Physiological Effects of Nutritional Support in Patients With Parkinson's Disease
Phase: NA
Conditions: Parkinson Disease, Idiopathic Parkinson Disease
Sponsor: Thomas Jefferson University

Cover Page to Accompany ClinicalTrials.gov Document 
 
 
 
 
Protocol and Statistical Analysis Plan: May 17, 2018 
For Protocol: 
Physiological Effects of Nutritional Support in Patients with 
Parkinson’s Disease 
 
 
 
Thomas Jefferson University IRB ID: 14D.141 
Clinical Trial Number: NCT02445651 
 

 
 
 
 
 
 
 
 
Physiological Effects of Nutritional Support in Patients with 
Parkinson’s Disease 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator: Daniel Monti, M.D. 
Director, Jefferson Myrna Brind Center of Integrative Medicine 
 
 
 
Co-Investigators:  
 
Andrew Newberg, MD, Director of Research, Jefferson Myrna Brind Center of Integrative 
Medicine, Thomas Jefferson University 
Anthony Bazzan, MD, Jefferson Myrna Brind Center of Integrative Medicine, Thomas 
Jefferson University 
Daniel Kremens, MD, Neurology, Thomas Jefferson University 
Tsao-Wei Liang, MD, Neurology, Thomas Jefferson University 
 
 
 
 
 
 
 
 
PD NutS Protocol Clean 2015_10_09 rev 2018_05_10 
 

 
1.0    INTRODUCTION............................................................................................................. 4 
1.1    
Introduction ................................................................................................................................................... 4 
1.2    
Oxidative Stress in PD .................................................................................................................................. 4 
1.3    
Nutritional Support in PD Patients ................................................................ Error! Bookmark not defined. 
1.4    
Use of N-acetyl cysteine in PD Patients ....................................................................................................... 6 
1.5    
Utilizing SPECT to measure the dopamine transporter in PD patients ................................................... 8 
1.6    
Utilizing Magnetic Resonance Spectroscopy (MRS) to measure changes in the chemical milieu in 
brain of PD patients ..................................................................................................................................................... 9 
2.0       OBJECTIVES ................................................................................................................. 10 
2.1 
Evaluate Nutritional Supplementation ........................................................................................................... 10 
2.1.1 ............................................................................................................................................................................. 10 
2.1.2 ............................................................................................................................................................................. 10 
2.1.3 ............................................................................................................................................................................. 10 
3.0       STUDY PLAN ................................................................................................................. 10 
3.1 Subject Recruitment ............................................................................................................................................ 10 
3.1.1 
Flow Chart .............................................................................................................................................. 12 
3.1.2 
Inclusion criteria ..................................................................................................................................... 13 
3.1.3 
Exclusion criteria .................................................................................................................................... 13 
3.2  
Registration Guidelines and Recruitment ................................................................................................. 14 
3.3  
Treatment Plan: ........................................................................................................................................... 14 
3.3.1 ........................................................................................................................................................................ 14 
3.3.2  
N-Acetylcysteine ...................................................................................................................................... 14 
3.4 
Criteria for Removal from / Cessation of Protocol ....................................................................................... 15 
3.4.1 
Measuring Endpoints: Endpoints .............................................................................................................. 15 
3.4.2  
Subject Withdrawal: ................................................................................................................................. 15 
3.4.3  
Missing Appointments:............................................................................................................................. 15 
3.5 
Adverse Events ................................................................................................................................................. 15 
3.6 
Data Collection and Submission Schedule ..................................................................................................... 16 
3.6.1 
Data Submission: ...................................................................................................................................... 16 
3.6.2 
Master files ............................................................................................................................................... 16 
3.7  
Measurement of Effect of the Nutritional Supplements............................... Error! Bookmark not defined. 
3.7.1  
Clinical Response ..................................................................................................................................... 16 
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3.7.2 
SPECT Imaging Procedure ....................................................................................................................... 16 
3.7.3 
MR Spectroscopy Procedure .................................................................................................................... 17 
3.8 
Statistical Considerations ................................................................................................................................ 17 
3.8.1    Descriptive and Exploratory Analyses: ....................................................................................................... 18 
3.8.2    Analyses for Primary Objectives: ............................................................................................................... 18 
3.8.3 
Image analysis with SPM: ........................................................................................................................ 18 
Rationale for using SPM. ................................................................................................................................... 18 
SPM analysis. ..................................................................................................................................................... 19 
Significance assessment. .................................................................................................................................... 19 
3.8.4 
Power Analysis: ........................................................................................................................................ 19 
3.8.5 
Randomization: Randomization will occur via a 2:2:1 ratio of the oral supplementation, intravenous/oral 
NAC, or waitlist control groups using the method of random permuted blocks with random block sizes without 
stratification. ........................................................................................................................................................... 20 
4.0  
RISKS............................................................................................................................... 20 
4.1 
N-acetyl cysteine: .............................................................................................................................................. 20 
4.2 
Oral Supplements: ........................................................................................................................................... 20 
4.2.1 
Supplements, Doses, and Risks .............................................................................................................. 20 
4.2.2 
Specific side effects have been reported for the supplements as below: ........... Error! Bookmark not 
defined. 
4.3 
Potential Risks of DaTScan: ............................................................................................................................ 21 
4.4 
Special Risk Factors: ....................................................................................................................................... 21 
4.5 
Risks of venous cannulation: ........................................................................................................................... 21 
4.6 
Magnetic Resonance Spectroscopy: ................................................................................................................ 21 
5.0 
REFERENCES ................................................................................................................ 22 
 
 
 
PD NutS Protocol Clean 2015_10_09 rev 2018_05_10 
 
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1.0    INTRODUCTION 
 
1.1    Introduction 
 
 
The overall goal of this study will be to determine whether NAC will help to support 
dopaminergic function in patients with Parkinson’s disease (PD). This SPECT study will utilize 
Ioflupane (DaTscan) single photon emission computed tomography to measure dopamine 
function, magnetic resonance spectroscopy (MRS) to measure inflammatory and oxidative stress 
markers, and neurological measures to assess clinical symptoms, in patients with PD who are 
given oral and IV infusions of NAC which is thought to support the dopamine system’s function.   
 
Parkinson’s disease (PD) is a devastating neurodegenerative disorder of unknown cause that 
affects more than a million Americans (Korell and Tanner, 2005).  Its cardinal features include 
tremor, rigidity, bradykinesia, and postural instability.  Depression is common, and a fourth to a 
half of all PD patients eventually develop dementia (Shulman et al., 2005).  The most prominent 
PD pathology is degeneration of dopaminergic neurons in the ventrolateral tier of the pars 
compacta of the substantia nigra in the midbrain, and the formation of α-synuclein cytoplasmic 
inclusions, termed Lewy bodies, throughout the brain (Fearnley and Lees, 1991). Unfortunately, 
by the time of clinical diagnosis, substantial neural damage has been wrought, with an 80% 
reduction in striatal dopamine and a 60-70% reduction of the neurons in the substantia nigra 
(Bernheimer et al., 2005).  It is believed that oxidative stress and inflammation play an important 
role in the pathophysiology of PD.  
 
