Mild Cognitive Impairment and Endurance Exercise in Parkinson's Disease
Phase: NA
Conditions: Parkinson Disease, Mild Cognitive Impairment
Sponsor: Northwestern University

PROTOCOL TITLE: Mild Cognitive Impairment and Endurance Exercise in Parkinson’s 
Disease
Page 1 of 35
PROTOCOL TITLE:
Mild Cognitive Impairment and Endurance Exercise in Parkinson’s Disease
PRINCIPAL INVESTIGATORS:
Daniel Corcos, PhD
Department of Physical Therapy & Human Movement Sciences
(312) 908-6792
Daniel.corcos@northwestern.edu
Jennifer G. Goldman, MD, MS
Department of Neurological Sciences
Rush University
(312) 563-2900
Jennifer_Goldman@rush.edu
VERSION NUMBER:
Version 12
VERSION DATE:
2/6/2019
IRB #: STU00202794 Approved by NU IRB for use on or after 1/8/2020
NCT03542474

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Disease
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Table of Contents 
1.0
Objectives ................................................................................................................3
2.0
Background..............................................................................................................3
3.0
Inclusion and Exclusion Criteria .............................................................................5
4.0
Study-Wide Number of Subjects: NA (not a multicenter study).............................7
5.0
Study-Wide Recruitment Methods: NA ..................................................................7
6.0
Multi-Site Research: NA .........................................................................................7
7.0
Study Timelines.......................................................................................................7
8.0
Study Endpoints.......................................................................................................8
9.0
Procedures Involved ..............................................................................................10
10.0
Data and Specimen Banking:.................................................................................20
11.0
Data and Specimen Management ..........................................................................20
12.0
Provisions to Monitor the Data to Ensure the Safety of Subjects: ........................21
13.0
Withdrawal of Subjects*........................................................................................21
14.0
Risks to Subjects*..................................................................................................22
15.0
Potential Benefits to Subjects ................................................................................22
16.0
Vulnerable Populations:.........................................................................................22
17.0
Community-Based Participatory Research: NA....................................................23
18.0
Sharing of Results with Subjects ...........................................................................23
19.0
Setting....................................................................................................................23
20.0
Resources Available ..............................................................................................23
21.0
Prior Approvals......................................................................................................24
22.0
Recruitment Methods.............................................................................................25
23.0
Local Number of Subjects .....................................................................................25
24.0
Confidentiality: NA ...............................................................................................25
25.0
Provisions to Protect the Privacy Interests of Subjects .........................................25
26.0
Compensation for Research-Related Injury...........................................................26
27.0
Economic Burden to Subjects................................................................................26
28.0
Consent Process.....................................................................................................27
29.0
Process to Document Consent in Writing..............................................................27
30.0
Drugs or Devices: NA ...........................................................................................27
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1.0
Objectives
1.1
The overall purpose and objective of this project is to test the hypothesis that 
high intensity endurance exercise causes beneficial brain adaptation in 
patients with mild cognitive impairment in Parkinson’s disease (PD-MCI). 
Aim 1 will determine the effect of high intensity endurance exercise on 
cognitive function and other clinical symptoms in PD-MCI. Aim 2 will 
determine the effect of high intensity endurance exercise on brain structure 
and function in PD-MCI. Aim 3 will determine the effect of high intensity 
endurance exercise on cortisol in PD-MCI. Aim 4 will determine the effect 
of high intensity endurance exercise on inflammation-related biomarkers 
found in blood in PD-MCI. Aim 5 will determine the effect of high intensity 
endurance exercise on peripheral levels of neurotrophic factors found in 
blood in PD-MCI.
1.2
Hypothesis 1 is that high intensity endurance exercise will improve 
cognitive function, specifically attention, executive function and memory in 
PD-MCI patients. In addition, high intensity endurance exercise will 
improve other PD-related symptoms such as sleep, fatigue, mood, health-
related quality of life, and motor function. 
Hypothesis 2 is that high intensity endurance exercise will modify brain 
structure and function as measured by structural MRI, diffusion tensor 
imaging (DTI), and resting state functional MRI (rsfMRI), specifically by: 
a) increasing hippocampal volume, b) increasing microstructural integrity of 
white matter pathways connecting different brain regions (e.g.,fronto-
striatal, fronto-parietal, and hippocampal regions, and c) enhancing 
functional connectivity among brain networks (e.g., default mode and 
central executive networks).
Hypothesis 3 is that high intensity endurance exercise will lead to decreased 
levels of cortisol and an increase in the magnitude of the cortisol awakening 
response (CAR).
Hypothesis 4 is that high intensity endurance exercise will lead to decreased 
levels of inflammation suggested by a decrease in levels of inflammation-
related biomarkers found in blood.
Hypothesis 5 is that high intensity endurance exercise will lead to increased 
levels of peripheral neurotrophic factors. 
2.0
Background
2.1
There is a growing interest in physical exercise as a treatment for PD 
symptoms and ultimately as a potential disease modification strategy. Most 
PD exercise studies have focused on motor function (Salgado, Williams et 
al. 2013), though our group also found improved executive function after 
balance/strengthening and progressive resistance training. (Corcos, 
Robichaud et al. 2013, David, Robichaud et al. 2015) The knowledge gap is 
that no study has specifically targeted PD-MCI patients to determine how 
exercise affects cognitive functions or the underlying neurobiology of PD-
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MCI. Thus, the central hypothesis is that high intensity endurance exercise 
not only will improve the cognitive function of patients with PD-MCI, but 
also will produce neurobiological changes in their brain and body.
We have just finished collecting data on the effect of high intensity 
endurance exercise regimens on parkinsonian motor signs in 129 never 
medicated patients with PD. Patients exercised 4 days a week at either 65% 
of their maximal heart rate or at 80% of their maximal heart rate. As such, 
we have considerable experience in using endurance exercise protocols.
2.2
We have no preliminary data for this study. The purpose of this IRB is to 
collect pilot data for a subsequent R01.
2.3
Parkinson’s disease (PD) is a neurodegenerative disorder that affects over 4 
million people older than age 50.(Dorsey, Constantinescu et al. 2007) While 
the motor features of PD are well-recognized and well-treated with 
dopaminergic medications, PD is also complicated by non-motor symptoms, 
which cause significant disability, lack effective therapies, and typically do 
not respond to dopamine replacement therapy. One of the most disabling 
non-motor symptoms in PD is cognitive impairment, which ranges from 
mild deficits to severe dementia.(Emre, Aarsland et al. 2007, Hely, Reid et 
al. 2008, Litvan, Goldman et al. 2012) In recent years, mild cognitive 
impairment (PD-MCI) has been identified as a frequent occurrence in PD 
and a precursor to PD dementia, which can develop in 80% of PD patients 
over time.(Hely, Reid et al. 2008, Litvan, Aarsland et al. 2011, Litvan, 
Goldman et al. 2012) Recent research has characterized the cognitive 
deficits of PD-MCI, developed diagnostic criteria, and identified 
neuroimaging markers of PD-MCI.(Goldman, Stebbins et al. 2012, 
Goldman, Holden et al. 2013, Goldman, Holden et al. 2015) However, there 
are currently no therapeutic interventions that can effectively improve the 
symptoms of PD-MCI or slow down or halt cognitive decline in 
PD.(Goldman and Weintraub 2015) 
While PD-MCI is a relatively new concept within the PD field, the idea of 
MCI as a state between normal cognitive aging and Alzheimer’s disease has 
been recognized for many years and has led to treatment trials with 
pharmacological and non-pharmacological interventions, including physical 
exercise training. For example, Baker and colleagues (2010)  have shown 
improved executive function in women with MCI and improved 
performance on the Trail B in men as a result of endurance exercise at 
between 75% and 85% heart rate reserve. Indeed, studies of exercise 
training, with a variety of techniques (e.g., endurance [also called aerobic], 
resistance, balance and tone training) demonstrate improvement in cognitive 
functions of MCI (non-PD) patients, as well as in some studies, other 
symptoms such as mood, sleep, fatigue and health-related quality of 
life.(Wang, Yu et al. 2014) Exercise also exerts neurobiological effects, as 
seen in animal models of exercise,(Silverman and Deuster 2014, Petzinger, 
Holschneider et al. 2015, Duzel, van Praag et al. 2016)as well as human 
studies of aging and MCI utilizing neuroimaging and other peripheral 
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biomarkers.(Voss, Prakash et al. 2010) Endurance exercise, in particular, 
has been linked to brain plasticity with magnetic resonance imaging (MRI) 
scans revealing structural changes (e.g., increased volume in the 
hippocampus, a key brain region for memory) and functional changes (e.g., 
increased connections among brain networks involved in cognitive 
processes) in aging adults and MCI patients.(Voss, Prakash et al. 2010, 
Erickson, Voss et al. 2011, ten Brinke, Bolandzadeh et al. 2015) Endurance 
exercise at between 65% and 75% maximal heart rate reserve can enhance 
the mental aspect of both health-related quality of life (HRQOL) and also 
global quality of life (global HQL).(Awick, Wojcicki et al. 2015) 
Exercise can affect neurobiological markers of stress (e.g., cortisol), 
inflammation (e.g., cytokines) and growth factors (e.g., brain-derived 
neurotrophic factor [BDNF], insulin-like growth factor [IGF-1]), and these 
peripheral markers may mediate exercise effects on brain structure and 
function. (Foster, Rosenblatt et al. 2011, Voss, Vivar et al. 2013). Cortisol is 
released during exercise as a contributory factor to both muscular and 
mitochondrial function. Aside from the influential effects of cortisol on the 
muscular system, the release of cortisol during exercise also modulates 
different neurotransmitters and influences both cognition and 
neuroplasticity. (Diamond, Bennett et al. 1992, Piazza, Rouge-Pont et al. 
1996, Joels and Krugers 2007, Sousa, Cerqueira et al. 2008, Mora, Segovia 
et al. 2012) Cortisol receptors can be found in brain regions involved in 
cognitive processing, such as the neocortex, cerebellum, and the 
hippocampus (Heffelfinger and Newcomer 2001) and it is widely 
recognized that glucocorticoids easily enter the brain and exert effects on 
cognition (de Quervain, Aerni et al. 2009). Cortisol levels in healthy elderly 
adults studied over a period of five years revealed that individuals with high 
basal cortisol levels and increasing cortisol levels over five years had 
hippocampal-dependent memory impairments and a 14% reduction in 
hippocampus volume when compared with individuals who either had 
moderate basal cortisol levels or decreasing cortisol levels over the five-year 
period.(Lupien, Fiocco et al. 2005) Flatter diurnal cortisol slopes have been 
associated with a decline over 4 years in visuospatial performance and 
visual memory in men, and in verbal fluency for women.(Beluche, Carriere 
et al. 2010) In the extreme, no morning cortisol response has been observed 
a 6 male patients with amnesia,(Wolf, Fujiwara et al. 2005) and also in 
patients with hippocampal damage.(Buchanan, Kern et al. 2004) In older 
adults diagnosed with MCI, the magnitude of the CAR and the extent of the 
subsequent drop in cortisol levels are both associated with level of 
fitness.(Tortosa-Martinez, Clow et al. 2015) It was shown that a three month 
exercise program improved fitness, increased the fall in cortisol 
concentration from the morning peak to midday, and enhanced indices of 
executive function in older adults with MCI. (Tortosa-Martinez, Clow et al. 
2015). Earlier peaking and greater magnitude of the CAR has also been 
associated with superior performance on executive function related tasks in 
older adults.(Evans, Hucklebridge et al. 2012) To the best of our knowledge, 
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the CAR has not been measured in individuals with Parkinson’s disease. 
Because the cortisol awakening response is distinct from circadian 
components of cortisol control, assessment of the CAR in individuals with 
PD may provide additional insight into additional neuroendocrine processes 
that other cortisol measures may not.(Stalder, Kirschbaum et al. 2016)
There is increasing evidence that inflammation is a contributing factor to 
both the pathogenesis and progression of PD (Beal, 2003; Chung et al., 
2010; Sawada, Imamura, & Nagatsu, 2006). Chronic inflammation mediated 
by microglial cells is a fundamental process contributing to the death of 
dopamine-producing neurons in the brain, and it is suggested that physical 
stress may facilitate the progression of neurodegenerative disorders such as 
PD (Sugama, 2009).  Regular physical activity tends to result in lower 
serum concentrations of inflammatory markers (Kasapis & Thompson, 
2005). Chronic exercise training is thought to reduce levels of inflammatory 
markers both directly by attenuating cytokine production by adipose tissue, 
skeletal muscle, and mononuclear cells, and indirectly through improved 
insulin sensitivity and endothelial function, decreased body weight, and by 
upregulating antioxidant enzymes (Kasapis & Thompson, 2005). 
Neurotrophic factors (NFs) are a family of proteins that play a significant 
role in the growth, survival, and maintenance of neurons (Rangasamy, 
Soderstrom, Bakay, & Kordower, 2010). Different proteins such as brain-
derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor 
(GDNF), insulin-like growth factor (IGF), and vascular endothelial growth 
factor (VEGF) have been classified as NFs, due to their ability to effect 
neuronal survival, differentiation, and maturation, and synaptogenesis (da 
Silva, Domingues, de Carvalho, Allodi, & Correa, 2016). Many studies have 
demonstrated the influence of trophic factors on neuroprotection, 
neurorestoration, and functional improvement in both PD animal models 
and some human clinical trials (Rangasamy et al., 2010). It has been 
suggested that NFs influence cell survival and restoration of dopaminergic 
cells in the nigrostriatial pathway (Petzinger et al., 2007; Tajiri et al., 2010; 
Tillerson, Caudle, Reveron, & Miller, 2003; Yoon et al., 2007). 
The exercise-induced benefits of improved brain plasticity, function, and 
health can be at least partially attributed to growth factors, primarily BDNF, 
IGF-1, VEGF, and GDNF (Cotman et al., 2007; Knaepen, Goekint, 
Heyman, & Meeusen, 2012). 
3.0
Inclusion and Exclusion Criteria
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3.1
Individuals will be screened for eligibility as follows. Participants will meet 
the criteria outlined below. Participants will be assessed for eligibility 
criteria by the PI and study team via telephone screening after referral by the 
Neurologist. The screening will last approximately 30 minutes. A telephone 
scipt will be used to screen participants.
3.2
Inclusion criterion:

