Projects Funded - Clinical
FACILITATING PATIENT STUDIES - "CLINICAL"
Below you will find information on several clinical studies that have been funded by the MSA Coalition.
Also be sure to check out the MSA Treatment Pipeline where you will discover many drugs or other therapies that are being developed to treat MSA. The MSA Coalition regularly maintains this listing so be sure to check back regularly for new highlights and updates.
**NEW CLINICAL STUDY: "Abdominal Binders to treat Orthostatic Hypotension in Multiple System Atrophy": Gregor Wenning, MD, PhD & Alessandra Fanciulli & Cecilia Raccagni (Medical University of Innsbruck, Austria)
MSA Coalition Grant #2020-05-002 – $50,000
Orthostatic hypotension (OH) is a key feature of multiple system atrophy (MSA). It is characterized by severe blood pressure drops upon standing and worsens quality of life by causing recurrent spells of dizziness, blackouts and falls. Drugs to treat OH can cause high blood pressure in the supine position, often limiting an effective treatment of OH itself. In patients with OH due to Parkinson’s disease, we showed that elastic abdominal binders combat OH, without inducing high blood pressure when lying down. Regular use of abdominal binders also significantly improved OH-related symptoms in daily life.
In MSA, the efficacy of elastic abdominal binders in treating OH has yet to be evaluated. It is also unclear, whether an optimized control of OH can ameliorate gait performance and global mobility in daily living. In this study, born from the cooperation between the Medical University of Innsbruck (Austria) and the Radboud University of Nijmegen (Netherlands), we plan to recruit 30 patients with the Parkinson variant of MSA to test whether wearing an elastic abdominal binder: i. reduces the fall in blood pressure upon standing; ii. improves gait performance, as measured by wearable sensors; iii. is safe and tolerable.
In a home-based setting of the study, we also plan to verify whether wearing an elastic abdominal binder for five consecutive days: i. ameliorates OH symptoms in daily living; ii. raises the blood pressure upon standing; iii. increases the number of walking bouts measured by physical activity wearable sensors. If their efficacy were confirmed, abdominal binders would represent a useful OH therapy for those patients with supine high blood pressure or at risk of developing it (ca. 50% of MSA patients). If wearable sensors were able to detect an improvement in gait and mobility, they may be applied to evaluate the functional impact of future OH therapies.
CLINICAL STUDY: Abdominal Binders to Treat Orthostatic Hypotension in Parkinsonian Syndromes (Ongoing 2021 – 2023)
The purpose of the present clinical trial is to determine whether the use of an elastic abdominal binder is effective in the non-pharmacological management of symptomatic, neurogenic orthostatic hypotension (OH) in individuals suffering from Parkinson’s disease (PD) or Parkinson variant multiple system atrophy (MSA-P).
1. Progress Report July 15, 2021 submitted by Prof. Dr. Gregor Wenning
Orthostatic hypotension (OH) is a key feature of multiple system atrophy (MSA) and affects about every third individual suffering Parkinson’s disease (PD). OH is characterized by blood pressure (BP) falls, which occur upon standing and significantly worsen quality of life by causing recurrent spells of dizziness, light-headedness, blackouts and falls. Drugs to treat OH can cause high blood pressure in the supine position, often limiting an effective treatment of OH itself. Elastic abdominal binders act in a physical, non-pharmacological way by applying pressure to the abdominal wall, therefore limiting venous blood pooling in this area. As a result, an increase in venous return to the heart should lead to BP stabilization upon standing, and subsequently to a reduction of severity or even prevent occurrence of orthostatic symptoms.
In people with OH due to PD, it was already shown that elastic abdominal binders combat OH, without inducing high blood pressure when lying down. Regular use of abdominal binders also significantly improved OH-related symptom burden in daily life and was overall well-tolerated. In MSA, the efficacy and safety of elastic abdominal binders in treating OH has yet to be evaluated. It is also unknown, whether an optimized control of OH can ameliorate gait performance and global mobility in daily living of people with Parkinsonian syndromes.
