NfL as a Biomarker for Neurologic Disease

Neurofilament light chain (NfL) has emerged as one of the most closely watched blood-based biomarkers in neurology, with potential applications across multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and other neurologic conditions. But how it should be used in clinical practice is still being worked out.What Is NfL?The appeal of NfL as a biomarker of neurodegenerative disease is straightforward: When axons are injured, this structural neuronal protein is released into cerebrospinal fluid and, at lower concentrations, into blood.The catch is equally important. NfL can indicate that neurons are being injured but generally not why. It rises in multiple neurodegenerative and inflammatory disorders and with normal aging, and levels can be influenced by comorbidities. Its strongest potential roles are in prognosis, monitoring disease activity, and measuring response to treatment rather than in making a diagnosis.Where Does NfL Testing Stand?Advances in ultrasensitive blood-based assays have made NfL reliably measurable without lumbar puncture and potentially scalable for routine clinical use.Serum NfL testing is now available through some clinical and specialty laboratories and is being incorporated into practice at some MS centers, but it is not yet a standardized routine test across neurology. Clinical implementation varies considerably in terms of assays, reference ranges, reporting, and how results are used, a recent review found.Shaheen Lakhan, MD, PhD“Analytically, the field is in a very strong place compared with even 5 or 10 years ago, but there are still unresolved issues around assay harmonization, reference standards, and whether absolute values are interchangeable across platforms,” Shaheen Lakhan, MD, PhD, neurologist and researcher based in Miami, told Medscape Medical News.“We increasingly understand what NfL is measuring biologically; we are still building the clinical algorithms that translate that measurement into individualized treatment decisions,” he noted.For Which Neurologic Conditions Is NfL Most Useful?At this point, the clinical validity of NfL is most compelling in MS and ALS.In MS, serum NfL correlates with inflammatory disease activity, new MRI lesions, relapses, prognosis, and response to disease-modifying therapy, suggesting it could complement neurologic examination and MRI rather than replace either one, Lakhan said.Robert J. Fox, MD, neurologist with the Mellen Center for Multiple Sclerosis at the Cleveland Clinic in Cleveland, Ohio, agreed. “I see serum NfL mainly serving as an additional surveillance of disease activity, added between routine clinical and MRI assessments, but not replacing them,” he told Medscape Medical News.Robert J. Fox, MDFox cautioned that NfL has limited sensitivity for new MRI activity and may increase a month or more after lesions appear. “Providers need to recognize the limited sensitivity and delayed response in NfL when interpreting NfL levels,” he told Medscape Medical News.“On the positive side,” said Fox, “unless there’s an obvious alternative explanation, like a head trauma or stroke, a rise in NfL is almost always from MS. Thus, the specificity of NfL rise for MS disease activity is very good.”In ALS, higher NfL levels are associated with faster decline and poorer survival, whereas treatment-associated reductions can provide an early pharmacodynamic signal. Notably, reductions in plasma NfL helped support accelerated FDA approval of tofersen for SOD1-ALS, a rare form of the condition.There is also growing evidence to support a role for NfL in Alzheimer’s disease, Huntington disease, traumatic brain injury, parkinsonian disorders, and other neurologic conditions, but these applications are less mature.Once a diagnosis is established, serial NfL measurements may be more informative than a single value. “I think the real promise of NfL is longitudinal rather than simply binary,” Lakhan told Medscape Medical News. “Serial measurements can show whether neuroaxonal injury is accelerating, stabilizing, or decreasing — and whether that trajectory changes after an intervention.”That makes NfL attractive in clinical trials, where it may provide an earlier objective signal than changes in disability or brain volume.What Questions Remain for NfL as a Biomarker?While NfL is beginning to move into clinical practice, particularly in MS, questions remain about how results should guide care. Fox told Medscape Medical News that “some MS providers are already using serum NfL routinely, but the right context for its use has remained unclear.”Lakhan said the “limiting issue is becoming less about whether we can obtain the number and more about whether clinicians know exactly how to interpret and act on it.”He said key outstanding questions include what magnitude of change is clinically meaningful for an individual patient, when a rise should trigger imaging or treatment escalation, when a fall can provide reassurance that therapy is biologically effective, and whether NfL-guided decisions ultimately improve patient outcomes.There is also a need for better harmonization across assays and laboratories, more robust age- and disease-adjusted reference ranges, and clearer accounting for important confounders.In Lakhan’s view, “NfL may become neurology’s closest equivalent to a blood-based vital sign of neuroaxonal injury. It can tell us how much stress or damage the nervous system is experiencing and whether that is changing over time, but it is not, by itself, a diagnosis.”Fox has served as a director, officer, partner, employee, advisor, consultant, or trustee for AbbVie; Astoria Biologica; Biogen; Bristol Myers Squibb; Galvani; Immunic Therapeutics; InnoCare Pharma; Kiniksa Pharmaceuticals; Novartis; Roche; Sanofi; SetPoint Medical; Siemens; Sudo Bioscience, Inc.; and TG Therapeutics, Inc.; and has received research grants from Sanofi and Synaptogenix. Lakhan had no relevant disclosures.