Male or female, ages 40-85

A diagnosis of idiopathic PD based on the UK PD brain bank 
criteria.(Hughes, Ben-Shlomo et al. 1992, Hughes, Daniel et al. 1992, 
Hughes, Ben-Shlomo et al. 2001)

A diagnosis of PD-MCI as determined by the Movement Disorder 
Society (MDS) Task Force PD-MCI diagnostic criteria (Litvan, Goldman 
et al. 2012) and a SCOPA-Cog score of 17-24 (Marinus, Visser et al. 
2003, Isella, Mapelli et al. 2013, Marras, Armstrong et al. 2013)

Hoehn and Yahr stage < or equal to 3

Stable medication regimen for > or equal to 30 days before entering the 
study

Living with a carepartner
 
Exclusion criterion:

PD subjects meeting MDS criteria for PD dementia (Emre, Aarsland et 
al. 2007) or having a SCOPA-Cog score less than or equal to 16, or PD 
subjects having normal cognition defined as a SCOPA-Cog Score of 
greater or equal to 25. 

Atypical or secondary parkinsonism as determined by referring 
Neurologist

Other disorders that might interfere with ability to perform high intensity 
endurance exercise (e.g. history of stroke, respiratory problems, traumatic 
brain injury, known advanced osteoarthritis, or neuromuscular disease).

