Clinical trial NCT06219915
Conditions: Parkinsonian Signs in Older Persons
Keywords: slow gait Parkinsonian signs
Sponsor: University of Michigan
Start date: 2024-03-15; Completion date: 2024-05-30
Enrollment: 13 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Walking with age becomes both slower and less 'automated', requiring more attention and brain resources. As a result, older adults have a greater risk of negative outcomes and falls. 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. Investigators have recently discovered that \~20% of older adults maintain fast walking speed even in the presence of small blood vessel brain changes and leg problems, thus appearing to be protected against these harmful factors. The investigators work suggests that the brain dopamine (DA) system may be a source of this protective capacity. Investigators have also shown that lower levels of dopamine are associated with slow walking. Investigators will be investigating the role of dopamine on slow walking and other parkinsonian signs in this double-blinded, placebo-controlled study using detailed clinical assessment, assessment of dopamine activity, and clinical interventions.

Detailed description:
Walking with age becomes both slower and less 'automated', requiring more attention and prefrontal resources. 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 systems. 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, investigators 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. The investigators work suggests that the nigrostriatal dopamine (DA) system may be a source of this resilience. As investigators recent findings suggest, DA neurotransmission positively predicts walking speed; 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 impairment. 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 areas.

The investigators 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. 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 study is an arm of a previously completed translational pilot biomechanistic target engagement study in older adults with slow walking and/or parkinsonian signs (NCT04325503). This sub-study will further investigate this biomechanistic target engagement using a double-blind, placebo-controlled study design.

The study will include elderly men and women age 60 or older with evidence of mild parkinsonian signs (MPS, or slow gait (\< 1m/s)).

Arms: arm 1: Participants will begin by taking 25mg of Carbidopa monotherapy three times per day (TID) for 3 days. On day four, participants will begin taking 1 tablet of Carbidopa-Levodopa (25/100mg) TID in addition to the Carbidopa monotherapy. On day seven, participants will increase to 1.5 tablets of Carbidopa-Levodopa (25/100mg) TID while maintaining 25mg Carbidopa monotherapy TID. The intervention will end after ten days of supplementation. arm 2: Participants will begin by taking a 25mg placebo tablet three times per day (TID) for 3 days. On day four, participants will begin taking a separate placebo tablet TID in addition to the original placebo. On day seven, participants will increase to 1.5 tablets of the second placebo TID while maintaining 25mg original placebo TID. The intervention will end after ten days of supplementation.
Interventions: intervention 1: Carbidopa 25 mg intervention 2: Carbidopa-Levodopa 25/100 mg intervention 3: Placebo 1 intervention 4: Placebo 2
Intervention descriptions: intervention 1: Participants will take one 25mg Carbidopa tablet 3 times a day for 10 days. intervention 2: Participants will take one 25/100mg carbidopa-levodopa tablet 3 times a day on days 4-6, then increase to 1.5 tablets 3 times a day on days 7-10. intervention 3: Participants will take one 25mg placebo tablet 3 times a day for 10 days. intervention 4: Participants will take one 100mg placebo tablet 3 times a day on days 4-6, then increase to 1.5 tablets 3 times a day on days 7-10.

Protocol documents:
Prot_SAP_001.pdf: 
Study Title:  Neurobiological Drivers of Mobility Resilience: The Dopaminergic System 
PI:   Fae Pongmala, PhD
Study ID:  HUM00156490-A
NCT#:  NCT06219915
Protocol Version IRB Approval Date:  12/17/2024


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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 extracellular vesicle (EV) levels after 1-week C-L Dopa
supplementation.
(b) Mean torque value for each leg during Biodex muscle strength test.
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 
maximal effort during a static knee extension and to limit countermovement.  At least three 


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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 


12 
Version 2.6 
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 
✓
✓ 
✓


13 
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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) 
✓ 
 
 
 
 
✓ 


14 
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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 
✓ 
 
 
 
 
✓ 


15 
Version 2.6 
 
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 
 
 
 
 
✓ 
 


16 
Version 2.6 
 
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)  
✓ 
 
 
 
 
✓ 


17 
Version 2.6 
 
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 
✓ 
✓ 
✓ 
✓ 
✓ 


18 
Version 2.6 
 
 
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 


19 
Version 2.6 
 
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. 


20 
Version 2.6 
 
  
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 


21 
Version 2.6 
 
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. 
 
 


22 
Version 2.6 
 
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. 


23 
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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. 
 


24 
Version 2.6 
 
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 


25 
Version 2.6 
 
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. 
 


26 
Version 2.6 
 
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 


27 
Version 2.6 
 
$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. 


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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 
 


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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] 
 

ICF_002.pdf: 
Study ID: HUM00156490  IRB: IRBMED  Date Approved: 2/22/2024  Expiration Date: 7/26/2024 
Consent Subtitle: Placebo-Controlled Sub-study 
Consent Version: v1.0 
Page 1 of 24 
 
 
Neurobiological drivers of mobility resilience: the 
dopaminergic system (RES) 
 
Placebo-Controlled Arm 
 
NCT06219915 
 
2/22/2024 
 
 


Study ID: HUM00156490  IRB: IRBMED  Date Approved: 2/22/2024  Expiration Date: 7/26/2024 
Consent Subtitle: Placebo-Controlled Sub-study 
Consent Version: v1.0 
Page 2 of 24 
 
