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Delving deeper into neurofilament light chain

Delving deeper into neurofilament light chain

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There is a desperate need for a biomarker for MND for both the diagnosis and demonstration of a biological effect as a result of a potential treatment. Recent work funded by the MND Association and others has found strong evidence to suggest that using a potential biomarker known as blood neurofilament light chain in place of the ALSFRS-R scale offers the first step towards the goal of more personalised and objective monitoring of disease activity for people living with MND. You can listen to Professor Martin Turner about this research below or continue reading to find out more.

Biomarkers are biological ‘fingerprints’ of MND; chemicals or compounds found in the body that indicate the presence of the disease or allow us to measure disease activity. The discovery of MND biomarkers would help neurologists to make faster diagnoses, determine if someone has a fast or slow progressing form of MND and enable more accurate prognoses to be made. Establishing reliable biomarkers of the disease would be invaluable to clinical trials as it would help to provide a more accurate measure of whether potential treatments are able to slow disease progression, by looking at the biomarker levels instead of symptom-based measurements.

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This research was carried out as part of project AMBRoSIA (A Multicentre Biomarker Resource Strategy In ALS). The project is a 5-year biobanking programme which is aimed at gathering biological and genetic samples from several hundred people living with MND, as well as from donors without the disease in the UK. The hope is that the resource will enable many research studies to be carried out, which will lead to the development of our understanding of various types of MND and the identification of biomarkers that could be a signature of the disease.

What did the study show?

The study evaluated potential biomarkers from the biological samples of 258 people living with MND, 80 patients with other neurological conditions and 101 people who did not have a neurological condition, who were often the family and friends of the people living with MND who came to the clinic. There were a range of potential biomarkers investigated but we will only discuss the leading potential biomarker, known as neurofilament light chain (NfL).

Neurofilaments form part of the internal scaffolding of nerve cells and are important in the maintenance of the axon, which is where electrical nerve impulses travel through. Motor neurones have the longest axons in the body, meaning they have the highest levels of neurofilaments. When motor neurones are dying these neurofilaments leak out and appear in the cerebrospinal fluid (CSF) and blood. NfL is now a well-known biomarker of nerve cell damage but is not specific for just MND as levels can be increased in a range of neurodegenerative conditions.

The study investigated both CSF and blood (plasma) NfL levels in all participants. They noted that NfL was found to reflect disease activity, meaning it mirrors the level at which the disease mechanisms for MND are active within the body. They also found that measuring CSF NfL did not provide any significant advantages over plasma NfL. This is advantageous to people living with MND, since blood tests for NfL are much more practical in a clinical setting, compared to measuring CSF which requires a lumbar puncture. This is made even more advantageous since the researchers noted that plasma NfL was strongly associated with survival and rate of disability progression, independent of any other factors that predict the likely course of the disease.

The study also found that plasma NfL was a potentially more sensitive reflection of the underlying disease process (i.e. what is happening at a biological level) than the measurement of ALSFRS-R, the current most common measure of disease progression for MND. This was suggested to be because NfL levels reflect disease activity over a narrow period of time whilst ALSFRS-R reflects disability progression that has built up over the time since the person living with MND has been diagnosed. This means that using plasma NfL measurements may have the potential to detect that the disease is slowing earlier compared to ALSFRS-R. Having a more sensitive measure is important since ALSFRS-R is a subjective measure of disease progression, dependent on the person’s opinion, honesty and how they feel on the day they are asked to complete it.

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This research also went on to evaluate the performance of plasma NfL as a way to measure if a drug might be working in a clinical trial. The researchers conducted trial simulations based on the data collected during AMBRoSIA to model the inclusion of plasma NfL compared to ALSFRS-R. The simulation results showed that using plasma NfL over ALSFRS-R may help to detect treatment effects in smaller group sizes and more quickly, which in turn might mean that clinical trials could recruit a smaller number of participants and be able to build confidence in any likely benefit sooner. This would help prioritise only the most promising drugs for the larger studies needed to prove benefit fully.

What are the take home messages from this research?

  • Blood level of NfL has value as an objective measure of disease activity used to support established clinical outcome measures in phase 3 trials.
  • NfL could be used as an outcome measure at earlier stages of drug development to help evaluate multiple drug targets, in small cohorts of participants, to determine which should be taken forward for the larger phase 3 trials. 
  • There is potential for NfL to have a role in an MND clinic to allow for more personalised and objective monitoring of disease activity.

Biomarkers for other diseases and conditions have been around for some time, e.g. glucose measurements in diabetes, but as of yet none are routinely used for MND. We are on the cusp of a number of potential biomarkers for MND and we have highlighted many of these in recent blogs, which you can read here. This work adds to the growing list of successes for MND biomarkers, with NfL showing potentially superior performance in association with key measures of the aggressiveness of ALS, specifically the rate of progression of functional decline as measured by the ALSFRS-R and survival. The future is certainly looking brighter in the investigation of biomarkers for MND.


Project AMBRoSIA is funded by the MND Association, from funds raised by the Ice Bucket Challenge in 2014 and with the generous support of London City Swim Foundation, The Linbury Trust in memory of Annette Page, prima ballerina, Paul and Julie Cook and all their family and friends and many other generous donors. The programme also wouldn’t have been established without the generosity of people living with and affected by MND selflessly donating samples, helping in the fight against the disease. We wish to send our heartfelt thank you to each and every person who has helped with this study and made research into these findings possible.

I joined the MND association as a Research Information Co-ordinator in September 2021. I graduated from the University of Nottingham with a PhD in Chemistry in 2020. After finishing my PhD, I joined an R&D company based in Nottingham where I spent my time synthesising potential new drug treatments for a wide variety of diseases. As part of my role I will help the team communicate the latest MND research on this blog, as well as on our twitter page (@MNDResearch).

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