Neurofilament light: An established neuronal injury biomarker

Neurological disorders affect hundreds of millions of people worldwide, representing a leading cause of death and imposing a significant long-term burden due to years lived with disability.1 Despite variations in their causes, symptoms, prognoses, and treatments, they all share neuronal injury.

Many researchers have focused on biomarkers like neurofilament light (NfL), a neuron-specific, axonal cytoskeleton protein that releases into the interstitial fluid and cerebrospinal fluid (CSF) when neuronal injury and damage occurs. NfL is emerging as a candidate for future investigations and its potential application to this research.

Neurofilament light: An established neuronal injury biomarker in CSF

Researchers have used NfL measurements in CSF as a substitute biomarker for determining neuronal damage for over 25 years.2,3 NfL levels in CSF are present in large numbers. This makes them a dependable sample type for determining the level of neuroaxonal injury in neurological conditions like Alzheimer’s Disease (AD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), traumatic brain injuries (TBIs) and others.

The Uman Diagnostics NfL ELISA kit4 has been used to analyze CSF NfL for years. This kit has provided consistent and exceptional performance. It is available commercially and is the preferred antibody pair for determining NfL in CSF.3

Migration to easily accessible sample types from CSF to blood

The availability of an NfL test for CSF has enhanced neurological research, drug development, diagnostics, and patient care. However, lumbar puncture for CSF collection is an invasive procedure that demands specialized skills, making it less than ideal for routine use and not well-suited for large-scale applications.

Several researchers investigated the possibility of a direct measurement of NfL in blood, offering an alternative that was less invasive, cost-effective, and more accessible.

In 2013, researchers began experiments to measure NfL in blood. The standard ELISA method exhibited an insufficient sensitivity in determining NfL levels in most samples. However, promising results were acquired using electrochemiluminescence (ECL) technology.

However, samples with mid to lower levels of NfL often fell below the limits of quantitation for the assay. This presented a challenge as accurately measuring samples from healthy subjects or individuals with minimal neuronal injury is vital for obtaining comprehensive data, enhancing disease understanding, and effectively stratifying patients based on their condition.

The advent of Simoa® digital technology marked a significant milestone, enabling precise measurement of NfL in blood for the first time.5,6

A blood-based biomarker assay of neurodegeneration with Simoa® Homebrew Assay

With the commercial availability of Simoa® ultrasensitive digital immunoassay technology, researchers in the field of fluid biomarkers for central nervous system (CNS) disorders finally witnessed the potential for a genuine transition towards blood-based measurements.

Simoa® technology’s open platform allows any laboratory to utilize the capabilities of homebrew kits and transfer conventional ELISAs into Simoa® immunoassays.

Scientists from the University of Gothenburg, working with NfL, initiated the successful transfer of the Uman Diagnostics antibodies onto the Simoa® platform with the homebrew kit.

Their research investigated NfL levels from a cohort of HIV-positive individuals at different disease stages, with varying presence of HIV-associated dementia (HAD), and following antiretroviral treatment (ART)-induced viral suppression.7 HAD refers to a form of CNS injury characterized by cognitive symptoms in HIV-infected individuals.

Before this study, assessing NfL in CSF was the primary method for evaluating HIV-associated CNS injury. However, these researchers made a notable breakthrough by showing that the rise in NfL levels after CNS injury could also be detected and measured in plasma samples.

Plasma NfL levels presented the same pattern as in CSF, with higher NfL levels in individuals with HAD and lower CD4+ cell counts (as shown in Figure 1).

Even though plasma NfL levels were 50-fold lower than CSF levels, 100 % of the samples could be measured, including samples from controls and subjects with low axonal injury. Detecting measurable NfL levels in all samples, including lower concentrations, highlights the excellent sensitivity and reliability of the Simoa® technology.

Plasma NfL levels are correlated with CSF levels across 8 cohorts. Plasma NfL is elevated in HIVinfected individuals with lower CD4+ counts and individuals with diagnosed HIV-associated dementia (HAD).

