Neuroimaging – can we see more clearly?

Plenary speaker Dr Massimo Filippi put this question to delegates on the second day of the 24th International Symposium on ALS/MND.

Opening the session on neuroimaging, Dr Filippi gave an excellent review on what we currently know about this area of research, and ultimately answering whether or not we can see more clearly in MND?

Neuroimaging - now and then.

Neuroimaging – now and then.

It’s all in your head – Magnetic Resonance Imaging (MRI)

Over the past ten years there have been significant advances in the identification of neuroimaging patterns in MND. Dr Filippi focused mainly on the use of MRI neuroimaging (a technique used to visualise changes in the brain). He stated: “Through the use of MRI we have been able to detect cortical thickness of the Cerebral cortex (the outermost layer of the brain), which is significantly reduced in MND”.

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Unravelling TDP43 toxicity

Background to TDP43

A characteristic sign of motor neurones affected by motor neurone disease is the clumps of protein visible down a microscope. Although these proteins have been observed in motor neurones from people affected by MND since the earliest descriptions in the 1870s, a key discovery was made when the identity of a protein, common to all types of MND, was unveiled as ‘TDP43’ in 2008.

Two years later a second protein called FUS was also been found to be common to all types of MND. More information on this aspect of MND can be found in an article on our research blog.

One of the exciting things about these two discoveries was that they were both linked to a set of biological pathways, known as RNA processing. The was the first major clue that RNA processing was involved in MND. When the discovery of genetic defect in the C9orf72 gene came along in 2011, that made a third MND-causing gene defect that linked to RNA processing.

The first session of the 24th International Symposium on ALS/MND after lunch yesterday was dedicated to the topic of RNA processing and dysregulation. Several of the talks presented work on understanding the role of TDP43 in MND.

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Just the TONiC for quality of life in MND

Following on from the two talks on genetic testing; the first day of the 24th International Symposium on ALS/MND continued with a number of high quality research talks on topics such as screening for cognitive change and RNA processing.

Miss Hikari Ando (The Walton Centre NHS Foundation Trust) presented her research on Friday 6 December 2013. Following on from a previous talk on quality of life she pitched her talk as ‘What people living with MND thought of quality of life’ and explained that ‘quality of life is not just something of physical decline’.

TONiC

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Same disease.. two very different mice!

The exact course, duration and rate of progression of MND often varies greatly from person to person; even when there is a known family history of the disease caused by a specific MND-causing gene (eg SOD1).

This same variability also occurs in mice. Researchers, funded by the MND Association, took two mice with the same SOD1 gene mutation from two different families (strains). By using these two mice the researchers identified a number of key changes in motor neurones that differ between fast and slow progressing forms of the disease.

Two mice… One gene

The SOD1 mouse

The SOD1 mouse model has been one of the most important MND research tools for scientists

Developing new disease models enables us to both understand the causes of MND and test potential new therapies.

Mice are commonly used in MND research and for the past 10 years or more, the SOD1 mouse model has been one of the most important research tools for scientists working in the field, particularly with testing potential new therapies.

Research published in September 2013 was carried out in a joint collaboration between Dr Caterina Bendotti (Mario Negri Institute for Pharmacological Research, Milan Italy) and Prof Pam Shaw (University of Sheffield, UK).

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Summary Applications Explained

Our call for preliminary summary applications for project grants is in full swing with the Online Summary Application Form currently live on our website. The deadline for receipt of summaries is 1 November 2013. We thought this would be a good opportunity to explain what this means.

What is a summary application?Natasha
Preliminary summary applications are designed to give an outline of the proposed work, its relevance to ‘classical’ MND and that the aims of the proposal fit with our Research Strategy.

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Screening for Cognitive and Behavioural Change in MND

sharon abrahams and princess royalMND Association-funded researcher Dr Sharon Abrahams (University of Edinburgh) has recently published an article on the Edinburgh Cognitive ALS Screen (ECAS) in the prestigious journal Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration.