 
UNIVERSITY OF MICHIGAN 
CONSENT TO BE PART OF A RESEARCH STUDY 
 
1. KEY INFORMATION ABOUT THE RESEARCHERS AND THIS STUDY 
 
Study title: 
Neurobiological drivers of mobility resilience: the dopaminergic system 
Company or agency sponsoring the study: 
National Institutes of Health (NIH) 
Names, degrees, and affiliations of the principal investigator and study coordinator (if applicable): 
Principal Investigator: Fay Pongmala, PhD, University of Michigan, Departments of Radiology and 
Neurology 
Coordinator(s): Robert Vangel, University of Michigan, Department of Radiology 
Jaimie Barr, University of Michigan, Department of Radiology 
1.1 Key Study Information 
You may be eligible to take part in a research study. This form contains important information that will 
help you decide whether to join the study. Take the time to carefully review this information. You 
should talk to the researchers about the study and ask them any questions you have. You may also wish 
to talk to others such as your family, friends, or other doctors about joining this study. If you decide to 
join the study, you will be asked to sign this form before you can start study-related activities. Before 
you do, be sure you understand what the research study is about. 
A research study is different from the regular medical care you receive from your doctor. Research 
studies hope to make discoveries and learn new information about diseases and how to treat them. You 
should consider the reasons why you might want to join a research study or why it is not the best 
decision for you at this time. 
 
Research studies do not always offer the possibility of treating your disease or condition. Research 
studies also have different kinds of risks and risk levels, depending on the type of the study. You may 
also need to think about other requirements for being in the study. For example, some studies require 
you to travel to scheduled visits at the study site in Ann Arbor or elsewhere. This may require you to 
arrange travel, change work schedules, find child care, or make other plans. In your decision to 
participate in this study, consider all of these matters carefully. 
 
This research is studying the use of an FDA approved medication for Parkinson’s disease called 
carbidopa-levodopa (C-L Dopa or Sinemet). C-L Dopa is used to increase the level of dopamine, a 
neurotransmitter that is depleted in PD, in the brain. In this study, we will be using this medication in 
people who are not diagnosed with PD but have some of its symptoms to investigate how dopamine 
relates to these symptoms. We will be using a placebo, a substance without an active drug, to compare 
participants with and without dopamine supplementation via C-L Dopa. You will be screened for these 
symptoms. If these are not present, you will not be eligible for the study and will be excluded. In this 
investigational study we will use this medication in a small number of people to learn about the 


Study ID: HUM00156490  IRB: IRBMED  Date Approved: 2/22/2024  Expiration Date: 7/26/2024 
Consent Subtitle: Placebo-Controlled Sub-study 
Consent Version: v1.0 
Page 3 of 24 
 
 
relationship between dopamine and slow walking in elderly subjects. Your health-related information 
will be collected and you may receive medications, will undergo extensive cognitive and motor testing, 
optional magnetic resonance image (MRI), dopamine PE2I PET-CT scan, wear an activity monitor for 
about a week, and complete an optional tissue biopsy for this research study. 
 
This study involves a process called randomization. This means that the drug you receive in the study is 
not chosen by you or the researcher. The study design divides study participants into separate groups, 
based on chance (like the flip of a coin), to compare different treatments or procedures. If you decide to 
be in the study, you need to be comfortable not knowing which study group you will be in. You will be 
randomized into one of two groups: 1) C-L Dopa or 2) placebo. 
 
There can be risks associated with joining any research study. The type of risk may impact whether you 
decide to join the study. For this study, some of these risks may include new symptoms from use of the 
carbidopa-levodopa such as nausea. More detailed information will be provided later in this document. 
This study may not offer any benefit to you now but may benefit others in the future by providing 
important new insights into the relationship between dopamine and slow gait in the elderly. 
We expect the amount of time you will participate in the study will be 10-14 days. However, this is an 
estimate, and this may vary depending on how many visits are needed to complete testing. 
You can decide not to be in this study. Alternatives to joining this study include not participating. 
Even if you decide to join the study now, you are free to leave at any time if you change your mind. 
More information about this study continues in Section 2 of this document. 


Study ID: HUM00156490  IRB: IRBMED  Date Approved: 2/22/2024  Expiration Date: 7/26/2024 
Consent Subtitle: Placebo-Controlled Sub-study 
Consent Version: v1.0 
Page 4 of 24 
 
 
 
2. PURPOSE OF THIS STUDY 
 
2.1 Study purpose: 
Symptoms that can occur in Parkinson's disease, like slow walking, are also common in elderly people. 
We have also shown that lower levels of dopamine are associated with slow walking. We propose to use 
an FDA-approved medication for Parkinson’s disease called carbidopa-levodopa that will increase the 
brain dopamine level to further investigate the relationship between dopamine and walking and balance 
problems. We will test this against a placebo. As a possible study option, we may also look at brain MRI 
to see if we see changes in connections within the motor control areas. We will perform detailed 
walking and other motor tests prior to and at the end of the medication treatment, and a dopamine 
PET-CT scan once during the study to assess dopamine levels in the brain. We will also administer 
general clinical tests (blood pressure, pulse, vision) and cognitive (memory, attention) tests. We will also 
ask you to complete questionnaires about your health, sleep and how you feel. Optionally, you may also 
complete a skin biopsy. The samples will be analyzed for alpha synuclein, the protein involved in 
Parkinson’s disease and related disorders. 
 
3. WHO MAY PARTICIPATE IN THE STUDY 
 
Taking part in this study is completely voluntary. You do not have to participate if you don't want to. 
You may also leave the study at any time. If you leave the study before it is finished, there will be no 
penalty to you, and you will not lose any benefits to which you are otherwise entitled. 
 