The purpose of this study is to evaluate whether NAC that has been shown to have either anti-
inflammatory or anti-oxidant effects that might support brain function in patients with PD, 
particularly with regard to the dopamine system. One arm of this study will receive intravenous 
and oral NAC, which is a strong antioxidant that increases brain glutathione, that may be 
beneficial in PD. The second arm will be a waitlist control receiving standard PD therapy. It 
should be noted that both arms will receive standard PD therapy. One arm will be augmented 
with the NAC.  Since we are not seeking specifically to determine the use of NAC as a treatment 
for PD, an IND is not required based upon current FDA guidelines.  
 
 
 
1.2    Oxidative Stress in PD 
 
A number of studies have suggested the importance of oxidative stress in the pathophysiology of 
PD. Oxidative stress itself is classically defined as a redox imbalance in which there is an excess 
formation of oxidants or a decrease in amount of function of antioxidants (1). The brain has 
difficulty withstanding substantial amounts of oxidative stress because of the presence of high 
amounts of polyunsaturated fatty acids, low levels of antioxidants such as glutathione, and 
increased iron content in specific areas such as the globus pallidus and the substantia nigra (SN) 
(2).  Finally, since neurons are in a post-mitotic state, they are unlikely to recover from an 
oxidative stress insult.   
 
The mechanism by which oxidative stress occurs begins with the production of reactive oxygen 
species such as superoxide anion (O2−U), hydrogen peroxide (H2O2) and hydroxyl radical 
PD NutS Protocol Clean 2015_10_09 rev 2018_05_10 
 
4 

(UOH), which are byproducts of metabolism of molecular oxygen by the mitochondria. 
Excessive formation of reactive oxygen and nitrogen species in PD may damage key cellular 
components such as lipids, proteins, and DNA.  Reactive nitrogen species such as nitric oxide 
(NO) and its metabolite peroxynitrite (PN) may also play a major role in PD. The “free radical 
hypothesis” has become prominent in attempting to explain the etiology of PD (3). Evidence for 
oxidative damage in the brain of PD patients includes the finding of an increase in the amount of 
lipid peroxidation products such as malondialdehyde and 4-hydroxynonenal, an increase in 
protein oxidation as evidenced by protein cross-linking and fragmentation, and an increase in the 
concentration of 8- hydroxy-2′-deoxyguanosine, a product of DNA oxidation (2).  
 
Additional evidence suggests that reactive oxygen species (ROS) that are derived from the 
combined presence of dopamine itself, low glutathione, and high iron concentrations are a major 
cause of dopaminergic cell loss in the brains of PD patients (4,5). Dopamine is chemically 
unstable and undergoes auto-oxidation to form dopamine quinones (DAQs) and superoxide 
anion radicals. This reaction is catalyzed by the presence of metals, oxygen, and enzymes such as 
tyrosinase. The DAQs can further act as oxidants thus supporting ROS formation. Auto-
oxidation of dopamine may be increased in the early stages of PD when dopamine turnover is 
increased to compensate for dying dopaminergic neurons (6).   
 
Glutathione is an important reducing agent in the neurons, which is found to be depleted in the 
brain of PD patients. Glutathione depletion may result from an accelerated loss of glutathione or 
diminished production. Glutathione is not the only antioxidant molecule reported to be altered in 
PD, but the magnitude of glutathione depletion appears to parallel the severity of the disease and 
is the earliest known indicator of nigral degeneration, apparently preceding detectable losses in 
striatal dopamine (7,8). 
 
Glial cells may also contribute to the problem of oxidative stress in PD even though such cells 
are protected from toxic levels of H2O2 by possessing high levels of glutathione and glutathione 
peroxidase that act to detoxify H2O2 to water. However, dopamine is metabolized into H2O2 in 
glial cells by monoamine oxidases (MAOs). The MAO-B isoform is particularly abundant in the 
substantia nigra and since the H2O2 produced in glial cells by MAO-B is highly membrane-
permeable, H2O2 can cross into neighboring dopaminergic cells. In the dopaminergic cells, 
H2O2 can react with free iron (Fe++) to produce the hydroxyl radical, which can damage 
cellular components.  
 
Iron content in the substantia nigra has been found to be elevated in PD compared to age-
matched controls. Increased levels of iron and Fe (II) enhance the conversion of H2O2 to the 
hydroxyl radical via the Fenton reaction. Furthermore, oxidative stress may enhance the levels of 
free iron via, for example, enhanced release of iron from ferritin by O2. It is not clear whether 
iron accumulation in the substantia nigra in PD patients is an early or late event and/or whether 
increased iron helps cause the neurodegenerative process or is a consequence of the pathological 
process. However, several lines of evidence suggest that iron accumulation along with 
subsequent oxidative stress may be a primary event in the degenerative process (9). For example, 
a number of iron chelators have been shown to attenuate MPTP toxicity suggesting that iron 
either mediates or accentuates the associated neuropathological events (10,11). Another study in 
mice showed that administration of a metal chelator, clioquinol (CQ), in dopaminergic midbrain 
PD NutS Protocol Clean 2015_10_09 rev 2018_05_10 
 
5 

neurons protected them from MPTP mediated neurodegeneration (12). This also resulted in 
attenuation of motor deficits associated with MPTP in the chelator treated mice.    
 
An additional component to the relationship between oxidative stress and PD is related to alpha-
synuclein, a prominent component of Lewy body aggregates (13) which are a pathological 
hallmark of PD. Previous studies have implicated the role of increased oxidative stress in the 
formation of synuclein aggregates (14,15). Conjugation of dopamine with α-synuclein impedes 
the usual transition from protoﬁbril to ﬁber resulting in accumulation of more cytotoxic 
protoﬁbrils in dopaminergic neurons. In addition, several studies have suggested that iron-related 
oxidative stress can promote α-synuclein aggregation (16,17). Furthermore, soluble nitrated α-
synuclein, which results from interactions with oxidated nitrogen species, appears to activate 
microglia to produce substantial amounts of ROS through modulation of speciﬁc ion channels 
(18).  
 
Overall, there appears to be substantial evidence that oxidative stress, and associated nitrosative 
stress, likely play a prominent role in the pathophysiology of PD. The normal homeostasis health 
of a neuron requires adequate maintenance of the redox potential in the cell. When oxidative 
stress occurs, the cell can no longer protect itself resulting in dysfunction and ultimately cell 
death. The question is whether interventions designed to restore the redox potential will be 
effective in attenuating the disease process.  
 
