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. 2024 Mar 11;81(4):373-383.
doi: 10.1001/jamaneurol.2024.0017. Online ahead of print.

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

Anne H Cross  1 , Jeffrey M Gelfand  2 , Simon Thebault  3 , Jeffrey L Bennett  4 , H Christian von Büdingen  5 , Briana Cameron  6 , Robert Carruthers  7 , Keith Edwards  8 , Robert Fallis  9 , Rachel Gerstein  10 , Paul S Giacomini  11 , Benjamin Greenberg  12 , David A Hafler  13 , Carolina Ionete  10 , Ulrike W Kaunzner  14 , Lay Kodama  6 , Christopher Lock  15 , Erin E Longbrake  13 , Bruno Musch  6 , Gabriel Pardo  16 , Fredrik Piehl  17 , Martin S Weber  18   19 , Steven Yuen  6 , Tjalf Ziemssen  20 , Gauruv Bose  21 , Mark S Freedman  21 , Veronica G Anania  6 , Akshaya Ramesh  6 , Ryan C Winger  6 , Xiaoming Jia  6 , Ann Herman  6 , Christopher Harp  6 , Amit Bar-Or  3
Affiliations

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

Anne H Cross et al. JAMA Neurol. .

Abstract

Importance: Biomarkers 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.

Objective: To identify CSF biological measures associated with progressive MS pathobiology.

Design, setting, and participants: This 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).

Exposures: Test-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 measures: Twenty-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]).

