Impact of hypertension on cerebral small vessel disease: A post-mortem study of microvascular pathology from normal-appearing white matter into white matter hyperintensities

Cerebral small vessel disease (SVD) is diagnosed through imaging hallmarks like white matter hyperintensities (WMH). Novel hypotheses imply that endothelial dysfunction, blood-brain barrier (BBB) disruption and neurovascular inflammation contribute to conversion of normal-appearing white matter (NAWM) into WMH in hypertensive individuals. Aiming to unravel the association between chronic hypertension and the earliest WMH pathogenesis, we characterized microvascular pathology in periventricular NAWM into WMH in post-mortem brains of individuals with and without hypertension. Our second aim was to delineate the NAWM-WMH transition from NAWM towards the center of WMH using deep learning, refining WMH segmentation capturing increases in FLAIR signal. Finally, we aimed to demonstrate whether these processes may synergistically contribute to WMH pathogenesis by performing voxel-wise correlations between MRI and microvascular pathology. Larger endothelium disruption, BBB damage and neurovascular inflammation were observed in individuals with hypertension. We did not observe gradual BBB damage nor neurovascular inflammation along the NAWM-WMH transition. We found a strong correlation between BBB damage and neurovascular inflammation in all individuals in both periventricular NAWM and WMH. These novel findings suggest that endothelium disruption, BBB damage and neurovascular inflammation are major contributors to SVD progression, but being already present in NAWM in hypertension.