BARCELONA—CSF levels of chitinase 3-like-1 protein and of the light subunit of neurofilaments predict conversion to multiple sclerosis (MS) and the development of neurologic disability in patients with clinically isolated syndrome (CIS), according to an overview presented at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Ongoing research will indicate whether combinations of CSF biomarkers provide more accurate prognoses than individual biomarkers do.
Clinical manifestations, disease course, radiologic findings, histopathologic characteristics of lesions, and response to treatment vary greatly among patients with MS. The heterogeneity of the disease creates a need for reliable biomarkers that may improve diagnosis, stratification, prediction of disease course, identification of new therapies, and development of personalized therapy, said Manuel Comabella, MD, Head of the Laboratory of the Clinical Neuroimmunology Unit at the MS Center of Catalonia in Barcelona.
Neurofilament Proteins
Previous studies indicate that CSF oligoclonal bands and the 14-3-3 protein individually predict conversion from CIS to MS. Newer research indicates that the levels of neurofilament proteins in CSF can help neurologists quantify axonal damage. Neurofilaments comprise heavy, medium, and light subunits, and neurofilaments’ axonal diameter is influenced by the degree to which they are phosphorylated. Pathologic processes that cause axonal damage release the neurofilament proteins into the CSF, where they can be detected.
Teunissen et al observed that CSF levels of the light subunit of the neurofilaments were significantly higher in patients with CIS who converted to clinically definite MS, compared with patients with CIS who did not convert. More recently, Modvig and colleagues found that levels of the light subunit of the neurofilaments predicted long-term disability, as measured by the MS severity scale and the nine-hole peg test, in patients with optic neuritis after more than three years of follow-up.
Levels of the light subunit of the neurofilaments also may predict disease progression in patients with MS. Investigators found that conversion from relapsing-remitting MS to secondary progressive MS was more likely among patients with high levels of the light subunit of the neurofilaments, compared with patients with intermediate or undetectable levels. Also, case reviews indicate that common MS therapies such as natalizumab or fingolimod modify CSF levels of the light subunit of the neurofilaments, “which suggests that they can be used as a biomarker to monitor the response to therapies and … the neuroprotective effects of treatments,” said Dr. Comabella.
Chitinase 3-Like-1 Protein
Investigators also have examined chitinase 3-like-1 protein as a potential biomarker. The protein results from strong proinflammatory cytokines such as TNF-α and IL-1β. Serum and plasma levels of the protein usually are elevated in people with disorders characterized by chronic inflammation.
Dr. Comabella and colleagues conducted a study to identify CSF biomarkers associated with conversion from CIS to MS. The investigators classified patients into two groups. One group included patients with CIS who had a normal MRI and were positive for IgG oligoclonal bands at baseline, and who converted to clinically definite MS during follow-up. The other group included patients with CIS who had a normal MRI at baseline and after five years of follow-up, were negative for IgG oligoclonal bands, and did not convert to MS during follow-up.
The investigators applied a mass-spectrometry-based proteomic approach to identify proteins that were present in different quantities in the CSF of patients who converted to MS, compared with those who did not. They found that CSF levels of chitinase 3-like-1 protein were significantly higher in patients who converted to MS, compared with those who did not. CSF levels of the protein also correlated with MRI abnormalities at baseline and with disability progression during follow-up. In addition, high levels of chitinase 3-like-1 protein were associated with a shorter time to MS.
These results prompted Dr. Comabella’s group to begin a study evaluating chitinase 3-like-1 protein as a prognostic biomarker for conversion to MS. The investigators examined more than 800 CSF samples from patients with CIS. They used multivariable Cox regression models to investigate the association between CSF chitinase 3-like-1 protein levels and the time to MS, based on Poser or 2005 McDonald criteria, and also based on the time to reach an Expanded Disability Status Scale score of 3.
CSF levels of chitinase 3-like-1 protein were a risk factor for conversion to MS, independent of other predictors such as IgG oligoclonal bands and MRI. Chitinase 3-like-1 protein levels were the only significant independent risk factor associated with the development of neurologic disability, with a hazard ratio of approximately 4. “A chitinase level of 170 ng/mL was the best cutoff that allowed us to classify protein levels into high and low, and 44% of the patients had protein levels above this cutoff,” said Dr. Comabella. Levels higher than 170 ng/mL were associated with a shorter time to MS and with faster development of disability.