Results: The 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 relevance: In 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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Cross reported grants from Genentech for financial support of the multicenter study and nonfinancial support from Genentech (help with statistical analysis) during the conduct of the study; consulting, speaking, and/or advisory board fees from Biogen, Bristol Myers Squibb, Janssen, Horizon, Novartis, Genentech, EMD Serono (Merck), TG Therapeutics, and Octave outside the submitted work; and having a patent for 15060-630 (015875; “Methods for simultaneous multi-angular relaxometry of tissue using magnetic resonance imaging”). Dr Gelfand reported grants from Hoffmann-LaRoche for research support to his institution for clinical trials during the conduct of the study; grants from Vigil Neurosciences for research support for clinical trials and personal fees from Arialys Consulting outside the submitted work; and service on trial steering committees for Hoffmann-LaRoche. Dr Bennett reported consulting, data monitoring board, and/or speaking fees from Roche-Genentech, Alexion-AstraZeneca, Amgen, Imcyse, Mitsubishi-Tanabe, Novartis, Beigene, Clene Nanomedicine, Antigenomycs, Reistone Bio, and TG Therapeutics outside the submitted work. Dr von Büdingen reported being a shareholder of Roche. Dr Cameron reported holding stock from Genentech/Roche outside the submitted work. Dr Carruthers reported grants from Genentech and Roche Canada and personal fees from Serono, Roche Canada, Biogen, Novartis, and Teva Canada during the conduct of the study and personal fees from Alexion outside the submitted work. Dr Giacomini reported grants, personal fees, and travel/educational grants from Roche during the conduct of the study; personal fees from Biogen, BMS-Celgene, EMD Serono, Genzyme-Sanofi, Novartis, Teva Innovation Canada, and Innodem Neurosciences and grants from the MS Society of Canada outside the submitted work; and being the chief medical officer of and having stock options in Innodem Neurosciences. Dr Greenberg reported grants from Genentech during the conduct of the study; personal fees from Alexion, Novartis, EMD Serono, Horizon, Genentech, Sandoz, Sanofi, Signant, TG Therapeutics, Cycle, Arialys, Clene, Syneos, PRIME, and GenrAb; grants from Anokion and Regeneron; and nonfinancial support from the Siegel Rare Neuroimmune Association outside the submitted work. Dr Hafler reported grants from Genentech and Roche during the conduct of the study and personal fees from Genentech, Sanofi, and GSK outside the submitted work. Dr Ionete reported grants from Genentech during the conduct of the study; and being a scientific advisor for Sanofi outside the submitted work. Dr Kaunzner reported clinical study support from Genentech during the conduct of the study and grants from Genentech and serving on advisory boards for Novartis and EMD Serono outside the submitted work. Dr Lock reported personal fees from Bristol Myers Squibb, Horizon Therapeutics, Diagnose Early, and InterX outside the submitted work. Dr Longbrake reported clinical trial support from Genentech during the conduct of the study; personal fees from Genentech, grants from Genentech and Biogen, and personal fees from Biogen, Janssen, TG Therapeutics, NGM Bio, Bristol Myers Squibb, EMD Serono, and Genzyme outside the submitted work. Dr Musch reported being a shareholder of Hoffmann-La Roche. Dr Pardo reported grants from Roche Genentech during the conduct of the study; grants from Biogen Idec, Sanofi Genzyme, Novartis Pharmaceuticals, EMD Serono, AbbVie, Bristol Myers Squibb, Celgene, TG Therapeutics, and Roche Genentech; personal fees from Biogen Idec, Sanofi Genzyme, Novartis Pharmaceuticals, EMD Serono, Bristol Myers Squibb, TG Therapeutics, Roche Genentech, and Janssen outside the submitted work; and having Progentec Diagnostics stock options. Dr Piehl reported clinical trial fees from Genentech during the conduct of the study; research support and/or grants from Merck, Janssen, UCB, and Swedish MRC; expert testimony fees from Novartis; and data monitoring committee fees from Roche and Lundbeck outside the submitted work. Dr Yuen reported being a shareholder of Hoffmann-La Roche. Dr Ziemssen reported grants and personal fees from Roche during the conduct of the study and grants, personal fees, and/or nonfinancial support from Sanofi, Teva, Novartis, Roche, Biogen, Sanofi, Bristol Myers Squibb, Almirall, and Merck outside the submitted work. Dr Bose reported grants from the Multiple Sclerosis Society of Canada, a TOHAMO innovation fund grant from IFPOC, and a Collaborate 2 Commercialize award from the Ontario Centre for Innovation and personal fees from Teva Pharmaceuticals, EMD Serono, Novartis, and Sanofi Genzyme outside the submitted work. Dr Freedman reported personal fees from Roche during the conduct of the study and personal fees from Sanofi-Genzyme, Alexion/AstraZeneca, Biogen Idec, Atara Biotherapeutics, EMD Serono/Merck Serono, Find Therapeutics, BMS/Celgene, Novartis, Setpoint Medical, Sandoz, and Teva Canada Innovation outside the submitted work. Dr Winger reported being a shareholder of Hoffmann-La Roche. Dr Herman reported being a shareholder in Hoffmann-La Roche outside the submitted work. Dr Harp reported being a stockholder of Genentech during the conduct of the study. Dr Bar-Or reported personal fees from Abata, Novartis, and Roche/Genentech and grants from Biogen, Novartis, and Roche/Genentech outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Profile of Study of Test Cohort
IRB indicates institutional review board; PPMS, primary progressive multiple sclerosis; RMS, relapsing multiple sclerosis.
Figure 2.
Figure 2.. Correlations Between Baseline Cerebrospinal Fluid (CSF) Biological, Magnetic Resonance Imaging (MRI), and Clinical Measures in the Combined Relapsing Multiple Sclerosis (RMS) and Primary Progressive Multiple Sclerosis (PPMS) Test Cohort
Spearman correlations between baseline biological measures and baseline MRI and clinical measures in the test cohort (combined RMS and PPMS subgroups). Less time since last MS relapse parameter only includes RMS cohorts. Red and blue shading represents positive and negative Spearman correlation, respectively (<.05). Bold squares denote significant Spearman correlations corrected for false discovery rate. CCL19 indicates chemokine C-C motif chemokine 19; CXCL10, C-X-C motif chemokine 10; CXCL12, C-X-C motif chemokine 12; CXCL13, C-X-C motif chemokine 13; EDSS, Expanded Disability Status Scale; Gd+, gadolinium enhancing; GFAP, glial fibrillary acidic protein; IL6, interleukin 6; LCN2, lipocalin 2; NfH, neurofilament heavy chain; NfL, neurofilament light chain; sBCMA, soluble B-cell maturation antigen; sCD27, soluble CD27; SEL, slowly expanding lesion; sTACI, soluble transmembrane activator and CAML interactor; sTREM2, soluble triggering receptor expressed on myeloid cells 2; T2LV, T2 lesion volume; YKL-40, chitinase-3-like protein 1. aP < .05. bP < .01. cP < .001.
Figure 3.
Figure 3.. Association of Ocrelizumab Treatment With Individual Patient Changes From Baseline in Primary and Exploratory Cerebrospinal Fluid (CSF) Biological Measure End Points in the Test Cohort During the 1-Year Treatment Period
A, B, and C, The 4 left graphs are the relapsing multiple sclerosis subgroup; the far right graph is the primary progressive multiple sclerosis (PPMS) subgroup. D, Red and blue shading represents increase and decrease, respectively. Bold squares denote comparisons with false discovery rate <.05. P values were computed using Wilcoxon signed rank test. LP indicates lumbar puncture; NfL, neurofilament light chain. aP < .01. bP < .001. cP < .05.
Figure 4.
Figure 4.. Association of Cerebrospinal Fluid (CSF) Glial Fibrillary Acid Protein (GFAP) Levels With Long-Term Disability Progression in an Independent Confirmation Cohort
A, Correlation between paired serum GFAP (sGFAP) and CSF GFAP (cGFAP) in the combined relapsing multiple sclerosis and primary progressive multiple sclerosis confirmation cohort (n = 68). B, Patients with high baseline median CSF GFP levels (>7200 pg/mL) were at greater risk for confirmed disability progression (CDP) on Expanded Disability Status Scale score over a median 15 years of follow-up compared with those with low baseline cGFAP levels. C, High baseline sGFAP was not associated with increased risk for subsequent CDP in the same cohort.
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