What question did this study set out to answer?

This research aims to elucidate the role of CHI3L1 as a biomarker for cognitive dysfunction in anti-NMDAR encephalitis.

January 6, 2026CNS Neuroscience & Therapeutics0 citationsOpen Access

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

YLYuhang LiChildren's Hospital of Chongqing Medical University RDRan DingWenzhou Medical University JYJ R YangChildren's Hospital of Chongqing Medical University

Key Points

This research aims to elucidate the role of CHI3L1 as a biomarker for cognitive dysfunction in anti-NMDAR encephalitis.
Established an active immunization mouse model of anti-NMDAR encephalitis using GluN1 356-385 peptide.
Performed hippocampal proteomic profiling and conducted behavioral tests to evaluate cognitive function.
Analyzed serum and CSF samples from a clinical cohort to assess biomarker levels.
Significant upregulation of CHI3L1 was observed in the hippocampus of model mice.
Elevated CHI3L1 levels correlated with impaired neurogenesis and cognitive deficits.
In a cohort of 83 children, CHI3L1 levels were significantly elevated compared to controls, correlating with persistent cognitive impairment.

Abstract

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 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.

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