Cerebral “microvascular” disease occurs in lacunar stroke, leukoaraiosis, vascular dementia and Alzheimer’s disease. It may arise from or contribute to insidious damage to the blood-brain barrier (BBB). We systematically reviewed the literature for evidence that BBB permeability is altered in patients with manifestations of cerebral microvascular disease. We found 31 BBB permeability studies (1953 individuals) of normal ageing or cerebral microvascular disease. In healthy humans, increasing age (10 comparisons, controls(C): subjects(S) = 357:336) was associated with increased BBB permeability (standardised mean difference (S.M.D.) 1.21, 95% confidence interval (CI) 0.60, 1.81, p < 0.01). BBB permeability was increased further inpatients with either vascular or Alzheimer's dementia compared with age-matched controls (26 comparisons, C:S = 510:547, S.M.D). 0.81, 99% CI 0.37, 1.26, p < 0.01); in vascular compared with Alzheimer's dementia (10 comparisons, C:S = 291:165, S.M.D. 0.71, 99% CI 0.12, 1.29, p < 0.01); and with worsening leukoaraiosis (5 comparisons,C:S = 122:88, S.M.D. 0.60, 99%CI 0.30, 0.89, p < 0.01). BBB permeability increases with normal ageing and maybe an important mechanism in the initiation or worsening of cerebral microvascular disease. Further studies on the role of BBB permeability are urgently needed. (C) 2007 Elsevier Inc. All rights reserved.