Members of the Autonomic Disorders Consortium and the MSA Coalition partnered together to host the Annual MSA Patient and Family Conference in Nashville Tennessee. The two-day event was attended by nearly 200 families and live streamed to reach over 2,000 online participants throughout the world. The presentations featured talks from leading MSA investigators from NYU, Vanderbilt University and Harvard Medical School.
Multiple system atrophy (MSA) is a disorder that affects the survival of particular cells within the brain, causing progressive loss of balance, coordination, speech and autonomic functions. MSA is caused by a rogue protein, known as alpha-synuclein, which attacks the white matter cells in the brain and kills off the nerves. The same protein is also responsible for Parkinson disease. These diseases, known as synuclienopathies have no cure, and MSA remains relentlessly progressive. Within just a few years, it leaves patients unable to walk, talk, or take care of themselves.
In recent years, academic medical centers, the NIH, the MSA Coalition, and the pharmaceutical industry have come together to stimulate much needed research in MSA. The Annual MSA Patient and Family Conference gave attendees the opportunity to learn how these collaborative efforts are helping pave the way to discover new treatments.
The biology of MSA
Dr. Horacio Kaufmann, Director of the Dysautonomia Center at NYU, opened the conference describing how recent discoveries in the biological underpinnings of MSA are helping us develop strategies to treat neurodegeneration. Proteins are encoded for in our DNA and consist of chains of amino-acids. They continuously fold and unfold forming a final structure with a biological function. Protein misfolding is at the heart of many degenerative neurological diseases. Nobel Laureate Dr. Stanley Prusiner, famous for discovering prion disorders like mad cow disease, showed that alpha-synuclein behaves remarkable similarly in MSA. Many now consider MSA a prion-like disorder, although it is not an infectious disease in the sense that it cannot pass from person to person.
Alpha-synuclein is expressed in tiny nerve endings and levels within the brain increase as we age. Alpha-synuclein is prone to misfolding, particularly when expressed in large amounts. Once it misfolds, it can convince other native alpha-synuclein proteins to adopt the same pathological confirmation, and spread from one cell to the next leaving a trail of widespread damage. “This discovery is important for a number of reasons” explained Dr. Kaufmann “as we now have a culprit to chase, we are developing different strategies that reduce its production, clean it from the cell, and stop it from spreading.”
International Progress in Clinical Research
Dr. Kaufmann went on to describe how the clinicians treating MSA are paying close attention to breathing and swallowing difficulties that are extremely common. Swallowing is a complex function that we take for granted. Around two-thirds of MSA patients have difficulty coordinating their swallowing, which means they are at high risk of misdirecting fluids, food or pills into the lung instead of the stomach. These repeated aspirations take a heavy toll on health and new international guidelines on the management of these aero-digestive problems in MSA are well underway. A group of MSA clinicians met in Italy for a 2-day meeting about dysphagia and stridor in MSA last week.
Dr. Lucy Norcliffe-Kaufmann spoke next about the Global MSA Natural History Study and the recent results suggesting that low blood pressure standing may be the key to detecting MSA in the pre-motor phase, before the difficulties with movement occur and the clinical diagnosis is made. MSA is a very rare disease, affecting around 15,000 Americans. “While MSA is uncommon, some people we see in clinic are at higher risk of developing it, mainly people who already have a fall in blood pressure on standing, REM sleep behavior disorder, who haven’t lost their sense of smell, with signs that the autonomic nerves outside the brain are there, but the bladder and bowels are not working properly”.
Dr. Norcliffe-Kaufmann also spoke about the Global MSA Registry (Register for GLOMSAR here). When trawling through the clinical records, information like when a symptom started, how quickly it deteriorated and how the patient feels about it is often missing. Surveys can fill that knowledge gap. The e-MSA survey was released this year. The project was a collaboration between NIH’s Rare Disease Clinical Research Consortium Network (RDCRN), The Autonomic Disorders Consortium, and the MSA Coalition. The results reveal some very interesting things. For example, mental health issues like laughing or crying uncontrollably, forgetfulness, and depression were very common in MSA and are clearly areas that deserve more attention. “In order to find out what matters the most to families living with MSA we need to capture the patient voice along with the standardized clinical data” explained Dr. Norcliffe-Kaufmann. “Ultimately, this should translate into better clinical care for the entire MSA population”.
