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

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.

Effects of ferrofluid and phytoalexin spirobrassinin on thioflavin-T-based fluorescence in cerebrospinal fluid of the elderly and multiple sclerosis patients.

It is well known that misfolded peptides/proteins can play a role in processes of normal ageing and in the pathogenesis of many diseases including Alzheimer's disease. Previously, we evaluated samples of cerebrospinal fluid from patients with Alzheimer's disease and multiple sclerosis by means of thioflavin-T-based fluorescence. We observed attenuated effects of magnetite nanoparticles operated via anti-aggregation actions on peptides/proteins from patients with Alzheimer's disease but not from those with multiple sclerosis when compared to age-related controls. In this study, we have evaluated the in vitro effects of anti-aggregation operating ferrofluid and phytoalexin spirobrassinin in the cerebrospinal fluid of patients with multiple sclerosis and Alzheimer's disease. We have found significant differences in native fluorescence (λ excitation = 440 nm, λ emission = 485 nm) of samples among particular groups (young controls < multiple sclerosis, Alzheimer's disease < old controls). Differences among groups were observed also in thioflavin-T-based fluorescence (young controls = multiple sclerosis < Alzheimer's disease < old controls) and the most marked change from native to thioflavin-T-based fluorescence was found in young controls (28-40 years old people). Both ferrofluid and spirobrassinin evoked drops in thioflavin-T-based fluorescence; however, ferrofluid was more efficient in old controls (54-75 years old people) and spirobrassinin in multiple sclerosis patients, both compared to young controls. The results are discussed especially in relation to aggregated peptides/proteins and liposoluble fluorescent products of lipid peroxidation. Based on the significant effect of spirobrassinin in vitro, we suggest that spirobrassinin may be of therapeutic value in multiple sclerosis.

Levels of 17ß-hydroxysteroid dehydrogenase type 10 in CSF are not a valuable biomarker for multiple sclerosis.

AIM: We aimed to characterize the role of mitochondrial 17ß-hydroxysteroid dehydrogenase type 10 (17ß-HSD10) overexpression in multiple sclerosis (MS) and to evaluate its use as a biomarker. Materials & methods: We estimated levels of 17ß-HSD10, amyloid ß 1-42, cyclophilin D, 17ß-HSD10-cyclophilin D complexes or 17ß-HSD10-parkin complexes in cerebrospinal fluid (CSF) samples. RESULTS: The increase in 17ß-HSD10 levels or in 17ß-HSD10-parkin complexes and links to leukocytes were found only in relapsing-remitting MS. The sensitivity of the biomarker was 64%, the specificity equaled 60-63% compared with controls. CONCLUSION: Increased CSF levels of 17ß-HSD10 in later stages of MS could be interpreted via its upregulation in demyelinated neuronal axons. CSF levels of 17ß-HSD10 are not the valuable biomarker for the early diagnosis or for the progression of MS.

Serum and cerebrospinal fluid heavy neurofilaments and antibodies against them in early multiple sclerosis.

Heavy neurofilaments (NFH) released from neurons during axonal injury induce a humoral immune response. We measured CSF and serum levels of NFH proteins and anti-NFH IgG antibodies in 19 patients with clinically isolated syndrome (CIS) converting to multiple sclerosis, in 20 stable CIS patients, 23 patients with multiple sclerosis (MS) and 32 control subjects using ELISA. CSF and intrathecal levels and CSF/serum ratios of anti-NFH antibodies were increased in the CIS patients early developing MS while NFH protein concentrations were similar among the groups. Changes associated with NFH are more pronounced for antibodies than for protein itself and may aid in prediction of CIS patients.

Serum and cerebrospinal fluid light neurofilaments and antibodies against them in clinically isolated syndrome and multiple sclerosis.

A release of light neurofilament subunits (NFL) into cerebrospinal fluid (CSF) and serum in multiple sclerosis (MS) may induce an immune response. We examined CSF and serum NFL levels and IgG antibodies against NFL in 19 patients with a clinically isolated syndrome (CIS) early converted into MS, 20 CIS-non-converters, 23 MS patients and 32 controls. CSF NFL levels were significantly higher in all patient groups. The highest CSF or intrathecally (IT) synthesized anti-NFL antibodies and CSF/serum ratios of anti-NFL antibodies were observed in CIS-converters. CSF NFL and CSF or IT anti-NFL antibodies could be surrogate biomarkers of axonal injury in early MS.