ABSTRACT NUMBER: ESOC2026A1671 BLOOD-BRAIN BARRIER DYSFUNCTION IN WHITE MATTER HYPERINTENSITY PENUMBRA ASSOCIATED WITH LESION VOLUME AND THIRTEEN-YEAR PROGRESSION

Abstract Background and aims The white matter hyperintensity (WMH) penumbra (perilesional tissue) may represent an earlier stage of cerebral small vessel disease than the WMH core, yet its pathophysiologic characteristics and relationship to WMH burden remain unclear. Understanding penumbral tissue changes could identify early intervention targets before irreversible lesion formation. We evaluated penumbral MRI markers of blood-brain barrier (BBB) permeability and microstructural integrity as predictors of WMH volume cross-sectionally and in terms of longitudinal WMH progression over 13.5 years. Methods 312 participants from GeneSTAR cohort underwent baseline and 13.5-year follow-up brain MRI. At follow-up, BBB permeability (K2 from dynamic susceptibility contrast MRI, Ktrans from dynamic contrast-enhanced MRI) and microstructural integrity (fractional anisotropy [FA] and microscopic FA [μFA; not confounded by fiber orientation dispersion than FA] from tensor-encoded diffusion MRI) were measured in WMH penumbra (3.5mm-perilesional zone). Linear mixed-effects models examined associations with cross-sectional WMH volume and longitudinal WMH progression, adjusting for age, sex, race, systolic blood pressure, and family clustering. Results Penumbra K2 was strongly associated with both cross-sectional WMH volume (β=48.6, p<0.001) and 13.5-year progression (β=14.4, p=0.013). Penumbra Ktrans showed no significant associations (p>0.15). Penumbra FA was inversely associated with both cross-sectional volume (β=-10.9, p<0.001) and progression (β=-4.8, p<0.001). Penumbra μFA was inversely associated with cross-sectional volume (β=-3.8, p=0.005) but not progression (p=0.13). Conclusions BBB dysfunction measured by K2 and microstructural damage measured by FA in WMH penumbra were associated with current lesion burden and long-term progression, supporting perilesional tissue as a critical therapeutic target for cerebral small vessel disease intervention. Conflict of interest Sarvin Sasannia: nothing to disclose; Hyeong-Geol Shin: nothing to disclose; Richard Leigh: nothing to disclose; Shimeng Wang: nothing to disclose; Jerry L. Prince: nothing to disclose; Lisa R. Yanek: nothing to disclose; Dhananjay Vaidya: nothing to disclose; Peter van Zijl: nothing to disclose; Linda Knutsson: nothing to disclose; Paul A. Nyquist: nothing to disclose