Elevated Blood Pressure Is Causally Associated With Larger Subcortical Gray Matter Structure Through Perivascular Clearance Routes

ABSTRACT Background This study aimed to investigate the association between elevated blood pressure (BP) and subcortical gray matter structures, and to elucidate the causality and underlying mechanisms. Methods This study enrolled 1012 participants from a multicenter, population‐based cohort study in China. Generalized linear models were used to evaluate the associations between different degrees of BP and subcortical gray matter volumes. Mendelian randomization analysis based on genome‐wide data was performed to investigate causal relationships. We further conducted mediation analysis to analyze whether these associations were mediated by dysfunctional brain clearance. Results Compared with the lowest group of systolic BP (SBP) < 120 mmHg and diastolic BP (DBP) < 80 mmHg, elevated BP was associated with larger subcortical gray matter volumes, including caudate volumes (SBP/DBP 130/80–140/90 mmHg: β = 0.19), putamen volumes (SBP/DBP 130/80–140/90 mmHg: β = 0.27; SBP/DBP ≥ 140/90 mmHg: β = 0.31), and pallidum volumes (SBP/DBP 120/80–130/80 mmHg: β = 0.25; SBP/DBP 130/80–140/90 mmHg: β = 0.28; SBP/DBP ≥ 140/90 mmHg: β = 0.25). Genetically determined hypertension was causally associated with increased volumes of subcortical gray matter (left caudate: β = 1.59; right caudate: β = 1.42; left putamen: β = 0.84; right putamen: β = 0.69; left pallidum: β = 0.59). The number of basal ganglia enlarged perivascular spaces (BG‐EPVS) mediated the relationship between elevated BP and larger volumes of subcortical gray matter. Conclusions Elevated BP is associated with larger subcortical gray matter volumes, mediated by an increased burden of BG‐EPVS. Our study provides novel evidence for the complex mechanisms linking higher BP levels to brain health.