Sex‐Specific Differences in Life Span Brain Volumes in Multiple Sclerosis

Abstract

Numerous sex-specific differences in multiple sclerosis (MS) susceptibility, disease manifestation, disability progression, inflammation, and neurodegeneration have been previously reported. Previous magnetic resonance imaging (MRI) studies have shown structural differences between female and male MS brain volumes. To determine sex-specific global and tissue-specific brain volume throughout the MS life span in a real-world large MRI database. METHODS: A total of 2,199 MS patients (female/male ratio of 1,651/548) underwent structural MRI imaging on either a 1.5-T or 3-T scanner. Global and tissue-specific volumes of whole brain (WBV), white matter, and gray matter (GMV) were determined by utilizing Structural Image Evaluation using Normalisation of Atrophy Cross-sectional (SIENAX). Lateral ventricular volume (LVV) was determined with the Neurological Software Tool for REliable Atrophy Measurement (NeuroSTREAM). General linear models investigated sex and age interactions, and post hoc comparative sex analyses were performed. RESULTS: Despite being age-matched with female MS patents, a greater proportion of male MS patients were diagnosed with progressive MS and had lower normalized WBV (P < .001), GMV (P < .001), and greater LVV (P < .001). In addition to significant stand-alone main effects, an interaction between sex and age had an additional effect on the LVV (F-statistics = 4.53, P = .033) and GMV (F-statistics = 4.59, P = .032). The sex and age interaction was retained in both models of LVV (F-statistics = 3.31, P = .069) and GMV (F-statistics = 6.1, P = .003) when disease subtype and disease-modifying treatment (DMT) were also included. Although male MS patients presented with significantly greater LVV and lower GMV during the early and midlife period when compared to their female counterparts (P < .001 for LVV and P < .019 for GMV), these differences were nullified in 60+ years old patients. Similar findings were seen within a subanalysis of MS patients that were not on any DMT at the time of enrollment. CONCLUSION: There are sex-specific differences in the LVV and GMV over the MS life span.

Sex is a defining feature of neuroimaging phenotypes in major brain disorders

“…In a recent lifespan study of brain volume trajectories of 2,199 MS patients (75.1% female, M age = 46 ± 11.6), significant age-by-sex interactions were observed for volumes in the lateral ventricle and total normalized gray matter (adjusted for head size using FSL's SEINAX). Post hoc analyses conducted in 10-year age bands (ranging from 18 to 60 + years) revealed significantly lower lateral ventricle volumes in female than male MS patients specifically between ages 40 and 60, whereas gray matter volumes were lower in male than female patients between ages 18 and 59, but not after age 60 (Jakimovski et al, 2020). The lack of significant sex differences after age 60 are consistent with many other studies discussed in this review, and may be driven by worsening of symptoms in females due to estrogen loss at menopause.…”

“…As CIS is not typically defined as an MS subtype in clinical research, direct comparison of results to other studies should be interpreted with caution. Indeed, exploratory statistical models that included MS subtype as a covariate predictor of imaging outcomes were significant, but post hoc analyses by subtype were not reported (Jakimovski et al, 2020).…”

Sex-specific signatures of intrinsic hippocampal networks and regional integrity underlying cognitive status in multiple sclerosis

“…Several pathophysiological processes, ranging from inflammatory demyelination, decreased dendritic and axonal density to neuronal cell loss and gliosis have been proposed as primers of regional hippocampal atrophy in MS. 52 , 53 One must be confident that additionally to sex, variation in the volumes of distinct hippocampal subfields might be attributed to different factors that selectively impact the integrity of the subfields, i.e. age, 54 , 55 brain volume changes during the life span, 56 cardiovascular, pro-inflammatory and APOEε4 risk factors. 57 …”

Structural and functional brain damage in women with multiple sclerosis: A mini-review of neuroimaging sex-based studies

“…Interestingly, in a total sample of 2,199 MS patients (female/male ratio of 1,651/548) age-matched followed through life, WMS, showed a greater proportion of RR course, lower lesion volume and greater GM and WM volumes from baseline to early and midlife. However, these differences were nullified in patients after 60-year-old, independently of the use or not of treatment ( 30 ). Likewise to Jakimovski et al ( 30 ), another study strengthens the notion that sex-related differences can disappeared with older age ( 31 ).…”

“…However, these differences were nullified in patients after 60-year-old, independently of the use or not of treatment ( 30 ). Likewise to Jakimovski et al ( 30 ), another study strengthens the notion that sex-related differences can disappeared with older age ( 31 ). In this study, WMS in pre- and post-menopausal phase were compared to age matched men group.…”