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 [ 11 C]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 [ 11 C]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