Individuals with known injury, disease, or condition that would affect the 
ability to perform endurance exercise.

Any other clinically significant medical condition, psychiatric condition, 
drug or alcohol abuse that would, in the judgment of the investigator, 
interfere with the subject’s ability to participate in the study.

“Vigorous athletes” participating in any exercise program 2X/week or 
more will be excluded.

Individuals with any type of implanted electrical device (such as a 
cardiac pacemaker or a neurostimulator), or a certain type of metallic clip 
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(i.e., an aneurysm clip in the brain) are not eligible for participation in the 
MRI study.

Persons who have had a long history of working in metal shops will be 
excluded unless they have had a previous orbital x-ray scan clearing them 
for participation in MRI studies.

Females who are pregnant or might be pregnant will be excluded from 
participation.

Individuals who are claustrophobic and unable to tolerate a brain MRI 
scan will be excluded.

Treatment with cholinesterase inhibitors or memantine (i.e., medications 
approved for treatment of dementia) or medications affecting cognition 
(i.e., anticholinergics)

Use of medications that might interfere with neuromuscular junction 
function such as D-penicillamine and aminoglycoside antibiotics.

Use of medications that might interfere with the BOLD contrast or heart 
response to exercise (e.g. β blockers).

Individuals at high risk for cardiovascular disease as defined in Table 2.2 
by the new ACSM guidelines.(Medicine 2014) 

Younger than 40 and older than 85. We exclude participants younger than 
40 because these young onset patients may not be typical of the majority 
of patients who get the disease later in life. We exclude participants older 
than 85 because of the limited evidence they can successfully complete a 
high-intensity endurance exercise program. We also exclude patients 
whose disease was diagnosed before the age of 40.

Individuals with known endocrine abnormalities or steroid use that could 
affect cortisol levels (e.g., Cushing’s syndrome, pituitary or adrenal gland 
disease or adrenalectomy, use of steroid-based medications.

Individuals with strong history of chronic inflammatory or autoimmune 
diseases or history of chronic use of NSAIDs, which could cause 
abnormal levels of inflammatory markers in the plasma.
3.3
We will exclude adults unable to consent, individuals who are not yet adults, 
pregnant women, prisoners and children from this study. 
4.0
Study-Wide Number of Subjects: NA (not a multicenter study) 
5.0
Study-Wide Recruitment Methods: NA  
6.0
Multi-Site Research: NA
7.0
Study Timelines
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7.1
The duration of an individual subject’s participation in the study will be 6 
months. Achieving full participant accrual will require enrolling up to 16 
participants over 18 months. The estimated date for the investigators to 
complete this pilot study is January 1, 2017.
8.0
Study Endpoints
8.1
Primary endpoints: 
The primary endpoint will be the mean change in cognitive function from 
baseline to 6-months as measured by global statistical test (GST) for 
attention/working memory, executive function, memory, and processing 
speed. The GSTs will be calculated from the following tests reflecting 
specific cognitive domains and administered in the cognitive test battery 
(Attention/working memory, Executive function, Memory, Processing 
Speed) including: 
Symbol Digit Modality Test,(Smith 1973) 
Trail Making Test-Parts A and B,(Reitan and Wolfson 1993) 
Raven’s Progressive Matrices,(Raven, Raven et al. 2003) 
Clock Drawing,(Goodglass and Kaplan 1983) 
Hopkin Verbal Learning Test-Revised (Word list learning and delayed 
recall),(Brandt and Benedict 2001) 
Free and Cued Selective Reminding Test,(Grober and Buschke 1987) 
Figural memory test,(Wilson, Gilley et al. 2000) 
Secondary endpoints: 
The secondary endpoints will include the following: 
a) Change from baseline to 6-months for clinical, behavioral, and 
additional cognitive measures including the following: 
1) Sleep (Pittsburgh Sleep Quality Index)(Buysse, Reynolds et al. 1989), 
(Epworth Sleepiness Scale),(Johns 1991) 
2) Fatigue (Fatigue Severity Scale),(Krupp, LaRocca et al. 1989) 
3) Mood (Hamilton Depression Scale),(Hamilton 1967) 
4) PD Neurol QOL (NINDS 2015) and Health-related quality of life 
(PDQ-39),(Hagell and Nilsson 2009) 
5) additional cognitive tasks 
Language: 
Boston Naming Test,(Kaplan 1983) 
Verbal fluency [semantic - animals, phonemic - letters];{{Morris, 
1989 #47 
Visuospatial: 
Judgment of Line Orientation,{Benton, 1978 #35 
Intersecting pentagons;{Bourke, 1995 #36}. 
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b) Change from baseline to 6-months for motor function including the 
following: 
1) Movement Disorder Society Unified PD Rating Scale [MDS-
UPDRS] part III motor score,(Goetz, Tilley et al. 2008) 
2) Mini Balance Evaluation Systems Test (mini-BESTest) 
(Franchignoni, Horak et al. 2010) 
3) Timed up and go (TUG) (Morris, Morris et al. 2001, Huang, Hsieh et 
al. 2011) 
4) The six-minute walk test (6MWT) (Schenkman, Ellis et al. 2011) 
5) The Activities-Specific Balance Confidence Scale (ABC) (Dal 
Bello-Haas, Klassen et al. 2011) 
6) The New Freezing of Gait Questionnaire (NFOG-Q)(Nieuwboer, 
Rochester et al. 2009)
Participants will wear an activity monitor for one week per month. 
This will allow us to collect average physical activity across one 
week time periods which will be used to analyze the impact of the 
intervention outside of the structured exercise sessions of the 
endurance exercise group. This will allow us to determine if the 
endurance exercise group alters its overall activity level over the 6 
month time period.
c) Change from baseline to 6-months for brain imaging measures including 
the following: 
1) Hippocampal volumes on structural MRI, 
2) Microstructural integrity of white matter pathways on diffusion tensor 
imaging (DTI), 
3) Functional connectivity among brain networks on resting state fMRI, 
4) Responses to task-based fMRI Digit Symbol Substitution Test. 
d) Change from baseline to 6-months for biospecimen measures including 
the following:
1) Salivary cortisol measurements; in addition, changes in salivary 
cortisol measures collected over 8 time points on two consecutive 
days will be explored at the pre-test and the post-test. We will 
measure cortisol at time points 0 minutes, 15 minutes, 30 minutes, 
45 minutes after the person wakes up.(Stalder, Kirschbaum et al. 
2016) In addition, we will measure cortisol at 3 hours, 6 hours, 9 
hours and 12 hours after awakening.(Edwards, Clow et al. 2001)
2) Soluable inflammatory biomarkers in plasma
3) Peripheral levels of neurotrophic factors in plasma
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e) We will collect the NINDS common data elements (CDE) for sex, 
ethnicity, date-of-birth, education level, family history, and employment 
status. 
8.2.   Safety Endpoints: There are no safety endpoints, but all participants will be 
monitored for safety and for adverse events.
Adverse Events (AEs) are defined as exercise-related discomforts (e.g., 
muscle and joint soreness/pain), minor injuries (e.g., strains, sprains), and 
non-injurious falls; and attrition is defined as the number of participants who 
withdraw from the study. Serious Adverse Events (SAEs) are defined as 
hospitalization, surgery, death, or permanent disability. We will keep 
detailed logs of all the training sessions so that we can monitor their 
progress in the endurance exercise program and assess compliance, which 
we will take to be completion of 80% of the prescribed exercise sessions. 
All participants will be prescreened for MRI scans as per Radiology 
guidelines to ensure MRI safety including screening for cardiac pacemakers, 
metal implants of any kind in the body, pregnancy, among other conditions.    
9.0
Procedures Involved
9.1
We will conduct a single coordination site, blinded-evaluator, open-label, 
intervention study of the effects of 6 months of high intensity endurance 
exercise on cognitive and other clinical/behavioral measures, brain imaging, 
and cortisol and blood specimens. These measures will be collected at 
baseline and then again at 6-months or at an early termination visit, should 
that occur. Cortisol will be collected twice at baseline on consecutive days 
and twice at 6 months on consecutive days. Blood will be drawn both at 
baseline and again at 6 months.
9.2
The research procedures and when they are performed are explained 
below.
Telephone Screening
Telephone screening will occur after referral by the Neurologist. The 
subject will learn about the study. The screen will rule out any 
medical conditions that preclude participation in endurance exercise 
training, brain MRI imaging, or behavioral testing. The screening 
will last approximately 30 minutes. None of the information attained 
from the screening will be recorded or utilized as research data. The 
screening will take place prior to scheduling the subject for any 
study related data collection and prior to consenting to take part in 
the research study. If the subject passes the telephone screening, they 
will be scheduled to come in for testing.
Baseline Visit
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Day 1 Afternoon
Obtain written consent and written HIPAA authorization. We will 
collect NINDS common data elements for sex, ethnicity, date-of-
birth, education level, PD disease history, medication history, family 
history, and employment status from all subjects. In addition, 
Movement Disorder Society-Unified Parkinson Disease Rating Scale 
(MDS-UPDRS) Part I, II, and IV of the MDS-UPDRS, and non-
motor rating scales will be administered. 
1. Informed consent and HIPAA Authorization – 20 minutes to 
complete
2. SCOPA-Cog – 15 minutes
3. NINDS common data elements – 20 minutes
4. MDS-UPDRS
a.
Part IA completed by rater – 10 minutes to administer
b. Part IB questionnaire completed by patient – 5 minutes to complete
c.
Part II questionnaire completed by patient – 5 minutes to complete
d. Part IV completed by rater – 5 minutes to administer
5. Montreal Cognitive Assessment  – 10 minutes to complete
6. Pittsburgh Sleep Quality Index  – 7 minutes to complete
7. Epworth Sleepiness Scale – 7 minutes to complete
8. Fatigue Severity Scale – 7 minutes to complete
9. Hamilton Depression Scale  – 10 minutes to complete
10. PD Neurol QOL – 10 minutes to complete
11. PDQ-39 Scale– 10 minutes to complete
12. Maximal graded exercise test – 1 hour to complete

