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”.

Read the rest of this entry »

Progress in the MND Oxford BioMOx project

MND Association funded researcher Dr Martin Turner at University of Oxford has identified a pattern of degeneration in the brains of people with MND that is linked to the level of disability.

This finding brings us closer to identifying a biomarker that can be used to speed up the diagnosis of MND, which can be delayed on average by a year since first symptoms.

This is the third finding to be announced since Dr Turner was awarded with the MRC/MND Association’s Lady Edith Wolfson Clinical Research Fellowship in 2008.

You can read more about this exciting finding on our website:

Progress in the Oxford BioMOx project | 2013 | MND Association.

Reference: Stagg CJ, Knight S, Talbot K, Jenkinson M, Maudsley AA, Turner MR, Whole-brain magnetic resonance spectroscopic imaging measures are related to disability in ALS. Neurology 2013; DOI 10.1212/WNL.0b013e318281ccec

Why we need biomarkers

Yesterday’s announcement by the biotechnology company Trophos SA of the lack of effectiveness of their compound olesoxime adds to the long list of drugs that have failed to live up to their early promise in the lab.

It’s a story that’s common across the world of neurodegenerative disease, including common conditions such as Parkinson’s disease and Alzheimer’s disease. The path from bench to bedside is fraught with pitfalls….

In their press release, Trophos suggested that trials have to be conducted when the ‘window of opportunity’ is greatest – the sooner a drug is administered the better its effect is likely to be. Otherwise, we don’t know whether these treatments genuinely do not work or is it simply a case of ‘too little, too late’?

Certainly, companies such as Biogen Idec have picked up on this, restricting the time limit for inclusion in their trial of dexpramipexole to two years from symptom onset, as opposed to the three year (and sometime longer) limit that has been used in previous trials. It means that Biogen Idec has to involve more local MND clinics to recruit the numbers needed, for the trial, which increases the cost, but they view this as necessary if they are to increase the chances of a positive result.

Similarly, the way MND manifests and progresses can be so different in one individual compared to the next, meaning that trials need to recruit large numbers of participants to reduce the statistical ‘noise’ – once again increasing the already high cost and complexity of the trial.

We will only make major inroads into earlier diagnosis and more accurate predictions of how the disease will progress if we can identify biomarkers – specific biochemical and/or structural changes that occur within the brain and spinal cord that provide us with a unique ‘fingerprint’ of MND. 

Biomarkers can also be tailored to look at the effects of specific drugs in trials. Even if it is unclear whether a drug is working on the ‘outside’ (on muscle function for example) it would at least be possible to confirm it was working on the ‘inside’ by reaching the right parts of the brain and spine and acting on the correct chemical processes.

In a nutshell, biomarkers would likely lead to smaller, faster and more accurate trials. That would mean trials could be performed more cheaply – and cheaper trials would almost certainly mean more trials.

This is why the MND Association sees biomarker research as so important. We are currently supporting three clinical biomarker projects (in London, Oxford and Sheffield) which are among the most comprehensive examples of this research in the world. Without the commitment and enthusiasm of those who participate, we wouldn’t be able to create these vital research resources which, as highlighted in previous postings, are beginning to generate promising early results.

But these projects are just the start. Their findings will need to be confirmed in much larger studies, involving the collaboration of MND clinics across many countries, collecting clinical data and samples to precise scientific protocols. This was the rationale behind a major biomarker funding initiative announced earlier this year under the European Union Joint Programme in Neurodegenerative Diseases (JPND). Established by 23 European countries, the JPND Research Call invited funding bids to assist the harmonisation of biomarker collections and the development of new methods of analysing the samples.

On Friday, JPND announced the four projects shortlisted on the basis of “scientific excellence” for a share of the €15 million (approx £12.6 million) research fund. One of these projects is SOPHIA (Sampling and biomarker OPtimisation and Harmonisation In ALS).

Co-ordinated by Prof Leonard van den Berg, the SOPHIA initiative will span up to 16 centres across 12 European countries, including the MND Association’s Sheffield and Oxford Care Centres. The precise level of funding has not yet been determined, but nonetheless this provides a fantastic platform on which major international biomarker research can be developed. We will of course keep you posted once the final outcome is known.

