Neurobiological Drivers of Mobility Resilience: The Dopaminergic System
Phase: PHASE1
Conditions: Parkinsonian Signs in Older Persons
Sponsor: University of Michigan

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Study Title: Neurobiological Drivers of Mobility Resilience: The Dopaminergic System 
PI: Fay Pongmala, PhD  
Study ID: HUM00156490  
NCT#: NCT06587217  
Protocol Version IRB Approval Date: 3/4/2026 
 
 

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Neurobiological drivers of mobility resilience: the dopaminergic system 
 
1. SPECIFIC AIM 
 
 
Walking with age becomes both slower and less ‘automated’, requiring more attention and 
prefrontal resources1,2. As a result, older adults have a greater risk of adverse mobility 
outcomes and falls. Walking disturbances in the elderly have been linked to changes in 
both cerebral, in particular small vessel disease (cSVD), and peripheral systems3. There 
is an urgent need to identify factors that can help compensate for these harmful factors 
and reduce walking impairments, as there are currently no effective treatments available. 
Although effective mobility is the end result of the functional capacity of both central and 
peripheral systems, the brain's unique modulatory and adaptive capacity may provide 
clues for novel interventions. For example, we have recently discovered that ~20% of older 
adults maintain fast walking speed even in the presence of age-related cSVD and 
peripheral system impairments, thus appearing resilient to these harmful factors. Our work 
suggests that the nigrostriatal dopamine (DA) system may be a source of this resilience. 
As our recent findings suggest, DA neurotransmission positively predicts walking speed4; 
it also attenuates the negative effects of age-related cSVD and peripheral system 
impairments on walking speed. These findings are consistent with post-mortem evidence 
that a combination of loss of nigral DA neurons and cSVD best predict age-related walking 
impairment5-7. The nigrostriatal DA system plays a critical role in motor control; nigrostriatal 
DA neurotransmission regulates the automated execution of overlearned motor tasks via 
its connections with sensorimotor cortical and subcortical areas8. 
 
We hypothesize that higher nigrostriatal DA neurotransmission drives resilience to cSVD 
and peripheral system impairments, via higher connectivity of sensorimotor networks, thus 
increasing automaticity of walking and reducing prefrontal engagement while walking. 
Resilience due to the nigrostriatal DA system is a novel and highly promising area of 
inquiry. Unlike cSVD and brain structural impairments, DA neurotransmission is potentially 
modifiable, thereby offering novel approaches to treat non-resilient elderly in a targeted 
fashion. This translational pilot study will use a biomechanistic target engagement study 
mechanisms targeting dopamine using Carbidopa / Levodopa (C-L Dopa) administration 
in low DA non-resilient elderly with minimal parkinsonian symptoms (MPS, such as slow 
walking) to determine change in synaptic DA in relationship to brain imaging connectivity 
changes and quantitative spatiotemporal kinematic motor tests. 
 
Recently, the first commercially available diagnostic tool for identifying alpha synuclein in 
cutaneous nerve fibers has been developed by CND Life Sciences (Syn-One TestTM). 
While traditional methods of identifying ɑ-synuclein in cerebrospinal fluid and serum have 
not proven diagnostically reliable24, recent skin biopsy tests have demonstrated more than 
90% sensitivity and specificity in synucleinopathies25. Skin biopsies have shown ɑ-
synuclein aggregation in over 80% of patients with idiopathic REM sleep behavior disorder 
(iRBD), which is currently the most clearly defined preclinical stage of LBD23. This 
indicates the accumulation of ɑ-synuclein begins a decade to fifteen years prior to the 
onset of LBD23. On this basis, we hypothesize that elderly adults with parkinsonian signs, 
without a diagnosis of a synucleinopathy, may have alpha synuclein present in peripheral 
nerve fibers.  
 

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Exploratory AIM: Does increased DA neurotransmission in non-resilient elderly with 
parkinsonian signs (incl. gait <1.0msec) with MPS affect spatiotemporal kinematics, such 
as cadence or double support time in a mechanistic target engagement study?  
Exploratory H1: One week of C-L Dopa treatment will change spatiotemporal kinematics, 
such as cadence or double support time, by increasing DA in elderly with parkinsonian 
signs. 
 
Exploratory H2: C-L Dopa treatment will have a biomechanistic effect on functional and 
metabolic mobility networks in the brain through increasing DA in elderly with parkinsonian 
signs. 
 
Exploratory H3: Elderly adults with parkinsonian signs will have alpha synuclein 
accumulating in skin peripheral nerve fibers.  
 
Exploratory H4: C-L Dopa treatment will have biomechanistic effect on skeletal muscle 
biomarkers 
 
2. BACKGROUND 
 
Rationale. This exploratory mechanistic target engagement study will assess the effect of 
brief DA supplementation on dopamine availability, nigro-striatal functional connectivity 
and mobility in a sample of older adults with parkinsonian signs. 
The study will screen elderly people for the presence of slow walking (not explained by 
peripheral or musculoskeletal reasons) and/or other parkinsonian signs. Subjects will be 
contacted for participation in this study from an existing database in the lab. However, if 
enough subjects can’t be recruited from this database then subjects will be recruited 
through external sources, such as a flyer posting, online registries, and the University of 
Michigan Movement Disorders Clinic and other physicians. These subjects will be 
screened using the telephone screening script, and after this screening they will be 
brought into the lab to screen for the presence of slow walking and/or other parkinsonian 
signs. If the clinical assessment does not show evidence for these parkinsonian signs then 
the person will be excluded from the C-L Dopa and imaging portions of the study (see 
study outline below). 
 
We will record eligibility, adherence, and tolerability to 1-week supplementation (3 days 
of carbidopa monotherapy and 7±3 days of C-L Dopa at one tablet PO TID for three 
days followed by an increase to 1.5 tablets PO TID the next day for the next 4 days (±3 
days)), and the effects of C-L Dopa on mechanistic imaging measures of DA 
sensorimotor functional connectivity and on clinical mobility functions. This translational 
aim will provide preliminary information about the targeted modifiability of the DA system 
in non-resilient elderly with parkinsonian signs. 
 
After the completion of the open-label study, we will be conducting a placebo-controlled, 
double-blinded study to further examine mechanistic measures of spatiotemporal gait 
measures, and sensorimotor functional connectivity s through dopamine 
supplementation via C-L Dopa. Participants in this sub-study will receive the same 
assessments as those in the open-label study. 
 
After the completion of the placebo-controlled sub-study, we will conduct an additional 
open-label study to further examine mechanistic spatiotemporal gait measures and 

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sensorimotor functional connectivity through DA supplementation, with the addition of 
skeletal muscle testing and other markers before and after DA supplementation. 
 
3. RESEARCH PLAN 
General Overview: 
Study design:  
 
1. Parent Study: Open-label study. An outline of the study is shown in Figure 1. After 
obtaining informed consent, subjects (max n=60) will undergo a screening exam to assess 
for parkinsonian signs, including slow walking speed. Elderly subjects without evidence of 
parkinsonian signs will be excluded from the C-L dopa and imaging portions of the study. 
 
Eligible subjects with evidence of parkinsonism (max n=20) will then complete a motor, 
including gait, cognitive test battery), and 3T brain MRI (optional) prior to starting the C-
L Dopa treatment portion of the study (Refer to Table 1 and Table 3). Subjects will be 
pre-treated with carbidopa monotherapy 25 mg TID PO for 3 days. Prior to initiating C-
L Dopa 25/100 one tablet PO TID for three days subjects will repeat a limited clinical 
test battery on day 4. Subjects will then increase to 1.5 tablets PO TID on day 7 (i.e., 
day 4 of C-L Dopa treatment) for the next 4 days (±3 days). Carbidopa monotherapy will 
be given to prevent possible side-effects of nausea and participants will stay on 25 mg 
carbidopa PO TID for the duration of the treatment period of the study. Participants are 
given the option to be clinically observed in the lab for their first dosage of C-L Dopa. 
This optional observation would be 60-120 min in length where the participant will take 
their first dose of C-L Dopa and be monitored by study personnel. After the week-long 
(±3 days) C-L Dopa 25/100 trial the complete test battery will be completed. A [11C]PE2I 
dopamine PET scan will be performed for assessment of overall nigrostriatal 
degeneration. This target engagement study will allow for biomechanistic assessment 
of hypothesized changes in the DA sensorimotor network and will allow us to correlate 
the C-L Dopa mechanistic effects on DA sensorimotor connectivity changes before/after 
target engagement as assessed with multimodal graph analytical network methods 
using optional post-treatment MRI of key relevant circuits related to DA. Dopamine PE2I 
PET scan will be used for post hoc covariate effects. 
 
 
Figure 1. Open-Label Study outline. 

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2. Sub-study 1: Double-blinded, placebo-controlled study. After obtaining informed 
consent, subjects (max n=40) will undergo a screening exam to assess for parkinsonian 
signs, including slow walking speed. Elderly subjects without evidence of parkinsonian 
signs will be excluded from the C-L dopa and imaging portions of the study. 
 
