Integration of Neuroimaging and Histopathology in a Squirrel Monkey Model of Spontaneous Cerebral Amyloid Angiopathy and Amyloid-Related Imaging Abnormalities
Cerebral amyloid angiopathy (CAA) is a prevalent cerebrovascular pathology in AD and contributes to amyloid-related imaging abnormalities (ARIA), a major complication of current anti-amyloid immunotherapy. Despite its growing clinical importance, critical gaps remain in the development of reliable biomarkers for antemortem diagnosis of CAA. Squirrel monkeys (SQMs) are a valuable non-human primate model with translational relevance due to their universal propensity to develop abundant CAA and spontaneous ARIA in geriatric animals. The present study employed R2*, the apparent transverse relaxation rate, which is sensitive to susceptibility-related tissue properties, including iron content and blood oxygenation levels, to monitor age-related brain pathology in SQMs with varying CAA severity. Young, early geriatric, and late geriatric SQMs underwent 7T MRI using a dual-purpose T2*-w 3D multi-gradient-echo sequence for high-resolution anatomy and quantitative R2* mapping, alongside T2-w/FLAIR imaging. Whole-brain and gray matter R2* increased with age. In contrast, white matter R2* showed an initial increase followed by a late-life reversal, likely reflecting age-related changes in myelin integrity, tissue microstructure, and tissue water content. MRI-histopathology correlation linked T2*-w MRI hypointensities to CAA-positive iron-laden vessels associated with perivascular inflammation and, in some cases, hemosiderin deposits. Here we confirmed the occurrence of ARIA-H and ARIA-E events in geriatric animals. SQMs provided a valuable opportunity to examine the underlying pathology of spontaneous ARIA-E, revealing distinctive tissue signatures associated with its manifestation. ARIA-E hyperintensities were characterized by reactive gliosis and BBB disruption, whereas more advanced lesions exhibited perivascular lymphocytic infiltration and evidence of myelin and axonal injury. The current study presents compelling evidence linking R2* alterations with CAA severity and ARIA-related tissue injury, providing a foundation for further advancing early detection of CAA, ARIA risk assessment, and treatment strategies.