 
 
 
 
 
1.3    Use of N-acetyl cysteine in PD Patients 
 
NAC is the N-acetyl derivative of the naturally occurring amino acid, L-cysteine. It is a common 
over-the-counter supplement and also is available as an injectable pharmaceutical that protects 
the liver in cases of acetaminophen overdose. In the exercise physiology literature, both oral and 
injectable NAC have been shown to reduce fatigue and improve recovery from exertion (19,20), 
which has interesting implications for exploring fatigue related to PD.  
 
Laboratory studies have suggested how NAC might have a beneficial effect in neurodegenerative 
disorders such as PD. For example, one study showed that NAC may reduce misfolded protein 
levels and ameliorate proteotoxicity through heat shock proteins (21). The authors suggested that 
their findings broaden the potential mechanisms of action for NAC in neurodegenerative 
proteinopathies. Another study tested the hypotheses that a combined exposure of nerve cells to 
oxidative stress caused by hydrogen peroxide and paraquat would elicit synergistic 
neurodegeneration and that this toxicity would be prevented by NAC (22). The findings revealed 
that when neuronal N2a cells received two hits of hydrogen peroxide the result was a severe loss 
of glutathione which was attenuated by NAC. In fact, NAC reduced the near-complete loss of 
cells after exposure to dual hydrogen peroxide hits. 
 
NAC can prevent oxidative damage, telomere shortening, and cell death in an in vitro model that 
disrupts mitochondrial electron transport function. Thus, NAC could act in vivo against 
programmed cell death in PD (23). Long-term treatment with NAC alters NF-kappaB signaling 
in the brain of mice by increasing cytoplasmic retention of NF-kappaB. This prevents the action 
of NF-kappaB as a transcription factor in the nucleus (24) Since increased activation of NF-
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kappaB may contribute to the pathology in models of Parkinson’s disease, it is possible that the 
modulating effect of NAC on NF-kappaB activity may be another mechanism by which NAC 
helps patients with PD (25,26).  
 
Another interesting study showed that NAC is a potent scavenger of both H2O2 and toxic 
quinones that are derived from dopamine which can contribute to cell death in PD. NAC also 
prevented dopamine-mediated inhibition of Na+, K+-ATPase activity suggesting another 
mechanism for the use of NAC in the treatment of PD (27). If NAC prevents Na+, K+-ATPase 
inhibition, it might counteract intracellular damage that leads to dopaminergic neuron death. 
A study of rat neurons found that NAC reduced methamphetamine induced neurotoxicity in 
dopaminergic neuronal cells (N27 cells) (28).  Thus, NAC prevents the methamphetamine 
induced mitochondrial dysfunction and enhanced oxidative stress that induces apoptotic cell 
death as well as oxidative stress markers. 
 
In animal studies, the administration of NAC has been shown to increase glutathione levels in the 
mouse brain (29,30). NAC also has been shown to reduce markers of oxidative damage (31), 
increase mitochondrial Complex I activity in nerve cells (32), and protect against dopamine cell 
death from MPTP toxicity (33,34,35).  
 
In a mouse study, oral NAC was observed to protect dopaminergic terminals against loss related 
to over-expression of α-synuclein (36). In α-synuclein over-expressing mice, NAC 
administration was associated with increased striatal tyrosine hydroxylase positive terminal 
density and a decrease in α-synuclein immuno-labeling. In addition, NAC administration 
significantly increased glutathione concentrations in the substantia nigra of mice over-expressing 
α-synuclein.  
A study of EAAC1(-/-) mice (these animals have neurons with impaired neuronal cysteine 
uptake, resulting in reduced neuronal glutathione content and chronic oxidative stress), showed 
substantially reduced neuronal loss when treated with NAC (37). The authors suggested that 
their approach may be a useful model for the chronic neuronal oxidative stress that occurs in PD 
and that the beneficial effects of NAC might provide an impetus for clinical evaluation of 
glutathione repletion in PD. 
Finally, in humans, an MRS study of 3 patients with PD showed that Blood glutathione increased 
after the start of an NAC infusion and reached a maximum at approximately 60 to 75 minutes 
(38). Brain glutathione also increased with maximal values observed at approximately 90 to 110 
minutes. Subjects who had the greatest percent change in blood glutathione after NAC infusion 
also had the greatest percent change in brain glutathione. The mean maximal percent change 
from baseline in brain glutathione was 55% in the PD patients and this was higher than the mean 
increase in patients with Gaucher’s disease or healthy controls. Interestingly, none of the subjects 
returned to their baseline brain glutathione levels even at 120 minutes after NAC infusion. The 
results suggest that NAC might be useful in preventing oxidative damage in PD patients.  
 
This also builds on a related study that investigated the possible direct benefit of intravenous 
glutathione using a randomized double blind placebo controlled study by Hauser et al (39) of 21 
PD patients.  The patients with PD had motor symptoms that were not adequately controlled on 
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medication. Subjects were randomly assigned to receive intravenous glutathione  1,400 mg or 
placebo three times a week for 4 weeks. NAC was well tolerated with no difference in adverse 
events between the placebo and NAC groups. There were no significant differences in changes in 
Unified Parkinson's Disease Rating Scale (UPDRS) scores. Over the 4 weeks of study 
medication administration, UPDRS ADL + motor scores improved by a mean of 2.8 units more 
in the glutathione group (P = 0.32), and over the subsequent 8 weeks worsened by a mean of 3.5 
units more in the glutathione group (P = 0.54). This data suggests an improvement that was not 
maintained consistently after completing intravenous glutathione. The lack of statistical 
significance was likely due to the small sample size and the confounding factor of different 
medications taken by patients. The authors point out that the results suggest the possibility of a 
symptomatic effect, which requires evaluation in a larger study. In addition, a longer treatment 
period may be required. However, since we are providing the supplements for a 3 month period, 
subjects would have to receive 36 glutathione infusions (3x per week for 12 weeks). The 
advantage of NAC is that it can be given both IV and orally so patients only need to have an 
injection 1x per week while they take the oral NAC every other day. Further, as the evidence 
above shows, NAC has the ability to increase glutathione levels in the brain. 
 
1.4    Utilizing SPECT to measure the dopamine transporter in PD patients 
 
A key component of our program is to evaluate the effects of NAC  on dopamine, using SPECT 
imaging, the relative function of key dopamine-containing regions of the brain in PD patients 
receiving oral and IV NAC.  Specifically, we will plan to study changes in the dopamine 
transporter (DAT) which reflects the overall health of the dopaminergic system. DAT 
availability declines with age and declines more rapidly in patients with PD. By measuring the 
DAT binding before and after receiving approximately 90 days of nutritional support, we can 
evaluate whether either of the arms receiving supplements helps to support dopamine function.  
 
