Tracer kinetic assessment of blood–brain barrier leakage and blood volume in cerebral small vessel disease: Associations with disease burden and vascular risk factors

Subtle blood–brain barrier (BBB) permeability increases have been shown in small vessel disease (SVD) using various analysis methods. Following recent consensus recommendations, we used Patlak tracer kinetic analysis, considered optimal in low permeability states, to quantify permeability-surface area product (PS), a BBB leakage estimate, and blood plasma volume (v(P)) in 201 patients with SVD who underwent dynamic contrast-enhanced MRI scans. We ran multivariable regression models with a quantitative or qualitative metric of white matter hyperintensity (WMH) severity, demographic and vascular risk factors. PS increased with WMH severity in grey (B = 0.15, Confidence Interval (CI): [0.001,0.299], p = 0.049) and normal-appearing white matter (B = 0.015, CI: [−0.008,0.308], p = 0.062). Patients with more severe WMH had lower v(P) in WMH (B = -0.088, CI: [−0.138,-0.039], p < 0.001), but higher v(P) in normal-appearing white matter (B = 0.031, CI: [−0.004,0.065], p = 0.082). PS and v(P) were lower at older ages in WMH, grey and white matter. We conclude higher PS in normal-appearing tissue with more severe WMH suggests impaired BBB integrity beyond visible lesions indicating that the microvasculature is compromised in normal-appearing white matter and WMH. BBB dysfunction is an important mechanism in SVD, but associations with clinical variables are complex and underlying damage affecting vascular surface area may alter interpretation of tracer kinetic results.