It is now recognised that, in up to 50% of people living with MND not only the motor system (walking, talking breathing etc) but also other areas of the brain, particularly those involved in thinking, language and behaviour are affected.

Frontotemporal Dementia

Cognitive and behavioural changes are increasingly common in MND. It is also well known that a small proportion of people living with MND display features of frontotemporal dementia.

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The UK MND DNA Bank opens its doors to researchers around the world

By 2011 the UK motor neurone disease (MND) DNA Bank had collected over 3,000 samples from people living with MND in the UK, their family members and healthy controls.

Several years since the first sample was taken, the MND Association can now proudly announce that the UK MND DNA Bank is ‘open for business’ to the worldwide MND research community.

The sun is leaving us, the nights are beginning to draw in and Christmas treats such as mince pies are beginning to fill the shops. MND researchers around the world, however, have been given an early Christmas present – the opening of the UK MND DNA Bank!

Freezer at BioBanking Solutions

Freezer at BioBanking Solutions

The story

At present, the cause of MND is thought to be a combination of subtle genetics, lifestyle and environmental factors. We know a small number of these genetic factors, but not all of them, thus the Association created the UK MND DNA Bank. Back in 2003, co-ordinated by the three MND care centres (King’s College London, Sheffield and Birmingham) a multicentre collaboration across the UK invited people living with MND to participate in a project, which hopes to answer the question: What causes MND?

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Attracting Promising Research – Project Grant Applications

Summer has gone and autumn has arrived, which means it is time to open our Online Summary Application Form for our next round of research grant applications.

This round is for project grant applications.  The deadline for summary applications is Friday 1 November 2013.

Reaching out for researchers

We currently fund ground breaking projects in a number of world class research institutes in Edinburgh, London, Oxford, Sheffield, Cardiff, Cambridge and Belgium among others.  This flexible approach allows us to fund the best and most promising research regardless of geographical location.

Good researchers are fundamental to good research and developing the MND research workforce, nationally and internationally, is a key element of our research strategy.chandran

Getting the best of the best

As with all of the research projects funded by the MND Association, our rigorous application process ensures we only fund projects of the highest quality and of direct relevance to MND.

The way that we fund research starts with a summary application, which is a concise outline of the proposed project. After the deadline date has passed a decision is made as to whether the summary is relevant to ‘classical’ MND and the project aims fit with our Research Strategy. If the summary does not fit, it’s rejected. If all criteria are met, the summary is reviewed by our Biomedical Research Advisory Panel (BRAP).

The reviewers’ comments and scores are then assessed using a two thirds majority rule. Each reviewer scores the summary application. A score under 50 is classed as unsuitable for funding, if it’s over 50 then the applicant is invited to submit a full application.

We are eagerly waiting for the next summary applications to be submitted and hope this year holds yet another exciting round of project grant applications!

More information:

For further information on our application processes please visit our website or see our Research Governance Overview.

New MND Association Lectureship in Translational Neuroscience

Dr Richard Mead based at the Sheffield Institute for Translational Neuroscience (SITraN) at the University of Sheffield has been awarded the Kenneth Snowman-MND Association Lectureship in Translational Neuroscience.

Dr Richard Mead, SITraN, UK

Dr Richard Mead, SITraN, UK

The five-year Kenneth Snowman-MND Association lectureship is aimed to embed preclinical expertise in motor neurone disease (MND) models within SITraN as a national resource.

Our Director of Research Development at the Association, Dr Brian Dickie, commented: “We are delighted to be able to help secure the position of an outstanding young scientist at one of the top European centres for MND research.

“Our understanding of the causes of MND and the reasons why motor neurons degenerate is increasing rapidly and we need more researchers like Dr Mead who are ideally placed to move this new understanding from the laboratory to the clinic.”

Read more about this story on our website: New MND Association Lectureship in Translational Neuroscience.

Jolly Good Fellows!

There’s a scene in the 1969 film Battle of Britain where Laurence Olivier, who plays the Air Chief Marshal, is in a meeting with his two Vice Marshals. One of them complains that they don’t have enough planes; the other is more concerned with keeping the airfields working. Olivier silences them both by telling them that the fight will be won or lost on one key factor – the number of trained pilots.

