Sex differences in Cerebral Small Vessel Disease: a systematic review and meta-analysis

Abstract

Background: Cerebral small vessel disease (SVD) is an important cause of acute ischemic stroke and vascular dementia. Several studies recruiting more males than females have reported sex differences regarding SVD incidence and severity, but it is unclear whether this reflects underlying sex-specific mechanisms or recruitment bias. This work aimed to systematically review and meta-analyze potential sex differences in SVD by assessing the male-to-female ratio (M:F) of recruited participants and incidence of SVD, risk factor presence, distribution and severity of SVD features. Methods: Full text of 228 studies from four databases of recent systematic reviews on SVD and an independent search of MEDLINE were evaluated against inclusion and exclusion criteria (registered protocol: CRD42020193995). Data from participants with clinical or non-clinical presentations of SVD with radiological evidence of SVD were extracted. Sex ratios of total participants or SVD groups were calculated and differences in sex ratios across time, countries, SVD severity and risk factors for SVD were explored. Results: Amongst 123 relevant studies (n = 36,910 participants) including 53 community-based, 67 hospital-based and 3 mixed studies, more males were recruited in hospital-based than in community-based studies (M:F = 1.16 (0.70) vs M:F = 0.79 (0.35), respectively; p <0.001). More males had moderate to severe SVD (M:F = 1.08 (0.81) vs M:F = 0.82 (0.47) in healthy to mild SVD; p <0.001), especially in stroke presentations where M:F was 1.67 (0.53). M:F of recent research (2015-2020) did not differ from that published pre-2015 and no geographical trends were apparent. There were insufficient sex-stratified data to explore M:F and risk factors for SVD. Conclusions: Our results highlight differences in male-to-female ratios in SVD that may reflect sex-specific variability in risk factor exposures, study participation, clinical recognition, genuine SVD severity, or clinical presentation and have important clinical and translational implications.

Phenotypic variability in 446 CADASIL patients: Impact of NOTCH3 gene mutation location in addition to the effects of age, sex and vascular risk factors

“…This is in line with data already obtained in a limited sample of this cohort 14 as well as, more generally in sporadic small vessel diseases. 48 We also found that any previous history of hypertension was independently associated with the occurrence of stroke manifestations, dementia and dependency as already reported. 42,49 We confirmed in parallel that hypertensive patients had more lacunes and microbleeds as already detected.…”

Circulating Metabolome and White Matter Hyperintensities in Women and Men

“…Previous literature on sex differences in WMH is not extensive. [65][66][67] Sex hormones may play a role, as they show direct effects on the endothelium 68 and multiple brain cells, including oligodendrocytes producing myelin 69 and neurons. 70 In our study, female hormonal status was not likely a major factor in the observed sex specificities, as female participants were likely menopausal (average age >60 years).…”

The global burden of cerebral small vessel disease in low- and middle-income countries: A systematic review and meta-analysis

“…This phenomenon was reported in a previous systematic review that reported a high male: female ratio in cohorts with higher SVD burden and among those with stroke. 62 While this may reflect recruitment bias seen in many hospital-based stroke treatment trials that include neuroimaging for cSVD, it may also imply that males develop higher cSVD severity, especially in stroke presentations which may, in turn, reflect male: female ratio differences in metabolomic. 63 Conversely, the male: female ratio did not predict cSVD prevalence in this meta-analysis, possibly due to the diluting effect of community-based studies in which cSVD prevalences are low.…”