Amyotrophic lateral sclerosis: Not just a motor neurone disease

Author: Dr Róisín McMackin, Signal Analysis Strand, Academic Unit of Neurology, TCD

We often interchange the terms “amyotrophic lateral sclerosis” (ALS) and “motor neurone disease” (MND). This is because ALS is the most common type of MND and of course anyone who has been directly or indirectly affected by ALS will be familiar with its devastating effects on movement, which is controlled by the motor neurones. However, it’s becoming apparent that ALS is not just a motor neurone disease, and understanding ALS requires us to explore much further.

Why is ALS referred to as a Motor Neurone Disease?

The motor neurones connect your brain to your muscles, typically via a pathway wherein “upper motor neurones” connect your brain to your spinal cord or brain stem, where they pass on messages to your “lower motor neurones”, which in turn carry on the message to your muscles, telling them to do what you want. ALS is the form of MND characterised by both the upper and lower motor neurones becoming ineffective and ultimately dying away. From when it was first described by Jean-Martin Charcot in 1874, until the late 20^th century, ALS was largely considered to selectively only affect these movement-controlling cells.  While this is a central, and very important component of the disease, the intense focus of ALS research on motor neurones specifically may be the reason we still do not understand a lot about ALS. For example, why do different people with ALS experience such different symptoms and why are the symptoms more severe in some people than others?

Early evidence that ALS affects the brain beyond the movement system

One of the biggest clues that ALS is not only a motor neurone disease was the recognition by neurologists that some people suffering with ALS were also developing cognitive and/or behavioural abnormalities. Cognition refers to those higher processes that we possess which enable us to act according to our will, rather than according to instincts or reflexes. This includes functions like paying attention, remembering, stopping ourselves from saying or doing things that are inappropriate and understanding the emotions of others.

Despite some reports of non-movement symptoms of ALS in the mid-20^th century, some experts considered that such problems may be a reflection of the distress caused by the disease, rather than a result of additional problems in the brain caused by ALS. Additionally, because ALS can cause loss of speech and movement functions, cognitive or behavioural differences can easily go undetected due to inability to express oneself physically. However, testing systems have now been developed which allow psychiatrists, psychologists and neurologists to account for these factors when checking for cognitive or behavioural problems in those with ALS. Many research studies using such tests have now revealed that those with ALS develop psychological changes at much greater prevalence than those without ALS. In fact, approximately half of those with ALS experience some form of these non-movement symptoms. We also now know that some people with ALS experience problems with language, and a small proportion experience problems with sensation. This begs the question, why do some people with ALS have these non-movement issues, while others do not?

ALS is a motor neurone disease, but also a network disorder

The neurones of the brain and spinal cord generate our ability to act, think, learn, feel and perform all the other functions that our nervous system generates. They do this by communicating to each other with a combination of electrical and chemical signals, to generate specific patterns of brain activity. Therefore, the nervous system is really one very large, very complicated network of connected cells, within which there are specific routes, or circuits, which are responsible for generating specific functions. In order to maintain these circuits, the cells feed each other, nourishing their healthy and functioning connections. So, if for some reason a disease causes one type of neurone to become unhealthy and waste away, the cells that link to it will lose this nourishment and, to some degree, become less healthy too. As a result, the circuits required to perform specific brain functions can become disconnected and less capable of doing their jobs.

In the case of ALS, for example, when the motor neurones begin to deteriorate, other neurones which link to them, for example the ones which are involved in cognition or behaviour, will lose some of their connections. This is likely to cause them harm, such that they in turn become less able to perform their functions, resulting in some of the non-movement symptoms we see in ALS. Based on this theory of how ALS progresses, many have come to consider ALS as a disorder of neural networks, not just a motor neurone disease.

The evidence that ALS is a network disorder

My own PhD research, and research performed by much of Prof. Orla Hardiman’s team as well as other international researchers, has been dedicated to demonstrating if/where ALS affects the brain beyond the motor neurones, how it affects these areas of the brain and how this relates to the symptoms of ALS.

There are several ways to investigate the brain’s neural networks.

One is to look at the physical structure of the different connections in the brain, using methods like magnetic resonance imaging (MRI) scans. In Prof. Hardiman’s team at Trinity College Dublin, this research is led by Prof. Peter Bede. This research has extensively demonstrated structural deterioration in brain areas other than where the upper motor neurones are, and shown that the physical connections which make up many important brain networks are affected by ALS.

