Abstract
Background and Objectives Neurodegeneration and astrocytic activation are pathologic hallmarks of progressive multiple sclerosis (MS) and can be quantified by serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP). We investigated sNfL and sGFAP as tools for stratifying patients with progressive MS based on progression and disease activity status.
Methods We leveraged our Comprehensive Longitudinal Investigation of MS at the Brigham and Women's Hospital (CLIMB) natural history study, which includes clinical, MRI data and serum samples collected over more than 20 years. We included patients with MS with a confirmed Expanded Disability Status Scale (EDSS) score ≥3 that corresponds with our classifier for patients at high risk of underlying progressive pathology. We analyzed sNfL and sGFAP within 6 months from the confirmed EDSS score ≥3 corresponding with our baseline visit. Patients who further developed 6-month confirmed disability progression (6mCDP) were classified as progressors. We further stratified our patients into active/nonactive based on new brain/spinal cord lesions or relapses in the 2 years before baseline or during follow-up. Statistical analysis on log-transformed sGFAP/sNfL assessed the baseline association with demographic, clinical, and MRI features and associations with future disability.
Results We included 257 patients with MS who had an average EDSS score of 4.0 and a median follow-up after baseline of 7.6 years. sNfL was higher in patients with disease activity in the 2 years before baseline (adjusted β = 1.21; 95% CI 1.04–1.42; p = 0.016), during the first 2 years of follow-up (adjusted β = 1.17; 95% CI = 1.01–1.36; p = 0.042). sGFAP was not increased in the presence of disease activity. Higher sGFAP levels, but not sNfL levels, were associated with higher risk of 6mCDP (adjusted hazard ratio [HR] = 1.71; 95% CI = 1.19–2.45; p = 0.004). The association was stronger in patients with low sNfL (adjusted HR = 2.44; 95% CI 1.32–4.52; p = 0.005) and patients who were nonactive in the 2 years prior or after the sample.
Discussion Higher levels of sGFAP correlated with subsequent progression, particularly in nonactive patients, whereas sNfL reflected acute disease activity in patients with MS at high risk of underlying progressive pathology. Thus, sGFAP and sNfL levels may be used to stratify patients with progressive MS for clinical research studies and clinical trials and may inform clinical care.
Glossary
- 6mCDP=
- 6-month confirmed disability progression;
- CV=
- coefficient of variation;
- EDSS=
- Expanded Disability Status Scale;
- FDA=
- Food and Drug Administration;
- GFAP=
- glial fibrillary acidic protein;
- HET=
- high-efficacy treatment;
- LET=
- low-efficacy treatment;
- MS=
- multiple sclerosis;
- NfL=
- neurofilament light chain;
- sGFAP=
- serum GFAP;
- sNfL=
- serum NfL
Footnotes
Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.
The Article Processing Charge was funded by the authors.
Submitted and externally peer reviewed. The handling editor was Scott S. Zamvil, MD, PhD, FAAN.
- Received March 14, 2022.
- Accepted in final form September 6, 2022.
- Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
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