To characterize cerebrospinal fluid (CSF) immune alterations associated with progressive multiple sclerosis (PMS) and identify cellular signatures distinguishing progressive from relapsing disease stages.

Along the course of multiple sclerosis (MS), patients may experience irreversible disability accumulation independent of relapses. This progressive phase can occur from disease onset (primary progressive MS, PPMS) or develop after a relapsing–remitting phase (secondary progressive MS, SPMS), both collectively referred to as PMS. The mechanisms underlying PMS involve neurodegenerative processes and axonal loss. However, cellular changes at the central nervous system (CNS) borders—particularly in the cerebrospinal fluid (CSF)—remain poorly characterized, despite their potential as sources of biomarkers and mechanistic insights.

To characterize CSF immune alterations associated with PMS, we combined large-scale retrospective flow cytometry of CSF cells from RRMS (n = 169), PMS (n = 56), and control donors (n = 74) with prospective single-cell transcriptomic profiling of CSF cells from 12 PMS and 12 RRMS patients.

We found that CSF immune profiles in MS shift from adaptive immune dominance, particularly B-cell expansion, in RRMS toward a myeloid-driven response in PMS. Total CD14? monocytes were increased in PMS and correlated with clinical surrogates of disease progression. Transcriptionally, these monocytes resembled border-associated macrophages (BAMs) and displayed features of disease-associated macrophages (DAMs) previously described in neurodegeneration, including enhanced antigen presentation and TREM2 overexpression. Induction of DAM-related molecules—both transcribed and soluble TREM2—was unique to SPMS and may support its differential diagnosis.

CSF immune alterations in PMS are characterized by a prominent expansion of myeloid cells with a disease-associated macrophage–like signature, suggestive of shared mechanisms with neurodegenerative disorders. These findings highlight potential stage-specific biomarkers and therapeutic targets for progressive MS.