 
The DAT mediates the reuptake of free dopamine from the synaptic cleft back into the axonal 
bouton (40).  The DAT complex includes a dopamine receptor portion, which is exposed to the 
intrasynaptic milieu.  When free dopamine in the intrasynaptic space binds to the receptor 
portion, a conformational change occurs in the structure of the transporter complex that 
physically moves, or “transports”, dopamine across the axonal membrane against a concentration 
gradient.  Once inside the axonal bouton, structurally intact dopamine molecules can then be 
conserved by being repackaged within the storage vesicles.  Alternatively, the level of dopamine, 
and hence the tone of the dopaminergic system, can be reduced by oxidative enzymes in the 
cytoplasm that make it unavailable for another transmission.  The rate at which dopamine is 
removed from the synaptic cleft is one of the primary mechanisms for maintaining constant 
dopaminergic tone. As a result, the regional concentration of transporters tends to reflect the tone 
of the dopamine nervous system in that area (41,42). This has made the DAT the focus of 
research in many neuropsychiatric diseases in which dopamine dysfunction has been implicated.  
 
Dopamine transporters may become one of the primary markers for Parkinson’s disease in living 
patients for several reasons. They are living parts of the neurons that are most affected by the 
disease, and reflect their health. They are physically coupled with almost all of the diencephalic 
cells that become dysfunctional. This explains why messenger RNA levels for the dopamine 
transporter are decreased in the midbrains of patients with Parkinson’s disease. Neuroimaging 
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studies reflect the same phenomenon by visualizing decreased transporter binding in the basal 
ganglia, that is, the distant regions to which the affected nigral cells project.  
 
 
 
Studies of the presynaptic dopamine transporters in patients with symptomatic Parkinson's 
disease have been consistently positive, regardless of whether PET (43,44) or SPECT (45) 
imaging agents have been used.   Exquisite sensitivity may reflect the observation that 
transporter concentrations decrease more rapidly than the number of axon terminals in animal 
models (46).  This tends to keep the intrasynaptic levels of free dopamine constant.  If the 
capacity of the sick neurons to produce dopamine decreases, then reducing the rate at which 
dopamine is removed from the synaptic cleft tends to move intrasynaptic dopaminergic levels 
back toward normal.  This suggests that the transporter can be an effective marker for studying 
longitudinal changes in dopaminergic tone, and thus help to assess the effectiveness of 
interventions to treat PD. 
 
One of the most widely used tracers for the evaluation of the DAT in PD patients is I-123 
isoflupane (FP-CIT or DaTSCAN). This tracer is approved for clinical use in the US. A number 
of research studies have shown that DaTSCAN is able to differentiate PD from controls (47,48) 
and other related disorders (49,50). DaTSCAN has also been shown to correlate with disease 
severity (51,52). Finally, DaTSCAN and related tracers have been utilized for the evaluation of 
different therapeutic interventions (53,54). For these reasons, DaTSCAN is an excellent tracer 
for evaluating whether oral supplementation as described in this study, supports dopamine 
function in the brain of PD patients. 
 
Thus, a key component of our program is to evaluate, using SPECT imaging, the relative 
function of key dopamine-containing regions of the brain in PD patients receiving oral and IV 
NAC.  Specifically, we will plan to study changes in the dopamine transporter (DAT) which 
reflects the overall health of the dopaminergic system. DAT availability declines with age and 
declines more rapidly in patients with PD. By measuring the DAT binding before and after 
receiving approximately 90 days of nutritional support, we can evaluate whether receiving NAC 
helps to support dopamine function. The SPECT DaTScan is capable of determining the 
improvements in dopamine function associated with NAC. 
  
1.6    Utilizing Magnetic Resonance Spectroscopy (MRS) to measure changes in the chemical 
milieu in brain of PD patients 
 
 It will also be beneficial to assess whether there are specific changes in levels of different 
molecules that are related to energy consumption and oxidative stress. Proton MR spectroscopy 
(1H-MRS) has been previously performed in Parkinson's disease (PD) and parkinsonian 
syndromes to evaluate in vivo concentrations of basal ganglia and cerebral cortex metabolites 
such as N-acetylaspartate (NAA), choline (Cho), and creatine (Cr) (55). This technique has been 
used to evaluate both the basal ganglia and motor cortex in PD patients (56,57). For example, 
one study showed a significant reduction in the NAA/Cr ratio in the motor cortex of PD patients 
compared with controls. Other studies have revealed inconclusive findings in the basal ganglia in 
PD patients. However, several studies have observed changes in MRS in PD patients in response 
to therapy. For example, one study demonstrated that after 6 months of therapy with pergolide, 
PD patients showed an improvement in motor performances and an increase in Cho/Cr ratios in 
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9 

the motor cortex (58). The authors concluded that dopaminergic therapy capable of improving 
motor function might restore the Cho/Cr ratio in the motor cortex. While there are no MRS 
studies of glutathione concentrations in PD patients, the glutathione level is associated with the 
level of oxidative stress and has been measured in several other pathological conditions such as 
head trauma, stroke, and Alzheimer’s disease (59,60,61). Thus, we plan to include MRS as an 
additional biomarker to evaluate the potential effects of the nutritional supplements and/or NAC 
on oxidative stress and cerebral activity in PD patients. 
 
2.0       OBJECTIVES 
2.1 
Evaluate Nutritional Supplementation with intravenous/oral NAC. 
 
2.1.1 To evaluate if oral supplementation or intravenous/oral NAC as described below helps to 
support dopamine function in the brain of patients with PD by measuring clinical symptoms. 
 
2.1.2 To evaluate whether intravenous/oral NAC helps to support dopamine function in the 
brain of patients with PD by measuring changes in the dopamine transporter using DaTScan 
SPECT imaging. 
 
2.1.3 To evaluate whether intravenous/oral NAC as described below helps to support changes 
in oxidative stress and metabolism, as measured by magnetic resonance spectroscopy (MRS), in 
patients with PD. 
 
3.0       STUDY PLAN 
3.1 Subject Recruitment 
 
Subjects may be pre-screened by telephone using a standardized script and screening form.  
Verbal consent and HIPAA Authorization to obtain the prescreening information will be 
obtained from subjects prior to the prescreening interview. If subjects are prescreened in person, 
a signed consent and HIPAA Authorization to obtain prescreening information will be obtained. 
Information collected during pre-screening will be incorporated into the research records as 
source documentation for subjects included in the study. If subjects are not eligible to participate 
in the study they will be asked if the information provided in during prescreening maybe retained 
for consideration in other studies. Prescreening information will be retained for an indefinite 
period on an official screening form that will be kept in a secure locked area that will only be 
used by persons involved with research with this research Study.  
 