A maximal graded exercise test (GXT) will be performed during 
intake day to determine HRmax. A resting 12-lead ECG will be 
recorded in the recumbent and upright positions immediately 
prior to the exercise test, as well as during the test. If the findings 
on the resting ECG do not contraindicate exercise, the exercise 
test will be performed. 

Contraindicators include the following: (a) ST-segment 
depression of more than 0.2 mV that is either horizontal, 
downsloping, or slowly upsloping (less than 1 mV/sec) and lasts 
for 0.08 sec, or ST-segment elevation greater than 0.1 mV; (b) 
chest pain or discomfort; (c) serious arrhythmias, including 
multifocal PVCs, ventricular tachycardia, frequent (>10/min) 
PVCs or couplets, or sustained atrial tachyarrhythmias; (d) A-V 
block or other conduction defects; (e) a fall of systolic blood 
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pressure of 10 mmHg or greater from the peak level with 
increasing exercise intensity; (f) diastolic blood pressure above 
110 mmHg or systolic above 220 mmHg; (g) dizziness; (h) 
ataxic gait; and (i) pallor or cyanosis. Subjects who have a 
positive GXT will be ineligible for participation in the study. 

Maximal aerobic power (VO2max) will be measured by indirect 
calorimetry (TruMax 2400, ParvoMedics, Sandy, UT) during the 
GXT. A warm-up period on the treadmill will be used to identify 
the walking speed that generates a HR that is 65-70% of the age-
predicted HRmax; for fit individuals, this may require increasing 
the elevation of the treadmill. After a brief rest interval to initiate 
the indirect calorimetry, the test will start at the designated 
walking speed (and grade). The treadmill grade will be increased 
by 2% every 2 minutes to volitional exhaustion or until the 
proctor stops the test because of abnormal responses to exercise. 
Night Before Testing: 
Last dose of antiparkinsonian medications no later than 8.30pm.
Last coffee and alcohol no later than 8.30 pm 
Day 2:
Imaging 8:30 to 10:00 AM 
MRI Data Acquisition
MRI data will be acquired using a state-of-the-art Prisma 3.0T whole-body 
clinical MRI system equipped with a high performance gradient system 
capable of on-axis (x, y and z) peak gradient of >=80 mT/m and 200 mT/m/ms 
slew rate, and a 64-channel head coil. The scanner is capable of implementing 
the Human Connectome Protocol (HCP) like sequences. The imaging 
protocols are designed for one-hour sessions, which in our extensive 
experience has been well tolerated by all types of PD patients. A headphone, 
which is a component of the dedicated task delivery system (Avotec system 
for the standard coil and earbuds from Sensimetrics for 64 channel coils), will 
be placed over the participant’s ears for operator-participant communication. 
Video stimuli will be delivered through a rear projection system at 
Northwestern. The fMRI task is described below.  
Scan#
Preferred Order NU
Scan Time 
(min:sec)
Total Time
Total Scan 
Time
0
Setup
10:00:00
10 min
0 min
1
Scout
0:14:00
10 min 14 sec
0 min 14 sec
2
T 1
4:22:00
14 min 36 sec
4 min 36 sec
3
T 2
3:52:00
18 min 28 sec
8 min 28 sec
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4
Resting fMRI – MB8 
A>>P
8:08:00
26 min 36 sec
16 min 36 sec
5
Resting fMRI – MB8 
P>>A
0:14:00
26 min 50 sec
16 min 50 sec
6
BO field mapping
2:15:00
29 min 05 sec
19 min 05 sec
7
Diffusion (NODDI) AP
10:52:00
39 min 57 sec
29 min 57 sec
8
Diffusion (NODDI) PA
0:33:00
40 min 30 sec
30 min 30 sec
MRI Imaging Session 
Scan #1. Auto-Align Scout (Scout, 12 seconds):  A single low resolution 
structural scout scan is collected in the sagittal orientation (TR/TE/flip angle 
= 3.15 ms/1.37 ms/8o, GRAPPA factor = 3, 1.6 mm isotropic voxels, 128 
contiguous slices). The imaging parameters are chosen to obtain a low 
resolution image which can be used for planning purposes.
Scan #2. T1w structural MRI (MPRAGE, 4 minutes 22 seconds): 
Volumetric/structural images are obtained using a high resolution three-
dimensional (3D) T1-weighted (T1WI) fast gradient echo sequence 
(TR/TE/flip angle = 2000ms/2.99ms/8o, TI=900 ms, GRAPPA = 2, Partial 
Fourier = 6/80.8 mm isotropic voxels, 208 contiguous slices). The imaging 
parameters are chosen to obtain excellent contrast among gray matter, white 
matter, and cerebral spine fluid (CSF).
Scan #3. T2w structural MRI (3 minutes 52 seconds): Volumetric/structural 
images are obtained using a high resolution three-dimensional (3D) T2-
weighted (T2WI) fast gradient echo sequence (TR/TE = 2500ms/370ms, 
GRAPPA = 3, 0.8mm isotropic voxels, 208 contiguous slices). The purpose 
of this scan is to delineate T2 lesions and assist in coregistration and 
alignment. 
Scan #4, and #5. Resting state BOLD fMRI (2 separate resting state scans, 8 
minutes and 8 seconds and 14 seconds): Whole brain activation fMRI is 
obtained with a single-shot gradient echo EPI sequence sensitized to BOLD 
effect (TR/TE/flip angle = 613ms/22ms/47o, 2mm isotropic voxels, 72 
interleaved slices, zero gap). Multiband technology is utilized to speed up 
data acquisition (MB = 8). The participant is instructed to focus his/her 
vision on the fixation point (a cross) on the screen, and try to keep their 
minds free of thought. 
Scan #6. B0 field mapping (2 minutes 15 seconds):  A dual-echo fast 3D 
gradient echo sequence is run to map the B0 field (TR/TE1/TE2/flip angle = 
733ms/4.92ms/7.38ms/50o, 2mm isotropic voxels, 72 contiguous slices).
Scan #7. and #8 dMRI (NODDI) scan (2 separate scans, 10 minutes 52 
seconds and 33 seconds): Whole brain diffusion MRI is obtained with a 
single-shot spin echo EPI sequence sensitized to diffusion effect (TR/TE/flip 
angle = 3200ms/70ms/90o/180o, 2.0 mm isotropic voxels, 69 interleaved 
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slices, zero gap.  64 directions are collected for b=1000, b=2000 and b=3000 
s/mm2), including 5 b = 0 (1 at the beginning and 4 at the end of the scan). 
Multiband technology is utilized to speed up data acquisition (MB = 3) 
along with GRAPPA = 2.
Blood draw – 15 minutes to complete

