Periodic Table of MND Research

Virtual Symposium (Vs)

Organised by the MND Association, the International Symposium on ALS/MND is the largest medical and scientific conference of its kind in the world. Usually held in conference venues globally, due to the COVID-19 pandemic this year’s event will take place on a virtual platform from 9 – 11 December.

Just eight months after being forced to cancel the Symposium in Montreal due to coronavirus, a dedicated team of technicians, staff and MND experts welcomed the world to the International Symposium on ALS/MND from a COVID-secure studio at the Association’s offices in Northampton. The move from a traditional Symposium to a fully virtual event had been a huge undertaking – with the programme being completely rewritten to suit an online platform. But once again the research community embraced the event, with more than 1,800 delegates registered for the three-day event from over 48 countries. The event was held over three days, running from around 1200 to 1800 GMT with live poster sessions each day (see programme for full details).

Lessons from COVID-19 (Cv)

The COVID-19 pandemic has generated unprecedented challenges across the world for those involved in ALS/MND research, clinical management and support. The closure of research laboratories has curtailed some of the momentum of the past decade that has propelled ALS/MND to the forefront of neurodegenerative disease research. The cessation of clinic visits, to protect patients and clinical staff alike, has greatly impeded the provision of the timely, co-ordinated multidisciplinary care that is so crucial in addressing the ever-changing needs of individuals as their disease progresses. Clinical trial recruitment, assessment and monitoring has been affected, jeopardizing the ability to interpret promising therapeutic outcomes. Above all, the pressures on those living with the disease and their families has been intense, with those most vulnerable to the effects to COVID-19 faced with the prospect of increased social isolation, compounding the challenges in accessing treatment. It is said that opportunity arises from adversity. Certainly, the rapid adjustment to this global upheaval has led to new approaches or acceleration of emerging initiatives in science, medicine and healthcare. We have witnessed an unparalleled global collaboration in COVID-19 research, accompanied the rapid, open source dissemination of new findings and the incorporation of innovative telemedicine and telemonitoring practices into clinical management and trials, together with the unprecedented fast-tracking of COVID-19 therapeutic studies.

Awards (Aw)

Each year several awards are presented at the Symposium, and this year was no exception:

Winner of the 2020 International Alliance of ALS/MND Associations Forbes Norris Award: Professor Ammar Al-Chalabi. The purpose of the Forbes Norris Award is to encourage a combination of two major qualities: management of and advances in understanding ALS/MND, to the benefit of people living with the disease. When presenting the award, Calaneet Balas, President and CEO of the ALS Association said that Professor Al-Chalabi ‘not only meets the criteria for the award, but exceeds it’ and his ‘contribution to the areas of research, literature and patient care is unparalleled, both nationally and globally’. We also extend our warmest congratulations to Ammar on receiving this award. Find out more on the Alliance website.

Winner of the 2020 International Alliance of ALS/MND Associations Humanitarian Award: Carol Birks, CEO of MND Australia. The Humanitarian Award is intended to recognise and encourage individuals and/or groups whose work makes, or has made, a contribution of international significance for people affected by ALS/MND. Calaneet Balas praised Carol for the huge contribution she has made to the global ALS/MND community. We would also like to extend our congratulations. Find out more on the Alliance website.

Satellite meetings (Sm)

Whilst the main Symposium runs over three days, Wednesday to Friday, there are also several satellite meetings in the days before. The International Alliance of ALS/MND Associations organises meetings to serve the broader ALS/MND community. These include the Annual Alliance Meeting for representatives of ALS/MND associations from around the world; the Allied Professionals Forum (APF) for healthcare professionals who specialise in ALS/MND and the ALS/MND Connect session designed specifically for people living with and affected by MND.

As a result of the continuing global uncertainty caused by the COVID-19 pandemic, the International Alliance, in consultation with the MND Association, ALS Canada and ALS Quebec, has taken the very difficult decision to move this year’s International Alliance Meetings and the Allied Professionals Forum to a virtual format where we will still have the opportunity for global collaboration and be able to work towards a world without ALS/MND.

For full details of this year’s satellite meetings, please go to our Symposium website.

SympWatch (Sw)

For the first time, you can watch a selection of full presentations from the 30th Symposium in Perth, Australia, 2019. To help guide you through the talks, SympWatch videos include useful ‘pop ups’ explaining some of the scientific language used by the researchers.

Here you can find a list of each SympWatch video, linked to the respective tile on the Periodic Table:

Project MinE (Pm)

More than 200,000 people worldwide are living with MND but little is known about the cause of this progressively degenerative neurological disease. There is still no treatment and the average life expectancy of people living with MND is three years.