3.1 Who can take part in this study? 
Elderly men and women who are 60 of age or older, can participate in this study. Participants should be 
willing and able to comply with study requirements. People who, in the opinion of the investigators, 
would be at increased risk or who are unable to perform or tolerate the research procedures will be 
excluded. People who have any contraindication for MRI imaging such as a pacemaker, metal 
fragment(s) in their body, or severe claustrophobia may not be eligible. 
3.2 How many people are expected to take part in this study? 
A total of 12 people are expected to participate in the treatment study but we expect to screen up to 40 
people for the presence of slow walking or other Parkinson signs. There will be 6 people in each of the 
two groups (active medication and placebo). 
 
4. INFORMATION ABOUT STUDY PARTICIPATION 
 
4.1 What will happen to me in this study? 
After having passed the initial screening process, and if you agree to take part in this study, you will be 
asked to sign this informed consent form before testing will begin. During the screening process we will 
ask questions to determine if you are eligible to participate in this study. 
A summary of the minimum and optional tests are shown in the table below: 
 
Study Events 
Visit 1 (Day 0) 
● Informed Consent 
● Randomization (like the flip of a coin, into one of the two groups) 
● General and clinical information 
● General medical and neurological exam 


Study ID: HUM00156490  IRB: IRBMED  Date Approved: 2/22/2024  Expiration Date: 7/26/2024 
Consent Subtitle: Placebo-Controlled Sub-study 
Consent Version: v1.0 
Page 5 of 24 
 
 
 
● (Optional) Visual assessments 
● (Optional) Smell Assessments 
● Motor Assessments 
● Memory, reasoning and mental concentration assessments 
● Questionnaires 
● ((Optional) MRI scan (can be performed on different day) 
● PE2I dopamine brain PET-CT scan (can be performed on different day) 
● (Optional) DXA scan 
● (Optional) Skin Biopsy (can be performed on different day) 
Day 1-3 
● Three-day carbidopa pre-treatment three times a day (or placebo) 
● (Optional) Assessment of daily life activity 
Visit 2 (Day 4) 
and Day4-6 
● Day 4 Repeat of limited clinical test battery from visit 1 prior to starting: 
● Day 4 Optional in-lab observation to take first C-L Dopa dose (or placebo) 
● Carbidopa-Levodopa medication three times a day combined with carbidopa 
medication three times per day (or placebo) 
● (Optional) Assessment of daily life activity 
Day 7-10 (±3) 
● Carbidopa-Levodopa medication three times a day combined with carbidopa 
medication three times per day (or placebo) 
● (Optional) Assessment of daily life activity 
Visit 3 (Day 10 
(±3)) 
● General and clinical information 
● General medical and neurological exam 
● (Optional) Visual assessments 
● Motor Assessments 
● Memory, reasoning and mental concentration assessments 
● Questionnaires 
● (Optional) Smell Assessments 
● (Optional) MRI scan 
● You can stop the Sinemet medication (or placebo) after you have completed all 
testing and return the bottle to the study staff. 


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Baseline clinical test day (Visit 1) 
Clinical tests: You will receive a physical and neurological examination ("medical check-up") including 
the measurements of weight, height, pulse and blood pressure as well as an evaluation of your ability to 
move and walk. We will also ask you questions about your health and medications and screen your 
cognitive abilities. We will also ask questions to see if you’re eligible to undergo (optional) MRI scans. In 
addition, we will ask you for some general demographic and clinical information. 
OPTIONAL: Smell and vision tests: Your sense of smell will be tested by administering tests that will 
assess your sense of smell. We will also test your visual acuity and do tests to assess for color blindness 
and contrast sensitivity. As a possible option we may also test your eye movements using video goggles 
that measure your eye movements while following a dot. You will also have your eyes tracked while 
viewing numbers on a computer screen. These tests will be performed unless there is a time constraint 
or testing materials are unavailable due to supplier shortages. 
Motor tests: Walking and balance tests will be performed while you will be walking on an electronic 
mat. Small sensors will also be put on your body (pelvis, ankles). You will undergo several balance tests. 
Fine movements of the hands, fingers and feet will be examined by finger and foot tapping devices and a 
pegboard test device (a timed test where subjects put pegs in holes). As a possible option, we may place 
small sensors at your wrist, ankles, and around your chest and waist to measure your body movements 
while you perform different balance and gait tasks. Some of the walking will be tested while walking on 
an electronic gait mat. 
Thinking and neurobehavioral tests:  The cognitive (thinking) tests are designed to get an overall 
estimate of your memory, concentration, and ability to think. These functions will be measured with 
standard tests. We will also ask you questions about your mood. Other questions are about sleep and 
fatigue. 
Assessment of daily life activity: As a possible option, you may be asked to wear an activity monitor 
during the medication administration to monitor your normal overall daily-life movement, so-called 
“actigraphy”. This device is very similar to a pedometer that some people use to count the number of 
steps that they take every day. We will provide instructions on how to attach this device to your body 
and when to use it. This requires also keeping track in a logbook when you are wearing the device and 
document selected activities (for example when you took the device off to take a shower or when you 
were playing sports). 
If the clinical assessment does not show evidence of slow walking and/or other Parkinsonian signs, then 
you will be excluded from the treatment and imaging parts of the study. 
OPTIONAL Skin Biopsy: You will have to option to complete a skin biopsy while in the lab. This will be 
performed by a neurologist and involves taking three small (<3mm) punches from the upper back and 
leg. We will utilize a general anesthetic (lidocaine) to alleviate discomfort from the procedure. No 
stitches are required as this is a minimally invasive procedure. Aftercare involves keeping the area 
covered and dry with bandages for 48 hours. The tissue samples will be shipped to CND Life Sciences 
who will stain the skin for alpha synuclein, the protein involved in Parkinson’s disease. This analysis will 
inform us if there is alpha synuclein present in the nerves throughout your body. There are additional 
exclusion criteria for the skin biopsy such as history of allergic reaction to lidocaine, use of 
anticoagulants (aspirin and Plavix alone is okay), or history of significantly impaired wound healing. If 
you are interested, the study team will review this criterion with you. 