30 mL of blood will be taken via antecubital blood draw by a 
trained nurse from the Clinical Research Unit. Blood will be 
collected into 10mL K2EDTA tubes (3 per subject) to collect 
plasma. Blood will be centrifuged at 100-1300RCF for 10min 
before plasma is collected and transferred to 500ul aluqouts. 
Plasma will be stored at -80 degrees until it is shipped on dry ice 
to Dr. Malu Tansey at Emory University. Half of the samples 
from each participant will be shipped to Emory University, while 
the other half will stay stored at the Clinical Research Unit as a 
back up, in case for any reason something happens to the 
shipment. Both the samples shipped to Emory University and 
stored in the Clinical Research Unit will be coded using subject 
study code numbers and will not contain any identifiable subject 
information. At Emory University, plasma will be subjected to 
multiplexed immunoassay for measurement of soluble 
inflammatory markers and neurotrophic factors. Emory University 
will destroy the samples following analysis. The Clinical Research 
Unit will destroy the back up samples left behind once they have 
received written authorization to do so from our research staff, 
which will happen as soon as the shipped samples are analyzed.
Behavioral testing session 1: (10:30 to 11:30)
Pending subject consent, some of the following behavioral tests may be video or audio 
recorded to aid in data analysis.
1) MDS-UPDRS, PART III, Motor Section: to measure PD disease severity 
– 15 minutes to administer
2) Mini Balance Evaluation Systems Test – 10 minutes to administer
3) Timed up and Go (3 trials) - 3 minutes to administer
4) Six-minute walk test – 7 minutes to administer
5) Activities-Specific Balance Confidence Scale – 15 minutes to administer
6) New Freezing of Gait Questionnaire – 10 minutes to administer
Testing is over for the day.  
The last dose of antiparkinsonian medications is taken no later than 8.30pm.
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Last coffee and alcohol no later than 8.30 pm.
Days 3:
Behavioral testing session 2: (8:30 to 10:25) 
Pending subject consent, some of the following behavioral tests may be video or audio 
recorded to aid in data analysis.
Cognitive testing: 
1. Montreal Cognitive Assessment, alternate version  – 10 minutes to 
complete
2. Symbol Digit Modality Test – 5 min to complete
3. Trail Making Test-Parts A and B – 10 min to complete
4. Raven’s Progressive Matrices –– 10 min to complete
5. Clock Drawing/copying – 10 min to complete
6. Hopkins HVLT-R Word list learning, delayed recall and recognition – 
10 min to complete
7. Free and Cued Selective Reminding Test, delayed recall and recognition 
– 15 min to complete
8. Figural memory test - to measure visual memory – 10 min to complete
9. Boston Naming Test (15 item) - 5 min to complete
10. Verbal fluency [semantic - animals, phonemic - letters] – 5 min to 
complete
11. Judgment of Line Orientation (15 item) - 10 min to complete
12. Intersecting pentagons – 5 min to complete
Day 4 and Day 5 (These will be 2 typical week days):
Cortisol Assessment 
We will collect saliva samples during the post-awakening period (0, 15, 30, 
and 45 minutes post-awakening) to measure the cortisol awakening 
response. We will also collect samples at approximately (3, 6, 9 and 12 
hours post-awakening) on two consecutive weekdays. The participant will 
be required to record and report their awakening and saliva sampling times. 
There will be objective measurement of awakening and sampling times in 
the 45 minutes post awakening.
Exercise Intervention
Intervention, Administration and Duration 
Subjects will exercise on a treadmill using procedures that have been used 
over the past two decades.(Kohrt, Malley et al. 1991, Kohrt, Spina et al. 
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1993, Kohrt, Spina et al. 1998) The regimen will include 5-10 min of warm 
up, 30 min of exercise at target HR and 5-10 min of cool down. They will 
exercise 3 days per week. The intervention group will be given a HR range 
to achieve during exercise sessions: 80.0%-85.0% HRmax. During the first 
8 weeks of training, exercise duration and intensity will be gradually 
increased to the target levels. Subjects will be instructed on monitoring HR 
and adjusting the exercise to remain in the target HR range (i.e., by 
changing treadmill speed and/or incline). During exercise, subjects will wear 
a heart rate monitor that captures and stores HR throughout the exercise 
bout. The exercise Research Assistant (RA) will electronically transfer the 
HR file from each exercise session (supervised and unsupervised) into the 
study database. 
During the first 2 weeks, subjects must exercise at a main study site under 
supervision of an Exercise training RA. All ‘on-site’ exercise sessions will 
be supervised by an exercise RA. After 2 weeks, the RA will determine 
whether the subjects may exercise off-site at a community fitness facility or 
at home to maximize the likelihood of compliance. If the subjects are 
exercising in their target HR range for the prescribed duration and have 
demonstrated to the exercise RA that they are able to operate the HR 
monitor, the subjects will exercise 2X/wk at the main site for 2 weeks and 
then 1X/wk for 2 weeks. Thereafter, if cleared by the RA, subjects will be 
expected to exercise on-site at least 1 x/month at the main site. Other 
exercise sessions will take place at the approved off-site facility. HR 
monitors must be worn for all sessions. HR data will be downloaded once 
weekly by an approved person at the facility or brought to a main site to be 
downloaded by the RA. In addition, the subject will be given an exercise 
diary log to document his/her wear time sessions on a weekly basis. The RA 
will check adherence to their prescription each week and will work with the 
participant as needed to assure appropriate adherence to the protocol. 
The intent of allowing exercise off site is to enhance recruitment, retention, 
and long-term adherence to exercise. Safety with respect to treadmill 
exercise will be established for each subject during the first two weeks of 
exercise at the main study site and also has been established in our previous 
work for 129 subjects with PD, Stages 1.5-3 of H&Y who exercised for up 
to 6 months without incident (Schenkman and Corcos, unpublished data). 
Additionally, many of the designated health clubs we work with are 
affiliated with hospitals and specialize in exercise programs for people with 
PD. 
The exercise training RA will assure exercise fidelity for each subject by 
comparing exercise sessions, duration and mean HR to the subject’s target 
on a weekly basis and by working with the subject to make necessary 
adjustments. 
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An optional online survey administered via email through REDCAP will be 
sent to participants following completion of the study. The purpose of the 
online survey is to better understand each subject’s experience and 
satisfaction with the study procedures. 
     
9.3
Procedures performed to lessen the probability or magnitude of risk and 
source records are described below:

Minimizing physical, psychological, and social risks: We see no 
psychological, social, or legal risks beyond those of participation in 
health-related research in general.  

Minimizing risks to confidentiality: These risks will be minimized by 
not including personal identifying information on the forms, and by 
conducting interviews and collection of personal information in a private 
setting.

