Neuroinflammation and White Matter Alterations in Obesity Assessed by Diffusion Basis Spectrum Imaging

Abstract

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 nonobese 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 corrected p < 0.05). Moreover, using region of interest analyses, average DBSI-RF and DBSI-FF values in the hippocampus were significantly greater and lower, respectively, in obese relative to non-obese individuals (Cohort 1: p = 0.045; Cohort 2: p = 0.008). Hippocampal DBSI-FF and DBSI-RF and amygdalar DBSI-FF metrics related to cognitive performance in Cohort 2. In conclusion, these findings suggest that greater neuroinflammation-related cellularity and lower apparent axonal density are associated with human obesity and cognitive performance. Future studies are warranted to determine a potential role for neuroinflammation in obesity-related cognitive impairment.

Cardiorespiratory Fitness and Performance in Multiple Domains of Executive Functions in School–Aged Adolescents

“…Studies have shown that excess body weight is not only associated with a lower CRF in adolescents ( Ortega et al, 2007 ), but also negatively and independently impacts EFs ( Tee et al, 2018 ). Although these mechanisms are poorly understood, it is believed that the state of low-grade inflammation generated by body fat can trigger neuroinflammatory and neuroplastic processes that modify brain connectivity ( Samara et al, 2020 ). These changes hinder communication between the inhibitory pre-frontal regions of the brain and its reward circuits, which may lead to predominantly hedonistic mechanisms, impairing the regulation of food intake and sedentary behavior ( Gupta et al, 2015 ; Samara et al, 2020 ).…”

“…Although these mechanisms are poorly understood, it is believed that the state of low-grade inflammation generated by body fat can trigger neuroinflammatory and neuroplastic processes that modify brain connectivity ( Samara et al, 2020 ). These changes hinder communication between the inhibitory pre-frontal regions of the brain and its reward circuits, which may lead to predominantly hedonistic mechanisms, impairing the regulation of food intake and sedentary behavior ( Gupta et al, 2015 ; Samara et al, 2020 ). There is conflicting literature in regards to the relationship between CRF and inhibitory control ( Stroth et al, 2009 ; Huang et al, 2015 ; Pindus et al, 2015 ; Tee et al, 2018 ; Westfall et al, 2018 ).…”

A systematic review of diffusion tensor imaging studies in obesity

“…It has been suggested that in obesity FA might be confounded by inflammatory factors, however, existing evidence is limited. Furthermore, a separate study indicated lower axonal density in obese group suggesting that inflammatory factors further promote WM damage 81 .…”

Resveratrol, Metabolic Dysregulation, and Alzheimer’s Disease: Considerations for Neurogenerative Disease

“…Importantly, obesity has been linked to insulin resistance and T2D by inducing pro-inflammatory signaling cascades that inhibit insulin signaling [ 12 , 33 , 34 ]. Obesity is also a strong predictor of cognitive impairment, with neuroinflammation playing a key role in developing the observed reductions in brain volume [ 13 , 19 , 35 , 36 , 37 , 38 ]. This connection between peripheral factors including inflammation, hyperinsulinemia, and hyperglycemia and brain health serves to highlight the role that metabolic diseases play in AD and the promising impact that T2D therapeutics may have in the prevention and treatment of neurodegenerative diseases [ 7 , 19 , 39 ].…”

“…(Neuro)inflammation offers an important connection for the metabolic impairments seen in AD [ 16 , 17 ]. The development of chronic, low-grade systemic inflammation is present early in both T2D and obesity, where pro-inflammatory cytokines are released from M1-type macrophages (TNF- , IL-6, IL-12, IL-18) [ 36 , 37 , 40 , 41 ]. Under healthy conditions, these cytokines are secreted acutely to mitigate infection through increased ROS and nitrous oxide (NO) generation [ 42 ].…”