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(initials) I discussed the optional skin biopsy and agree to participate in the procedure. 
 
(initials) I discussed the optional skin biopsy and do not agree to participate in the 
procedure. 
 
Baseline imaging day (Part of Visit 1) 
OPTIONAL DXA scan: An optional brief (~ 10 minute) DXA (bone mineral density/fat soft tissue) scan can 
be performed during the clinical test battery of visit 1 while you are at the Functional Neuroimaging, 
Cognitive & Mobility Laboratory at Domino's farms. 
 
(initials) I discussed participating in an optional DXA scan and I agree to participate. 
 
(initials) I discussed participating in an optional DXA scan and I do not agree to participate. 
OPTIONAL MRI scan(s): Optional MRI scans allow the investigators to visualize the brain in detail by 
using a large magnet. An MRI scan of the brain involves lying on a table, which slides into a scanner. You 
will be instructed to remove all jewelry and other metal-containing objects for the MRI scan. During the 
MRI scan loud noises may be heard. The MRI scan will be performed in FDA-approved MRI scanner at 
the Department of Radiology at the University of Michigan Hospital. 
 
(initials) I discussed participating in an optional single brain MRI scan and I agree to 
participate. 
 
(initials) I discussed participating in an optional single brain MRI scan and I do not agree to 
participate. 
PET-CT scan: The PET-CT scan will allow the investigators to “see” the specific marker of dopamine (a 
chemical messenger molecule in the brain). A single dopamine PE2I PET-CT scan will be performed. To 
establish this, in separate sessions, a radiotracer will be injected into your vein through an i.v. 
(intravenous line or plastic “tube” inserted in an arm vein). A tracer refers to a small amount of a 
radioactive substance that does not alter body function, but that can be detected (imaged) in the PET-CT 
scanner. The PET-CT scanner looks like a hollow machine resembling an X-ray scanner (CT or CAT). 
Images of your brain will be obtained over a period of time. During the PET-CT scans we also may take 
blood samples for further analysis of tracer characteristics. Women of childbearing potential will be 
required to provide a urine sample for a urine pregnancy test within 48 hours prior to the PET-CT scan. If 
one of these scans fails, they may be repeated. 
 
(initials) I discussed participating in the brain dopamine PE2I PET-CT scan and I agree to 
participate. 
Medication Involvement 
You will be asked to participate in the following study with a medication that may affect your dopamine 
receptors. The FDA has approved both medications for use in Parkinson’s disease; carbidopa 
monotherapy (Lodosyn) and Carbidopa/Levodopa (C-L Dopa or Sinemet) are approved to treat motor 
symptoms of Parkinsons Disease. Both medications will be given at the standard FDA-approved doses. 
We will also be using a placebo. The placebo will look identical in appearance to C-L Dopa but will not 
contain the active ingredient. At the start of the study, you will be randomized (50/50) into one of the 


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two groups. Neither you nor the researchers will know what form of medication you are taking, but the 
study team will perform monitoring throughout the study to check for side effects. 
Carbidopa Monotherapy: You will be pre-treated with carbidopa or placebo three times a day for the 
first 3 days. The purpose of this pre-treatment period is to reduce possible side-effects, including 
nausea, which may occur with carbidopa-levodopa. This carbidopa monotherapy or placebo may be 
started on the same day of visit 1 when you are completing baseline testing or a day following 
completion. 
Carbidopa-levodopa (C-L Dopa or Sinemet): After completing the 3-day pre-treatment with 
carbidopa/placebo, you will begin taking carbidopa-levodopa (C-L Dopa or Sinemet) or placebo three 
times per day for approximately 7 days (+/- 3 days). You will continue taking carbidopa/placebo in 
addition to carbidopa-levodopa/placebo. After 3 days (study days 4-6), you will increase the dose of 
carbidopa-levodopa/placebo if you are not having side effects. You will stay on this dose for the 
remainder of the study. 
 
You are given the option to come into the lab for your first dosage of carbidopa-levodopa/placebo. This 
optional visit would be 60-120 min in length where you will take their first dose of carbidopa- 
levodopa/placebo and be monitored by study personnel. This visit is completely optional, if participants 
do not wish to come into the lab to take this first dose they can still participate in the study. 
 
We will call you during the treatment period to see how you are doing and if you may have possible 
side-effects. You should also call us if you experience difficulties on the medications. 
 
(initials) I discussed participating in the optional observation during visit 2 to take the first 
dose of carbidopa/levodopa (or placebo) and I agree to participate. 
 
(initials) I discussed participating in the optional observation during visit 2 to take the first 
dose of carbidopa/levodopa (or placebo) and I do not agree to participate. 
 
