The Role of Neurofilament Light Chain in MS Management

Multiple sclerosis (MS) is characterized by inflammatory and neurodegenerative processes that vary across individuals and over time. Standard clinical tools, including relapse assessment, MRI, and disability scales capture aspects of disease activity but generally have limitations and can be insensitive in detecting ongoing neuroaxonal injury.

Neurofilament light chain (NfL) has gained increasing attention over the years for its potential as a blood-based biomarker for predicting disease activity and monitoring treatment response in patients with MS. A recent review examines NfL as a biomarker that reflects axonal damage and evaluates evidence for its use alongside existing measures in MS care.

Biological Basis of NfL

NfL is a cytoskeletal protein that contributes to axonal structure and stability. Under physiologic conditions, small amounts are released into cerebrospinal fluid and blood as part of normal neuronal turnover. Elevated concentrations occur when axonal injury increases release beyond baseline levels.

The review details that NfL elevations are not specific to MS and are observed in a range of neurologic and systemic conditions, including neurodegenerative disease, stroke, trauma, and metabolic disorders. In MS, increased NfL may reflect focal inflammatory injury associated with relapses and/or non-relapse-related compartmentalized inflammation as well as neurodegenerative processes. Elevations have been reported across relapsing and progressive phenotypes, including early and presymptomatic stages.

Evidence for Prognostic Associations

Multiple prospective studies summarized in the review demonstrate associations between baseline serum NfL levels and subsequent clinical and radiologic outcomes. In phase 3 trials of ofatumumab and ocrelizumab, higher baseline NfL levels were associated with greater on-study MRI lesion activity and rates of brain and thalamic volume loss, and higher risk of confirmed disability progression. These associations were observed in both relapsing and primary progressive populations.

Long-term observational studies extending beyond 10 years similarly reported that higher early NfL levels correlated with faster accumulation of disability milestones measured by the Expanded Disability Status Scale. The review notes that most studies could not fully distinguish whether these outcomes were driven by relapse-related injury, non-relapsing progressive processes, or a combination of both.

Monitoring Treatment Response Over Time

Serum NfL concentrations generally decline after initiation of disease-modifying therapies, with larger reductions reported in patients treated with higher-efficacy agents. These changes are interpreted as group-level indicators of reduced neuroaxonal injury following treatment. However, the review also describes that a proportion of patients continue to exhibit elevated NfL despite treatment, including those receiving therapies that substantially suppress relapse activity. In such cases, persistently elevated NfL has been associated with increased risk of future disability progression in clinical trial populations.

These findings suggest that NfL measurements may provide information on ongoing injury that is not captured by relapse counts alone, although individual-level interpretation remains limited by variability.

Detection of Subclinical Disease Activity

Several studies in the review examined whether changes in serum NfL correspond with subclinical MRI activity. In some cohorts, increases in serum NfL were observed in proximity to the development of new gadolinium-enhancing lesions, indicating that serum NfL measurements can reflect inflammatory activity between imaging intervals. Other studies reported that NfL increases occurred after radiologic detection of lesions rather than before.

Use in Relapse Assessment and Special Populations

The review also discusses the potential role of serum NfL in distinguishing relapses from pseudorelapses. Because pseudorelapses are not associated with new axonal injury, stable NfL levels may be reassuring and potentially support conservative management during symptom worsening.

Additional applications explored include monitoring during pregnancy and in older patients discontinuing therapy, with the caveat that age, pregnancy-related physiology, and comorbidities independently affect NfL levels.

Confounding Variables and Measurement Limitations

Interpretation of NfL is influenced by multiple confounders. Age-related increases are well documented, with greater variability observed in individuals older than 60 years. Body mass index, renal function, smoking status, diabetes, and other neurologic conditions also affect measured levels.

The review emphasizes that overlap between NfL values in people with MS and healthy controls limits the utility of single cross-sectional measurements. Longitudinal assessment, using the patient as their own reference, is presented as a more reliable approach. Studies of biological and analytical variability suggest that changes of approximately 23% to 31% may be required to exceed expected fluctuation.

Assay Availability and Standardization Challenges

Several commercial serum NfL assays are available or in late-stage development, using ultrasensitive platforms adapted for routine blood testing. Differences among assays result in variability in absolute values, and standardized reference ranges and cutoff thresholds are not yet established.

Although some assays have received FDA Breakthrough Device designation, none have full regulatory approval at the time covered by the review. Cost, reimbursement, and access to compatible laboratory platforms are identified as practical barriers.

Integration With Other Biomarkers

The review describes ongoing research into combining NfL with other biomarkers, such as glial fibrillary acidic protein (GFAP), to capture complementary aspects of disease biology. Evidence suggests that NfL is more closely associated with inflammatory injury and relapse activity, whereas GFAP is more strongly associated with disease progression.

Across the evidence reviewed, serum NfL is presented as a biomarker with demonstrated associations to disease activity and progression at the population level. However, its clinical use requires consideration of confounding factors, assay variability, and longitudinal context.

Reference:
Bar-Or A, Nicholas J, Feng J, Sorrell F, Cascione M. Exploring the clinical utility of neurofilament light chain assays in multiple sclerosis management. Neurol Neuroimmunol Neuroinflamm. 2025;12(4):e200427. doi:10.1212/NXI.0000000000200427