Natural History Study of Synucleinopathies
Natural History Study of Synucleinopathies
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.