Recent research on fluid biomarkers in multiple sclerosis (MS) frames an emerging picture of two aspects of the disease: inflammatory activity measured with neurofilament light chain (NfL), and disease progression independent of relapses, with promising results suggested by emerging markers like glial fibrillary acidic protein (GFAP).
MS fluid biomarkers reached an important turning point in 2024 with published guidance from a consensus panel of the Consortium of Multiple Sclerosis Centers (CMSC) for using blood and cerebrospinal fluid (CSF) NfL to manage the disease.
"Guidance was necessary since the use of fluid biomarkers is a rapidly expanding field," said lead guideline author Mark Freedman, MD, MSc, of the University of Ottawa in Ontario.
"Especially for NfL, there are now several assays becoming available, all with their own nuances," Freedman continued. "We needed to put the data into perspective and spell out what we have learned and what we still need to get from ongoing studies."
Neurofilament Light
Neurofilament levels are elevated in the CSF and blood in several neurologic conditions, including amyotrophic lateral sclerosis, traumatic brain injury, and MS. It is an established marker of axonal injury.
Early research led by Jens Kuhle, MD, PhD, of the University of Basel in Switzerland, showed high correlations between CSF and serum NfL levels, and between serum NfL and MRI measures of disease activity in MS.
Since then, numerous studies have shown that serum NfL can show ongoing neurodegeneration in MS. More recent research suggested it may predict disease worsening, both with and without relapses. Elevated NfL has been correlated with gadolinium-enhancing lesions, T2 lesion volume, brain atrophy measures, disability progression, treatment response, and other outcomes.
Overall, values of serum NfL increase with age and decrease with higher body mass index. Effective treatment can lower serum NfL levels, and reductions were seen in relapsing and primary progressive MS patients who received the anti-CD20 drug ocrelizumab (Ocrevus).
As a biomarker, NfL has uncertainties, but it also has large-scale reference databases to help assess increases on the individual level. Future work will guide clinicians about appropriate percentile cutoffs for specific situations corrected for age and BMI.
"I think for NFL, it's prime time to move carefully to clinical practice, in the context of MRI plus patient history," Kuhle, a co-author on the CMSC guidance, noted. "It can likely add important information for escalating and especially de-escalating MS treatments."
"We don't want to substitute NfL for MRI, but NfL is a proof of principle for blood measurements characterizing the disease and a first example how these candidates can move all the way to clinical practice," he added.
The CMSC guidance says a baseline value should be established and that changes in NfL -- 40% is suggested, though Kuhle noted this is somewhat arbitrary, especially since NfL is strongly age dependent -- can inform treatment decisions.
For example, if NfL levels have not decreased (or have increased) within 6 months of starting disease-modifying treatment, clinicians should consider changing therapy or escalating to a higher-efficacy drug, the guidelines suggest. In contrast, a low or normal range NfL level would support the decision to keep a patient on current therapy.
Clinical and MRI data should be factored into decisions to escalate therapy or the frequency of NfL testing, the guidance recommends.
A 2024 review of translation of NfL into clinical practice in neurologic diseases emphasized that standardization and cross-compatibility of emerging analytic platforms are key to translating NfL into clinical practice.
GFAP
GFAP is an intermediate filament of astrocytes that has been proposed as a biomarker to identify disease progression in MS. Several studies have suggested serum GFAP may reflect MS disease severity, especially slowly insidious disease progression.
In 2023, Kuhle and colleagues compared serum NfL and serum GFAP using samples from the longitudinal Swiss MS Cohort.
Their findings suggested that GFAP was more strongly associated with disease progression than NfL. GFAP may serve as a biomarker that reflects specific chronic disease processes manifested as progression independent of relapse activity (PIRA), making it potentially complementary to NfL, the researchers noted.
"This was a pilot study," Kuhle said. "The aspiration was that GFAP would be covering progression better than NfL for the individual case. The data we published is quite promising towards that."
The group is analyzing more samples from the Swiss MS Cohort. "There are some good initial results from this larger cohort that GFAP is prognostic for PIRA in patients treated with highly effective treatment like B-cell depletion, but also in patients treated with oral treatments like fingolimod," Kuhle said.
Additional information will be presented at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) meeting later this year, he added.
Other Potential Markers
Though compelling, NfL and GFAP are imperfect markers, MS pathophysiology remains incompletely understood, and the search for ideal MS biomarkers -- particularly for early diagnosis -- has an ongoing history spanning decades that includes multiple forms of imaging and a variety of combined measures.
In 2023, Swedish researchers reported that a combination of 11 proteins could predict long-term disability outcomes in MS. In 2024, a research group in Wales studied 24 protein biomarkers and found that certain combinations could better differentiate MS from other disorders and better predicted sustained disability.
More recently, researchers at the University of California San Francisco (UCSF) identified an autoantibody signature in a subset of MS patients up to 5 years before clinical symptoms were seen. The autoantibodies appeared to bind to both human cells and common pathogens and were associated with higher levels of NfL.
These findings could lead to earlier diagnosis and treatment for some MS patients, the researchers noted. "Over the last few decades, there's been a move in the field to treat MS earlier and more aggressively with newer, more potent therapies," said co-author Michael Wilson, MD, of UCSF. "A diagnostic result like this makes such early intervention more likely, giving patients hope for a better life."
Disclosures
The Consortium of Multiple Sclerosis Centers (CMSC) organized the consensus conference on NfL guidance in MS.
Freedman reported relationships with Alexion/AstraZeneca, Biogen Idec, EMD Serono/Merck Serono, Find Therapeutics, Hoffman La-Roche, Horizon Therapeutics, Novartis, Sandoz, Sanofi-Genzyme, Teva Canada Innovation, Actelion/Janssen, Atara Biotherapeutics, Bayer Healthcare, Celestra Health, and Setpoint Medical.
Kuhle reported relationships with the Swiss MS Society, Swiss National Research Foundation, University of Basel, Progressive MS Alliance, Alnylam, Bayer, Biogen, Bristol Myers Squibb, Celgene, Immunic, Merck, Neurogenesis, Novartis, Octave Bioscience, Quanterix, Roche, Sanofi, and Stata DX.
Wilson reported relationships with Roche/Genentech, Novartis, Takeda, WebMD, and CDI Labs.