The “Abdominal Binders to treat Orthostatic Hypotension in Parkinsonian Syndromes (ABOH-PS)” study is a monocentric, randomized, placebo-controlled, double-blinded, crossover phase II clinical trial with an open-label treatment-extension phase, conducted at the Department of Neurology, Medical University, Innsbruck, Austria. The study team, led by MSA-experts Prof. DDr. Gregor K. Wenning (principle investigator) and DDr. Alessandra Fanciulli (project co-coordinator), as well as gait-expert DDr. Cecilia Raccagni (project co-coordinator), aims to recruit 30 individuals with symptomatic OH due to either the Parkinson variant of MSA or PD to test whether wearing an elastic abdominal binder:
- reduces the fall in BP upon standing;
- improves gait performance (measured by wearable sensors); and
- is safe and tolerable.
In a home-based setting of the study, it is additionally planned to verify whether wearing an elastic abdominal binder for five consecutive days:
- ameliorates OH symptoms in daily living;
- raises the BP upon standing;
- increases the number of walking bouts measured by physical activity wearable sensors.
If their efficacy were confirmed, elastic abdominal binders would represent a useful OH therapy for those individuals with supine high BP or at risk of developing it (approximately 50%), or individuals on polypharmacy. If wearable-sensors were able to detect an improvement in gait and mobility, they may be applied to evaluate the functional impact of future OH therapies.
With the financial support of the MSA Coalition, this project was officially started January 1st, 2021. After finalization of the research protocol and the clarification of administrative and regulatory aspects (approval of the Innsbruck’s ethical committee, clinic direction, trial center, as well as the Austrian Federal Office for Safety in Health Care), the active recruitment process started in May 2021.
** NEW CLINICAL STUDY: "Mobility in Atypical Parkinsonism: a Trial of Physiotherapy" - Grant: “Inside the gait – a new era on the horizon for atypical parkinsonian disorders”: Gregor K. Wenning, MD, PhD (Medical University of Innsbruck, Austria)
MSA Coalition Grant #2016-09-008 – $50,000
Multiple system atrophy (MSA) and Progressive Supranuclear Palsy (PSP) are rare and devastating neurological conditions. There is currently no therapy that can halt or slow the progression of these diseases. Clinical trials with a large number of patients are urgently needed to test the efficacy of therapeutic agents. In addition, an early and reliable diagnosis of MSA and PSP and the discrimination of these diseases from the more benign idiopathic Parkinson’s disease can be a challenge for the neurologist, especially at early stages.
Emerging data show that instrumented gait analysis using wearable sensors can provide a great amount of clinically relevant information which could help to better characterize these diseases and to quantify their progression characteristics and rates in an objective, rater-independent way. Moreover, new findings show that these sensors may be able to detect risk-of-fall associated gait parameters. This is particularly relevant in the clinical assessment and in the follow-up of patients with atypical parkinsonian disorders where the gait impairment and the risk of fall are even more prominent compared to idiopathic Parkinson’s disease.
Based on emerging findings in favor of the feasibility of wearable sensors in the clinical practice, we aim to propose a new objective tool in the diagnostic workup, individualized progression assessment, and therapeutic response of atypical parkinsonian disorder patients.
Clinical Study: Mobility in Atypical Parkinsonism: a Trial of Physiotherapy (Mobility_APP)
Patients with atypical parkinsonism often show gait and mobility impairment manifesting in early disease stages.
In order to maintain mobility and physical autonomy as long as possible for these patients, we will examine the effect of two types of physiotherapy in patients with multiple system atrophy (MSA), progressive supranuclear gaze palsy (PSP) and idiopathic Parkinson’s disease (IPD).
The study is divided into an ambulant daily in-patient physiotherapy phase, followed by a home-based training phase. At the beginning and the end of the study, the patients daily activity will be recorded for one week using Physical Activity Monitoring (PAM) sensors.
The aim of this double-blind, randomized-controlled study is to determine effective physiotherapy in patients with atypical parkinsonian syndromes in order to maintain mobility for as long as possible.