Minimizing risks associated with testing protocol: 

Clinical assessments:  Possible risks associated with clinical 
evaluations are minimal but may include fatigue, emotional 
distress, or embarrasment related to some questions on thinking 
and mood; to minimize these, we will provide breaks in the testing 
schedule and ask questions in a sensitive, non-judgmental manner. 

MRI Imaging: All potential participants will be screened for 
eligilibity for a MRI scan as per Radiology guidelines for safety 
precautions including cardiac pacemaker, metallic implants of any 
kind in the body, pregnancy, among others. Prior to entering the 
MRI scan, subjects will be asked again about these safety 
precautions to determine eligibility for MRI scan. Other possible 
risks include claustrophobia, boredom, noise, or discomfort from 
lying supine which will be minimized by talking with the subject 
periodically during the scanning, providing ear plugs, and 
providing cushioning. The movement tests are associated with 
minimal risks, such as stiffness or pain from performing maximal 
voluntary contractions. This risk will be minimized by providing 
rest breaks between trials, excluding participants who experience 
hand pain or other adverse events, and monitoring discomfort.  If 
an individual requires emergency medical care, 911 will be called 
immediately. This has never happened previously and we have 
tested more than 100 individuals.

Exercise testing: We are using an endurance exercise protocol that 
we have extensive experience with. Participants are very closely 
supervised over the first 2 weeks of training to make sure that they 
are safe and can perform the exercise protocol. 

Medication withdrawal: All subjects are offered hotel 
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accomodations near the testing facility on the nights prior to testing 
days during which they are asked to withdrawal from anti-
Parkinsonian medication in order to avoid the need to commute to 
the testing facility while off medication. A research assistant will 
meet the subjects each morning at the hotel ad will accompany the 
subject via wheelchair, if needed, to the testing facility. 

The risk associated with blood draws are minimal and are reduced 
in this study because trained personnel who have extensive 
venipuncture experience, and are trained in aseptic technique, will 
implement the blood drawing procedures in a clean room.

No drugs and devices will be used in the research - NA. 

Data collection forms will be used to record the study data and are 
attached. Forms for test measures are attached for the following tests: 
1. SCOPA-Cog
2. NINDS Demographics, CDE
3. MDS UPDRS parts 1,2, 3 (motor) and 4
4. PD Neurol QOL,
5. MOCA
6. Pittsburgh Sleep Quality Index, 
7. Epworth Sleepiness Scale, 
8. Fatigue Severity Scale, 
9. Hamilton Depression Scale,
10. Health-related quality of life (PDQ-39),
11. Mini Balance Evaluation Systems Test
12. Timed up and Go (3 trials)
13. Six-minute walk test
14. Activities-Specific Balance Confidence Scale  
15. New Freezing of Gait Questionnaire
16. MoCA Alternate version
17. Symbol Digit Modality Test, 
18. Trail Making Test-Parts A and B, 
19. Raven’s Progressive Matrices, 
20. Clock Drawing, 
21. Hopkins HVLT-R, 
22. Free and Cued Selective Reminding Test, 
23. Figural memory test, , 
24. Boston Naming Test, 
25. Verbal fluency [semantic - animals, phonemic - letters], 
26. Judgment of Line Orientation, 
27. Intersecting pentagons, 
9.4 The data that will be collected is outlined in Table 1.
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Table 1
Dependent Measures
Baseline
Each ex 
session
Each mo
6 mo
Primary Measures
Cognitive Measures: Symbol Digit 
Modality Test, Trail Making Test-Parts A 
and B, Raven’s Progressive Matrices, 
Clock Drawing, Word list learning and 
delayed recall, Free and Cued Selective 
Reminding Test, Figural memory test, 
X
X
Secondary Measures
National Institute of Neurological 
Disorders and Stroke common data 
elements
X
MDS-UPDRS I, II, IV 
X
X
Sleep (Pittsburgh Sleep Quality Index, 
Epworth Sleepiness Scale
X
X
Fatigue (Fatigue Severity Scale)
X
X
Mood (Hamilton Depression Scale)
X
X
PDQ-39
X
X
Cognitive Measures: Boston Naming 
Test, Verbal Fluency, Judgment of Line 
Orientation, Intersection pentagons, 
Spatial working memory
X
X
MDS-UPDRS III
X
X
Neuro-QOL
X
X
Mini Balance Evaluation Systems Test 
(Mini-BESTest)
X
X
Timed Up and Go
X
X
6 minute walk test
X
X
Activities-Specific Balance Confidence 
Scale (ABC scale)
X
X
New Freezing of Gait Questionnaire 
(NFOG-Q)
X
X
Activity Monitor
X
MRI: Hippocampal volumes 
X
X
MRI: DTI measures 
X
X
MRI: Functional connectivity
X
X
Serious Adverse Events (SAEs) and 
Adverse Events (AEs)
X
Attrition
X
EE training log
X
Levodopa Equivalent
X
X
Cortisol (2 consecutive time points)
X (8)
X (8)
Blood Draw
X
X
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10.0
Data and Specimen Banking: 
10.1 The primary investigator and co-investigators will have access to the 
raw data. Research staff at Northwestern University will be restricted 
assess to the online database for data entry and report generation. 
Any data viewed by others/collaborators will be de-identified. Hard 
copies of data collection forms will be stored in a locked office or 
laboratory. Data entered into spreadsheets will be kept on password 
protected computer drives.
10.2 Participants will be requested to conduct the saliva sampling 
protocol in their domestic setting on two weekdays. Saliva sampling 
will commence in the post-awakening period and across the day. 
Saliva will be collected by salivettes. Prior to saliva sampling (30 
min) participants will be instructed to take nil by mouth bar (except 
water). During the post-awakening period they will be asked to 
refrain from brushing their teeth to avoid abrasion and vascular 
leakage. SMS text messages will be used to send reminders to 
participants to complete saliva samples. Electronic devices will be 
used to record awakening and saliva sampling times (actigraph & 
trackcaps respectively). Participants will received detailed verbal and 
written instructions on the study protocol. Saliva samples will be 
stored in the freezer at -80°C in a special purpose labatory on the 7th 
floor of 645 N. Michigan Avenue. For salivary cortisol assay, the 
Salimetrics High Sensitivity Salivary Cortisol Enzyme Immunoassay 
Kit will be used. This assay captures the full range of salivary 
cortisol levels (0.003 to 3.0μg/dL) requiring only 25 uL of saliva per 
test. A built-in pH indicator detects acidic or basic samples.  
10.3 The data will be shared with Rush University Medical Center. The 
data will not be identifiable when shared. Cortisol data will be 
shared with Dr. Angela Clow and Nina Smyth at the University of 
Westminster. Data shared with the University of Westminster will be 
de-identified. Data that can be used for descriptive statistics 
including but not limited to gender, age, disease duration, MDS-
UPDRS scores, and cognitive data will also be shared with the 
University of Westminster. No data shared with the University of 
Westminster will be identifiable data. 
11.0
Data and Specimen Management
11.1 We are collecting pilot data primarily for feasibility, though statistical 
analyses may be conducted to provide descriptive data of the subject cohort, 
baseline and 6-month test scores, and potentially exploratory analyses of 
change in outcome measures or correlations of variables. 
11.2 Since we are collecting pilot data, there is no power analysis.
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11.3 The research will be conducted in compliance with state and federal laws, 
including the Health Insurance Portability and Accountability Act (HIPAA 
that require researchers to protect and maintain confidentiality of an 
individual’s health information. All subjects will be asked to sign an 
“Authorization To Use and Disclose (Release) Health Information For a 
Research Study”. Access to all study datasets will be password protected. 
All research staff will be trained in proper research procedures. We have 
extensive experience in data capture, data flow and data management based 
on our SPARX Phase II clinical trial.(Moore, Schenkman et al. 2013) We 
will use REDCap (Research Electronic Data Capture) to define and manage 
our own data collection forms. This service is provided through the 
Northwestern University Clinical and Translational Institute.
11.4 Quality control is addressed at the point of data collection, data entry, and 
data analysis.

