Neuroinflammation and white matter alterations in obesity assessed by Diffusion Basis Spectrum Imaging

Human obesity is associated with low-grade chronic systemic inflammation, alterations in brain structure and function, and cognitive impairment. Rodent models of obesity show that high-calorie diets cause brain inflammation (neuroinflammation) in multiple regions, including the hippocampus, and impairments in hippocampal-dependent memory tasks. To determine if similar effects exist in humans with obesity, we applied Diffusion Basis Spectrum Imaging (DBSI) to evaluate neuroinflammation and axonal integrity. We examined diffusion-weighted magnetic resonance imaging (MRI) data in two independent cohorts of obese and non-obese individuals (Cohort 1: 25 obese/21 non-obese; Cohort 2: 18 obese/41 non-obese). We applied Tract-based Spatial Statistics (TBSS) to allow whole-brain white matter (WM) analyses and compare DBSI-derived isotropic and anisotropic diffusion measures between the obese and non-obese groups. In both cohorts, the obese group had significantly greater DBSI-derived restricted fraction (DBSI-RF; an indicator of neuroinflammation-related cellularity), and significantly lower DBSI-derived fiber fraction (DBSI-FF; an indicator of apparent axonal density) in several WM tracts (all correcte

Structural and cognitive correlates of body mass index in healthy older adults

Obesity, commonly measured with body mass index (BMI), is associated with numerous deleterious health conditions and may be a modifier of age-related alterations in brain integrity. Research suggests that white matter integrity observed using diffusion tensor imaging (DTI) is altered with high BMI, but the integrity of specific tracts remains poorly understood. Additionally, no studies have examined fractional anisotropy (FA) of tract integrity in conjunction with neuropsychological evaluation with elevated BMI among older adults. It was hypothesized that elevated BMI would be independently associated with lower white matter integrity and cognitive performance. It was also hypothesized that age and BMI would interact in relation to measures of white matter integrity and cognitive performance. Sixty two healthy older adults aged 51 to 81 were evaluated using DTI and neuropsychological evaluation. Associations were examined between BMI, FA in tracts connecting frontal and temporal lobes, and cognitive ability in domains of executive function, processing speed, and memory. Hierarchical linear regressions were utilized to determine the impact of BMI on FA and cognitive function after accounting for demographics, followed by a test for a BMI by age interaction on FA and cognitive indices. Secondary analyses assessed the sensitivity of DTI diffusivity metrics to elevated BMI, and related tract FA to cognitive performance. After controlling for initial demographic relationships, elevated BMI was associated with lower FA in the uncinate fasciculus, though there was no evidence of an age by BMI interaction relating to FA in this tract. No relationships between BMI and cognition were observed. Secondary analyses did not suggest that DTI diffusivity metrics provide unique information about tract integrity related to high BMI. Overall, results suggest elevated BMI is associated with altered integrity of the uncinate fasciculus. This white matter tract connects frontal and temporal lobes and is involved in memory function. There was no evidence of an age by BMI interaction on FA of the uncinate fasciculus, and BMI did not relate to cognitive performance. Future studies should examine measures of cardiovascular health and systemic inflammation to identify factors influencing relationships between BMI and white matter integrity

Early life factors and white matter microstructure in children with overweight and obesity: The ActiveBrains project

