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

Joanna M. Wardlaw* (Corresponding Author), Stephen J. Makin, Maria C. Valdés Hernández, Paul A. Armitage, Anna K. Heye, Francesca M. Chappell, Susana Muñoz-Maniega, Eleni Sakka, Kirsten Shuler, Martin S. Dennis, Michael J. Thrippleton

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

162 Citations (Scopus)
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IntroductionSmall vessel disease (SVD) is a common contributor to dementia. Subtle blood-brain barrier (BBB) leakage may be important in SVD-induced brain damage.MethodsWe 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.ResultsIn 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.DiscussionBBB leakage increases in normal-appearing white matter with WMH and predicts worsening cognition. Interventions to reduce BBB leakage may prevent SVD-associated dementia.
Original languageEnglish
Pages (from-to)634-643
Number of pages10
JournalAlzheimer's and Dementia
Issue number6
Early online date27 Oct 2016
Publication statusPublished - 1 Jun 2017

Bibliographical note

We thank the participants, their relatives, and carers for their time and patience in contributing to the study, the staff of NHS Lothian Stroke Services, and the Brain Research Imaging Centre Edinburgh for their assistance in recruiting and assessing the patients. Funding: Wellcome Trust (WT088134/Z/09/A), Row Fogo Charitable Trust, Scottish Funding Council Scottish Imaging Network A Platform for Scientific Excellence collaboration, Age-UK Disconnected Mind Study, NHS Lothian R+D Department, and The Brain Research Imaging Centre Edinburgh ( Conflict of interest: All authors report grants from Wellcome Trust, grants from Row Fogo Charitable Trust, grants from Age UK, and grants from Scottish Funding Council, during the conduct of the study. Role of the funding source: The funders had no role in the planning, execution, analysis of the study, or preparation of the manuscript or decision to submit. The authors hold the data.


  • blood brain barrier
  • small vessel disease
  • stroke
  • white matter hyperintensities
  • dementia


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