It is almost certain that the disease has a genetic basis. Project MinE is a large-scale research initiative devoted to discovering the genetic cause of MND. The ultimate goal is to identify genes that are associated with the disease. The function of these genes may lead to disease pathways for which treatment can be developed. In order to reach this ambitious objective, Project MinE plans to map the full DNA profiles of at least 15,000 people with MND and compare them to DNA profiles of 7,500 control subjects to uncover associations between specific variations in genes and MND. Many new genes have already been identified including C21orf72, NEK1, KIF5A and GLT8D1.

The MND Association has been one of the largest contributors to Project MinE in terms of samples and funding, having supported the sequencing of around 2,200 samples from our award-winning UK MND Collections resource (we won the 2019 Biobank of the Year Award), and we would like to thank the people living with MND and their families who contributed their blood samples to the UK MND Collections.

We were absolutely delighted that this year’s Healey Centre International Prize for Innovation in ALS was awarded to Project MinE for developing the largest single disease whole genome sequencing project in the world. The award was virtually presented to the team during the Closing Session of the Symposium by Dr Merit Cudkowicz, Director of the Healey Center at Mass General Hospital and Regan Asnes Healey from the Healey Family.

We extend our warmest congratulations to everyone involved in the project.

People with MND (Pw)

People living with MND, their carers and families are at the heart of everything we do, and our reason for organising the Symposium every year. Whilst the event is aimed primarily at scientists and healthcare professionals, this year’s virtual platform presents an opportunity for the general public to attend without having to leave their own homes. Registration is £45 and allows full access to the programme, platform presentations, ePoster Hall with live poster presentations, the Sponsor/Exhibitor hall and much more. Visit our registration page to register by 23.59 on Thursday 3 December.

The ALS MND Patient Fellows Symposium Program helps people with ALS/MND to participate in the Symposium, and this year has paid the registration fee for 12 people with MND to attend the virtual event.

Poster presentations (Po)

Researchers who would like to present at the Symposium must submit an abstract – an overview of their research and findings. This year, a Programme Committee decided who would be given the opportunity to present their work with a poster and we have almost 400 poster presentations that can be accessed in the ePoster Hall on the virtual platform.

Giving researchers the opportunity to talk about their work with the wider MND research community with a poster means that more exciting and innovative work can be shared. This year, posters will be supported with a ‘Lightning Explainer’ video, and live poster sessions will allow opportunity for question and answer sessions with presenters.

You can read all poster abstracts online. Where we have mentioned a specific poster in a tile on the periodic table, we have included the code for that poster, for example RNM-03. This tells you that the abstract for that poster can be found in the Respiratory and Nutrition Management section and it is abstract number three. Click on the number to be redirected to the relevant abstract book.

Plenary speakers (Pl)

Every year we invite a number of plenary speakers who are experts in their respective fields, and this year is no exception. Twenty-five world experts in MND research and clinical care will provide an overview of a variety of topics across the ALS/MND research and clinical management spectrum. You can read abstracts of these platform presentations online. All platform presentations have a code beginning with ‘C’ followed by a number (e.g. C10). This will help you locate the specific abstract mentioned throughout the periodic table topics.

This year’s plenary speakers are:

Dr Rudolph E Tanzi, Mass General Hospital and Harvard Medical School, USA: The Stephen Hawking Memorial Lecture – Targeting neuroinflammation across neurodegenerative diseases (C1)

Prof Adriano Aguzzi, Institute of Neuropathology, University of Zurich, Switzerland: Prions, prionoids and neurodegeneration (C2)

Associate Prof Daryl A Bosco, University of Massachusetts Medical School, USA: Protein dysregulation in ALS (C3)

Prof Serena Carra, University of Modena and Reggio Emilia, Italy: Protein quality control of biomolecular condensates: Implications for amyotrphic lateral sclerosis and frontotemporal dementia (C4)

Dr Merit Cudkowicz, Sean M Healey & AMG Center for ALS at Mass General Hospital, USA: The REFALS phase 3 study of levosimendan in patients with ALS (C5)

Dr Ralph Kern, President and Chief Medical Officer, BrainStorm Cell Therapeutics: NurOwn ALS Phase 3 clinical trial update (co-presenter) (C6)

Dr Sabrina Paganoni, Healey Center for ALS at Massachusetts General Hospital and Harvard Medical School, USA: Functional and long-term survival benefit of AMX0035 in ALS: Results of the CENTAUR and Open Label Extension trials (C7)

Prof Orla Hardiman, Trinity College Dublin, Ireland: The power of ALS patient registries in the age of personalised medicine (C8)

Prof Carolyn Young, The Walton Centre NHS Foundation Trust, Liverpool, UK: Improving patient reported outcome measures in ALS/MND (C9)