Figure 1. Plasma NfL levels are correlated with CSF levels across 8 cohorts. Plasma NfL is elevated in HIV-infected individuals with lower CD4+ counts and individuals with diagnosed HIV-associated dementia (HAD). Image Credit: Gisslén et al.7

Simoa® Blood NfL: Pilot studies on a multitude of applications

The study of CNS injury in HIV-infected individuals provided proof that the use of blood NfL as a substitute biomarker for neuronal injury was a viable concept. Numerous publications followed, looking to validate the viability of NfL as a blood-based biomarker and its capability of correlating with CSF measurements.

In 2016, numerous publications provided proof of NfL as a blood-based biomarker for mild concussion in American football athletes,8 progressive supranuclear palsy,9 MS,10 frontotemporal dementia,11 TBI12 and Creutzfeldt-Jakob disease.13

To date, many of the studies have reaffirmed a strong relationship between CSF and blood NfL levels and established connections between NfL and critical disease parameters. NfL has been found to classify disease subgroups with baseline NfL levels often connected to short and long-term outcomes.

Better accessibility to blood samples and the opportunity to conduct longitudinal studies resulted in researchers delving deeper into each application. The dataset was enriched, and a profound understanding of the role of NfL in many neurological disorders was gained.

An influential publication compared the Simoa® immunoassay to standard ELISA and electrochemiluminescence (ECL), establishing the fundamentals for continuing use of blood NfL with Simoa®.6

The study’s main objective was the analytical evaluation of the relationship between CSF and serum. This was across samples with varying levels of NfL using the Uman Diagnostics antibodies previously mentioned.

The results determined correlations between paired CSF and serum samples were strongest when the Simoa® immunoassay was used (as shown in Figure 2). All the samples using Simoa® technology were within the measurable range. However, over 50 % of the samples with medium and low NfL levels could not be measured using the other two methods.

This underscored the superior performance and sensitivity of Simoa® immunoassays in measuring low levels of blood NfL and providing measurements that correlate with CSF NfL. This trend has continued over the years, establishing the Simoa® immunoassay as the gold standard for NfL measurement in blood.14

CSF and serum correlation for NfL using different assay platforms with the same antibody pairs and calibrators. Correlation between CSF and serum NfL is the strongest using Simoa® immunoassay.

Figure 2. CSF and serum correlation for NfL using different assay platforms with the same antibody pairs and calibrators. The correlation between CSF and serum NfL is the strongest using Simoa® immunoassay. Image extracted from Kuhle et al.6

NfL measurement in blood: Step by step in the path to clinical implementation

Prior to 2017, the scientific community consistently regarded blood NfL as an informative biomarker for neuronal injury, primarily due to the Simoa® homebrew NfL assay. As its application expanded into large-scale clinical research, including clinical trials and multi-center longitudinal studies, the demand for a standardized assay ensuring ultra-sensitivity, accuracy, and precision became crucial.

In response to this crucial requirement, in 2017, Quanterix provided a pioneering solution with the launch of the Simoa® NfL Advantage assay kit, which offered compatibility with all Simoa® bead-based platforms. This innovative kit offered ultra-sensitivity while maintaining control of accuracy and precision. This gave researchers and clinicians a reliable and consistent tool for NfL measurements.

Quanterix acquired Uman Diagnostics in 2019, ensuring a continual supply of the best-performing and substantially validated reagents for NfL measurement. The strategy solidified Quanterix’s commitment to providing innovative technology and supporting the highest level of confidence in blood NfL measurements for neurological research, diagnostics, drug development, and disease monitoring.

Since its inception, the progress in using blood-based measurements of NfL in clinical research settings has been remarkable. The diligent work of researchers and clinicians worldwide utilizing Simoa® technology has significantly improved our understanding of the factors influencing NfL levels.

In addition, the establishment of reliable age and body mass index-adjusted normative ranges has provided valuable insights into the potential occurrence of neuronal damage.16

The level of knowledge surrounding blood NfL has impacted various neurodegenerative diseases, including MS, in a profound way. For patients with MS, increased NfL levels compared to normal ranges indicate a heightened risk for future clinical or MRI disease activity.

The FDA granted the Quanterix Simoa® NfL test with Breakthrough Device Designation as a prognostic aid in assessing the risk of disease activity in patients diagnosed with relapsing-remitting MS (RRMS).17

This test is instrumental in evaluating new disease-modifying agents during clinical trials and closely monitoring individual patients for treatment response. It has the potential to assist healthcare providers in diagnostics, prognostics, and therapeutic monitoring, empowering clinicians to provide personalized and improved patient care.

