A CSF disease-associated macrophage signature defines progressive multiple sclerosis

Area of Science:

• Neuroimmunology
• Cellular Biology
• Biomarker Discovery

Background:

• Multiple sclerosis (MS) progression leads to irreversible disability.
• Cerebrospinal fluid (CSF) cellular changes are known biomarkers in relapsing-remitting MS (RRMS).
• Cellular changes in progressive MS (PMS) remain understudied.

Purpose of the Study:

• To investigate CSF cellular and molecular signatures in primary and secondary progressive MS (PMS).
• To identify potential biomarkers for MS progression and differential diagnosis.

Main Methods:

• Retrospective flow cytometry of CSF cells from RRMS, PMS, and controls.
• Prospective CSF single-cell transcriptomics.
• Confirmatory CSF ELISA and analysis of age-matched/Alzheimer's disease patient data.

Main Results:

• CSF CD14+ monocytes are increased in PMS and correlate with progression markers.
• These monocytes exhibit a chronically activated, antigen-presenting phenotype, resembling border-associated macrophages (BAMs).
• Monocytes share features with disease-associated microglia/macrophages (DAMs); TREM2 induction is noted in secondary progressive MS (SPMS).

Conclusions:

• Identified MS stage-specific CSF signatures.
• Detected shared cellular features of degeneration in PMS patients' CSF.
• Highlighted potential of CSF monocytes and TREM2 as biomarkers for PMS and SPMS diagnosis.