Natural History Study of Synucleinopathies



Status:Recruiting
Conditions:Other Indications, Parkinsons Disease, Cardiology, Neurology, Psychiatric
Therapuetic Areas:Cardiology / Vascular Diseases, Neurology, Psychiatry / Psychology, Other
Healthy:No
Age Range:18 - Any
Updated:12/21/2018
Start Date:June 2011
End Date:July 2020

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Synucleinopathies are a group of rare diseases associated with worsening neurological
deficits and the abnormal accumulation of the protein α-synuclein in the nervous system.
Onset is usually in late adulthood at age 50 or older. Usually, synucleinopathies present
clinically with slowness of movement, coordination difficulties or mild cognitive impairment.
Development of these features indicates that abnormal alpha-synuclein deposits have destroyed
key areas of the brain involved in the control of movement or cognition. Patients with
synucleinopathies and signs of CNS-deficits are frequently diagnosed with Parkinson disease
(PD), dementia with Lewy bodies (DLB) or multiple system atrophy (MSA).

However, accumulation of alpha-synuclein and death of nerve cells can also begin outside the
brain in the autonomic nerves. In such cases, syncucleinopathies present first with symptoms
of autonomic impairment (unexplained constipation, urinary difficulties, and sexual
dysfunction). In rare cases, hypotension on standing (a disorder known as orthostatic
hypotension) may be the only clinical finding. This "pre-motor" autonomic stage suggests that
the disease process may not yet have spread to the brain.

After a variable period of time, but usually within 5-years, most patients with abnormally
low blood pressure on standing develop cognitive or motor abnormalities. This stepwise
evolution indicates that the disease spreads from the body to the brain. Another indication
of this spread is that acting out dreams (i.e., REM sleep behavior disorder, RBD) a problem
that occurs when the lower part of the brain is affected, may also be the first noticeable
sign of Parkinson disease.

The purpose of this study is to document the clinical features and biological markers of
patients with synucleinopathies and better understand how these disorders evolve over time.
The study will involve following patients diagnosed with a synucleinopathy (PD/DLB and MSA)
and those believed to be in the "pre-motor" stage (with isolated autonomic impairment and/or
RBD). Through a careful series of follow-up visits to participating Centers, we will focus on
finding biological clues that predict which patients will develop motor/cognitive problems
and which ones have the resilience to keep the disease at bay preventing spread to the brain.
We will also define the natural history of MSA - the most aggressive of the
synucleinopathies.

α-synuclein is a small protein of 140 amino acids that is highly expressed in the brain. It's
function remains poorly understood.10 Synucleinopathies are a group of neurodegenerative
diseases associated with the abnormal accumulation of α-synuclein within cytoplasmic
inclusions in neurons or oligodendroglia. These α-synuclein containing cytoplasmic aggregates
occur throughout the brain, producing cell death and specific motor, autonomic and cognitive
dysfunction in four phenotypically distinct synucleinopathies. When α-synuclein deposition
occurs in neurons it aggregates into Lewy bodies, producing Parkinson disease (PD), dementia
with Lewy bodies (DLB) or pure autonomic failure (PAF). Whereas in multiple system atrophy
(MSA) neuronal death probably occurs as a consequence of α-synuclein aggregation in
oligodendroglia.

A characteristic feature of the synucleinopathies is that they can all begin with varying
degrees of autonomic dysfunction as the sole clinical feature - implying an initial diagnosis
of isolated (pure) autonomic failure 11. After a variable period of time, but usually less
than 5 years, only a small number of patients remain with a pure autonomic failure phenotype,
but careful follow-up is lacking 11. Most patients develop cognitive or motor abnormalities
(or both) and the patient is then diagnosed with PD, DLB or MSA.

This stepwise clinical progression suggests that the neurodegenerative process can in rare
cases remain confined to autonomic neurons12, but more frequently spreads to affect
additional areas of the central nervous system (CNS). This unique feature of the
synucleinopathies poses diagnostic challenges and potential therapeutic opportunities.

The challenges are first, to determine whether PAF is a distinct disease or is always a
prodromal phase of PD, DLB or MSA and second, to discover biomarkers that predict spread to
motor and cognitive neurons. Such biomarkers would allow testing of disease-modifying
strategies to delay or stop the neurodegenerative process in the pre-motor or pre-dementia
phase. Aim 2 will focus on defining the natural history of MSA, the most aggressive of the
synucleinopathies. This prospective observational study will establish disease-specific
milestones for use in future clinical trials.

Obstacles to identifying biomarkers predicting further CNS involvement are that most medical
centers only see patients with synucleinopathies when they already have developed motor and
cognitive involvement, and that PAF and MSA are rare disorders. In this context the Autonomic
Disorders Consortium (ADC) within the Rare Diseases Clinical Research Network (RDCRN) of the
National Institutes of Health (NIH) was created with the objective of providing a better
understanding of the variability, progression, and natural history of neurodegenerative
synucleinopathies. Continuing this observational study, and increasing its power by including
additional academic centers from the U.S., South America, and Europe, will allow us to define
the natural history of these diseases and establish the sensitivity and specificity of the
proposed biomarkers.

Inclusion Criteria:

1. Both male and female patients will be included

2. Aged 18 or over

3. Referred to any of the participating consortium sites with orthostatic intolerance,
defined as symptoms of dizziness or lightheadedness in the standing position that
disappear when supine.

Exclusion Criteria:

1. Diabetes according to the American Diabetes Association criteria

2. Congestive heart failure

3. Lupus or other collagen vascular disease

4. Systemic illness thought to be responsible for the orthostatic intolerance

5. Drug-induced orthostatic hypotension (i.e., the use of alpha-blockers, diuretics,
tricyclic antidepressants or others thought by the investigator to play an important
role in the patient's orthostatic hypotension)

6. Isolated vasovagal syncope

7. Inability to comply with the protocol, e.g. uncooperative attitude, inability to
return for follow-up visits, and unlikelihood of completing the study.
We found this trial at
6
sites
330 Brookline Ave
Boston, Massachusetts 02215
617-667-7000
Phone: 617-632-0864
Beth Israel Deaconess Medical Center Beth Israel Deaconess Medical Center (BIDMC) is one of the...
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Boston, MA
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500 S State St
Ann Arbor, Michigan 48109
(734) 764-1817
Phone: 734-936-8281
University of Michigan The University of Michigan was founded in 1817 as one of the...
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Ann Arbor, MI
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2325 Montañeses
Buenos Aires, C1428
Principal Investigator: Marcelo Merello, MD
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Buenos Aires,
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Nashville, Tennessee 37232
Phone: 615-936-1748
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Nashville, TN
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New York, New York 10016
Principal Investigator: Horacio Kaufmann, MD
Phone: 212-263-7225
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New York, NY
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Rochester, Minnesota 55905
Phone: 507-284-0336
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Rochester, MN
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