Abstract
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.
Highlights
Cerebral small vessel disease (SVD) develops from pathological changes in the blood vessels supplying the brain and is an underlying cause of about 20% of all strokes and the most substantial contributor to vascular dementia (1)
We included 30 studies for qualitative analysis, of which 15 studies provided data for meta-analysis (Figure 1). Of these 15, 10 cross-sectional studies were meta-analyzed with data previously extracted from 24 crosssectional studies published between 1946 and 2015 (3) while 5 studies were included in the additional meta-analysis of regional variability in cerebral blood flow (CBF) within white matter hyperintensities (WMH) and normal appearing white matter (NAWM)
Longitudinal findings were mixed, the largest studies (n = 575 + 252) found baseline global CBF was not associated with WMH progression (19), as such there is no definite association between low CBF and increasing WMH long term
Summary
Cerebral small vessel disease (SVD) develops from pathological changes in the blood vessels supplying the brain and is an underlying cause of about 20% of all strokes and the most substantial contributor to vascular dementia (1). WMH can be reversible, establishing initial processes involved in WMH development may help identify targets to prevent SVD progression and related pathology (4, 5). Our previous systematic review and meta-analysis of WMH and CBF found that more severe WMH burden was associated with lower CBF, this association weakened when studies of patients with dementia and poor age matching of controls were excluded (3). Dementia, and other vascular risk factors contribute to CBF reductions and can confound the relationship between WMH burden and CBF (3). There were few data on sub-regional brain tissue CBF and longitudinal WMH changes in our previous review (3), as most studies only examined whole brain and/or cortical CBF
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