Multiple System Atrophy

What Causes Multiple System Atrophy?

MSA is caused by deterioration of the parts of the brain that control movement and automatic body processes, including the cerebellum, basal ganglia, and brain stem.

Scientists don’t know what causes brain degeneration in MSA, but research has shown that people with MSA accumulate proteins called alpha-synuclein in their brains. Alpha-synuclein accumulation has also been associated with other degenerative brain disorders, including Parkinson’s disease and Lewy body dementia.

Is Multiple System Atrophy Hereditary?

In most cases, MSA does not seem to be inherited. Most people with MSA have no family history of the disorder.

How Is Multiple System Atrophy Detected?

Early diagnosis of MSA is challenging because its symptoms often so closely resemble those of Parkinson’s and several other neurological diseases. Both Parkinson’s and MSA most often occur after the age of 40 and exhibit many of the same movement-related symptoms. Therefore, MSA is often misdiagnosed as Parkinson’s in its early stages.

MSA typically differs from Parkinson’s in several ways, including:

• Symptoms and impairments progress more rapidly in MSA.
• People with MSA don’t respond well to levodopa, a drug used to treat Parkinson’s.
• Automatic functions such as blood pressure and bladder control are more profoundly affected in MSA.
• Speech is more often affected in MSA.
• Muscle stiffness and slow movements are more prominent in MSA. Tremors are more pronounced in Parkinson’s.

How Is Multiple System Atrophy Diagnosed?

No test or exam can definitively detect MSA. When a patient presents with symptoms characteristic of MSA, doctors are likely to administer tests and exams to rule out other possible causes, including Parkinson’s disease. The diagnostic process may include:

• Physical exams and neurological exams to rule out other possible causes of the symptoms
• Magnetic resonance imaging (MRI) or positron emission tomography (PET) scans to look for brain degeneration in the parts of the brain associated with MSA
• Tests to look for abnormalities in blood pressure, possibly including a procedure called a tilt table test
• Tests of the body’s automatic functions, including sweating, bladder and bowel function, heart function, and pupil responses
• Sleep studies to look for sleep disturbances commonly associated with MSA

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How Is Multiple System Atrophy Treated?

No treatment will stop the progression of MSA or reverse the effects of its symptoms. Instead, most treatments aim to reduce the impact of symptoms, improve quality of life, and prevent life-threatening complications. Possible treatment options include:

• Some drugs used to treat Parkinson’s, such as levodopa, may minimally and temporarily ease movement symptoms in about a third of cases. However, the drugs’ effectiveness usually decreases significantly over time and may lower the patient’s blood pressure.
• Low blood pressure may be treated with drugs such as fludrocortisone, ephedrine, L-threo-dihydroxyphenylserine, or midodrine hydrochloride. However, doctors will usually first try to increase blood pressure with non-drug approaches, such as increasing the patient’s daily salt consumption.
• Continuous positive pressure ventilation (CPAP) may be used to treat sleep apnea.
• Botulinum toxin may help control involuntary movements.
• Sildenafil, tadalafil, or vardenafil may be used to treat sexual dysfunction. However, these drugs may also lower blood pressure as a side effect and must be used carefully.
• Physical therapy and speech therapy may help lessen the impact of some symptoms.
• Feeding tubes, breathing assistance, catheterization, and mobility aids may become necessary as symptoms worsen.

How Does Multiple System Atrophy Progress?

MSA symptoms worsen rapidly, and most people with the disorder will suffer from severe impairments within a few years after symptoms first appear. Most people survive 7-10 years after symptoms start, but survival rates vary widely from case to case.

Severe long-term complications can include:

• Injuries or bone fractures from falls
• Disrupted sleep
• Difficulty swallowing
• Loss of the ability to walk and move, eventually leading to being bed-ridden
• Loss of the ability to speak
• Respiratory infections such as pneumonia

How Is Multiple System Atrophy Prevented?

There is no known way to prevent MSA.

Multiple System Atrophy Caregiver Tips

• Educate yourself about the disease, its effects, and the side effects of medications used to treat it. People with MSA are also at higher risk of developing depression and anxiety. Be on the lookout for the warning signs of these conditions.
• Encourage a healthy lifestyle. There is no cure for MSA, but there are ways to manage symptoms and maintain a good quality of life for as long as possible. Facilitate healthy eating habits and get as much exercise as possible.
• Join a support group for caregivers. Caregivers are at risk of developing physical and mental health issues, too. So take time for yourself, and get the help you need when you feel overwhelmed.