We plan on recruiting up to 65 subjects over 3 years with the goal of recruiting 28 subjects who 
will receive  approximately 90 days of combined intravenous/oral NAC, and then 14 subjects 
who will be in the waitlist control group receiving standard of care to be evaluated initially and 
then  approximately 90 days later.  This will allow for an attrition rate of up to one third.  At the 
conclusion of the study, those in the waitlist control group will be given the option to receive a 
trial of oral/intravenous NAC if the data suggests that NAC is effective.  All of the study subjects 
must be clinically diagnosed with PD by a referring neurologist. Subjects may be assessed using 
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structured examinations (i.e., the Unified Parkinson’s Disease Rating Scale (UPDRS) or 
Movement Disorder Society (MDS) Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) 
and/or the Hoehn and Yahr scale. Diagnostic criteria will be applied using structured 
questionnaires, clinical interviews, and neurological examinations.  Additional information is 
gathered, whenever possible, from family members, caregivers, review of previous medical 
records, and physical and laboratory examination.  Subjects may take PD medications, but must 
be on a stable dose for at least 1 month prior to entering into the study.  
 
To receive a diagnosis of clinically probable Parkinson’s disease, the disease must be 
progressive, and at least two of the three cardinal signs of PD must be present (bradykinesia, 
rigidity, and tremor).  Additionally, at least two of the following must also exist: (a) asymmetry 
of signs, (b) asymmetry at onset, (c) absence of characteristics of alternative diagnoses, (d) 
absence of another etiology known to cause similar features (e.g. neuroleptics).  
 
PD NutS Protocol Clean 2015_10_09 rev 2018_05_10 
 
11 

 
 
3.1.1 Flow Chart 
 
 
 
Informed Consent 
Form 
Initial Evaluation {N = 65 
subjects}: 
Neurological evaluations (MMSE, 
POMS, PD-39) for PD symptoms 
Randomization 
Prescreening 
Meets all inclusion and 
exclusion criteria 
NO 
NOT Eligible 
  YES 
Eligible 
Completed Scans: 
SPECT and MRS 
scans 
  YES 
NO 
Removed from 
Study 
Intravenous/Oral NAC Group 
{N = 28}: 
IV NAC 1x a week plus oral 
NAC 600mg 2x/day for 
approximately 3 months until 
the final evaluation 
Waitlist Control Group  
{N = 14}: for approximately 3 
months until the final evaluation 
Final Evaluation 
approximately 90 days into 
waitlist period: 
DaT scan, MRS scan, and 
neurological reevaluation to 
test response 
Final Evaluation 
approximately 90 days after 
beginning supplements: 
DaT scan, MRS scan, and 
neurological reevaluation to 
test response  
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3.1.2 Inclusion criteria 
  
 
 
1. 
Clinical diagnosis of PD 
2. 
Age 30-80 years old 
3. 
Physically independent, ambulatory  
4. 
Hoehn and Yahr score of I-III inclusive. 
5. 
On stable antiparkinsonian medication for at least one month 
6. 
Women of childbearing potential will confirm a negative pregnancy test and must 
practice effective contraception during the period of pilot study.  In addition, male 
subjects who have a partner of childbearing age should practice effective contraception.   
 
3.1.3 Exclusion criteria 
  
 
 
1. 
Known allergy to iodine, cobalt, or NAC that will be given in the study. 
2. 
Previous brain surgery. 
3. 
Score on Mini-Mental Status examination of 25 or lower. 
4. 
Wheelchair-bound or bed-ridden, non-ambulatory. 
5. 
Intracranial abnormalities that may complicate interpretation of the brain scans (e.g., 
stroke, tumor, vascular abnormality affecting the target area). 
6. 
History of head trauma with loss of consciousness > 48 hours. 
7. 
Any medical disorder or physical condition that could reasonably be expected to interfere 
with the assessment of parkinsonian syndrome symptoms, or with any of the study 
assessments including the SPECT imaging. 
8. 
Patients with evidence of a significant psychiatric disorder by history/examination that 
would prevent completion of the study will not be allowed to participate. 
9. 
Patients with current alcohol or drug abuse 
10. 
Pregnant or lactating women. 
11. 
Enrollment in active clinical trial/ experimental therapy within the prior 30 days. 
12. 
Pending surgery during the course of the study. 
13. 
History of very low blood pressure. 
14. 
History of thrombocytopenia or clotting disorders. 
15. 
Cancer patients receiving active chemotherapy. 
16. 
History of active gallstone problems or a bile duct obstruction. 
17. 
Severe gastroesophageal reflux disease. 
18. 
History of uncontrolled diabetes, asthma, gastroesophageal reflux disease, thyroid 
conditions.  
19. 
History of severe kidney disease (if a patient reports this problem, a serum creatinine will 
be checked to assess GFR and if it is less than 30, they will be excluded), 
20. 
History of Leber’s disease, a hereditary eye disease. 
21. 
History of uncontrolled hypercalcemia 
22. 
History of active sarcoidosis, histoplasmosis, or lymphoma. 
PD NutS Protocol Clean 2015_10_09 rev 2018_05_10 
 
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23. 
Patients taking medications that might interact with NAC involved in this study will be 
evaluated on a case by case basis by the PI or study physician. These medications 
include: Medications for high blood pressure; Medications that slow blood clotting; 
Medications for diabetes; Nitroglycerin. 
 
3.2  
Registration Guidelines and Recruitment  
 
 
Study subjects initially will be recruited by referral from the Jefferson Movement Disorders 
Clinic and local neurology groups. If any recruitment materials are developed, they will not be 
distributed without IRB approval. 
 
The subject population is derived from the greater Philadelphia area, which represents a racially 
and economically diverse population.  We will make efforts for this protocol to be widely 
accessible, including offering the procedures protocol without charge to the subject.  
 
3.3  
Treatment Plan:  
 
3.3.1 Informed consent will be obtained from all subjects before protocol specific activities are 
carried out.  The subject will be informed about the limited data on oral supplementation and 
intravenous/oral NAC to support brain health in PD patients, possible risks and benefits, and 
possible adverse events. Informed consent will be documented by use of written consent form 
approved by the Institutional Review Board at Thomas Jefferson University and signed by the 
subject or the subject’s legal guardian.  History, physical and neurological examination, and 
initial SPECT and MRS procedures (see below) will begin within 14 days of the informed 
consent process. Subjects will be receive either intravenous/oral NAC, or be placed on the 
waitlist control.   
 
