N-Acetylcysteine for Neuroprotection in Parkinson's Disease

Parkinson's disease (PD) is a neurodegenerative disorder in which deficits of the primary
intracellular antioxidant, glutathione (GSH), are postulated to mediate increased oxidative
stress and mitochondrial dysfunction in the pathogenic cascade leading up to the loss of
nigrostriatal dopaminergic neurons that is the hallmark of the disorder. Therefore, there is
currently great interest in treatment strategies that can maintain, restore and/or elevate
intracellular GSH levels. However, GSH does not readily cross the blood-brain barrier or the
membranes of most cells, including neurons, so that direct dietary supplementation of the
antioxidant has not proved viable in increasing its intracellular concentration. On the other
hand, since the bioavailability of cysteine, which does cross both the blood-brain barrier
and most cell membranes, is rate-limiting in the GSH synthesis pathway, this amino acid and
its non-toxic derivatives, such as N-acetylcysteine (NAC), are being investigated as
potential precursors that can be supplied through dietary means to spur in situ synthesis and
elevation of brain GSH. The overall objective of this Exploratory/Developmental (R21) study
is to use noninvasive proton magnetic resonance spectroscopy (1H MRS) to determine (a)
whether levels of GSH are decreased in vivo in the brain of 30 patients with Parkinson's
disease (PD) compared to matched controls, as has been found in postmortem brain; (b) whether
GSH levels in PD brain increase significantly following 30 days of daily supplementation with
1800mg or 3600mg of NAC compared to baseline and placebo, and (c) whether any such increases
in brain GSH would be dose-dependent and be associated with a change in the participants'
oxidative stress profiles. Additionally, a clinical assessment battery, including
quantitative tests of motor function, will be performed to investigate potential associations
between the NAC intervention, brain GSH levels, oxidative stress markers, and clinical
presentation. If successful, this study will represent the first objective documentation of
whether there is a GSH deficit in living PD brain that dietary NAC supplementation can
mitigate, thereby providing a compelling justification for investigating such neuroprotective
strategies in larger controlled clinical trials.

Inclusion Criteria:

- Diagnosis of idiopathic PD according to the United Kingdom Parkinson's Disease Society
Brain Bank criteria (UKPDSBB) criteria (only for PD group

- Age 50 to 75 years

- Able to give informed consent for study participation

- Not on any medication for PD (anticholinergic agents allowed)

Exclusion Criteria:

- Unable to give informed consent

- Unable to undergo a brain MRI

- PD duration ≥15 years

- Receiving dopamine receptor blocking agents, including typical neuroleptics,
prochlorperazine, and metoclopramide

- Diagnosis of major depression or other axis I psychopathology

- Modified Mini-Mental Status Exam (MMSE) ≤ 24/30

- Diagnosis of chronic or persistent illnesses that could affect oxidative stress
status, such as diabetes or congestive heart failure

- Significant concomitant medical disease limiting life expectancy to less than 12
months from study inclusion

- Diagnosis of primary mitochondrial disorder, epilepsy, stroke, multiple sclerosis or
other neurodegenerative diseases such as Alzheimer's disease or ALS