Is nerve injury related to symptom onset site in MND?

Is nerve injury related to symptom onset site in MND?

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My name is Alicia Northall and I’m a postdoctoral researcher at the University of Oxford. My research focuses on how we can use different types of brain imaging to understand MND.

In our brains, specific areas control the movement of different body parts (see image below). As we know, MND is a complex disease with a lot of variation between individuals who are affected. For example, symptoms may start in different body parts for different individuals. Understanding why this happens may help us predict the disease onset site or progression across the body in the future. During my PhD, I used brain imaging (MRI) to describe what goes wrong in the brains of people living with MND, in as much detail as possible. This work showed that tiny structural changes in the motor area of the brain reflects the site of symptom onset in MND (for example, in the hand area in upper limb onset MND).

Specific areas of the brain control the movement of different body parts

My interest in this feature of MND was recently reignited at the International Symposium on ALD/MND that took place in Basel (Switzerland) in December 2023. More specifically, the talk given by Haley Cropper titled ‘Focal corticospinal tract degeneration below the brainstem of ALS patients suggests a dying back of upper motor neurons’ (C71). Haley is an MD/PhD student at the University of Illinois at Chicago, working in the Loeb lab. She is interested in whether nerve injury is associated with the symptom onset site in MND.

How could nerve injury be linked to MND?

The development of the MND is complex with many different contributors, including genetic and environmental influences. One specific hypothesis regarding environmental influence is nerve injury, which can be caused by many factors. Famous cases of MND in professional athletes have questioned whether nerve injury can influence an individual’s risk of developing MND. For example, Lou Gehrig was a famous baseball player who developed MND, which led to the alternative term ‘Lou Gehrig’s disease’ in the United States. It remains unclear whether this association reflects a real relationship between nerve injury and MND. Haley’s work addresses specifically whether the location of nerve injury (regardless of the cause) is related to symptom onset site in people with MND.

Spinal cord injury matches symptom onset site

Haley and colleagues collected data from 18 individuals with MND. From previous MRI images, they noted that 15 of the individuals had nerve injury in the spinal cord. They also found that the location of this injury reflected the individual’s symptom onset site. Interestingly, looking at their medical and lifestyle history, showed that some of the individuals had an athlete or veteran history which highlights the role of environmental-related nerve injury. This work suggests that previous nerve injury may influence where symptoms start in MND, although further research is needed.

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What does this tell us about disease spread?

Haley and colleagues also investigated brain tissue collected from 8 individuals who died from MND. They measured how healthy the cells were along a pathway from the spinal cord up to the brain, through the medulla. The medulla, located at the base of the brain, plays an important role in passing messages between the brain and spinal cord (see image below). They showed that many cells and the insulating fatty tissue that surrounds them, known as myelin, were lost in the spinal cord and the medulla (lower portion). In contrast, they showed that fewer cells and less myelin was lost in the brain regions (including the pons and midbrain; upper portion). These findings suggest that the spinal cord and medulla were more affected than brain regions in these individuals with MND. This finding supports the ‘dying back’ hypothesis, where cell loss starts in the spinal cord before affecting the brain. However, we cannot rule out the possibility that different changes in the brain could influence the spinal cord and medulla, known as the ‘dying forward’ hypothesis.

The pathway from the spinal cord up to the brain

It is important to note that the number of participants was very small in this research. In addition, we cannot understand the direction of disease spread between the brain and spinal cord from data collected at a single timepoint. To achieve this, we would need to collect data from individuals before they develop MND, which is very difficult to predict. Haley’s research suggests that previous nerve injury could potentially contribute to the site of onset of MND. However, there are other factors, such as genetics, which would also need to be considered. Further research is now needed to fully understand any potential link between previous nerve injury and MND.

Next steps

Haley presented evidence that nerve injury may influence the symptom onset site in MND. In addition, this may provide evidence for the ‘dying back’ hypothesis regarding how the disease spreads between the brain and spinal cord. This work could help unravel how MND affects the brain and spinal cord differently in different individuals. Understanding more about why MND varies so much between individuals could open the doors to a more personalised approach to care and treatment. Haley and colleagues now plan to further investigate whether drugs can prevent this disease spread.

We would like to thank Alicia for taking the time to write this blog and also for being a Symposium Communications Ambassador. You can follow Alicia on Twitter/X here.

The MND Association’s vision is a world free from MND. Realising this vision means investing more in research, further developing partnerships with the research community, funding bodies and industry, while ensuring that advances in understanding and treating MND are communicated as quickly and effectively as possible. Our Research Development team, composed of 11 members, work hard to achieve this. Principally, the Research Information team within this are involved in communication activities including this MND Research blog.