CLN - Ask The Expert
Neurofilament light chain (NfL) is a cytoskeletal protein that maintains neuronal structural integrity. In patients with axonal damage, NfL can serve as a nonspecific indicator of severity and can be measured in cerebrospinal fluid and plasma. In particular, the ability to measure NfL in plasma provides a less invasive option for assessing conditions involving neuro-axonal damage such as multiple sclerosis (MS). This biomarker may also facilitate a reduction in the use of more expensive monitoring tools such as MRI. NfL may detect relapse earlier than MRI, allowing providers to rapidly step up treatment in certain patients while minimizing exposure to potent medications in others.
Because NfL reflects axonal damage but does not indicate a specific cause, it is not recommended for use in diagnosis. Its primary value lies in prognosis, monitoring disease progression, and assessing the efficacy of disease-modifying therapy (DMT). Accordingly, in 2023, the MS consortium recommended NfL testing for these purposes in confirmed MS cases. Together with the patient’s clinical presentation, clinicians can use NfL to optimize the dose of DMT, extend the interval between doses, and potentially switch or discontinue treatment altogether in certain patients.
Apart from MS cases, NfL may be useful in other neurodegenerative conditions including amyotrophic lateral sclerosis (ALS). Studies show a correlation between plasma NfL levels and ALS progression. Although no official guidance exists for NfL use in ALS, the Food and Drug Administration (FDA) recently granted accelerated approval for Tofersen, an ALS treatment that showed a 55% reduction in plasma NfL levels in patients with SOD1-ALS. Therefore, NfL may be useful for monitoring Tofersen therapy in ALS.
As more providers become aware of NfL, laboratorians should be prepared for an increase in test requests.
When deciding whether to offer NfL testing, labs should first figure out the expected test volume. In low volume scenarios, offering NfL as a send-out test makes the most sense. With higher volumes, labs should consider in-house NfL testing. Consultations with neurologists and other clinicians will provide a sense of how much volume is expected.
Labs considering in-house NfL testing will have to validate their assay as a laboratory developed test (LDT) since there are no FDA-approved options. To do this, labs must determine reference intervals, analytical sensitivity and specificity, test accuracy and precision, reportable range, and clinical validity.
Determining reference intervals is an especially significant challenge when validating an NfL assay. Since NfL levels change with age, multiple age-specific reference intervals are needed, which greatly increases the scale and complexity of this validation. Selection of reference individuals is further complicated by the fact that other conditions that may influence NfL concentrations, including diabetes, heart, and kidney disease, are more common in older patient populations. Labs should carefully define inclusion and exclusion criteria to ensure accurate final reference intervals and should also collaborate with neurologists on this process.
After validation, clinical implementation can commence. For labs that already offer NfL as a send-out test and are implementing a different test method in-house, an extensive rebaselining period may be needed since NfL methods are not standardized. The lab should communicate adequately with clinicians about the change in testing platform and anticipated changes in results to prevent erroneous interpretation of test results. Labs may also create mechanisms to closely monitor NfL testing to ensure that providers are ordering the test for the right patients and to answer the right clinical questions.
In conclusion, NfL may provide a less expensive and less invasive option for monitoring neurodegenerative conditions including MS. As demand for this testing increases, labs should strive to provide access to it. Labs considering in-house testing should understand the challenges involved in NfL test validation, collaborate with clinicians to create test utilization criteria, and evaluate the impact on patient care post-implementation.
Interested in learning more? Attend the ADLM 2026 roundtable, “Neurofilament light chain testing from start to finish: Challenges and implementation strategies for multiple sclerosis management,” on Monday, July 27 in Anaheim, California.
Onyeka Obidi, PhD, is a clinical chemistry fellow at the Medical College of Wisconsin in Milwaukee.