Eligible subjects with evidence of parkinsonism (max n=12, n=6 in each group) will then 
be randomized to either receive a placebo or the active form of C-L Dopa. Participants will 
be randomized according to gender and age (+/-7 years). These subjects will then 
complete a motor, including gait, and cognitive test battery prior to starting the C-L Dopa 
supplementation portion of the study. These participants will have the option to complete 
a skin biopsy procedure to look for alpha synuclein in peripheral nerves at any of their 
three visits. Subjects will be pre-treated with carbidopa monotherapy 25 mg TID PO or the 
placebo TID PO for 3 days. Participants in both groups will receive the same number of 
tablets and follow the same administration schedule. Prior to initiating C-L Dopa 25/100 
or placebo one tablet PO TID for three days subjects will repeat a limited clinical test 
battery on day 4. Subjects increase to 1.5 tablets C-L Dopa PO TID on day 7 (i.e., day 4 
of C-L Dopa supplementation) for the next 4 days (±3 days). Carbidopa monotherapy will 
be given to prevent possible side-effects of nausea and participants will stay on 25 mg 
carbidopa PO TID for the duration of the supplementation period of the study. Participants 
are given the option to be clinically observed in the lab for their first dosage of C-L Dopa 
or placebo. This optional observation would be 60-120 min in length where the participant 
will take their first dose of C-L Dopa and be monitored by study personnel. After the week-
long (±3 days) C-L Dopa 25/100 trial the complete test battery will be completed. A  
[11C]PE2I dopamine PET scan will be performed for assessment of overall nigrostriatal 
degeneration in addition to a 3T brain MRI (optional). These scans can occur before, 
during, or after the intervention.  
 
3. Sub-study 2: Open-label study. After obtaining informed consent, subjects (max n=20 
to allow for screen failures or attrition) will undergo a screening exam to assess for 
parkinsonian signs, including slow walking speed. Elderly subjects without evidence of 
parkinsonian signs will be excluded from the C-L dopa and imaging portions of the study. 
 

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Eligible subjects with evidence of parkinsonism (max n=6 for net study completion) will 
then complete a test battery involving motor testing, muscle testing, cognitive testing, 
fasted blood draw, and muscle biopsy prior to starting the C-L Dopa supplementation 
portion of the study. Subjects will be pre-treated with carbidopa monotherapy 25 mg TID 
PO for 3 days. Participants will repeat a limited clinical test battery on day 4 prior to 
initiating the C-L Dopa 25/100 TID. Subjects increase to 1.5 tablets C-L Dopa PO TID on 
day 7 (i.e., day 4 of C-L Dopa supplementation) and continue for the next 4 days (±3 days). 
Carbidopa monotherapy will be given to prevent possible side-effects of nausea and 
participants will stay on 25 mg carbidopa PO TID for the duration of the supplementation 
period of the study. Participants are given the option to be clinically observed in the lab for 
their first dosage of C-L Dopa. This optional observation would be 60-120 min in length 
where the participant will take their first dose of C-L Dopa and be monitored by study 
personnel. After the week-long (±3 days) C-L Dopa 25/100 trial the complete test battery 
including fasted blood draw and muscle biopsy will be repeated. A [11C]PE2I dopamine 
PET scan will be performed for assessment of overall nigrostriatal degeneration in addition 
to a 3T brain MRI (optional). These scans can occur before, during, or after the 
intervention.  
 
Subjects who completed the parent study or sub-study 1 may be invited to participate in 
sub-study 2.  
 
 
Subjects: 
 
Eligibility: Non-resilient elderly non-PD subjects (F/M, age 60 yrs or older) with evidence 
of mild parkinsonian signs (MPS, slow gait (< 1m/s)). The UPDRS motor component (part 
III) will used to assess for evidence of parkinsonian signs, including bradykinesia, tremor, 
rigidity, and gait disturbances.  
 
Inclusion: 
1) Age 60 or older (M/F) 
2) Evidence of mild parkinsonian signs (incl. MPS, slow gait (< 1m/s)) 
 
 
Exclusion:  
1) Evidence of  prior established diagnosis and/or treatment for PD13. 
2) Presence of clinically significant degenerative joint disease and/or neuropathy 
interfering with proper assessment of the motor UPDRS exam. 
3) Presence of significant dementia. 
4) History of stroke with residual clinical deficit interfering with walking.  
5) For optional MR imaging only: Participants in whom magnetic resonance imaging (MRI) 
is contraindicated including, but not limited to, those with a pacemaker, presence of 
metallic fragments near the eyes or spinal cord, or cochlear implant. 
6) For optional brain imaging only: Severe claustrophobia precluding neuroimaging 
procedures. 
7) Participants that have been on monoamine oxidase inhibitors (MAOIs) within 2 weeks 
prior to starting study. 
8) Inability to stand or walk without an assistive device 
9) Hypersensitivity to the carbidopa, levodopa, and tablet components. 
10) History of myocardial infarction (MI) with residual arterial, nodal or ventricular 
arrhythmia 

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11) History of peptic ulcer 
12) Chronic wide angle glaucoma 
13) Narrow angle glaucoma 
14) Major psychotic disorder 
15) Severe cardiovascular or pulmonary disease, bronchial asthma, renal, hepatic or 
endocrine disease 
16) Subjects on dopamine D2 receptor antagonists, dopamine depleting agents, and 
metoclopramide. 
17) Any other medical history determined by investigators to preclude safe participation. 
18) For sub-study 1 optional skin biopsy and sub-study 2 muscle biopsy only: 
1. Subjects who are dependent on alcohol 
2. Subjects who are unable/unwilling to refrain from nicotine/tobacco use for 12 
hours prior the biopsy procedure 
3. Subjects who are taking certain blood thinners or anti-coagulant medications may 
be excluded from the biopsies. Aspirin or Plavix are considered safe, it will up to 
the discretion of the investigators to review medications to confirm eligibility.  
4. Subjects who have a history of allergic reaction to local anesthesia for skin 
biopsies 
5. Subjects with significantly impaired wound healing or history of scarring or keloid 
formation 
6.  Subjects whose synucleinopathy may be explained by other causes: 
a. Cortical dementia of Alzheimer’s type 
b. Encephalitis 
c. Whipple’s disease 
d. Toxin exposure 
e. Repeated head injury 
f. 
Stepwise disease progression suggestive of vascular etiology 
 
Study Timeline:  
The open-label study will be performed over 2 years with anticipated net recruitment and 
completion of half of the subjects per year. A milestone of success will be recruitment of 
5 subjects who have completed the CL Dopa treatment by the end of year 1. The last 2 
months will be used for data analysis and report writing. 
 
The placebo-controlled study (sub-study 1) will be performed over 2 years with anticipated 
net recruitment and completion of half of the subjects per year. The last 2 months will be 
used for data analysis. 
 
Sub-study 2 will be performed over 1 year with anticipated net recruitment and completion 
of all 6 subjects within 10 months. The last 2 months will be used for data analysis and 
report writing. 
 
Dissemination plan:  
Study findings will be published in peer-reviewed journals and presented at scientific 
meetings.  
 
Design: Within-subject study design using after-before difference measures. 

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Sample size: This is an exploratory pilot project to generate sample size effects for future 
larger scale studies, with a net study completion goal of 20 treated subjects for the open-
label and 12 subjects for the placebo-controlled study (sub-study 1). The net study 
completion goal for the muscle testing study (sub-study 2) will be 6 treated subjects. 
 
Impact: This project will elucidate the neurobiology of gait slowing at spatiotemporal 
kinematics, structural and functional levels of analysis, increasing our understanding of 
the interplay between these aging-associated processes and the brain network changes 
underlying late life mobility disorders. Additionally, if elderly adults with parkinsonian signs 
have alpha synuclein in their peripheral nerve fibers, they may be in the early stages of a 
synucleinopathy. Lastly, this study aims to elucidate the relationship between skeletal 
muscle biomarkers and motor performance in older non-resilient adults without 
Parkinson’s and examine the relationship between DA neurotransmission and muscle 
health. 
  
Table 1: Main components of the Test Battery, including detailed gait and balance assessments 
Test 
Primary outcome parameter 
Admin. Time 
 
 
 
Gait: Timed walking tests (single & dual task gait).  
Optional: Electronic gait assessments using mats (Zeno 
Walkways, Protokinetics) and/or sensors (APDM) under 
single and dual test conditions and challenged gait.  
Assessment of standard 
spatiotemporal gait 
parameters & variability 
measures 
2 min 
Dynamic balance: Mini-BESTest 3, 
with optional APDM sensors  
Total Mini-BESTest score 
15 min 
Balance confidence/fear of falling: The Activities-specific 
Balance Confidence (ABC) scale 4 
Total ABC score 
5 min 
Cognitive-motor dual task: Stroop stepping mat 
Errors and reaction time 
10 min 
 
 
Total: 45 min 
 
Primary Outcome variables, open-label study: 
 
(a) Biomechanical gait and postural parameters  
(b) Cognition (see Table 2) 
 
Primary Outcome Measure: Placebo-controlled study (sub-study 1): 
(a) Gait speed as measured during iTUG portion of the Mini-BESTest 
Secondary Outcome Measures: Placebo-controlled study (sub-study 1): 
(a) Parkinson’s disease cognitive rating scale (PDCRS) total score 
(b) Stroop stepping mat: reaction time and total errors 
Primary Outcome Measure: Open-label muscle testing study (sub-study 2): 
(a) Gait speed as measured during iTUG portion of the Mini-BESTest 

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Exploratory Outcome Measures: Open-label muscle testing study (sub-study 2) 
(a) Quantify the change in blood extracellular vesicle (EV) levels after 1-week C-L 
Dopa supplementation. 
(b) Skeletal muscle biomarkers  
(c) Mean torque value for each leg during Biodex muscle strength test. 
(d) Cognition (see table 2) 
 
Study Treatment: 
 
Carbidopa Monotherapy: Due to the small risk of nausea and vomiting from taking C-L 
Dopa, all subjects will be pretreated with carbidopa 25 mg orally (PO) three times a day 
(TID) monotherapy for 3 days prior to starting C-L Dopa. 
  
C-L Dopa administration: A low dose (25/100 1 tablet orally (PO) three times a day (TID) 
of C-L Dopa immediate release will be used for the first three days of C-L Dopa treatment 
then if no side-effects will be increased on day 4 of the C-L Dopa treatment to 1.5 pills TID 
PO. All participants will continue to take carbidopa 25 mg TID PO for the whole duration 
of the treatment period.  
 
