Sex-Specific Patterns of Body Mass Index Relationship with White Matter Connectivity

Abstract

Background: Obesity is an increasingly recognized modifiable risk factor for Alzheimer’s disease (AD). Increased body mass index (BMI) is related to distinct changes in white matter (WM) fiber density and connectivity. Objective: We investigated whether sex differentially affects the relationship between BMI and WM structural connectivity. Methods: A cross-sectional sample of 231 cognitively normal participants were enrolled from the Knight Alzheimer Disease Research Center. Connectome analyses were done with diffusion data reconstructed using q-space diffeomorphic reconstruction to obtain the spin distribution function and tracts were selected using a deterministic fiber tracking algorithm. Results: We identified an inverse relationship between higher BMI and lower connectivity in the associational fibers of the temporal lobe in overweight and obese men. Normal to overweight women showed a significant positive association between BMI and connectivity in a wide array of WM fibers, an association that reversed in obese and morbidly obese women. Interaction analyses revealed that with increasing BMI, women showed higher WM connectivity in the bilateral frontoparietal and parahippocampal parts of the cingulum, while men showed lower connectivity in right sided corticostriatal and corticopontine tracts. Subgroup analyses demonstrated comparable results in participants with and without positron emission tomography or cerebrospinal fluid evidence of brain amyloidosis, indicating that the relationship between BMI and structural connectivity in men and women is independent of AD biomarker status. Conclusion: BMI influences structural connectivity of WM differently in men and women across BMI categories and this relationship does not vary as a function of preclinical AD.

Edge Density Imaging Identifies White Matter Biomarkers of Late-Life Obesity and Cognition

“…Disrupted structural connectome in these fibers, notably in the fornix, AF, and IFOF have been noted with conversion to AD from mild cognitive impairment [56][57][58]58]. Similarly we have shown changes in the connectivity in these WM fibers with increasing BMI in healthy older adults [15]. These associational WM fibers connect the medial temporal lobe to other parts of the limbic system.…”

“…Later work confirmed an independent relationship between obesity and white matter (WM) integrity in adults. Higher body-mass index (BMI), waist circumference or waist-to-hip ratio in mid-life adults is predictive of lower fractional anisotropy (FA) and decreased connectivity in the WM [9][10][11][12][13][14][15]. These mechanisms are shown to as least partly mediate the link between obesity and disrupted WM integrity and connectome through reduction of axonal density and demyelination [16][17][18].…”

“…Implementation of graphtheoretical approaches with diffusion MRI tractography has identified such large-scale relationships, a framework referred to as the structural WM connectome [27]. Using such techniques, decreased WM connectivity with higher BMI has been identified in the brain's taste-reward circuitry that regulates food intake, as well as in several WM tracts associated with cognition [15,[28][29][30]. Among the more recently developed graph-theory based analyses, edge density imaging/index (EDI) is a technique that uses tractography to map the anatomical routes that individual pairs of gray matter regions use to communicate with one another [31].…”

A Cross-Sectional Study of Alzheimer-Related Proteins in Women with Polycystic Ovary Syndrome

“…Insulin resistance leads to changes in insulin signaling through the PBK/AKT and MAPK pathways, leading to metabolic effects and cell homeostasis [47]; changes in insulin resistance may contribute to the sustained chronic inflammatory response in the AD brain that facilitates neurofibrillary tangle development and β-amyloid plaques [48]. Obesity is common in both PCOS and T2D, and obesity is also associated with an increased risk of AD [49]. This, then, presents a complex milieu, with insulin resistance leading to increased obesity because of compensatory hyperinsulinemia [50]; however, conversely, obesity, through mechanisms of chronic inflammation, adipokine activation and mitochondrial dysfunction [18], leads to insulin resistance, so a vicious cycle may result.…”

Vascular risk factors modulate gender-specific aging of brain white matter structural network

“…Although prior studies have investigated the effects of VRFs on the architecture of the WM network [7][8][9][10] , most studies have focused on only a single VRF, and their results varied considerably due to small sample sizes and heterogeneity. For example, a recent study found no significant association between obesity and aging WM network architecture 11 , but Rahmani and colleagues identified gender-specific effects of increasing body mass index on WM network 12 . Therefore, large, homogeneous cohorts with comprehensive surveys are necessary to compare the effect sizes and the patterns of impairment caused by VRFs on the WM network, particularly with regards to gender-related effects.…”