The serum proteome and exosome characteristics of cognitive impairment in the Post Acute COVID-19 Syndrome: lasting dysregulation of metabolism, coagulation and immune pathways

Background: Cognitive impairment following COVID-19 hospitalization is a commonly observed symptom, though its biological correlates remain unclear. The objective of this study was to investigate serum proteomes and circulating extracellular vesicles (EVs), including exosomes, for the purpose of uncovering differences between cognitively impaired and cognitively intact participants, at a minimum of two months following hospitalization for COVID-19. Methods: Consecutive adult participants were enrolled from the COVID-19 outpatient clinic after hospitalization for COVID-19 and during their initial follow-up visit. Data gathered included demographic information, medical and patient histories, neurocognitive and affective assessments, as well as biochemical evaluations aimed at identifying reversible cognitive impairment. Serum samples collected were subsequently analyzed for proteomic profiles and characteristics of circulating EVs. Results: The study recruited 67 consecutive patients. After propensity score matching for age, gender, education, and disease severity, 31 cognitively impaired participants were matched with 31 cognitively intact participants. Twenty-five proteins, including A2M, PZP, and PXLDC2 were determined as differentially abundant between groups. Enrichment analysis identified protein-protein interaction networks related to immune function, coagulation, and lipid metabolism. Enriched cellular components involved the presence of blood nanoparticles, including exosomes. The latter find was corroborated by observed differences in measurements of circulating vesicular and exosomeal content between the groups. Discussion: We report on differentially abundant proteins between cognitively impaired and cognitively intact individuals with a history of COVID-19 hospitalization, and provide a role for prolonged immune, metabolic and coagulation defects, along with perturbed EV communication. The identified proteins and pathways have been previously linked to amnestic mild cognitive impairment and Alzheimer’s disease (AD), suggesting potential pathophysiological interactions.