Taking the study medications: We will provide you with an information sheet with specific instructions 
on how much medication you should take and how many times per day. You should take doses ½ hour 
before each meal three times per day. You can take doses with a fruit or fruit drink if preferred. If you 
regularly take iron supplements, you may be asked to take them at night before bed, as they may 
potentially reduce the intended effects of the study medications. 
 
It is important that if you are in this study that you call the study team at your earliest convenience if 
you experience any unexpected (mild or serious) side effects. If you experience any serious problems 
that may require immediate attention, please call 911 or go to a nearby emergency room. 
Some assessments throughout this protocol may be performed remotely using Zoom for Health at U of 
M or over a telephone call. 
Limited clinical test day prior to starting Sinemet/placebo (Visit 2) 
A selected number of tests from Visit 1 screening day will be repeated on this clinical visit. 


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Follow-up clinical test day while taking Sinemet/placebo (Visit 3) 
Most clinical test components from Visit 1 screening day will be repeated on this clinical visit. 
Follow-up imaging day (Part of Visit 3) 
The MRI and PE2I PET-CT scan may occur also at the end of the study. 
As a subject participating in this research study, you have certain responsibilities that may apply to this 
study, such as ensuring that you arrive at all of your scheduled appointments, take your study 
medication as directed, and report any adverse reactions you may have during the study. 
4.2 How much of my time will be needed to take part in this study? 
Most of the testing for this study takes place at the Functional Neuroimaging, Cognitive and Mobility 
Laboratory located at Domino’s Farms, Suite B1000 and Suite B1200 in Ann Arbor. MR and PET-CT 
imaging will take place at the University of Michigan Health System Hospital (University Hospital). 
The baseline clinical testing day (Visit 1) will require 4-6 hours at the Functional Neuroimaging, Cognitive 
and Mobility Laboratory. The (optional) MRI scan that will take approximately 75 minutes and a brain 
dopamine PE2I PET-CT scan will also be performed. The MRI and/or PET-CT scans may occur on the 
same day as the clinical testing but will more likely require a separate visit or visits. The baseline clinical 
visit day will take approximately 1-2 days. 
Following this, subjects will be in the medication phase of the study and be taking carbidopa pre- 
treatment medication (or placebo) during days 1-3 prior to returning to the lab on day 4 for a repeat but 
limited clinical test battery. On day 4 subjects will start carbidopa-levodopa (Sinemet) (or placebo) to be 
taken three times per day while continuing carbidopa. 
This study participation will require you to come back for a follow-up visit at day 10 (±3 days), which will 
contain most clinical testing (4-6 hours). You may complete the brain imaging at this time. This is Visit 3, 
and this visit will require 1-2 days. 
4.3 When will my participation in the study be over? 
Study participation will end after all testing has been completed. 
4.4 What will happen with my information and/or biospecimens used in this study? 
Your biospecimens and collected information may be shared with National Institute of Health (NIH). 
With appropriate permissions, your biospecimens and collected information may also be shared with 
other researchers, here, around the world, and with companies. 
Your identifiable private information or identifiable biospecimens may be stripped of identifiers and 
used for future research studies or distributed to another researcher for future research studies without 
additional informed consent. 
 
5. INFORMATION ABOUT STUDY RISKS AND BENEFITS 
 
5.1 What risks will I face by taking part in the study? What will the researchers do to protect me 
against these risks? 


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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 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. 


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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. 
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. 
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(s): 
There is a likely 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. 
The MRI scanner makes loud, vibrating noises. 
You will wear foam earplugs to reduce the loud noises made by the scanner and prevent any hearing 
damage. 


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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. 
In very rare situations, 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 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-CT scan(s): 
There is an infrequent risk of bruising, bleeding, infection, or soreness associated with intravenous 
and/or arterial catheter placement during the PET-CT scan, 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-CT 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 will be exposed to radiation from the PET-CT transmission scans, 
and the Dopamine PET radiotracer. 
The risk of a 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). In 
the event of a technical failure, this scan may be repeated, which would expose you to a maximum 


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exposure of 7.6 mSv. 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 to with these two tracers is less than 16% of this amount. 
There is no minimum level of radiation exposure that is recognized as being free of the risk of causing 
genetic defects (cellular abnormalities) or cancer. 
Exposure to an (optional) DXA scan will be less than 0.1% of annual background radiation. 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-CT 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-CT/DXA scanning session 
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-CT or DXA studies 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-CT/DXA scanning session. 
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. 
You are given the option to come into the lab for your first dosage of C-L Dopa. This optional visit 
would be 60-120 min in length where you will take your 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 you are 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. You will receive three days of carbidopa monotherapy. 


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You should take the medication 30 minutes before a meal with a piece of fruit and with fruit juice to 
reduce chances of nausea and vomiting. Also, you should not take the medication with or after a 
protein filled meal, because this will increase the chance of nausea. 
There is an infrequent risk of sleepiness or nasal congestion after taking a C-L Dopa pill. There is a very 
rare risk of falling asleep without warning while taking C-L Dopa. 
You are given the option to come into the lab for your first dosage of C-L Dopa. This optional visit 
would be 60-120 min in length where you will take your 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 of 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. 
You are given the option to come into the lab for your first dosage of C-L Dopa. This optional visit 
would be 60-120 min in length where you 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. 
You 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 you will take your first dose of 25/100 C-L Dopa and be 
monitored by study personnel. 
If these symptoms are experienced at home, please contact the study team immediately. Medication 
use may be suspended, and further action taken, including withdrawal from the 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. 
You are given the option to come into the lab for your first dosage of C-L Dopa. This optional visit 
would be 60-120 min in length where you will take your first dose of 25/100 C-L Dopa and be 
monitored by study personnel. 
Please lay down until the symptoms pass. 
If these symptoms are experienced at home, please contact study the team immediately. Medication 
use may be suspended, and further action taken, including withdrawal from the 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. 


