The effects of age and hypertension on cerebral small‐vessel disease differ between men and women at midlife: The PREVENT Dementia study

Abstract

AbstractBackgroundSex differences exist in the prevalence, prognosis, and clinical manifestation of cerebral small vessel disease (SVD) and dementia. Given the role of SVD in cognitive impairment – both directly and through accelerating neurodegenerative pathology – understanding sex differences in SVD risk factors could inform targeted intervention strategies. In this longitudinal study, we examined sex differences in the effects of age and hypertension on SVD at midlife.Method185 cognitively‐healthy midlife adults underwent 3T MRI at baseline and two‐year follow‐up. SVD markers were white matter hyperintensities (WMH) volume, enlarged perivascular spaces, microbleeds, lacunes, and global SVD burden (composite score of all four SVD markers). Piecewise linear regression analysis estimated change‐points in age, beyond which WMH accelerates. To examine sex as a moderator of age and hypertension on SVD cross‐sectionally, interaction analysis was conducted in general linear models, adjusting for age and education. To assess interactions on longitudinal SVD progression, linear mixed effects models were fitted, adjusting for the same covariates and random intercept of subjects.ResultMales were twice as likely to have hypertension compared to females (males:53.8%, females:26.4%, X 2=7.97, p=.005). Interaction analysis demonstrated that the effect of hypertension on SVD was amplified in females, compared to males, both cross‐sectionally (WMH: t=2.42, p=.017) and longitudinally (WMH progression: t=3.37, p<.001; new microbleeds: t=2.57, p=.011) (Fig 1). Findings remained consistent when additionally controlling for antihypertensive medication. In terms of age, piecewise linear regression estimated a WMH change‐point at age 50.2 (SE=3.2) in the whole sample, 50.6 years (SE=3.8) in males, but was undetectable in females (Fig 2). Sex*age interaction demonstrated that the effect of age on global SVD burden was amplified in males compared to females (t=‐2.43, p=.016) (Fig 3). Sex*age*hypertension interaction showed that hypertension intensified the effect of age on global SVD burden in males but not females (t=‐2.67, p=.008), for whom hypertension was a stronger predictor than age.ConclusionOlder men (especially those with hypertension) and women with hypertension (regardless of age) were at greatest risk of SVD. Our findings highlight the importance of hypertension management as early as midlife in relation to SVD, but suggest that this may be especially effective for women.