Dr Fernando Vieira, ALS Therapy Development Institute, USA: Assessment of ALS disease progression from accelerometer and voice recordings using machine learning with application to the evaluation of real-world drug efficacy (C10)

Dr Hemali Phatnani, New York Genome Center (NYGC), USA: Spatiotemporal dynamics of molecular pathology in ALS (C11)

Prof Ekaterina Rogaeva, University of Toronto, Ontario, Canada: DNA methylation studies in ALS and age acceleration (C12)

Dr Christine Vande Velde, Université de Montréal and Université de Montréal Hopsital Research Center (CRCHUM): Defective RNA metabolism in ALS: TDP-43 loss of function and stress granule dynamics (C13)

Prof Adriano Chiò, Department of Neuroscience, University of Turin, Italy: ASOs for neuromuscular diseases: Yesterday, today and tomorrow (C14)

Prof Aaron D Gitler, Stanford University, USA: Modulating disease modifying genes in ALS (C15)

Dr Agessandro Abrahoo (co-presenter), University of Toronto and Dr Lorne Zinman (co-presenter), University of Toronto and Sunnybrook Research Institute, Canada: MR-guided focused ultrasound: A new frontier in the delivery of biotherapeutics for ALS (co-presenter) (C16)

Dr Angela Genge, Montreal Neurological Institute and Hospital, Quebec, Canada; Dr Rachel Burman, King’s MND Care and Research Centre, London, UK; Dr Caterina Bendotti, Mario Negri Institute for Pharmacological Research (IRFMN) and Bruce A J Virgo – Bruce is living with MND: Lessons from COVID-19 (C17)

Dr Michael J Strong, Western University, Canada: Are we there yet? Measuring nonmotor progression in amyotrophic lateral sclerosis (C18)

Dr William W Seeley, University of California, San Francisco, USA: Selective vulnerability in frontotemporal dementia and amyotrophic lateral sclerosis (C19)

Prof Jeremy D Schmahmann, Harvard Medical School and Massachusetts General Hospital, USA: The role of the cerebellum in cognition: Implications for ALS (C20)

Aled Edwards, CEO, Structural Genomics Consortium (SGC), Toronto, Canada: Open drug discovery: From genes to affordable medicines (C21)

Prof Matthew Kiernan, University of Sydney, Australia: ALS Diagnostic Criteria: The Gold Standard (C22)

Healthcare professionals (Hp)

As well as researchers, many healthcare professionals attend the Symposium to help expand their existing knowledge of MND. All fields are represented at the Symposium from respiratory experts to physiotherapists. It is a chance for them to hear innovative talks and view exciting posters from experts in their field from nutritional support to quality of life and learn about new techniques and ways to improve their practice.

Helping to educate healthcare professionals is a priority for the MND Association as this will help those affected by MND have a better multi-disciplinary care plan, as well as improving their quality of life. As part of this education the Association runs conferences, study days and online learning for professionals on a range of topics. Find out more about these events for healthcare professionals.

Programme committee (Pc)

This year’s Symposium Programme Committee are:

– Kevin Talbot (Chair of Programme Committee), Professor of Motor Neuron Biology, University of Oxford
– Ammar Al-Chalabi (Incoming Chair of Programme Committee), Professor of Neurology and Complex Disease Genetics), King’s College London
– Brian Dickie, Director of Research Development, Motor Neurone Disease Association
– Nick Cole, Head of Research, Motor Neurone Disease Association
– Heather Durham, Professor, Montreal Neurological Institute, McGill University
– Angela Genge, Director of the Clinical Research Unit, Montreal Neurological Institute, McGill University
– Nick Goldup, Director of Care, Motor Neurone Disease Association
– Sanjay Kalra, Professor of Neurology, Neuroscience and Mental Health Institute, University of Alberta
– Janice Robertson, Professor and Canada Research Chair in ALS, Tanz Centre for Research in Neurodegenerative Diseases
– David Taylor, Vice President, Research, ALS Canada

Neuromuscular junction (Nj)

The neuromuscular junction (NMJ) is a chemical synapse formed by the contact between a motor neuron and a muscle fibre. It is at the NMJ that a motor neuron can transmit a signal to the muscle fibre, causing muscle contraction. Muscles require innervation (literally meaning ‘to put nerves into’, so when nerves go into muscle fibre, they innervate that muscle) to function and even to just maintain muscle tone to avoid the muscle from wasting away. In the NMJ nerves from the central nervous system and peripheral nervous system are linked and work together with muscles. Motor neurons release a neurotransmitter called acetylcholine which crosses the synapse at the NMJ and binds to receptors on the muscle fibre which results in a muscle contraction.

