Phenylbutyrate Response as a Biomarker for Alpha-synuclein Clearance From the Brain

This is a Phase I clinical trial of phenylbutyrate in 20 Parkinson patients and 20 age- and
sex-matched normal control subjects to see if phenylbutyrate can increase the removal of
alpha-synuclein from the brain into the bloodstream. All subjects will receive 20 grams/day
of phenylbutyrate in the liquid form phenylbutyrate-triglyceride taken as one teaspoonful
three times per day with meals. Blood will be drawn on two days prior to starting
phenylbutyrate to measure alpha-synuclein concentrations. Phenylbutyrate-triglyceride will
then be started and the change in plasma alpha-synuclein will be measured on day 1, 7, 14,
and 21 days while taking phenylbutyrate. After 21 days, the drug will be stopped and a final
blood sample will be measured at 28 days to see if plasma alpha-synuclein has fallen to its
pre-phenylbutyrate level. No effects on Parkinson symptoms are expected during this short
trial. Please note that although taking any type of Parkinson's drugs for symptomatic
treatment disqualifies you, if you and your neurologist are willing and able to have you off
Parkinson medication for six weeks before and during the trial, you may be eligible to
participate.

Inclusion Criteria:

- Idiopathic Parkinson's disease with mild symptoms;

- May be on treatment with dopamine agonists provided that the treating neurologist
agrees:

1. that the drugs can be stopped for at least three weeks prior to participating in
the phenylbutyrate study, and

2. for the 4-week duration of the study.

- Age and sex matched normal control subjects from spouses and the general population;

- In good general health;

- Controlled hypertension, or

- Controlled hypercholesterolemia with medication.

Exclusion Criteria:

- Pregnant women;

- Current treatment with:

1. L-3,4-dihydroxyphenylalanine (L-DOPA);

2. monoamine oxidase (MAO) inhibitors,

3. catechol-O-methyl transferase (COMT) inhibitors;

4. histone deacetylase (HDAC) inhibitors;

5. prednisone or other corticosteroids, or

6. probenecid.

- Severe cardiopulmonary disease such as:

1. congestive heart failure, or

2. emphysema requiring supplemental oxygen;

- Renal disease with serum creatinine greater than 2.5;

- History of:

1. depression in the prior year;

2. epilepsy;

3. stroke;

4. prior brain surgery;

5. dementia, or

6. psychosis.