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

Joanna M Wardlaw,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

doi:10.1016/j.jalz.2016.09.006

Abstract

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.

Highlights

Worldwide, 36 million people are estimated to be living with dementia [1]
Vascular risk factors did not predict outcome. In this large stratified patient cohort, that subtle increases in blood-brain barrier (BBB) leakage appear to be widespread in normal-appearing white matter and more pronounced in white matter hyperintensities (WMH), increasing with the visible severity of tissue damage
BBB leakage in normal-appearing white matter and in WMH was worst in patients with severe WMH, with hypertension and increased pulse pressure

Summary

Introduction

Cerebral small vessel disease (SVD) causes about 40% of these dementias, alone or in mixed pathologies [2]. SVD causes a fifth of the 15 million strokes that occur per year worldwide [1]. These threemillion SVD (or lacunar) strokes are not severe; so, most lacunar stroke patients survive physically independent, but 36% have mild cognitive impairment or dementia [3]. The frequent cognitive impairment may reflect the association of lacunar stroke with other SVD features [4]. These features (white matter hyperintensities [WMH], lacunes, and microbleeds) are typically regarded as clinically “silent”

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Results

Conclusion