Clinical trial NCT04325503
Conditions: Parkinsonian Signs in Older Persons
Keywords: slow gait Parkinsonian signs
Sponsor: University of Michigan
Start date: 2021-02-08; Completion date: 2022-06-30
Enrollment: 14 participants; Allocation: NA; Intervention model: SINGLE_GROUP

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 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 translational pilot study will use a biomechanistic target engagement study in older adults with slow walking and/or other parkinsonian signs.

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

Arms: arm 1: carbidopa and carbidopa-levodopa treatment for parkinsonian signs in older persons using standard dosing, frequency for a duration for 1-2 weeks
Interventions: intervention 1: carbidopa
Intervention descriptions: intervention 1: carbidopa and carbidopa-levodopa standard treatment

Protocol documents:
Prot_SAP_001.pdf: 
 
Title: Neurobiological drivers of mobility resilience: the Dopaminergic System 
 
 
NCT: 04325503 
 
Document Date: 10/21/2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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 to determine change in synaptic DA in relationship to brain 
imaging connectivity changes and quantitative motor tests. 
Exploratory AIM: Does increased DA in non-resilient elderly with parkinsonian signs (incl. 
gait <1.0msec) improve walking in a mechanistic target engagement study?  
Exploratory H1: One week of C-L Dopa treatment will improve walking by increasing DA 
in elderly with parkinsonian signs. 
 
Exploratory Hy2: C-L Dopa treatment will have a mechanistic effect on functional and 
metabolic mobility networks in the brain in elderly with parkinsonian signs. 
 
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. 


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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. 
 
3. RESEARCH PLAN 
General Overview: 
Study design: 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, [18F]FDG PET scan (optional), 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. 
An (optional) [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 [18F]FDG and MRI of key relevant circuits related 
to DA. Dopamine PE2I PET scan will be used for post hoc covariate effects. 
 
 


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Figure 1. Study outline. 
 
 
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 
11) History of peptic ulcer 
12) Chronic wide angle glaucoma 


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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. 
18) Any other medical history determined by investigators to preclude safe participation. 
 
Study Timeline:  
The 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. 
 
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. 
 
Sample size: This is an exploratory pilot study to generate sample size effects for future 
larger scale studies, with a net study completion goal of 20 treated subjects. 
 
Impact: Data collected in the proposed study may help identify a novel therapeutic 
approach to gait slowing in non-resilient elderly with parkinsonian signs, which could have 
large public health ramifications given the prevalence and serious morbidity of non-specific 
parkinsonism in the elderly. This project also will elucidate the neurobiology of gait slowing 
at 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. Exploring patient-level moderators of response to C-L Dopa may 
provide useful information to guide differential therapeutics and develop personalized 
medicine for non-resilient elderly.  
 
Testing: 
  
Table 1: Main components of the Test Battery, including detailed gait and balance assessments 
Test 
Primary outcome parameter 
Admin. Time 
Motor: MDS-UPDRS 2 
PIGD UPDRS sub-score 
15 min 
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 
 
 
Total: 35 min 
 
Primary Outcome variables: 


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(a) Biomechanical gait and postural parameters  
(b) Cognition 
(c) Optional: Brain network connectivity analysis of DA networks using multi-modal MRI 
and metabolic connectivity based on FDG PET. 
 
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 administration: 
C-L Dopa 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 administration: 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. 
 
 
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.). 
 


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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. 
   
Clinical and functional assessment of motor features: 
Several well-validated balance, gait, and fall-associated scales and tests will be used to 
further assess functional mobility in PD (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. 
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). 
 
Biological samples: 
Saliva samples may be collected for analysis of dopamine and other related genotypes. 
Samples will be processed and analyzed at laboratories the Department of Human 
Genetics, or at other intra- or extramural institutions. 
 
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 
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. 


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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 on a 
separate day prior to starting study drug treatment. 
 
PET imaging (optional): 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 
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. [18F]FDG and [11C]PE2I PET ligands 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±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. 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 
✓  
 
✓ 
 
 
✓ 


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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 
✓ 
 
✓ 
 
 
✓ 
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 
✓ 
 
 
 
 
✓ 


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Mayo Sleep Questionnaire (22) 
✓ 
 
 
 
 
✓ 
FSS 
✓ 
 
 
 
 
✓ 
Optional: Insomnia Questionnaire 
✓ 
 
 
 
 
✓ 
Optional: Somnolence VAS 
✓ 
 
✓ 
 
 
✓ 
Snellin Test 
✓ 
 
 
 
 
✓ 
Optional: Rabin 
✓ 
 
 
 
 
✓ 
Adverse event assessment 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Optional MRI 
✓ 
 
 
 
 
✓ 
Optional FDG PET 
✓ 
 
 
 
 
✓ 
Optional PE2I PET (will occur only 
1 time) 
✓ 
 
 
 
 
✓ 
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 
 
✓ 
✓ 
✓ 
✓ 
✓ 
 
Analysis: 
Statistical analysis: 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.  
 