Important milestones on the road of NfL discovery to diagnostics.

Figure 3. Important milestones on the road of NfL discovery to diagnostics. Image Credit: Quanterix

The utilization of blood NfL with individual patients is becoming increasingly prevalent. Its effectiveness has been proven as a Laboratory Developed Test (LDT) in medical centers worldwide and at Quanterix.18 Its application may even extend beyond the monitoring of MS patients to the evaluation of general brain health.

An influential publication from 2021 interviewed neurologists in a memory clinic, revealing that they found Simoa® serum NfL measurement to be invaluable in confirming or ruling out neurodegeneration.19 Figure 3 offers a visual representation of important milestones of the Simoa® NfL assay.

From discovery to diagnostics: Awaiting the next breakthrough

The development of an assay for measuring blood phosphorylated tau protein at residue 181 (p-Tau 181) levels closely mirrors NfL. Like NfL, p-Tau 181 was first discovered in a project utilizing Quanterix’s homebrew assay. It has proven to be valuable for understanding the progression of Alzheimer’s Disease (AD) pathology.

Quanterix launched the Simoa® Advantage p-Tau 181 assay kit and a p-Tau 181 LDT (LucentAD),20,21 after the initial discovery, paving the way for its utilization in AD research and clinical implementation.

As researchers continue to discover important biomarkers utilizing the ultrasensitive Simoa® technology, improved clinical research and diagnostics will follow. These advancements offer non-invasive, simple, accessible, cost-effective, and scalable methods that offer great promise for the enhancement of patient care.

