Cerebral small vessel disease (SVD) is a major contributor to stroke and dementia, characterized by white matter hyperintensities (WMH) on neuroimaging. WMH are associated with reduced cerebral blood flow (CBF) cross-sectionally, though longitudinal associations remain unclear. We updated a 2016 systematic review, identifying 30 new studies, 27 cross-sectional (n = 2,956) and 3 longitudinal (n = 440). Cross-sectionally, 10/27 new studies (n = 1,019) included sufficient data for meta-analysis, which we meta-analyzed with 24 previously reported studies (n = 1,161), total 34 (n = 2,180). Our meta-analysis showed that patients with lower CBF had worse WMH burden (mean global CBF: standardized mean difference (SMD): −0.45, 95% confidence interval (CI): −0.64, −0.27). Longitudinally, associations between baseline CBF and WMH progression varied: the largest study (5 years, n = 252) found no associations, while another small study (4.5 years, n = 52) found that low CBF in the periventricular WMH penumbra predicted WMH progression. We could not meta-analyse longitudinal studies due to different statistical and methodological approaches. We found that CBF was lower in WMH than in normal-appearing white matter in an additional meta-analysis (5 cross-sectional studies; n = 295; SMD: −1.51, 95% CI: −1.94, −1.07). These findings highlight that relationships between resting CBF and WMH are complex. Further longitudinal studies analyzing regional CBF and subsequent WMH change are required to determine the role of CBF in SVD progression.

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].

Cerebral small vessel disease is a major contributor to stroke and dementia, characterised by white matter hyperintensities (WMH) on neuroimaging. WMH are associated with reduced cerebral blood flow (CBF) cross-sectionally, though longitudinal associations remain unclear. We updated a 2016 meta-analysis, identifying 30 studies, 27 cross-sectional (n=2956) and 3 longitudinal (n=440), published since 2016. Cross-sectionally, we meta-analysed 10 new studies with 24 previously reported studies, total 34 (n=2180), finding lower CBF to be associated with worse WMH burden (mean global CBF: standardised mean difference: -0.45, 95% confidence interval (CI): -0.64,-0.27). Longitudinally, the association of baseline CBF with WMH progression varied: the largest study (5 years, n=252) found no associations, while another small study (4.5 years, n=52) found that low CBF in the periventricular WMH penumbra predicted WMH progression. We could not meta-analyse longitudinal studies due to different statistical and methodological approaches. We found lower CBF within WMH compared to normal appearing white matter (novel meta-analysis; 5 cross-sectional studies; n=295; SMD: -1.51, 95% CI: -1.94,-1.07). These findings highlight that relationships between resting CBF and WMH are complex and that more longitudinal studies analysing regional CBF and subsequent WMH change are required to determine the role of CBF in small vessel disease progression.

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.