Chitinase 3-like 1: prognostic biomarker in clinically isolated syndromes

Abstract

Chitinase 3-like 1 (CHI3L1) has been proposed as a biomarker associated with the conversion to clinically definite multiple sclerosis in patients with clinically isolated syndromes, based on the finding of increased cerebrospinal fluid CHI3L1 levels in clinically isolated syndrome patients who later converted to multiple sclerosis compared to those who remained as clinically isolated syndrome. Here, we aimed to validate CHI3L1 as a prognostic biomarker in a large cohort of patients with clinically isolated syndrome. This is a longitudinal cohort study of clinically isolated syndrome patients with clinical, magnetic resonance imaging, and cerebrospinal fluid data prospectively acquired. A total of 813 cerebrospinal fluid samples from patients with clinically isolated syndrome were recruited from 15 European multiple sclerosis centres. Cerebrospinal fluid CHI3L1 levels were measured by enzyme-linked immunosorbent assay. Multivariable Cox regression models were used to investigate the association between cerebrospinal fluid CHI3L1 levels and time to conversion to multiple sclerosis and time to reach Expanded Disability Status Scale 3.0. CHI3L1 levels were higher in patients who converted to clinically definite multiple sclerosis compared to patients who continued as clinically isolated syndrome (P = 8.1 × 10(-11)). In the Cox regression analysis, CHI3L1 levels were a risk factor for conversion to multiple sclerosis (hazard ratio = 1.7; P = 1.1 × 10(-5) using Poser criteria; hazard ratio = 1.6; P = 3.7 × 10(-6) for McDonald criteria) independent of other covariates such as brain magnetic resonance imaging abnormalities and presence of cerebrospinal fluid oligoclonal bands, and were the only significant independent risk factor associated with the development of disability (hazard ratio = 3.8; P = 2.5 × 10(-8)). High CHI3L1 levels were associated with shorter time to multiple sclerosis (P = 3.2 × 10(-9) using Poser criteria; P = 5.6 × 10(-11) for McDonald criteria) and more rapid development of disability (P = 1.8 × 10(-10)). These findings validate cerebrospinal fluid CHI3L1 as a biomarker associated with the conversion to multiple sclerosis and development of disability and reinforce the prognostic role of CHI3L1 in patients with clinically isolated syndrome. We propose that determining cerebrospinal fluid chitinase 3-like 1 levels at the time of a clinically isolated syndrome event will help identify those patients with worse disease prognosis.

Novel CSF biomarkers to discriminate FTLD and its pathological subtypes

“…Thus, this data also highlights the impact that the heterogeneity within each FTLD subtype can have on the CSF biomarker profile. CSF YKL‐40 was also increased in different acute inflammatory disorders indicating that YKL‐40 is an inflammatory marker likely reflecting astrogliosis 40, 41, 42, 43, 44. Thus, the different levels of YKL‐40 levels across different pathological groups may indicate a different inflammatory response.…”

CSF neuroinflammatory biomarkers in bipolar disorder are associated with cognitive impairment

“…It is primarily secreted by activated macrophages, neutrophils, chondrocytes, tumor cells, and vascular smooth muscle cells. It has also been hypothesized that activation of astrocyte cells in response to inflammation produces high levels of YKL-40 (Canto et al, 2015). YKL-40 is a biomarker for glial activation, and increased CSF levels have been found in inflammatory CNS disorders, such as multiple sclerosis, with normalization after immunosuppressive treatment (Malmestrom et al, 2014), and in bacterial meningitis (Ostergaard et al, 2002).…”

Pharmacodynamic effects of daclizumab in the intrathecal compartment

“…CHI3L1 has been reported as a prognostic biomarker in clinically isolated syndromes 25. It is expressed by macrophages/microglia (and also by reactive astrocytes) in actively demyelinating MS lesions and by CD14 low monocytes in the CSF 25. While our dynamic observations suggest pathogenic role of activated members of myeloid lineage (e.g., macrophages, microglia, and myeloid DCs) in axonal damage associated with MS, correlation cannot prove causation.…”

“…Finally, treatment‐induced reduction of CHI3L1 levels in CSF also correlated with inhibition of axonal damage measured by CSF NFL and with clinical efficacy measured by both EDSS and CombiWISE. CHI3L1 has been reported as a prognostic biomarker in clinically isolated syndromes 25. It is expressed by macrophages/microglia (and also by reactive astrocytes) in actively demyelinating MS lesions and by CD14 low monocytes in the CSF 25.…”