Neurofilament Light Chain: Just How Far Can One Biomarker Go?


Neurofilament light chain has emerged as a biomarker with utility across the breadth of neurology, but just how much can it actually help?

Charlotte Teunissen, Prof.Dr.Ir

Charlotte Teunissen, Prof.Dr.Ir

A study published in 1996 in the Journal of Neurochemistry introduced the first use of a triplet protein as a measurement of axonal damage in patients with Alzheimer disease and amyotrophic lateral sclerosis (ALS). The protein, called neurofilament light chain (NfL), had been used for decades in animal studies, but its potential in humans was unclear.1

Now, more than 2 decades later, the clinical understanding of NfL’s potential as a biomarker in neurological illness and injury has expanded tremendously. In addition to ALS and Alzheimer disease, its utility has been explored in other dementias, multiple sclerosis (MS), stroke, and movement disorders such as Parkinson disease.2-6 Thus far, it has been evaluated as a diagnostic tool and as a measure of intervention, gaining use as a differentiator of certain pathologies5 and as a prognosticator of others.7

The protein’s nonspecificity limits its value as a diagnostic tool, but it does offer value in its sensitivity and ability to be measured efficiently in cerebrospinal fluid (CSF) and plasma. As a byproduct of axonal degeneration, NfL’s role in therapeutic development appears to be one of its strongest areas of potential.

Although the biomarker has shown that it holds potential across the breadth of neurology, it still has quite a way to go in a number of disease states. Just how useful can it be? Has the field, in light of quickly expounded research and excitement, overstated its potential?

“If you look into monitoring of treatment response, it can have value in maybe any neurodegenerative disease,” Charlotte Teunissen, Prof.Dr.Ir, professor of clinical chemistry and associate professor of neuroscience and neurodegeneration at Amsterdam University Medical Centers, told NeurologyLive. “It can also be used to monitor side effects of cancer treatments, for example. In the dementia trials, it's being used in almost every trial that's currently set up. But I don't think it will help in every disease—and it may not help in every disease, but it's something that we need to find out.”

“We first need to see proof of concept in a specific disease, and then it can be implemented more widely,” she added.

According to the FDA, there are 4 categories in which a biomarker can land: first, as a diagnostic biomarker, in which case sensitivity and specificity for the disease in question are optimized; second, as a predictive biomarker, a measurable tool which can provide insight into treatment response likelihood; third, a prognostic biomarker, which can be compared over time to determine future disease course; and fourth, a pharmacodynamic biomarker, which reacts in response to treatment.8

WATCH: Robert J. Fox, MD on Neurofilament Light as a Biomarker of Treatment Response

Based on current knowledge, NfL only fits a single role as a prognostic biomarker, with some potential to be utilized in clinical trials as a pharmacodynamic marker. Specifically in ALS, it appears that it holds value as a prognostic tool, adding insight on the aggressiveness of the disease beyond what clinicians can glean from conducting bedside exams.7

In ALS, higher levels of NfL in serum and blood correlate with a more severe or faster pace of disease progression. The possibility of using NfL as a pharmacodynamic biomarker is limited by a major, yet-to-be-achieved milestone in ALS: an effective, disease-modifying therapy.

For example, levels of NfL decrease in response to treatment in spinal muscular atrophy (SMA) as well as in MS, where much research has been conducted and yielded similar results.9-12

Ultimately, the analytical and clinical characterization of NfL suggest that it has the ideal properties to become a useful pharmacodynamic biomarker, but for now, it is limited, at least in ALS, by the therapeutic pipeline.

A similar challenge is faced in the dementia space, where the current pool of investigational agents has struggled to demonstrate clinical benefit and break through to the market. For now, Teunissen noted that NfL may hold some promise in differentiating frontotemporal dementia from psychiatric disorders.

“We offer it as a routine analysis…there are a couple of physicians that request the analysis, mostly to exclude neurological diseases,” she explained. “It's going to be used in any case where there is some doubt to whether it's a neurological or neurodegenerative disease or not—if it's psychiatric or otherwise,” she said.

For now, NfL remains a valuable biomarker alongside additional outcomes in mid-phase clinical development in order to show biological signal and proof-of-principal. In MS, the hope is that it can become a formal surrogate marker in the development of interventions for the disease. Teunissen is confident that this is where it may play a significant role.