Drug Supplies: Formulation, Preparation and Dispensing 
 
Carbidopa Monotherapy: 
Carbidopa will be prepared and dispensed by the Research Pharmacy at the University of 
Michigan. 
 
C-L Dopa: 
C-L Dopa will be prepared and dispensed by the Research Pharmacy at the University of 
Michigan. 
 
Placebo: 
The placebo will be prepared and dispensed by the Research Pharmacy at the University 
of Michigan.  
 
Drug Storage and Drug Accountability 
 
Carbidopa Monotherapy: Drug will be stored and accounted for at the Research Pharmacy 
at the University of Michigan per their established standing operating procedures.   
 
C-L Dopa: Drug will be stored and accounted for at the Research Pharmacy at the 
University of Michigan per their established standing operating procedures. 
 
Placebo: Drug will be stored and accounted for at the Research Pharmacy at the 
University of Michigan per their established standing operating procedures. 
 
Concomitant Medications 
 
Use of both carbidopa monotherapy and C-L Dopa, has been contraindicated with 
concurrent use with nonselective monoamine oxidase inhibitors (MAOIs) or use within the 
last 14 days. 

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Use of C-L Dopa with concurrent antihypertensive medications may increase the risk of 
symptoms related to orthostatic hypotension. Study staff will closely monitor participants 
and ask them to discontinue C-L Dopa if severe symptoms present. 
 
Concomitant use of phenytoin and papaverine may reduce indicated effects of C-L Dopa. 
However, the use of these medications with C-L Dopa does not present any additional 
risks. 
 
 
 
Other Considerations 
 
High protein diets have the potential to impair C-L Dopa absorption as the levodopa 
ingredient competes with certain amino acids for transport across the gut wall or across 
the blood-brain barrier. For this reason, participants will be instructed to take the study 
drugs at least ½ hour before each meal (i.e., breakfast, lunch & supper).  However, the 
pre-meal intake of these drugs can be combined with non-proteineous supplements, like 
fruit juices or fruits (banana, apple sauce, etc.). 
 
Iron salts or multi-vitamins containing iron salts have the potential to decrease the 
bioavailability of carbidopa and levodopa. Participants taking iron salts will be asked to 
supplement at the end of the day to minimize the potential C-L Dopa absorption 
reductions. 
 
Clinical Testing: 
Clinical assessment (see also Table 3) includes a general demographic, medical and, 
neurological examination, the measurement of visual acuity, (optional) visual contrast 
sensitivity (Rabin test), (optional) color blindness (Munsell 15), orthostatic vital signs, 
weight and height in all subjects, general motor assessment, including the Movement 
Disorder Society revised UPDRS examination (13), modified Hoehn & Yahr (14) to provide 
assessment of general motor impairments of PD. Questionnaires to assess overall 
sedentarism and physical activity will be administered. Detailed cognitive testing will also 
be performed. 
   
Functional assessment of motor features: 
Several well-validated balance, gait, and fall-associated scales and tests will be used to 
further assess functional mobility 7 (see Table 3). In addition to these motor examinations 
we will also use questionnaires to assess for the presence of gait festination and freezing 
of gait 15-17. In addition, finger tapping and Grooved Pegboard testing will be used to 
provide quantitative measures of upper limb bradykinesia and motor dexterity. Optionally, 
foot tapping will be used as a measure of lower limb bradykinesia. A specialized mobility 
and postural control test battery to capture gait and postural functions will also be 
performed. Some tasks may be performed while performing a secondary cognitive task 
(e.g. counting backwards by 3s). 
 
Muscle Strength Testing: 
Biodex Strength Test: Participants will sit (~85° hip flexion) on an ergometer (Biodex 
System 4). The upper body will be stabilized with straps across the thorax and abdomen. 
Knee joint axis of rotation will be aligned with the measurement axis of the system. The 
leg being tested will be strapped around the mid-thigh. The knee angle will be placed at 
90° to cancel the effect of gravity on the test. Participants will be instructed to perform 

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maximal effort during a static knee extension and to limit countermovement.  At least three 
maximal voluntary contractions will be recorded. A fourth and possibly fifth trial will be 
performed if the value reached during the last trial is higher than the preceding ones, or if 
the difference between trials was greater than 10%.  Participants will be encouraged 
verbally throughout the test. Biodex testing for isometric strength is established as the gold 
standard in the field and highly reliable28. Protocol for biodex isometric testing on knee 
extensors taken from prior studies at University of Manitoba29.  
 
Grip strength will be measured using a handheld Dynamometer. 
 
Muscle Testing will be assessed during visit 1 only. 
 
Biological samples: 
Optional saliva samples may be collected for analysis of dopamine and other related 
genotypes for the open-label study only. Samples will be processed and analyzed at 
laboratories the Department of Human Genetics, or at other intra- or extramural 
institutions. (For sub-study 1 only) Tissue samples may be collected via a biopsy 
procedure. Deidentified samples will be sent to CND Life Sciences Laboratory which will 
stain the tissue for alpha synuclein. The distribution of alpha synuclein and nerve fiber 
density will be evaluated.  
 
Skeletal Muscle Biopsy (sub-study 2 only) 
 
The modified muscle biopsy technique was introduced nearly 60 years ago [22] 
and is a fundamental component of muscle health research (e.g., insulin sensitivity, 
inflammation). This technique is used commonly in the medical research field (as indicated 
by large scale consortiums [e.g., NIH funded MoTrPAC]) and is currently utilized at the 
University of Michigan. Members of the research team have been involved with muscle 
biopsies for ~15 y, totaling >1000 muscle biopsies in populations including athletes, 
elderly, obese, type 2 diabetics31-33. Dr. Jacob Haus, PhD will perform the muscle biopsies 
which are critical to completion of study objectives.  
Muscle biopsies will be obtained before and after the 1-week C-L Dopa 
supplementation period. Muscle samples (~200 mg; approximately the size of a pea) will 
be obtained from the vastus lateralis muscle (thigh muscle) following local anesthetic 
delivery using the modified muscle biopsy technique30,31,32,34. Muscle tissue will be quickly 
trimmed of excess connective tissue and fat, blotted with gauze to remove blood, and 
processed specific to future analysis. Subjects will be instructed on how to care for the 
wound and supplied with ice and pressure bandages after each biopsy to reduce 
inflammation and any soreness. A member of the research team will follow-up with each 
participant the day after a muscle biopsy. All muscle biopsies will be performed and 
analyzed in laboratories within the University of Michigan. Participants who use 
tobacco/nicotine will be asked to refrain from use for at least 12 hours prior to the biopsy 
procedure. 
 
 
Blood Sampling 
 
Blood samples will be obtained before and after the 1-week C-L Dopa 
supplementation period for assessments of extracellular vesicles (EV). ~20mL of whole 
blood will be collected at each timepoint for analysis. Participants will be asked to arrive 
to the laboratory in a fasted state for the blood draw.  

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. Plasma will be separated from blood samples collected in vacutainer tubes via 
centrifugation before and after 1-week C-L Dopa supplementation.  
Extracellular vesicle (EV) analysis will be performed at the laboratory of Dr. Gagan 
Deep at Wake Forest University (Winston-Salem, North Carolina). Plasma samples will 
be deidentified, then shipped to Dr. Deep at which point total EVs (TE) will be isolated 
from the plasma using a modified precipitation method described previously34,35. A 
material transfer agreement (MTA) will be established prior to shipment of any samples. 
 
One extra tube of blood will be stored for additional analysis if needed. 
 
Neurocognitive and functional status assessments: 
Table 2 provides an overview of the detailed neuropsychological examination. We will 
assess global cognitive changes over time based on the MMSE 18, MoCA 19, and a 
composite z-score encompassing the major cognitive domains from the test battery. 
 
Table 2. Components of the neuropsychological test battery 
Overall mental status 
Optional: Mini Mental State Exam 18 
Montreal Cognitive Assessment Scale 19 
Parkinson’s disease cognitive rating scale26 
Attention 
D-KEFS: Trail Making Test, Stroop Color Word Interference Test 20 
Learning & Memory 
Optional: California Verbal Learning Test – II 21 
Executive/Working 
Memory 
D-KEFS: Trail Making Test 
Information processing 
speed 
D-KEFS: Trail Making Test 20 
Digit Symbol test,  
Optional: Reaction time 
Optional: Falling stick test 
 
MR imaging (optional): MR imaging will be performed on a 3 Tesla Philips Achieva 
system (Philips) utilizing a 15-channel head coil and the ‘ISOVOX’ exam card protocol 
primarily designed to yield isotropic T1 spoiled gradient (SPGR) spatial resolution. This 
protocol consists of a number of different sequences including a standard T1-weighted 
series of a 3D inversion recovery-prepared turbo-field-echo will be performed in the 
sagittal plane with repetition time/echo time/inversion time = 9.8/4.6/1041 ms; turbo factor 
= 200; single average; field of view = 240 x 200 x 160 mm; acquired matrix = 240 x 200. 
Slices (n = 160) will be reconstructed to 1mm isotropic resolution. This sequence 
maximizes contrast among grey matter, white matter and CSF and provides high 
resolution delineation of cortical and subcortical structures. Other standard sequences 
include FLAIR, DTI, resting state functional connectivity MRI, or other relevant series.  The 
brain MRI scan can be performed on the same day as the clinical assessment or anytime 
throughout the supplementation period. 
 
