Objective : To identify potential cerebrospinal fluid (CSF) biomarkers of multiple sclerosis (MS) using quantitative proteomics and to analyze the diagnostic power of their CSF and serum concentrations at different disease stages.
Background: Clinical symptoms, MRI and CSF analysis allow diagnosis of MS with a good sensitivity. However, biomarkers predicting the delay of conversion to remitting-relapsing MS (RRMS) after a clinically isolated syndrome (CIS) and of evolution to progressive MS (PMS) are needed for optimized treatment.
Methods : We performed a quantitative proteomic analysis of CSF pools from symptomatic controls (n = 21) and patients with RRMS (n = 21), followed by the evaluation of the diagnostic and prognostic value of some differentially expressed proteins in a larger cohort of patients at different disease stages (29 controls, 40 CIS, 38 RRMS and 16 PMS).
Results : 22 of the 527 unique proteins quantified exhibited significantly different levels in CSF from controls and RRMS patients. These include chitinase 3-like 1 (CHI3L1) and chitinase 3-like 2 (CHI3L2), two members of the chitinase family that lack chitinase enzymatic activity. CHI3L1 level increased concomitantly with the disease stage in CSF and serum, while CSF CHI3L2 level was maximal in RRMS patients. ROC curves showed a good performance of CSF CHI3L1 and CHI3L2 levels and of serum CHI3L1 levels for MS diagnosis, and indicated that CSF CHI3L1 and CHI3L2 levels accurately discriminated patients with RRMS and PMS. Moreover, CIS patients with higher levels of CHI3L1 in CSF (>189mg/l) and serum (>35mg/l) converted more rapidly to RRMS (log-rank test, p<0.05 and p<0.001 respectively). In addition, a strong CHI3L1 and CHI3L2 expression was detected in brain of patient with MS, especially in astrocytes and microglial cells located in white matter plaques, but not in control brain.
Conclusion : CSF CHI3L1 and CHI3L2 levels and serum CHI3L1 concentration might reflect the extent of MS pathology and help to define the disease stage and prognosis at diagnosis.
Study supported by ARSEPand CFSEP Disclosure: Dr. Thouvenot has received personal compensation for activities with Teva Neuroscience as a scientific advisory board member, and with Biogen Idec and Novartis as a speaker. Dr. Hinsinger has nothing to disclose. Dr. Galeotti has nothing to disclose. Dr. Nabholz has nothing to disclose. Dr. Urbach has nothing to disclose. Dr. Rigau has nothing to disclose. Dr. Demattei has nothing to disclose. Dr. Lehmann has nothing to disclose. Dr. Camu has received personal compensation for activities with Novartis. Dr. Labauge has nothing to disclose. Dr. Castelnovo has nothing to disclose. Dr. Brassat has received personal compensation for activities with Schering AG, Biogen Idec, Serono Inc., and Sanofi-Aventis Pharmaceuticals Inc., as a speaker. Dr. David-Axel has nothing to disclose. Dr. Casez has received personal compensation for activities with AstraZeneca Pharmaceuticals, Biogen Idec, Novartis, and Teva Neuroscience as a speaker. Dr. Bockaert has nothing to disclose. Dr. Marin has nothing to disclose.