Blood-brain barrier disruption and increased free water are associated with worse cognitive performance in patients with chronic cerebrovascular disease

Progression of cerebral small vessel disease (CSVD) is associated with cognitive decline. Blood-brain barrier disruption (BBBD) and fluid extravasation to the interstitial space may contribute to progression of white matter hyperintensities (WMH). We hypothesized that increased free water (FW) would colocalize with BBBD and relate to cognitive performance. Patients with ischemic stroke/TIA at least 3 months prior with at least early confluent WMH were studied cross-sectionally with the Montreal Cognitive Assessment (MoCA), diffusion tensor imaging, and dynamic susceptibility contrast imaging. White matter (WM) was segmented into WMH, WMH penumbra, and normal appearing white matter (NAWM). Colocalization of elevated FW and BBBD and their associations with MoCA performance were evaluated. 58 patients were included (mean age 69, 36 % female). Higher BBBD colocalized with elevated FW. Elevated FW in all white matter, NAWM, WMH penumbra, and WMH lesions was associated with lower MoCA score. Increased BBBD in all WM, NAWM, and WMH penumbra was associated with lower MoCA. In WMH penumbra, both elevated FW and increased BBBD were independently associated with lower MoCA. We found agreement between 2 different biomarkers implicated in the pathogenesis of CSVD that independently demonstrated association with cognitive performance when measured in the area of postulated disease activity.