Profiling the Cerebrospinal Fluid Proteome in Progressive Multiple Sclerosis: Treatment Effects and Associations with
Sahla El Mahdaoui1, Peter Kosa2, Mika Komori2
1Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital - Rigshospitalet, Glostrup, Denmark. sahla.el.mahdaoui.01@regionh.dk.
Abstract:
Treatment options for progressive MS (PMS) are limited in numbers and efficacy, which is most pronounced in patients with inflammatory disease activity. Immunoglobulin M (IgM) oligoclonal bands (OCBs) may identify a subset of PMS with more active inflammatory disease. The effects of natalizumab and methylprednisolone on intrathecal inflammation and the association of IgM OCBs with other biomarkers in PMS is uncertain. In the current study, we investigated the cerebrospinal fluid (CSF) proteome of untreated patients with PMS, effects of natalizumab and methylprednisolone, and associations of IgM OCBs with disease activity and CSF biomarkers. We found a reduction of BCMA, SLAMF7, granzyme A, IgG, and desmoglein-2 with both therapies, as well as natalizumab-specific reductions of VCAM-1, CD48, MDC, MMP-9, sE-selectin, and CHIT1, and methylprednisolone-specific reductions of DR3, IgD, RTN4, and increases of sCD206, LYVE1, sCD163 and MMP-3. IgM OCBs were associated with reduced levels of PIGR, higher levels of NFL and VEGF, and more contrast-enhancing lesions. The study suggests T and B cell activity biomarkers as treatment-responsive CSF biomarkers in PMS. Additionally, we found natalizumab to reduce adhesion molecules and methylprednisolone to increase myeloid biomarkers. Lastly, we confirm that IgM OCBs are associated with a more inflammatory MRI and CSF profile.
Insights
This study reveals that treatments for progressive multiple sclerosis (MS) impact specific biomarkers in cerebrospinal fluid (CSF). Immunoglobulin M (IgM) oligoclonal bands (OCBs) indicate a more inflammatory MS profile.
Area of Science:
- Neuroimmunology
- Proteomics
- Biomarker Discovery
Background:
- Limited treatment efficacy for progressive multiple sclerosis (PMS), especially with active inflammation.
- Immunoglobulin M (IgM) oligoclonal bands (OCBs) may identify a subset of PMS with heightened inflammatory activity.
- Uncertainty regarding the effects of natalizumab and methylprednisolone on intrathecal inflammation and IgM OCBs in PMS.
Purpose of the Study:
- To investigate the cerebrospinal fluid (CSF) proteome in untreated PMS patients.
- To evaluate the effects of natalizumab and methylprednisolone on intrathecal inflammation.
- To explore associations between IgM OCBs and disease activity/CSF biomarkers in PMS.
Main Methods:
- Analysis of the CSF proteome in untreated PMS patients.
- Assessment of treatment effects (natalizumab, methylprednisolone) on CSF biomarkers.
- Correlation analysis of IgM OCBs with MRI activity and CSF biomarkers.
Main Results:
- Both natalizumab and methylprednisolone reduced BCMA, SLAMF7, granzyme A, IgG, and desmoglein-2.
- Natalalizumab specifically reduced VCAM-1, CD48, MDC, MMP-9, sE-selectin, and CHIT1.
- Methylprednisolone specifically reduced DR3, IgD, RTN4, and increased sCD206, LYVE1, sCD163, and MMP-3.
- IgM OCBs correlated with reduced PIGR, elevated NFL and VEGF, and increased contrast-enhancing lesions.
- T and B cell activity biomarkers were identified as treatment-responsive CSF biomarkers in PMS.
- Natalizumab decreased adhesion molecules; methylprednisolone increased myeloid biomarkers.
- IgM OCBs confirmed association with a more inflammatory MRI and CSF profile.
Conclusions:
- T and B cell activity biomarkers are suggested as treatment-responsive CSF biomarkers in PMS.
- Natalizumab demonstrates effects on adhesion molecules, while methylprednisolone impacts myeloid biomarkers.
- IgM OCBs are confirmed indicators of a more inflammatory disease phenotype in PMS.