After approximately 90 days of receiving the supplements, subjects will undergo a follow up 
evaluation, which includes repeat neurological assessments, SPECT, and MRS. Note that 
subjects will continue taking the oral NAC until the scans are completed. Subjects will also 
continue to take their current Parkinson’s medication regimen so that they will continue to 
receive standard of care treatment throughout the study. It is hoped that their standard of care 
treatment will remain constant throughout the course of the study, but their referring neurologist 
may adjust their medications as medically necessary. 
 
3.3.2  N-Acetylcysteine will be obtained from the Jefferson Pharmacy (NAC is also called 
Acetadote; Cumberland Pharmaceuticals).  NAC is an intravenous (IV) medication for the 
treatment of acetaminophen overdose. Acetylcysteine is the nonproprietary name for the N-
acetyl derivative of the naturally occurring amino acid, L-cysteine (N-acetyl-L-cysteine, NAC). 
Acetadote is supplied as a sterile solution in vials containing 200 mg/mL acetylcysteine. The pH 
of the solution ranges from 6.0 to 7.5. Acetadote contains the following inactive ingredients: 0.5 
mg/mL disodium edetate, sodium hydroxide (used for pH adjustment), and Sterile Water for 
Injection, USP. 
 
PD NutS Protocol Clean 2015_10_09 rev 2018_05_10 
 
14 

For the oral supplement, NAC is obtained by the Jefferson Pharmacy at 908 Walnut Street and 
supplied by Vital Nutrients (produced under GMP) as a 600mg capsule of N-acetyl cysteine. The 
following inactive ingredients are also included: Ascorbyl Palmitate, Gelatin, Rice, Silica. The 
capsules contain no coatings, binders, fillers, or dairy, wheat, eggs, soy, yeast, commercial 
sugars, starch, preservatives, or hydrogenated oil. 
 
NAC doses will be prepared for each patient by the study nurse. The dose will be 50mg/kg in 
approximately 200ml of D5W infused over approximately one hour 1x per week. The IV bag 
containing NAC is labeled as a research medication. Subjects will also receive 600mg NAC 
tablets supplied by the Jefferson Pharmacy and will take 1 tablet 2x per day on the days that they 
do not receive the IV NAC. 
 
3.4 
Criteria for Removal from / Cessation of Protocol 
 
3.4.1 Measuring Endpoints: Endpoints will be measured after receiving oral/intravenous NAC, 
or being on the waitlist for 90 days. Any serious adverse events also will result in immediate 
discontinuation of the subject from the study. 
 
3.4.2  Subject Withdrawal: The subject may withdraw from the study at any time for any 
reason. 
 
3.4.3  Missing Appointments: Missing a total of 5 or more days of the supplements or 5 doses 
of the intravenous NAC as per the PI.  
 
 
All reasons for discontinuation of procedure will be documented in study flow sheets.  
 
 
3.5 
Adverse Events 
 
The OHRP defines an adverse event as “any untoward or unfavorable medical occurrence in a 
human subject, including any abnormal sign, symptom, or disease, temporally associated with 
the subject’s participation in the research.”  Adverse events can additionally be classified as an 
unanticipated problem, meaning it was not expected to occur during the course of the research.  
If an unexpected adverse event were to occur, it then needs to be determined whether or not it is 
due to the research being conducted.  If the event is a result of the research procedures, most 
likely the event is directly connected to the subject’s participation in the research. It is also vital 
to determine whether an adverse event is serious.  The OHRP defines a serious adverse event as 
one that a) results in death, b) is life-threatening, c) results in patient hospitalization or 
prolongation of existing hospitalization, d) results in persistent or significant 
disability/incapacity, e) results in congenital anomaly, or f) jeopardizes the subject’s health to the 
point where they may need medical or surgical intervention. If the adverse event is unexpected, 
related to the research, and serious (where it is causing harm to subjects), then it is also classified 
as an unanticipated problem and must be reported to the Thomas Jefferson University Hospital 
IRB.  All adverse events will be reported in accordance with Jefferson IRB Adverse Events 
Report. The IRB shall be notified in a written safety report if any serious and unexpected adverse 
PD NutS Protocol Clean 2015_10_09 rev 2018_05_10 
 
15 

experience associated with the use of the oral or intravenous nutritional supplements occurs.   
 
3.6 
Data Collection and Submission Schedule  
 
3.6.1 Data Submission: Data must be submitted according to the protocol requirements for all 
subjects registered, whether or not assigned treatment is administered. 
 
3.6.2 Master files, such as case report forms and progress reports, are monitored by the study 
coordinator, Nancy Wintering.  Case report forms will include eligibility checklist, demographic 
data, baseline history, adverse events, and off-study documents.  These will be completed by 
study staff under the supervision of the investigators or the project manager.     
 
 
3.7.  
Clinical Response 
 
Subjects will be evaluated utilizing the UPDRS scores to determine any improvements in PD 
symptoms. Subjects will also be evaluated using the Profile of Moods Scale, Beck Depression 
Inventory, Mini-Mental Status Exam, and Parkinson’s disease Questionnaire-39. These will be 
obtained initially and after approximately 90 days of taking the supplements. 
 
3.7.1 SPECT Imaging Procedure 
 
 
(a) Subject Preparation - An indwelling catheter needle will be inserted into an antecubital vein. 
DaTSCAN will be administered through the indwelling line. 
 
(b) DaTSCAN SPECT Imaging Procedure – Subjects will receive a standard of care DaTScan 
initially and after completing the NAC regimen. Subjects will be asked to arrive at the Nuclear 
Medicine SPECT Center on the day of the study. A signed informed consent form will be 
documented after all questions have been answered. Women of childbearing potential must have 
had a negative pregnancy test within 48 hours before proceeding with the SPECT study. The 
intravenous catheter will be inserted and capped. Approximately 30 minutes prior to injection of 
the DaTSCAN, the patient will be given an oral dose of lugol’s solution, which is the standard of 
care for these scans. Lugol’s solution helps to protect the thyroid from additional radioactive 
exposure from the DaTSCAN tracer. DaTSCAN (4-5 mCi, ± 20%) will be injected 
intravenously. After injection of the DaTSCAN, the venous catheter will be removed, and then 
the subject permitted to get off the examination table. Subjects can then take a break for lunch. 
Subjects will receive an MRI to assist with anatomic delineation. In addition, the MRI session 
will be utilized in order to obtain data via MR Spectroscopy (MRS), which can provide a 
measure of various metabolites, such as glutathione, in specific brain structures (please see 
below).   
 