It’s a rather cheesy film, but I used that story earlier this month to illustrate the importance of investing in bringing through the next generation of researchers in our battle to defeat MND.  We organised a ‘get together’ of our Lady Edith Wolfson Clinical Fellows at the Sheffield Institute for Translational Neuroscience (SITraN) to share their research findings with the donor who has so generously supported the scheme. The ‘get together’ also provided a wonderful opportunity for them to exchange information and expertise with each other, as well as all the staff of SITraN, who over the course of the day were frequently shuttling between the lecture room and their labs.

The Fellowships are aimed at attracting and training the brightest and the best Clinician-Scientists (or ‘Doctor-Doctors’ as I sometimes call them – with both a medical degree and a science PhD). Even so, I couldn’t resist using this cartoon in my introduction, although the reality is very different for our Fellows – the bar is set very high and even applicants for the Junior Fellowships need to have considerable research experience and be fully ‘lab tested’.

image courtesy of www.vadlo.com

image courtesy of http://www.vadlo.com

Our host for the day was one of the world’s most respected MND ‘Doctor-Doctors’, SITraN Director Prof Pam Shaw, who welcomed everyone to the meeting and provided an overview of the multidisciplinary expertise and collaborative philosophy that underpins SITraN. Prof Shaw also has a great belief in the importance of nurturing the next generation of talent and it is no surprise that almost half of the Clinical Fellows in the programme are based at SITraN.

Are fit and active people more likely to develop MND?

Our first research presentation was from Dr Ceryl Harwood (Sheffield) who is carrying out research on the epidemiology of MND. Specifically, she is addressing the question of whether physical activity is a risk factor for MND. As she explained, this has been a long standing theory, showing us a quote from a medical journal written over 50 years ago which stated:

”Nothing has been said about the possible role in aetiology of a previous habit of athleticism. I have the uncomfortable feeling that a past history of unnecessary muscular movement carried out for no obvious reason may be followed in later life by the development of motor neurone disease in a statistically significant number of cases”

She outlined the plausibility that physical activity may contribute to a complex interplay between biological and genetic processes that may predispose an individual to develop the disease. Generating the evidence, however, is no easy matter, but she has developed and validated a novel questionnaire to measure physical history in adulthood, using data from a diabetes study in the 1990s where over 1,000 people had detailed measures taken of their actual energy expenditure.

A hundred of these participants have recently agreed to undergo rigorous face-to-face interviews and their responses were correlated with actual physical measures from over 15 years previously. In other words, she can now assess how accurately peoples’ recollection of their physical activity – both day to day work and vigorous exercise – links with their actual energy expenditure at the time. This questionnaire is now being used to compare the physical activity profiles in up to 350 people with MND and 700 control participants in Yorkshire and surrounding counties.

Should the results support the theory that physical activity is a predisposing factor in MND, she will be perfectly placed to delve into the genetic factors that underpin the selective vulnerability of motor neurons.

Repetition is bad….

Dr Pietro Fratta

Dr Pietro Fratta

Next up to the lectern was Dr Pietro Fratta, (University College London) who has been immersing himself in the mysteries of how the C9orf72 gene can cause neurodegeneration – especially MND and a related condition called Frontotemporal Dementia (FTD).

Like a needle on a vinyl record can sometimes stick and repeat the same fragment of music again and again, this gene sometimes carries a repeat in its genetic code – specifically with the letters GGGGCC occurring again and again.  Dr Fratta has examined many DNA samples from MND and FTD patients and finds that these ‘repeat expansions’ are very large indeed, occurring between 700 and 4000 times!

The process through which these repeat expansions cause nerves to die is still a mystery, but Dr Fratta showed results from his lab which suggests that rather than losing its normal function, the C9orf72 gene gains some additional activity, turning it into a ‘rogue’ gene. He and his colleagues have recently shown that the repeat expansions can lead to the formation of very stable chemical structures called G-quadruplexes that have been implicated in causing nerve damage in other disorders.

