Chitinase-1 in cerebrospinal fluid and white matter injury in patients with progressive multiple sclerosis.

OBJECTIVE

In patients with progressive multiple sclerosis (PMS), previous studies reported increased cerebrospinal fluid (CSF) concentrations of inflammatory biomarkers, but these correlated only weakly with structural damage. We aimed to identify inflammatory CSF biomarkers that associate with tissue damage in PMS.

METHODS

We performed four substudies: [1] A cross-sectional exploratory study of patients with primary (PPMS) or secondary progressive MS (SPMS) (n = 38) in whom we explored correlations between CSF concentrations of 1128 proteins and CSF neurofilament light chain (NFL) and myelin basic protein. [2] A cross-sectional confirmatory study where a protein of main interest, chitinase-1 (CHIT1), was analyzed in 104 patients with PPMS (n = 78) or SPMS (n = 26) and compared with 38 symptomatic controls. [3] Associations between CSF concentrations of CHIT1 and other disease biomarkers including CSF- and magnetic resonance imaging (MRI)-based measures of white matter injury in patients with PPMS (n = 59). [4] A longitudinal study of effects of treatment with methylprednisolone, natalizumab, dimethyl fumarate, or placebo on CHIT1 in CSF in patients with PMS.

RESULTS

Substudy [1] identified three proteins that correlated with CSF NFL: soluble B-cell maturation antigen, CC chemokine ligand 22, and CHIT1. CHIT1 showed a strong correlation with CSF NFL (ρ = 0.61, q = 0.008) and was selected for further analyses. Substudy [2] showed that patients with progressive MS had higher CSF concentrations of CHIT1 than symptomatic controls (all p < 0.001). In substudy [3], CSF concentrations of CHIT1 correlated with increased lesion volume (p < 0.001) and decreased magnetization transfer ratio (p = 0.001) of lesions, decreased fractional anisotropy (p < 0.001) and increased mean diffusivity of normal-appearing white matter (p = 0.044) and lesions (p = 0.005) in patients with PPMS. Substudy [4] showed that natalizumab treatment reduced CSF CHIT1 concentrations (p = 0.005) in PMS.

CONCLUSION

CSF CHIT1 concentrations are associated with neuroaxonal and white matter injury in patients with PPMS and responsive to disease-modifying therapy in PMS.