Studies have revealed the important involvement of muscles and NMJs in the initial stages of MND. But where does motor neuron degeneration begin? Both ‘dying-forward’ (where the motor neurons degenerate by glutamate excitotoxicity) or ‘dying-back’ (in which motor neuron degeneration starts at the NMJ and progresses toward the cell body) processes have been suggested and it is possible that both processes occur independently of each other. Regardless, it is acknowledged that degeneration to the NMJ, leading to skeletal muscle wasting, is a key point in MND clinical symptom onset and disease progression.

Mitochondria (Mt)

Mitochondria are organelles – specialised units within a cell that have a specific function – and are essential for a variety of cellular processes. These include providing energy for the cell (bioenergetics), calcium homeostasis – which regulates the concentration of calcium ions in the fluid outside the cell, lipid biosynthesis – the production of lipids (fats) which are the main form of stored energy in most organisms, and apoptosis – normal and controlled cell death.

Mitochondrial dysfunction is a common feature of many neurodegenerative diseases including MND. Disruption of mitochondrial structure, bioenergetics and stabilisation of calcium ions has been widely reported in people with MND and models of the disease and has been suggested to be directly involved in the development of the disease.

Modelling MND (Mo)

In order to understand what goes wrong in MND, researchers need to study ‘something’ that, to all intents and purposes, mimics the biology of the disease. Ideally that ‘something’ has to be readily available, tangible, accessible, and available with a large enough number of samples so that any findings can be reproduced and confirmed.

There is currently no way to visualise all the complex interactions that happen in MND. For example, observing all the biology of motor neurons in living people is impossible, and so researchers use models of the disease. Animal models are, at present, the best way to study the complexities of MND. However, researchers are developing new models that effectively copy aspects of the disease. Induced pluripotent stem cells (IPSCs) have emerged as a model for neurodegenerative diseases because they retain the genetic background of patients and can be reprogrammed into any cell type, including many cells found within the central nervous system (CNS).

There are generally three types of models that are used to research MND:

In vitro (meaning ‘in the glass’) models use isolated cells in a lab dish, with the most widely used being induced pluripotent stem cells (iPSCs). These are skin cells taken from people with MND that are transformed into stem cells – cells with the potential to turn into different types of cells, including motor neurons.

In vivo (meaning ‘within the living’) models include testing in living organisms, with the most widely used animals being zebrafish, fruit flies, worms or mice.

In silico (meaning ‘in silicon’ as in silicon microchips) modelling, while not as common, is used to perform a computer simulation.

Coming soon ()

Nutrition (Nu)

Eating and drinking form an emotive part of our lives, bringing us comfort and pleasure. Being nourished is not just about calories – for most of us, the enjoyment of food and flavour is incredibly important to quality of life. Knowing how to maintain this when living with MND can make a huge difference.

With MND, the way a person eats and drinks may need to be adapted to help them get the nutrition and fluids their body needs. They may experience difficulties with chewing and swallowing, problems with hand and arm control, reduced mobility (making food preparation difficult) and fatigue, which can make the effort of eating and drinking tiring in itself.

Weight loss in MND is associated with faster disease progression and shorter survival and has several possible causes. These include loss of appetite, difficult in swallowing and hypermetabolism, which is an increase in the rate at which energy is burned – even though mobility may be limited, a person ‘burns off’ more calories than they consume.

Some people with MND choose to have a gastrostomy – a surgical opening through the abdomen into the stomach. This allows tube feeding – a way of passing specially prepared food and fluids straight into the stomach.

Respiration (Re)

MND can affect the way a person breathes by weakening the muscles that control breathing. Although this cannot be reversed, there are treatments that can help reduce symptoms such as disturbed sleep, fatigue and anxiety, and enable the person to breathe more effectively.

When breathing becomes weaker a machine may be used to support breathing. This is known as assisted ventilation. There are two types of assisted ventilation: non-invasive ventilation (NIV), where a machine supports breathing by boosting the intake of normal air through a mask, and tracheostomy ventilation, where a tube is inserted into the windpipe through the front of the neck, which enables a ventilator to support breathing.

The use of ventilation may not be suitable for everyone. If appropriate, it may help to relieve breathing problems but will not stop the progress of the disease.

Psychological support (Ps)

Being diagnosed with an illness like MND can be overwhelming for both the person with MND and those close to them. The challenges ahead are likely to cause emotions that are difficult to manage. Personal circumstances, culture and beliefs will affect response, and each experience is individual, but natural responses to a difficult diagnosis are to be expected.

