Arizona Alzheimer's Disease Core Center

The coronavirus SARS-CoV-2 (Covid-19 or 2019-nCoV) emerged in Wuhan, China, in late 2019 and thenrapidly spread worldwide. It causes severe acute respiratory syndrome (SARS) with substantial morbidity andmortality. Little is yet known whether the CNS is involved, but other coronaviruses are known to invade thebrain. There is as yet, however, no published data on the presence or neuropathological consequences ofCNS SARS-CoV-2 in infected humans. This project aims to fill this important knowledge gap.The Arizona ADCC became the NIA's first statewide AD Center in 2001. Since then, it has establishedClinical and Neuropathology Cores that are world-class resources of longitudinally assessed individuals, and,together with an extraordinary ancillary Brain and Body Donation Program, annually contribute on average 80autopsied subjects. In this supplemental application we propose to conduct important studies probing theextent and consequences of SARS-CoV-2 CNS infection in an estimated 100 or more subjects coming toautopsy over an 18 month period spanning the global pandemic. The project is supported by an extremelystrong, multidisciplinary team. Specific Aim 1 will determine the prevalence of CNS infection with SARS-CoV-2in consecutive autopsies, using postmortem nasal swab, postmortem blood serology and assay of multiplebrain regions for SARS-CoV-2 RNA. Specific Aim 2 will assess the gene expression effects of brain regionalSARS-CoV-2 infection using RNAseq transcriptomics. Deconvolution analysis will infer gene expressionchanges separately for neurons, microglia, astrocytes, oligodendrocytes and endothelial cells. Hypotheticalgene expression effects would include those typical for inflammatory responses, cell death and demyelination.Additionally, this analysis will put SARS-CoV-2 findings into perspective vs other microbial or viral presence asdetected by their specific transcripts, reflecting past pathogen exposure history. Specific Aim 3 will determinethe neuropathological correlates of the findings from Specific Aims 1 and 2, by surveying the brain for typicalviral-associated histopathology including meningitis, encephalitis, microglial nodules, perivascular mononuclearcell cuffing and demyelination, and by determining with immunohistochemistry and in-situ hybridization whetherspecific cell types are infected. These findings may yield critical clues useful for devising diagnostic andtherapeutic strategies for possible neurological manifestations of SARS-CoV-2 and the planned studies providean unprecedented opportunity to survey the prevalence and extent of brain invasion by a novel pathogenduring a worldwide pandemic.