In our previous blog, we explained what biomarkers are and what they can be used for. In this blog, we dive further into the world of biomarkers, specifically looking at how they might be used in MND.
Why are biomarkers needed for MND?
There are currently no tests that can say for sure that someone does or does not have MND. Instead, MND is typically diagnosed after a process of elimination, once other diseases, which cause similar symptoms, have been ruled out. This elimination process can result in long diagnostic delays while the symptoms are initially thought to be caused by another problem. By the time someone gets a diagnosis of MND, symptoms can already be very advanced and affecting both the arms and legs and the bulbar muscles (the muscles that affect breathing and swallowing). The delay getting a diagnosis can also delay access to MND specific care and support, as well as access to clinical trials and potential treatments.
There is also a lot of variation in how long people live for when they have been diagnosed with MND. Although the average survival is 3 years from diagnosis, some people’s symptoms progress much faster than this and other people may progress much slower than this. Researchers are getting closer to understanding why there are differences in disease progression. However, for someone who has just been diagnosed with MND, there is currently no way of knowing how quickly their disease will progress.
This is where biomarkers can help…
Researchers are looking for markers in the body, such as specific molecules that can be detected in body fluids, or changes in the body that can be seen with imaging, that will help to diagnose MND. If someone presents to their neurologist with symptoms of MND that could be mistaken for another disease, measuring biomarkers may help to determine whether the person has MND more quickly. If there is a way of finding a unique ‘signature’ of MND, by, for example, taking a blood sample or taking a scan of the brain and spinal cord, this would help to enable faster diagnoses which could lead to earlier access to care, potential treatments and clinical trials.
Biomarkers are also needed for MND to tell the difference between someone with fast-progressing disease and someone with slow-progressing disease. This could mean that when someone is diagnosed with MND, they will be given more accurate predictions about how fast their MND is likely to progress. Also, some drugs may only be effective in people with slow or fast progressing disease, so biomarkers may help to define these different groups and tell us more about which clinical trials or treatments people may be best suited to.
As there is currently no cure for MND, biomarkers can also help with drug discovery. If researchers can use biomarkers that are shared between models of MND and people with MND, they will be able to monitor the effects of potential treatments more accurately in MND models in the laboratory. This will mean that when drugs are tested in clinical trials, they are more likely to show the same effects that were seen in the models of MND.
Do we already have biomarkers for MND?
There are lots of different types of biomarkers currently being investigated for MND. One example of these is called Neurofilament.
Neurofilament is currently the most widely used biomarker in MND. But what exactly is it and how can it help people with MND?
Motor neurons are very long cells and, just like the Eiffel tower, they have a complex scaffolding structure that helps them to maintain their shape. Rather than being made of iron beams like the Eiffel tower, the scaffolding within a motor neuron is made up of proteins called neurofilaments. As motor neurons are the longest cells in the body, they contain more neurofilaments than any other type of cell in the body.
When someone has MND, this internal scaffolding can break down. When the motor neuron dies, the cell membrane, which is the outer layer of the cell, also begins to break. This means that the neurofilament proteins spill out of the cell and into the surrounding areas.
Neurofilament levels can be measured in the blood and cerebrospinal fluid (CSF). The amount of neurofilament in the blood and CSF is a direct indicator for neuron damage in the body. Although it is not specific for MND, higher levels of neurofilament are found in people with MND compared to healthy people.
If the level of neurofilament changes, it shows if there is a change to the amount of neuron damage in the body. This can be really useful for clinical trials, as we will explain in the next blog of the series.
Neurofilament also shows promise as an early detector of MND in people who do not have any symptoms. In people with a known risk of MND, for example those with a known genetic risk factor who do not yet have symptoms, monitoring of neurofilament levels might provide an indication of the disease developing before any symptoms appear. This could allow pre-symptomatic carriers of MND risk genes to be recruited into clinical trials for preventative treatments.
But why have I heard it being called NfL?
To add just a little more complexity, neurofilament proteins can actually be categorised into three types. Neurofilament light chain (NfL), neurofilament medium chain (NfM) and neurofilament heavy chain (NfH). They are essentially just different types of scaffolding poles that all make up the internal skeleton in the neuron. Measuring just one specific type of neurofilament might provide a more accurate measure of disease diagnosis and progression than measuring all types together, but research is still confirming this.
Other biomarkers being studied for MND
There are many different biomarkers being studied to see if they could be good markers of disease progression and onset in MND. Click on the drop-down menu to find out more about some of the other types of biomarkers currently being studied for MND.
What about biomarkers for genetic MND?
Some research is focused on finding biomarkers specifically for genetic forms of MND. For example, people who have MND caused by mutations in the SOD1 gene can have higher amounts of SOD1 protein in their blood and CSF. This biomarker was actually used to monitor the effects of a gene therapy called Tofersen in clinical trials, as the drug was shown to reduce the amount of SOD1 protein in the CSF. You can read more about how biomarkers can be used in clinical trials in our next blog.
In clinical trials involving both familial MND and sporadic MND (where there is no known family history of MND), people with different genetic forms of MND may also respond differently to treatments. Biomarkers can help observe these differences and identify those with different forms of genetic MND. One such example was a trial examining the effect of lithium on MND symptoms. This trial identified that those who had a change in a gene called UNC13A experienced different effects of lithium therapy compared to those without, even though overall the trial had a negative result. Lithium is now being re-tested in a clinical trial for people with MND who have the UNC13A gene change.
Biomarkers for genetic MND might one day be able to provide a quicker and easier way of knowing whether someone has a genetic form of MND than the current genetic testing methods, which are very expensive, slow and can be hard to access.
What is the future looking like for MND biomarkers?
Although there has been a lot of progress in the discovery of biomarkers for MND, there are still no definitive biomarkers for the diagnosis of MND.
The rapidly developing field of artificial intelligence and machine learning is offering more promise for the identification of new biomarkers. Combining modern intelligence technology with genetic, clinical, imaging and biomarker data might help to identify novel combinations of biomarkers that, when used together, can provide a more accurate insight into MND. This may help to provide more efficient ways of diagnosing, tracking progression of and treating MND.
Biomarkers can be an incredibly useful tool for clinical trials because they reduce the need to measure symptoms as an indicator of whether a drug is effective and provide a more accurate measure of whether a drug is able to slow disease progression. Read our next blog post to find out more about clinical trials.