Promising news for keeping the motor neurone neighbourhood safe

There was standing room only in the first of the dedicated scientific sessions of the Symposium last week. All had gathered to hear Prof Stan Appel inform them of the latest chapter of this story on the role of inflammation in MND.

Listening to his presentation I got the gist of the overall positive message – a real step forward in MND research – but to report in any more detail of how and why was a step too far for my brain when I was in Sydney! Reading through my notes when I got back to the office, I was determined to get to the bottom of this science. It helped me to write a non-technical summary of it as I went. It’s perhaps a bit more technical than our normal blog posts – but I couldn’t resist the opportunity to (try and) share my new found knowledge. So here goes:

Inflammation is one response of the immune system. The immune system is a community of cells that exist within your body to protect it from damage and to maintain its status quo. Given its important function, it is perhaps reassuring to know that how it works is mind-blowingly complex!

In the brain and spinal cord, a slightly different defence system exists in comparison to the rest of the body. It is now common knowledge that motor neurones are surrounded by cells that support their function – known as glial cells. Within the community of these glial cells there are ‘police’ cells called microglia. Prof Appel’s lab has contributed many elegant studies to a consensus of research showing that in MND these police cells operate a delicate balance between protecting the environment around motor neurones and triggering a toxic atmosphere. Gradually the toxic atmosphere prevails.

In Sydney, Prof Appel discussed another component of this defence system, ‘regulator T-cells’. Continuing the police analogy, T-cells patrol the blood, rather than the brain and spinal cord tissue of microglia. As their name suggests, regulator T cells regulate the response rate of removing toxins and maintaining a healthy environment, in particular they regulate microglia by sending out specific chemical signals.

Prof Appel wanted to know how the interaction of T-cells with microglia is affected in MND. He found that a large ‘police presence’ (or high numbers) of regulator T-cells influence microglia to maintain their protection of motor neurones. In other words, large numbers of regulator T-cells kept motor neurone death at low level, showing itself as a slower phase of disease progression. As the levels of regulator T-cells get lower, the microglia turn toxic and the rate of progression of the disease speeds up. These conclusions were based on studies in mice models of MND and in patients at different stages of MND – by analysing blood samples for the presence of regulator T-cells and comparing this with what they knew of their symptoms.

This information presents two opportunities to MND researchers – firstly if therapies can be developed to maintain the levels of these regulator T-cells they may slow down the disease; and in the meantime, chemical markers in the blood, used in these studies, may be a valuable biomarker to measure the rate of progression.

Windows to the brain

With the huge advances in biology, it can seem that areas such as brain scanning are relatively stagnant, but we are starting to see a growing momentum in the field, allowing researchers to learn more about the ‘real time’ events occurring in individuals with MND.

Hand in hand with the improving technology that allows us to visualise the structures and connections inside people’s brains, as the scanners get more powerful, are the new ideas and techniques that researchers are applying. These help them to get the most from their studies by pooling their data and analysing it in different ways.

Giving the plenary presentation on this neuroimaging session, titled ‘The Past, Present and Future of Neuroimaging in MND’ was Dr Martin Turner, one of our Medical Research Council/ MND Association Lady Edith Wolfson Clinical Research Fellows, who heads the groundbreaking Biomarkers in Oxford project (BioMOx).

Dr Turner described the potential uses of the three main imaging technologies: PET (positron emission tomography) MRS (magnetic resonance spectroscopy) and, in particular, MRI (magnetic resonance imaging) which have developed considerably over the past decade, giving a ‘world tour’ of the results from the leading centres in MND neuroimaging. Indeed, he spent so much time highlighting the work of others that he only briefly mentioned his own very recent and exciting research from the BioMOx study, where he has used advanced imaging techniques to compare how the brains of people with MND are physically linked up (called structural connectivity) with how the brain actually works (called functional connectivity) as compared to unaffected ‘controls’. Having just read his latest findings on the flight over, I think they deserve a slightly fuller mention.

Second results published from BioMOx project
In the study, 25 people with ALS, the most common form of MND, took part in this part of the study, as well as 15 healthy individuals.

As the motor neurones in the brain degenerate, he saw an increase in functional connectivity and activity in other parts of the brain, associated indirectly with movement. This ‘boundary shift’ described by Dr Turner has an extended pattern of activity beyond standard motor systems.

