Developments in BioMOx

Medical Research Council (MRC)/ MND Association Lady Edith Wolfson Senior Clinical Research fellow, Dr Martin Turner writes about recent developments in his BioMox study.

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

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

My first ever blog. I decided to share developments in ‘BioMOx’ – the Oxford Study for Biomarkers in MND, which has been funded through the MND Association’s pioneering Lady Edith Wolfson Fellowship scheme (in conjunction with the Medical Research Council).

About BioMOx

Between 2009 and 2013, over 70 people living with MND (and some healthy people of similar age for comparison), took part in a new type of patient-based study. Men and women of all ages (from 28 to 86), some with primary lateral sclerosis (PLS) as well as a range of the more common amyotrophic lateral sclerosis (ALS) types, all gave up their time to attend for a day or two of tests in Oxford. Read the rest of this entry »

Taking part in BioMOx..

To end volunteer week, Katy Styles, who is a Campaigns contact for the East Kent Development Group of the MND Association, blogs about her and her husband Mark’s experience of volunteering to take part in the Biomarker’s in Oxford (BioMOx) study.

It started as an innocuous question following a neurology appointment at the Oxford MND Care Centre, Mark and I asked “Now what can we do for you?”

Following a phone call and some form filling, Mark and I had volunteered to take part in Dr Martin Turner’s BioMOx Project. Mark as a person with MND and me as a control of the same age.

We didn’t know what to expect as we were scheduled to take part in two days worth of tests, which included two scans and a written test. In between time in the scanners however, we were able to enjoy everything Oxford has on offer. Read the rest of this entry »

MND Association fellowships awarded to promising clinicians | 2013 | MND Association

Two MND clinicians have been awarded Medical Research Council (MRC) /MND Association Lady Edith Wolfson Clinical Research Fellowships to help advance our understanding of MND while moulding future experts.

The MND Association Lady Edith Wolfson Clinical Research Fellowship scheme plays a vital role in helping us strengthen and translate emerging knowledge from the lab to treatment strategies for people living with the motor neurone disease, while creating new innovative and exciting scientific leaders in the field.

These new fellowships, granted to Dr Martin Turner and Dr Jemeen Sreedharan will drive us forward to achieve the Association’s aim of unlocking the secrets of this cruel disease to identify promising new treatments.

Our Director of Research Development Dr Brian Dickie commented, “These new fellowships represent £2.6 million of investment not only in cutting-edge science, but also in the career development of two future leaders in MND research and treatment.”

Read more about this story on our website: MND Association fellowships awarded to promising clinicians | 2013 | MND Association.

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

Season’s Greetings!

We thought we’d share this fantastic festive photo of (to our knowledge) the world’s first ‘gingerbread MRI scanner’, lovingly created by students at the Oxford Centre for Functional MRI of the Brain (FMRIB) and kindly sent to us by Dr Martin Turner, lead investigator on the BioMOx study.

Gingerbread MRI Scanner

Gingerbread MRI Scanner

Many thanks to everyone who has so enthusiastically participated in BioMOx and our other clinical research studies, which are helping to improve both our understanding of MND and future approaches to treatment. This research simply couldn’t happen without you!

With very best wishes for the Christmas period.

The MND Association’s Research Development Team

More information on BioMOx:

Discussing MND in Dublin

Delegates to last weekend’s ENCALS (European Network for the Cure of ALS) meeting in Dublin were met with uncharacteristic hot and sunny weather – enjoyed by the numerous Stag and Hen parties wandering the city centre, but not by the 200 people ensconced in the impressive, new Biomedical Sciences Institute at Trinity College, from 8am to 7pm, for a packed programme of presentations and debate.

ENCALS was established to help develop the standards of clinical and biomedical MND research across Europe and create a more collaborative environment for researchers, industry, funding agencies and Patient Associations. However, the meeting had a very transatlantic flavour, thanks to the participation of several of the leading researchers from North America.

With around 40 speakers, as well as numerous poster presentations, there is too much to cover in a few hundred words, so I’ll focus on just a few of the key themes that were covered. I also apologise for the quite technical language, which may make for hard reading, but is a positive in that it reflects the increasing complexity and sophistication of MND research.

Can we block the ‘molecular funnel’?

The opening speaker, Prof Teepu Siddique, from Northwestern University in Chicago, spoke on The molecular funnel of neurodegeneration. His view of MND is that it may have a large number of different causes, but the way a motor neurone dies will probably be similar, no matter what the original cause. We’re currently finding lots of new genetic factors involved in the disease, but we don’t understand how many of these genes work in health, much less how they malfunction in disease. So, the mouth of our funnel is getting wider.

Prof Siddique’s view is that by focusing on the cellular changes that are common to all forms of the disease, it gives us possible therapeutic targets that could be relevant to all forms of MND. It’s easier to block the funnel at its narrowest point.