Common but manageable autonomic symptoms
Dr. Amanda Peltier covered the topic of autonomic problems in MSA. The autonomic nervous system is a network of nerves that extend out from the brain and spinal cord to the organs and control all the automatic processes. These nerves control the processes we take for granted, things like our circulation, heart rate, breathing, sweating, gut motility, tears and sexual function. As Dr. Peltier, an Associate Professor in Neurology at Vanderbilt University and a member of the Autonomic Disorders Consortium explained, “As a neurologist caring for patients with MSA, one of my main priorities is to prevent patients from falling and hitting their head”. She described practical tips and tricks that can be used to fight low blood pressure standing and which drugs can be useful.
Dr. Cyndya Shibao spoke about the clinical trials that are currently underway to help develop new therapies for patients with MSA that suffer from low blood pressure standing (read more here). MSA affects a particular type of nerve cells in the brain and spinal cord. For the most part, MSA spares the nerves that control the caliber of the blood vessels, which are outside the brain essentially leaving them intact. These so-called sympathetic neurons communicate via neurotransmitters, tiny chemical messengers which pass from one nerve cell to another. Once released, the cell recycles the unused transmitter by taking it back up and clearing it away from the junctions between nerves. As Dr. Shibao explained, “we can harness the fact that these sympathetic nerves are intact in MSA patients and capable of releasing neurotransmitters that signal for the blood vessels to constrict”. Using pharmacological strategies that block the reuptake of these chemical messengers will allow them to stay around longer and should help prevent episodes of extremely low blood pressure when the patients are going to be upright and active.
Dr. Daniel Claassen closed the clinical session by speaking about the types of difficultly with movement that patients with MSA have and the difference between the cerebellar and parkinsonian forms. He spoke about the causes of falls in MSA and how to tell if a drug to help movement is effective. Families also had the opportunity to attend workshops to learn how to manage problems including difficulties with swallowing, speech and bladder issues – organized by the Vanderbilt medical team.
Clinician scientist Dr. Vikram Khurana, who joined the Board of the MSA Coalition this year, ended the meeting with an overview of the basic science of MSA. Basic science is research done at the bench, which drives innovation by helping to understand a disease. The findings can then by applied and tested in the clinic. Dr. Khurana explained how understanding the behavior of alpha-synuclein in cell models is helping shape our discovery of new treatments aimed at lessening the burden of misfolded protein in the brain.
Standing on the shoulders of giants
The Conference honored Dr. David Robertson, who defined many of the autonomic issues in MSA and helped to assemble the first advocacy group for MSA, known as the Shy-Drager Foundation, which later became the MSA Coalition. Dr. Robertson retired from Vanderbilt’s Autonomic Dysfunction Center this year, which he helped found in 1978. Dr. Italo Biaggioni, described his legacy and the countless autonomic clinician scientists that he went on to inspire.
It is very encouraging to see how quickly the science of MSA is moving – Italo Biaggioni, MD, PI of the Autonomic Disorders Consortium
A brighter future for MSA
The MSA Patient and Family Conference gave those living with the disease the opportunity to learn key advances that are being made in MSA. A major partner in this progress are of course the patients who give up their time to participate in clinical research, be it new treatment trials, observational natural history studies or registry surveys. Dr. Italo Biaggioni, Principal Investigator of the Autonomic Disorders Consortium commented “It is very encouraging to see how quickly the science of MSA is moving. The Consortium has played an important role in fostering international collaborations through our joint projects. Ultimately, we are all working towards the same goal of developing better treatments. We will get there faster if we all work together”.
Stay tuned for video links to the talks