PET imaging: All PET data will be acquired at the University of Michigan PET facility on 
a Siemens BioGraph TruePoint Model 1094 PET/CT scanner, which produces 109 
slices, has an axial field-of-view of 22.0 cm with slice thickness of 2.027 mm, and 
intrinsic image resolution 4.2 mm full-width at half maximum (FWHM). Image 
reconstruction for both tracers will be done with fully 3D-iterative OSEM, using 4 
iterations, 16 subsets, and post-reconstruction files of 3.0 mm FWHM, yielding images of 
~5.0 FWHM. One low-dosage CT scan (130 kVp, 30 eff mAs, 6 x 3mm collimation, pitch 
=1, rotation time =0.6 second) of the head will be performed prior to each brain PET 

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scan for attenuation correction purposes. “As low as reasonably achievable” (ALARA) 
techniques will be utilized to minimize subject radiation exposure. 
Subjects will be studied supine, with eyes and ears unoccluded, resting quietly in a dimly 
lit room. [11C]PE2I PET ligand are non-approved radiopharmaceutical that will be used in 
accordance with Food and Drug Administration regulations (21 CFR 361.1). All tracers 
are prepared following standard synthesis routines at the University of Michigan PET 
Chemistry and Cyclotron facilities. 
 
Daily life activity levels (optional): Overall activity levels during medication therapy will 
also be assessed. Subjects will be asked to wear an accelerometer based actigraphy 
device (Actigraph or ActivPAL) for the duration of the carbidopa monotherapy and 
carbidopa-levodopa mechanistic study. 
 
Compliance Monitoring Phone Call: A compliance phone call will be performed by a 
research staff member during the 7 day±3 C-L Dopa medication stage. 
 
Timeline: Refer to table 3 for timeline and test details. Day 0 may be completed over 
multiple visits. Once all tasks listed under Day 0 are completed Day 1 will start. Day 9(±3) 
tasks will be performed while participant is still taking C-L Dopa and may require multiple 
visits. 
 
Table 3. Open-label study: Detailed components, test protocol, and timeline 
 
Pre-Rx (Day 
0) 
Baseline 
Day 
1-3 
Day 
4 
Day 
4-6 
Day 
7-
10(±3) 
Day 10  
(±3) 
Informed Consent 
✓ 
 
 
 
 
 
Demographic Information 
✓ 
 
 
 
 
 
Inclusion/Exclusion Criteria 
✓ 
 
 
 
 
 
Clinical & Neurological 
Assessment 
✓ 
 
 
 
 
✓ 
Optional: Saliva sample 
✓ 
 
 
 
 
 
MDS-UPDRS 
✓  
 
✓ 
 
 
✓ 
Mini-BESTest (optional: APDM 
Sensored) 
✓ 
 
✓ 
 
 
✓ 
Regular timed walking single & 
dual-task  
Optional: Zeno Walkways Single, 
Dual, and challenged gait Task  
✓ 
 
 
✓ 
 
 
✓ 
Optional: APDM Mobility 
assessments 
✓ 
 
✓ 
 
 
✓ 
Optional: Oculovestibular  
✓ 
 
 
 
 
✓ 
Pegboard   
✓ 
 
✓ 
 
 
✓ 
Finger tapping 
✓ 
 
✓ 
 
 
✓ 
Foot tapping 
✓ 
 
✓ 
 
 
✓ 

14 
Version 2.7 
 
Optional: Reaction Time Test/ 
Optional: React Stick Test 
✓ 
 
 
 
 
✓ 
Optional: Four Square Step Test 
✓ 
 
 
 
 
✓ 
Optional: Maximum Step Length 
Test 
✓ 
 
 
 
 
✓ 
Activity questionnaire 
✓ 
 
 
 
 
✓ 
Balance confidence/fear of falling: 
The Activities-specific Balance 
Confidence (ABC)  
✓ 
 
 
 
 
✓ 
Optional: New-FOGQ 
✓ 
 
 
 
 
✓ 
Optional: Short FES-I 
✓ 
 
 
 
 
✓ 
Sensonics UPSIT 
✓ 
 
 
 
 
optional: ✓ 
Optional: Eyetech OCAT 
✓ 
 
 
 
 
✓ 
MoCA 
✓ 
 
✓ 
 
 
✓ 
Optional: MMSE 
✓ 
 
 
 
 
✓ 
DKEFS-STROOP 
✓ 
 
 
✓ 
 
 
✓ 
DKEFS-TMT 
✓ 
 
 
✓ 
 
 
✓ 
Optional: CVLT 
✓ 
 
 
 
 
✓ 
Information processing 
 
✓ 
 
✓ 
 
 
✓ 
General Feeling Questionnaire 
✓ 
 
 
 
 
✓ 
Apathy Evaluation Scale 
✓ 
 
 
 
 
✓ 
Geriatric depression scale 
✓ 
 
 
 
 
✓ 
Spielberger anxiety scale 
✓ 
 
 
 
 
✓ 
Optional: BPRS 
✓ 
 
 
 
 
✓ 
Epworth Sleepiness Scale 
✓ 
 
 
 
 
✓ 
Mayo Sleep Questionnaire (22) 
✓ 
 
 
 
 
✓ 
FSS 
✓ 
 
 
 
 
✓ 
Optional: Insomnia Questionnaire 
✓ 
 
 
 
 
✓ 
Optional: Somnolence VAS 
✓ 
 
✓ 
 
 
✓ 
Snellen Test 
✓ 
 
 
 
 
✓ 
Optional: Rabin 
✓ 
 
 
 
 
✓ 
Adverse event assessment 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Optional Skin Biopsy 
✓ 
 
 
 
 
 
Optional MRI 
✓ 
 
 
 
 
✓ 
PE2I PET (will occur only 1 time) 
✓ 
 
 
 
 
✓ 

15 
Version 2.7 
 
Optional DEXA 
✓ 
 
 
 
 
 
Optional 90-120 minute 
observation (post medication) after 
first intake 
 
 
 
✓ 
 
 
Carbidopa Monotherapy 25 mg 
TID PO 
 
✓ 
✓ 
✓ 
✓ 
✓ 
C-L Dopa 25/100 1 tablet PO TID 
 
 
✓ 
✓ 
 
 
C-L Dopa 25/100 1.5 tablet PO TID 
 
 
 
 
✓ 
✓ 
Compliance Monitoring Phone Call 
 
✓ 
 
 
✓ 
 
Optional: Actigraphy 
 
✓ 
✓ 
✓ 
✓ 
✓ 
 
 
 
 
 
 
 
 
Table 4. Sub-study 1: Placebo-controlled, double-blinded study: Detailed components, test protocol, and timeline 
 
Pre-Rx (Day 
0) 
Baseline 
Day 
1-3 
Day 
4 
Day 
4-6 
Day 
7-
10(±3) 
Day 10  
(±3) 
Informed Consent 
✓ 
 
 
 
 
 
Demographic Information 
✓ 
 
 
 
 
 
Inclusion/Exclusion Criteria 
✓ 
 
 
 
 
 
Clinical & Neurological 
Assessment 
✓ 
 
✓ 
 
 
✓ 
MDS-UPDRS 
✓  
 
✓ 
 
 
✓ 
Mini-BESTest (optional: APDM 
Sensored) 
✓ 
 
✓ 
 
 
✓ 
Regular timed walking single & 
dual-task  
Optional: Zeno Walkways Single, 
Dual, and challenged gait Task  
✓ 
 
 
✓ 
 
 
✓ 
Optional: APDM Mobility 
assessments 
✓ 
 
✓ 
 
 
✓ 
Pegboard   
✓ 
 
✓ 
 
 
✓ 
Finger tapping 
✓ 
 
✓ 
 
 
✓ 
Optional: Foot tapping 
✓ 
 
✓ 
 
 
✓ 
Optional: Reaction Time Test/ 
Optional: Reaction Stick Test 
✓ 
 
 
 
 
✓ 
Optional: Four Square Step Test 
✓ 
 
 
 
 
✓ 
Optional: Maximum Step Length 
Test 
✓ 
 
 
 
 
✓ 
Activity questionnaire 
✓ 
 
 
 
 
✓ 

16 
Version 2.7 
 
Balance confidence/fear of falling: 
The Activities-specific Balance 
Confidence (ABC)  
✓ 
 
 
 
 
✓ 
Optional: New-FOGQ 
✓ 
 
 
 
 
✓ 
Optional: Short FES-I 
✓ 
 
 
 
 
✓ 
MoCA 
✓ 
 
✓ 
 
 
✓ 
PDCRS 
 
 
 
 
 
 
Optional: MMSE 
✓ 
 
 
 
 
✓ 
DKEFS-STROOP 
✓ 
 
 
✓ 
 
 
✓ 
DKEFS-TMT 
✓ 
 
 
✓ 
 
 
✓ 
Optional: CVLT 
✓ 
 
 
 
 
✓ 
General Feeling Questionnaire 
✓ 
 
 
 
 
✓ 
Apathy Evaluation Scale 
✓ 
 
 
 
 
✓ 
Geriatric depression scale 
✓ 
 
 
 
 
✓ 
Spielberger anxiety scale 
✓ 
 
 
 
 
✓ 
Optional: BPRS 
✓ 
 
 
 
 
✓ 
Epworth Sleepiness Scale 
✓ 
 
 
 
 
✓ 
Mayo Sleep Questionnaire (22) 
✓ 
 
 
 
 
✓ 
FSS 
✓ 
 
 
 
 
✓ 
Optional: Insomnia Questionnaire 
✓ 
 
 
 
 
✓ 
Optional: Somnolence VAS 
✓ 
 
✓ 
 
 
✓ 
Optional: Snellen Test 
✓ 
 
 
 
 
✓ 
Optional: Rabin 
✓ 
 
 
 
 
✓ 
Adverse event assessment 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Optional Skin Biopsy 
✓ 
 
 
 
 
 
Optional MRI 
✓ 
PE2I PET  
✓ 
Optional DEXA 
✓ 
 
 
 
 
 
Optional 90-120 minute 
observation (post medication) after 
first intake 
 
 
 