He discussed how the degradation of incorrectly formed or damaged proteins is a classic hallmark of all forms of MND. While the way in which the proteins are damaged may differ from one form of MND to the next, it’s the cell’s inability to correctly deal with these proteins that may be a good target. If we can normalise or improve this process, it may keep the motor neurones functioning for longer.

Prof Orla Hardiman, the meeting organiser from Dublin, discussed the need for much larger and more detailed study of large numbers of patients, to attempt to unpick the environmental influences that undoubtedly exist.

A question that many people often ask is whether MND is occuring more often in younger people that in the past. Intriguingly, Prof Hardiman’s ‘population-based’ research using the Irish MND Register suggests the opposite – the average age of symptom onset is getting older. She suggests that continued improvement in medicine and diet means that the population in general is healthier, so our ‘biological age’ is slowing. If age-related diseases such as MND are linked to ‘biological age’ rather than ‘actual age’, it would explain this surprising trend.

Good Genes/Bad Genes

While factors that cause or predispose towards MND are clearly the subject of intensive research, there is of course also interest in factors that might prevent or slow the disease. Some of these potentially ‘good’ genetic variants are being explored:

  • Prof Wim Robberecht’s group (University of Leuven) is examining the function of a gene called ephA4, which appears to correlate with longer survival in humans. This work is supported by studies in zebrafish and mouse models of MND.
  • Prof Kevin Talbot (University of Oxford) showed data that suggests that by increasing activity of a gene called smn1 might be beneficial to motor neurones. This is a strategy that is being followed for a predominately childhood motor neurone disease called Spinal Muscular Atrophy, so if these approaches work in this particular condition, they might be of benefit in other, adult onset motor neurone diseases.
  • Prof Robert Brown (University of Massachusetts) presented early data from a study of a variant in a gene called sarn1, which appears to protect motor neurones from damage….at least in fruit flies and mice. Work is ongoing to see whether it also has relevance in humans.

In contrast, Dr Andrea Calvo (University of Torino) provided information from Italian patients confirming studies in other populations that a variation in the unc13A gene can speed up disease progression.  However, the important issue about these disease-modifying genes – and it doesn’t matter whether they speed up or slow down MND – is that they all represent potential therapeutic targets.

Not just about the motor neurones!

We know that motor neurones do not die alone. Other parts of the brain and spine can be affected, but it’s the motor neurones that ‘bear the brunt’. 

Dr Sharon Abrahams (University of Edinburgh) provided an excellent overview of the range of cognitive and behavioural changes that can occur in the disease, indicating damage to other part of the brain, in particular the frontal lobe. Thankfully, the ‘real world’ effects of frontal lobe changes are usually subtle, but the fact that they can be picked up by psychological tests and MRI scans will help in defining specific ‘subtypes’ of MND which may require additional approaches to managing the disease.

Dr Martin Turner (University of Oxford) outlined evidence from a number of clinical research studies, including his own that nerve cells, called interneurones, might be involved early in the disease. These particular neurones usually play a role in calming down motor neurones, so if they are damaged or lost, the motor neurones themselves become over-excited and stressed, which leads ultimately to their degeneration.

Dr Turner’s evidence comes mainly from clinical imaging and electrophysiology studies in MND patients, but his theory was supported by a presentation from Dr Tennore Ramesh (University of Sheffield) who works with zebrafish models of MND. He showed results using zebrafish that carry a human SOD1 gene known to cause MND. The fish develop a form of MND in adulthood, but the very earliest signs of nerve damage actually occurs in specific types of interneurones that connect with the motor neurones, with the motor neurone damage occurring much later, closer to the onset of symptoms.

Presentations also covered the role of non-neuronal support cells, such as microglia and astrocytes, both of which have been the subject of extensive research in recent years, as they appear to play a role in the speed of progression of the disease. Prof Jeff Rothstein (Johns Hopkins University) introduced a new cellular player to the MND field, called the oligodendrocyte. These specialised cells have been known for many years to play a role in helping neurones to carry electrical signals, as well as helping them to maintain energy levels. Although they are known to be involved in multiple sclerosis, they hadn’t attracted much attention in MND.

Prof Rothstein showed that in human post mortem MND brain tissue, there is evidence that the brain has been making oligodenrocytes. This is certainly very clear in SOD1 mice, where  a massive production of new oligodendrocytes occurs. However the total number of these cells was not increased in the mice, suggesting that older oligodendrocytes were being killed and getting replaced.

He suggested that the new ‘immature’ oligodendrocytes are not nearly as efficient in their supporting role, especially when it comes to supporting motor neurones in maintaining their energy balance. This provides two possible treatment approaches – either try to keep the existing oligodendrocytes healthier or find a way of making sure that their replacements reach their full functional maturity.

I’ve no doubt we’ll be hearing a lot more about these cells in the future.

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.

Follow

Get every new post delivered to your Inbox.

Join 2,130 other followers