Brain Perivascular Space Morphometry Reflects Neuropsychological and Shared Familial Microvascular Architecture Beyond Vascular Risk

Abstract Background Brain perivascular spaces (PVS) are emerging MRI markers of microvascular function and waste metabolite clearance. While PVS enlargement has been linked to aging and vascular risk, it remains unclear whether PVS morphology reflects shared familial microvascular characteristics and how these are shaped by individual vascular, physiological, and neuropsychiatric factors. In this study, we investigated whether PVS morphometry captures these familial characteristics, further modulated by individual determinants. Methods We analyzed 1,183 participants from the Stratifying Depression and Resilience Longitudinally (STRADL) family-based cohort, including 324 individuals with first-degree relatives. Automated MRI segmentation quantified PVS volume, count, density, and median length in the centrum semiovale and basal ganglia. Linear mixed-effects models assessed associations with age, hypertension, hair cortisol, depressive symptom scores, and hand grip strength while accounting for familial clustering. Results In 1050 individuals (59.5% female; mean age 59.3 ±10.1 years) PVS burden increased with age (PVSvolume%ROI β=0.18, 95%CI[0.11, 0.26], p<0.0001), current depressive symptoms across both regions (PVS density: CSO, β=0.092, [0.023, 0.16], p=0.009; BG, β=0.11, [0.043, 0.18], p=0.002), and with higher hair cortisol (PVS count β=0.08, [0.003, 0.15], p=0.041) and weaker grip strength (PVSvolume%ROI β=-0.09, [-0.16, -0.02], p=0.013), in the centrum semiovale. Familial clustering was significant for PVS volume (β=0.22, [0.096, 0.52], p=0.013) and median length (β=0.28, [0.16, 0.49], p=0.0003), independent of other factors. Conclusions PVS morphology reflects neuropsychiatric and shared familial microvascular architecture, with both inherited and individual factors contributing to PVS burden and morphometry, and supporting the use of PVS morphometry as a neuroimaging marker of cerebral microvascular health.