b, Uniform manifold approximation and projection (UMAP) of 38,217 nuclei from the medial frontal cortex of 8 control individuals (including 1 patient with influenza) and 8 patients with COVID-19. Coloured triangles denote the brain regions that were studied for each patient. We created an interactive data browser ( ) to provide researchers with a comprehensive resource to further investigate the molecular mechanisms of the effects of SARS-CoV-2 on the brain.Ī, Study design. Here we characterized the transcriptomes of 65,309 nuclei isolated from the brains of 14 control individuals and 8 patients with COVID-19 (Fig. This is in part because the high-quality, fresh-frozen human brain tissue from patients with COVID-19 needed for single-cell transcriptomic studies is largely inaccessible, and methods to isolate human brain barrier cells have only recently emerged 22, 23. Critically, a comprehensive assessment across specific cell types in the brain affected by severe COVID-19 is missing. Thus, much attention has been paid to whether SARS-CoV-2 can be detected in the brain, which has yielded inconsistent results 9, 17, 18, 19, 20, 21. Neuropathology may arise from direct virus neuroinvasion or indirectly from peripheral infection and its attendant immune response 16. These symptoms are more prevalent in patients who are hospitalized 1, 12, 13 and may persist as ‘long COVID’, which consists of ‘brain fog’, difficulty in concentrating and fatigue 14, 15.Ĭellular and molecular approaches are required to understand the neurological changes that may contribute to symptoms reported in patients with COVID-19. Patients with COVID-19 can suffer neurological and psychiatric symptoms that range from loss of smell and headache to encephalitis and stroke 1, 2, 3, 9, 10, 11. Our findings and public dataset provide a molecular framework to understand current observations of COVID-19-related neurological disease, and any such disease that may emerge at a later date. Across cell types, perturbations associated with COVID-19 overlap with those found in chronic brain disorders and reside in genetic variants associated with cognition, schizophrenia and depression. Synaptic signalling of upper-layer excitatory neurons-which are evolutionarily expanded in humans 7 and linked to cognitive function 8-is preferentially affected in COVID-19. We discover microglia and astrocyte subpopulations associated with COVID-19 that share features with pathological cell states that have previously been reported in human neurodegenerative disease 4, 5, 6. Although our systematic analysis yields no molecular traces of SARS-CoV-2 in the brain, we observe broad cellular perturbations indicating that barrier cells of the choroid plexus sense and relay peripheral inflammation into the brain and show that peripheral T cells infiltrate the parenchyma. Here we profile 65,309 single-nucleus transcriptomes from 30 frontal cortex and choroid plexus samples across 14 control individuals (including 1 patient with terminal influenza) and 8 patients with COVID-19. However, an unbiased understanding of the cellular and molecular processes that are affected in the brains of patients with COVID-19 is missing. Although SARS-CoV-2 primarily targets the respiratory system, patients with and survivors of COVID-19 can suffer neurological symptoms 1, 2, 3.
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