Emerging Cerebrospinal Fluid Biomarkers of Disease Activity and Progression in Multiple Sclerosis

Abstract

ImportanceBiomarkers distinguishing nonrelapsing progressive disease biology from relapsing biology in multiple sclerosis (MS) are lacking. Cerebrospinal fluid (CSF) is an accessible fluid that most closely reflects central nervous system biology.ObjectiveTo identify CSF biological measures associated with progressive MS pathobiology.Design, Setting, and ParticipantsThis cohort study assessed data from 2 prospective MS cohorts: a test cohort provided serial CSF, clinical, and imaging assessments in a multicenter study of patients with relapsing MS (RMS) or primary progressive MS (PPMS) who were initiating anti-CD20 treatment (recruitment: 2016-2018; analysis: 2020-2023). A single-site confirmation cohort was used to assess CSF at baseline and long-term (>10 year) clinical follow-up (analysis: 2022-2023).ExposuresTest-cohort participants initiated standard-of-care ocrelizumab treatment. Confirmation-cohort participants were untreated or received standard-of-care disease-modifying MS therapies.Main Outcomes and MeasuresTwenty-five CSF markers, including neurofilament light chain, neurofilament heavy chain, and glial fibrillary acid protein (GFAP); 24-week confirmed disability progression (CDP24); and brain magnetic resonance imaging measures reflecting focal injury, tissue loss, and progressive biology (slowly expanding lesions [SELs]).ResultsThe test cohort (n = 131) included 100 patients with RMS (mean [SD] age, 36.6 [10.4] years; 68 [68%] female and 32 [32%] male; Expanded Disability Status Scale [EDSS] score, 0-5.5), and 31 patients with PPMS (mean [SD] age, 44.9 [7.4] years; 15 [48%] female and 16 [52%] male; EDSS score, 3.0-6.5). The confirmation cohort (n = 68) included 41 patients with RMS and 27 with PPMS enrolled at diagnosis (age, 40 years [range, 20-61 years]; 47 [69%] female and 21 [31%] male). In the test cohort, GFAP was correlated with SEL count (r = 0.33), greater proportion of T2 lesion volume from SELs (r = 0.24), and lower T1-weighted intensity within SELs (r = –0.33) but not with acute inflammatory measures. Neurofilament heavy chain was correlated with SEL count (r = 0.25) and lower T1-weighted intensity within SELs (r = –0.28). Immune markers correlated with measures of acute inflammation and, unlike GFAP, were impacted by anti-CD20. In the confirmation cohort, higher baseline CSF GFAP levels were associated with long-term CDP24 (hazard ratio, 2.1; 95% CI, 1.3-3.4; P = .002).Conclusions and RelevanceIn this study, activated glial markers (in particular GFAP) and neurofilament heavy chain were associated specifically with nonrelapsing progressive disease outcomes (independent of acute inflammatory activity). Elevated CSF GFAP was associated with long-term MS disease progression.

Association of serum glial fibrillary acidic protein with progression independent of relapse activity in multiple sclerosis

“…However, after adjusting our analysis for relevant MRI activity three months apart from the PIRA event (PIRMA), CSF GFAP was indeed independently associated with PIRMA. This finding is in line with a number of previous studies [ 12 , 41 , 42 ]. GFAP is the predominant intermediate filament protein within astrocytes.…”

“…After the development of an in-house method to measure GFAP in CSF [ 30 ], we demonstrated for the first time an association between CSF GFAP and disease progression in MS [ 12 ]. Further, a very recent study demonstrated a strong association between CSF GFAP and nonrelapsing progressive MS biology [ 42 ]. In that study, CSF GFAP was found to correlate with slowly expanding lesions (SELs), higher EDSS scores and lower thalamic volume.…”

“…In that study, CSF GFAP was found to correlate with slowly expanding lesions (SELs), higher EDSS scores and lower thalamic volume. Interestingly, CSF GFAP was found to be expressed by a greater proportion of astrocytes from chronic active MS lesions compared with inactive lesions or control white matter [ 42 ]. Taken together, these and our findings reinforce the notion that GFAP may be more specific to the smouldering compartmentalized inflammation that is associated with PIRA.…”

Single-cell profiling indicates a high similarity between immune cells in the cerebrospinal fluid and in meningeal ectopic lymphoid tissue in experimental autoimmune encephalomyelitis

“…Possibly, this altered phenotype favors accumulation of those myeloid cells in the CSF. In line with our data, studies have demonstrated that B cell depletion by aCD20 mAbs like rituximab and ocrelizumab in MS patients led to a strong reduction of CSF B cells and, to a lesser degree, T cells ( 48 – 50 ). To our knowledge, no data regarding CSF macrophages in B cell depleted CSF has been published.…”

Digital Pathology Identifies Associations between Tissue Inflammatory Biomarkers and Multiple Sclerosis Outcomes

“…CHI3LI is associated with increased clinical severity and spinal cord volume loss [ 45 , 49 ]. The presence of reactive astrocytes, which are incompletely reflected by glial fibrillary acidic protein (GFAP) expression, are a pathological hallmark of MS. Clinically, CSF and serum GFAP levels correlate modestly with progression, independent of relapse activity [ 47 , 50 ]. We would seek to include an assessment of axonal injury and astrocyte reactivity in future DP studies.…”