Gaucher's Disease, Parkinson's Disease
Conditions
Keywords
Parkinson's disease, Gaucher's disease, Control
Brief summary
The investigators are interested in determining if the investigators are able to detect changes in brain chemistry using Magnetic Resonance Spectroscopy (MRS) in individuals with Parkinson's disease (PD), those with Gaucher's disease (GD), and those without neurological disorders (healthy controls) when they are given the antioxidant N-acetylcysteine (NAC). This study will combine information from a medical history, a physical examination and disease rating scales with results obtained using MRS brain scans and pharmacokinetic studies from blood samples. This research will require 1 visit that will require about 4 to 5 hours of time. During this study, participants will provide their medical history, be examined and undergo a rating scale for about one hour; the brain scan and pharmacokinetic studies will require 1.5-2 hours of time; in total the study will take about 4-5 hours.
Detailed description
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 and GD. 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, intravenous 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), Gaucher's disease (GD), and control participants. Specific Aims: 1. Quantitate baseline plasma and red blood cell GSH concentrations in those with PD and GD and controls; and characterize NAC and GSH pharmacokinetics after a single intravenous NAC administration. 2. Quantitate brain GSH levels (as ascertained through MRS) in those with PD and GD and controls at baseline and after a single intravenous 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.
Interventions
DRUGN-acetylcysteine
Single, intravenous administration of N-acetylcysteine
Sponsors
Rare Diseases Clinical Research Network
National Center for Advancing Translational Sciences (NCATS)
National Institute of Neurological Disorders and Stroke (NINDS)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
University of Minnesota
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Brain GSH | Baseline and up to 110 minutes post-NAC administration | change in brain GSH levels from baseline to post-NAC administration (90 - 110 minutes) in all subjects |
Countries
United States
Participant flow
Recruitment details
Subjects were primarily recruited from the investigators' clinics at the University of Minnesota, and from research volunteers signed up with the University's Center for Magnetic Resonance Research.
Pre-assignment details
Groups were not assigned in this study. All subjects received the same intervention.
Participants by arm
| Arm | Count |
|---|---|
| NAC in PD single intravenous administration of N-acetylcysteine in PD patients | 3 |
| NAC in GD single intravenous administration of N-acetylcysteine in GD patients | 3 |
| NAC in Controls single intravenous administration of N-acetylcysteine in control subjects | 3 |
| Total | 9 |
Baseline characteristics
| Characteristic | NAC in GD | NAC in Controls | NAC in PD | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 3 Participants | 3 Participants | 8 Participants |
| Age, Continuous | 44 years STANDARD_DEVIATION 23.58 | 58 years STANDARD_DEVIATION 0 | 54.33 years STANDARD_DEVIATION 3.21 | 52.11 years STANDARD_DEVIATION 13.46 |
| Region of Enrollment United States | 3 participants | 3 participants | 3 participants | 9 participants |
| Sex: Female, Male Female | 0 Participants | 2 Participants | 3 Participants | 5 Participants |
| Sex: Female, Male Male | 3 Participants | 1 Participants | 0 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 3 | 0 / 3 | 0 / 3 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 | 0 / 3 |
Outcome results
Primary
Brain GSH
change in brain GSH levels from baseline to post-NAC administration (90 - 110 minutes) in all subjects
Time frame: Baseline and up to 110 minutes post-NAC administration
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NAC in PD | Brain GSH | 55 percent increase from baseline | Standard Deviation 24.4 |
| NAC in GD | Brain GSH | 41 percent increase from baseline | Standard Deviation 16.3 |
| NAC in Controls | Brain GSH | 34 percent increase from baseline | Standard Deviation 19.8 |