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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. 
Please refer to the medication package insert for a comprehensive list of potential C-L Dopa side effects. 
Given the very low dose, we do not anticipate any significant withdrawal symptoms when stopping the 
medication as this is not observed at the study dose in clinical practice. 
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 punch biopsy. 
While receiving a punch 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 to the site of biopsy immediately following 
administration to stop any bleeding. 
 
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. Participants 
will be instructed on how to care for the three punch sites following the biopsy according to CND 
Life Sciences guidelines. 


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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. 
 
Additionally, there may be a risk of loss to confidentiality or privacy. See Section 9 of this document for 
more information on how the study team will protect your confidentiality and privacy. 
As with any research study, there may be additional risks that are unknown or unexpected. 
 
5.2 What happens if I get hurt, become sick, or have other problems as a result of this research? 
The researchers have taken steps to minimize the risks of this study. Even so, you may still have 
problems or side effects, even when the researchers are careful to avoid them. Please tell the 
researchers listed in Section 10 about any injuries, side effects, or other problems that you have during 
this study. You should also tell your regular doctors. 
 
5.3 If I take part in this study, can I also participate in other studies? 
Being in more than one research study at the same time, or even at different times, may increase the 
risks to you. It may also affect the results of the studies. You should not take part in more than one 
study without approval from the researchers involved in each study. 
 
5.4 How could I benefit if I take part in this study? How could others benefit? 
You may not receive any personal benefits from being in this study. However, others may benefit from 
the knowledge gained from this study. Participation in this study may provide important new insights 
into better treatment options for walking disturbances and balance problems affecting older adults. This 
may ultimately result in development of pharmaceuticals for these issues. 
 
5.5 Will the researchers tell me if they learn of new information that could change my willingness to 
stay in this study? 
Yes, the researchers will tell you if they learn of important new information that may change your 
willingness to stay in this study. If new information is provided to you after you have joined the study, it 
is possible that you may be asked to sign a new consent form that includes the new information. 
 
6. ALTERNATIVES TO PARTICIPATING IN THE STUDY 
 
6.1 If I decide not to take part in this study, what other options do I have? 
You do not have to participate in this study. You may drop out of the study at any time without penalty. 


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This study will involve investigational treatments for walking disturbances and balance problems 
affecting older adults. Please note that there may be other experimental treatments. Your doctor can 
tell you more about these other treatments, their risks and their possible benefits. You should have this 
discussion about the risks and benefits or other alternatives prior to making your decision about 
whether or not you wish to take part in this research study. 
 
 
7. ENDING THE STUDY 
 
7.1 If I want to stop participating in the study, what should I do? 
You are free to leave the study at any time. If you leave the study before it is finished, there will be no 
penalty to you. You will not lose any benefits to which you may otherwise be entitled. If you choose to 
tell the researchers why you are leaving the study, your reasons for leaving may be kept as part of the 
study record. If you decide to leave the study before it is finished, please tell one of the persons listed in 
Section 10 “Contact Information”. 
 
7.2 Could there be any harm to me if I decide to leave the study before it is finished? 
There is no harm in leaving the study before it is finished. However, if you decide to leave the study 
during some of the procedures, we may ask you to stay until it is deemed safe to leave. Please notify the 
study investigators immediately if you decide to leave the study so we can determine that is safe for you 
to stop taking the medication. 
 
7.3 Could the researchers take me out of the study even if I want to continue to participate? 
Yes. There are many reasons why the researchers may need to end your participation in the study. 
Some examples are: 
• 
The researcher believes that it is not in your best interest to stay in the study. 
• 
You become ineligible to participate. 
• 
Your condition changes and you need treatment that is not allowed while you are taking part in 
the study. 
• 
You do not follow instructions from the researchers. 
• 
The study is suspended or canceled. 
 
8. FINANCIAL INFORMATION 
 
8.1 Who will pay for the costs of the study? Will I or my health plan be billed for any costs of the 
study? 
The study will pay for research-related items or services that are provided only because you are in the 
study. If you are not sure what these are, see Section 4.1 above or ask the researchers for a list. If you 
get a bill you think is wrong, call the researcher’s telephone number listed in Section 10.1. 
 
If you are injured or in the event of a medical emergency, dial 911 or visit your nearest Emergency 
Room. If you believe the study has made you sick or caused you injury, contact one of the people listed 
in section 10 of this document (Contact Information). If taking part in the study makes you sick or causes 
you injury, you or your insurance provider will be billed for all costs of treatment as the study does not 
provide compensation for sickness or injury caused by the study. It is possible that your insurance will 
not cover these costs. 


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You or your health plan will pay for all the things you would have paid for even if you were not in the 
study, like: 
• 
Health care given during the study as part of your regular care 
• 
Items or services needed to give you study drugs or devices 
• 
Monitoring for side effects or other problems 
• 
Deductibles or co-pays for these items or services. 
 
If you do not have a health plan, or if you think your health plan may not cover these costs during the 
study, please talk to the researchers listed in Section 10 below or call your health plan’s medical 
reviewer. 
 
By signing this form, you do not give up your right to seek payment if you are harmed as a result of 
being in this study. 
 
