Sex Differences in Cerebral Small Vessel Disease: A Systematic Review and Meta-Analysis

Abstract

Background: Cerebral small vessel disease (SVD) is a common cause of stroke, mild cognitive impairment, dementia and physical impairments. Differences in SVD incidence or severity between males and females are unknown. We assessed 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: We assessed four recent systematic reviews on SVD and performed a supplementary search of MEDLINE to identify studies reporting M:F ratio in covert, stroke, or cognitive SVD presentations (registered protocol: CRD42020193995). We meta-analyzed differences in sex ratios across time, countries, SVD severity and presentations, age and risk factors for SVD. Results: Amongst 123 relevant studies (n = 36,910 participants) including 53 community-based, 67 hospital-based and three mixed studies published between 1989 and 2020, 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], and stroke presentations where M:F was 1.67 (0.53). M:F did not differ for recent (2015-2020) vs. pre-2015 publications, by geographical region, or age. 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 severity and amongst those presenting with stroke that have important clinical and translational implications. Future SVD research should report participant demographics, risk factors and outcomes separately for males and females. Systematic Review Registration: [PROSPERO], identifier [CRD42020193995].

Keywords: cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL); cerebral small vessel disease (SVD); lacunar stroke; sex differences; vascular dementia (VaD).

Figure 1

Study selection flow diagram. AD, Alzheimer's Disease; MCI, mild cognitive impairment.

Figure 2

Sex ratio of SVD studies across study setting and time. (A) Comparison of sex ratios per study type. Significant differences were found between sex ratios of community-based (CB) and hospital-based (HB) studies (p_corrected < 0.001). (B) Correlation between the sex ratio difference and the size of the recruited sample. Δ sex ratio = |sex ratio of general population – sex ratio of each study|. Given that the mean age of the participants of the included studies was 67, general population sex ratio corresponds to 70-year old population (89 males per 100 females) (22). There was a negative correlation between Δ sex ratio and the size of the population recruited in community studies (yellow, rho_Spearman = −0.46, p < 0.001) but not in hospital studies (blue, rho_Spearman = −0.10, p = 0.43). (C,D) Comparison of sex ratios across time. No significant differences were found between sex ratios of recent studies compared with those previously published considering all included studies (n_2015−2020 = 53 vs. n_1989−2014 = 67, U = 1,814, p = 0.75), (C) CB studies (n_2015−2020 = 22 vs. n_1989−2014 = 31, U = 372, p = 0.58) or (D) HB studies (n_2015−2020 = 31 vs. n_1993−2014 = 36, U = 551, p = 0.93). ***p < 0.001.

Figure 3

Sex ratio of SVD studies across the world. Colored world maps representing the mean sex ratio of the total number of participants of (A) community-based and (B) hospital-based studies. Darker shades in the color gradient correspond to higher sex ratios (i.e., more males than females). The tables on the right specify the country of recruited participants, the number of included studies and the total population of included studies per study type. Neither multicentre nor mixed studies were represented in these maps. AUS, Australia; BRA, Brazil; CAN, Canada; CHN, China; DEU, Germany; EGY, Egypt; ESP, Spain; FRA, France; HKG, Hong Kong; IRL, Ireland; ISR, Israel; ITA, Italy; JPN, Japan; KOR, Korea; MEX, Mexico; NLD, The Netherlands; POL, Poland; PRT, Portugal; SGP, Singapore; SVN, Slovenia; SWE, Sweden; TWN, Taiwan; UK, United Kingdom; USA, The United States of America.

Figure 4

Sex ratio across SVD severity and presentation. Sex ratio of healthy to mild SVD compared with (A) moderate to severe SVD and (B) stratified moderate to severe SVD. Significant differences were found between SVD severity groups i.e., sex ratios of healthy to mild SVD and moderate to severe SVD (A; U = 3,031, p < 0.001). Significant differences were also found between SVD presentation groups (H = 36.58, df = 3, p < 0.001) i.e., stroke presentations of SVD compared with healthy to mild covert SVD, moderate to severe covert SVD or cognitive SVD (B; p_corrected < 0.001, p_corrected < 0.001, p_corrected = 0.003, respectively). **p < 0.01, ***p < 0.001.