Abstract Number: Esoc2026a571 Cortical Microinfarcts in Cerebral Amyloid Angiopathy: Evidence for a Double-Hit Mechanism Driven by Cortical Superficial Siderosis

Abstract Background and aims Cerebral amyloid angiopathy (CAA) is a cerebral small vessel disease characterized by hemorrhagic and non-hemorrhagic brain injuries. This study aims to determine the spatiotemporal relationship between cortical CMI and cSS in CAA, with the hypothesis that cSS can promote local ischemic injury. Methods Patients with probable CAA (Boston Criteria v2.0) were recruited from a prospective Massachusetts General Hospital cohort. CAA-related radiological manifestations—including CMI and cSS—were quantified at baseline and at 24-month follow-up 3T-MRI. Multivariate logistic regression and generalized linear models were applied to assess associations between baseline radiological features and their predictive value on radiological progression. We compared the local density of cortical CMIs—CMI Density Index, CDI—in regions with and without overlaid cSS. Results Among 74 probable CAA, 26 (35%) had cortical CMIs (n=135, 39% underlying cSS). At baseline, cortical CMI count demonstrated an exponential relationship with cSS volume (Exp(B)=1.12 95%CI 1.07–1.18; p0.001) and with lobar lacunes count (Exp(B)=1.65 95%CI 1.52–1.80; p0.001). The CDI was markedly higher in cSS-covered vs. non-cSS regions (median: 20.84 0.00–56.95 vs. 0.49 0.11–0.89; p=0.010). Follow-up scans (n=36) revealed 23 incident cortical CMIs (43% underlying cSS). Baseline cSS volume predicted incident CMI occurrence (OR:1.41 95%CI 1.02-1.95; p=0.036), whereas baseline CMI did not predict cSS progression. Conclusions Our findings demonstrate an interplay between CMI and cSS, with cSS possibly triggering local ischemic injury. Further studies should identify the driving pathophysiology of this association, a possible therapeutic target for preventing cSS-induced cortical injury. Conflict of interest This work was funded by the National Institutes of Health (R01AG047975 to A.V., K08NS131530 to M.G.K., and R00AG059893 to S.J.v.V.) and the American Heart Association (23SCEFIA1152994 to M.G.K. and 814728 to S.J.v.V.). Financial Disclosure: MP reports fees from Novartis, Lilly, Eisai, Biogen, and research support from Novartis and Nutricia. MGK reports fees from Roche. SJvV reports consulting fees from Eisai and industry support from Therini Bio and Sanofi.