Not surprisingly, the brain has a great capacity to compensate and adapt to damage (recovery from stroke being a prominent example). However, Dr Turner’s study also shared that people with slower progressing forms of MND had much lower levels of increased connectivity than those progressing rapidly, which was more than controls. This wasn’t simply due to people with a slow progression being at an earlier stage of the disease, as those with a slow progression at relatively advanced steps of MND were also included.

He speculates that the increased functional connectivity might actually be an active contributor to disease progression. One possibility is that in recruiting additional brain areas, together with some possible ‘rewiring’ occurring, it is altering with the complex balance of ’excitation and inhibition’ – in other words the way other neurons in the brain send positive or negative signals that control how active the motor neurons are.

This study demonstrates yet another step forward towards the development of robust clinical test for MND to speed up the diagnosis process. Although there is a lot of work to done to confirm these findings, we’re definitely heading in the right direction.

OK – back to the meeting!
Dr Turner highlighted one of the major challenges – namely the question of whether we can apply these techniques to clinical trials (as has been done in multiple sclerosis and which has revolutionised the search for treatments). However, several problems need to be overcome, not least the fact that patients taking part in a trial may be very different in their disease presentation and/or at different stages of the disease. So there is still a lot of noise in the system, which is why Phase III clinical trials often need to involve several hundred patients. Performing multiple MRI scans on each participant would add huge cost to any study.

Dr Turner also highlighted the challenge, but also a tremendous opportunity, to perform ‘comparative MRI’, linking the events going on in mouse models of the disease with those in man. Dr Robyn Wallace, from University of Queensland, elaborated on this theme with her presentation of imaging data from the SOD1 mouse. Using an intensely powerful scanner (10 times more powerful than a standard hospital scanner) she could show evidence of degeneration of the motor nerve tracts in the mouse spinal cord and was able to see these changes from around symptom onset. This is the first study to show that this form of MRI can show changes in the same mouse as the disease progresses. She also performed very detailed MRI studies on the intact spinal cord removed from mice – examination of the spinal column on its own improves the resolution and also allowed her to immediately perform the detailed histological examination of the tissue changes that had occurred. It is hoped that this very detailed work will help in the interpretation of human MRI scans in the future.

Finding out when MND begins
How early can we measure changes in man? Since 1997, Dr Mike Benatar from Emory University, has been performing studies on individuals who carry the SOD1 gene mistake (mutation) but have not yet shown any symptoms of MND, in an attempt to answer the question of when the neurodegenerative process begins, as opposed to when the first symptoms appear. Certainly, research from other fields, such as Huntington’s disease, Parkinson’s disease and Alzheimer’s disease, indicates that the process can start years before.

Dr Benatar reported his findings using both MRI and MRS. To date, he has not been able to show any major ‘structural’ differences (nerve cells that are physically connected in the brain) in his ‘pre-inherited ALS (the most common form of MND)’ individuals compared to healthy individuals of the same age, but he is seeing some metabolic changes using MRS, which can measure the relative signals of a small number of different chemicals in the spinal cord. He is continuing with the study, but extending the range of inherited forms of the disease to include inherited cases of ALS patients and ‘pre-inherited ALS’ volunteers carrying TDP-43, FUS, VCP and C9ORF72 genetic causes.

PS
For those of you who might ask how MRI scans work, here’s a very brief explanation:
Magnetic resonance imaging (MRI) is based on the concept that some molecules in the brain, in particular water molecules, will line up in a particular direction in a strong magnetic field. If a brief pulse of radio waves is then applied from a different direction, it causes the molecules to change direction briefly and then ‘wobble’ as they realign themselves back to the magnetic field.

The amount of wobble and the time taken for the molecules to return to a rest are like a fingerprint. Using computer analysis, MRI can pick up changes in brain structure, connectivity and even brain activity.

Read our official press release on day two of the symposium.

A quick peruse of the posters

Sometimes, presenters’ reactions to hearing that they’ve been given a poster presentation, rather than a talk is that of disappointment. I disagree. I feel it is a great opportunity to have a more in depth two way discussion than is ever possible during the 2-3 minutes allocated to questions after a talk.

