Blood‐brain barrier failure as a core mechanism in cerebral small vessel disease and dementia: evidence from a cohort study

Abstract Introduction Small vessel disease (SVD) is a common contributor to dementia. Subtle blood‐brain barrier (BBB) leakage may be important in SVD‐induced brain damage. Methods We assessed imaging, clinical variables, and cognition in patients with mild (i.e., nondisabling) ischemic lacunar or cortical stroke. We analyzed BBB leakage, interstitial fluid, and white matter integrity using multimodal tissue‐specific spatial analysis around white matter hyperintensities (WMH). We assessed predictors of 1 year cognition, recurrent stroke, and dependency. Results In 201 patients, median age 67 (range 34–97), BBB leakage, and interstitial fluid were higher in WMH than normal‐appearing white matter; leakage in normal‐appearing white matter increased with proximity to WMH ( P < .0001), with WMH severity ( P = .033), age ( P = .03), and hypertension ( P < .0001). BBB leakage in WMH predicted declining cognition at 1 year. Discussion BBB leakage increases in normal‐appearing white matter with WMH and predicts worsening cognition. Interventions to reduce BBB leakage may prevent SVD‐associated dementia.