White Matter Free Water and PSMD as Neuroimaging Biomarkers of Cerebral Amyloid Angiopathy Severity

Cerebral amyloid angiopathy (CAA) is a cerebral small vessel disease (cSVD) characterized by β-amyloid deposition in cortical and leptomeningeal vessels. Free water (FW) and peak width of skeletonized mean diffusivity (PSMD) are diffusion-weighted MRI biomarkers of cSVD. Although PSMD has been associated with CAA, it is unknown whether FW reflects CAA-related tissue injury. We investigated whether FW is elevated in CAA compared with non-CAA participants with cognitive complaints and assessed FW's neuroimaging and cognitive associations in CAA compared with PSMD.

We retrospectively analyzed individuals with cognitive symptoms from an ongoing single-center cohort, stratified into CAA and non-CAA groups. FW and PSMD metrics were compared between groups. Within the CAA group, we explored FW's and PSMD's association with conventional MRI markers of cSVD and with cognitive scores using multiple and simple linear regression models, respectively. In addition, we performed a longitudinal analysis to investigate whether baseline FW and PSMD are associated with changes in cognitive scores between 2 time points.

Eighty-five participants with CAA (age 75.3 [54.9-95.9] years; 49.4% female) and 38 non-CAA participants (age 71.6 [56.3-86.1] years; 44.7% female) were included. FW was higher in the CAA group (CI 0.04-0.07; p < 0.0001). Within the CAA group, FW was associated with cerebral microbleeds (β = 2.32^-4; CI 6.42^-5 to 3.99^-4; p = 0.007), white matter hyperintensities volume (β = 9.37; CI 5.46-13.28; p < 0.0001), cortical superficial siderosis (β = 7.09^-2; CI 1.43^-2 to 0.13; p = 0.02), and perivascular spaces in the centrum semiovale (β = 9.92^-2; CI 4.57^-2 to 0.15; p = 0.0004). Higher FW and PSMD were associated with worse Mini-Mental State Examination (β = -19.32; CI -37.81 to -0.83; p = 0.04 and β = -0.74; CI -1.48 to -0.003; p = 0.05) and executive function (β = -9.04; CI -15.95 to -2.14; p = 0.01 and β -0.56; CI -0.82 to -0.31; p < 0.0001), whereas higher PSMD was also associated with worse memory (β = -0.31; CI -0.6 to -0.02; p = 0.04). In the longitudinal analysis, there was an association between FW and memory decline in participants with CAA (β = -3.21; CI -6.3 to -0.13; p = 0.04), which did not remain after correcting for multiple comparisons (false discovery rate-adjusted p = 0.083).

Both FW and PSMD capture clinically relevant aspects of CAA-related brain injury.