There is the potential that the research evaluations may have caused you anxiety or worries about your 
health. You may need or want to investigate these health concerns further for an appropriate diagnosis. 
However, any procedures or tests, including the MRI scan, should be obtained separately if your doctor 
believes that you require those tests for your diagnosis. These additional studies and appropriate 
treatment, if necessary, will not be paid for by this study. 
8.2 Will I be paid or given anything for taking part in this study? 
You will receive $50 for a completed MRI scan. You will receive $75 for a completed PE2I PET-CT 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). 
 
8.3 Who could profit or financially benefit from the study results? 
Researchers conducting the study, the University of Michigan, and other researchers that obtain your 
de-identified samples and clinical data will not profit directly from them. However, if research using your 
samples leads to new tests, drugs, or other commercial products as a result of knowledge gained using 
your samples, you will not share in any profits. 


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9. CONFIDENTIALITY OF SUBJECT RECORDS AND AUTHORIZATION TO RELEASE YOUR PROTECTED 
HEALTH INFORMATION 
Research can lead to new discoveries, such as new tests, drugs, or devices. Researchers, their 
organizations, and other entities, including companies, may potentially benefit from the use of the data 
or discoveries. You will not have rights to these discoveries or any proceeds from them. 
 
 
The information below describes how the confidentiality of your research records will be protected in 
this study, and any sub-studies described in this document. 
 
9.1 How will the researchers protect my information? 
Your research records will be stored in a secure location to which only the investigators have access. All 
research records will be stored under code numbers, without attached names or other identifying 
information. The “key” linking these records to subject names will be stored in a separate, locked 
(electronic) file. The storage location for the MRI and PET-CT brain scans will be in protected computer 
files that are accessible only to investigators within the University who are participating in the research 
project. If the radiologist orders any X-rays for MRI screening purposes, the order requisition and test 
results may become part of your regular medical record. 
This research is covered by a Certificate of Confidentiality from the National Institutes of Health. The 
researchers with this Certificate may not disclose or use information, documents, or biospecimens that 
may identify you in any federal, state, or local civil, criminal, administrative, legislative, or other action, 
suit, or proceeding, or be used as evidence, for example, if there is a court subpoena, unless you have 
consented for this use. Information, documents, or biospecimens protected by this Certificate cannot be 
disclosed to anyone else who is not connected with the research except, if there is a federal, state, or 
local law that requires disclosure (such as to report child abuse or communicable diseases but not for 
federal, state, or local civil, criminal, administrative, legislative, or other proceedings, see below); if you 
have consented to the disclosure, including for your medical treatment; or if it is used for other scientific 
research, as allowed by federal regulations protecting research subjects. 
The Certificate cannot be used to refuse a request for information from personnel of the United States 
federal or state government agency sponsoring the project that is needed for auditing or program 
evaluation by the National Institutes of Health (NIH) which is funding this project or for information that 
must be disclosed in order to meet the requirements of the federal Food and Drug Administration (FDA). 
You should understand that a Certificate of Confidentiality does not prevent you from voluntarily 
releasing information about yourself or your involvement in this research. If you want your research 
information released to an insurer, medical care provider, or any other person not connected with the 
research, you must provide consent to allow the researchers to release it. 
The Certificate of Confidentiality will not be used to prevent disclosure as required by federal, state, or 
local law of harm to self or others. 
The Certificate of Confidentiality will not be used to prevent disclosure for any purpose you have 
consented to in this informed consent document. 


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A description of this clinical trial will be available on http://www.clinicaltrials.gov/, as required by U.S. 
Law. This Web site will not include information that can identify you. At most, the Web site will include a 
summary of the results. You can search this Web site at any time. 
 
9.2 What protected health information (PHI) about me could be seen by the researchers or by other 
people? Why? Who might see it? 
Signing this form gives the researchers your permission to obtain, use, and share information about you 
for this study, and is required in order for you to take part in the study. 
 
Medical information and billing records are protected by the privacy regulations of the federal Health 
Insurance Portability and Accountability Act of 1996 (HIPAA). This type of information is called 
protected health information (PHI). PHI about you may be obtained from any hospital, doctor, and 
other health care provider involved in your care, including: 
• 
Hospital/doctor's office records, including test results (X-rays, blood tests, urine tests, etc.) 
• 
Mental health care records (except psychotherapy notes not kept with your medical records) 
• 
Alcohol/substance abuse treatment records 
• 
All records relating to your condition, the treatment you have received, and your response to 
the treatment 
• 
Demographic information 
• 
Personal identifiers 
 
There are many reasons why information about you may be used or seen by the researchers or others 
during or after this study. Examples include: 
• 
The researchers may need the information to make sure you can take part in the study. 
• 
The researchers may need the information to check your test results or look for side effects. 
• 
University, Food and Drug Administration (FDA) and/or other government officials, auditors, 
and/or the IRB may need the information to make sure that the study is done in a safe and 
proper manner. 
• 
Study sponsors or funders, or safety monitors or committees, may need the information to: 
o Make sure the study is done safely and properly 
o Learn more about side effects 
o Analyze the results of the study 
• 
Insurance companies or other organizations may need the information in order to pay your 
medical bills or other costs of your participation in the study. 
• 
The researchers may need to use the information to create a databank of information about 
your condition or its treatment. 
 
• 
Information about your study participation may be included in your regular UMHS medical 
record. 
• 
If you receive any payments for taking part in this study, the University of Michigan accounting 
department may need your name, address, Social Security number, payment amount, and 
related information for tax reporting purposes. 


