Relation Between Sex, Menopause, and White Matter Hyperintensities

Abstract

Background and ObjectivesMounting evidence implies that there are sex differences in white matter hyperintensity (WMH) burden in older people. Questions remain regarding possible differences in WMH burden between men and women of younger age, sex-specific age trajectories and effects of (un)controlled hypertension, and the effect of menopause on WMH. Therefore, our aim was to investigate these sex differences and age dependencies in WMH load across the adult life span and to examine the effect of menopause.MethodsThis cross-sectional analysis was based on participants of the population-based Rhineland Study (30–95 years) who underwent brain MRI. We automatically quantified WMH using T1-weighted, T2-weighted, and fluid-attenuated inversion recovery images. Menopausal status was self-reported. We examined associations of sex and menopause with WMH load (logit-transformed and z-standardized) using linear regression models while adjusting for age, age-squared, and vascular risk factors. We checked for an age × sex and (un)controlled hypertension × sex interaction and stratified for menopausal status comparing men with premenopausal women (persons aged 59 years or younger), men with postmenopausal women (persons aged 45 years or older), and premenopausal with postmenopausal women (age range 45–59 years).ResultsOf 3,410 participants with a mean age of 54.3 years (SD = 13.7), 1,973 (57.9%) were women, of which 1,167 (59.1%) were postmenopausal. We found that the increase in WMH load accelerates with age and in a sex-dependent way. Premenopausal women and men of similar age did not differ in WMH burden. WMH burden was higher and accelerated faster in postmenopausal women compared with men of similar age. In addition, we observed changes related to menopause, in that postmenopausal women had more WMH than premenopausal women of similar age. Women with uncontrolled hypertension had a higher WMH burden compared with men, which was unrelated to menopausal status.DiscussionAfter menopause, women displayed a higher burden of WMH than contemporary premenopausal women and men and an accelerated increase in WMH. Sex-specific effects of uncontrolled hypertension on WMH were not related to menopause. Further studies are warranted to investigate menopause-related physiologic changes that may inform on causal mechanisms involved in cerebral small vessel disease progression.

Associations between abdominal adipose tissue, reproductive span, and brain characteristics in post-menopausal women

“…Based on recent studies suggesting that tissue-specific age prediction can provide further detail ( Beck et al, 2022 , de Lange et al, 2020a , Eavani et al, 2018 , Voldsbekk et al, 2021 ), we estimated GM and WM brain age separately. WMH volume derived from T2 fluid-attenuated inversion recovery (FLAIR) images was examined as an additional measure, as a number of studies indicate higher WMH prevalence in females compared to males ( Alqarni et al, 2021 , Jorgensen et al, 2018 , Lohner et al, 2022 , Sachdev et al, 2009 , Than et al, 2021 , Van Den Heuvel et al, 2004 ) and recent evidence points to sex-specific associations between cardiometabolic risk factors and WMH pathology ( Alqarni et al, 2021 ). Sex differences in WMH prevalence have been observed to primarily emerge after the age of 50 ( Wen et al, 2009 ), which is close to the average age of menopause (51 years, ( InterLACE, 2019 )), or specifically after the menopause ( Jorgensen et al, 2018 , Lohner et al, 2022 , Than et al, 2021 ), indicating a link between WMHs and female endocrine ageing processes ( Thurston et al, 2016 ).…”

“…WMH volume derived from T2 fluid-attenuated inversion recovery (FLAIR) images was examined as an additional measure, as a number of studies indicate higher WMH prevalence in females compared to males ( Alqarni et al, 2021 , Jorgensen et al, 2018 , Lohner et al, 2022 , Sachdev et al, 2009 , Than et al, 2021 , Van Den Heuvel et al, 2004 ) and recent evidence points to sex-specific associations between cardiometabolic risk factors and WMH pathology ( Alqarni et al, 2021 ). Sex differences in WMH prevalence have been observed to primarily emerge after the age of 50 ( Wen et al, 2009 ), which is close to the average age of menopause (51 years, ( InterLACE, 2019 )), or specifically after the menopause ( Jorgensen et al, 2018 , Lohner et al, 2022 , Than et al, 2021 ), indicating a link between WMHs and female endocrine ageing processes ( Thurston et al, 2016 ). We used Bayesian linear models to assess relationships between the brain measures and VAT and ASAT, and included interaction terms to test if associations varied depending on reproductive span.…”

Associations of macular microvascular parameters with cerebral small vessel disease in rural older adults: A population-based OCT angiography study

“…It has been hypothesized that estrogens can increase tissue perfusion of the retina and brain probably by reducing vascular resistance, protecting against oxidative stress, and stimulating synaptogenesis in premenopausal women ( 34 , 35 ). However, estrogen levels decline markedly after the menopause, the vascular protection of estrogen disappears and women become more susceptible to vascular changes and diseases in the brain ( 34 , 36 ).…”

White matter hyperintensity distribution differences in aging and neurodegenerative disease cohorts

“…In the MCI, V-MCI, and PD-CIE groups, women had significantly lower WMH volumes for bilateral occipital lobes. Sex specific differences in prevalence of WMHs might also be in part due to differences in prevalence of and susceptibility to underlying associated risk factors such as hypertension, diabetes and obesity, hypercholesterolemia, alcohol abuse, and smoking ( Bonberg et al, 2022 , Lohner et al, 2022 ). While we did not have this data available, investigating the prevalence of vascular risk factors in 51,338 Canadians, the Canadian Longitudinal Study of Aging (CLSA) have reported higher prevalence of hypertension, heart disease, diabetes, and midlife obesity in men, whereas women had higher rates of late life obesity ( Griffith et al, 2019 ).…”