Another approach is to look at how the circuits in the brain are functioning, using methods like electroencephalography (EEG) or transcranial magnetic stimulation (TMS). In Prof. Hardiman’s team at Trinity College Dublin, this research is led by Prof. Bahman Nasseroleslami. This is the team that I undertook my PhD with, and within which I continue to work today as a postdoctoral fellow. Using EEG and TMS, we have found extensive evidence that areas of the brain involved in cognition and behaviour can malfunction in ALS, and the extent to which they malfunction relates to changes in cognition and behaviour that individuals with ALS experience. Importantly, we also have found evidence that those who experience more severe malfunction in the brain beyond the motor neurones experience more severe movement symptoms and faster disease progression.

What difference does it make if ALS is a network disorder or a motor neurone disease?

While our research, and other research internationally, is important for understanding ALS overall, we perform this research with the intention of making a difference to the lives of those affected as soon as possible. We hope this ‘network’ research will produce real-life benefits in the following ways:

Improving our ability to predict individual prognoses

Our limited knowledge on why each individual with ALS develops different symptoms which worsen at different rates prevents neurologists from being able to give very specific predictions about what each person will experience. This uncertainty is, of course, very distressing to those affected as well as their family and loved ones.

We know from epidemiological research that those who experience non-movement symptoms, such as cognitive and behavioural change, on average, experience more severe forms of ALS. This indicates that deterioration of the brain’s networks beyond the motor neurones is relevant to explaining why different people with ALS have very different, quite unpredictable, experiences of the disease. Our findings that changes in brain areas/connections not typically associated with movement relate to movement decline and disease progression rates support this. Further, they provide us with non-invasive- and economically-recordable measurements that can help us to predict each individual’s prognosis.

We are now researching if we can use an array of measurements which test specific brain circuits required for movement, sensation, cognition, behaviour and language in order to “see” what pattern of networks are affected in each individual with ALS and therefore predict how each diagnosed individual will experience ALS. If successful, individuals diagnosed with ALS, or even those predicted to get ALS in future, could undergo these tests in the hospital, enabling their doctor to inform them much more specifically about what they can expect to happen to them.

Improving ability to detect useful new drug therapies

Our currently limited ability to predict ALS symptoms is not only distressing for those affected, but it is also limiting the ability of drug companies to detect if potential therapies are working.

Consider a hypothetical clinical trial where 20 people with ALS are recruited. 10 people are given the drug and 10 people are given a placebo, something that looks like the drug but is known to have no effect. This “placebo-controlled” trial design is used so that the drug company can tell if the drug works without the results being caused by the process of receiving a drug (and not the drug itself), known as ‘the placebo effect’. Suppose the test of whether the drug works or not is if those who get the real drug show less decline in their motor function than those receiving the placebo.

Now consider that we can’t predict how those 20 people will be affected by ALS. Say 7 people progress very rapidly, while 13 progress very slowly, and those 7 rapid progressing individuals are all, by chance, assigned to the real drug group. The group given the drug will now be found to show more decline in their movement functions than the placebo group. Therefore, the drug will be found not to be therapeutic (even if it is therapeutic) and may no longer be investigated. However, this is not the case, this is purely due to the unpredictable variation in ALS symptoms not being accounted for.

Currently, drug companies try to avoid this happening by only recruiting people who meet very stringent medical criteria. They hope this will mean that all recruits will have a more similar ALS progression rate that won’t affect the drug trial findings. This, however, may not be successful. Additionally, it means that many ALS patients who want to take part in clinical trials are not allowed to.

If we are able to develop a set of measurements which allow us to more accurately predict how each person will be affected by ALS, these tests could be taken in each person who wants to take part in a drug trial. The volunteers could then be divided up in such a way that the real drug- and placebo drug-treated groups contain matching proportions of those with similar prognoses. As a result, many more ALS patients would be able to participate in clinical trials, and those clinical trials would be less prone to not detecting useful drug therapies.

Overall, understanding ALS as a network disorder has the potential to improve the quality of life of those affected by ALS, and improve our ability to find new ALS therapies. Our progress to date would not have been possible without the help of all those with ALS and their friends and family who have participated in our research. We are so grateful for your time and interest in this research and would be delighted to hear from anyone, with or without a diagnosis of ALS, that would like to take part in our studies to help us move forward in this research. If you’d like to hear more information about our results so far or taking part in future research, please email me at mcmackr@tcd.ie or contact me by call/text at 0894888697.

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About the Organisation

The Irish Motor Neurone Disease Association (IMNDA) supports people living with Motor Neurone Disease (MND), their families and carers by providing services and supports throughout Ireland including home visits by specialist MND nurses and the supply of specialised equipment on loan. The IMNDA also represents and advocates for people living with MND, their families and carers at a national level.

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