Imaging – the imaging center conducts tests for quality control of the 
imaging data. A quality control scan is run every day before data 
acquisition begins.

All of our data is double checked for accuracy by a member of our 
research team. Periodically we have our data checked by a person who is 
not directly involved in the laboratory.
11.5 Study-wide handling of data and specimens is described below:

Our data consists of analog data and text.

Our data is stored on hard disks and backed up regularly.

Our data is stored indefinitely.

The clinical coordinator, statistician and students and post- doctoral 
fellows will have access to the data.

The clinical coordinator is responsible for receipt of the data.

The data will not be transported.

The cortisol data will initially stored in a freezer at -80°C before being 
shipped out for analysis.
12.0
Provisions to Monitor the Data to Ensure the Safety of Subjects: 
This study does not involve more than minimal risk.
13.0
Withdrawal of Subjects*
13.1 Participation in this study will be stopped by the investigator without 
subject consent if circumstances arise which warrant doing so.  This 
would include injury that would limit participation in the exercise 
portion of the study or if the person became ill during the research, 
they may have to drop out, even if they would like to continue.  The 
investigators, Daniel Corcos, PhD and Jennifer G. Goldman, M.D. 
will make the decision and let the person know if it is not possible 
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for them to continue.  The decision may be made to protect the 
health and safety of the participant. 
13.2 Subjects may withdraw for the research at any time point. Subjects 
will be asked if they would be willing to take part in the post-test.  
14.0
Risks to Subjects*
14.1 Overall, potential foreseeable risks associated with participation in 
the study are very unlikely and of low risk. 

The potential risks of endurance exercise includes injury to 
tendons, ligaments, joints, and muscles. There is little likelihood of 
any physical risk as a result of participation in this research project. 
The exercise and testing procedures have been well established for 
people with Parkinson’s disease. The use of a well-trained personal 
trainer further reduces any possible risks.

During exercise testing there is a chance that subjects could fall, 
feel pain in their muscles or joints, feel dizzy or faint, have 
irregular heartbeats, have a stroke or heart attack, or die. The risk 
of death from an exercise stress test has been estimated to be 1 in 
100,000. The risk of a heart attack is about 4 in 10,000 and the risk 
of a problem that would require hospitalization (for example, chest 
pain) is about 2 in 1,000.  To minimize this risk, only subjects at 
low to moderate risk will be allowed to particiate in exercise 
testing. Subjects can request to terminate the exercise test at any 
point during testing. ACSM subject screening and testing 
guidelines will be followed. The exercise test will be administered 
by an exercise physiologist who is Advanced Cardiac Life Support  
(ACLS) certified and has automated external defibrillator (AED) 
experience. The exercise physiologist administering the test will 
also have knowledge of appropriate contraindications, risk, and 
risk assessment of testing, the absolute and relative indications for 
termination of the exercise test, knowledge of cardiac arrhythmias, 
and the ability to recognize and treat serious arrhythmias if they 
arise. 

There are no known hazards to diffusion magnetic resonance imaging, 
functional magnetic resonance imaging, other than the discomfort 
associated with confinement and remaining stationary for the duration of 
the testing procedure. We have found that training in the MR simulation 
scanner helps to reduce the stress associated with the noise and 
confinement of the actual MR scanner environment. Testing of all 
participants will be terminated immediately should they become 
distressed. We will carefully screen out individuals who have an 
implanted electrical device (such as a cardiac pacemaker or a 
neurostimulator), or a certain type of metallic clip (i.e., an aneurysm clip 
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in the brain). These devices can malfunction and cause harm to the patient 
in the magnet environment. We will also carefully screen individuals who 
are claustrophobic to reduce any adverse events. We anticipate that most 
patients will come by limousine to the testing facility when off 
medication. Under no circumstance will we allow a patient to drive when 
off medication.

Risk associated with blood draws: pain, a bruise at the point where blood 
is taken, redness and swelling of the vein and infection, and a rare risk of 
fainting. These risks associated with blood draws are minimal, and are 
reduced in this study because trained personnel who have extensive 
venipuncture experience, and are trained in aseptic technique, will 
implement the blood drawing procedures in a clean room.
14.2     N/A
14.3
N/A
14.4
N/A
15.0
Potential Benefits to Subjects
15.1 Individuals who participate in this research may get in better 
physical shape. They may be able to more easily perform daily 
activities, and may experience improvements in the symptoms 
associated with Parkinson’s disease. There is also the possibility of 
improved cognition. The duration is the time course of the study (6 
months) plus a few extra months.
15.2 N/A
16.0
Vulnerable Populations: 
Participants in this study may have mild cognitive impairment but will not 
have dementia as determined by the referring Neurologist and screening 
criteria. Cognitive impairment will be assessed by the clinicians and study 
personnel through interview of the patient (and their caregiver) and 
cognitive testing to determine the presence of cognitive impairment, 
clinical diagnosis of dementia, and capacity to consent. This information 
will be used to determine if the person is able to understand the 
information relevant to making a decision about the study and appreciate 
what it means to participate or not participate in the study. Patients who 
are considered for study participation will have a caregiver or legal 
representative present as part of the inclusion criteria. If the subject does 
not have the capacity to consent, they will be exluded from the study. 
Because the criteria for participation in the study requires only a mild 
cognitive impairment, eligible participants will have the capacity to 
consent. 
17.0
Community-Based Participatory Research: NA
18.0
Sharing of Results with Subjects
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18.1 No specific results are shared with subjects. It is possible that we 
may observe what might be considered abnormalities on brain scans. 
We might also observe scores on some of the tests that we 
administer that are considered outliers. We share these results with 
the neurologist of the subject and let the neurologist decide whether 
or not to share the result with the patient. 
19.0
Setting
19.1 The locations where our research team will conduct the research are 
described below:

Participants with PD who are currently taking medication for 
PD will be recruited from the outpatient Neurology Movement 
Disorder practices at Northwestern University and Rush 
University Medical Center in Chicago, IL. All potential 
participants will be invited to the study by their primary 
neurologist.

All research procedures will be performed at Northwestern 
University Department of Physical Therapy & Human 
Movement Sciences using one of two dedicated research 
rooms. All of the brain scanning will be conducted at Olson 
Pavilion, 710 N Fairbanks – Lower Concourse.

There will be no community advisory board.

There will be no research conducted outside of the institution.

Participants will initially exercise at Northwestern University 
or a local gym or fitness facility of their choosing until they are 
comfortable exercising independently, after which they will 
exercise either at home or in community exercise facilities of 
their own choosing.
20.0
Resources Available
20.1 NIH has funded Dr. Corcos, one of the PIs of this study, 
continuously since 1986. He is currently the co-PI on the SPARX 
NIH sponsored Phase II Clinical Trial on the effects of endurance 
exercise in Parkinson’s disease. He has published more than 170 
research articles. He has chaired 2 different study sections at NIH. 
The other PI is Dr. Jennifer G. Goldman who is a Movement 
Disorders specialist at Rush University Medical Center. She is an 
expert on cognitive impairment in Parkinson’s disease, in particular 
PD-MCI. They have a very experienced research team (Dr. David 
and Ms. Skender) that has helped him conduct one clinical trial and 
who are currently working on another clinical trial. Dr. Corcos has 
performed all aspects of this research study on this patient 
population in Chicago. Dr. Goldman has treated hundreds of patients 
with Parkinson’s disease.
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20.2 It is feasible for us to recruit up to 16 participants. The sections of 
Movement Disorders at Northwestern University and Rush 
University Medical Center see over 180 patients with Parkinson’s 
disease every week, and 2,900 patients every year. Approximately 
25% of these patients have MCI.
The PIs will each be devoting at least 10% effort to conducting and 
completing this research. This is ample for the protection of patients.
The facilities include:

One room that is dedicated to collection of functional data, cognitive 
data and other questionnaire data. This room has a couch and is very 
quiet should patients need to rest at any time (room number 1124).

