exercise. Design, Setting, and Participants All preexercise and postexercise data for this 20-week randomized clinical trial of 109 children aged 8 to 11 years with overweight or obesity were collected from November 21, 2014, to June 30, 2016, with neuroimaging data processing and analyses conducted between June 1, 2017, and December 20, 2021. All 109 children were included in the intention-to-treat analyses; 90 children (82.6%) completed the postexercise evaluation and attended 70% or more of the recommended exercise sessions and were included in per-protocol analyses. Interventions All participants received lifestyle recommendations. The control group continued their usual routines, whereas the exercise group attended a minimum of 3 supervised 90-minute sessions per week in an out-of-school setting. Main Outcomes and Measures Intelligence, executive function (cognitive flexibility, inhibition, and working memory), and academic performance were assessed with standardized tests, and hippocampal volume was measured with magnetic resonance imaging. Results The 109 participants included 45 girls (41.3%); participants had a mean (SD) body mass index of 26.8 (3.6) and a mean (SD) age of 10.0 (1.1) years at baseline. In per-protocol analyses, the exercise intervention improved crystallized intelligence, with the exercise group improving from before exercise to after exercise (mean z score, 0.62 [95% CI, 0.44-0.80]) compared with the control group (mean z score, –0.10 [95% CI, –0.28 to 0.09]; difference between groups, 0.72 SDs [95% CI, 0.46-0.97]; P < .001). Total intelligence also improved significantly more in the exercise group (mean z score, 0.69 [95% CI, 0.48-0.89]) than in the control group (mean z score, 0.07 [95% CI, –0.14 to 0.28]; difference between groups, 0.62 SDs [95% CI, 0.31-0.91]; P < .001). Exercise also positively affected a composite score of cognitive flexibility (mean z score: exercise group, 0.25 [95% CI, 0.05-0.44]; control group, –0.17 [95% CI, –0.39 to 0.04]; difference between groups, 0.42 SDs [95% CI, 0.13-0.71]; P = .005). These main effects were consistent in intention-to-treat analyses and after multiple-testing correction. There was a positive, small-magnitude effect of exercise on total academic performance (mean z score: exercise group, 0.31 [95% CI, 0.18-0.44]; control group, 0.10 [95% CI, –0.04 to 0.24]; difference between groups, 0.21 SDs [95% CI, 0.01-0.40]; P = .03), which was partially mediated by cognitive flexibility. Inhibition, working memory, hippocampal volume, and other brain magnetic resonance imaging outcomes studied were not affected by the exercise program. The intervention increased cardiorespiratory fitness performance as indicated by longer treadmill time to exhaustion (mean z score: exercise group, 0.54 [95% CI, 0.27-0.82]; control group, 0.13 [95% CI, –0.16 to 0.41]; difference between groups, 0.42 SDs [95% CI, 0.01-0.82]; P = .04), and these changes in fitness mediated some of the effects (small percentage of mediation [approximately 10%-20%]). The effects of exercise were overall consistent across the moderators tested, except for larger improvements in intelligence among boys compared with girls. Conclusions and Relevance In this randomized clinical trial, exercise positively affected intelligence and cognitive flexibility during development among children with overweight or obesity. However, the structural and functional brain changes responsible for these improvements were not identified

Maternal prepregnancy body mass index and offspring white matter microstructure: results from three birth cohorts

Prepregnancy maternal obesity is a global health problem and has been associated with offspring metabolic and mental ill-health. However, there is a knowledge gap in understanding potential neurobiological factors related to these associations. This study explored the relation between maternal prepregnancy body mass index (BMI) and offspring brain white matter microstructure at the age of 6, 10, and 26 years in three independent cohorts. Maternal BMI was associated with higher FA and lower MD in multiple brain tracts in offspring aged 10 and 26 years, but not at 6 years of age. Future studies should examine whether our observations can be replicated and explore the potential causal nature of the findings.This work was supported by the European Union’s Horizon 2020 research and innovation program [grant agreement no. 633595 DynaHEALTH] and no. 733206 LifeCycle], the Netherlands Organization for Health Research and Development [ZONMW Vici project 016.VICI.170.200]. The PREOBE cohort was funded by Spanish Ministry of Innovation and Science. Junta de Andalucía: Excellence Projects (P06-CTS-02341) and Spanish Ministry of Economy and Competitiveness (BFU2012-40254-C03-01). The first phase of the Generation R Study is made possible by financial support from the Erasmus Medical Centre, the Erasmus University, and the Netherlands Organization for Health Research and Development (ZonMW, grant ZonMW Geestkracht 10.000.1003). The Northern Finland Birth Cohort 1986 is funded by University of Oulu, University Hospital of Oulu, Academy of Finland (EGEA), Sigrid Juselius Foundation, European Commission (EURO-BLCS, Framework 5 award QLG1-CT-2000-01643), NIH/NIMH (5R01MH63706:02

Chilean version of the INECO Frontal Screening (IFS-Ch) : psychometric properties and diagnostic accuracy