3. Presentation (June 2019): The Diagnostic Scope of Sensor-Based Gait Analysis in Atypical Parkinsonism
4. Published Article (May 2019): Gait and postural disorders in parkinsonism: a clinical approach
5. Published Article (January 2019): The Diagnostic Scope of Sensor-Based Gait Analysis in Atypical Parkinsonism: Further Observations
6. Published Article (June 2018): Sensor-based gait analysis in atypical parkinsonian disorders.
7. Conclusions and Outlook (View Full Final Report – December 2018)
Our study addressed the primary research question whether MSA patients can benefit from a standardized physiotherapy based on guidelines for PD. Additionally, the study aimed to investigate whether physiotherapy effects are sustainable. The most important clinically relevant finding was that gait of MSA patients is improving after an intensive in-hospital in-patient physiotherapy program. Thinking further, this finding after such a short treatment duration is even surprising in relation to the motor impairment of MSA patients. Still, most of these therapeutic effects were not significantly worsening after a low-dose unsupervised in-home training program. However, our data indicate a
tendency not to maintain the same improvement levels showed after an intensive physiotherapy in-hospital. Therefore, an intensive in-patient in-hospital physiotherapy seems to be a more effective intervention than a low-dose in-home training. There are several possible explanations for this result. Firstly, it may be hypothesized that patients at home without supervision of an expert are not
performing the training program properly. Secondly, it may reflect that patients do not have enough time during the 5-day long in-hospital physiotherapy to learn properly the training program and being able to reproduce it correctly at home. Another possible explanation is the lack of compliance and adherence to the training plan.
The current study was the first-ever assessment of physiotherapy in MSA patients. Further studies are needed to confirm and implement our results. For patients with PD, there is strong evidence that the introduction of an activity coach in the intervention plan, who guides patients towards a more active lifestyle through periodic coaching sessions enhances patients´ motivation and promotes
physical activity . Therefore, an activity coach may educate patients about the benefits and the importance of physical activity, may help to overcome any perceived barriers to engaging in physical activity and set systemic goals, therefore improving patients´ motivation, well-being and levels of independence.
** NEW CLINICAL STUDY: "Synuclein-One Study" - Grant: “Biomarker Development in MSA”: Roy Freeman, MD (Beth Israel Deaconess Medical Center MA)
MSA Coalition Grant #2013-12-005 – $25,000
There is currently an unmet need for a biomarker in Multiple System Atrophy. A reliable biomarker could contribute to the diagnosis, treatment and disease modification of MSA by improving diagnostic accuracy, defining disease progression and providing an objective measure of the response to disease modifying interventions. Successful development of a biomarker for MSA would therefore assist in the evaluation and enhance the efficacy of drugs or other interventions that have neuroprotective qualities and offer the possibility of slowing, halting or reversing the rapid progression of MSA. This study in human subjects, will determine whether alpha-synuclein deposits in cutaneous autonomic nerves is a valid biomarker for multiple system atrophy.
CLINICAL STUDY: Synuclein-One Study (Ongoing 2021 – 2022)
The Synuclein-One Study will be evaluating α-synuclein in patients with Parkinson’s disease, Multiple System Atrophy, Dementia with Lewy bodies and Pure Autonomic Failure. Using a simple diagnostic test will improve clinical accuracy in diagnosing, earlier diagnosis, and distinguish between neurodegenerative diseases.
1. May 2019: MSA Coalition Funded Research Honored as “Abstract of Distinction” at the American Academy of Neurology Annual Meeting.
The abstract entitled “Cutaneous Alpha-Synuclein Deposition in Multiple System Atrophy” has been identified as a 2019 Abstract of Distinction by the American Academy of Neurology at this year’s Annual Meeting. The Abstracts of Distinction program recognizes the top scientific achievement in each abstract topic area and is awarded to only a small number of superior abstracts. There are 24 Abstracts of Distinction this year that were carefully selected from the 3000+ abstracts submitted for the 2019 Annual Meeting in Philadelphia, PA.
