Cerebral blood flow in small vessel disease: A systematic review and meta-analysis

Abstract

White matter hyperintensities are frequent on neuroimaging of older people and are a key feature of cerebral small vessel disease. They are commonly attributed to chronic hypoperfusion, although whether low cerebral blood flow is cause or effect is unclear. We systematically reviewed studies that assessed cerebral blood flow in small vessel disease patients, performed meta-analysis and sensitivity analysis of potential confounders. Thirty-eight studies (n = 4006) met the inclusion criteria, including four longitudinal and 34 cross-sectional studies. Most cerebral blood flow data were from grey matter. Twenty-four cross-sectional studies (n = 1161) were meta-analysed, showing that cerebral blood flow was lower in subjects with more white matter hyperintensity, globally and in most grey and white matter regions (e.g. mean global cerebral blood flow: standardised mean difference-0.71, 95% CI -1.12, -0.30). These cerebral blood flow differences were attenuated by excluding studies in dementia or that lacked age-matching. Four longitudinal studies (n = 1079) gave differing results, e.g., more baseline white matter hyperintensity predated falling cerebral blood flow (3.9 years, n = 575); cerebral blood flow was low in regions that developed white matter hyperintensity (1.5 years, n = 40). Cerebral blood flow is lower in subjects with more white matter hyperintensity cross-sectionally, but evidence for falling cerebral blood flow predating increasing white matter hyperintensity is conflicting. Future studies should be longitudinal, obtain more white matter data, use better age-correction and stratify by clinical diagnosis.

Keywords: Cerebral blood flow; cerebral small vessel disease; meta-analysis; systematic review; white matter hyperintensities.

Figure 1.

PRISMA flow diagram of literature search.

Figure 2.

(a) Forest plot showing standard mean differences in global and grey matter CBF in patients with WMH in dementia and non-dementia studies. CBF in different brain regions was analysed in subgroups. (b) Forest plot showing standard mean differences in white matter CBF in patients with WMH in dementia and non-dementia studies. CBF in different brain regions was analysed in subgroups. CBF: cerebral blood flow; WMH: white matter hyperintensity.

Figure 3.

Sensitivity analysis: SMDs of CBF in different brain areas in patients with moderate to severe WMH against those with negative to mild WMH. In each brain area, we showed the SMD of CBF in all studies, after excluding dementia studies and furthermore excluding studies without age-matching [number of studies] (number of participants). SMD: standard mean difference; CBF: cerebral blood flow; GM: grey matter; WM: white matter; WMH: white matter hyperintensity; CI: confidence interval.