(c) Image Acquisition and Processing - The dose of DaTSCAN will be injected in an antecubital 
vein, and SPECT images acquired at approximately 3 hours post injection for about one hour.  
This will enable us to obtain quantitative regional uptake values as determined by our previously 
described reference region method. All scans will be performed on a Philips Forte gamma 
camera or equivalent camera equipped with ultra-high resolution collimators. All the images will 
PD NutS Protocol Clean 2015_10_09 rev 2018_05_10 
 
16 

be reconstructed using filtered back projection. Chang's first order correction method is used to 
compensate for photon attenuation. 
Manual demarcation of brain regions - A set of standardized templates containing small ROIs 
will be fit on each DaTSCAN. Within the x-y plane, small ROIs in the template will be smaller 
than the actual structures they represent in order to minimize resolution-induced problems with 
ill-defined edges. To reduce the effects of volume averaging in the axial direction, the small 
ROIs will not be placed on the slices that contained the upper most and lower most portions of 
the structures they represent. This will tend to limit the small ROIs to the central aspect of 
structures they represent. The primary outcome measure will be the specific uptake values at 3 to 
4 hours post administration, when the distribution of DaTSCAN has approached a transient, near 
equilibrium like state that reflects the ratio of k3/k4, which is related to binding potential. This 
allows for a quantitative assessment of dopamine transporter activity. Again, scanning at this 
time of a pseudo-equilibrium state allows for quantitative analysis using a region of interest 
analysis with a background region as an index of nonspecific binding. 
As described above, it is probably not necessary to account for volumetric changes especially 
since the ROIs will be smaller than the actual structures.  However, since all scans will have 
MRI correlation for adequate placement, volumes of the basal ganglia structures can be 
determined and utilized as an additional analysis. The reference region has typically been the 
cerebellum or the brain regions above the level of the basal ganglia, corresponding to areas of the 
brain, which have very low concentrations of DAT. However, values will be obtained for both 
whole brain regions above the basal ganglia and cerebellar regions in order to confirm the 
findings.  
Statistical Parametric Mapping (SPM) will also be performed on the images in order to compare 
the pre- and post-intervention scans in PD subjects. SPM is currently considered to be a highly 
successful analytical tool for evaluating of SPECT brain images, and will be included in the 
analysis.  
3.7.3 MR Spectroscopy Procedure 
 
 
A brain proton magnetic resonance spectroscopic imaging (1H MRS) will be performed in the 
Department of Radiology at Thomas Jefferson University and Hospital over approximately one 
hour.  The sections of the brain scanned will be oriented obliquely along the AC/PC line. 
Cortical and subcortical structures such as the basal ganglia will be evaluated for the following 
metabolites: glutathione; N-acetylaspartate (or NAA, an indicator of neuronal integrity), 
creatine+phosphocreatine (CR, important in cell energetics), choline (CHO, involved in cell 
membrane biosynthesis/degradation), and lactate (LAC, end product of glycolysis or anaerobic 
metabolism). Statistical Parametric Mapping will be used to determine the differences in the 
concentrations of the various metabolites before and after receiving intravenous/oral NAC. In 
addition, connectivity and resting cerebral blood flow can be measured during the same imaging 
session. 
 
3.8 
Statistical Considerations 
 
 
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3.8.1    Descriptive and Exploratory Analyses: The initial analyses of the data will be descriptive 
in nature. Using means, standard deviations, median, and range, the distribution volume ratios 
(DVRs) will be described for each time point before and after subjects have used the nutritional 
supplementation for approximately 90 days. Similarly, the clinical scores will be described for 
each time point. Graphical methods, such as plots of measurements over time, histograms, and 
boxplots are important tools for understanding the quality of the data, and assessing assumptions 
underlying statistical models (such as normality). Transformations will be applied as necessary 
to satisfy these assumptions.  Plots of all of the measured variables over time will be important to 
assess longitudinal patterns of change.   
 
3.8.2    Analyses for Primary Objectives: To evaluate whether intravenous/oral NAC helps to 
support dopamine function in the brain of patients with PD by measuring changes in the 
dopamine transporter. To accommodate the longitudinal nature of the data, a Heterogeneous 
Random Coefficients Model (62,63) will be fit for the DVRs in each region for the DaTSCAN 
binding and each neurobehavioral score (i.e. UPDRS scores). This model can also account for 
both between and within subject heterogeneity and will accommodate modeling potentially 
nonlinear therapeutic effects over time.  The random coefficients model is more flexible in terms 
of modeling the changes in DVRs and neuropsychological tests over time than repeated 
measures analyses of variance.  The random coefficients model also has fewer restrictions on the 
correlation structure between multiple measures within subjects. ANCOVA will be used in order 
to determine if there are correlations between the pre-intervention neuropsychological and 
clinical measures and the longitudinal outcome measures after receiving oral or intravenous 
supplementation.  This analysis will also evaluate whether the DaTSCAN DVRs can be utilized 
as a predictor for outcome.  To determine if there is a correlation between changes in DAT 
binding and symptom severity, Pearson product-moment correlations will be computed unless 
the normality assumption is violated, in which case the Spearman rank correlation will be 
computed.  
 
3.8.3 Image analysis with SPM: 
 
Rationale for using SPM. The traditional method for analyzing brain SPECT images involves the 
placement of a number of ROI's on the image (as described above), and measuring the mean 
counts within that ROI. It has long been known that ROI definition, particularly on functional 
images, is time-consuming, subjective and prone to operator bias (64). Small regular ROI's are 
capable of resolving localized changes between images, although they are subject to a loss of 
specificity due to problems associated with multiple comparisons. Alternatively, large ROI's 
encompassing an entire brain structure may dilute small activation foci with a subsequent loss of 
sensitivity. Unless a study is strongly hypothesis driven, and comparisons between images are 
only made in highly specific regions; ROI analysis lacks the power to distinguish regional 
variations between a set of images accurately. The solution to this problem has been the 
development of pixel-based statistical analyses where the regions are effectively reduced to 
single pixels (65).  Our group has applied SPM, and other voxel-based techniques, to cerebral 
blood flow and binding site studies previously (66) and has considerable experience in these 
methods. 
PD NutS Protocol Clean 2015_10_09 rev 2018_05_10 
 
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SPM analysis. A typical SPM analysis of a set of brain scans can be reduced to three essentially 
independent steps: image normalization, statistical analysis, and significance assessment.  Once 
images are normalized to a standard template, pixel-by-pixel statistical tests are performed 
comparing the individual scans and correcting for inter-scan and inter-subject variability. This 
leads to the generation of (uncorrected) parametric images of significant differences.  In the 
absence of absolute quantification, an important feature of SPM is the method of normalizing 
each individual scan to prevent inter-subject and inter-scan variability masking regional changes. 
The regional activity is normalized to a reference value derived independently from each image. 
This reference must accurately reflect an unbiased baseline of activity not affected by the disease 
or activation under study. For cerebral binding sites, the normalizing factor is usually a measure 
of background activity such as counts in the cerebellum. This is the background region used in 
the equilibrium model of DaTSCAN binding, giving a semi-quantitative measure of tracer 
uptake that is proportional to the binding potential. 
 