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• 
Federal or State law may require the study team to give information to government agencies. 
For example, to prevent harm to you or others, or for public health reasons. 
 
The results of this study could be published in an article, but would not include any information that 
would let others know who you are. 
 
9.3 What happens to information about me after the study is over or if I cancel my permission to use 
my PHI? 
As a rule, the researchers will not continue to use or disclose information about you, but will keep it 
secure until it is destroyed. Sometimes, it may be necessary for information about you to continue to be 
used or disclosed, even after you have canceled your permission or the study is over. 
 
Examples of reasons for this include: 
• 
To avoid losing study results that have already included your information 
• 
To provide limited information for research, education, or other activities. (This information 
would not include your name, social security number, or anything else that could let others 
know who you are.) 
• 
To help University and government officials make sure that the study was conducted properly 
As long as your information is kept within the University of Michigan Health System, it is protected by 
the Health System’s privacy policies. For more information about these policies, ask for a copy of the 
University of Michigan “Notice of Privacy Practices”. This information is also available on the web at 
http://www.uofmhealth.org/patient+and+visitor+guide/hipaa. Note that once your information has 
been shared with others as described under Question 9.2, it may no longer be protected by the privacy 
regulations of the federal Health Insurance Portability and Accountability Act of 1996 (HIPAA). 
 
9.4 When does my permission to use my PHI expire? 
Your permission expires at the end of the study, unless you cancel it sooner. You may cancel your 
permission at any time by writing to the researchers listed in Section 10 "Contact Information" (below). 
If you withdraw your permission, you may no longer be eligible to participate in this study. 
 
 
10. CONTACT INFORMATION 
 
10.1 Who can I contact about this study? 
 
Please contact the researchers listed below to: 
• 
Obtain more information about the study 
• 
Ask a question about the study procedures or treatments 
• 
Talk about study-related costs to you or your health plan 
• 
Report an illness, injury, or other problem (you may also need to tell your regular doctors) 
• 
Leave the study before it is finished 
• 
Express a concern about the study 
Principal Investigator: Fay Pongmala, PhD 
Mailing Address: UM Functional Neuroimaging, Cognitive, and Mobility Laboratory 
24 Frank Lloyd Wright Dr., Suite B1000, Box #362, Ann Arbor MI 48105 
Telephone: 734-998-8400 


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Study Coordinator: Robert Vangel and Jaimie Barr 
Mailing Address: UM Functional Neuroimaging, Cognitive, and Mobility Laboratory 
24 Frank Lloyd Wright Dr., Suite B1000, Box #362, Ann Arbor MI 48105 
Telephone: 734-998-6894 
You may also express a question or concern about a study by contacting the Institutional Review 
Board listed below: 
University of Michigan Medical School Institutional Review Board (IRBMED) 
2800 Plymouth Road 
Building 520, Room 3214 
Ann Arbor, MI 48109-2800 
Telephone: 734-763-4768 (For International Studies, include the appropriate calling codes.) 
Fax: 734-763-1234 
e-mail: irbmed@umich.edu 
 
If you are concerned about a possible violation of your privacy or concerned about a study you may 
contact the University of Michigan Health System Compliance Help Line at 1-866-990-0111. 
When you call or write about a concern, please provide as much information as possible, including the 
name of the researcher, the IRBMED number (at the top of this form), and details about the problem. 
This will help University officials to look into your concern. When reporting a concern, you do not have to 
give your name unless you want to. 
 
 
11. RECORD OF INFORMATION PROVIDED 
 
11.1 What documents will be given to me? 
Your signature in the next section means that you have received copies of all of the following 
documents: 
• 
This "Consent to be Part of a Research Study" document. (Note: In addition to the copy you 
receive, copies of this document will be stored in a separate confidential research file and may be 
entered into your regular University of Michigan medical record.) 


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Sig-A 
Consent to Participate in the Research Study 
I understand the information printed on this form. I have discussed this study, its risks and potential benefits, 
and my other choices with  
. My questions so far have been answered. 
I understand that if I have more questions or concerns about the study or my participation as a research subject, 
I may contact one of the people listed in Section 10 (above). I understand that I will receive a copy of this form 
at the time I sign it and later upon request. I understand that if my ability to consent or assent for myself 
changes, either I or my legal representative may be asked to re-consent prior to my continued participation in 
this study. 
Print Legal Name:  
 
Signature:  
 
Date of Signature (mm/dd/yy):  
 
Sig-D 
Consent to Collect for Unspecified Future Research 
This project involves the option to allow the study team to keep your identifiable specimens/data for use in 
future research. I understand that it is my choice whether or not to allow future use of my specimens. I 
understand that if my ability to consent or assent for myself changes, either I or my legal representative may be 
asked to re-consent prior to my continued participation in this study. 
 
 Yes, I agree to let the study team keep my specimens for future research. 
 
 No, I do not agree to let the study team keep my specimens for future research. 
Print Legal Name:  
 
Signature:  
 
Date of Signature (mm/dd/yy):  
 
 
12. SIGNATURES 
 
 
 


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Sig-G 
Principal Investigator or Designee 
I have provided this participant and/or his/her legally authorized representative(s) with information about this 
study that I believe to be accurate and complete. The participant and/or his/her legally authorized 
representative(s) indicated that he or she understands the nature of the study, including risks and benefits of 
participating. 
Printed Legal Name:  
   
Title:  
  
Signature:  
 
Date of Signature (mm/dd/yy):