Identification of brain-enriched proteins in CSF as biomarkers of relapsing remitting multiple sclerosis

Lincoln I Wurtz; Evdokiya Knyazhanskaya; Dorsa Sohaei; Ioannis Prassas; Sean Pittock; Maria Alice V Willrich; Ruba Saadeh; Ruchi Gupta; Hunter J Atkinson; Diane Grill; Martin Stengelin; Simon Thebault; Mark S Freedman; Eleftherios P Diamandis; Isobel A Scarisbrick

doi:10.1186/s12014-024-09494-5

Identification of brain-enriched proteins in CSF as biomarkers of relapsing remitting multiple sclerosis

Clin Proteomics. 2024 Jun 16;21(1):42. doi: 10.1186/s12014-024-09494-5.

Authors

Lincoln I Wurtz^{1

2}, Evdokiya Knyazhanskaya², Dorsa Sohaei³, Ioannis Prassas^{4

5}, Sean Pittock^{6

7}, Maria Alice V Willrich⁸, Ruba Saadeh⁸, Ruchi Gupta⁹, Hunter J Atkinson⁹, Diane Grill⁹, Martin Stengelin¹⁰, Simon Thebault^{11

12}, Mark S Freedman¹¹, Eleftherios P Diamandis¹³, Isobel A Scarisbrick^{14

15}

Affiliations

¹ Medical Scientist Training Program, Mayo Clinic, Rochester, MN, USA.
² Mayo Clinic Alix School of Medicine, Mayo Clinic, Rochester, MN, USA.
³ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
⁴ Mount Sinai Hospital, Toronto, Canada.
⁵ Laboratory Medicine Program, University Health Network, Toronto, Canada.
⁶ Department of Neurology, Mayo Clinic, Rochester, MN, USA.
⁷ Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN, USA.
⁸ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
⁹ Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
¹⁰ Meso Scale Diagnostics, LLC. (MSD), Rockville, MD, USA.
¹¹ Department of Medicine and The Ottawa Research Institute, Ottawa, Canada.
¹² Division of Multiple Sclerosis, Department of Neurology, The University of Pennsylvania, Philadelphia, USA.
¹³ Lunenfeld-Tanenbaum Research Institute (LTRI), Sinai Health System, Toronto, Canada.
¹⁴ Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN, USA. Scarisbrick.Isobel@mayo.edu.
¹⁵ Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN, 55905, USA. Scarisbrick.Isobel@mayo.edu.

Abstract

Background: Multiple sclerosis (MS) is a clinically and biologically heterogenous disease with currently unpredictable progression and relapse. After the development and success of neurofilament as a cerebrospinal fluid (CSF) biomarker, there is reinvigorated interest in identifying other markers of or contributors to disease. The objective of this study is to probe the predictive potential of a panel of brain-enriched proteins on MS disease progression and subtype.

Methods: This study includes 40 individuals with MS and 14 headache controls. The MS cohort consists of 20 relapsing remitting (RR) and 20 primary progressive (PP) patients. The CSF of all individuals was analyzed for 63 brain enriched proteins using a method of liquid-chromatography tandem mass spectrometry. Wilcoxon rank sum test, Kruskal-Wallis one-way ANOVA, logistic regression, and Pearson correlation were used to refine the list of candidates by comparing relative protein concentrations as well as relation to known imaging and molecular biomarkers.

Results: We report 30 proteins with some relevance to disease, clinical subtype, or severity. Strikingly, we observed widespread protein depletion in the disease CSF as compared to control. We identified numerous markers of relapsing disease, including KLK6 (kallikrein 6, OR = 0.367, p < 0.05), which may be driven by active disease as defined by MRI enhancing lesions. Other oligodendrocyte-enriched proteins also appeared at reduced levels in relapsing disease, namely CNDP1 (carnosine dipeptidase 1), LINGO1 (leucine rich repeat and Immunoglobin-like domain-containing protein 1), MAG (myelin associated glycoprotein), and MOG (myelin oligodendrocyte glycoprotein). Finally, we identified three proteins-CNDP1, APLP1 (amyloid beta precursor like protein 1), and OLFM1 (olfactomedin 1)-that were statistically different in relapsing vs. progressive disease raising the potential for use as an early biomarker to discriminate clinical subtype.

Conclusions: We illustrate the utility of targeted mass spectrometry in generating potential targets for future biomarker studies and highlight reductions in brain-enriched proteins as markers of the relapsing remitting disease stage.

Keywords: Biomarkers; CSF; Multiple sclerosis; Proteomics.

Abstract

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