Peripheral neuroimmune alterations associated with cognitive vulnerability in Long COVID

Background: Cognitive dysfunction is frequent in Long COVID (LC) and has been linked to altered inflammatory signaling.^1,2 However, studies integrating peripheral neuroimmune markers with neuropsychological assessment remain scarce.^3,4 We investigated circulating neurotrophic, glial, and inflammatory mediators and their associations with cognitive outcomes in LC. Methods: Twenty-two individuals with cognitive symptoms 5-13 months after SARS-CoV-2 infection and 23 age- and sex-matched pre-pandemic controls were included. LC participants underwent norm-referenced neuropsychological assessment. Fourteen plasma mediators were quantified by enzyme-linked immunosorbent assay. Associations between molecules and cognitive outcomes were examined in linear regressions adjusted for post-infection interval, apolipoprotein E ε4, and depressive symptoms. Ethics approval: CAAE 69991923.1.0000.5147. Results: LC participants were predominantly female (86%; mean age=34 years). None required acute hospitalization. Diminished cognitive performance (z<-1.4) concentrated in processing speed (46%), executive functions (27%), and episodic memory (23%). LC had reduced plasma levels of NGF (p=0.039; r_rb=0.37), GDNF (p=0.026; r_rb=0.40), NT-4 (p=0.017; r_rb=0.43), IL-10 (p=0.002; r_rb=0.56), and TNF (p=0.0007; r_rb=0.60). The largest reductions were observed for sTREM2 (p<0.0001; r_rb=0.96), CX3CL1 (p<0.0001; r_rb=0.90), and IL-18 (p<0.0001; r_rb=0.89). Most associations linked higher levels of plasma markers to poorer cognitive performance, whereas higher sTREM2 and CX3CL1 were associated with better attention and higher IL-18 with better verbal fluency. sTREM2 associations remained significant after multiple-testing correction. Conclusion: Cognitive deficits in LC were accompanied by altered levels of plasma neuroimmune markers. Marked reductions in sTREM2, CX3CL1, and IL-18 and their associations with preserved cognitive performance highlight these pathways for further investigation.