Serum Chitotriosidase Links to Activated Glia at Chronic Active Lesion Rims in Multiple Sclerosis Brain

OBJECTIVE: The objective of this study was to explore the association between 18 kDa translocator protein (TSPO)-positron emission tomography (PET)-measurable glial activation and serum chitotriosidase (CHIT1) in people with multiple sclerosis (pwMS), and its expression in postmortem MS brain tissue. METHODS: In this cross-sectional study, 89 pwMS (19 progressive MS [PMS] and 70 relapsing-remitting MS [RRMS]) and 16 age- and sex-matched healthy controls underwent [¹¹C]PK11195 TSPO-PET. Serum CHIT1 concentration was measured using enzyme-linked immunosorbent assay (ELISA). T1-weighted hypointense lesions were phenotyped as rim-active, overall-active, or inactive based on [¹¹C]PK11195-binding in lesion centers and edges. Spearman correlation was used to analyze associations between CHIT1 and study variables. Postmortem CHIT1 and TSPO expressions were assessed immunohistochemically and by re-analyzing spatial transcriptomics as well as single-nucleus and pseudobulk RNA-sequencing datasets. RESULTS: CHIT1 correlated positively with the number (ρ = 0.33, 95% confidence interval [CI] = 0.01-0.58, p = 0.038), volume (ρ = 0.39, 95% CI = 0.08-0.63, p = 0.013), and percentage (ρ = 0.31, 95% CI = 0.003-0.57, p = 0.046) of rim-active lesions and with TSPO-binding in the T1-weighted perilesional area (ρ = 0.36, 95% CI = 0.05-0.61, p = 0.020) in the exploratory CHIT1-high cohort divided based on median CHIT1 concentration in pwMS (22.1 ng/ml). CHIT1 correlated with GFAP (ρ = 0.23, 95% CI = 0.003-0.44, p = 0.042) and neurofilament light chain (NfL; ρ = 0.26, 95% CI = 0.03-0.46, p = 0.022) in the pwMS cohort. Spatial transcriptomics demonstrated significantly higher CHIT1 expression in active lesions and at the edge of chronic active lesions than in white matter (ANOVA p < 0.0001; post hoc multiple comparison analysis p < 0.0001). INTERPRETATION: High serum CHIT1 correlated with the presence of TSPO-PET-identified chronic active lesions. The potential utility of serum CHIT1 as a biomarker for concomitant detrimental glial activation at the edge of chronic active lesions in MS brain warrants further validation. ANN NEUROL 2026.