Perilesional white matter gradients reveal microstructural differences in cerebral amyloid angiopathy versus Alzheimer's disease

INTRODUCTION: White matter hyperintensities (WMHs) are common in both Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA), yet their spatial tissue characteristics and microstructural differences remain poorly understood. METHODS: We analyzed 351 participants: 184 amyloid beta (Aβ)-positive AD and mild cognitive impairment (MCI), 139 Aβ-negative cognitively normal controls (CN), and 28 probable CAA. Multimodal magnetic resonance imaging metrics were used to estimate spatial gradient parameters for periventricular WMHs (pWMH) and deep WMHs (dWMH). RESULTS: CAA demonstrated distinctive free-water fraction (FWF), fractional anisotropy (FA), mean diffusivity (MD), and plasma volume within pWMH, as well as spatial gradient parameters of pWMH. These pWMH spatial gradient parameters produced area under the curve (AUC) values of 0.71 (FWF), 0.72 (MD), and 0.79 (FA) when distinguishing CAA from AD/MCI. We retested a subset of the cohort after 1 to 2 years (AUCs: FWF = 0.89, MD = 0.79, FA = 0.85). DISCUSSION: Spatial gradient parameters reflect disease-specific microstructural and vascular changes, providing insights into CAA and AD pathology.