Human brain matters: Navigating the neuropathology of <scp>COVID</scp> ‐19

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused millions of deaths worldwide. Although the incidence of severe acute cases has declined, the prevalence of long COVID, also known as post-acute sequelae of COVID-19 (PASC), is rising. The pathological mechanisms underlying severe COVID-19, along with the relationship to neurological disorders and potential risk for neurodegeneration, remain poorly understood. The aim of this narrative review is to summarize neuropathological features described in postmortem human COVID-19 brains (n = 352). Furthermore, analysis of biofluids and neuroimaging from PASC patients underline long-term changes in the proteome and CNS response following the infection. Postmortem brain studies from severe COVID-19 patients highlight disruption of the fluid-brain barriers and vascular dysregulation defined by endothelial inflammation and disruption, hemorrhages, and hypoxic-ischemic damage. Neuroinflammation, including astrogliosis, microglia nodules and infiltration of adaptive immune cells, has been reported in the olfactory bulb, medulla oblongata, midbrain and cerebellum. Neuronal damage was demonstrated in the hippocampus, midbrain and cerebellum in severe COVID-19 and protein aggregation was observed in the midbrain and entorhinal cortex. Neuropathological burden and elevated blood and/or cerebrospinal fluid (CSF) levels of proinflammatory cytokines (e.g. IL-6) and neuro-axonal proteins (e.g. NfL) correlated with severity of anosmia, memory deficits, and cerebellar ataxia. Elderly patients and/or patients with underlying neurological diseases were more susceptible and had worsened symptoms. Potential disease mechanisms underlying neurological symptoms observed in severe COVID-19 are vascular and fluid-brain barrier abnormalities, chronic neuroinflammation, persistent axonal damage and protein aggregation. In PASC patients, an altered biofluid proteome with increased neuronal proteins and pro-inflammatory cytokines was observed. The pathological burden in affected brain regions may contribute to manifestations such as anosmia, memory deficits, and cerebellar ataxia.