The impact of chronic hypertension on small vessel disease – neuroinflammation beyond white matter hyperintensities

Abstract

Introduction: The major vascular cause of dementia is cerebral small vessel disease (SVD). The diagnosis of SVD relies on MRI findings, including white matter hyperintensities (WMH) amongst others. Chronic hypertension and neuroinflammation are recognized as important risk factors for SVD and for the conversion of normal-appearing white matter (NAWM) into WMH. Unfortunately, most studies investigating the role of neuroinflammation in WMH relied on peripheral blood markers as a proxy for inflammation in the brain itself. Whether such markers accurately capture inflammatory changes within the cerebral white matter remains unknown. Therefore, we aimed to comprehensively investigate the impact of hypertension on perivascular- and neuroinflammation in both WMH and NAWM. Methods: We conducted high-field (7 Tesla) MRI on human post-mortem brains (n=22) of elderly people with chronic hypertension (n = 17) and age-matched controls (n=5) to assess SVD burden, focusing on the analysis of WMH by Fazekas score severity and volumetry. After careful evaluation, brain axial biopsies were taken, from which paraffin sections were cut and (immuno-histochemistry (IHC)) performed to examine neuroinflammation mediated by both microglia and astroglia, and perivascular inflammation. To accurately co-register our MRI findings to IHC data, we developed a custom written MATLAB script to compare changes in WMH on MRI to microscopical changes in IHC. Results: WMH were characterized by more activated microglia and astrogliosis compared to surrounding NAWM. Notably, hypertension was associated with a larger (perivascular) inflammatory response in both WMH and NAWM, suggesting that neuroinflammation plays a crucial role in the pathogenesis of WMH in individuals with hypertension. Discussion: Our results indicate that neuro(vascular)inflammation at the level of the brain itself is involved in the etiology of WMH. Future therapeutic strategies focusing on multitarget interventions including antihypertensive treatment as well as treatment against neuroinflammation may ameliorate WMH progression.