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

IF 7.5 1区医学 Q1 CLINICAL NEUROLOGY

Annals of Neurology Pub Date : 2026-10-06 DOI:10.1002/ana.78386

Venla Ahola, Maija Saraste, Edoardo Pedrini, Joel Tuomaala, Luzia Buchholz, Markus Matilainen, Johanna Lindenberg, Eeva-Christine Brockmann, Maria Sofia Martire, Sofia Sandgren, David Leppert, Jens Kuhle, Tanja Kuhlmann, Martina Absinta, Laura Airas

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引用次数: 0

Abstract

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.

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血清壳三酸苷酶与多发性硬化症脑慢性活动性病变边缘活化的胶质细胞有关。

目的：探讨多发性硬化症（pwMS）患者18 kDa转运蛋白(TSPO)-正电子发射断层扫描(PET)-可测量胶质活化与血清壳三醇苷酶（CHIT1）的关系及其在死后脑组织中的表达。方法：在这项横断面研究中，89名pwMS患者（19名进展性MS [PMS]和70名复发缓解型MS [RRMS]）和16名年龄和性别匹配的健康对照接受了[11C]PK11195 TSPO-PET检查。采用酶联免疫吸附法（ELISA）测定血清CHIT1浓度。根据[11C] pk11195在病变中心和边缘的结合，t1加权的低信号病变被表型为边缘活跃、整体活跃或不活跃。采用Spearman相关分析CHIT1与研究变量之间的关系。通过重新分析空间转录组学以及单核和伪体rna测序数据集，评估死后CHIT1和TSPO的表达。结果：在基于pwMS中位CHIT1浓度（22.1 ng/ml）划分的CHIT1高探索性队列中，CHIT1与边缘活动病变的数量（ρ = 0.33, 95%可信区间[CI] = 0.01 ~ 0.58, p = 0.038）、体积（ρ = 0.39, 95% CI = 0.08 ~ 0.63, p = 0.013）、百分比（ρ = 0.31, 95% CI = 0.003 ~ 0.57, p = 0.046）和t1加权病变周围区域tspo结合（ρ = 0.36, 95% CI = 0.05 ~ 0.61, p = 0.020）呈正相关。在pwMS队列中，CHIT1与GFAP （ρ = 0.23, 95% CI = 0.003-0.44, p = 0.042）和神经丝轻链（NfL; ρ = 0.26, 95% CI = 0.03-0.46, p = 0.022）相关。空间转录组学显示，CHIT1在活动性病变和慢性活动性病变边缘的表达明显高于白质（ANOVA p）。解释：高血清CHIT1与tspo - pet鉴定的慢性活动性病变存在相关。血清CHIT1作为MS脑慢性活动性病变边缘伴随有害胶质细胞激活的生物标志物的潜在效用有待进一步验证。Ann neurol 2026。

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来源期刊

Annals of Neurology 医学-临床神经学

CiteScore

18.00

自引率

1.80%

发文量

270

审稿时长

3-8 weeks

期刊介绍： Annals of Neurology publishes original articles with potential for high impact in understanding the pathogenesis, clinical and laboratory features, diagnosis, treatment, outcomes and science underlying diseases of the human nervous system. Articles should ideally be of broad interest to the academic neurological community rather than solely to subspecialists in a particular field. Studies involving experimental model system, including those in cell and organ cultures and animals, of direct translational relevance to the understanding of neurological disease are also encouraged.