This study was supported by the Spanish Ministry of Economy and Competitiveness (DEP2013-47540, DEP2016-79512-R, and DEP2017-91544-EXP), the European Regional Development Fund, the European Commission (No 667302) and the Alicia Koplowitz Foundation. This study was partially funded by the UGR Research and Knowledge Transfer Fund (PPIT) 2016, Excellence Actions Programme. Units of Scientific Excellence; Scientific Unit of Excellence on Exercise and Health (UCEES) and by the Regional Government of Andalusia, Regional Ministry of Economy, Knowledge, Entreprises and University and European Regional Development Fund (ERDF), ref. SOMM17/6107/UGR. In addition, this study was further supported by the SAMID III network, RETICS, funded by the PN IthornDthornI 2017-2021 (Spain). Additional funding was obtained from the Andalusian Operational Programme supported with European Regional Development Funds (ERDF in English, FEDER in Spanish, project ref: B-CTS-355-UGR18). PS-U is supported by a grant from ANID/BECAS Chile/72180543. IE-C is supported by the Spanish Ministries of Economy and Competitiveness (RTI2018-095284-J-100), and Science and Innovation (RYC2019-027287-I). JV-R is supported by a grant from the Spanish Ministry of Science, Innovation and Universities (FJCI-2017-33396). Funding for open access charge: Universidad de Granada/CBUA. We would like to thank all the families participating in the ActiveBrains. We are grateful to Ms. Ana Yara Postigo-Fuentes for her assistance with the English language. We also acknowledge everyone who helped with the data collection and all of the members involved in the fieldwork for their effort, enthusiasm, and support. This work is part of Ph.D. Thesis conducted in the Biomedicine Doctoral Studies of the University of Granada, Spain.Background & aims: Exposure to a suboptimal environment during the fetal and early infancy period's results in long-term consequences for brain morphology and function. We investigated the associations of early life factors such as anthropometric neonatal data (i.e., birth length, birth weight and birth head circumference) and breastfeeding practices (i.e., exclusive and any breastfeeding) with white matter (WM) microstructure, and ii) we tested whether WM tracts related to early life factors are associated with academic performance in children with overweight/obesity. Methods: 96 overweight/obese children (10.03 +/- 1.16 years; 38.7% girls) were included from the ActiveBrains Project. WM microstructure indicators used were fractional anisotropy (FA) and mean diffusivity (MD), derived from Diffusion Tensor Imaging. Academic performance was evaluated with the Battery III Woodcock-Munoz Tests of Achievement. Regression models were used to examine the associations of the early life factors with tract-specific FA and MD, as well as its association with academic performance. Results: Head circumference at birth was positively associated with FA of the inferior fronto-occipital fasciculus tract (0.441; p = 0.005), as well as negatively associated with MD of the cingulate gyrus part of cingulum (-0.470; p = 0.006), corticospinal (-0.457; p = 0.005) and superior thalamic radiation tract (-0.476; p = 0.001). Association of birth weight, birth length and exclusive breastfeeding with WM microstructure did not remain significant after false discovery rate correction. None tract related to birth head circumference was associated with academic performance (all p > 0.05). Conclusions: Our results highlighted the importance of the perinatal growth in WM microstructure later in life, although its possible academic implications remain inconclusive.Spanish Government DEP2013-47540 DEP2016-79512-R DEP2017-91544-EXPEuropean Commission European Commission European Commission Joint Research Centre 667302Alicia Koplowitz FoundationUGR Research and Knowledge Transfer Fund (PPIT) 2016, Excellence Actions ProgrammeEuropean Commission SOMM17/6107/UGRSAMID III network, RETICS - PN I+D+I 2017-2021 (Spain)Andalusian Operational Programme - European Regional Development Funds B-CTS-355-UGR18ANID/BECAS Chile 72180543Spanish Government RTI2018-095284-J-100 FJCI-2017-33396 RYC2019-027287-

Allostatic load and disordered white matter microstructure in overweight adults

Overweight and stress are both related to brain structural abnormalities. The allostatic load model states that frequent disruption of homeostasis is inherently linked to oxidative stress and inflammatory responses that in turn can damage the brain. However, the effects of the allostatic load on the central nervous system remain largely unknown. The current study aimed to assess the relationship between the allostatic load and the composition of whole-brain white matter tracts in overweight subjects. Additionally, we have also tested for grey matter changes regarding allostatic load increase. Thirty-one overweight-to-obese adults and 21 lean controls participated in the study. Our results showed that overweight participants presented higher allostatic load indexes. Such increases correlated with lower fractional anisotropy in the inferior fronto-occipital fasciculi and the right anterior corona radiata, as well as with grey matter reductions in the left precentral gyrus, the left lateral occipital gyrus, and the right pars opercularis. These results suggest that an otherwise healthy overweight status is linked to long-term biological changes potentially harmful to the brain

