Clinical trial NCT01470027: N-Acetylcysteine for Neuroprotection in Parkinson's Disease
Official title: N-Acetylcysteine for Neuroprotection in Parkinson's Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Parkinson Disease
Keywords: magnetic resonance spectroscopy
N-acetylcysteine
antioxidant
glutathione
Lead sponsor: Weill Medical College of Cornell University
Sponsor class: OTHER
Collaborators: name: National Institute on Aging (NIA)
First posted: 2011-11-10
Enrollment: 50
Sex: ALL
Minimum age (years): 50
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The overall objective of this developmental/exploratory study is to use noninvasive proton magnetic resonance spectroscopy (1H MRS) to assess (a) whether brain levels of the antioxidant glutathione (GSH) are decreased in vivo, as has been found in postmortem brain, in 30 patients with Parkinson's disease (PD) compared to matched controls; (b) whether GSH levels in PD brain increase significantly following 30 days of daily supplementation with 1800mg or 3600mg of N-acetylcysteine (NAC) compared to placebo and to baseline, 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. In addition, 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Change of Cerebral Glutathione Levels as Measured by Proton Magnetic Resonance Spectroscopy
timeFrame: at baseline and 4 weeks after intervention start
Secondary outcomes:
measure: Unified Parkinson's Disease Rating Scale (UPDRS) Parts I-V (Total Score Reported)
timeFrame: at baseline and 4 weeks after intervention start
measure: Mini Mental State Examination (MMSE)
timeFrame: at baseline and 4 weeks after intervention start
measure: Hamilton Depression Rating Scale (HAM-D)
timeFrame: at baseline and 4 weeks after intervention start
measure: 9-Hole Peg Board Test (9-HPT)
timeFrame: at baseline and 4 weeks after intervention start
measure: 10-Meter Walk Test
timeFrame: at baseline and 4 weeks after intervention start
measure: Beck Anxiety Inventory
timeFrame: at baseline and 4 weeks after intervention start
measure: Parkinson's Disease Quality of Life Questionnaire (PDQLQ)
timeFrame: at baseline and 4 weeks after intervention start
Other outcomes:
Locations:
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
Study officials:
affiliation: Weill Medical College of Cornell University
name: Dikoma C. Shungu, Ph.D.
role: PRINCIPAL_INVESTIGATOR
References: