Cross-sectional and longitudinal differences in peak skeletonized white matter mean diffusivity in cerebral amyloid angiopathy

Objectives: To test the hypotheses that peak skeletonized mean diffusivity (PSMD), a measure of cerebral white matter microstructural disruption, is 1) increased in patients with cerebral amyloid angiopathy (CAA) compared to normal control (NC), mild cognitive impairment (MCI), and Alzheimer's disease (AD); 2) associated with neuropsychological test performance among CAA patients; and 3) increased more quickly over one year in CAA than in AD, MCI, and NC. Methods: Ninety-two participants provided a medical history, completed a neuropsychological assessment, and had a magnetic resonance (MR) exam including diffusion tensor imaging (DTI) from which PSMD was calculated. A 75-minute neuropsychological test battery was used to derive domain scores for memory, executive function, and processing speed. Multivariable analyses controlling for age and sex (and education, for cognitive outcomes) were used to test the study hypotheses. Results: PSMD was higher in the CAA group (mean 4.97 x 10(-4) mm(2)/s) compared to NC (3.25 x 10(-4) mm(2)/s), MCI (3.62 x 10(-4) mm(2)/s) and AD (3.89 x 10(-4) mm(2)/s) groups (p < .01). Among CAA patients, higher PSMD was associated with slower processing speed (estimated -0.22 standard deviation (SD) change in processing speed z score per SD increase in PSMD, 95% CI -0.42 to -0.03, p = .03), higher WMH volume [beta = 0.74, CI 0.48 to 1.00], and higher CAA SVD score [beta = 0.68, CI 0.24 to 1.21] but was not associated with MMSE, executive function, memory, CMB count, or cortical thickness. PSMD increased over 1-year in all groups (p < .01) but without rate differences between groups (p = .66). Conclusions: PSMD, a simple marker of diffuse global white matter heterogeneity, is increased in CAA. Our findings further support a role for white matter disruption in causing cognitive impairment in CAA.