Persistent Neuropsychiatric Symptoms and Inflammatory Biomarkers in COVID-19 Survivors: A Two-Year Prospective Study

Background There is limited long-term prospective data on post-COVID-19 neuropsychiatric symptoms (NPS), hindering our understanding of symptom progression beyond 12 months. The biological mechanisms behind persistent NPS remain unclear, with most hypotheses based on acute-phase data. This study examined the longitudinal associations of inflammatory, oxidative stress, and neurodegeneration biomarkers with post-COVID-19 NPS. Methods This prospective study followed 232 patients hospitalized for COVID-19 for 24 months post-discharge. Depression, anxiety, fatigue, and cognitive function were assessed using validated clinical scales at 3-6, 12, and 24 months. Serum biomarkers of inflammation, neurodegeneration, and oxidative stress were measured at baseline, 3, 6, and 12 months. K-means clustering was used to identify biomarker profiles at baseline. Linear mixed-effects models examined associations between clusters and longitudinal NPS outcomes, adjusting for age, sex, and ethnicity. Results Neuropsychiatric symptom burden remained high for up to 24 months, with depression more common in females and cognitive impairment in Hispanics. Inflammatory markers were elevated during hospitalization; most normalized over time, except for interferon gamma-induced protein 10 (IP-10) and neurofilament light chain (NfL), which persisted elevated through 12 months. Cluster analysis revealed two distinct baseline biomarker profiles. Mixed-effects models indicated that female sex predicted higher depression, anxiety, and fatigue, while Hispanic ethnicity was associated with lower cognitive function. Conclusions Post-COVID-19 NPS persist for at least 24 months, particularly in female and Hispanic individuals. The persistence of NPS, accompanied by sustained alterations in selected inflammatory and neurodegeneration-related biomarkers, highlights the need for long-term monitoring and further research to clarify their clinical significance.