Persistent symptoms of COVID-19 survivors constitute long COVID syndrome, also called post-acute sequelae of SARS-CoV-2 infection (PASC). Neurologic manifestations of PASC (Neuro-PASC) are particularly debilitating, long lasting, and poorly understood. To gain insight into the pathogenesis of PASC, we leveraged a well-characterized group of Neuro-PASC (NP) patients seen at our Neuro-COVID-19 clinic who had mild acute COVID-19 and never required hospitalization to investigate their plasma proteome. Using the SomaLogic platform, SomaScan, the plasma concentration of >7000 proteins was measured from 92 unvaccinated individuals, including 48 NP patients, 20 COVID-19 convalescents (CC) without lingering symptoms, and 24 unexposed healthy controls (HC) to interrogate underlying pathobiology and potential biomarkers of PASC. We analyzed the plasma proteome based on post-COVID-19 status, neurologic and non-neurologic symptoms, as well as subjective and objective standardized tests for changes in quality-of-life (QoL) and cognition associated with Neuro-PASC. The plasma proteome of NP patients differed from CC and HC subjects more substantially than post-COVID-19 groups (NP and CC combined) differed from HC. Proteomic differences in NP patients 3-9 months following acute COVID-19 showed alterations in inflammatory proteins and pathways relative to CC and HC subjects. Proteomic associations with Neuro-PASC symptoms of brain fog and fatigue included changes in markers of DNA repair, oxidative stress, and neutrophil degranulation. Furthermore, we discovered a correlation between NP patients lower subjective impression of recovery to pre-COVID-19 baseline with an increase in the concentration of the oxidative phosphorylation protein COX7A1, which was also associated with neurologic symptoms and fatigue, as well as impairment in QoL and cognitive dysfunction. Finally, we identified other oxidative phosphorylation-associated proteins correlating with central nervous system symptoms. Our results suggest ongoing inflammatory changes and mitochondrial involvement in Neuro-PASC and pave the way for biomarker validation for use in monitoring and development of therapeutic intervention for this debilitating condition.