Comments: This exploratory open label pilot study will investigate the feasibility for future 
clinical trials of C-L Dopa therapy in non-resilient elderly with parkinsonian signs.  
 
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. Vikas Kotagal, Assistant Professor 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 


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modification submission will be prepared for review by the IRB. All data collected on 
research subjects will be kept confidential as detailed above. 
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 
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: 
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. 
 
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. 
 


13 
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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. 
 
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 
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 tracers [11C]PE2I and [18F]FDG. 
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). Exposure to a single FDG PET-CT scan is 3.7 
mSv (which is also slightly above the level of annual natural background radiation). 
 
The maximum amount of radiation you will be exposed to from this research project 
will be approximately 11.1 mSv for the FDG and PE2I scans combined. In the event 


14 
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of a technical failure, one (1) of these scans may be repeated, which would expose 
you to a maximum exposure of 14.7 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 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. 
 
 
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 


15 
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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. 
 
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. 
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. 
You understand that you should not operate machinery or drive until these symptoms 
have disappeared. 
There is an infrequent risk of orthostatic hypotension, 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. 
 


16 
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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. 
 
Subject compensation (as described in informed consent form): 
You will receive $50 for each completed MRI scan. You will receive $50 for each 
completed FDG PET scan and 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. 
 
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. We will reimburse to a maximum of $300 for lodging and 
meals. You will receive a voucher for valet parking at the University Hospital. Parking at 
Domino's Farms is free. 
 
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. We will reimburse to a maximum of $300 for lodging and 
meals. 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). 
 
Remote consent and remote assessments: 


17 
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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. 
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. 


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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] 

ICF_000.pdf: 
Page 1 of 19
Consent Subtitle: ________________________
Consent Version: ________________________
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):
Nicolaas Bohnen, MD, PhD, University of Michigan, Departments of Radiology and Neurology 
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), but in this study, we will be using this medication in people who are not 
diagnosed with Parkinson's disease but have symptoms that can be seen with this disorder and thus is considered 
investigational. 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 its effect on elderly subjects with slow walking. Your health-related information will be collected as 
well as subjects will receive medications, undergo extensive cognitive and motor testing, two optional magnetic 
resonance images (MRIs), two optional brain glucose FDG PET scans and one optional dopamine PE2I PET scan, 
wear an activity monitor for about a week, and optional saliva donation for genetic testing for this research study.   
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 better treatment options for slow gait in the elderly. This may ultimately result in development of 
pharmaceuticals for this treatment. More information will be provided later in this document.
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.
Study ID: HUM00156490   IRB: IRBMED   Date Approved: 8/11/2022   Expiration Date: 8/10/2023


Page 2 of 19
Consent Subtitle: ________________________
Consent Version: ________________________
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 below.
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 in order 
to determine if this may improve walking and balance problems. As a possible study option, we may also look at 
brain MRI and glucose PET scans to see if we see changes of improved 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. A dopamine brain PET scan is also optional. 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.
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 20 people are expected to participate in the treatment study but we expect to screen up to 60 people 
for the presence of slow walking or other Parkinson signs.
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.  
Study ID: HUM00156490   IRB: IRBMED   Date Approved: 8/11/2022   Expiration Date: 8/10/2023


Page 3 of 19
Consent Subtitle: ________________________
Consent Version: ________________________
An outline of the study is shown below:
Note: C-L Dopa = carbidopa-levodopa (Sinemet)
A summary of the minimum and optional tests are shown in the table below:
Study Events
Visit 1 (Day 0)
●
Informed Consent
●
General and clinical information
●
General medical and neurological exam
●
Visual assessments
●
Smell Assessments
●
Motor Assessments
●
Memory, reasoning and mental concentration assessments
●
Questionnaires
●
(Optional) Saliva Sample: (If there is no evidence of slow walking/Parkinson signs 
then you will stop with the study at this time. If there is evidence of slow 
walking/Parkinson signs, then you will continue with the imaging and treatment 
portions of the study.)
●
(Optional) MRI scan (can be performed on different day)
●
(Optional) FDG or optional PE2I dopamine brain PET scan (can be performed on 
different day)
●
(Optional) DXA scan 
Day 1-3
●
Three-day carbidopa pre-treatment 1 tablet three times a day
●
(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
●
Carbidopa-Levodopa 1 tablet three times a day combined with carbidopa 1 tablet 
Study ID: HUM00156490   IRB: IRBMED   Date Approved: 8/11/2022   Expiration Date: 8/10/2023