Many symptoms and practical problems can be eased with the right support. This can reduce worry and help manage challenging emotions when they arise. Talking therapies, cognitive behaviour therapy, mindfulness techniques, and complementary therapies can all help.

Caregivers need support too to help them face the challenges ahead. Finding ways to work together as a team, being aware of each other’s mood, having open conversations and sharing feelings can help.

No-one understands the challenges of caring for someone with MND better than their caregiver, but as the care demands increase, physical and emotional stress can impact heavily on carers. Even if family and friends help, external care support is worth exploring. This may include respite care – giving the carer time to care for themselves.

Physical activity (Ph)

The stories about MND and physical activity that make it into the media feature prominent sports people who have been very active for a number of years. While this is good for raising awareness of the disease, it also raises concerns for people living with MND.

Most concerns fall into two categories: did the amount of physical activity I undertook before my diagnosis cause my MND and can I continue with physical activity after my diagnosis, or will this make my MND worse?

Physical activity ranges from gentle exercise, like walking, to more vigorous daily activity like working out at a gym, to the levels achieved by professional sportspeople and elite athletes.

Exercise is widely recommended to the general population due to its benefits to health and wellbeing. It improves the cardiovascular, respiratory, musculoskeletal, and endocrine functions and leads to psychological wellbeing. Many people with MND specifically ask whether they can safely continue to exercise regularly without fear of accelerating their disease. At present, there is no firm evidence that exercise exerts a harmful effect, although avoidance of very strenuous activity would seem to be sensible. Low-grade, managed exercise programmes may even be of benefit.

For many people with MND, exercise played an integral role in their pre-diagnosis lives. A wish to continue exercising, in the hope it will have positive effects on endurance and strength, is understandable. While pre-diagnosis exercise is likely to have involved aerobic training and strengthening programmes, research has shown that moderate exercise can slow functional decline whereas high intensity training can be detrimental.

Caregiver support (Cs)

When someone is diagnosed with MND, the changes affect not only the person with the disease but also those close to them. Becoming a carer for someone with MND can be very challenging and, over time, the level of care needed will increase – sometimes rapidly.

Supporting someone with MND can often feel emotionally overwhelming but there can be many positive emotions, such as satisfaction when a task or challenge is successfully completed, especially if this has involved both the carer and the person with MND. It is important that the carer takes time to look after their own needs, even if this feels impossible when facing the challenges of supporting someone with MND.

Palliative care (Pa)

This section talks openly about death and end of life decisions.

The aim of hospice and palliative care is to give the best possible quality of life with a life-shortening illness. For maximum benefit to people with MND, this type of care is recommended from the point of diagnosis onward.

Palliative care refers to specialised care services that focus on quality of life and symptom control when an individual has an illness that can’t be cured. This includes practical help, medication to ease symptoms and support for the individual and their family. Palliative care isn’t just for end of life. It may be given earlier in a person’s illness in conjunction with other therapies treating the condition.

Palliative care is of utmost importance in MND and focusing on managing symptoms and improving quality of life of people living with the disease is a priority of healthcare professionals. Because of the nature of the disease, it is important for those affected by MND to know about the symptoms they should expect as the disease progresses, and how best to manage them. Research is always ongoing to find out how best to manage symptoms and when to utilise life-sustaining measures.

Thinking about end of life is rarely an easy task. Some of the decisions that need to be made are very difficult and everyone’s experience will be different. People may have troubling thoughts such as ‘what will happen?’, ‘will it hurt?’ and ‘will I lose control?’. It is normal to expect heightened emotions when facing end of life decisions, but it has been reported that people feel relieved and much calmer having made their plans and knowing what is likely and less likely to happen. Every individual’s needs and preferences will be personal to them but can be influenced by those around them, leaving them feeling angry, guilty, sad and even relieved. These are all normal and expected reactions to challenging circumstances. With support from health and social care professionals, and family and friends, difficult feelings usually become more manageable over time.

Cognitive change (Cc)

Up to half of people with MND experience changes to how they think and behave, and these affect people in different ways. For some they will have little effect on daily life, while others will need significant day-to-day support. In a small number of cases, people with MND develop frontotemporal dementia (FTD).

People with MND may experience changes to their thinking and learning, language and communication and behaviour and emotions. It may become more difficult for them to make and carry out plans, process information and solve problems. They may find it harder to recognise words when reading or writing, have difficulty spelling or find it hard to follow conversations. They might also begin to lack enthusiasm, find it difficult to manage emotions and behave inappropriately in social situations.

If a person is affected by FTD they will experience symptoms similar to those already described but with greater severity. With FTD, memory is not usually affected although it may appear that it is due to difficulties with concentration and taking in new information.

