Post-COVID neurological manifestations are associated with neuroinflammation, increased autoantibody burden, and...

Neurological manifestations represent commonly persistent features of post-COVID conditions (PCC), but mechanisms underlying their pathogenesis remain unclear. In this study, participants with neuro-PCC (n = 29), mostly presenting with persistent headache, fatigue, sleep disturbances, anosmia/dysgeusia, cognitive complaints, and/or paresthesia, recovered from COVID-19 (n = 32), and non-infected controls (n = 32), all matched for sex and age, had paired serum samples from acute phase (0-14 days) and two time points of convalescence (3-6 months and 9-12 months) assessed for antinuclear antibodies (ANA), antibodies to extractable nuclear antigens (ENA), antineutrophil cytoplasmic antibodies (ANCA), and autoantibodies against cytokines using Luminex assays. Biomarkers of neuroinflammation, including neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), total Tau protein, and neurogranin were quantified by Ella ELISA and complement activation was determined by increased C5b-9 levels. Patients with neuro-PCC showed a greater number of neurological symptoms during acute phase, with increased frequency of headache and fatigue, and a higher prevalence of obesity and cardiovascular comorbidities. GFAP remained elevated for up to one year after infection, independently of symptom persistence. However, only patients with neuro-PCC exhibited a transient increase in NfL levels during acute phase, and persistent complement activation throughout follow-up. No specific autoantibody was associated with neuro-PCC, but these patients exhibited a higher cumulative autoantibody burden. Multivariable logistic regression analysis showed that hospitalization and the neurological burden during the acute phase were associated with neuro-PCC, whereas anti-cytokine autoantibody counts showed an inverse trend. Increased complement activation and a higher autoantibody burden suggest a broad and nonspecific immune activation that may contribute to a sustained low-grade neuroinflammatory state, potentially driving the persistence of neurological symptoms after COVID-19.