✓ 
 
 
Carbidopa Monotherapy 25 mg 
TID PO 
 
✓ 
✓ 
✓ 
✓ 
✓ 
C-L Dopa 25/100 1 tablet PO TID 
 
 
✓ 
✓ 
 
 
C-L Dopa 25/100 1.5 tablet PO TID 
 
 
 
 
✓ 
✓ 
Compliance Monitoring Phone Call 
 
 
 
 
✓ 
 

17 
Version 2.7 
 
Optional: Actigraphy 
Give to pt 
✓ 
✓ 
✓ 
✓ 
✓ 
 
 
Table 5. Sub-study 2: Open-label, exploratory muscle testing study. Detailed components, test protocol, and 
timeline 
 
Pre-Rx (Day 
0) 
Baseline 
Day 
1-3 
Day 
4 
Day 
4-6 
Day 
7-
10(±3) 
Day 10  
(±3) 
Informed Consent 
✓ 
 
 
 
 
 
Demographic Information 
✓ 
 
 
 
 
 
Inclusion/Exclusion Criteria 
✓ 
 
 
 
 
 
Blood Sample Collection (fasted) 
✓ 
 
 
 
 
✓ 
Skeletal Muscle Biopsy 
✓ 
 
 
 
 
✓ 
Muscle Biopsy Phone call 
Followup 
✓(next day) 
 
 
 
 
✓(next day) 
Biodex Muscle Strength Test 
✓ 
 
 
 
 
 
Dynamometer Grip Strength Test 
✓ 
 
 
 
 
 
Clinical & Neurological 
Assessment 
✓ 
 
✓ 
 
 
✓ 
MDS-UPDRS 
✓  
 
✓ 
 
 
✓ 
Mini-BESTest (optional: APDM 
Sensored) 
✓ 
 
✓ 
 
 
✓ 
Regular timed walking single & 
dual-task  
Optional: Zeno Walkways Single, 
Dual, and challenged gait Task  
✓ 
 
 
✓ 
 
 
✓ 
Optional: APDM Mobility 
assessments 
✓ 
 
✓ 
 
 
✓ 
Pegboard   
✓ 
 
✓ 
 
 
✓ 
Finger tapping 
✓ 
 
✓ 
 
 
✓ 
Optional: Foot tapping 
✓ 
 
✓ 
 
 
✓ 
Optional: Reaction Time Test/ 
Optional: Reaction Stick Test 
✓ 
 
 
 
 
✓ 
Optional: Four Square Step Test 
✓ 
 
 
 
 
✓ 
Optional: Maximum Step Length 
Test 
✓ 
 
 
 
 
✓ 
Activity questionnaire 
✓ 
 
 
 
 
✓ 
Balance confidence/fear of falling: 
The Activities-specific Balance 
Confidence (ABC)  
✓ 
 
 
 
 
✓ 

18 
Version 2.7 
 
Optional: Dual-task Impact on 
Daily-living Activities 
Questionnaire (DIDA-Q) 
✓ 
 
 
 
 
✓ 
Optional: New-FOGQ 
✓ 
 
 
 
 
✓ 
Optional: Short FES-I 
✓ 
 
 
 
 
✓ 
MoCA 
✓ 
 
✓ 
 
 
✓ 
PDCRS 
✓ 
 
✓ 
 
 
✓ 
Optional: MMSE 
✓ 
 
 
 
 
✓ 
DKEFS-STROOP 
✓ 
 
 
✓ 
 
 
✓ 
DKEFS-TMT 
✓ 
 
 
✓ 
 
 
✓ 
Optional: CVLT 
✓ 
 
 
 
 
✓ 
General Feeling Questionnaire 
✓ 
 
 
 
 
✓ 
Apathy Evaluation Scale 
✓ 
 
 
 
 
✓ 
Geriatric depression scale 
✓ 
 
 
 
 
✓ 
Spielberger anxiety scale 
✓ 
 
 
 
 
✓ 
Optional: BPRS 
✓ 
 
 
 
 
✓ 
Epworth Sleepiness Scale 
✓ 
 
 
 
 
✓ 
Mayo Sleep Questionnaire (22) 
✓ 
 
 
 
 
✓ 
FSS 
✓ 
 
 
 
 
✓ 
Optional: Insomnia Questionnaire 
✓ 
 
 
 
 
✓ 
Optional: Somnolence VAS 
✓ 
 
✓ 
 
 
✓ 
Optional: Snellen Test 
✓ 
 
 
 
 
✓ 
Optional: Rabin 
✓ 
 
 
 
 
✓ 
Adverse event assessment 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Optional MRI 
✓ 
PE2I PET  
✓ 
Optional DEXA 
✓ 
 
 
 
 
 
Optional 90-120 minute 
observation (post medication) after 
first intake 
 
 
 
✓ 
 
 
Carbidopa Monotherapy 25 mg 
TID PO 
 
✓ 
✓ 
✓ 
✓ 
✓ 
C-L Dopa 25/100 1 tablet PO TID 
 
 
✓ 
✓ 
 
 
C-L Dopa 25/100 1.5 tablet PO TID 
 
 
 
 
✓ 
✓ 
Compliance Monitoring Phone Call 
 
 
 
 
✓ 
 
Optional: Actigraphy 
Give to pt 
✓ 
✓ 
✓ 
✓ 
✓ 

19 
Version 2.7 
 
 
Analysis: 
Statistical analysis: For all studies and sub-studies, we anticipate that 90% of eligible 
subjects will complete the 1-week C-L Dopa supplementation; the effect of C-L Dopa 
administration on brain connectivity and mobility measures will be tested using a repeated 
measures design.  
 
Data safety-monitoring plan:  This study will adhere to a data safety-monitoring plan 
where the principal investigator will be responsible for regular (at least annual) monitoring 
of general progress of the study, such as subject recruitment, perform interim statistical 
analysis on the data (only when statistically feasible), review of outcome and adverse 
event data to determine whether there is any change to the anticipated benefit-to-risk ratio 
(which may require modification or termination of the study protocol), assessment of 
external scientific or medical developments that may have an impact on the safety of study 
participants or the ethics of the study. Dr. Amelia Heston, Instructor of Neurology, will 
serve as an independent safety officer and will review twice yearly safety reports. The 
monitoring process will also include a review of study procedures aimed at the protection 
of the privacy of the research subjects and confidentiality of the research data. Adverse 
events will be reported to the IRB adverse events reporting guidelines. If the protocol 
needs to be modified or there is a change in the level of risk to subjects for this study, a 
modification submission will be prepared for review by the IRB. All data collected on 
research subjects will be kept confidential as detailed above. 
All study staff will be extensively trained in test administration to ensure the integrity of 
collected data. In the event that language differences present a barrier to data collection, 
strategies to ensure proper collection will be employed, including seeking help from other 
team members, slowing down testing pace, or using translaters if necessary. 
Risks (as described in informed consent form): 
The known or expected risks will be defined as: Likely - occurring in more than 25% of 
people (more than 25 out of 100 persons); Common – occurring in 10% - 25% of people 
(in 10 to 25 out of 100 persons); Infrequent - occurring in 1 - 10% of people (1 to 10 out of 
100 people); Rare - occurring in less than 1% of people (fewer than 1 out of 100 persons); 
or Very Rare - occurring in less than 0.1% of people (fewer than 1 in 1,000 persons). 
 
The known or expected risks will be described in normal script. 
The actions that the researchers take to minimize these risks will be described in italic 
script, as demonstrated in this paragraph. 
 
General risks: 
There is a very rare risk of breach of confidentiality, which may affect privacy, self-esteem, 
social standing, employability, and insurability. 
Section 9.1 will provide more detailed information on how we protect your privacy. In 
general, study records will be kept in databases maintained by the investigators. These 
databases are kept separate from medical records, are protected by passwords, and 
only accessible to personnel involved in the study. If you withdraw from the study at 
any time, a record of the withdrawal and the reasons given for withdrawing may be 
kept as part of the study record. 
 
There is a rare risk that you may experience some minor anxiety (‘test anxiety’), become 
worried, or have an anxiety reaction in response to any of these tests and procedures. For 

20 
Version 2.7 
 
example, you become worried about your health, or you may experience a sudden fear of 
the confined space while in the scanner. 
Trained research staff will conduct all tests and procedures. The staff will be prepared 
to respond to your anxiety, concerns and behavioral changes, by temporarily 
suspending testing, breaking up testing sessions into several brief visits if needed, 
and/or answering your questions. During the MRI scans you will be able to talk to 
technologists throughout the scan and indicate right away if you wish to stop the study 
and leave the scanner. At the option of your personal physician, (s)he may prescribe 
sedation with lorazepam (Ativan) or diazepam (Valium) to be taken before the scan in 
accordance with the prescription directions. 
 
None of the test results, including brain images, and procedures in this study will be 
reviewed or interpreted for making a medical diagnosis. Any result or abnormality that 
would be indicative of current or future disease will most likely not be discovered. However, 
if we do find a clinically relevant result or abnormality that deserves additional medical 
attention, we will communicate this to you and you will be urged to visit your primary health 
care provider. The research results of the brain images and genetic testing will NOT be 
communicated back to you. 
You should consult your personal doctor if you have any health concerns 
 
Clinical tests: 
There is a very rare risk of physical fatigue during the clinical examination. 
Trained research staff will conduct all the tests and administer all the questionnaires. 
The staff will be prepared to respond to your concerns by temporarily suspending 
testing and/or breaking up testing sessions into several brief visits if needed. 
 
There is a common risk that you may have a dry mouth after providing the saliva sample. 
You may drink some water after providing the sample. 
 
Smell and vision tests: 
There is a very rare risk of a mild allergic reaction to the scents of the smell identification 
test. 
Testing will be discontinued if you experience an allergic reaction that prevents you 
from continuing the examination. 
 
