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CHIT1 at Diagnosis Reflects Long-Term Multiple Sclerosis Disease Activity
Emanuela Oldoni1,2, Ide Smets1,2,3, Klara Mallants1,2
1KU Leuven - Department of Neurosciences, Laboratory for Neuroimmunology, Leuven, Belgium.
Objective:
Evidence for a role of microglia in the pathogenesis of multiple sclerosis (MS) is growing. We investigated association of microglial markers at time of diagnostic lumbar puncture (LP) with different aspects of disease activity (relapses, disability, magnetic resonance imaging parameters) up to 6 years later in a cohort of 143 patients.
Methods:
In cerebrospinal fluid (CSF), we measured 3 macrophage and microglia-related proteins, chitotriosidase (CHIT1), chitinase-3-like protein 1 (CHI3L1 or YKL-40), and soluble triggering receptor expressed on myeloid cells 2 (sTREM2), as well as a marker of neuronal damage, neurofilament light chain (NfL), using enzyme-linked immunosorbent assay and electrochemiluminescence. We investigated the same microglia-related markers in publicly available RNA expression data from postmortem brain tissue.
Results:
CHIT1 levels at diagnostic LP correlated with 2 aspects of long-term disease activity after correction for multiple testing. First, CHIT1 increased with reduced tissue integrity in lesions at a median 3 years later (p = 9.6E-04). Second, CHIT1 reflected disease severity at a median 5 years later (p = 1.2E-04). Together with known clinical covariates, CHIT1 levels explained 12% and 27% of variance in these 2 measures, respectively, and were able to distinguish slow and fast disability progression (area under the curve = 85%). CHIT1 was the best discriminator of chronic active versus chronic inactive lesions and the only marker correlated with NfL (r = 0.3, p = 0.0019). Associations with disease activity were, however, independent of NfL.
Interpretation:
CHIT1 CSF levels measured during the diagnostic LP reflect microglial activation early on in MS and can be considered a valuable prognostic biomarker for future disease activity. ANN NEUROL 2020;87:633-645.
Insights
Chitotriosidase (CHIT1) levels in cerebrospinal fluid during diagnosis predict multiple sclerosis (MS) disease activity and disability progression. Early CHIT1 measurement in MS patients offers valuable prognostic insights.
Area of Science:
- Neuroimmunology
- Neurology
- Pathogenesis of Multiple Sclerosis
Background:
- Growing evidence implicates microglia in multiple sclerosis (MS) pathogenesis.
- Investigating early microglial markers may predict long-term disease course in MS patients.
Purpose of the Study:
- To assess the association of microglial markers in cerebrospinal fluid (CSF) at diagnosis with subsequent MS disease activity.
- To determine if CSF chitotriosidase (CHIT1) levels can predict disease progression and lesion characteristics in MS.
Main Methods:
- Measured CSF levels of CHIT1, chitinase-3-like protein 1 (CHI3L1), and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in 143 MS patients at diagnostic lumbar puncture.
- Correlated these markers with clinical outcomes, MRI parameters, and neurofilament light chain (NfL) levels up to 6 years post-diagnosis.
- Analyzed microglial marker expression in postmortem brain tissue RNA data.
Main Results:
- CSF CHIT1 levels at diagnosis correlated significantly with reduced lesion tissue integrity and increased disease severity years later.
- CHIT1 levels predicted disability progression in MS patients, distinguishing slow from fast progressors (AUC=85%).
- CHIT1 was the best discriminator of chronic active vs. inactive lesions and correlated with NfL, independent of NfL levels.
Conclusions:
- CSF CHIT1 levels measured at the time of diagnosis serve as a prognostic biomarker for future multiple sclerosis disease activity.
- Early assessment of microglial activation via CHIT1 can inform prognosis and patient management in MS.
- CHIT1 reflects early microglial activation and is a valuable predictor of long-term MS outcomes.
