Clinical Laboratory Evaluation of Chronic Autonomic Failure

Objective:

In dysautonomias, altered functions of one or more components of the autonomic nervous system
adversely affect 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 (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. Dementia with Lewy bodies (DLB) is another
form of autonomic synucleinopathy. This observational study continues and expands on Protocol
03-N-0004, Clinical Laboratory Evaluation of Primary Chronic Autonomic Failure. The objective
is to conduct multi-modality testing of catecholaminergic and autonomic systems in patients
with nOH. The goals are to: (a) build up a roster of well characterized patients for future
experimental therapeutic trials; (b) test predictions derived from the catecholaldehyde
hypothesis for the pathogenesis of autonomic synucleinopathies; (c) follow the natural
history of nOH; and (d) discover new clinical entities involving catecholaminergic
neurodegeneration.

Study Population:

The study population consists of patients with nOH identified by on site screening at the NIH
Clinical Center. Comparison groups include patients with iatrogenic CAF (e.g., status-post
cardiac transplantation, renal sympathetic ablation, bilateral thoracic sympathectomies) and
Healthy Volunteers (HVs).

Design:

This is an observational pathophysiology/natural history study with a planned duration of 3
years. Descriptive statistics will be done in diagnostic groups with nOH.

Outcome Measures:

The primary outcome measure is results of clinical laboratory research tests in nOH patients.
Neuroimaging data are from MRI and from 18F-DOPA and 18F-dopamine PET scanning. Neurochemical
data are from assays of catechols in plasma and cerebrospinal fluid. Immunofluorescence
microscopy data are from analyses of immunoreactive tyrosine hydroxylase and AS in skin
biopsy samples. Neurobehavioral rating scale data are from the University of Pennsylvania
Smell Identification Test (UPSIT), Montreal Cognitive Assessment (MoCA), and Uniform
Parkinson s Disease Rating Scale (UPDRS). Correlation analyses will be done among individual
values for outcome measures. A secondary outcome measure is estimated non-specific binding of
11C-methylreboxetine, based on studies of patients with iatrogenic CAF and desipraminetreated
HVs.

- INCLUSION CRITIERIA:

Inclusion Critieria: Patients referred for orthostatic hypotension. This is the main
subject cohort.

- Previously studied and diagnosed with one of the forms of nOH or else newly accrued
with a referral diagnosis of orthostatic hypotension, and

- 18 years or older, and

- Able to provide own consent to participate or have an existing Legally Authorized
Representative (LAR).

If a patient has already been diagnosed as having nOH under NIH Clinical Protocol
03-N-0004, this satisfies the inclusion criteria for that patient. If a patient has not
been diagnosed previously as having nOH under a protocol of the CNCS, then the patient may
be included if documentation in the referral letter or in a copy of outside autonomic
function testing results indicate OH. Previous enrollment in NIH Clinical Protocol
03-N-0004 is not required for enrollment in this study. We do plan to recruit participation
intothis study after NIH Clinical Protocol 03-N-0004 has been closed.

If a patient has been referred for OH, then the patient gives consent at the NIH Clinical
Center (and therefore is accrued) and then has screening testing at the NIH Clinical Center
to confirm that the OH is neurogenic. We anticipate that all patients referred for OH will
be shown to have nOH upon screening testing at the NIH Clinical Center. At the time of
screening, exclusionary abnormal laboratory test results (e.g., high serum creatinine
indicating renal failure) may come to light, in which case they will be withdrawn from the
study; however, the patient would have been accrued.

Inclusion criteria: Control patients with iatrogenic CAF

- Patients with heart transplants, status post bilateral endoscopic thoracic
sympathectomies, or pre- and post-renal sympathetic ablation, and

- 18 years or older, and

- Able to provide own consent to participate.

Inclusion criteria: Healthy Volunteers:

- Age 18 years or older

- Able to give informed consent

EXCLUSION CRITIERIA:

Patient Group Referred for Orthostatic Hypotension

- A medical condition that in the judgment of the Principal Investigator would place the
subject at substantially increased acute medical risk, or

- A disqualifying condition such as: hepatic or renal failure, symptomatic congestive
heart failure, severe anemia, psychosis, refractory ventricular arrhythmias, currently
symptomatic coronary heart disease, cerebrovascular disease with current symptoms
(e.g., recent transient ischemic attacks), diabetes or

- Secondary form of CAF, such as diabetic autonomic neuropathy, or

- Pregnant or lactating, or

- Being treated currently (within 2 weeks of anticipated protocol participation) with a
medication known to interfere with the cell membrane norepinephrine transporter, which
would obviate obtaining scientifically valid results (e.g., tricyclic antidepressant).

- Condition that may cause difficulty or inability to insert a catheter into a vein, or

- Unable to tolerate lying still for up to 1 hour during the procedures, or

- Refusal to undergo certain procedures. These include: (1) IV catheter and blood
drawing; (2) DNA extraction, storage, and analysis; (3) PET scanning; and (4) skin
biopsies, or

- History of keloid, or

- Unable to travel safely to the NIH CC, or

- Lacking consent capacity, unless a Durable Power of Attorney (DPA) is in place.

- Subordinates of study investigators or relatives of the PI or AIs.

Patient Control Group with Iatrogenic CAF

- A medical condition which in the judgment of the Principal Investigator would place
the subject at substantially increased acute medical risk, or

- A disqualifying condition such as: hepatic or renal failure, symptomatic congestive
heart failure, severe anemia, psychosis, refractory ventricular arrhythmias, currently
symptomatic coronary heart disease, cerebrovascular disease with current symptoms
(e.g., recent transient ischemic attacks), or diabetes or

- Pregnant or lactating, or

- Being treated currently (within 2 weeks of anticipated protocol participation) with a
medication that would obviate obtaining scientifically valid results (e.g., tricyclic
antidepressant).

- Condition that may cause difficulty or inability to insert a catheter into a vein, or

- Unable to tolerate lying still for up to 1 hour during the procedures, or

- Refusal to undergo certain procedures. These include: (1) IV catheter and blood
drawing; and (2) PET scanning, or

- Unable to travel safely to the NIH CC, or

- Lacking consent capacity, or

- Subordinates of study investigators or relatives of the PI or AIs.

Healthy Volunteer Group

- A medical condition which in the judgment of the Principal Investigator would place
the subject at substantially increased acute medical risk, or

- A disqualifying condition such as: hepatic or renal failure, symptomatic congestive
heart failure, severe anemia, psychosis, refractory ventricular arrhythmias, currently
symptomatic coronary heart disease, cerebrovascular disease with current symptoms
(e.g., recent transient ischemic attacks), diabetes or

- Pregnant or lactating, or

- Being treated currently (within 2 weeks of anticipated protocol participation) with a
medication that would obviate obtaining scientifically valid results (e.g., tricyclic
antidepressant).

- Condition that may cause difficulty or inability to insert a catheter into a vein, or

- Unable to tolerate lying still for up to 1 hour during the procedures, or

- Refusal to undergo certain procedures. These include: (1) IV catheter and blood
drawing; (2) PET scanning, or

- Unable to travel safely to the NIH CC, or

- Lacking consent capacity, or

- Subordinates of study investigators or relatives of the PI or AIs.