Progress in a rare disease: Highlights from the 6th International Congress on Multiple System Atrophy

Elizabeth Jameson in a patient with a rare brain disease (MS) that turns her MRIs in to art.

New York City, 2018

The 6th International MSA Congress (, held recently in New York City, marked a paradigm shift in the treatment of neurodegenerative brain diseases.

Multiple System Atrophy is a rare disease affecting potentially 50,000 Americans. Symptoms appear in the mid 50s and progress rapidly. MSA is the most fatal of a group of diseases known collectively as synucleinopathies.

At the core of the disease process is the protein alpha-synuclein, which is also implemented in Parkinson disease and dementia with Lewy bodies. Like all proteins in the body, alpha-synuclein continuously folds and unfolds, forming a final shape with a biological function. For reasons that are not entirely clear, it can misfold, adopting a pathological confirmation that spreads from cell-to-cell – in a domino effect.

In MSA, these pathological strains of alpha-synuclein cluster together in oligodendroglia cells, which provide vital support for multiple neurons throughout the central nervous system. The loss of one oligodendroglia cell impacts multiple neurons, which is why MSA progresses so rapidly.

Oligodendroglia provide support for nerves by insulating the axons with myelin. They are the most susceptible cells in MSA. When one dies, it kills off multiple nerve cells.

The MSA Congress

Currently, there is no cure and no way to stop the progressive impairment in movement, speech, balance and loss of autonomic function that occurs in patients. Despite the brutality of the disease and its challenges, the international MSA research community has been working to tackle this rare fatal synucleinopathy. MSA is now getting the recognition it deserves.  Momentum is building and with over 260 participants, the 6th International MSA Congress was the largest meeting dedicated to this rare deadly form of Parkinsonism.

The Congress brought leaders in the field of clinical medicine and basic science to discuss ways to advance treatment. Several recent discoveries have changed MSA from a once neglected rare movement disorder into a key disease at the heart of finding a cure for other neurodegenerative brain diseases.

The 2-day intensive Congress, held at NYU School of Medicine and organized by the Dysautonomia Center, covered the MSA from its biological underpinnings to the management of symptoms at the bedside. The ambitious program was delivered by leaders in the field of neurodegenerative research who see MSA as an important disease to tackle.

The Congress included representatives from academia, industry, patient advocacy and the NIH. It opened with a plenary lecture from Dr. Stanley Prusiner, who won the 1997 Nobel Prize in Physiology and Medicine for his revolutionary concept of proteins as infectious agents. In 2013, the Prusiner laboratory in San Francisco changed our thinking about MSA.

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Plenary Speak at the 6th International MSA Congress and Nobel Prize Winner Dr. Stanley B. Prusiner. The Prusiner laboratory showed the transmissibility of the MSA protein in animals, which lead to the thinking of MSA as a prion disorder.

Prusiner had been working with tissue from patients with Parkinson disease. Somewhat by chance, he was sent samples from MSA patients. He showed that when mice genetically engineered to be susceptible to neurodegeneration were injected with the MSA protein, they had a rapid neurological decline and pathological changes in the brain identical to MSA patients (Link to paper: here). This paved the way for MSA to be thought of as a prion disorder, where the infectious pathological forms of alpha-synuclein protein can be transmissed from cell-to-cell.  Prusiner discussed his journey with infectious proteins and why MSA should be considered a prion disease.  He also showed how destroying the protein takes away its infectivity.

The findings offer new hope in finding a treatment for MSA and illustrate what is truly at the core of the disease process. These insights are something that we can build upon to develop new treatments that specifically target MSA.

– Dr. Patrik Brundin, MD, PhD – Professor for Neurodegenerative Science

Disease-modifying Treatments: A Time for Hope

A key focus of the MSA Congress was disease-modifying treatments, which are treatments that target the cause of the disease and stop, slow or reverse its progression.  The session on Disease Modifying Treatments was Chaired by Patrik Brundin and Werner Poewe. One possible approach discussed was the use of vaccines. Dr. Thomas M. Wisniewski, a neurologist at NYU and collaborator with the Center, spoke about the work being done with deer who have chronic wasting disease – another prion disorder. Vaccinating deer populations was shown to manipulate their immune response to target these infectious proteins and protect the animals at risk. Down the line, such an approach might also be possible for patients at risk of MSA.

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Dr. Thomas M. Wisniewski has lead work showing vaccinating at risk populations can offer protection against prion disorders

However, clearly different approaches to therapy are needed. While it will be fundamentally important to stop the spread of the protein, for those living with the disease for some time, we also need to restore function. The speakers reviewed what we have learnt from past clinical trials and those that are underway. This included testing strategies to block inflammation, using stem cells to support neuronal survival, and active immunization against the toxic MSA alpha-synuclein strain.

The ARTEMIS CONSORTIUM is a collaborative effort funded by the European Union to develop a treatment for MSA. Members of the Consortium spoke about the different approaches being developed that will stop the production of alpha-synuclein, block its transmission to other cells, and safely clear toxic aggregates that have already formed in the cells.

Collectively, these efforts mean that there are possible treatments for MSA in the pipeline that target the cause of the disease.