There is a very rare risk that you may experience some minor eye strain when doing the 
vision tests. 
Rest breaks will be provided if needed. Any minor eye strain will disappear shortly after 
the test. 
 
Motor testing: 
Many of the tests are comparable to normal standing and walking conditions that you may 
experience in everyday-life. Nonetheless, there is an infrequent risk of falling or near-
falling during these tests which may result in fall-related injuries. 
Trained research staff will remain in close proximity to you at all times, and observe 
(‘spot’) you to prevent you from falling. 
 
There is a very rare risk that the sensors to measure overall movement and balance may 
become detached and that you may trip. You may also trip on the pressure sensitive mat. 
We will regularly check the sensors for appropriate attachment and you will be closely 
monitored. 

21 
Version 2.7 
 
  
Eye movements will be measured with video eye goggles (videonystagmography or VNG) 
while you are making small eye movements. There is rare risk that these protocols may 
cause some eye strain discomfort. 
Rest breaks will be provided if needed. Any minor eye strain will disappear shortly after 
the test. 
 
Muscle Testing: 
There is a risk of pressure or muscle fatigue when using the handheld dynamometer and 
Biodex equipment. 
Experienced personnel will assist in muscle testing and stop testing if discomfort 
occurs. 
 
Neuropsychological and neurobehavioral tests: 
There is an infrequent risk of boredom, frustration, and/or mental and physical fatigue 
during the neuropsychological and neurobehavioral testing. 
Trained research staff will conduct all the tests and administer all the questionnaires. 
The staff will be prepared to respond to your concerns by temporarily suspending 
testing and/or breaking up testing sessions into several brief visits if needed. 
 
MRI scan: 
There is a minor risk of discomfort or anxiety from being in the confined space of the MRI 
scanner.  
We will provide pads and blankets to make you as comfortable as possible. You will 
be able to talk to us throughout the study, and you will be able let us know right away 
if you want to stop the study and get out of the scanner. 
 
There is a rare risk of hearing damage or loss due to loud, vibrating noises generated by 
the MRI scanner. 
You will be provided foam earplugs to reduce the loud noises made by the scanner 
and prevent any hearing damage. 
 
Some studies, like this one, have the potential to cause "peripheral nerve stimulation" 
(PNS). PNS is a light touching sensation on the skin surface, lasting only for a few 
seconds. It may cause mild discomfort, but is not harmful to you. 
The MRI machine is operated within FDA guidelines so the potential for inducing PNS 
is low. 
 
Sometimes, subjects report a temporary, slight dizziness, light-headedness or nausea 
during or immediately after the scanning session. 
If you feel dizzy or light-headed, we will have you get up slowly from the scanner. 
 
Because the strong electromagnetic fields can move metal objects and cause heating, 
there is a risk that loose objects (jewelry, keys) outside your body could be accelerated by 
the magnetic field and strike you, causing you injury. There is also a risk that the magnetic 
fields could disturb a metal fragment in your body, interfere with an implanted device, such 
as a pacemaker or neurostimulator, or cause metal (including foil-backed medication 
patches) on or in your body to heat up, causing you harm. 
We keep the environment around the MRI scanner completely free of loose metal 
objects that could be moved by the magnetic field, and we will make sure that you 
have no metal on your body that could be affected by the MRI scanner. We will also 

22 
Version 2.7 
 
ask you questions and have you complete an MRI screening form to make sure that 
you have no metal inside your body that would cause you harm during the MRI scan. 
 
There is the potential that a magnetic resonance image may reveal an abnormality that is 
already in your body, such as a cyst or tumor. Many such abnormalities are not clinically 
significant, but you may need or want to investigate them further. Such a finding might 
require additional studies, and maybe even treatment, which would not be paid for by the 
investigators, the sponsor, or the University of Michigan. 
 
PET scans: 
There is an infrequent risk of bruising, bleeding, infection, or soreness associated with 
intravenous catheter placement, similar to the risks associated with routine blood testing. 
Also, you may feel dizzy or lightheaded or may rarely even faint when the tube is put in or 
taken out. 
We will use highly trained personnel for placement and removal of the IV. 
 
 There is a very rare risk that you could experience an allergic reaction to the PET tracer. 
This could involve itching, skin rash or shortness of breath shortly after injection. However, 
because of the very small tracer amounts used in PET imaging, the risk is very rare. 
A physician will be available and an emergency cart is located in the PET Facility for 
treatment of any adverse reactions that may occur. 
 
During the course of this study, you may potentially be exposed to radiation from the DXA 
scan, the PET/CT transmission scans and the PET tracer [11C]PE2I. 
The biological effect of radiation in humans is measured in terms of Sieverts (Sv) or 
mSv (1/1000 Sv), which is a unit of uniform whole body exposure. Exposure to a single 
PE2I PET-CT scan is 3.8 mSv (which is slightly above the annual level of natural 
background radiation of about 3 mSv).  
 
The maximum amount of radiation you will be exposed to from this research project 
will be approximately 3.81 mSv for the PE2I scan. In the event of a technical failure, 
one (1) of scan may be repeated, which would expose you to a maximum exposure of 
7.62 mSv. In the case of re-recruitment of a prior participant who previously completed 
a brain PE2I PET-CT scan and will undergo a repeat brain PE2I PET-CT scan, the 
additional radiation exposure will be 3.81 mSv for a total of 7.62 mSv. Participants will 
not exceed 2 brain PE2I PET-CT scans per year for this study The effects on the body 
of this radiation exposure will be added to your overall lifetime radiation risk. The US 
Federal Government requires that the annual amount of radiation exposure of 
radiation workers does not exceed 50 mSv per year; the maximum radiation you will 
be exposed is about 3/10th of this amount. Exposure to an (optional) DXA scan is less 
than 0.1% of annual background radiation exposure. Your lifetime radiation risk also 
includes any radiation you may have received in the past for diagnosis or treatment, 
and any such radiation you may be exposed to in the future. Please inform the 
investigators if you have had any major radiation exposure in the past, particularly in 
the past year, such as medical treatment with X-rays or radioactivity, or diagnostic X-
rays, CT-scans or nuclear medicine scans. No PET scans will be performed on 
pregnant, nursing, or potentially pregnant women. A urine pregnancy test will be 
performed on all women of childbearing potential within 48 hours prior to the PET/DXA 
scanning session. 
 
 

23 
Version 2.7 
 
Genetic testing: 
We will be testing for multiple genes that are related to clinical symptom presentation. 
There is a very rare risk that the genetic information we obtain from your samples could 
prove embarrassing to you, if somebody were able to link the genetic information with you. 
We have a system of double-coding the genetic information, so that it is extremely 
unlikely that the genetic information would be connected with you. Most importantly, 
we will break the link between the genetic information and you once the study is 
completed, thus removing this risk entirely. 
 
The federal Genetic Information Nondiscrimination Act (GINA) generally makes it 
illegal for health insurance companies, group health plans, and most employers to 
discriminate against you based on your genetic information. This law does not protect 
you against genetic discrimination by companies that sell life insurance, disability 
insurance, or long-term care insurance. Under this law: 
- 
Health insurance companies and group health plans may not request your 
genetic information that we obtain from this research 
- 
Health insurance companies and group health plans may not use your genetic 
information when making decisions regarding your eligibility or premiums 
- 
Employers with 15 or more employees may not use your genetic information 
that we obtain from this research when making a decision to hire, promote, or 
fire you or when setting the terms of your employment 
- 
 
GINA does not apply to the following groups; however, these groups have policies in 
place that provide similar protections against discrimination: 
- 
Members of the US Military receiving care through Tricare 
- 
Veterans receiving care through the Veteran’s Administration (VA) 
- 
The Indian Health Service 
- 
Federal employees receiving care through the Federal Employees Health 
Benefits Plans 
 
Assessment of daily life activity: 
There is a very rare risk of the movement monitor(s) (Actigraph or ActivPAL) detaching, 
which may result in a trip during the daily life monitoring of overall movement (actigraphy). 
It should be noted that the actigraphy only measures overall movement. Neither devices 
record your geographical location or specific activities that you were performing, neither 
can this be derived at a later point from the data that is stored in the Actigraph or ActivPAL. 
You will receive instruction for proper attachment of the Actigraph and/or ActivPAL 
system. 
 
C-L Dopa-specific risks:  
There is a common risk of nausea and an infrequent risk of vomiting. 
Participants are given the option to come into the lab for their first dosage of C-L Dopa. 
This optional visit would be 60-120 min in length where the participant will take their 
first dose of 25/100 C-L Dopa and be monitored by study personnel. The peak dosage 
time for C-L Dopa is 60-90 min, so if a participant is going to experience nausea or 
vomiting it would be in the first 60-90 min after taking a dose. 
 
The Carbidopa Monotherapy is done to reduce the chance of nausea and vomiting 
before starting C-L Dopa. All participants will receive three days of carbidopa 
monotherapy as a pre-treatment and will stay on this dose during the C-L Dopa 
treatment period. 

24 
Version 2.7 
 
 
Participants will be informed to take medication 30 minutes before a meal with a piece 
of fruit and with fruit juice to reduce chances of nausea and vomiting. Also, participants 
will be informed to not take medication with or after a protein filled meal, because this 
will increase the chance of nausea. 
There is an infrequent risk of sleepiness. There is a very rare risk of falling asleep without 
warning while taking C-L Dopa.   
Participants are given the option to come into the lab for their first dosage of C-L Dopa. 
This optional visit would be 60-120 min in length where the participant will take their 
first dose of 25/100 C-L Dopa and be monitored by study personnel. If you experience 
any episodes of sudden sleep onset or excessive daytime sleepiness, please contact 
the study team immediately. Medication use may be suspended, and further action 
taken, including withdrawal from the study. 
You understand that you should not operate machinery or drive until these symptoms 
have disappeared. 
There is an infrequent risk orthostatic hypotension when taking C-L Dopa. Participants 
taking antihypertensive medications (e.g. Hydrochlorothiazide, Atenolol, etc.) may be at 
higher risk of experiencing symptoms such as dizziness or lightheadedness when 
standing up after sitting. 
Participants are given the option to come into the lab for their first dosage of C-L Dopa. 
This optional visit would be 60-120 min in length where the participant will take their 
first dose of 25/100 C-L Dopa and be monitored by study personnel. 
 