Augmentative & alternative comms (Ac)

Augmentative and alternative communication (AAC) tools are vital for people living with MND. As their disease progresses, they may experience slurred speech or even completely lose the ability to speak (dystharia). To ensure that people with MND can continue to have a voice in making decisions regarding their care, technology can facilitate communication when speech is impaired. AACs can be as simple as using hand gestures, facial expression and writing, but can also include using high tech devices to communicate.

Genetics (Ge)

Around 5-10% of people with MND have a family history of the disease known as inherited MND. This is caused by a mistake in the genetic code that holds the instructions for making every protein in our bodies. This mistake may be passed down from parent to child.

There are a growing number of genes which have been associated with MND. The most common of these are SOD1, TARDBP, FUS and C9ORF72. Other extremely rare causative genes have also been identified. These discoveries represent major breakthroughs because they can provide important clues as to how motor neurons are damaged in MND and may advance our understanding of all types of the disease.

Lifestyle & environment (Le)

The causes of MND are still not fully understood. Around 90% of people with MND have a sporadic form of the disease – when the disease appears for no apparent reason and with no known familial link. Sporadic MND is thought to be caused by a combination of genetic, environmental and lifestyle influences.

Exposure to these factors has been extensively studied. This is known as epidemiology (see Epidemiology tile). Epidemiological studies have identified possible links with prior exposure to mechanical and/or electrical trauma, military service, high levels of physical activity, agricultural chemicals and a variety of heavy metals. However, these are all only suspected contributory risk factors and the evidence from studies is often circumstantial or conflicting and offers no clear conclusions.

Understanding the causes and mechanisms of motor neuron degeneration is essential to the development of new treatments. Only by understanding what goes wrong in MND can scientists identify potential drug targets and other therapies.

Inflammation (In)

Although MND is not a disease of the immune system, there is evidence from studies of patients that the levels of some types of immune cells in the blood can play a role in the speed at which the disease progresses.

Neuroinflammation is commonly seen in neurodegenerative diseases, including MND, and animal studies have shown active roles of glial (support) and immune cells in the development of MND.

Neuroinflammation is an inflammatory process thought to originate primarily from central nervous system (CNS) cell types such as microglia and astrocytes. Both cells have pro-and anti-inflammatory functions meaning that they can offer protection against cell injury or can become destructive.

For example, astrocytes are key homeostatic cells (they have the ability to maintain internal stability) that play numerous supportive roles in maintaining the brain environment. In MND, astrocytes change their shape and molecular expression patterns, and are referred to as reactive or activated astrocytes. Reactive astrocytes in MND lose their beneficial functions and gain detrimental roles. In addition, interactions between motor neurons and astrocytes are impaired in MND.

Epidemiology (Ep)

Epidemiology is the study of the frequency, pattern, causes and risk factors of health-related states and events (not just diseases) in specified populations such as neighbourhoods, countries or globally. Epidemiological information is used to plan and evaluate strategies to prevent illness and as a guide to the management of patients in whom disease has already developed.

The causes of MND are still not fully understood. Between 80-90% of people with MND have a sporadic form of the disease – when the disease appears for no apparent reason and with no known familial link. Sporadic MND is thought to be caused by a combination of genetic, environmental and lifestyle influences. Although exposure to these risk factors, which include electric shock, military service, high levels of physical activity, agricultural chemicals and heavy metals, have been extensively studied the evidence gathered offers no clear conclusions. Epidemiological studies may help us to understand the causes and mechanisms of motor neuron degeneration and, in so doing, identify potential drug targets and other therapies.

Motor neurone disorders (Md)

It has long been debated whether ALS/MND is one disease, or whether we should look at it as a collection of multiple conditions with similar symptoms and disease mechanisms. We are observing a large amount of variation in terms of speed of disease progression, length of survival, type of onset (bulbar or limb), absence/presence of frontotemporal dementia and its degree, as well as cause of the disease (e.g. involvement of specific genes).

This is especially important when investigating the effectiveness of a new drug in clinical trials, which might not work in the same way across all MND subgroups. A good example of this is the drug lithium, which was found not to be effective in treating MND, until the data re-analysis found that there was an improvement in people with a specific genetic variation (UNC13A). As a result of this, the MAGNET platform trial, part of the TRICALS research initiative of which the MND Association is a key member, is due to start recruiting people with the UNC13A variation to test lithium carbonate as a treatment for MND in this sub-group of people.

Diagnosis and Diagnostic Tools (Dd)

MND is difficult to diagnose early as it can mimic other neurological diseases, and early symptoms such as muscular weakness, slurred speech or a change in ability to perform everyday tasks such as buttoning clothes may be attributed to ‘getting older’. Over time, however, an individual or a family member may realise that worsening symptoms may be something more than a sign of ageing.