Page 4 of 19
Consent Subtitle: ________________________
Consent Version: ________________________
three times per day
●
(Optional) Assessment of daily life activity
Day 7-10 (±3)
●
Carbidopa-Levodopa 1.5 tablets three times a day combined with carbidopa 1 tablet 
three times per day
●
(Optional) Assessment of daily life activity
Visit 3 (Day 10 
(±3))
●
General and clinical information
●
General medical and neurological exam
●
Visual assessments 
●
Motor Assessments
●
Memory, reasoning and mental concentration assessments
●
Questionnaires
●
(Optional) Smell Assessments
●
(Optional) MRI scan
●
(Optional) FDG brain PET scan
●
You can stop the Sinemet medication after you have completed all testing and return 
the bottle to the study staff.
●
You can stop the Sinemet medication after you have completed all testing and return 
the bottle to the study staff.
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 and 
take a saliva sample. 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. 
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 where you will be wearing 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.
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.
Study ID: HUM00156490   IRB: IRBMED   Date Approved: 8/11/2022   Expiration Date: 8/10/2023


Page 5 of 19
Consent Subtitle: ________________________
Consent Version: ________________________
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).
OPTIONAL Sub-study: Saliva sample/Genetic testing: A small saliva sample will be taken to look for genetic factors 
related to how your body handles dopamine. To this end, we are collecting a saliva sample to analyze a sample of 
your DNA. You may decline to provide a sample for genetic analysis. If you decline to participate in the genotyping 
study, you can still do the all the other parts of the study. Your sample will be given a special code, which we will 
keep separate from your name. In fact, it will only be linked to your name by a second code. The samples may be 
stored and analyzed in laboratories at the Department of Human genetics, University of Michigan, or at other 
locations. Research teams will analyze the genetic samples for variants in the DNA sequence. Once analysis is 
performed, we will break the links between the DNA and your name. There is a risk that someone could use 
information from the sample you submitted, via DNA, to identify you if it were matched with another DNA 
samples provided by you. However, any user of this sample must agree not to use it for that purpose, and the risk, 
while real, is small. You have the right to withdraw from this research project at any time. If possible, any samples 
you contributed will be discarded if you request this; however, because of the sample and data-marking, we may 
not always be able to identify which samples were donated by you.  We will not be returning results to donors.
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.
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.
__________(initials) I discussed participating in an optional repeat brain MRI scan and I agree to participate.
__________(initials) I discussed participating in an optional repeat brain MRI scan and I do not agree to 
participate.
OPTIONAL PET scans: The optional PET scans will allow the investigators to “see” the specific marker of glucose 
(sugar) use in the brain (called FDG PET) and dopamine (a chemical messenger molecule in the brain). You may 
receive an FDG PET scan before and at the end of the C-L Dopa treatment. A single dopamine PE2I PET scan is also 
optional. 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 scanner. The PET 
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 scans we also may take blood samples for further analysis of tracer 
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characteristics. Women of childbearing potential may be required to provide a urine sample for a urine pregnancy 
test within 48 hours prior to the PET scan. If one of these scans fails, they may be repeated.
__________(initials) I discussed participating in an optional single brain FDG PET scan and I agree to participate.
__________(initials) I discussed participating in an optional single brain FDG PET scan and I do not agree to 
participate.
__________(initials) I discussed participating in an optional repeat brain FDG PET scan and I agree to participate.
__________(initials) I discussed participating in an optional repeat brain FDG PET scan and I do not agree to 
participate.
__________(initials) I discussed participating in an optional brain dopamine PE2I PET scan and I agree to 
participate.
__________(initials) I discussed participating in an optional brain dopamine PE2I PET scan and I do not 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.
Carbidopa Monotherapy: You will be pre-treated with carbidopa, 25 mg (one tablet) three times a day, for 3 days 
prior to initiating carbidopa-levodopa (C-L Dopa or Sinemet) and will stay on this medication during the time that 
you will be treated with carbidopa-levodopa. Carbidopa is given to prevent or reduce possible side-effects of 
nausea, which may occur with carbidopa-levodopa. This carbidopa monotherapy may be started on the same day 
of visit 1 when you are completing of all baseline testing or a day following completion. You should take the 
carbidopa medication ½ hour before each meal three times per day. You can combine it with a fruit or fruit drink if 
preferred. 
Carbidopa-levodopa (C-L Dopa or Sinemet): You will receive a medication called carbidopa-levodopa (C-L Dopa or 
Sinemet) for approximately 7(+/-3) days. After completing the 3-day pre-treatment with carbidopa you will take 
carbidopa-levodopa 25/100 as ONE pill three times per day for 3 days (study days 4-6) while continuing taking 
carbidopa 25 mg three times per day at the same time. If you have no side-effects, you will increase carbidopa-
levodopa 25/100 to 1.5 pills three times per day (while continuing combining this with carbidopa 25 mg three 
times per day). You will stay on this dose for the remaining four treatment days of this study, which is study day 
10 (±3 days). We will provide you with an information sheet with specific instructions on how many pills you 
should take and how many times per day. You are given the option to come into the lab for your first dosage of 
carbidopa/levodopa. 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. This visit is completely optional, if participants do not 
wish to come in to the lab to takes this first dose they can still participate in the study. You should take the 
carbidopa medication ½ hour before each meal three times per day. You can combine it with a fruit or fruit drink if 
preferred. 
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 and I agree to participate.
__________(initials) I discussed participating in the optional observation during visit 2 to take the first dose of 
carbidopa/levodopa and I do not want to participate.
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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 (Visit 2)
A selected number of tests from Visit 1 screening day will be repeated on this clinical visit.
Follow-up clinical test day while taking Sinemet (Visit 3)
Most clinical test components from Visit 1 screening day will be repeated on this clinical visit.
OPTIONAL: Follow-up imaging day (Part of Visit 3)
The MRI and FDG PET scans will be repeated as part of the follow-up visit. The single dopamine PE2I PET scan may 
occur also at the end of the study (and treatment).
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 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, as well as an (optional) MRI scan that will take approximately 75 minutes and an (optional) 
FDG PET scan that will take approximately 45 minutes at the University Hospital. An optional brain dopamine PE2I 
PET scan may also be performed. The MRI and/or PET 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 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) 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), an (optional) MRI (75 minutes), and an (optional) repeat FDG PET scan (45 min). 
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. 
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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?
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.
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.
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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.
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 
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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 scan(s):
There is an infrequent risk of bruising, bleeding, infection, or soreness associated with intravenous and/or arterial 
catheter placement during the PET 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 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 be exposed to radiation from the PET transmission scans, the Dopamine 
and FDG PET radiotracers.
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). Exposure to a single FDG PET-CT scan is 3.7 
mSv (which is also slightly above the level of annual natural background radiation). The maximum amount of 
radiation you will be exposed to from this research project will be approximately 11.1 mSv for the FDG and 
PE2I dopamine PET scans combined. In the event of a technical failure, one (1) of these scans may be repeated, 
which would expose you to a maximum exposure of 14.7 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 3/10th of this amount. 
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 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
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.
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No PET 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/DXA scanning session.
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.
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.
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.
You understand that you should not operate machinery or drive until these symptoms have disappeared.
There is an infrequent risk of orthostatic hypotension, 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. 
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 study dose in clinical practice.
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.
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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.
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 
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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.
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 each completed MRI scan. You will receive $50 for each completed FDG PET scan and 
dopamine 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.
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. We will reimburse to a 
maximum of $300 for lodging and meals. 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.
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.
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.
Study ID: HUM00156490   IRB: IRBMED   Date Approved: 8/11/2022   Expiration Date: 8/10/2023


