Journal
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY
Volume 81, Issue 9, Pages 666-695Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/jnen/nlac056
Keywords
Amygdala; Cytokine; Deafferentation; Encephalitis; Microglia; Olfactory bulb; SARS-Cov-2
Categories
Funding
- National Institute on Aging [P30AG19610, P30AG072980, 3P30AG019610-20S1, NOT-AG-20-022]
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Brains of 42 COVID-19 decedents and 107 non-COVID-19 controls were studied. SARS-CoV-2 viral sequences were detected in the brains of COVID-19 subjects, suggesting the possible entry of the virus through the olfactory bulb. Gene expression changes related to immune response, neuronal constituents, and olfactory/taste receptor genes were observed in the brains of COVID-19 patients.
Brains of 42 COVID-19 decedents and 107 non-COVID-19 controls were studied. RT-PCR screening of 16 regions from 20 COVID-19 autopsies found SARS-CoV-2 E gene viral sequences in 7 regions (2.5% of 320 samples), concentrated in 4/20 subjects (20%). Additional screening of olfactory bulb (OB), amygdala (AMY) and entorhinal area for E, N1, N2, RNA-dependent RNA polymerase, and S gene sequences detected one or more of these in OB in 8/21 subjects (38%). It is uncertain whether these RNA sequences represent viable virus. Significant histopathology was limited to 2/42 cases (4.8%), one with a large acute cerebral infarct and one with hemorrhagic encephalitis. Case-control RNAseq in OB and AMY found more than 5000 and 700 differentially expressed genes, respectively, unrelated to RT-PCR results; these involved immune response, neuronal constituents, and olfactory/taste receptor genes. Olfactory marker protein-1 reduction indicated COVID-19-related loss of OB olfactory mucosa afferents. Iba-1-immunoreactive microglia had reduced area fractions in cerebellar cortex and AMY, and cytokine arrays showed generalized downregulation in AMY and upregulation in blood serum in COVID-19 cases. Although OB is a major brain portal for SARS-CoV-2, COVID-19 brain changes are more likely due to blood-borne immune mediators and trans-synaptic gene expression changes arising from OB deafferentation.
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