Neuropathological correlates of MRI-observed hypointense lesions in the APP23 mouse model of cerebral amyloid angiopathy

Cerebral amyloid angiopathy (CAA) is a small vessel disease associated with hemorrhagic lesions including microbleeds and intracerebral hemorrhage. Growing evidence suggests vascular remodeling may be a critical step leading to CAA-related vessel rupture. The APP23 mouse model is one of few models of cerebral amyloidosis that develop spontaneous microbleeds, visible on T2*-weighted MRI as hypointense lesions. However, it remains unknown whether this model recapitulates the microbleed-associated vascular remodeling observed in human tissue. In this study, we used in-vivo 9.4 T MRI and histopathology to study the neuropathological correlates of MRI-observed hypointense lesions in 18- and 24-month-old APP23 transgenic (Tg) mice and wildtype (WT) littermates (12 Tg, 17 WT). Tg mice had more cortical and deep lesions (<i>p</i> < 0.001, <i>p</i> < 0.001)). Brains were serially sectioned from a subset of these mice (11 Tg, five WT) and lesions retrieved. All cortical lesions were microbleeds (and in Tg mice). However, 96% of deep lesions (Tg and WT) were calcifications, suggesting caution is needed when interpreting deep hypointense lesions as microbleeds. A qualitative analysis of histopathologically-confirmed microbleeds revealed vascular remodeling including vessel wall thickening and decreased vascular amyloid-β at most vessel rupture sites, resembling human findings, suggesting APP23 mice may be an appropriate model to study mechanisms of CAA-related hemorrhage.