There are over 200 posters being presented at this International Symposium. Before heading anywhere near the room where they’re on display I mark off a selection of posters to visit. Sometimes they are topics I know something about, or people that I know – for example MND Association grantees, or I sometimes choose topics that I don’t know anything about – the latter to find just what they are about. In one blog post (and the time available to write it) I can’t do justice to the topics that I did learn more about, but here is a bit of a taster:

Split hand wasting – this definitely fell into the latter category above! Two posters reported on how two quite closely connected muscles in your hand waste at different rates in people with MND. (The muscle groups are the thenar muscles and the abductor digiti minimum in case you want to look them up). Parvathi Menon’s poster established that it may be possible to use the ratio of the two different muscles as a way to diagnose MND and as a possible biomarker. Jocelyn Zwicker’s study investigated the electrophysiological nature of this observation.

Early conclusions from Neuralstem safety clinical trial included: Injections in the lumbar section of the spinal cord are well tolerated by people with MND are various disease stages. Participants experienced significant discomfort from the stomach / GI effects of the immunosuppressant drugs they received. Permission has been given by the FDA to advance the trial to cervical sections of the spinal cord, neuroprotection at this level may help with diaphragm function.

Does riluzole have an affect on Dexpramipexole?: Using the results from the previous, phase II, clinical trial for dexpramipexole, the authors described how the use of riluzole and dexpramipexole neither adds to, nor takes away from the effect of dexpramipexole on survival or progression. They conclude that it would be useful to confirm this in the phase III clinical trial currently underway across multiple sites across the world.

Read our official press release on day two of the symposium.

Mediating the delicate balance between protection and damage

The Opening Session theme on how the disease progresses within the Central Nervous System (CNS) continued with the presentation by Prof Stan Appel from Baylor College of Medicine, Huston on neuroinflammation.

Examination of post-mortem brain and spinal cords from people with MND shows clear evidence of inflammation (although Prof Appel was quick to point out that this is not the same as occurs in ‘primary’ inflammatory conditions such as multiple sclerosis). Similar patterns are seen in human MND spinal cord and in SOD1 mice, suggesting that at least for this aspect of the disease, SOD1 mice may be a good model of human MND.

He went on to explain how migroglia, the ‘innate’ immune cells of the CNS, help mediate a delicate balance between protection and damage. The speed of progression in MND appears to be dictated by this balance.

Prof Appel showed that SOD1 mice exhibit two phases of disease: an early slow phase, where the microglia release a series of protective factors, and a rapid secondary progressive phase where levels of these protective markers fall and are replaced by a rise in ‘pro-inflammatory’ toxic factors. Of course, strains of lab mice are so inbred that they are genetically very similar and develop the disease in a uniform manner. Humans on the other hand are very different, as is the way the disease progresses between one individual and the next, so the two stages of disease are not easy to demonstrate in MND patients. However, by examining the inflammatory factors present in patients with very rapid progression against those with slower progression, he was able to show that the factors associated with the second ‘rapid progression’ phase in mice were also present in the rapidly progressing patients. He suggested that this may assist clinicians in predicting how the disease is likely to progress in patients at an early stage in the disease.

It is relatively easy in cell culture studies to tilt this balance from protective to toxic, but could the balance be tilted the other way in patients, as a therapeutic strategy? Certainly, in response to a question from the floor, he suggested that greater attempts should be made in this direction, commenting, “The whole issue of immunosuppressant drugs in MND needs to be re-opened. But – you can’t just take down all immune responses in an uncontrolled way. You need drugs that are much more selective”.

Read our official day one symposium press release on our website.

Collaboration between cancer and MND researchers produces exciting results

It’s been a busy couple of weeks for exciting research results! Hot on the heels of the publication of Dr Turner’s imaging study, MND Association-funded researchers who pioneered a state-of the art technique adapted from cancer research have just published results describing some of the earliest events in MND-related degeneration.

Prof Giampietro Schiavo and colleagues at Cancer Research UK worked with Prof Linda Greensmith, an experienced MND researcher at University College London, to modify a process known as ‘multiphoton microscopy’, which had previously been used to visualize the migration of cancer cells. This allowed them to watch important ‘cargo’ being transported around motor neurones.