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

Mechanisms linking obesity and its metabolic comorbidities with cerebral grey and white matter changes

Obesity is a preventable risk factor for cerebrovascular disorders and it is associated with cerebral grey and white matter changes. Specifically, individuals with obesity show diminished grey matter volume and thickness, which seems to be more prominent among fronto-temporal regions in the brain. At the same time, obesity is associated with lower microstructural white matter integrity, and it has been found to precede increases in white matter hyperintensity load. To date, however, it is unclear whether these findings can be attributed solely to obesity or whether they are a consequence of cardiometabolic complications that often co-exist with obesity, such as low-grade systemic inflammation, hypertension, insulin resistance, or dyslipidemia. In this narrative review we aim to provide a comprehensive overview of the potential impact of obesity and a number of its cardiometabolic consequences on brain integrity, both separately and in synergy with each other. We also identify current gaps in knowledge and outline recommendations for future research

Associations Between Cardiorespiratory Fitness, Adiposity, and White Matter Integrity

White matter (WM) is essential for transmitting neural signal between brain regions, and supporting healthy brain aging and cognitive function. Risk for WM deterioration is heightened in overweight and obesity, whereas increasing cardiorespiratory fitness may promote WM integrity. However, there is a lack of research comparing adiposity and cardiorespiratory fitness with WM. Further, it is not clear whether increasing cardiorespiratory fitness may outweigh the influence of excess adiposity on WM integrity in middle adulthood. In a sample of adults with overweight and obesity, we examined whether cardiorespiratory fitness and adiposity associate with WM integrity, both independently and jointly. We assessed WM pathways sensitive to cardiorespiratory fitness, adiposity, or both, and tested potential interactions. Baseline data from 125 middle-aged participants (Mage = 44.33 ± 8.60), with overweight or obesity (MBMI = 32.45 ± 4.19), were included in the study. Fitness was assessed via a submaximal graded exercise test. To quantify adiposity, whole body estimates of body fat % were calculated using dual-energy X-ray absorptiometry. Diffusion weighted images were acquired during an MRI protocol. We conducted whole-brain voxelwise analyses using the FMRIB’s Software Library randomise function to examine main effects of adiposity and fitness, as well as the interaction term, on WM integrity. After controlling for age, gender, and years of education, there were no significant main effects of adiposity or cardiorespiratory fitness on FA (all p > .05). There was a significant interaction (p = .03) such that with higher fitness levels, greater adiposity was associated with higher WM integrity, whereas with lower fitness levels greater adiposity was negatively associated with WM integrity. This pattern of findings was unexpected, and may be a function of the unique nature of the sample or related to the confounding effects of WM lesions or local inflammation. Future work may focus on accounting for the influence of WM lesions, and extending the analysis to older adults and patient populations

Dysfunction of the hypothalamic-pituitary adrenal axis and its influence on aging: the role of the hypothalamus

As part of the hypothalamic-pituitary adrenal (HPA) axis, the hypothalamus exerts pivotal influence on metabolic and endocrine homeostasis. With age, these processes are subject to considerable change, resulting in increased prevalence of physical disability and cardiac disorders. Yet, research on the aging human hypothalamus is lacking. To assess detailed hypothalamic microstructure in middle adulthood, 39 healthy participants (35-65 years) underwent comprehensive structural magnetic resonance imaging. In addition, we studied HPA axis dysfunction proxied by hair cortisol and waist circumference as potential risk factors for hypothalamic alterations. We provide first evidence of regionally different hypothalamic microstructure, with age effects in its anterior-superior subunit, a critical area for HPA axis regulation. Further, we report that waist circumference was related to increased free water and decreased iron content in this region. In age, hair cortisol was additionally associated with free water content, such that older participants with higher cortisol levels were more vulnerable to free water content increase than younger participants. Overall, our results suggest no general age-related decline in hypothalamic microstructure. Instead, older individuals could be more susceptible to risk factors of hypothalamic decline especially in the anterior-superior subregion, including HPA axis dysfunction, indicating the importance of endocrine and stress management in age