Blood-Brain Barrier Breakdown is a Sensitive Biomarker of Cognitive and Language Impairment in Patients with White Matter Hyperintensities

Abstract

Introduction: Similar white matter hyperintensities (WMH) burden may have varied cognitive outcomes in patients with cerebral small vessel disease (CSVD). This study aimed to evaluate whether blood-brain barrier (BBB) permeability is associated with cognitive impairment (CI) heterogeneity in patients with WMH.

Methods: We recruited 51 participants with WMH. We evaluated WMH burden using the Fazekas scale and WMH volume on structural magnetic resonance imaging (MRI), and assessed BBB permeability using dynamic contrast-enhanced (DCE)-MRI. We used permeability-surface area product (PS) from the Patlak model to represent BBB permeability. All patients underwent Mini-Mental State Examination (MMSE), Boston Naming Test (BNT) and animal verbal fluency test (VFT) for cognitive assessment. We divided patients into CI and non-CI groups based on their MMSE scores (< 27 or ≥ 27) and used multiple linear regression models to investigate the associations between MRI parameters and cognitive function.

Results: Patients in the two groups did not differ in Fazekas scores and WMH volume. However, patients in the CI group showed significantly higher PS in the WMH regions than those in non-CI group (1.89 × 10^-3 versus 1.00 × 10^-3, p = 0.032 in periventricular WMH [PVWMH]; 1.27 × 10^-3 versus 0.74 × 10^-3, p = 0.043 in deep WMH [DWMH]), indicating the breakdown of BBB in the CI group. In all patients with WMH, increased BBB permeability in PVWMH and DWMH was significantly associated with lower cognitive and language function after adjustment for age, education level (EL) and intracranial volume (ICV). In the CI group, this correlation remained significant. WMH volume was not associated with cognitive performance in either all patients or those with CI.

Conclusion: BBB impairment might be a more sensitive indicator for cognitive and language dysfunction than WMH volume in patients with WMH and possibly explains the heterogeneity of cognitive performance in patients with similar WMH burden.

Keywords: Blood–brain barrier; Cerebral small vessel disease; Cognitive impairment; Dynamic contrast-enhanced magnetic resonance imaging; White matter hyperintensities.