References and further reading

  1. GBD 2016 Neurology Collaborators. Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019;18(5):459-480. doi:10.1016/S1474-4422(18)30499-X
  2.  Rosengren LE, Karlsson JE, Karlsson JO, Persson LI, Wikkelsø C. Patients with amyotrophic lateral sclerosis and other neurodegenerative diseases have increased levels of neurofilament protein in CSF. J Neurochem. 1996;67(5):2013-2018. doi:10.1046/j.1471-4159.1996.67052013.x
  3. Bridel C, van Wieringen WN, Zetterberg H, et al. Diagnostic Value of Cerebrospinal Fluid Neurofilament Light Protein in Neurology: A Systematic Review and Meta-analysis. JAMA Neurol. 2019;76(9):1035-1048. doi:10.1001/jamaneurol.2019.1534
  4.  Petzold A, Altintas A, Andreoni L, et al. Neurofilament ELISA validation. J Immunol Methods. 2010;352(1-2):23-31. doi:10.1016/j.jim.2009.09.014
  5. Rissin DM, Kan CW, Campbell TG, et al. Single-molecule enzyme-linked immunosorbent assay detects serum proteins at sub femtomolar concentrations. Nat Biotechnology. 2010;28(6):595-599. doi:10.1038/nbt.1641
  6. Kuhle J, Barro C, Andreasson U, et al. Comparison of three analytical platforms for quantification of the neurofilament light chain in blood samples: ELISA, electrochemiluminescence immunoassay and Simoa. Clin Chem Lab Med. 2016;54(10):1655-1661. doi:10.1515/cclm-2015-1195
  7. Gisslén M, Price RW, Andreasson U, et al. Plasma Concentration of the Neurofilament Light Protein (NFL) is a Biomarker of CNS Injury in HIV Infection: A Cross-Sectional Study EBioMedicine. 2015;3:135-140. Published 2015 Nov 22. doi:10.1016/j.ebiom.2015.11.036
  8. Oliver JM, Jones MT, Kirk KM, et al. Serum Neurofilament Light in American Football Athletes over the Course of a Season. J Neurotrauma. 2016;33(19):1784-1789. doi:10.1089/neu.2015.4295
  9. Rojas JC, Karydas A, Bang J, et al. Plasma neurofilament light chain predicts progression in progressive supranuclear palsy. Ann Clin Trans Neurol. 2016;3(3):216-225. Published 2016 Feb 1. doi:10.1002/acn3.290
  10. Bergman J, Dring A, Zetterberg H, et al. Neurofilament light in CSF and serum is a sensitive marker for axonal white matter injury in MS. Neurol Neuroimmunology Neuroinflammation. 2016;3(5):e271. Published 2016 Aug 2. doi:10.1212/NXI.0000000000000271
  11. Rohrer JD, Woollacott IO, Dick KM, et al. Serum neurofilament light chain protein is a measure of disease intensity in frontotemporal dementia. Neurology. 2016;87(13):1329-1336. doi:10.1212/WNL.0000000000003154
  12. Shahim P, Gren M, Liman V, et al. Serum neurofilament light protein predicts clinical outcome in traumatic brain injury. Sci Rep. 2016;6:36791. Published 2016 Nov 7. doi:10.1038/srep36791
  13. Steinacker P, Blennow K, Halbgebauer S, et al. Neurofilaments in blood and CSF for diagnosis and prediction of onset in Creutzfeldt-Jakob disease. Sci Rep. 2016;6:38737. Published 2016 Dec 8. doi:10.1038/srep38737
  14.  Alagaratnam J, von Widekind S, De Francesco D, et al. Correlation between CSF and blood neurofilament light chain protein: a systematic review and meta-analysis. BMJ Neurol Open. 2021;3(1):e000143. Published 2021 Jun 16. doi:10.1136/bmjno-2021-000143
  15. Quanterix Announces Agreement to Acquire Uman Diagnostics, World’s Leading Neurofilament Light (NfL) Antibody Supplier. Quanterix. Jun 26, 2019. https://ir.quanterix.com/news-releases/news-release-details/quanterix-announces-agreement-acquire-umandiagnostics-worlds
  16. Benkert P, Meier S, Schaedelin S, et al. Serum neurofilament light chain for individual prognostication of disease activity in people with multiple sclerosis: a retrospective modelling and validation study. Lancet Neurol. 2022;21(3):246-257. doi:10.1016/S1474-4422(22)00009-6
  17. Quanterix Granted Breakthrough Device Designation From U.S. FDA For NfL Test For Multiple Sclerosis. Quanterix. April 22, 2022. https://www. quanterix.com/press-releases/quanterix-granted-breakthrough-device-designation-from-us-fda-for-nfl-test-for-multiple-sclerosis/
  18. Quanterix Expands Laboratory Developed Test Menu With Launch Of Neurofilament Light Chain Test. Quanterix. Jan. 9, 2023. https://www. quanterix.com/press-releases/quanterix-expands-laboratory-developed-test-menu-with-launch-of-neurofilament-light-chain-test/
  19. Willemse EAJ, Scheltens P, Teunissen CE, Vijverberg EGB. A neurologist’s perspective on serum neurofilament light in the memory clinic: a prospective implementation study. Alzheimer’s Res Ther. 2021;13(1):101. Published 2021 May 18. doi:10.1186/s13195-021-00841-4
  20. Quanterix Launches First PTau-181 Plasma Laboratory Developed Test For Clinical Diagnostic And Research Applications In The U.S. Quanterix. July 27, 2022. https://www.quanterix.com/press-releases/quanterix-launches-first-ptau-181-plasma-laboratory-developed-test-for-clinical-diagnostic-and-research-applications-in-the-us/
  21. Quanterix Launches LucentAD Biomarker Blood Test To Aid Physician Diagnosis Of Alzheimer’s Disease In Patients. Quanterix. July 06, 2023. https://www.quanterix.com/press-releases/quanterix-launches-lucentad-biomarker-blood-test-to-aid-physician-diagnosis-of-alzheimers-disease-in-patients/

About Quanterix

From discovery to diagnostics, Quanterix’s ultrasensitive biomarker detection is fueling breakthroughs only made possible through its unparalleled sensitivity and flexibility. Quanterix’s Simoa® technology has delivered the gold standard for earlier biomarker detection in blood, serum or plasma, with the ability to quantify proteins that are far lower than the Limit of Quantification (LoQ) of conventional analog methods.

Its industry-leading precision instruments, digital immunoassay technology and CLIA-certified Accelerator laboratory have supported research that advances disease understanding and management in neurology, oncology, immunology, cardiology and infectious disease. Quanterix has been a trusted partner of the scientific community for nearly two decades, powering research published in more than 2,500 peer-reviewed journals.


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Last updated: Aug 1, 2024 at 4:57 AM

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