If these symptoms are experienced at home, please contact study team immediately. 
Medication use may be suspended, and further action taken, including withdrawal from 
study.  
There is an infrequent risk of insomnia, anxiety, confusion, abnormal dreams, 
hallucination, psychosis, diarrhea, and constipation. 
Participants are given the option to come into the lab for their first dosage of C-L Dopa. 
This optional visit would be 60-120 min in length where the participant will take their 
first dose of 25/100 C-L Dopa and be monitored by study personnel. 
 
If these symptoms are experienced at home, please contact study team immediately. 
Medication use may be suspended, and further action taken, including withdrawal from 
study.  
 
There is a common risk of dizziness and headache. There is a rare risk of chest pain, 
dystonia, urinary frequency, ischemia, back pain, muscle cramps, and shoulder pain. 
Participants are given the option to come into the lab for their first dosage of C-L Dopa. 
This optional visit would be 60-120 min in length where the participant will take their 
first dose of 25/100 C-L Dopa and be monitored by study personnel. 
 
Please lay down until symptoms pass. 
 

25 
Version 2.7 
 
If these symptoms are experienced at home, please contact study team immediately. 
Medication use may be suspended, and further action taken, including withdrawal from 
study.  
 
There is a rare risk of psychological changes while taking C-L Dopa. These may include 
the development of depression/suicidal tendencies, libido changes, increased urges to 
gamble, spend money, or practice binge-eating.  
Participants are given the option to come into the lab for their first dosage of C-L Dopa. 
This optional visit would be 60-120 min in length where the participant will take their 
first dose of 25/100 C-L Dopa and be monitored by study personnel. Monitoring will 
continue during the medication period in the form of weekly phone-call check ins.  
 
If these symptoms are experienced at home, please contact study team immediately. 
Medication use may be suspended, and further action taken, including withdrawal from 
study.  
 
  
Given the very low dose of C-L Dopa we do not anticipate any significant withdrawal 
symptoms when stopping the medication as this is not observed at the 25/100 TID PO 
dose in clinical practice. Please refer the package insert for a comprehensive list of 
potential side effects. 
 
While taking the placebo, you will not be ingesting any active ingredient. Placebos are 
commonly used in research and some patients do report side effects. There is an 
infrequent risk of nausea and a rare risk of vomiting while taking a placebo medication. 
Additionally, there is an infrequent risk of drowsiness and a rare risk of allergic 
reactions, such as skin rashes to the placebo.  
 
While we will not know if you are receiving a placebo or the active drug C-L Dopa, 
researchers will closely monitor all participants for side effects. All participants will 
be given the option to take the first dose in the lab, so the study team can help 
monitor reactions. Participants can take the medication 30 minutes before a meal 
with a piece of fruit or juice to reduce the chances of nausea and vomiting. If you 
experience any drowsiness, do not operate machinery or drive.  
Biopsy Specific Risks: 
There is a rare risk of an allergic reaction to local anesthesia.  
Participants will be screened for any allergies to drugs to avoid the possibility of an 
allergic reaction. A physician will be administering the anesthesia and biopsy after 
receiving specialized training.  
 
There is a rare risk of severe pain or nerve damage during the administration of the biopsy. 
While receiving a biopsy typically causes temporary discomfort, severe pain is not 
anticipated. To prevent this, a local anesthesia will be used, and only trained 
research staff will be completing the biopsy visits. Biopsies are frequently 
performed in a clinical setting and are deemed safe. Research staff has been 
trained on the correct positioning and pressure to apply during the biopsy. The 
procedure itself will be performed by a clinician. 
 
There is a rare risk of excessive bleeding after the biopsy procedure.  
Participants will be screened for bleeding disorders and blood thinning 
medications. The biopsy will be performed by a clinician who can apply pressure 

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to the site of biopsy immediately following administration to stop any bleeding. 
Subjects will be instructed that they should report any bleeding or opening of the 
wound immediately for follow up care. Subjects will be supplied with ice and 
pressure bandages after each biopsy to reduce inflammation and any soreness 
after the biopsy. A member of the research team will follow-up with participants the 
day after each muscle biopsy. 
 
There is an infrequent risk of wound infection after the biopsy.  
Participants will be provided with bandages to keep the punch site dry and 
covered. Participants will be screened for infection risk factors such as 
immunocompromising conditions. Subjects will be instructed that they should 
report any bleeding or opening of the wound immediately for follow up care. 
Subjects will be supplied with ice and pressure bandages after each biopsy to 
reduce inflammation and any soreness after the biopsy. A member of the research 
team will follow-up with participants the day after each muscle biopsy.  
 
There is a rare risk of a stress reaction occurring before, during, or following the biopsy 
for those uncomfortable with blood or the tools used during the procedure, or for those 
with a history of stress reactions.  
This risk is possible for participants who experience a stress reaction in healthcare 
environments or with procedures involving tools such as needles. Stress 
reactions can include a hypertensive (elevated blood pressure) response, chest 
pains, headaches, or difficulty breathing. Subjects are informed what is involved 
in the biopsy procedure so they can decide on if they are comfortable completing 
the procedure. Additionally, trained study team members will monitor the 
participants throughout the biopsy to determine if a stress reaction is occurring. 
In the case of a reaction, the study team will monitor vitals, have the participant 
remain seated or lying down, and can provide water as needed. An on-site 
neurologist can also check on the patient if needed.   
 
 
 
Blood draw specific risks: 
 
There is an infrequent risk of bruising, bleeding, or soreness at the injection site. There 
is a very rare risk for infection. There is a rare risk that you may feel dizzy, lightheaded, 
or faint after the injection.  
 
Blood drawing, iv catheter insertions, and injections will be performed by a 
certified and experienced research technician or other health care professional 
who is also trained in blood borne pathogens control. Aseptic techniques will be 
used in accordance with University of Michigan guidelines. You can lie down if 
you feel dizzy, lightheaded or faint after an injection. 
 
 
Open-label study: Subject compensation (as described in informed consent form): 
You will receive $50 for each completed MRI scan. You will receive $50 for each 
completed PE2I PET scan. Payment for completion of the detailed clinical baseline test 
day will be $100 and $100 for follow-up. You will also receive $50 for completing the limited 
clinical test day and medication phase of the study. Compensation for your time and effort 
after full study completion may total a maximum of $500. 
 

27 
Version 2.7 
 
Overnight accommodations may be provided depending on personal circumstances or if 
you live far away. We will discuss with you the need for these accommodations as the 
research appointment(s) are being arranged. If eligible, overnight lodging can be arranged 
through the UMHS Patient and Visitor Accommodations Program either by a study team 
member or by you. However, you may decide to make alternative arrangements. In that 
case, please discuss with the study team first if you are eligible for reimbursement prior to 
making any reservations. We can only reimburse for expenses that have been approved 
in advance by the study team. You will need to provide receipts to the study team before 
expenses can be reimbursed. You will receive a voucher for valet parking at the University 
Hospital. Parking at Domino's Farms is free. 
 
You will be paid after your last study visit or, in case you decide to withdraw from the study, 
you will be paid for the parts that you have completed. You will be paid by check, which 
will be sent to your home address. Alternatively, you may request a payment coupon for 
cash payment at the University Hospital. We do not keep cash for immediate payment. 
 
If you receive payment of $600 or more for taking part in this study, the University of 
Michigan accounting department will collect your name, address, social security number, 
payment amount, and related information. For tax reporting purposes this information must 
be sent to the Internal Revenue Service (IRS). 
 
Placebo-controlled study (sub-study 1): Subject compensation (as described in 
informed consent form): 
You will receive $50 for a completed MRI scan. You will receive $75 for a completed PE2I 
PET scan. Payment for completion of the detailed clinical baseline test day will be $30 
($10 for screening, $20 for remaining tests). and $30 for follow-up. You will also receive 
$15 for completing the limited clinical test day and medication phase of the study. You will 
receive $40 for completion of the optional skin biopsy Compensation for your time and 
effort after full study completion may total a maximum of $240. You will receive a voucher 
for valet parking at the University Hospital. Parking at Domino's Farms is free. Participants 
who are consented and then deemed ineligible following the screening will be 
compensated the $10 for the screening visit.  
 
You will be paid after your last study visit or, in case you decide to withdraw from the study, 
you will be paid for the parts that you have completed. You will be paid by check, which 
will be sent to your home address. Alternatively, you may request a payment coupon for 
cash payment at the University Hospital. We do not keep cash for immediate payment. 
 
If you receive payment of $600 or more for taking part in this study, the University of 
Michigan accounting department will collect your name, address, social security number, 
payment amount, and related information. For tax reporting purposes this information must 
be sent to the Internal Revenue Service (IRS). 
 
Exploratory Muscle Testing Study (sub-study 2): Subject compensation (as 
described in informed consent form) 
You will receive $50 for a completed MRI scan. You will receive $75 for a completed PE2I 
PET scan. Payment for completion of the detailed clinical baseline test day will be $30 
($10 for screening, $20 for remaining tests). and $30 for follow-up. You will also receive 
$15 for completing the limited clinical test day and medication phase of the study. You will 
receive $50 for each completed muscle biopsy and $25 for each completed blood draw. 
Compensation for your time and effort after full study completion may total a maximum of 

28 
Version 2.7 
 
$350. You will receive a voucher for valet parking at the University Hospital. Parking at 
Domino's Farms is free. Participants who are consented and then deemed ineligible 
following the screening will be compensated the $10 for the screening visit.  
 