If something more than ageing is suspected, an appointment with a GP should be made. However, the rarity of MND means that many GPs will see only one or two cases in their entire careers so the disease may not be something they immediately think of. If they suspect a neurological cause of symptoms, they will make a referral to a neurologist who will carry out appropriate tests.

No one test can provide a definitive diagnosis of MND. MND is primarily diagnosed on detailed history of symptoms observed during a physical examination along with a series of tests to rule out other mimicking diseases. If other family members have been diagnosed with MND, or are suspected to have had undiagnosed MND, a full family history will also be taken as this may be an indication that there is a problem with one of the genes associated with the disease (this may already be known). Early symptoms of MND can be similar to those seen in other, more treatable conditions and appropriate tests can exclude the possibility of other conditions. These may include muscle and imaging tests, such as electromyography (EMG) and magnetic resonance imaging (MRI), and laboratory tests on blood and urine to look for biomarkers of disease such as increased levels of creatine kinase which can be present when muscles start to break down.

Because most people with MND die within around two and a half years from symptom onset, it is vital that speedier and reliable diagnostic tools are developed as quickly as possible so that treatment and symptom management can be started at the earliest possible opportunity.

Progression & prognosis (Pr)

A prognosis is defined as a likely course of a medical condition. ALS/MND is a progressive and fatal neurodegenerative disease, with an average life expectancy of two to three years. However, individual prognosis can be highly variable – from weeks to decades. Several prognostic factors are known, such as site of onset (bulbar or limb), age at symptom onset, delay from onset to diagnosis, and the use of riluzole and non-invasive ventilation (NIV).

While we wait for an established tissue biomarker (a signature of a biological change), measures of clinical progression are currently the standard for monitoring disease progression. The most widely used measure is the revised ALS Functional Rating Scale (ALSFRS-R), which is a 12-item clinical chart assessing patient’s functional abilities. Each item asks about specific abilities (such as speech, swallowing, dressing, or walking) and is rated on a 5-point scale from ‘0’ severe disability) to ‘4’ (normal functioning). A cumulative score gives a physician a considered view on the person’s disease status (where 48 marks means normal functioning).

Other measures focus on more specific symptoms of the disease, including motor neurone loss, reduced breathing ability, or assessment of behaviour and thinking abilities.

Because the way in which MND develops and progresses differs so widely between people living with the disease, the development and validation of ways in which to predict progression is a recognised research priority.

Biomarkers (Bi)

There is currently no diagnostic test for MND. Because of its relatively rare nature and non-specific symptoms, it is currently diagnosed by exclusion, whereby clinicians must rule out a whole range of other neurological and muscular conditions before giving a diagnosis of MND.

Finding a simple and pain-free test that would make this process easier and faster, would likely increase the effectiveness of existing and emerging treatments. These tests require searching for what is called a ‘biomarker’ – a signature of a biological change occurring in a specific disease (or a group of diseases). Some biomarkers have been identified for MND and are being tested to develop them into clinical tests.

Another reason to look for biomarkers is to keep track of the progression of the disease. Researchers are now testing various measures to see how biomarkers might change as the disease progresses, and whether these differ in people with rapid progression from those with a slower progression rate. However, due to the current lack of biomarkers, other measures of functional ability are used in clinics instead. While these are informative and provide us with a good estimate of disease progression, they are not as accurate as biological markers.

It is also recognised that the development and integration of objective markers of disease activity in MND is a key aim in advancing new drug development, as they can be used to track progression during clinical trials.

Telehealth (Te)

Telehealth, or telemedicine, involves the use of technology to allow healthcare professionals to monitor an individual’s health and deliver care remotely. For example, it could assist in the diagnosis and management of a condition. The ultimate goals of using this technology are to increase access to care for people, decrease the frequency of clinical visits and reduce clinical costs.

For people with reduced mobility, telehealth means no long commutes to short, but critical, assessments and no waiting around. From previous studies, people taking part in remote assessments expressed higher satisfaction with the overall care they were given and appreciated remaining in the comfort of their own homes. People living long distances away from services or with increasing disease related disability are most likely to utilise telehealth.

The risk of severe COVID-19 infection is higher for people with serious underlying medical conditions such as MND and, during the ongoing pandemic, clinics have worked exceptionally hard to find ways to deliver effective virtual appointments and monitoring. Because of positive feedback from clinic users, many are looking at ways to continue with this even after the COVID-19 crisis passes.

Pre-clinical testing (Pt)

Before a drug can be tested in clinical trials (in humans), it must first be examined in a lab to provide an insight into its mechanism (how it is likely to work in the body), safety, and preliminary effectiveness. These studies can be done in cells in a lab dish (in vitro), in animals (in vivo) or using computer modelling (in silico).

