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

Abstract

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 GluN1peptide. 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 DCXimmature neurons and increased SOX2neural 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.