Many people with MSA also suffer from other brain and mental health-related issues, a situation called co-morbidity. Here are a few of the disorders commonly associated with MSA:

• Some people with MSA also suffer from depression.
• Some people with MSA have a co-existing anxiety disorder.

Multiple System Atrophy Brain Science

Scientists don’t know precisely what causes MSA, but they do know that the disorder is always associated with abnormal accumulations of a protein called alpha-synuclein. As this protein builds up in the brains of people with MSA, it forms clumps in brain cells called glial cells. Glial cells are vital for the health and function of nerve cells in the brain, and they seem to be damaged and eventually destroyed by the accumulation of protein clumps. The result is the gradual scarring and degeneration of tissue in various parts of the brain.

MSA affects many areas of the brain, but degeneration in two regions seems to be responsible for many of the disorder’s symptoms. These types of degeneration include:

• Striatonigral degeneration. This degeneration impairs communication between the substantia nigra and the striatum, two brain areas that play a role in movement and coordination.
• Olivopontocerebellar atrophy. This deterioration affects structures called the olives, pons, and cerebellum. These parts of the brain are in and near the brain stem, and they help control many vital body functions, both involuntary and voluntary.

Multiple System Atrophy Research

Title: Randomized Double-Blind Placebo-Controlled Adaptive Design Trial Of Intrathecally Administered Autologous Mesenchymal Stem Cells In Multiple System Atrophy

Stage: Recruiting

Principal investigator: Wolfgang Singer, MD

Mayo Clinic 

Rochester, MN

Multiple system atrophy (MSA) is a rare, rapidly progressive, and invariably fatal neurodegenerative disease for which there is no disease-modifying treatment. Recent insights into pathophysiologic mechanisms suggest a crucial role in the deprivation of neurotrophic factors, which have been shown to be secreted by mesenchymal stem cells (MSCs). In a recent phase I/II study, adipose-derived autologous MSCs were delivered intrathecally to patients with early MSA utilizing a dose-escalation design. At a dose of 50 million MSCs, injections were generally well-tolerated, but a thickening of cauda equina nerve roots was observed, which was either asymptomatic or associated with low back pain. The rate of disease progression assessed using the Unified MSA Rating Scale (UMSARS) was markedly slower compared to a matched control group. An even more favorable side effect profile and virtual lack of disease progression were seen in an add-on cohort receiving 25 million MSCs per injection. Neurofilament light chain, an index of central axonal degeneration, decreased in all patients receiving that dose. MSC administrations resulted in a marked, dose-dependent increase of neurotrophic factors in CSF. The 2-year survival was significantly higher than observed in natural history cohorts.

Based on these findings, researchers are now conducting a double-blind, placebo-controlled, adaptive design phase II trial of adipose-derived intrathecal autologous MSCs in MSA to establish optimal treatment frequency and simultaneously derive placebo-controlled efficacy and safety data in preparation for a multicenter phase III trial. Up to 76 adult subjects with MSA will be enrolled. To ensure a homogenous patient population with comparable rates of disease progression, we will restrict the study to early cases while still fulfilling the strictest diagnostic consensus criteria. Participants will undergo a subcutaneous fat biopsy to derive autologous MSCs, which are cultured, expanded, and prepared for delivery in Mayo’s Cell Therapeutics Lab. In the first phase, subjects will be randomized 1:1:1 to receive 25 million MSCs at two different injection intervals (every six months or every three months) as the two active arms or lactated Ringer’s solution as the placebo arm. After half the subjects have been enrolled, a recruitment hold will allow for an interim futility and efficacy analysis to select the “winner” active treatment assuming futility criteria are not met. The study will then restart recruiting the second half of the subjects utilizing 2:1 randomization (“winner” active: placebo). Patients undergo clinical assessments at baseline, 3, 6, 9, and 12 months to derive the primary endpoint, the rate of disease progression assessed using UMSARS total and a mixed-effects regression model. MRI of the head and lumbar spine will be completed at baseline and 12 months to expand safety data and assess the atrophy rate of selected brain regions using morphometric measures as surrogate markers of disease progression. Spinal fluid before and after administrations, as well as stem cell product media, will be collected to further explore the biological properties and effects of MSCs and to explore selected spinal fluid markers as biomarkers of disease progression.

