Snapshot: What is Neurofilament light protein (NfL)?

Nerve cells (aka neurons) are unique cells in that they have long, and thin extensions called axons which form connections with and talk to other neurons. This particular shape of neurons determines how quickly they can get their messages to other cells. You can think of the axons in the brain like the wires connecting all the components of a dense electrical network.

NfL stands for Neurofilament light protein (Not to be confused with the national football league!). Neurofilaments are proteins found in our neurons. They are important for helping these cells hold their structure and size. We know this is important for their ability to send messages to other neurons. NfL is the smallest unit of three types of neurofilaments (light, medium and heavy). There is a lot of NfL found in the axons of neurons.

A large neuron with long interconected axons
A cortical neuron stained green with antibody to NfL. Image courtesy of GerryShaw on Wikimedia.

How do you measure NfL levels?

Like other proteins, NfL levels can be measured in fluids using tools known as immunoassays. These tools make use of antibodies generated by the immune systems to capture and count the protein of interest. It has been possible to measure NfL in cerebrospinal fluid (CSF) – the clear fluid that surrounds the brain and has lots of brain proteins – since 2005. In recent years, immunoassay technology has improved significantly, permitting the quantification of proteins previously too low in concentration to detect. One of these technologies is Single Molecule Array (Simoa) and has made it possible to measure NfL reliably in blood.

Why is NfL used as a biomarker?

Biomarkers are biological characteristics that can be measured and that tell us about a particular biological or disease process or response to a therapy. They can be used to make drug development more efficient. NfL is released into CSF after brain injury and also in many neurodegenerative diseases. This makes it a biomarker of neuronal injury. The problem with CSF is that it requires a safe but relatively invasive medical procedure called a lumbar puncture or spinal tap to collect. It would be a lot easier for both patients and doctors if we could get the same information from a blood test. Being able to quantify NfL – a brain protein – in blood, and more importantly, that it reflected what was happening in the brain was very exciting for many diseases.

In neurodegenerative diseases with effective disease modifying therapies (such as Multiple Sclerosis and Spinal Muscular Atrophy), a lowering of NfL reflects the clinical benefit in response to these therapies. In another genetic neurodegenerative disease caused by a CAG expansion, Huntington’s disease, NfL increase has been shown to be the earliest detectable change in asymptomatic gene carriers who are very far from their predicted age of disease onset. Many results like these suggest that NfL could help monitor disease even before symptoms appear, decide when to start therapies, and tell us if a drug is improving the health of neurons.

What NfL research is being done in ataxia research?

So what about ataxias? You will be pleased to know that Ataxia researchers have also jumped on the NfL band wagon. We previously wrote an article on two independently published studies in SCA3 which showed in many patients that NfL levels increased as Ataxia severity got worse, they were correlated with a measure of clinical severity (SARA) and increased with the level of brain loss (atrophy). One of the studies showed NfL levels increased with a higher number of CAG repeats in someone’s SCA3 mutation. There is also work using mouse models of SCA3 to understand this biomarker further. Two studies have now shown that NfL is also increased in Friedreich’s ataxia. With more research, NfL could potentially be used to design better clinical trials for ataxias and to monitor disease.

If you would like to learn more about NfL, take a look at this article by NeurologyLive.

Snapshot written by Dr. Lauren Byrne and edited by Dr. Gülin Öz.

A promising biomarker to track disease progression in SCA3

Written by Dr. Ambika Tewari Edited by Dr. Gulin Oz

Neurofilament light chain could provide a reliable readout of how far an SCA3 patient’s disease has progressed

How often have you heard that the most effective way to treat a disorder is early intervention? In reality, “early” is not possible for many disorders because patients receive a diagnosis only after the appearance of symptoms. But what if there was a way we could tell that a patient will develop a disease – even before they have any symptoms? Thankfully, that’s exactly what researchers in the field of biomarkers are trying to do. Biomarkers are biological indicators that are not only present in patients before the manifestation of symptoms, but can also be used to measure disease progression. In the SCA field, there have been a recent series of articles that have shed light on a promising biomarker for SCA3.

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease, is the most common dominantly-inherited ataxia. It is caused by an expansion of CAG repeats (a small segment of DNA that codes for the amino acid glutamine) in the ATXN3 gene. An important feature of SCA3, as well as in other spinocerebellar ataxias, is the progressive development of symptoms. Symptoms usually occur across decades, and can be divided into three major phases: asymptomatic, preclinical, and symptomatic. In the asymptomatic phase, there is no evidence of clinical symptoms (even though the patient has had the SCA-causing mutation since birth). In the preclinical stage, patients show unspecified neurological symptoms such as muscle cramps and/or mild movement abnormalities. By the symptomatic (i.e., clinical) stage, patients have significant difficulty walking.

A Spinal Cord Motor Neuron sample stained purple.
Neurofilament light chain (NfL) is an important building block of neurons. But when neurons are damaged, NfL is released. Image of a spinal cord motor neuron courtesy of Berkshire Community College.

Currently in SCA research, disease progression is measured using the Scale for the Assessment and Rating of Ataxia (SARA). A score of 3 or more on the SARA differentiates clinical and preclinical groups. Structural and functional brain imaging methods (such as MRI) also track the progressive nature of the disease, like the SARA, but give us a visual picture of changes in the brain. Together, these methods have provided the SCA community with important insights into the clinical spectrum of each specific disease and its rate of progression. And, with the exciting progress we have recently made in the realm of SCA3 therapeutics, a biomarker that is cost-effective and easy to measure (like in a blood test) could provide a convenient way to assess how effective a potential treatment is.

