Sex differences in white matter bundle properties across menopausal transition states

Abstract

AbstractBackgroundWomen develop Alzheimer’s disease (AD) at a 2:1 rate compared to men. Changes associated with menopause exacerbate a midlife bioenergetic crisis that, when unsuccessfully resolved, leads to white matter degradation and ultimately brain atrophy. Understanding how white matter structural properties differ between sexes and evolve over midlife transitions may provide insight into the exacerbated AD risk for women. Here, we report differences in white matter bundle properties comparing pre‐ (n = 40, 44.1±3.34y), peri‐ (n = 60, 49.6±3.90y), and post‐menopausal women (n = 70, 56.0±4.12y) to age‐matched males.MethodDiffusion weighted MRI was acquired for each participant. Data were preprocessed with QSIPrep and analyzed using a fixel‐based approach implemented in MRtrix (v. 3.0.3). Fiber density (FD), cross‐section (FC), and a combined density/cross‐section metric (FDC) were compared between sexes after controlling for age, education, APOE ε4 carrier status, and total brain volume (FC and FDC only). Continuous covariates were standardized to 2 standard deviations. Analyses were conducted using connectivity‐enhanced fixel‐based permutation analyses and thresholded at family‐wise error corrected p<0.05.ResultPre‐, peri‐, and post‐ menopausal women exhibited greater FD and FDC in the corpus callosum, inferior occipto‐frontal fasciculus, cortico‐spinal, and cingulum bundles. By contrast, males had greater fiber cross section in the splenium of the corpus callosum (compared to pre‐), (compared to peri‐), and in fibers near the left uncinate fasciculus and inferior longitudinal fasciculus (compared to both peri‐ and post‐menopausal women). After controlling for age, education, total brain volume, and APOE ε4 carrier status, a smaller cluster of fibers in the left splenium survived multiple comparisons correction demonstrating greater fiber cross‐section in post‐menopausal women compared to peri‐menopausal women.ConclusionWomen across menopausal transition states exhibited greater fiber density than their age‐matched male counterparts in commissural and association tracts, which agrees with previous work demonstrating stronger inter‐hemispheric connections in women. However, peri‐ and post‐menopausal females exhibited 4‐8% decrease in fiber cross section in uncinate fasciculus fibers, which have been implicated in Alzheimer’s related cognitive decline. These findings suggest that reductions in white matter cross‐section, particularly in regions associated with Alzheimer’s disease, may begin for women in menopause and be an early indicator of neurodegenerative risk.