He is currently studying how these structures interact with other cellular components, interfering with normal neuronal function. He is also starting to look at possible therapeutic approaches in a collaboration with the UCL School of Pharmacy to develop compounds that will bind to and hopefully inactivate these structures.

Over lunch, we were given a guided tour of the superb SITraN labs by Prof Shaw. Although I strongly believe that research is only as good as the researchers doing the work, there’s no doubt that having a purpose built institute filled with state-of-the art technology certainly doesn’t do any harm!

Then it was back into the lecture room for our afternoon presenters.

A Sheffield double act

The post-lunch session was kicked off by Dr Robin Highley, a neuropathologist who has recently completed his Fellowship and now divides his time equally between pathology duties and MND research. Dr Highley’s area of expertise is in how neurons edit the genetic instructions into precise ‘blueprints’ to make proteins, the essential building blocks of every cell in our body.

He used an entertaining analogy of making dresses form a pattern to describe the process of how DNA is made into RNA copies which can be ‘tailored’ into slightly different protein designs (to find out more about how DNA makes RNA and subsequently proteins see our earlier blog post).

Dr Johnathan Cooper-Knock

Dr Johnathan Cooper-Knock, MRC/MND Association Lady Edith Wolfson Clinical Research Fellow

Using a variety of approaches he has looked at gene expression (which genes are being switched on and off) and gene splicing (how the RNA copies are edited) patterns in both inherited and non-inherited MND, as well as in non-MND states. He finds changes occurring in thousands of genes, but by performing searches on databases of the ‘function’ of each gene he can then sort them into different groups (which are then involved in key cellular processes). This provides important clues as to which cellular pathways are altered in MND, which will help researchers around the world to focus their attention on the most common changes and hopefully start addressing the question of how these may be slowed or stopped.

Dr Highley focused his talk mainly on the TDP-43 and SOD1 forms of inherited MND, with his colleague and fellow ‘Fellow’(!) Dr Johnathan Cooper-Knock, concentrating on the C9orf72 form (the most common cause of inherited MND). Through the MND Association’s DNA Bank  he has been able to obtain a large number of cell lines from patients with C9orf72 MND, along with detailed clinical information, which will allow him to compare patterns between those with fast progressing and those with more slowly progressing disease.

Although at a much earlier stage in his research, having started only 6 months ago, Dr Cooper-Knock has already identified some specific gene expression effects that may be distinct to the C9orf72 form of the disease. For more details about Dr Cooper-Knock’s work see our earlier blog post about his fellowship.

BioMOx and beyond

It was fitting that Dr Martin Turner (Oxford) gave the closing presentation. Not only was Dr Turner the first recipient of a Lady Edith Wolfson Fellowship, but he has recently been awarded a new five-year Senior Clinical Fellowship through the programme – these are highly prestigious awards, with only one in seven applicants successful.

Dr Martin Turner

Dr Martin Turner, MRC/MND Association Lady Edith Wolfson Clinical Research Fellow

Titling his talk ‘BioMOx and beyond’ Dr Turner outlined the challenge of identifying a specific signature of MND. He showed that whilst there is unlikely to be a single test for MND, a combination of tests (involving brain scanning and eye tracking techniques together with chemical analysis of blood, urine or cerebrospinal fluid) are showing some promise in aiding and speeding up the diagnosis, as well as predicting how the disease is likely to progress within an individual.

He highlighted the importance of international collaboration, such as the new formal link with Dr Mike Benatar in Miami, who for several years has been studying people at risk of developing inherited MND. Indeed, Dr Turner apologised for missing the morning speakers at Sheffield as he had been busy with one of Dr Benatar’s study participants in his MRI scanner at Oxford!

On the subject of international collaboration, our most recent Clinical Fellow, Dr Jemeen Sreedharan, was unfortunately unable to attend as the first two years of his Fellowship is based at the University of Massachusetts, returning to the University of Cambridge to complete his research. We look forward to having him at the next Fellows get-together!

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