Elevated CHI3L1 as a Potential Biomarker of Cognitive Dysfunction in Anti-NMDAR Encephalitis: Evidence From Clinical Results and Mice Model.

BACKGROUND: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is frequently associated with long-term cognitive impairment. However, the underlying mechanisms remain poorly understood, and reliable biomarkers for predicting cognitive outcomes are lacking. METHODS: We established an active immunization mouse model of anti-NMDAR encephalitis by immunizing with the GluN1(356-385) peptide. Hippocampal proteomic profiling was performed, followed by molecular and histological validation. Behavioral tests were used to assess cognitive function. In parallel, serum and cerebrospinal fluid (CSF) samples were analyzed from a clinical cohort of children with anti-NMDAR encephalitis to evaluate expression of the targeted biomarker and its association with clinical outcomes. RESULTS: Proteomic analysis and subsequent validation revealed significant upregulation of chitinase-3-like protein 1 (CHI3L1) in the hippocampus of model mice, primarily derived from astrocytes. Elevated CHI3L1 levels were observed in parallel with impaired hippocampal neurogenesis, reflected by decreased DCX(+) immature neurons and increased SOX2(+) neural progenitors. These changes were accompanied by cognitive deficits in behavioral tests. In parallel, we analyzed a pediatric cohort of 83 children with anti-NMDAR encephalitis. CHI3L1 levels in both serum and CSF were significantly elevated compared to controls. While CHI3L1 levels showed no association with modified Rankin Scale scores at one-year follow-up, higher CHI3L1 levels in serum and CSF were significantly correlated with persistent cognitive impairment. CONCLUSIONS: Our findings provide preliminary evidence that astrocyte-derived CHI3L1 may contribute to disrupted hippocampal neurogenesis and cognitive dysfunction in anti-NMDAR encephalitis. CHI3L1 may serve as a potential biomarker for cognitive prognosis and a therapeutic target for reducing long-term neurological sequelae.