Title: Facilitating Diagnostics and Prognostics of Parkinsonian Syndromes Using Neuroimaging

Stage: Recruiting

Principal Investigator: Richard B. Dewey, MD

UT Southwestern Medical Center

Dallas, TX

Management of patients with parkinsonian symptoms has two critical gaps: (1) there are no clinically accepted biomarkers that may be used to inform disease progression rate in an individual with Parkinson’s disease (PD), and (2) no biomarkers exist to inform the differential diagnosis of conditions that exhibit parkinsonian symptoms and signs. This 2-year study aims to develop a multi-modal neuroimaging biomarker that enables the prediction of disease progression rate in PD and a biomarker that enables the differential diagnosis of PD, multiple systems atrophy (MSA), progressive supranuclear palsy (PSP), and healthy controls.

This study consists of two parts; neuroimaging of a defined population of mid to late-stage PD subjects currently followed at UT Southwestern Medical Center and recruitment of new subjects with PD, MSA, and PSP who will be followed clinically over two years and who will undergo neuroimaging.

Participants will be asked to undergo several types of neuroimaging, which will be analyzed using machine learning techniques.

At each study visit of the newly recruited cohorts, appropriate clinical scales will be performed based on their diagnosis and used to track and measure disease severity and progression.

Title: Clinical Laboratory Evaluation of Chronic Autonomic Failure

Stage: Recruiting

Principal Investigator: David S. Goldstein, MD

National Institute of Neurological Disorders and Stroke (NINDS)

Bethesda, MD

Objective: In dysautonomias, altered function of one or more autonomic nervous system components adversely affects health. A subset of dysautonomias consists of chronic autonomic failure (CAF) syndromes. A key sign of CAF is orthostatic hypotension (OH) due to sympathetic neurocirculatory failure (neurogenic OH, or nOH). Primary CAF has been classified based on clinical manifestations into three forms pure autonomic failure (PAF), multiple system atrophy (MSA), and Parkinson s disease with OH (PD+OH). All three forms involve deposition of the protein alpha-synuclein (AS) in neurons (PD, PAF) or glial cells (MSA) and therefore are called autonomic synucleinopathies. Clinical assessment alone often is inadequate for distinguishing among these conditions in individual patients. This observational study continues and expands on Protocol 03-N-0004, Clinical Laboratory Evaluation of Primary Chronic Autonomic Failure. The overall objective is to refine and conduct multi-modality testing of catecholaminergic and autonomic systems in patients with CAF. The goals are to (a) improve the differential diagnosis of CAF via laboratory biomarkers; (b) track the natural history of CAF by follow-up testing; (c) apply clinical laboratory biomarkers to gain insights into underlying pathophysiological mechanisms of CAF; and (d) build up rosters of well-characterized patients for future experimental therapeutic trials.

Study Population: The study population consists of patients with neurodegenerative CAF identified by on-site screening at the NIH Clinical Center. Comparison groups include control patients with iatrogenic CAF (e.g., status-post cardiac transplantation, pre/post bilateral thoracic sympathectomies) or PD without OH (PD No OH) and Healthy Volunteers (HVs). MSA patients are included to build up a subject roster for a planned clinical trial.

Design: This is an observational pathophysiology/natural history study with a planned duration of 5 years. Descriptive statistics will be done in diagnostic groups with neurodegenerative CAF.

Outcome Measures: The study is hypothesis generating/exploratory. The primary outcome measure is the results of clinical laboratory research tests. Neurobehavioral rating scales include the University of Pennsylvania Smell Identification Test (UPSIT), Montreal Cognitive Assessment (MoCA), and Uniform Parkinson s Disease Rating Scale (UPDRS). Neurochemical data are from assays of catechols and related compounds in plasma or cerebrospinal fluid. Neuroimaging data are from 18F-DOPA, 18F-dopamine, 13N-ammonia, and 11C-methylreboxetine positron emission tomographic (PET) scanning and MRI. Immunofluorescence microscopy is used to quantify immunoreactive tyrosine hydroxylase and AS in skin biopsy samples. Correlation analyses are done among individual values for outcome measures.