Neuroglial biomarkers in autoimmune encephalitis: advances in diagnosis, prognosis, and pathophysiological insights

Autoimmune encephalitis (AE) presents with a diverse spectrum of neuropsychiatric symptoms, often leading to diagnostic challenges and delays in treatment. Neuroglial biomarkers may improve AE diagnosis, disease monitoring, and prognostication. This review examines the diagnostic and prognostic value of fluid biomarkers in AE, focusing on markers of neuroaxonal damage, synaptic dysfunction, astroglial activation, and amyloid metabolism. A systematic search of PubMed, Cochrane, and Scopus databases (from inception until November 26, 2024) was performed. Of the 1,270 articles screened, 31 studies met the inclusion criteria. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis was the most frequently investigated subtype (70% of studies). Neurofilament light chain (NfL) was the most widely analyzed biomarker, with elevated levels in both cerebrospinal fluid and serum, aiding in the differentiation of AE from primary psychiatric disorders and in the early identification of checkpoint inhibitor-related neurotoxicity. NfL and total tau (t-Tau) were consistently higher in paraneoplastic than non-paraneoplastic AE. Despite some variability across studies, amyloid-beta (Aβ) 42 and Aβ40, as well as phosphorylated tau (p-Tau), were altered in AE compared to controls, although generally to a lesser extent than in Alzheimer's disease. Higher baseline NfL and YKL-40 correlated with disease severity, and NfL reductions post-immunotherapy were linked to treatment response. Despite consistent heterogeneities in sampling timing, these findings highlight the potential of neuroglial biomarkers as diagnostic and prognostic tools in AE. Future studies should explore longitudinal biomarker dynamics and refine their clinical applications.