This MSA Coalition funded work, led by MSA Coalition grantee, Dr. Roy Freeman, MD, Beth Israel Deaconess Medical Center, Boston, MA seeks to fill an unmet need for a biomarker in multiple system atrophy by way of skin sample testing for levels of the protein alpha-synuclein in MSA patients, Parkinson Disease patients, and healthy controls. A reliable biomarker could contribute to the diagnosis, treatment and disease modification of MSA by: (1) improving diagnostic accuracy; (2) increasing cohort homogeneity in clinical trails; (3) promoting early diagnosis, ideally in the pre-motor state; (4) defining disease progression and (5) providing an objective measure of the response to disease modifying interventions. Successful development of a biomarker for MSA would assist in the evaluation and enhance the efficacy of drugs or other interventions that have neuroprotective qualities and offer the possibility of slowing, halting or reversing the rapid progression of MSA.
2. NIH Grant (July 2016): Dr. Roy Freeman obtained a grant from NIH ($252,643) to continue this study
1. BIDMC Newsletter article (Summer 2014): Below the surface
** NEW CLINICAL STUDY: " Insulin Resistance in Multiple System Atrophy" - Grant: “Plasma exosomal IRS-1pS312 as biomarker for MSA”: Wassilios Meissner, MD, PhD (University of Bordeaux, France)
MSA Coalition Grant #2017-10-005 – $50,000
No specific diagnostic test is currently available for multiple system atrophy (MSA). It is also difficult to predict how the disease will evolve in each individual patient over time. To overcome these limitations, current research focuses on the development of body fluid biomarkers, i.e. the identification of substances that are easily measurable in the blood or other body fluids and that reflect fundamental disease mechanisms. The hope is that these biomarkers will help to make the right diagnosis more easily and to better predict how the disease will evolve in each individual patient. Doctors expect that these biomarkers will also allow to better measure the efficacy of new treatments in clinical studies.
In a recent experimental study, we have found changes reminiscent of diabetes in brains of deceased MSA patients and mice that mimic some features of MSA. We have further observed in these MSA mice that a drug used for the treatment of diabetes protects neurons and the amount of this protection correlates with a
blood biomarker called IRS-1pS312, which was measured in small blood vesicles called exosomes. Exosomes are released from brain cells and can cross the blood brain barrier. Therefore, the measurement of these vesicles in the blood provides a perfect window to monitor changes in brain activity.
The overall objective of the proposed study is to assess the usefulness of this easily accessible blood biomarker for the diagnosis and prognosis of MSA. This biomarker may also prove helpful for the assessment of the efficacy of antidiabetic drugs in future treatment trials in MSA patients.
CLINICAL STUDY: Insulin Resistance in Multiple System Atrophy (IRAMS)(Ongoing 2020 – 2023)
Multiple system atrophy (MSA) patients have a poor prognosis with a median survival ranging between 6 and 10 years. MSA belongs to the synucleinopathies, which are characterized by the abnormal accumulation of alpha-synuclein. We have recently shown brain insulin resistance (i.e. reduced insulin signaling) in post-mortem brain tissue of MSA patients and transgenic MSA mice, as illustrated by increased protein levels of insulin receptor substrate-1 phosphorylated at serine 312 (IRS-1pS312). Additionally, exendin-4, an approved anti-diabetic drug targeting glucagon-like peptide-1 (GLP-1) receptors, was capable of decreasing brain levels of IRS-1pS312 and preserving dopamine neurons in transgenic MSA mice. We further observed an inverse correlation between plasma neural-derived exosomal IRS-1pS312 levels and survival of dopamine neurons in transgenic MSA mice.
The aim of this study is to further characterize peripheral and central insulin resistance in MSA patients, thereby validating this target for future treatment trials. For this purpose, fasting blood glucose and insulin levels will be determined in samples of MSA patients and healthy controls for a homeostatic model assessment of insulin resistance (HOMA). Additionally, IRS-1pS312 will be measured in neural-derived plasma exosomes of MSA patients and healthy controls.
