ABSTRACT NUMBER: ESOC2026A1670 REGIONAL VARIATION IN BLOOD-BRAIN BARRIER PERMEABILITY AND MICROSTRUCTURAL INTEGRITY OF WHITE MATTER HYPERINTENSITY PENUMBRA

Abstract Background and aims White matter hyperintensity (WMH) penumbra represents transitional tissue surrounding WMH lesions. We characterized blood-brain barrier (BBB) permeability and microstructural integrity across WMH, penumbra, and normal-appearing white matter (NAWM) using MRI. Methods 350 participants from the GeneSTAR prospective cohort underwent brain MRI with dynamic susceptibility contrast MRI (DSC-MRI) for K2, dynamic contrast-enhanced MRI (DCE-MRI) for Ktrans, and tensor-encoded diffusion MRI for fractional anisotropy (FA) and microscopic FA (μFA). WMH penumbra was defined as 3.5mm perilesional zone. Regional differences across WMH, penumbra, and NAWM were assessed using Wilcoxon signed-rank tests. Results BBB permeability exhibited distinct spatial patterns. Ktrans was highest in penumbra, intermediate in WMH, and lowest in NAWM (all pairwise p<0.001). K2 was significantly higher in penumbra compared to WMH (p<0.001). Microstructural integrity showed regional variation: FA was lowest in WMH, intermediate in NAWM, and highest in penumbra (all pairwise p<0.001). μFA demonstrated a progressive gradient from WMH (median 0.65) through penumbra (0.80) to NAWM (0.80; all pairwise p<0.001). Available data: K2 (WMH n=321, penumbra n=330); Ktrans (NAWM n=332, penumbra n=332, WMH n=332); FA and μFA (NAWM n=288, penumbra n=288, WMH n=277). Conclusions The WMH penumbra exhibits peak BBB dysfunction despite relatively preserved microstructure, representing a critical transition zone in cerebral small vessel disease. These spatial variations support the penumbra as an early disease front where vascular dysfunction precedes structural damage. Conflict of interest Sarvin Sasannia: nothing to disclose; Hyeong-Geol Shin: nothing to disclose; Richard Leigh: nothing to disclose; Shimeng Wang: nothing to disclose; Jinwei Wang: nothing to disclose; Jerry L. Prince: nothing to disclose; Filip Szczepankiewicz: nothing to disclose; Peter van Zijl: nothing to disclose; Linda Knutsson: nothing to disclose; Paul A. Nyquist: nothing to disclose