Objective: This study sought to analyze the psychometric properties and diagnostic accuracy of the Chilean version of the INECO Frontal Screening (IFS-Ch) in a sample of dementia patients and control. Methods: After adapting the instrument to the Chilean context and obtaining content validity evidence through expert consultation, the IFS-Ch was administered to 31 dementia patients and 30 control subjects together with other executive assessments (Frontal Assessment Battery [FAB], Modified version of the Wisconsin Card Sorting Test [MCST], phonemic verbal fluencies [letters A and P] and semantic verbal fluency [animals]) and global cognitive efficiency tests (Mini mental State Examination [MMSE] and Addenbrooke's Cognitive Examination-Revised [ACE-R]). Caregivers of dementia patients and proxies of control subjects were interviewed with instruments measuring dysexecutive symptoms (Dysexecutive Questionnaire [DEX]), dementia severity (Clinical Dementia Rating Scale [CDR]) and functional status in activities of daily living (Activities of Daily Living Scale [IADL] and Technology-Activities of Daily Living Questionnaire [T-ADLQ]). Convergent and discriminant validity, internal consistency reliability, cut-off points, sensitivity and specificity for the IFS-Ch were estimated. Results: Evidence of content validity was obtained. Evidence of convergent validity was also found showing significant correlations (p<0.05) between the IFS-Ch and the other instruments measuring: executive functions (FAB, r=0.935; categories achieved in the MCST, r=0.791; perseverative errors in the MCST, r= -0.617; animal verbal fluency, r=0.728; A verbal fluency, r=0.681; and P verbal fluency, r=0.783), dysexecutive symptoms in daily living (DEX, r= -0.494), dementia severity (CDR, r= -0.75) and functional status in activities of daily living (T-ADLQ, r= -0.745; IADL, r=0.717). Regarding reliability, a Cronbach's alpha coefficient of 0.905 was obtained. For diagnostic accuracy, a cut-off point of 18 points (sensitivity=0.903; specificity=0.867) and an area under curve of 0.951 were estimated to distinguish between patients with dementia and control subjects. Discussion: The IFS-Ch showed acceptable psychometric properties, supported by evidence of validity and reliability for its use in the measurement of executive functions in patients with dementia. The diagnostic accuracy of the IFS-Ch for detecting dementia patients was also considered acceptable

Puntos de cribado de un densitómetro periférico de calcáneo para el diagnóstico de osteoporosis

Objetivo: Determinar los T-score de un densitómetro periférico de calcáneo para obtener una especificidad del 90% en el diagnóstico de osteoporosis y densidad mineral ósea (DMO) normal. Material y métodos: Se realizaron densitometrías por absorciometría dual de rayos X (DXA) en calcáneo (PIXI-LUNAR) y central (HOLOGIC) a 693 mujeres remitidas para estudio de osteoporosis. Se calculó mediante curvas ROC (receiver operator characteristic curve) la sensibilidad y especificidad de los distintos T-scores del densitómetro periférico para el diagnóstico de osteoporosis y normalidad. Resultados: La edad media era de 58,2 ± 9,6 años (30 y 93 años). Los T-score del PIXI para detectar osteoporosis y normalidad con una especificidad del 90% fueron -1,3 y + 0,6 respectivamente. Conclusión: Un T-score inferior a -1,3 o superior a +0,6 a nivel del calcáneo indican alta probabilidad de osteoporosis y normalidad respectivamente. Sólo debería realizarse densitometría central cuando la DMO periférica se encontrase entre estos valores.Proyecto financiado por la Generalitat Valenciana – Conselleria de Sanitat – DOGV 5337 – 1.09.2007 – Resolución 20.10.200

The relationship between physical activity, apolipoprotein E ε4 carriage, and brain health

Background Neuronal hyperexcitability and hypersynchrony have been described as key features of neurophysiological dysfunctions in the Alzheimer’s disease (AD) continuum. Conversely, physical activity (PA) has been associated with improved brain health and reduced AD risk. However, there is controversy regarding whether AD genetic risk (in terms of APOE ε4 carriage) modulates these relationships. The utilization of multiple outcome measures within one sample may strengthen our understanding of this complex phenomenon. Method The relationship between PA and functional connectivity (FC) was examined in a sample of 107 healthy older adults using magnetoencephalography. Additionally, we explored whether ε4 carriage modulates this association. The correlation between FC and brain structural integrity, cognition, and mood was also investigated. Results A relationship between higher PA and decreased FC (hyposynchrony) in the left temporal lobe was observed among all individuals (across the whole sample, in ε4 carriers, and in ε4 non-carriers), but its effects manifest differently according to genetic risk. In ε4 carriers, we report an association between this region-specific FC profile and preserved brain structure (greater gray matter volumes and higher integrity of white matter tracts). In this group, decreased FC also correlated with reduced anxiety levels. In ε4 non-carriers, this profile is associated with improved cognition (working and episodic memory). Conclusions PA could mitigate the increase in FC (hypersynchronization) that characterizes preclinical AD, being beneficial for all individuals, especially ε4 carriers