Research update by Wassilios Meisner (July 2018)
According to the specific aims of the awarded grant, experiments were performed to establish a methodology for isolating oligodendrocyte-derived exosomes from plasma, similar to its methodology for isolating neuron-derived exosomes from plasma. These experiments are ongoing, but have not yet resulted in a definitively valid methodology. In parallel, approvals for shipping samples from Bordeaux and Salerno to the partner in Baltimore were obtained.
** NEW ** “Deep brain stimulation of globus pallidus internus and externus in MSA-P”: Alfonso Fasano, MD PhD & Andres Lozano, MD PhD (Toronto Western Hospital, Toronto, ON Canada)
MSA Coalition Grant #2021-09-003 – $35,500
Multiple System Atrophy (MSA) is a severe form of neurodegenerative parkinsonism with no cure and very limited response to medications. The most prescribed drug is L-dopa, which is instead successfully used in Parkinson’s disease. Deep brain stimulation (DBS) is a brain pacemaker also used to treat Parkinson’s and consists in the placement of two electrodes in deep structures of the brain, either the subthalamic nucleus (STN) or the internal part of the globus pallidus (GPi). Most PD patients are nowadays treated with stimulation of the STN as stimulating the GPi – albeit safer – is not very effective in treating the slowness that these patients also have. Worldwide not more than 40 MSA patients have been treated with DBS, targeting the STN in the vast majority of the cases and resulting in very disappointing results ranging from no effect to worsening of the baseline condition. Animal studies and observations in PD patients have meanwhile shown that stimulating the external part of the globus pallidus (GPe) improves slowness. Dr Alfonso Fasano from the Toronto Western Hospital (Toronto, Canada) will complete a pilot DBS trial taking advantage of a novel type of electrode able to stimulate multiple targets at the same time. He already enrolled 5 MSA patients with predominant parkinsonism who underwent the simultaneous stimulation of GPi and GPe. Dr Fasano’s initial experience with this novel approach has proven to be safe and effective in treating dystonia, rigidity and slowness of MSA patients to an extent not seen before with medications. MSA coalition support will be instrumental in completing the trial and analyzing all the collected data. Although finding a cure is certainly the most important aim of current MSA research, physicians and researchers should not stop looking for better ways to treat patients from a symptomatic standpoint.
“Global MSA Registry & Study Group”: Florian Krismer, M.D. (Innsbruck Medical University, Austria) and Lucy Norcliffe-Kaufmann, Ph.D. (New York University NY)
MSA Coalition Grant #2018-12-001 – $38,600
MSA Coalition Grant #2017-10-001 – $30,000
MSA Coalition Grant #2016-09-001 – $60,000
MSA Coalition Grant #2015-04-001 – $50,000
MSA Coalition Grant #2013-12-001 – $44,232
This project aims to establish the first-ever global registry dedicated to Multiple System Atrophy patients. Facilitating future worldwide clinical trials, the registry will be used to notify all patients that meet study entry criteria for clinical trials in MSA on an international scale. The registry will also provide a means for sharing anonymous patient information to define the disease specific characteristics and establish the definitive natural history of MSA. Registered patients will be followed thoroughly and periodically to identify potential biological markers of disease risk and severity in a global, worldwide longitudinal prospective study.
1. Published article (April 2015): “Multiple System Atrophy: The case for an international collaborative effort”
Building Hope Through Research
Since 2013, the Multiple System Atrophy Coalition has funded 55 MSA focused research projects for a total of $3.5 Million.
Explore the links below to learn more about our research goals and the outcomes of our funded projects.
Click on each category to read about these exciting research projects.
- Pathogenesis: Uncovering the cause of MSA
- Diagnostic Biomarkers: Improving methods for better diagnosis
- Preclinical: Evaluating potential new treatments in the lab
- Clinical: Facilitating clinical studies of potential new treatments in MSA patients
We are making an impact!