Targeted proteomic profiling of serum and CSF reveals CASP-8 as a candidate biomarker in anti-NMDAR encephalitis

Anti-NMDA receptor (NMDAR) encephalitis is an autoimmune disorder of the central nervous system involving both B- and T-cell activation. In this exploratory study, targeted proteomics was used to characterize protein expression profiles in serum and cerebrospinal fluid (CSF) from patients with anti-NMDAR encephalitis. Samples from eight patients and 16 age- and sex-matched symptomatic controls were analyzed in a retrospective case-control design. Protein concentrations in serum and CSF were quantified using Proximity Extension Assay (PEA) technology targeting 182 proteins related to immunity, synaptic regulation, and neuronal maintenance. Linear regression identified seven significantly altered proteins in CSF and three in serum after Bonferroni correction (p < 0.00027). In CSF, six proteins associated with immune signaling and neuronal support (ADA, CCL19, CXCL5, BMP-4, FGF-5, CDH3) were decreased, while the protease CASP-8 was elevated. In serum, proteases CTSC and CASP-8 were increased, whereas ADA, a key regulator of purine metabolism and immune signaling, was decreased. Strong to moderate correlations between CSF and serum levels were observed for ADA (r = 0.606, p = 0.013) and CASP-8 (r = 0.526, p = 0.037). Longitudinal CSF data from two patients revealed dynamic changes in CXCL5, CCL19, and CASP-8 corresponding to disease activity and treatment response. Overall, these findings revealed distinct yet related proteomic signatures in serum and CSF, suggesting compartment-specific immune responses involving both innate and adaptive pathways. The consistent elevation of CASP-8 highlights its potential as a biomarker of disease activity and warrants further investigation.