While there is only a limited number of clinical trials, there are many compounds currently being investigated that could have the potential to be developed into ALS/MND treatments.

In general, only an extremely small proportion of compounds tested in pre-clinical studies get to the final drug approval stage, reflecting the rigorous and strict process assuring that only safe and effective drugs are tested in clinical trials and approved.

Trial design (Td)

As we learn more and more about MND, and move ever closer to precision medicine, a revolution in clinical trial design has begun. Clinical trials are an essential part of drug development and, fuelled by a desire to compare multiple treatments in different sub-groups of patients with related conditions, and to minimise the time between clinical trials, innovatively designed platform trials have begun throughout the UK and the rest of the world.

Traditional clinical trials tend to follow the same format – participants are randomly split into either a group that will receive a single trial drug or a placebo group which will receive a ‘dummy’ drug and, if we’re lucky, we end up with a ‘one-drug-fits-most’ treatment option.

One of the major hurdles for people with MND who want to take part in a clinical trial is meeting the inclusion criteria. Traditionally, clinical trials will only recruit participants who, for example, are within a few months of symptom onset/diagnosis, However, follow-up studies in some clinical trials have found that the trial drug worked better at later stages of the disease, meaning that people who were further progressed may have benefitted from being included in the trial from the beginning. Researchers are now looking at ways to split broader groups of participants into sub-groups so that more people can be included in trials.

Platform trials can find beneficial treatments with fewer patients in less time and with greater probability of success than a traditional clinical trial. In an era of personalised medicine, platform trials provide the innovation needed to efficiently evaluate modern treatments and speed up the process of finding a cure for MND.

The MND Association is a leading participant in TRICALS (Treatment and Research Initiative to Cure ALS), the largest European MND research enterprise to date. TRICALS brings together the very best experts from top research centres across 14 countries in a unique collaboration to find effective treatments for MND. TRICALS is sponsoring the MAGNET (Multi-arm, Adaptive, Group-sequential trial NETwork) adaptive platform trial, which will enable the investigation of multiple treatments at the same time.

Clinical trials (Ct)

Clinical trials are research studies in human volunteers that determine whether potential treatments are safe and effective. Traditionally, clinical trials have strict guidelines about who can take part. Clinical trials are usually conducted in four progressive phases which check for safety and efficacy, establish the correct dosage and method of delivery, and assess the drug’s ability to treat the condition it is designed for.

Clinical trials take many years to complete and are often extremely costly. At any stage the drug can be deemed too dangerous, or inefficient, to take into the next phase. To speed up the process, clinical trials are beginning to incorporate a biomarker element (a biological characteristic) into their design. Monitoring levels of specific biomarkers during a trial will help establish if the drug or intervention being tested is influencing disease progression. Researchers are also looking to ‘repurpose’ drugs that are already licensed to treat other diseases/conditions, as potential treatments for MND.

Several clinical trials of potential new treatments have been completed and some are still in progress. So far only one drug, riluzole, has been proven to have enough of an impact on the disease to warrant its licensing for general use in the UK.

Gene therapy (Gt)

There are a growing number of genes which have been associated with MND. The most common of these are SOD1, TARDBP (TDP-43), FUS and C9ORF72. Other extremely rare genes have also been identified to be causative. There are currently no treatments to prevent the effects of the gene damage that is being passed from one generation to another. However, research is underway to find such treatments. An emerging innovative approach has been gene therapy.

Gene therapy is designed to introduce genetic material into cells to alter how faulty/missing genes work in order to correct genetic disorders. It is expected at the very least to alleviate the symptoms and slow the progression of MND. Gene therapy may even prevent the disease when a faulty gene is diagnosed if treated at an early enough stage.

Approved treatments (At)

At present, the only drug licensed for the treatment of MND in the UK is riluzole. When first approved, it was thought that riluzole increased life expectancy by around three months. New evidence suggests that riluzole may actually increase life expectancy by as much as 19 months in some people.

Another drug, edaravone, has been approved to treat MND in Japan, South Korea, the USA, Canada, Switzerland, China and Indonesia, based on a six-month placebo-controlled study in Japanese ALS patients. Edaravone is thought to increase survival by 2-4 months. In May 2018, Mitsubishi Pharma (the developers of edaravone) applied to the European Medicines Agency (EMA) for approval of edaravone to treat MND in the EU. However, in May 2019 they withdrew their application.

Although these drugs have been in use for several years, continuous real-world evaluation is carried out to establish long term effectiveness and side effects.

Other drugs are available to manage the symptoms of MND. However, these have no impact on survival.

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