Significance assessment. The statistical parametric maps represent significant differences at the 
pixel-level. However, in a typical brain image, there are many thousands of pixels, and the 
probability that many of them will be significant purely by chance is high, even for tight 
thresholds. The final step in SPM assesses the significance of clusters of suprathreshold pixels, 
correcting for the effects of such a large number of correlated multiple comparisons using the 
theory of random Gaussian fields. Statistically significant differences between and baseline and 
post-treatment scans will be assessed at each voxel with a threshold of P < 0.001. To correct for 
correlated multiple comparisons, clusters of voxels which survive this threshold will be assessed 
further using the theory of random Gaussian fields (67,68), which calculates the significance of 
clusters based on their peak height and spatial extent.  Due to the limited volume of the striatum, 
the small volume correction will be used within SPM, allowing a more sensitive test.  With this 
technique, differences in DaTSCAN binding between baseline and post-treatment scans will be 
assessed, and statistic images generated showing significant regional differences. A correlational 
analysis with various neuropsychological parameters such as the UPDRS, profile of mood scale, 
and Parkinson’s Disease Questionnaire will also be performed with SPM. Similar analysis will 
be performed for the MRS data, which will compare the concentration of the specific molecules 
measured by MRS before and after three months of the nutritional supplementation program. 
 
3.8.4 Power Analysis:  We view this study primarily as a pilot study to assess changes in 
physiological and clinical measures and determine the effect size for powering future, larger 
trials. However, we estimated the sample size needed based upon prior research we have 
performed evaluating DAT imaging in the study of PD patients. We have previously found that 
the PD patients can have variability in their DVR measures of dopamine binding of 
approximately 10%. If we expect a 5-10% improvement in the treatment groups, for an 80% 
power to detect a significant change of p=0.05, we would need approximately 28 subjects in the 
treatment arms and approximately 14 subjects in the control arm. The statistical analyses for the 
proposed study will consist of 1) repeated measures two-way ANOVA, and 2) linear regression. 
Both methods are more powerful than simple t-tests on which these estimates are based.  Thus, 
we plan to recruit up to 65 subjects, to allow for attrition which could be as high as one third, 
who would then be randomized into the two groups in a 2:1 ratio until the groups are complete.  
PD NutS Protocol Clean 2015_10_09 rev 2018_05_10 
 
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3.8.5 Randomization: Randomization will occur via a 2:1 ratio of the NAC group and the 
waitlist control groups using the method of random permuted blocks with random block sizes 
without stratification.  
 
 
4.0  
RISKS 
 
4.1 
N-acetyl cysteine: Oral NAC has few side-effects and is commonly used as an over-the-
counter supplement worldwide. Oral NAC has good, but variable absorption from the gut 
(69,70), making it problematic as the sole mode of supplementation in a clinical study. Injectable 
NAC is used at lower doses for exercise fatigue and higher doses primarily as a liver protector. 
The dosages in this study are consistent with those used in the exercise physiology literature 
(71). Side effects increase with higher dosage, and the most common associated adverse 
reactions in the literature attributed to IV NAC administration are rash, urticaria, and pruritus. 
The frequency of adverse events has been reported to be between 0.2% and 20.8%, and they 
most commonly occur during the initial loading dose of acetylcysteine at dosages higher than 
what will be used in this study. Other side effects with greater than 1% occurrence include 
nausea and bronchospasm, again at higher dosages. A hypersensitivity reaction to NAC has been 
reported as a rare occurrence. NAC should be used with caution in patients with asthma. Please 
note that the oral and intravenous NAC dose used in this study is the same as one we have used 
in a study of NAC in women with breast cancer. We have found the NAC to be generally well 
tolerated at the doses we will be using in the current study. 
 
4.2 
Oral NAC/intravenous Supplements:  
4.2.1 Supplements, Doses, and Risks 
General Risks: No formal interaction studies have been performed in the literature. Thus, it is 
possible that they may interact with each other and produce side effects as described below or 
additional side effects.  Any supplement could result in an allergic reaction. We will ask subjects 
to report any unusual feelings they have while receiving the supplements. In addition, the 
supplements could interact with different medications. We will evaluate to determine if patients 
are taking any of the following: 
 
1. Medications for high blood pressure. 
2. Medications that slow blood clotting.  
3. Medications for diabetes. 
4. Nitroglycerin. 
 
We will review each patient’s medications to determine if there may be some potential risk for 
taking the NAC. For medications used for moderate to severe conditions as determined by the PI, 
subjects will be excluded. For medications used for mild conditions, we will discuss with the 
patient and also their doctor how to closely monitor any changes in their response to the 
medications while on the study.  
 
PD NutS Protocol Clean 2015_10_09 rev 2018_05_10 
 
20 

4.3 
Potential Risks of DaTScan:  The I-123 DaTSCAN is a commercially available 
radioactive tracer that will be used according to its dose, route, and indication, but results in 
some exposure to ionizing radiation.  The amount is acceptable for the research subjects who will 
directly benefit by receiving full clinical reads of these scans that their referring physician can 
utilize for determination of prognosis and treatment planning. Subjects will be required to lie still 
on the imaging table for 30-60 minutes, which can be uncomfortable. 
 
 
 
 
 
 
4.4 
Special Risk Factors:  Injection of DaTscan requires the routine clinical pre-
administration of Lugol’s solution in order to protect the thyroid from radioactive exposure. The 
Lugol’s solution is usually given in juice; it sometimes causes people to have a temporary 
strange taste in their mouth or a feeling of discomfort in their salivary glands.  
 
 
 
 
 
 
4.5 
Risks of venous cannulation:  Venous cannulation is a routine clinical procedure that 
carries minimal risks when performed by trained personnel.  It is possible that bruising could 
occur in some subjects.  There is a theoretical risk of phlebitis or infection, which is very remote.   
 
4.6 
Magnetic Resonance Spectroscopy: MRS is performed in an MRI scanner, requires a 
magnetic field. MRS can be dangerous if a person has metal or metallic objects in their body. 
Subjects will be thoroughly screened to ensure that they have no metal in their body. Because of 
the magnetic field, metallic objects can move into the scanner and potentially injure the patient. 
All precautions are taken to ensure that no such metallic objects are in the scanning room that 
could result in an injury. The MRS requires the patient to lie still for approximately 1 hour, 
which can be uncomfortable, or be claustrophobic. 
 
 
PD NutS Protocol Clean 2015_10_09 rev 2018_05_10 
 
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5.0 
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