CNS Uptake of Intranasal Glutathione

Objectives

Primary Aim: To determine whether intranasal reduced glutathione, (in)GSH, is capable of
augmenting CNS glutathione levels.

Hypothesis: Mean MRS glutathione concentration will rise from baseline following
administration of 1 cc 200 mg/ml (in)GSH.

Design and Outcomes:

This pilot study seeks to obtain baseline data regarding the feasibility of MRS to detect a
change in CNS glutathione concentration following administration of 200 mg (in)GSH. CNS
glutathione levels will be measured using magnetic resonance spectroscopy (MRS), with the
putamen as the region of interest. Baseline brain GSH concentrations will be measured by
MRS at approximately the same time each day in all individuals before and after
administration of study medication.

Outcome Measure: Describe the change in mean GSH concentration following administration of
(in)GSH. The data analysis will be ipsative- results will be reported as percent change
from the individual's own baseline GSH concentration.

Interventions and Duration:

If a participant communicates he/she understands the study, meets inclusion criteria, and
provides informed consent, individuals will be scheduled for a single visit at the
University of Washington for MR imaging (MRI), clinical evaluation, and blood draw. (~ 3
hours). Participants will be asked to be optimally medicated at the time of study visit, to
the best of their ability.

Sample Size and Population:

This is a proof-of-concept pilot trial. Based on the data from the single test subject, a
sample size of 15 would provide 80% power to detect an increase in CNS glutathione
concentrations between pre- and post- administration values, if we are willing to accept an
alpha value of 0.2.

1.1 Primary Aims

Primary Aim: To determine whether intranasal reduced glutathione, (in)GSH, is capable of
augmenting CNS glutathione concentration. (Region of Interest: putamen)

Hypothesis: Mean MRS glutathione concentration will rise from baseline approximately 15
minutes following administration of 200 mg/ml (in)GSH in 1 cc saline.

1.2 Secondary Objectives

Hypothesis: Baseline CNS glutathione concentrations and RBC glutathione concentrations will
be correlated.

1. To determine whether brain MRS [glutathione] and red blood cell (RBC) glutathione levels
are correlated.

Outcome: A ROC curve will be drawn between mean brain [glutathione] and RBC total
glutathione.

Inclusion Criteria:

- Age > 18 years.

- Ability to attend a 3 hour study visit in Seattle, WA.

- Ability to read and speak English.

- Have three or more of the required positive criteria for PD from Step 3 of the UK
Brain Bank Diagnostic Criteria for Parkinson's Disease.

- A modified Hoehn & Yahr Stage 2-3. (bilateral disease, not severely disabled.)

Exclusion Criteria:

- Any contra-indication to magnetic resonance imaging, including pacemaker, pacemaker
wires, aneurysm clip, or any electronic implant, weight over 136 kg (300 lb), metal
embedded in soft tissue or in the eye, prosthetic eye, claustrophobia, substance
abuse, use of recreational drugs, pregnancy, or other medical contraindications.

- A history of epilepsy, stroke, brain surgery, or structural brain disease.

- The presence of other serious illnesses (discretion of study clinician, e.g.
concurrent cancer treatment.)

- Pregnant.

- A history of sulfur sensitivity, e.g. reaction N-acetylcysteine, MSM, SAMe.

- A recent history of asthma.

- Supplementation with glutathione (oral, intravenous, intranasal, or nebulized) or the
glutathione precursor, N-acetylcysteine, for six months prior to baseline study
visit.

- History of sensitivity to sulfur containing medications/ supplements, i.e. NAC, MSM.

- Current drug or alcohol use or dependence.

- Inability/unwillingness to provide informed consent. (e.g. diagnosis of dementia,
confusion about study goals or participation.)

- Acute infection (e.g. upper respiratory, dermal) in the previous 30 days.

- Diagnosis of any mental illness, ever. (Mental illness has been associated with
glutathione depletion.)

- Diagnosis of any chronic disease, ever. (e.g. Hep C, autoimmune disease, etc.)

- Head tremor or head dyskinesia that cannot be comfortably controlled for 90 minutes.