You will be paid after your last study visit or, in case you decide to withdraw from the study, 
you will be paid for the parts that you have completed. You will be paid by check, which 
will be sent to your home address. Alternatively, you may request a payment coupon for 
cash payment at the University Hospital. We do not keep cash for immediate payment. 
 
If you receive payment of $600 or more for taking part in this study, the University of 
Michigan accounting department will collect your name, address, social security number, 
payment amount, and related information. For tax reporting purposes this information must 
be sent to the Internal Revenue Service (IRS). 
your name, address, social security number, payment amount, and related information. 
For tax reporting purposes this information must be sent to the Internal Revenue Service 
(IRS). 
 
Remote consent and remote assessments: 
Data may be collected remotely (using Zoom for Health at U of M) or telephone call if 
feasible for assessment. Remote electronic consent may be obtained using SignNow, this 
is being done to reduce physical interactions between subjects and study staff. 
 
References 
1. 
Bohnen NI, Muller ML, Kuwabara H, Cham R, Constantine GM, Studenski SA. 
Age-associated striatal dopaminergic denervation and falls in community-dwelling 
subjects. J Rehabil Res Dev. 2009;46(8):1045-1052. 
2. 
Goetz CG, Fahn S, Martinez-Martin P, et al. Movement Disorder Society-
sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-
UPDRS): Process, format, and clinimetric testing plan. Movement disorders : 
official journal of the Movement Disorder Society. 2007;22:41-47. 
3. 
Franchignoni F, Horak F, Godi M, Nardone A, Giordano A. Using psychometric 
techniques to improve the Balance Evaluation Systems Test: the mini-BESTest. J 
Rehabil Med. 2010;42(4):323-331. 
4. 
Powell LE, Myers AM. The Activities-specific Balance Confidence (ABC) Scale. J 
Gerontol A Biol Sci Med Sci. 1995;50A(1):M28-34. 
5. 
Shao X, Kilbourn MR. A simple modification of GE tracerlab FX C Pro for rapid 
sequential preparation of [11C]carfentanil and [11C]raclopride. Appl Radiat Isot. 
2009;67(4):602-605. 
6. 
Chan GL, Holden JE, Stoessl AJ, et al. Reproducibility studies with 11C-DTBZ, a 
monoamine vesicular transporter inhibitor in healthy human subjects. J Nucl Med. 
1999;40(2):283-289. 
7. 
Koeppe RA, Frey KA, Kuhl DE, Kilbourn MR. Assessment of extrastriatal vesicular 
monoamine 
transporter 
binding 
site 
density 
using 
stereoisomers 
of 
[11C]dihydrotetrabenazine. J Cereb Blood Flow Metab. 1999;19(12):1376-1384. 
8. 
Logan J, Fowler JS, Volkow ND, Ding YS, Wang GJ, Alexoff DL. A strategy for 
removing the bias in the graphical analysis method. J Cereb Blood Flow Metab. 
2001;21:307-320. 
9. 
de la Fuente-Fernandez R, Ruth TJ, Sossi V, Schulzer M, Calne DB, Stoessl AJ. 
Expectation and dopamine release: mechanism of the placebo effect in 
Parkinson's disease. Science. 2001;293(5532):1164-1166. 

29 
Version 2.7 
 
10. 
Louis ED, Tang MX, Mayeux R. Parkinsonian signs in older people in a community-
based study: risk of incident dementia. Archives of neurology. 2004;61(8):1273-
1276. 
11. 
Bohnen NI, Albin RL, Koeppe RA, et al. Positron emission tomography of 
monoaminergic vesicular binding in aging and Parkinson disease. J Cereb Blood 
Flow Metab. 2006;26:1198-1212. 
12. 
Newman RP, LeWitt PA, Jaffe M, Calne DB, Larsen TA. Motor function in the 
normal aging population: treatment with levodopa. Neurology. 1985;35(4):571-3. 
13. 
Goetz, C.G., et al., Movement Disorder Society-sponsored revision of the Unified 
Parkinson's Disease Rating Scale (MDS-UPDRS): Process, format, and clinimetric 
testing plan. Mov Disord, 2007. 22(1): p. 41-7. 
14. 
Hoehn, M.M. and M.D. Yahr, Parkinsonism: onset, progression and mortality. 
Neurology, 1967. 17(5): p. 427-42. 
15. 
Giladi, N., et al., Gait festination in Parkinson's disease. Parkinsonism Relat 
Disord, 2001. 7(2): p. 135-138. 
16. 
Giladi, N., et al., Construction of freezing of gait questionnaire for patients with 
Parkinsonism. Parkinsonism Relat Disord, 2000. 6(3): p. 165-170. 
17. 
Giladi, N., et al., Validation of the freezing of gait questionnaire in patients with 
Parkinson's disease. Mov Disord, 2009. 24(5): p. 655-61. 
18. 
Folstein, M.F., S.E. Folstein, and P.R. McHugh, "Mini-mental state". A practical 
method for grading the cognitive state of patients for the clinician. J Psychiatr Res, 
1975. 12(3): p. 189-98. 
19. 
Nasreddine, Z.S., et al., The Montreal Cognitive Assessment, MoCA: a brief 
screening tool for mild cognitive impairment. J Am Geriatr Soc, 2005. 53(4): p. 695-
9. 
20. 
Delis, D., E. Kaplan, and J. Kramer, Delis-Kaplan Executive Function System (D-
KEFS): Examiner's manual. 2001, San Antonio, TX: The Psychological 
Corporation. 
21. 
Delis, D., et al., California Verbal Learning Test Manual, Adult Version. 2nd ed. 
2000, San Antonio, TX: The Psychological Corporation. 
22. 
Boeve BF, Molano JR, Ferman TJ, Smith GE, Lin SC, Bieniek K, Haidar W, 
Tippmann-Peikert M, Knopman DS, Graff-Radford NR, Lucas JA, Petersen RC, 
Silber MH. Validation of the Mayo Sleep Questionnaire to screen for REM sleep 
behavior disorder in an aging and dementia cohort. Sleep medicine. 
2011;12(5):445-53. Epub 2011/02/26. doi: S1389-9457(11)00010-4 [pii] 
23.       Doppler K, Antelmi E, Kuzkina A, et al. Consistent skin α-synuclein positivity in 
REM sleep behavior disorder – A two center two-to-four-year follow-up study. 
Parkinsonism Relat Disord. 2021;86:108-113. 
doi:10.1016/j.parkreldis.2021.04.007 
 
24.  
The utility of α-synuclein as biofluid marker in neurodegenerative diseases: a 
systematic review of the literature | Biomarkers in Medicine. Accessed October 
27, 2023. https://www.futuremedicine.com/doi/full/10.2217/BMM.14.105 
 

30 
Version 2.7 
 
25.       Gibbons C, Wang N, Rajan S, et al. Cutaneous α-Synuclein Signatures in Patients 
With 
Multiple 
System 
Atrophy 
and 
Parkinson 
Disease. 
Neurology. 
2023;100(15):e1529-e1539.  
26.  
Rosca EC, Simu M. Parkinson's Disease-Cognitive Rating Scale for Evaluating 
Cognitive Impairment in Parkinson's Disease: A Systematic Review. Brain Sci. 
2020;10(9):588. Published 2020 Aug 25. doi:10.3390/brainsci10090588 
27.  
Ramasamy, R., S.F. Yan, and A.M. Schmidt, The diverse ligand repertoire of the 
receptor for advanced glycation endproducts and pathways to the complications 
of diabetes. Vascul Pharmacol, 2012. 57(5-6): p. 160-7. 
28. 
Feiring, D. C., Ellenbecker, T. S., & Derscheid, G. L. (1990). Test-retest reliability 
of the Biodex isokinetic dynamometer. Journal of Orthopaedic & Sports Physical 
Therapy, 11(7), 298-300. 
29. 
Ogborn, D. I., Bellemare, A., Bruinooge, B., Brown, H., McRae, S., & Leiter, J. 
(2021). Comparison of common methodologies for the determination of knee flexor 
muscle strength. International Journal of Sports Physical Therapy, 16(2), 350. 
30. 
Bergstrom, J., Muscle electrolytes in man. Scand. J. Clin. Lab Invest. Suppl., 1962. 
68: p. 1-110. 
31. 
Haus, J.M., et al., Contractile and connective tissue protein content of human 
skeletal muscle: effects of 35 and 90 days of simulated microgravity and exercise 
countermeasures. Am J Physiol Regul Integr Comp Physiol, 2007. 293(4): p. 
R1722-7.  
32. 
Lemoine, J.K., et al., Muscle proteins during 60-day bedrest in women: impact of 
exercise or nutrition. Muscle Nerve, 2009. 39(4): p. 463-71.  
33. 
Williamson, D.L., et al., Aberrant REDD1-mTORC1 responses to insulin in skeletal 
muscle from type 2 diabetics. Am J Physiol Regul Integr Comp Physiol, 2015: p. 
ajpregu 00285 2015. 
34. 
Ramteke A, Ting H, Agarwal C, et al. Exosomes secreted under hypoxia enhance 
invasiveness and stemness of prostate cancer cells by targeting adherens junction 
molecules. Mol Carcinog 2015;54(7):554-65. doi: 10.1002/mc.22124 [published 
Online First: 2013/12/19] 
35.  
Patterson SA, Deep G, Brinkley TE. Detection of the receptor for advanced 
glycation endproducts in neuronally-derived exosomes in plasma. Biochem 
Biophys Res Commun 2018;500(4):892-96. doi: 10.1016/j.bbrc.2018.04.181 
[published Online First: 2018/04/28]