Continue reading “A promising biomarker to track disease progression in SCA3”

Spotlight: The Neuro-D lab Leiden

Principal Investigator: Dr. Willeke van Roon-Mom

Location: Leiden University Medical Centre, Leiden, The Netherlands

Year Founded: 1995

What disease areas do you research?

What models and techniques do you use?

A group photo of members of the Neuro-D lab Leiden standing outside on a patio.
This is a group picture taken during our brainstorm day last June. From left to right: Boyd Kenkhuis, Elena Daoutsali, Tom Metz, Ronald Buijsen, Willeke van Roon-Mom (PI), David Parfitt, Hannah Bakels, Barry Pepers, Linda van der Graaf and Elsa Kuijper. Image courtesy of Ronald Buijsen.

Research Focus

What is your research about?

The Neuro-D research group studies how diseases develop and progress at the molecular level in several neurodegenerative diseases. They focus on diseases that have protein aggregation, where the disease proteins clump up into bundles in the brain and don’t work correctly.

We focus strongly on translational research, meaning we try to bridge the gap between research happening in the laboratory to what is happening in medical clinics. To do this we use more “traditional” research models like animal and cell models. But we also use donated patient tissues and induced pluripotent stem cell (iPSC) models, which is closer to what is seen in medical clinics.

Our aim is to unravel what is going wrong in these diseases, then discover and test potential novel drug targets and therapies.

One thing we are doing to work towards this goal is identifying biomarkers to measure how diseases progress over time. To do this, we use sequencing technology and other techniques to look at new and past data from patients.

Why do you do this research?

So far there are no therapies to stop the progression of ataxia. If we can understand what is happening in diseases in individual cells, we can develop therapies that can halt or maybe even reverse disease progression.

Identifying biomarkers is also important, because it will help us figure out the best time to treat patients when we eventually have a therapy to test.

Stylized logo for the Dutch Center for RNA Therapeutics
The Neuro-D lab Leiden is part of the Dutch Center for RNA Therapeutics, which focuses on RNA therapies like antisense oligonucleotides. Logo designed by Justus Kuijer (VormMorgen), as 29 year old patient with Duchenne muscular dystrophy.

Are you recruiting human participants for research?

Yes, we are! We are looking for participants for a SCA1 natural history study and biomarker study. More information can be found here. Please note that information about this study is only available in Dutch.

Fun Fact

All our fridges and freezers have funny names like walrus, seal, snow grouse and snowflake.

For More Information, check out the Neuro-D lab Leiden website!


Written by Dr. Ronald Buijsen, Edited by Celeste Suart

Snapshot: What is a biomarker?

A biomarker is any biological-based measurement that provides useful information regarding a person’s health. For example, blood test results showing increased glucose levels can be used as a biomarker for diabetes. A blood test showing an increased white blood cell count is a biomarker for infection. There are many sources of biomarkers beyond blood biomarkers. MRI, CT, and x-ray scans are all examples of imaging biomarkers. Scored motor assessments can also be used as biomarkers. For example, police use the field sobriety test as a biomarker for alcohol consumption.

Biomarkers can be used to:

  • Diagnose an existing disease or predict a patient’s prognosis.
  • Track disease progression.
  • Determine whether experimental drugs prevent, improve, or slow progression of disease within clinical trials.

close up photo of a measuring tape on a white background, with the end fading off into the distance.
Biomarkers act like a measure tape for diseases. Photo by Pixabay on Pexels.com

What are current biomarkers for spinocerebellar ataxias (SCAs)?

There are multiple biomarkers that are commonly used for patients with ataxia. DNA sequencing from saliva or blood samples of undiagnosed patients with ataxia symptoms can be used to diagnose or rule out SCAs caused by known genetic mutations. The Scale for the Assessment and Rating of Ataxia (SARA) scoring is a common motor assessment used to measure and track severity of ataxia-related balance and coordination issues in patients. MRI scans and other brain imaging techniques can be used to examine brain abnormalities or loss of brain cells.

Why do we need better biomarkers for SCAs?

In an ideal clinical trial, a patient would receive the potential treatment and then undergo a simple assessment (i.e. give a blood sample) shortly after that could conclusively determine whether the drug is working. Thankfully, many potential ataxia treatments are currently in development or are already being tested in clinical trials for patients with SCAs. Unfortunately, we currently do not have an easy, cheap, and sensitive way to measure whether ataxia symptoms are worsening or improving in a relatively short amount of time.

How can we identify better biomarkers for the SCAs?

Researchers are actively seeking better biomarkers for SCAs in animal and cell models of ataxia. There are also multiple ongoing “Natural History” and biomarker clinical trials that focus on different types of SCA diseases. These clinical studies aim to improve our understanding of the SCAs and identify new biomarkers to improve ataxia diagnosis and drug development. These studies may track patients over months or years, and can involve multiple tests, including blood or cerebrospinal fluid samples, brain imaging, or SARA scoring.

If you would like to learn more about biomarkers, take a look at these resources by the ALS Association and News Medical.

Snapshot written by Dr. Lauren Moore and edited by Dr. Gulin Oz.