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. 2015 Apr;21(5):550-61.
doi: 10.1177/1352458514549397. Epub 2015 Mar 2.

Glial and neuronal markers in cerebrospinal fluid predict progression in multiple sclerosis

M Alba Mañé Martínez  1 , Bob Olsson  2 , Laura Bau  3 , Elisabet Matas  3 , Álvaro Cobo Calvo  3 , Ulf Andreasson  2 , Kaj Blennow  2 , Lucia Romero-Pinel  3 , Sergio Martínez-Yélamos  3 , Henrik Zetterberg  4
Affiliations

Glial and neuronal markers in cerebrospinal fluid predict progression in multiple sclerosis

M Alba Mañé Martínez et al. Mult Scler. 2015 Apr.

Abstract

Objective: To investigate glial and neuronal biomarkers in cerebrospinal fluid (CSF) samples from patients with relapsing-remitting multiple sclerosis (RRMS) and clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS), and to evaluate their ability to predict conversion from CIS to clinically definite MS (CDMS) and also disability progression in MS.

Methods: CSF levels of neurofilament light protein (NFL), t-tau, p-tau, glial fibrillary acidic protein (GFAP), S-100B, human chitinase 3-like 1 protein (YKL-40), monocyte chemoattractant protein-1 (MCP-1), α-sAPP and β-sAPP; and Aβ38, Aβ40 and Aβ42, were analyzed in 109 CIS patients and 192 RRMS patients. The mean follow-up time of these 301 patients was 11.7 ± 6.4 years.

Results: High levels of NFL were associated with early conversion from CIS to CDMS (hazard ratio (HR) with 95% confidence interval (CI): 2.69 (1.75 - 4.15); p < 0.0001). High levels of YKL-40 and GFAP were associated with earlier progression in the Expanded Disability Status Scale (EDSS), score 3: YKL-40 (HR (95% CI): 2.78 (1.48 - 5.23); p = 0.001) and GFAP (HR (95% CI): 1.83 (1.01 - 3.35); p = 0.04). High levels of YKL-40 were associated with earlier progression to EDSS 6 (HR (95% CI): 4.57 (1.01 - 20.83); p = 0.05).

Conclusions: CSF levels of NFL in CIS patients are an independent prognostic marker for conversion to CDMS. Whereas, CSF levels of YKL-40 and GFAP are independent prognostic markers for disability progression in MS.

Keywords: Biomarkers; cerebrospinal fluid; chitinase 3-like 1 protein; diagnostics; disability progression; glial fibrillary acidic protein; multiple sclerosis; neurofilament light protein; prognostic markers.

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Conflict of interest statement

Conflict of interest: M Alba Mañé Martínez received research support from the Fundació Hospital Universitari de Tarragona Joan XXIII and Fundació Institut d’Investigació Biomèdica de Bellvitge (IDIBELL); and received research support, funding for travel and congress expenses from Biogen Idec, Teva Pharmaceutical Industries, Sanofi-Aventis, Merck Serono, Novartis and Bayer Schering Pharma.

Laura Bau received research support, funding for travel and congress expenses from Biogen Idec, Teva, Sanofi-Aventis, Merck Serono, Novartis and Bayer Schering pharmaceuticals.

Elisabet Matas received research support, funding for travel and congress expenses from Biogen Idec, Teva, Sanofi-Aventis, Merck Serono, Novartis and Bayer Schering pharmaceuticals.

Alvaro Cobo Calvo received research support, funding for travel and congress expenses from Biogen Idec, Teva, Sanofi-Aventis, Merck Serono, Novartis and Bayer Schering pharmaceuticals.

Kaj Blennow has served on the advisory board for Innogenetics of Belgium.

Lucia Romero-Pinel received research support, funding for travel and congress expenses from Biogen Idec, Teva, Sanofi-Aventis, Merck Serono, Novartis and Bayer Schering pharmaceuticals.

Sergio Martínez-Yélamos received honoraria compensation to participate in advisory boards, collaborations as a consultant and scientific communications from Biogen Idec, Teva, Sanofi-Aventis, Merck Serono, Novartis and Bayer Schering pharmaceuticals; and received research support, funding for travel and congress expenses from Biogen Idec, Teva, Sanofi-Aventis, Merck Serono, Novartis and Bayer Schering pharmaceuticals.

Ulf Andreasson, Bob Olsson and Henrik Zetterberg report no disclosures.

Figures

Figure 1.
Figure 1.
NFL levels and conversion from CIS to CDMS. The Kaplan-Meier estimator was used to assess the time to develop CDMS. The median of CSF biomarker levels (NFL = 1150 ng/L) in the CIS group (n = 109) was established as the cut-off value, and used to classify CIS patients into two groups (high or low), respectively. The graph represents the survival distribution function in patients with high levels of NFL (n = 53) and low levels of NFL (n = 50). We display the median time to CDMS in years (with 95% CI). CDMS: Clinically-definite multiple sclerosis; CIS: clinically-isolated syndrome; MS: multiple sclerosis; NFL: neurofilament light protein; y: year/s
Figure 2.
Figure 2.
YKL-40 and GFAP levels and disability progression in the relapsing forms of MS. We used a Kaplan-Meier estimator to assess the time to reach EDSS 3. The median of CSF biomarker levels (YKL-40 = 101 ng/mL and GFAP = 300 ng/L) in the relapsing-remitting forms of MS (CIS and RRMS) group (n = 301) was established as the cut-off value to classify MS patients into two groups (high or low), respectively. The mean survival time in years plus 95% CI are displayed. The time to reach EDSS 3 was significantly shorter in patients with high levels of (a) YKL-40 (n = 140) and (b) GFAP (n = 146), compared with patients with low levels of (a) YKL-40 (n = 140) and (b) GFAP (n = 155). aBecause YKL-40 was the last biomarker to be analyzed, 21 samples did not have enough volume left for the analysis. CIS: clinically-isolated syndrome; CSF: Cerebrospinal fluid; EDSS: Expanded Disability Status Scale; GFAP: glial fibrillary acidic protein; MS: multiple sclerosis; RRMS: relapsing–remitting MS; y: years; YKL-40: human chitinase 3-like 1 protein
Figure 3.
Figure 3.
YKL-40 levels and disability progression in the relapsing forms of MS. We used a Kaplan-Meier estimator to assess the time to reach EDSS 6. The median of CSF biomarker levels (YKL-40 = 101 ng/mL) in relapsing-remitting forms (CIS and RRMS) group (n = 301) was established as the cut-off value to classify MS patients into two groups (high or low), respectively. Mean survival time in years (y) with 95%CI are displayed. The time to reach EDSS 6 was significantly shorter in patients with high levels of YKL-40 (n = 140), compared with patients with low levels of YKL-40 (n = 140). aBecause YKL-40 was the last biomarker to be analyzed, 21 samples did not have enough volume left for the analysis. CIS: clinically-isolated syndrome; CSF: Cerebrospinal fluid; EDSS: Expanded Disability Status Scale; MS: multiple sclerosis; RRMS: relapsing–remitting MS; y: years; YKL-40: human chitinase 3-like 1 protein
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