Acute Neurological Manifestations in COVID‐19 Are Associated With Complement Activation and Glia‐Promoted Neuroinflammation

Pathophysiological mechanisms of neurological manifestations in COVID-19 are not fully known yet. In this case-control study, proteomic analysis was used to characterize cerebrospinal fluid (CSF) samples from COVID-19 patients with acute neurological manifestations primarily categorized as: isolated refractory headache (n = 12), encephalopathy (n = 24), and inflammatory neurological diseases (IND) (n = 13). Individuals with non-inflammatory, non-infectious neurological conditions (n = 8) were included as controls. Differentially expressed proteins (DEPs) in neuro-COVID-19 were associated with the complement system, function/activation of microglia/macrophages, inflammatory responses, and neuronal function/homeostasis. Functional enrichment analysis of DEPs and/or proteins specifically detected in neuro-COVID-19 groups indicated activation of complement and coagulation cascades, and synapse pruning in encephalopathy and IND. Upregulated complement activation was confirmed by increased CSF levels of C3a and soluble C5b-9. Biological processes of neuroinflammation, migration of immune cells into the central nervous system, activation of glia cells (microglia and astrocytes), and tissue remodeling were also present in IND. In turn, processes associated with disturbed organization/formation of neuron projections were related to encephalopathy and isolated headache. CSF from patients with isolated refractory headache was enriched for proteins related to neurons and to the cerebral cortex, cerebellum, and basal ganglia. Meanwhile, CSF from encephalopathy and IND patients was mostly enriched for proteins mapped to the cerebral cortex, choroid plexus, and thalamus. Moreover, CSF from IND patients had an increased proportion of microglia-related proteins. These findings support a model in which cases of IND and encephalopathy are associated with blood-brain barrier disruption potentially induced by complement activation and glia-promoted neuroinflammation, resulting in the involvement of distinct brain structures in COVID-19.