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Prospective Outcome Analysis of Multiple Sclerosis Cases Reveals Candidate Prognostic Cerebrospinal Fluid Markers

Elif Everest, Ugur Uygunoglu, Melih Tutuncu, Alper Bulbul, Umut Inci Onat, Mehmetcan Unal, Timucin Avsar, Sabahattin Saip, Ugur Bilge, Eda Tahir Turanli , Aksel Siva


We prospectively analysed our previous MS cohort with initial cerebrospinal fluid (CSF) proteomics data to reveal disability markers after 8.2±2.2 years of follow-up.


Multiple sclerosis (MS) is a chronic neuro-inflammatory and neurodegenerative disease of the central nervous system with a complex pathophysiology and clinical course. Numerous studies have revealed potential prognostic markers, including magnetic resonance imaging (MRI) parameters [1–3] and disease- and progression-related cellular pathways, most of which are related to immune system dysregulation [4], blood-brain barrier disruption [5], oligodendrocyte death [6], and axonal loss [7].


Patients in the unfavourable course group had significantly higher ARMSS scores than those in the favourable course group based on the last follow-up (7.0±1.7 vs. 1.7±0.9, P<0.0001). CSF A2M and apo-AI levels were significantly higher in patients with unfavourable course than in patients with favourable course (P = 0.0015 and P = 0.0016, respectively, Fig 2A and 2B), while CD36 levels were not different between the two groups (Fig 2C). The difference in CD36 level was still insignificant when three outlier values were excluded from the analysis. CSF haptoglobin level was not significantly different between the two groups.


 In our study, CSF haptoglobin showed an increase in the unfavourable course group, suggesting a prognostic indication for worsening disability. In a previous study, a higher CSF haptoglobin level was observed in neuromyelitis optica (NMO) patients compared with MS cases and patients with other neurological diseases (OND), and CSF haptoglobin level and index were also significantly positively correlated with EDSS in NMO cases, similar to that observed in our MS cohort [26]. While CSF haptoglobin levels were similar between MS and OND in this analysis, another study revealed a significant increase in CSF haptoglobin level in MS compared with OND [27]. Given the anti-inflammatory and anti-oxidative functions of haptoglobin, initial CSF haptoglobin levels in patients with worsened disability over time might have increased in response to increased oxidative stress—known to be strongly associated with neurodegeneration—as a compensatory mechanism


In conclusion, we provide novel candidate CSF protein biomarkers—as well as clinical and radiological parameters that are compatible with the literature—at the initial stages of clinical MS that may predict long-term disability outcomes in MS patients. Confirming these data in larger MS cohorts, preferably with longer follow-up periods and in different sample types of patients, as well as correlating them with other suggested prognostic predictors, such as novel MRI findings, optical coherence tomography, and serological biomarkers (e.g., serum neurofilament light chain and GFAP), may contribute to improved treatment decision-making in MS.


We thank Prof. Michael Lenardo for providing us with ELISA kits for alpha-2-macroglobulin, apo-AI, and CD36.

Citation: Everest E, Uygunoglu U, Tutuncu M, Bulbul A, Onat UI, Unal M, et al. (2023) Prospective outcome analysis of multiple sclerosis cases reveals candidate prognostic cerebrospinal fluid markers. PLoS ONE 18(6): e0287463.

Editor: Gorica Maric, Faculty of Medicine, University of Belgrade, SERBIA

Received: January 18, 2023; Accepted: June 6, 2023; Published: June 20, 2023

Copyright: © 2023 Everest et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper.

Funding: This work was funded by the Acibadem University, Scientific Research Projects. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

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