CSF chitinase 3-like 1 is associated with iron rims in patients with a first demyelinating event.

BACKGROUND: Chronic active lesions with iron rims have prognostic implications in patients with multiple sclerosis. OBJECTIVE: To assess the relationship between iron rims and levels of chitinase 3-like 1 (CHI3L1), neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in patients with a first demyelinating event. METHODS: Iron rims were identified using 3T susceptibility-weighted imaging. Serum NfL and GFAP levels were measured by single-molecule array assays. CSF (cerebrospinal fluid) CHI3L1 levels were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Sixty-one patients were included in the study. The presence of iron rims was associated with higher T2 lesion volume and higher number of gadolinium-enhancing lesions. In univariable analysis, having ⩾2 iron rims (vs 0) was associated with increased CSF CHI3L1 levels (ß = 1.41; 95% confidence interval (CI) = 1.10-1.79; p < 0.01) and serum NfL levels (ß = 2.30; 95% CI = 1.47-3.60; p < 0.01). In multivariable analysis, however, only CSF CHI3L1 levels remained significantly associated with the presence of iron rim lesions (ß = 1.45; 95% CI = 1.11-1.90; p < 0.01). The presence of ⩾2 iron rims was not associated with increased serum GFAP levels in univariable or multivariable analyses. CONCLUSION: These findings support an important contribution of activated microglia/macrophages to the pathophysiology of chronic active lesions with iron rims in patients with a first demyelinating event.

CSF Chitinase 3-Like 2 Is Associated With Long-term Disability Progression in Patients With Progressive Multiple Sclerosis.

OBJECTIVE: This study aimed to identify long-term prognostic protein biomarkers associated with disease progression in patients with progressive multiple sclerosis (MS). METHODS: CSF samples were collected from a discovery cohort of 28 patients with progressive MS who participated in a clinical trial with interferon beta. Patients were classified into high and low disability progression phenotypes according to numeric progression rates (NPR) and step-based progression rates (SPR) after a mean follow-up time of 12 years. Protein abundance was measured by shotgun proteomics. Selected proteins from the discovery cohort were quantified by parallel reaction monitoring in CSF samples from an independent validation cohort of 41 patients with progressive MS classified also into high and low disability progression phenotypes after a mean follow-up time of 7 years. RESULTS: Of 2,548 CSF proteins identified in the discovery cohort, 10 were selected for validation based on their association with long-term disability progression: SPATS2-like protein, chitinase 3-like 2 (CHI3L2), plasma serine protease inhibitor, metallothionein-3, phospholipase D4, beta-hexosaminidase, neurexophilin-1, adipocyte enhancer-binding protein 1, cathepsin L1, and lipopolysaccharide-binding protein. Only CHI3L2 was validated, and patients with high disability progression exhibited significantly higher CSF protein levels compared with patients with low disability progression (p = 0.03 for NPR and p = 0.02 for SPR). CHI3L2 levels showed good performance to discriminate between high and low disability progression in patients with progressive MS (area under the curve 0.73; sensitivity 90% and specificity 63%). CONCLUSIONS: Although further confirmatory studies are needed, we propose CSF CHI3L2 as a prognostic protein biomarker associated with long-term disability progression in patients with progressive MS. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that high CSF CHI3L2 levels identified higher disability progression in patients with progressive MS.

CSF SERPINA3 Levels Are Elevated in Patients With Progressive MS.

OBJECTIVE: To identify biomarkers associated with progressive phases of MS and with neuroprotective potential. METHODS: Combined analysis of the transcriptional and proteomic profiles obtained in CNS tissue during chronic progressive phases of experimental autoimmune encephalomyelitis (EAE) with the transcriptional profile obtained during the differentiation of murine neural stem cells into neurons. Candidate biomarkers were measured by ELISA in the CSF of 65 patients with MS (29 with relapsing-remitting MS [RRMS], 20 with secondary progressive MS, and 16 with primary progressive MS [PPMS]) and 30 noninflammatory neurologic controls (NINCs). RESULTS: Integrative analysis of gene and protein expression data identified 2 biomarkers, the serine protease inhibitor Serpina3n and the calcium-binding protein S100A4, which were upregulated in chronic progressive EAE and whose expression was induced during neuronal differentiation. Immunofluorescence studies revealed a primarily neuronal expression of S100A4 and Serpina3n during EAE. CSF levels of SERPINA3, the human ortholog of murine Serpina3n, and S100A4 were increased in patients with MS compared with NINCs (SERPINA3: 1,320 vs 838.6 ng/mL, p = 0.0001; S100A4: 1.6 vs 0.8 ng/mL, p = 0.02). Within the MS group, CSF SERPINA3 levels were significantly elevated in patients with progressive forms, mainly patients with PPMS compared with patients with RRMS (1,617 vs 1,129 ng/mL, p = 0.02) and NINCs (1,617 vs 838.6 ng/mL, p = 0.0001). Of interest, CSF SERPINA3 levels significantly correlated with CSF neurofilament light chain levels only in the PPMS group (r = 0.62, p = 0.01). CONCLUSION: These results point to a role of SERPINA3 as a biomarker associated with the progressive forms of MS, particularly PPMS.

Chitinases and chitinase-like proteins as biomarkers in neurologic disorders.

Chitinases are hydrolytic enzymes widely distributed in nature. Despite their physiologic and pathophysiologic roles are not well understood, chitinases are emerging as biomarkers in a broad range of neurologic disorders, where in many cases, protein levels measured in the CSF have been shown to correlate with disease activity and progression. In this review, we will summarize the structural features of human chitinases and chitinase-like proteins and their potential physiologic and pathologic functions in the CNS. We will also review existing evidence for the role of chitinases and chitinase-like proteins as diagnostic and prognostic biomarkers in inflammatory, neurodegenerative diseases, and psychiatric disorders. Finally, we will comment on future perspectives of chitinase studies in neurologic conditions.