Serum contactin-1 as a biomarker of long-term disease progression in natalizumab-treated multiple sclerosis.

BACKGROUND: Natalizumab treatment provides a model for non-inflammation-induced disease progression in multiple sclerosis (MS). OBJECTIVE: To study serum contactin-1 (sCNTN1) as a novel biomarker for disease progression in natalizumab-treated relapsing-remitting MS (RRMS) patients. METHODS: Eighty-nine natalizumab-treated RRMS patients with minimum follow-up of 3 years were included. sCNTN1 was analyzed at baseline (before natalizumab initiation), 3, 12, 24 months (M) and last follow-up (median 5.2 years) and compared to 222 healthy controls (HC) and 15 primary progressive MS patients (PPMS). Results were compared between patients with progressive, stable, or improved disability according to EDSS-plus criteria. RESULTS: Median sCNTN1 levels (ng/mL,) in RRMS (baseline: 10.7, 3M: 9.7, 12M: 10.4, 24M: 10.8; last follow-up: 9.7) were significantly lower compared to HC (12.5; p ⩽ 0.001). It was observed that 48% of patients showed progression during follow-up, 11% improved, and 40% remained stable. sCNTN1 levels were significantly lower in progressors both at baseline and at 12M compared to non-progressors. A 1 ng/mL decrease in baseline sCNTN1 was consistent with an odds ratio of 1.23 (95% confidence interval 1.04-1.45) (p = 0.017) for progression during follow-up. CONCLUSION: Lower baseline sCNTN1 concentrations were associated with long-term disability progression during natalizumab treatment, making it a possible blood-based prognostic biomarker for RRMS.

Contactin-1 and contactin-2 in cerebrospinal fluid as potential biomarkers for axonal domain dysfunction in multiple sclerosis.

BACKGROUND: Contactin-1 and contactin-2 are important for the maintenance of axonal integrity. OBJECTIVE: To investigate the cerebrospinal fluid levels of contactin-1 and contactin-2 in multiple sclerosis patients and controls, and their potential use as prognostic markers for neurodegeneration. METHODS: Cerebrospinal fluid contactin-1 and contactin-2 were measured in relapsing-remitting multiple sclerosis (n = 41), secondary progressive multiple sclerosis (n = 26) and primary progressive multiple sclerosis patients (n = 13) and controls (n = 18), and in a second cohort with clinically isolated syndrome patients (n = 88, median clinical follow-up period of 2.3 years) and controls (n = 20). Correlations/linear regressions were analysed with other baseline cerebrospinal fluid axonal damage markers and cross-sectional/longitudinal magnetic resonance imaging features. RESULTS: Contactin-1 and contactin-2 levels were up to 1.4-fold reduced in relapsing-remitting multiple sclerosis (contactin-1: p = 0.01, contactin-2: p = 0.02) and secondary progressive multiple sclerosis (contactin-1: p = 0.05, contactin-2: p = 0.02) compared to controls. In clinically isolated syndrome patients, contactin-1 tended to increase when compared to controls (p = 0.07). Both contactin-1 and contactin-2 correlated with neurofilament light, neurofilament heavy and magnetic resonance imaging metrics differently depending on the disease stage. In clinically isolated syndrome patients, baseline contactin-2 level (ß = -0.42, p = 0.04) predicted the longitudinal decline in cortex volume. CONCLUSION: Cerebrospinal fluid contactin-1 and contactin-2 reveal axonal dysfunction in various stages of multiple sclerosis and their inclusion to the biomarker panel may provide better insight into the extent of axonal damage/dysfunction.

Multicenter immunoassay validation of cerebrospinal fluid neurofilament light: a biomarker for neurodegeneration.

AIM: Neurofilament light (NfL) chain, a putative cerebrospinal fluid biomarker, can support neurodegenerative disease diagnosis and indicate disease severity and prognosis. Universal validation protocols when used to measure biomarkers can reduce pre and analytical laboratory variation, thus increasing end-user confidence in the consistency of validation data across sites. METHODOLOGY: Here, a commercially available NfL ELISA (UmanDiagnostics, Umeå, Sweden) was validated in a multicentered setting using comprehensive newly developed standard operating procedures. RESULTS: The data showed good assay sensitivity and intra and interassay precision. Interlaboratory precision was, however, suboptimal. CONCLUSION: The UmanDiagnostics assay is suitable for the quantification of NfL in human cerebrospinal fluid. However, sources of interlaboratory variation in the data require further investigation.