The imaging center at Northwestern University is where the brain 
imaging will occur and is very well equipped for all of the proposed 
studies.
We have previously conducted a very similar endurance exercise 
program and had 77 people with PD enroll in the program. We have 
conducted all of the imaging experiments on more than 100 patients. 
We do not expect to need any medical or psychological resources. 
We do have access to all medical and psychological resources of the 
Department of Neurology should such a need arise.
Our staff is very well trained. They have extensive experience in 
conducting similar studies. They have all read the IRB. We have 
weekly meetings to make sure everyone knows their specific duties.
21.0
Prior Approvals
21.1 We will be using the exercise facilities at NU or community fitness 
facilities to train participants in the endurance exercise protocol. No 
community fitness facilities will be engaged in the research. We will 
attain premission from community fitness facilities to have an RA 
accompany the research subject for the first few weeks of the 
exercise protocol to ensure that the subject is familiar with the 
protocol and equipment. 
22.0
Recruitment Methods
22.1 We will commence enrolling subjects and collecting data as soon as 
we receive IRB approval. Men and women with PD who are 
currently taking medication for PD will be recruited from the 
outpatient neurology practices at Northwestern University and Rush 
University Medical Center. They are located 4 miles apart in 
Chicago. All potential participants will be invited to the study by 
their primary neurologist. Nothing beyond recruitment will occur at 
Rush University Medical Center.
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22.2 Subjects will come from outpatient neurology practices at 
Northwestern University and Rush University Medical Center in 
Chicago, IL.
22.3 Neurologists at Northwestern University or Rush University Medical 
Center will invite individuals to participate in the study if they have 
idiopathic PD, age 40-85, H&Y stage < or equal to 3, and able and 
willing to sign informed consent. They will be excluded if they have 
any condition that precludes taking part in an exercise intervention 
or undergoing MRI, have no cognitive impairment as assessed by the 
SCOPA Cog scores greater than or equal to 25, PD dementia, or if 
they are unwilling to comply with the study procedures. 
22.4 Participants with PD will be recruited through Neurologists at 
Northwestern University and Rush University Medical Center. 
Flyers will be posted at Northwestern University. 
22.5 There are no payments made to subjects for participation in the 
study. To avoid subjects having to pay for meals out of pocket, 
VISA gift cards pre-loaded with $320 will be given on each testing 
day to cover meals for both the subject and his or her caregiver who 
may accompany the subject. They will each be allowed $40 per 
person per meal for breakfasts, and $60 per person per meal for 
lunches and dinners. The cards will be reloaded daily and receipts 
will be collected for any expenses charged to the card. The subject 
will turn in the card to the RA at the end of the final day of testing. 
However, if the subjects for any reason do utilize their own money 
for subject related expenses such as meals, transportation, or 
parking, they will be required to turn in receipts in order to be 
reimbursed. Within a week, these receipts will be turned in to the 
accounting department for reimbursement. The accounting 
department will mail it to the subject within 40 business days from 
the last day of the subject’s visit.
23.0
Local Number of Subjects
23.1 The total number of subjects to be accrued locally is up to 16.
23.2 We will study up to 16 patients in a pilot study.
23.3 Allowing for the possibility of screen failures or study drop-outs, we 
may need to recruit 16 participants.
24.0
Confidentiality: NA
25.0
Provisions to Protect the Privacy Interests of Subjects 
25.1 The only people who will know that a participant is a research 
subject are members of the research team. No information about 
participants or information provided by the participants during the 
research will be disclosed to others without their written permission, 
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except: 1) if necessary to protect participant's rights or welfare (for 
example, if they are injured and need emergency care or when the 
Institutional Review Board monitors the research or consent 
process); or 2) if required by law. 
25.2 Subjects who choose to be in this study will be informed that they 
have the right to be treated with respect, including respect for the 
decision whether or not to continue or stop participating in the study. 
All examinations and procedures will be thoroughly explained to 
each subject to ensure subjects feel at ease with the questions, 
examinations, and procedures involved. Subjects will be informed 
that if at any point they feel uncomfortable about answering any 
questions on any questionnaires or surveys, they will not be required 
to answer that question. Subjects will be informed that they are free 
to choose to stop being in the study at any time, and that choosing 
not to be in this study or to stop being in this study will not result in 
any penalty or loss of benefit to which they are entitled.  
Specifically, the choice not to be in this study will not negatively 
affect the right to any present or future medical treatment.
25.3 The NU research staff will obtain a release from the patient to access 
medical records from Rush University Medical Center.
26.0
Compensation for Research-Related Injury
26.1 Minimal risk is when the probability and magnitude of harm or 
discomfort anticipated in the proposed research are not greater, in 
and of themselves, than those ordinarily encountered in daily life or 
during the performance of routine physical or psychological 
examinations or tests. The proposed research does not exceed 
minimal risk. In the event of research-related injury, subjects will not 
be compensated for medical care required because of an untoward 
outcome resulting from participation in the research study. Subjects 
should seek medical treatment through his or her doctor or treatment 
center of choice.  
26.2 If a participant becomes ill or get san injury or illness as a result of 
study (medications, devices or procedures), they should seek medical 
treatment through their doctor or treatment center of choice. They 
should promptly tell the study doctor about any illness or injury.  
The hospital [university, researchers] will not pay for medical care 
required because of a bad outcome resulting from their participation 
in this research study. This does not keep them from seeking to be 
paid back for care required because of a bad outcome.
27.0
Economic Burden to Subjects
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27.1 The tests and procedures completed for this study will be at no cost 
to the subjects. Subjects will be given reimbursement for expenses 
related to hotel stay, food and parking. Every subject will be offered 
hotel accomodations during the nights that they are asked to start 
withdrawl from medication (the night of baseline visit and the night 
of Day 1 testing). To avoid subjects having to pay for meals out of 
pocket, VISA gift cards pre-loaded with $320 will be given on each 
testing day to cover meals for both the subject and his or her 
caregiver who may accompany the subject. They will each be 
allowed $40 per person per meal for breakfasts, and $60 per person 
per meal for lunches and dinners. The cards will be reloaded daily 
and receipts will be collected for any expenses charged to the card. 
The subject will turn in the card to the RA at the end of the final day 
of testing. If subjects become ill or injured as a result of this study, 
they will be advised to seek medical treatment through their medical 
doctor or treatment center of choice, which will be at his or her own 
expense and may lead to added costs for the subject or the subject’s 
insurance company.
28.0
Consent Process
28.1 “SOP: Informed Consent Process for Research (HRP-090)” will be 
followed in order to obtain consent from each individual subject. On 
arrival to Northwestern University Department of Physical Therapy 
and Human Movement Science for data collection, subjects will be 
re-oriented on the study protocol, will be given an opportunity to ask 
any questions, and will sign an informed consent. If there is a 
significant change to the research protocol or if there is new 
information that may alter an individual’s willingness to participate 
in the research, subjects will be provided an updated informed 
consent document and consent will be re-obtained. 
29.0
Process to Document Consent in Writing
29.1 We will be following “SOP: Written Documentation of Consent 
(HRP-091)” to document consent in writing from all subjects. On 
arrival to Northwestern University Department of Physical Therapy 
and Human Movement Science for data collection, subjects will be 
re-oriented on the study protocol by a study team member, will be 
given an opportunity to ask any questions, will be walked through all 
sections on all pages of the informed consent, and will sign the 
informed consent.
29.2 A copy of the consent document is attached.
30.0
Drugs or Devices: NA
Relevant Literature:
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