MSA Coalition Board Member Pam Bower travelled to London back in February to attend an important MSA research meeting. She shares her notes below:
Notes from the 2nd UK MSA Research Symposium
Queens Square, London UK – Feb 27, 2014
By Pam Bower
Over a dozen MSA researchers spoke throughout the day in this jam packed event.
A few highlights –
It is still a mystery of how the misfolded protein alpha-synuclein gets into the brain cells in MSA. Alpha-synuclein which is a protein, misfolds in MSA and aggregates in clumps inside a type of glial cells which are the helper cells to neurons – the oligodendrocytes. Alpha-synuclein itself originates in neurons. Understanding how it migrates to the helper cells will help unlock the mystery of how the disease originates. Doing major work on understanding the origin (pathogenesis) of the disease is the team in Innsbruck, Austria led by Prof Gregor Wenning.
Prof Wenning summarized all the available animal models of MSA (there are now 4 models) and how work with them is helping to unravel the mystery of the origin of the disease. Each type of mouse model displays particular symptoms and/or brain pathology that mimics human MSA but there is no one perfect model to mimic all aspects of MSA. Prof Wenning discussed the 9 or 10 steps that we now know about that lead to the death of glial cells and neurons in MSA. Much more experimental work is needed to clear this up further. Only by uncovering the underlying cause can we hope to find an effective treatment in future. One exciting recent finding is that when MSA mice are innoculated with alpha-synuclein brain homogenates, the actual disease seems to spread in a prion-like fashion. This is a very important clue to be worked out.
Prof Wenning also went over some recent clinical trial results. Although the drugs Minocycline, Rasagiline and Rifampicin all showed negative results in arresting the disease in humans, they did show some interesting results in mice, this all helps in understanding how the disease progresses. Minocycline in particular was interesting in that it was shown to suppress microglial activation in mouse models of MSA… this means that inflammation is involved in MSA and the drug was shown to improve this. Rasagiline also showed neuronal rescue in mice but at high dose, the dose used in the human trial was very low due to concerns of the drug company about safety. Could a higher dose have been tolerated in humans or a low dose have helped if used much sooner in the disease progression?
Things to watch… MPO inhibitors such as Minocycline, Anti-aggregation compound ANLE 138b now in Phase 1 for Parkinson’s Disease, Alpha-synuclein immunization (drug company: Affiris)
Still in question… whether Mesenchymal stem cell transplants actually work for MSA.. waiting for results of the Mayo clinic stem cell trial currently in progress.
Another exciting line of research happening in the Innsbruck lab is work with grafts in mouse models that help the cells make better use of dopamine. In MSA there is still dopamine produced but the cells lose ability to use it effectively.
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Dr Nadia Magdalinou spoke about Cerebrospinal fluid studies in MSA. The oligomeric version of alpha-synuclein may be the cause of the disease. Measuring total alpha syn in the CSF may be the most promising biomarker to detect the disease much earlier. A combination of imaging and biomarkers is used now to better to diagnose Alzheimer’s Disease so a similar combination may be required to diagnose MSA.
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Prof Henry Houlden reviewed what we know about the genetics of MSA. Candidate genes have been reviewed such as the tau gene, the ApoE gene for Alzheimers and the C9orf72 gene for a common form of ALS. None of these have been found in MSA patients. Genome Wide Association Studies are a powerful tool to identify genetic risk factors for sporadic diseases. These have been done now for many other diseases. Prof John Hardy also discussed this in his talk and mentioned that there is a critical number of cases that must be studied before any useful genetic data can be found. He thinks 2000 cases is the minimum number that will lead to any concrete findings. In Alzheimer’s it took 2000 cases to find 3 genes, 6000 cases to find 6 genes and 30,000 cases to find 25 genes. These 25 genes map to 3 pathways – the ameloid peptide process, cholesterol metabolism, and innate immunity. Parkinson’s disease is similar – 16,000 cases were studied to find 25 genes. These genes control mitophagy and autophagy – internal metabolism of the cell. For MSA only 1000 cases have been studied and there is “no secure finding”. Prof Hardy actually doubts the Japanese gene finding in CoQ2. Prof Houlden also mentioned that the UK team could not replicate the Japanese finding using European MSA patient dna. What they did find though was coQ10 levels in the brains of MSA cases were lower than in controls.
