Natural History Study of 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.