“For example, currently in trials of the last 2 years to define whether a treatment is superior, you need to define whether there is decrease in relapse rate and relapse intensity in MS. If NfL indeed proves to be a good surrogate marker of treatments response—we would see the reaction within 6 months,” Teunissen explained. “That would be the ideal scenario, and then I think it can go in the direction of cholesterol with cardiac diseases,” she said, alluding to how cholesterol response is of often used as a proof of concept for therapies addressing cardiovascular conditions.

While this surrogacy has not yet been established for NfL, she expects it can have a similar effect, particularly for the indication of acute inflammatory-based disease activity found in relapsing-remitting MS. “It could really be used for monitoring effects of the drugs,” she said.

The future of NfL’s also lies in its convenience as a biomarker. Across a number of neurologic diseases, the push to detect biomarkers in the blood due to availability and ease of access compared with CSF, is a major focus of research, and Teunissen expects that NfL won’t be in a category all its own for long.

“NfL is an abundant protein and we have a very quick antibody to detect it, but I expect that other markers will also come—neuro-specific markers we are able to detect in blood,” she said. “NfL is the pioneer and the frontrunner, but I don't think it will stay on its own.”

Teunissen said that she’d like to see real-world inflammation studies to identify an optimal cut-off point in different diseases. As well, she’d like to see reference methods developed, which the field learned from Alzheimer biomarkers, which can help harmonize normal values for individuals across different assays and technologies.

Looking ahead, verifying the validity of blood NfL measurement may be the most important opportunity with the potential for the largest clinical impact. As a measure reflective of therapeutic response and disease progression, the potential of NfL at the bench and the bedside seems infinite, but more longitudinal data are required to fully elucidate its place in the clinical conversation.


1. Rosengren LE, Karlsson JE, Karlsson JO, Persson LI, Wikkelso C. Patients with amyotrophic lateral sclerosis and other neurodegenerative diseases have increased levels of neurofilament protein in CSF. J Neurochem. 1996;67:2013—2018. doi: 10.1046/j.1471-4159.1996.67052013.x

2. Zhao Y, Xin Y, Meng S, He Z, Hu W. Neurofilament light chain protein in neurodegenerative dementia: A systematic review and network meta-analysis. Neurosci Biobehav Rev. 2019;102:123-138. doi: 10.1016/j.neubiorev.2019.04.014.

3. Preische O, Schultz SA, Apel A, et al. Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer's disease. Nat Med. 2019;25(2):277-283. doi: 10.1038/s41591-018-0304-3.

4. Bjornevik K, Munger KL, Cortese M, et al. Serum Neurofilament Light Chain Levels in Patients With Presymptomatic Multiple Sclerosis. JAMA Neurol. Published online 2019. doi: 10.1001/jamaneurol.2019.3238.

5. Marques TM, van Rumund A, Oeckl P, et al. Serum NFL discriminates Parkinson disease from atypical parkinsonisms. Neurology. 2019;92(13):e1479-e1486. doi: 10.1212/WNL.0000000000007179.

6. Uphaus T, Bittner S, Gröschel S, et al. NfL (Neurofilament Light Chain) Levels as a Predictive Marker for Long-Term Outcome After Ischemic Stroke. Stroke. Published online 2019. doi: 10.1161/STROKEAHA.119.026410.

7. Poesen K, Van Damme P. Diagnostic and Prognostic Performance of Neurofilaments in ALS. Front Neurol. 2019;9:1167. doi: 10.3389/fneur.2018.01167.

8. About Biomarkers and Qualification. US Food and Drug Administration website. Updated June 28, 2019. Accessed February 14, 2020.

9. Darras BT, Crawford TO, Finkel RS, et al. Neurofilament as a potential biomarker for spinal muscular atrophy. Ann Clin Transl Neurol. 2019;6(5):932-944. doi: 10.1002/acn3.779.

10. Olsson B, Alberg L, Cullen NC, et al. NFL is a marker of treatment response in children with SMA treated with nusinersen. J Neurol 266;2129—2136 (2019) doi:10.1007/s00415-019-09389-8.

11. Wong YYM, Bruijstens AL, Barro C. Serum neurofilament light chain in pediatric MS and other acquired demyelinating syndromes. Neurology. 2019;93(10):e968-e974. doi: 10.1212/WNL.0000000000008057.

12. Chitnis T, Gonzalez C, Healy BC, et al. Neurofilament light chain serum levels correlate with 10-year MRI outcomes in multiple sclerosis. Ann Clin Transl Neurol. 2018;5(12):1478-1491. doi: 10.1002/acn3.638.

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