In their report published this week in the journal PNAS, the researchers have described how the transport of nerve-nourishing substances from the end of the neurone where it connects to the muscle back up towards the neurone’s ‘control centre’ in the spinal cord is slowed at the very earliest stages of MND. This suggests that transport systems could be a key target for drug development. Further details on the research are available on our website.

A key element of our strategy is to increase the capacity of the MND research workforce. Encouraging experts from other fields to collaborate with established MND researchers is one way of achieving this so we are really pleased to see the alliance between Profs Schiavo and Greensmith bear fruit. This is a great example of ‘thinking outside the box’ to progress MND research and the cross-fertilisation of knowledge and ideas between scientists working in different research areas.

Reference: Bilsland LG, Sahai E, Kelly G et al. Deficits in axonal transport precede ALS symptoms in vivo. Proc Natl Acad Sci U S A. 2010 Nov 8. [Epub ahead of print] doi:10.1073/pnas.1006869107

Top neuroimaging researchers meet in Oxford

Hot on the heels of Kelly’s posting on Tuesday on the new MRI findings by researchers at Oxford, the same group was yesterday hosting the 1st Neuroimaging Symposium in ALS/MND - a three-day conference, co sponsored by the MND Association, bringing together neurologists, physicists and psychologists from ten different countries across the world. I attended the opening day to see what was happening.

Such is the technical nature of neuroimaging, it kept my brain cells firing just trying to understand the jargon, with phrases like ‘Warped Space’, ‘Deformation Field’  ‘Jacobian Modulation’, ‘Voxels’, Biased Field Correction’ and so on. It was like hearing a script from Star Trek…

“The engines canna’ take it captain – that last hit from the Voxels damaged the deformation field. If I canna’ correct the biased field we’ll fall oot o’ warped space.”  

Whether or not I actually understood everything, it reinforced the importance of these ‘hothouse’ meetings, bringing together leading investigators from distinct disciplines to review the strengths and current limitations of their field of research, to look ahead at future developments in the field, to develop standards for collating and analysing data from many centres across the world and, most importantly, to find ways of collaborating more effectively.

I’m a great believer in not reinventing the wheel, so it was good to hear a presentation from the field of multiple sclerosis (MS) research. Neuroimaging has transformed MS research, being used to monitor the disease and provide an objective way of assess the impact of treatments, thus encouraging more drug companies to try to develop therapies.

The MS field has a long-standing imaging network and so part of the first day was devoted to looking at how we might learn from their experience and adapt their model for the needs of the MND research community. Of course, the MS network was kicked off by a large grant from the European Union, so an additional challenge for the MND research community will be to find the funding to allow these international collaborations to take place.

By 6pm my brain was full, so I headed back to Northampton, leaving the other delegates to another two days of serious ‘hard-core’ science…

First results from BioMOx study have been published!

We are pleased to announce that the first results from the Oxford Study for Biomarkers in MND/ALS (known as BioMOx) study have been published in the prestigious journal Neurology.

From this study, a common signature of nerve damage has been identified in the brains of people living with MND using an advanced MRI technique.

The findings demonstrate the importance of MRI in the development of a new biomarker for MND as well as being a significant stepping stone forwards toward two of our research goals – to identify disease markers, and to develop the research workforce.

MND Association’s Press Release
MND Association’s News in Research Article

Identifying disease markers
One of our research aims (set out in our research strategy 2010-2015) that we are working towards is that through our funding, we will have contributed to the identification of disease markers. By funding the BioMOx project (which is ongoing), we are already moving towards this aim.

Developing the research workforce
The BioMOx project is led by Dr Martin Turner from the University of Oxford who was awarded with the Medical Research Council (MRC)/ MND Association Lady Edith Wolfson Clinical Research Fellowship in 2008. This project is ongoing and means that we are not only funding cutting edge research, but we are also aiding Dr Martin Turner to develop his career as an MND clinician and a researcher.

As research is only as good as the researcher, it is important for us to continue to develop the UK basic research capacity by encouraging young clinicians into MND research. We currently fund four fellowships – our most recent of which was announced last month to Dr Pietro Fratta from the University of Sheffield.

Journal article reference: Filippini et al. Corpus callosum involvement is a consistent feature of amyotrophic lateral sclerosis Neurology November 2, 2010 75:1645-1652 

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