Project 1:
Detailed assessment of the role of somatic genomic copy number variants (CNVs) in multiple system atrophy
Lead Applicant: Prof Christos Proukakis, UCL Queen Square Institute of Neurology
The Wrong Number
In an inherited form of Parkinson’s disease there is a genetic mutation in which there are more copies than usual of the gene that produces the protein alpha-synuclein. The result is that more of this protein is produced in brain cells and gets laid down as damaging inclusions in the cells.
MSA, on the other hand, is largely not inherited. So why am I even mentioning this? Well, a comparatively recent discovery by Prof Chris Proukakis is that such mutations can arise not from inheritance from one’s parents but later on during the body’s development or through ageing. He and his team have discovered that sets of mutated cells with duplications of the alpha-synuclein gene (known as SNCA) are often found in those areas of the brain which atrophy in MSA. How and why these so-called ‘somatic’ mutations are caused are mysteries that remain to be revealed further down the line. MSA is not the only neurological disease where this phenomenon appears to exist.
Right now there is a need to confirm the close association of Copy Number Variations (CNVs) – as these mutations involving extra copies of the genes are called – with the presence of inclusions in the same cells. They also need to prove that the CNVs actually cause the excess alpha-synuclein through the normal transcription processes in the cell and therefore are drivers of the disease.
Along the way some important anomalies need to be cleared up such as why sometimes inclusions occur without CNVs and why sometimes CNVs don’t give rise to inclusions. There could be other MSA-promoting conditions and other somatic mutations that cause the same thing. And it could also be that an element of the experimental technique used to reveal protein inclusions could be partly failing and need changing. Such factors need to be explored to get the accurate picture.
All this is an illustration of how complex biology is, particularly at the cellular level. At the risk of delving into philosophy, this is an example of why researchers must be painstaking and take care not to jump to quick conclusions following what appears to be a significant insight. Without thoroughly investigating and understanding what and how something is going wrong, it is not possible to come up with a tailored remedy that stands a chance of working. Good research is not cheap but we are fortunate in the field of neurology to have an abundance of excellent and dedicated researchers.
Project 2:
ClearSpeechTogether versus standard NHS speech intervention: A single, mixed method, rater-blinded pilot randomised controlled trial for people living with MSA-C
Lead Applicant: Anja Lowit, Strathclyde University, Glasgow.
Speech and communication
The word ‘Research’ might make you think of labs, white coats and test tubes and as such rather alien to your everyday life and the struggles that MSA brings. But the MSA Trust has decided to focus a good proportion of its funding effort on clinical research – research whose relevance to you, the MSA patient or carer, is more immediately obvious.
A notable example from this year’s grant awards is a research project to do with speech. As you probably know only too well, MSA often adversely affects speech. Volume drops, articulation suffers and you find your intelligibility declines. As communication is such a vital aspect of everyday life, this can be hard to take.
What can be done? Speech and Language Therapists (SLTs) are key. For those people with speech problems who are referred to the NHS, a standard Speech and Language Therapy course is likely initially to provide you with six weekly one hour one-to-one sessions with a therapist in which speech and communication difficulties are systematically addressed. The patient is taken through a number of different exercises and strategies aimed at having an enduring effect. This can be very beneficial but, of course, is quite expensive in terms of the use of the therapist’s time. It also begs the question of what further therapy might be needed for a progressive condition like MSA once the initial course is over.
What if a good proportion of the therapy was conducted in a group setting? The team running this project has already explored a programme, called ClearSpeech Together, with people who have other sorts of ataxia in which initial individual sessions with an SLT are followed up with frequent sessions in groups where the members follow a programme of exercises together. The SLT is still actively engaged but their time is used interacting with more people at once. Other important advantages are that patients are involved in mutual delivery of the therapy and are drawn into active participation with the others in the group thereby reinforcing the communication skills and strategies that easily get lost with conditions like ataxia and MSA. They feel better supported socially and psychologically than with individual SLT sessions. The work so far has shown that not only is this approach effective and a good use of therapists’ time but is also accepted well by the patients. The groups have often continued after the formally prescribed courses have finished, becoming valued social as well as therapeutically-targetted gatherings.
This particular project to be funded is aimed at testing out the feasibility and effectiveness of this approach amongst people with MSA-C over two years. If it has a positive outcome, a larger project will be designed with a view to making it standard within the NHS.
Project 3:
Is Multiple System Atrophy a distinct strain of alpha-synucleinopathy?
