Abstract Details Title COVID-19 Postmortem Neuropathology: 2025 Update Topic Infectious Disease Presentation(s) P1 - Poster Session 1 (11:45 AM-12:45 PM) Poster/Presentation Number 10-006 Objective An update of postmortem neuropathology of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). Background An initial cohort of 144 postmortem cases presented in 2021 showed: 1) elevated serum cytokines and procoagulant levels increasing the risk for thrombotic brain infarcts; 2) immunohistochemical localization IHC) of virus in olfactory bulbs as a mode of CNS entry; 3) hypoxia-ischemia in a minority not accounting for other findings; and 4) no pediatric cases. The later cohort of 150 cases presented in 2023 showed: 1) postmortem cases of childhood multisystem inflammatory syndrome(MIS-C), meningoencephalitides, and CNS angiitis; 2) a 2-fold increase in interstitial brainstem inflammation and focal perivascular T-cell infiltrates; 3) stable frequency of viral RNA (20%) in fresh-frozen paraffin embedded tissue blocks (FFETBs) by IHC and in situ hybridization (ISH). Design/Methods Seven new COVID-19 postmortem cases and 193 published cases are analyzed. Results Seven unpublished COVID-19 patients age 23 to 95 years included 2 HIV-1, and incidental lymphoproliferative, breast, prostate, or pancreatic cancers, in whom histopathology showed: 1) type 3 hypersensitivity vasculitis (in 6 cases) comprising acute neutrophilic endotheliitis in FFETBs of cortex, subcortex and cerebellum, with mural transmigration and perivasculitis; and 2) one case of microglial nodule formation. Of 193 published cases: 1) positive SARS-CoV-2 viral isolation was noted in one case (60 negative cases); 2) inflammatory microvasculopathy (neutrophilic or T-cell) with perivasculitis, focal or diffuse interstitial and leptomeningeal inflammation were noted in one-third (61 cases); 3) microglial activation and microglial formation was observed in 9% (18 cases); and 4) all 10 cases in one series showed pTau- and thioflavin-S-negative neocortical foci of AB amyloid suggesting a link to cognitive sequelae. Conclusions Despite the overall generally favorable prognosis, systemic and CNS inflammation contribute to mortality of COVID-19 neurological illness. The importance of autopsy studies resides in elucidating early humoral and adaptive immune responses underlying mechanisms of the morbid neurological illness. Authors/Disclosures David S. Younger, MD, DrPH, MPH, MS PRESENTER Dr. Younger has nothing to disclose.