Neuroimmune determinants of cognitive and psychological burden in post‐ COVID syndrome: A cross‐sectional study in a Caucasian cohort

Abstract

Post‐COVID syndrome is increasingly recognized as a multidimensional condition characterized by persistent cognitive, psychological, and functional impairment. Emerging evidence suggests a role for systemic inflammation; however, the integration of inflammatory, neuropsychological, and functional domains remains insufficiently explored. In this cross‐sectional study, 360 individuals with prior SARS‐CoV‐2 infection were evaluated. Systemic inflammatory markers, including interleukin‐6 (IL‐6) and C‐reactive protein (CRP), were assessed alongside validated neuropsychological measures, including PHQ‐9, BDI, STAI, and MoCA. Composite indices were constructed to quantify inflammatory burden, neuropsychological burden, and functional impairment. Correlation analyses and multivariable regression models were applied to evaluate independent associations between variables. Inflammatory burden demonstrated strong positive correlations with neuropsychological burden ( ρ ≈0.6, p < .001) and was independently associated with long COVID‐related neurological manifestations in regression models. Neuropsychological burden was strongly associated with functional impairment ( ρ ≈0.6, p < .001), indicating clinically meaningful translation of cognitive and affective dysfunction into real‐world disability. Disease severity during acute infection was positively associated with long‐term neurological burden, while time since infection showed an inverse relationship, suggesting partial recovery dynamics. Vascular risk burden did not demonstrate a consistent positive association with cognitive impairment after adjustment. Systemic inflammatory burden is strongly associated with neurocognitive and psychological dysfunction in post‐COVID syndrome, with downstream effects on functional status. These findings support a neuroimmune‐associated framework linking inflammation to persistent neurological burden and highlight the potential role of inflammatory markers in risk stratification. Further longitudinal and interventional studies are required to clarify causal mechanisms and therapeutic implications.