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Consent Subtitle: ________________________
Consent Version: ________________________
9. CONFIDENTIALITY OF SUBJECT RECORDS AND AUTHORIZATION TO RELEASE YOUR PROTECTED HEALTH 
INFORMATION
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 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. 
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.)
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Page 16 of 19
Consent Subtitle: ________________________
Consent Version: ________________________
●
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.
●
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 
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Consent Subtitle: ________________________
Consent Version: ________________________
“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.
9.5 Will I be contacted for other studies?
No, unless you indicate by initialing below that you may be contacted by researchers at the University of Michigan 
for studies for which you may eligible. If you agree to be contacted for other studies, we will keep your name and 
contact information in a separate password-protected database.
_________ (initials) I agree to be contacted about other research studies for which I may qualify. If I cancel my 
permission for this study, I will not be contacted for other studies.
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: Nicolaas Bohnen, MD, 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
Study Coordinator: Miriam Bohnen
Mailing Address:  UM Functional Neuroimaging, Cognitive, and Mobility Laboratory
24 Frank Lloyd Wright Dr., Suite B1000, Box #362, Ann Arbor MI 48105
Telephone: 1-877-998-1098
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.
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Page 18 of 19
Consent Subtitle: ________________________
Consent Version: ________________________
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.)
12.  SIGNATURES
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): ________________________
Consent for Participating in Genetic Sub-Study Testing
I understand that by signing below, I am also voluntarily agreeing to participate in the genetic testing aspects 
of this study.  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): ________________________
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Consent Subtitle: ________________________
Consent Version: ________________________
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/data.  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/data for future research.
_____ No, I do not agree to let the study team keep my specimens/data for future research.
Print Legal Name: ___________________________________________________________________
Signature: _________________________________________________________________________
Date of Signature (mm/dd/yy): ______________________________
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): ________________________
Study ID: HUM00156490   IRB: IRBMED   Date Approved: 8/11/2022   Expiration Date: 8/10/2023