Expansive spatial pattern of Aβ deposition in patients with cerebral amyloid angiopathy: A three-dimensional surface-to-depth analysis.

Cerebral amyloid angiopathy (CAA) is a neurodegenerative condition characterized by amyloid-β (Aβ) deposition in small vessel walls, often coexisting with Alzheimer's disease due to impaired Aβ clearance. However, the spatial distribution of Aβ within the human brain remains unclear as the vascular network's complexity and scale hinder visualization by conventional thin-slice analysis. To address this, we performed three-dimensional (3D) volumetric imaging of the cerebrovascular network and Aβ deposition in autopsied brains with CAA using advanced tissue clearing and light-sheet fluorescence microscopy, labeling for smooth muscle actin (SMA) and Aβ. We found prominent Aβ deposition and SMA loss in leptomeningeal and superficial cortical segments, which were anatomically contiguous with deeper Aβ-positive segments, indicating a surface-to-deep progression pattern of Aβ extension. The perivascular plaque density was significantly lower around Aβ-positive vessels. This technology may provide further insights into CAA pathology and is recommended for research on the 3D pathology of neurological disorders.