Lead Applicant: Professor Steve Gentleman, Department of Brain Sciences, Imperial College London, Burlington Danes Building,
Hammersmith Hospital Campus London
Antibodies take the strain
MSA, Parkinson’s and Dementia with Lewy Bodies are called synucleinopathies because all involve the mis-folding and laying down of inclusions in brain cells of a protein called alpha-synuclein. It seems that molecules of this protein, which usually go around in the cells singly, mis-fold and then begin to join together first in small numbers (when the groups of molecules are called oligomers) and then in greater numbers to form fibrils. It is a bit like ‘spoons inside a drawer’. Moreover it seems that once this process begins, unfolded molecules are induced to join in by the initial oligomers. Prion diseases progress this way.
Now in Parkinson’s these aggregates of misfolded alpha-synuclein are laid down in nerve cells (neurons) in particular parts of the brain whereas in MSA they are laid down in a different type of brain cell called glial cells in different parts of the brain and are called Glial Cytoplasmic Inclusions (GCIs). Why the difference? Evidence over the last few years has suggested that alpha-synuclein can misfold in more than one way. This means that there can be various so-called ‘strains’ of this misfolded and aggregated protein. And as you have guessed, a particular strain is believed to have properties that incline it to affect neurons and another has properties that incline it to affect glial cells in other parts of the brain. Glial cells are the sort of cell that supports and nourishes neurons and when they are affected and stop working, neurons also die and the various symptoms of MSA develop.
This project is centred on perfecting the ability to detect the different strains of alpha-synuclein using specially generated anti-bodies. We usually know antibodies as proteins used by the immune system to identify and neutralise foreign objects such as pathogenic bacteria and viruses. But they can be created to recognise and stick like labels to other entities such as our misfolded protein. In this case there has been success in producing antibodies that can bind to particular strains with a good deal of specificity. This project will continue this work and use various novel techniques to detect and make visible in post-mortem brain tissue when this occurs. These new techniques, it is hoped, will enable the researchers to explore and verify the pathological processes involved in MSA at the cellular level especially regarding the role of the different strains of the aberrant protein.
They will then go on to find out whether they can detect the binding of the antibodies to the MSA-specific strain of alpha-synucelin in cerebrospinal fluid (CSF). If so, this would provide a way of confirming, while they were still alive, and ideally at an early stage, that a person had MSA and not, say, Parkinson’s.
Furthermore, once there is a way of firmly diagnosing MSA and tracking its progress, the effect of potential new treatments could be more precisely measured.
In addition the great hope is that specific antibodies could be used to attach to and remove deposited alpha-synuclein – on the assumption that this is a root cause of the disease.
Project 4:
An MSA Clinical Pathways Platform and Patient Registry – Monitoring disease, quality of care and developing evidence-based care algorithms, starting with a Dysphagia Clinical Care Pathway.
Lead Applicant: Dr Viorica Chelban, Queen Square Institute of Neurology University College London
Hard to Swallow
Impaired swallowing (known as dysphagia) is a troubling and distressing feature of MSA which develops during the disease. This is clear if you look at the MSA section of the HealthUnlocked online Forum. (https://healthunlocked.com/msa-trust/posts) On average dysphagia is moderately serious after 5 years or so. Aspiration pneumonia – food and liquids going into the lungs instead of the stomach – can occur as the problem get worse. I know; my wife died of it. And that is why in serious cases patients may undergo a procedure known as a PEG – Percutaneous Endoscopic Gastrostomy. A tube is fitted which passes through the abdomen straight into the stomach through which food and liquids can be passed. Without it patients can become malnourished and dehydrated. Gastrostomies may be called for in a number of other neurological and non-neurological conditions including Parkinson’s and Motor Neurone Disease. But in MSA a body of evidence for when and how PEGs should be employed and what the outcomes are likely to be in terms of effective disease management and quality of life has not yet been built up. This project intends to address that.
The meat of the project is to create a national registry of MSA patients focussing on swallowing difficulties. The data for each patient will look back at when difficulties appeared, how they progressed and what treatment was given – including whether a gastrostomy was recommended and, if carried out, how effective, acceptable and beneficial it was. More data will be added as patients are monitored and their condition progresses. As we know, the symptoms and progress of MSA manifest themselves in such a variety of ways in separate individuals that the only way to get a meaningful overall picture is to collect and compare a lot of real data. This is what this register will enable and has not been done comprehensively before. But more than that, patients, carers and clinical specialists will all be actively involved in contributing their detailed experiences and insights into swallowing impairments and their treatments. Online questionnaires and surveys and other methods such as working groups, conferences and consultations will be used to structure the register, acquire the case data, analyse the information and draw out conclusions that are important for clinical practice and for the best management of dysphagia in MSA.
Of course, that will not be the end of the story. The ultimate aim is actually to formulate a Clinical Care Pathway for the management of swallowing problems in MSA. The detailed patterns that are discerned from the richness of the registry data will provide an evidence base for what treatments are most effective in different varieties of cases – including in what circumstances certain treatments should be avoided. The Care Pathway as elaborated would then be an invaluable and specific tool, universally promoted, for improving and optimising clinical practice in this area.