Evaluation of Primary Chronic Autonomic Failure

Objective:

In dysautonomias, altered functions of one or more components of the autonomic nervous system
adversely affect health. Primary dysautonomias have been classified clinically into chronic
autonomic failure (CAF) syndromes that include pure autonomic failure (PAF), multiple system
atrophy (MSA), and Parkinson disease (PD) with autonomic failure (manifested especially by
neurogenic orthostatic hypotension (OH)). Clinical assessment alone is often inadequate for
correct diagnosis and does not provide insights into mechanisms or identify new therapeutic
targets. This protocol calls for continuous development and assessment of physiological,
neuropharmacologic, neurochemical, neuroimaging, and other clinical laboratory approaches, to
identify lesion types and sites in CAF and improve diagnosis, increase mechanistic
understanding, and incite novel therapeutics. PAF, MSA, and PD exemplify alpha
synucleinopathies, in which deposits of the protein alpha-synuclein occur in Lewy bodies in
catecholamine-producing neurons (PD, PAF) or in the cytoplasm of glial cells (MSA). Only the
Lewy body forms of synucleinopathy are consistently associated with loss of catecholaminergic
neurons. Under this protocol we have obtained evidence that patients with Lewy body diseases
have decreased ability to take up intra-neuronal catecholamines from the cytoplasm into
storage vesicles. Cytoplasmic catecholamines are cytotoxic, such as by enzyme-catalyzed
conversion to highly reactive catecholaldehydes. By studying CAF patients we hope to make
discoveries that will yield a unifying, integrative concept for the pathogenesis and
different clinical manifestations of Lewy body diseases. Autonomic function testing under
this protocol is also required for screening purposes for entry into other protocols of the
Clinical Neurocardiology Section. Moreover, comprehensive autonomic function testing is
requested in patients of the NIH Undiagnosed Diseases Program. Finally, in a long-term
project as a member of the Autonomic Rare Diseases Clinical Research Consortium we are
applying this testing to study the natural history of neurogenic OH.

Study Population:

The study population consists of patients with idiopathic, or primary, CAF, with emphasis on
PAF, MSA, and PD. Comparison groups include healthy volunteers (HVs), patients with PD who do
not have OH, and patients with iatrogenic CAF such as from bilateral thoracic
sympathectomies.

Design: Subjects undergo multiple physiological, neuropharmacologic, neurochemical, and
neuroimaging, and other tests, to see if the results by different modalities agree and point
to specific sites and types of lesions.

Outcome Measures:

Physiological outcome measures include hemodynamic responses to the Valsalva maneuver,
orthostasis, and altered temperature at skin of the back. Neuropharmacologic measures include
cardiovascular responses to test drugs that probe specific components of the autonomic
nervous system. Neurochemical measures include plasma, cerebrospinal fluid, microdialysate,
urine, and skin biopsy tissue levels of catecholamines and related compounds. Neuroimaging
measures include positron emission tomographic scanning after injection of 18F-dopamine,
18F-DOPA, 13N-ammonia, or 11C-methylreboxetine.

- INCLUSION CRITERIA:

The subjects are patients with known or suspected primary CAF, based on referral
information and confirmation of the clinical diagnosis at the intake evaluation. They are
classified by results of the intake evaluation and then undergo comprehensive autonomic
function testing.

Patients with primary or iatrogenic CAF are included. Control patients have been previously
diagnosed with PD or MSA without OH, confirmed at the time of the intake evaluation.

Healthy Volunteers 18 years old or older are included. People at increased risk for PD or
CAF consent in this study as if they were patients (e.g., to enable DNA extraction and
storage).

All subjects must be able to provide their own consent to participate or have an existing
Durable Power of Attorney (DPA) in place.

EXCLUSION CRITERIA:

Age: People younger than 18 years old are excluded.

Risk: A candidate subject is excluded if, in the judgment of the Principal Investigator or
Clinical Director, protocol participation would place the subject at substantially
increased acute medical risk. This includes the risks associated with air travel to the
NIH. A candidate subject is excluded if, in the opinion of the Principal Investigator or
Clinical Director, the medical risk outweighs the potential scientific benefit.

Disqualifying Conditions A candidate subject is excluded if there is a disqualifying
condition. Examples of disqualifying conditions are hepatic or renal failure (defined by
serum creatinine more than 1.5 g/dL), symptomatic congestive heart failure, severe anemia,
psychosis, refractory ventricular arrhythmias, and symptomatic coronary heart disease.
Patients are excluded from further participation if the results of the intake evaluation
lead to a diagnosis of a secondary form of CAF, such diabetic autonomic neuropathy.
Candidate subjects who are unable to give their own consent and who do not have an existing
DPA in place are excluded. Pregnant or lactating women are excluded from the study.

Medications Patients with known or suspected allergy or hypersensitivity to any test drug
are excluded from receiving that drug. Patients are not to discontinue any medications
before the patient or the patient s doctor discusses this with the Principal Investigator,
Research Nurse, or Nurse Practitioner. If it is decided that discontinuing medications
would be unsafe, then the patient may be excluded from all or part of the study.

Herbal Medicines and Dietary Supplements Certain herbal medicines or dietary supplements
are known or suspected to interfere with the experimental results, and such herbal
medicines or dietary supplements may be disallowed before enrollment in the study. For many
herbal medicines or dietary supplements, the mechanisms of action and therefore the
possible effects on the experimental results are unknown. In cases where the subjects wish
to continue their herbal medicines or dietary supplements while on study, and search of the
available medical literature fails to identify effects that are known or expected to
interfere with the experimental results, then the subjects may participate.

Practical Limitations Patients in whom we feel it would be difficult to insert a catheter
into a vein may be excluded. Subjects who are not expected clinically to tolerate lying
still during the procedures may be excluded.

Pregnancy Pregnant or lactating women are excluded from the protocol overall. In women with
child-bearing potential, blood testing for pregnancy will be done with 24 hours before
initial testing (except for obtaining the medical history and physical examination) or any
testing involving radioactivity under the protocol. Repeat pregnancy testing will be done
before any procedure or drug administration under the protocol that takes place more than
one week from a previous pregnancy test. Participants will not start or remain in the study
if pregnancy test is positive.

Refusal to Undergo Certain Procedures Candidate subjects are excluded if they refuse to
undergo certain procedures. These are: (1) IV catheter; (2) electrocardiogram; (3) blood
drawing; (4) DNA extraction and storage (patients and non-HV controls only); and (5) DNA
analysis (patients and non-HV controls only).