EXPRESS: Disentangling MRI-derived blood-brain barrier leakage into vascular permeability and surface area

Background: In neurovascular and neurodegenerative diseases, blood-brain barrier (BBB) disruption can be subtle, diffuse, and MRI-derived measures are confounded by microvascular architecture. Therefore, we aimed to disentangle MRI-derived blood-brain barrier leakage rate (K i ) into intrinsic vascular permeability (P) and surface area (S). Methods: In this cross-sectional study, 45 patients with cSVD and 26 elderly controls underwent dynamic contrast-enhanced (DCE) MRI to determine K i and vessel architecture imaging (VAI) to estimate S. These measures were used to calculate P. Results: Compared to normal-appearing white matter (NAWM), K i was higher in WMH (β=0.297, p<0.001) and deep gray matter (DGM) (β=0.210, p=0.007). P was higher in WMH (β=0.410, p<0.001) and similar between NAWM and DGM. S was smaller in WMH (β=-0.467, p<0.001) and larger in DGM (β=0.540, p<0.001). K i (β=0.289, p=0.007) and P (β=0.249, p=0.021) were only higher in patients than controls in concentric shells surrounding WMH. S was smaller in WMH of patients than controls (β=-0.085, p=0.049). With age, K i (β=0.260, p=0.008) and P increased (β=0.273, p<0.001), while S decreased (β=-0.079, p=0.025). Conclusion: Disentangling P and S from the BBB leakage rate provides two biologically more specific and interpretable measures, which have counteracting effects on the BBB leakage in aging and disease.