Susceptibility to MSA

The news that a family member has an incurable brain disease is worrisome, especially as the question arises as to whether this may be inheritable. Aside from some very rare MSA cases in Japan, there is no evidence to support direct inheritability. However, our susceptibility to MSA could theoretically have a genetic basis. Dr. Sonja Scholz and Dr. Henry Holden, leading researchers in the field of MSA genetics, have been paving the way for collaborative efforts to assemble biological samples to look for genes that may contribute to risk.  As Dr. Andrew Singleton pointed out, if we can find genetic contributors that increase our susceptibility, this may give us a window into the beginnings of the disease process.

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Different strategies will be needed at the different stages of the disease, including protecting those at risk, blocking alpha-synuclein production, stopping its spread, clearing toxic forms from the cell, reducing inflammatory damage, and restoring nerve function.


The Neurobiology of MSA

While MSA shares the same pathological hallmark of misfolded alpha-syunclein as more common diseases like Parkinson’s and Lewy body dementia, it does have some distinct biological differences. Parkinson disease and Lewy body dementia affect the nerves and progress more slowly, whereas MSA affects the oligodendroglial cells and progresses rapidly. Speakers in the Neurobiology and Neuropathology Session focused on why certain regions in the brain might be more prone to synuclein-mediated degeneration and the possible role of the microbiome in promoting its spread.

Biomarkers of disease diagnosis and progression

The success of any clinical trial depends on our abilities to quickly measure whether a drug is effective. For a disease that affects multiple systems, like MSA, this creates quite a challenge. The panelists, speakers, and chairs discussed ways to measure the disease process including sampling cerebrospinal fluid, imaging the brain, and various tests that can be carried out in blood or plasma to look at the burden of synuclein and neurodegeneration. This led into a lively roundtable discussion coordinated by Dr. Alberto Palma, in which participants were asked to vote on their top choice for a biomarker in a hypothetical clinical trial. With disease-modifying treatments in the pipeline, there is an urgent need to decide how best to plan trials with the highest chance of success.

Progress in Clinical Science

While basic science can pave the way towards new therapies, clinical research will shape our understanding of the disease and the two must advance in parallel. Dr. Kailash Bhatia and Dr. Steven Frucht addressed key issues in the diagnosis of MSA, including how to spot rare variants like early-onset MSA and patients that begin with stridor due to vocal cord paralysis – once thought to be a late complication of the disease.

Early diagnosis is critical to intervening earlier to stop the spread of synuclein. By the time the patient has reach the full clinical criteria to diagnose probable MSA, they must have already lost a significant degree of function and nerve cells in the brain. A round-table discussion lead by the Congress Chair Horacio Kaufmann and Dr. Ron Postuma highlighted the need for earlier diagnosis and the constellation of clinical signs that can specifically point to a diagnosis of MSA.

While prodromal criteria for Parkinson disease have been developed and it is possible to calculate an individual’s probability of having Parkinson disease, doing this for MSA poses a separate set of challenges. Recognizing that MSA patients can present in different clinics – from autonomic neurology, sleep medicine, movement disorders and urology – means that it is important that all specialists are aware that they should continuously assess whether their patient has other key symptoms that might indicate the early stages of a neurodegenerative synucleinopathy and of MSA.

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The Round Table Discussion on the Early Diagnosis of MSA discussed the importance of detecting key clinical symptoms as soon as possible. These symptoms should be continuously reassessed to capture the diagnostic clues as they emerge.

Symptomatic Treatment

The quest to find treatments that improve the symptoms of MSA is important. While symptomatic treatments don’t necessary target the cause of the disease, they do make patients feel better.

Dr. Italo Biaggioni discussed the cause of the blood pressure issues in patients with MSA and the new strategies being developed to combat the highs and lows – including automatic abdominal binders and new treatments that enhance the function of the remaining autonomic nerves (find out more about these trials here). Dr. Pietro Cortelli discussed sleep disorders, which occur often in patients with MSA, including how to manage sleep disordered breathing and REM sleep behavior disorder. Dr. Angelo Antonini reviewed the cognitive and psychiatric aspects of MSA, which were long considered exclusion criteria. With better recognition clinicians are noticing the high prevalence of depression in patients with MSA and learning what can be done to treat it.

The future for MSA research

The meeting adjourned with the announcement of the travel awardees. With the support of a R13 grant from the NIH’s Rare Disease Clinical Research Network (RDCRN) it was possible to support 20 top investigators from the world’s best laboratories to attend the meeting. A dedicated poster session was held for trainees and young investigators where a panel of senior scientists chose the best work. Awards were given to David Marmion, Violetta Refolo and Giacomo Compagnoni.



Inspiring the next generation of scientists and clinicians to take on MSA is essential for progress in the disease. Science progresses through ideas, commitment and challenges, which will ultimately bring us closer to our shared goal of finding a cure for one of the most aggressive brain diseases. Attracting the brightest minds to this challenge is essential.

The 6th International MSA Congress was supported by the NIH, the Movement Disorders Society, Theravance BioPharma, Lundbeck, Biogen, Finapres Medical Systems and the MSA Coalition, with endorsements from the American Autonomic Society and the European Federation of Autonomic Societies.

The meeting was held in New York City, March 1-2, and Chaired by Dr. Horacio Kaufmann, MD.