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Prof David Burn spoke about MSA registries, databases and clinical networks. The MSA Trust is providing funding to ensure that the UK clinical centers can form a network to work together more closely. This will be a platform for trials and biomarkers and allow for longitudinal studies. Databases will allow capture of critical information on dna, rna, serum protein and csf measurements. There will also be quality of life questionnaires and active requests for brain tissue donation. Patients will be actively recruited with all stages of the disease and a special focus will be placed on early stage disease. They would like to collaborate with US groups as well. (NOTE: This would be a very good reason to host a US MSA Research symposium in 2015!) Prof Burn spoke of 2014-15 being a time of change for MSA with exciting collaborative opportunities for MSA research.
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Prof Huw Morris spoke about Improving Management of MSA. Currently many people lack a definite diagnosis in the early stages, they may eventually be told PD and given a PD drug to try. It would be better to tell people atypical parkinsonism as a working diagnosis. should provide as much info as needed with early follow up. Give info on the MSA trust and the trust nurses. Provide information on creating an advanced care plan and deciding on whther a peg, trach or ventilator will be part of this plan. Key notes on improvement to management of MSA: 1. people should all have their lying and standing bp measured 2. They should have an MRI 3. they should be given a definitive interim diagnosis.. if there is uncertainty of which type of parkinson plus disorder they have they should at least be told “atypical parkinsonism” and not be left without any sort of diagnosis 4. The diagnostic criteria of MSA of possible or probable should be explained 6. There should be documented assessments from OT, PT, ST etc 7. should be offered the chance to participate in research trials 8. should be offered info on palliative care 9. they should have a written care plan. In the UK 7 centers will join up for longitudinal study and standards of care should come out of this.
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Prof John Hardy discussed MSA Resarch – The way ahead. Where are we and where do we need to go? “For all things collaboration will be essential” For genetics, for stem cell work, for understanding the spread of pathology and for clinical trials. Stem cells offer some prospect of treatment. They can now turn skin cells into neurons or glia in the dish. Can now model the disease much more effectively in the dish. Cells from MSA patients should be made more freely available. The Coriel cell depository is open access. MSA-P and MSA-C skin cells must be deposited there and shared. “MSA will be dragged along in Alzheimer and Parkinsons research”. All are protein deposition disorders. All involve mutations is deposited protein, many have sporadic variants, these diseases all show spread or “Braak hypothesis”. There is evidence of cell to cell transmission, the diseases show different strains ie MSA-P, MSA-C. In mouse models antibody treatment is effective. The disease jumps from neuron to neuron or from neuron to glia. Antibody treatment might work for AD or PD, if so MSA will be tested very quickly thereafter. Five years ago we did not know what we know now – we know more about the spread of the disease, the underlying biochemistry and the genetics. We are now seeing strong parallels with AD and PD and this offers real hope we will eventually move to treatments. How can we be sure MSA does get dragged along? PD is MSA’s big brother, MSA needs good relations with PD organizations. MSA might actually be a better system to use to test PD. MSA needs separate identity and separate charity but needs crossover with PD organizations and PD patients who may actually turn out to have MSA.
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Dr Helen Ling also brought up the long duration variant of MSA in her talk. Dr Tony Lang from Toronto had called to inform them of a patient under his care who had been confirmed on autopsy to have MSA, he had lived 18 years with symptoms. the UK brain bank was checked looking for similar cases and a few were discovered. These were all MSA-P patients who were misdiagnosed as PD in the first 10 years. They had a modest response to levadopa. A concern with these patients is that they may be offered Deep Brain Stimulation which can help PD but has a very poor prognosis in MSA patients and can lead to other complications.