Oral N-acetylcysteine for the Treatment of Parkinson's Disease

Oxidative stress is implicated in the pathogenesis of a number of neurodegenerative diseases
such as Parkinson's disease (PD). Further, levels of glutathione (GSH), a prevalent
endogenous antioxidant, are decreased in the postmortem substantia nigra (SN) of individuals
with PD, indicating increased oxidative stress, although this has yet not been confirmed in
vivo. Increases in intracellular oxidative stress have also been observed in primary
fibroblast cultures obtained from patients with GD, where enzyme replacement therapy
resulted in increases in total GSH. The hypothesis that oxidative stress plays a key role in
the neurodegeneration associated with PD suggests that antioxidants may be useful in
altering disease progression.

N-acetylcysteine (NAC) is a well-known antioxidant that is thought to act both as a free
radical scavenger and as a cysteine donor for the synthesis of GSH. NAC may be beneficial in
the treatment of PD. Magnetic resonance spectroscopy (MRS) methods may be able to determine
if there are effects from NAC on central nervous system GSH levels. In addition, use of red
blood cell (RBC) measurements of GSH, if correlated with brain concentrations, could serve
as an easily measured biomarker to help characterize and monitor response to therapy. The
investigators therefore propose to conduct a study of the effect of a single, oral dose of
NAC on central (brain) measures of GSH and peripheral (RBC) measures of GSH in people with
PD and healthy controls, through the use of simultaneous MRS techniques and pharmacokinetic
studies. The investigators hypothesis and specific aims are as follows:

Hypothesis: RBC and brain GSH concentrations will increase following oral NAC
administration in individuals with Parkinson's disease (PD) and control participants.

Specific Aims:

1. Quantitate baseline plasma and red blood cell GSH concentrations in those with PD and
controls; and characterize NAC and GSH pharmacokinetics after a single oral NAC
administration.

2. Quantitate brain GSH levels (as ascertained through MRS) in those with PD and controls
at baseline and after a single oral NAC administration simultaneously with Aim 1.

3. Construct a pharmacokinetic model to evaluate the relationship between peripheral
(plasma and RBC) and central (brain) GSH measurements.

Inclusion Criteria:

1. All participants must be 18 years or older.

2. All enrollees must understand and cooperate with requirements of the study in the
opinion of the investigators and must be able to provide written informed consent.

3. Individuals with medically stable Parkinson's disease (in the opinion of the
investigator).

4. All participants must not have taken antioxidants coenzyme Q-10, vitamin C, or
vitamin E for 3 weeks prior to the study.

5. Absence of dementia in all subjects, as determined by pre-scanning cognitive
assessment.

6. Control subjects who are able to undergo MRS

Exclusion Criteria:

1. Inability to undergo MRI scanning without sedation

2. Medically unstable conditions in any group as determined by the investigators

3. Pregnant or lactating or those women of child-bearing age that are not using
acceptable forms of contraception

4. Diagnosis of asthma that is presently being treated with ANY medication, or past
history of asthma/bronchospasm resulting in an emergency room visit, hospitalization
or treatment

5. Unable to adhere to study protocol for whatever reason