Effects of Exercise on Glymphatic Functioning and Neurobehavioral Correlates in Parkinson's Disease
Phase: NA
Conditions: Parkinson's Disease and Parkinsonism, Glymphatic System
Sponsor: Vanderbilt University Medical Center

 
 
 
1 
 
 
 
 
 
 
Protocol Title: 
Effects of Exercise on Glymphatic Functioning and Neurobehavioral Correlates 
in Parkinson’s Disease 
Protocol Date: June 4, 2024 
NCT04140708 
 
 

 
 
 
2 
 
Effects of Exercise on Glymphatic Functioning and 
Neurobehavioral Correlates in Parkinson’s Disease 
. 
Principal Investigator: Daniel O. Claassen MD 
 Sponsor: Vanderbilt University Medical Center 
  
Funded by: Department of Defense & National Institute of Health 
Version Number:  v.5.0 
4-JUNE-2024 
 
 

 
 
 
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1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
Effects of Exercise on Glymphatic Functioning and Neurobehavioral 
Correlates in Parkinson’s Disease 
 
Study Description: 
This study will assess patients with a clinical diagnosis of Parkinson’s 
disease (PD) over prior and following participation in a 12-week 
community-based exercise program, assessing neuroimaging (beta-
amyloid deposition, glymphatic flow), and clinical severity (motor, 
cognitive, sleep disturbance, mood). 
 
Objectives: 
 
Primary Objective:  
Evaluate the glymphatic functioning and beta-amyloid burden response to 
12 weeks of a community-based exercise course in PD patients. 
 
Secondary Objectives:  
Quantify the association between glymphatic functioning, beta-amyloid 
burden, and neurobehavioral dysfunction in PD. 
Evaluate the degree to which neuroimaging-based response to exercise 
mediates clinical improvement in PD. 
Tertiary Objectives: 
 
Evaluate whether the association between glymphatic functioning, beta-
amyloid burden, and neurobehavioral dysfunction in PD differs between 
cognitively healthy and cognitively impaired PD phenotypes. 
Evaluate whether the neuroimaging and clinical response to exercise 
differs between cognitively healthy and cognitively impaired PD 
phenotypes. 
Quaternary Objectives: 
Develop a normative reference group for the Brief Estimate of Seconds 
Test (BEST) to facilitate PD score interpretation and establish how PD-
related neurodegeneration affects time perception. In addition, determine 
how BEST scores correlate with disease severity, neuroanatomical ROIs, 
and neuropsychometric cognitive data collected in the previous objectives. 
 
 
Endpoints: 
Primary Endpoints:  
Glymphatic flow (DTI-ALPS score) 
PET/CT (cortical:cerebellar SUVr ratio)  
Secondary Endpoints (also used for Tertiary Endpoints):  
Unified Parkinson’s Disease Rating Scale III (UPDRS-3) 
Actigraphy 
Mini-BEST-est 
Freezing Gait Questionnaire 
6-minute Walk Tesdt 
Hopkins Verbal Learning Test-Revised (HVLT) 
Trail Making Test – A & B (TMT) 
Stroop Test (Stroop) 

 
 
 
4 
Letter Fluency (FAS) 
Simon Task (Simon) 
PROMIS – Sleep Disturbance short forms (PROMIS-Sleep) 
Hospital Anxiety and Depression Scale (HADS) 
Tertiary Endpoints: 
Clinical Dementia Rating Scale (CDR) 
Brief Estimate of Seconds Test (BEST) 
Quaternary Endpoints: 
Brief Estimate of Seconds Test (BEST) 
 
Study Population: 
PD cohort: Patients with a clinical diagnosis of Parkinson’s, as defined by 
neurologic examination, from ages 55-80, with and without mild cognitive 
impairment (MCI) 
Healthy cohort: healthy adults (ages 18-90) without neurological or 
psychiatric/developmental pathology. 
 
Phase: 
Observational 
Description of Sites: 
Vanderbilt University Medical Center 
Description of Study 
Activities: 
PD cohort: MRI Brain scan, PET/CT Brain scan, Neurological and 
Neuropsychological exams, continuous Actigraphy, 12-week community-
based exercise program 
Healthy cohort: Neuropsychological exam 
Study Duration: 
PD cohort: 36 months 
Healthy cohort: 24 months 
Participant Duration: 
 
Medical Monitor:  
PD cohort: 3 months 
Healthy cohort: 1 day 
Katherine McDonell, MD, will act as the independent medical/research 
monitor overseeing this study. The research monitor may perform 
functions such as observing enrollment procedures for individuals, groups, 
or units; overseeing study interventions; overseeing data matching, data 
collection, and analysis. The research monitor shall have authority to stop 
a research protocol in progress, remove human subjects from the research 
protocol if necessary, and protect the safety of human subjects until the 
IRB assesses the monitor’s report, and shall have the responsibility to 
promptly report their observations and findings to the IRB or other 
designated official and the HRPO. 
 
 
 
 
 
 
 
 
 
 
 
1.2 
SCHEMA: PD COHORT 

 
 
 
5 
 
 
 
Screening
Week 0, Day 0
•Obtain informed consent
•Obtain history, screen potential participants by inclusion and exclusion criteria
Baseline
Week 1, Day 1-7
•MRI brain scan
•PET brain scan
•Neurological & Neuropsychological exam
Interval
Week 2-13, Day 8-91
•Baseline PT assessment
•Twice-weekly participation in community-based exercise program
•Continuous actigraphy & Neurametrix
•Follow-up PT assessment
Week 14, Day 92-99
•MRI brain scan
•PET brain scan
•Neurological exam, neuropsychological exam, document
End of Study Assessments

 
 
 
6 
 Schedule of Activities (SoA) – Assessment Only  
 
Procedures 
Screening 
Day - 0 
Baseline (VUMC) 
Day 1-7 
Baseline (RSB; first 
day) 
Interval / Exercise 
Day 8-91 
Follow-up (RSB; last 
day) 
Follow-up 
(VUMC)  
Day 92-99  
Informed consent 
x 
 
 
 
 
 
Demographics / Medical history / Exclusion 
& Inclusion 
x 
 
 
 
 
 
Vital Signs/orthostatic blood pressure/ 
weight  
 
x 
 
 
 
 
Blood sample 
 
x 
 
 
 
x 
Neurologic exam 
 
x 
 
 
 
x 
UPDRS-3 
X (on-med) 
X (off-
med 
 
 
 
x 
Neuropsychological exam (all cognitive 
measures) 
 
x 
 
 
 
x 
Questionnaires (sleep, mood) 
 
x 
 
 
 
x 
Actigraphy 
 
      x--------------------------------------------------------x 
MRI Brain 
 
x 
 
 
 
x 
PET/CT Brain 
 
x 
 
 
 
x 
Physical status assessment (Mini-BESTest, 
Freezing Gait Questionaire, 6-minute Walk 
Test) 
 
 
x 
 
x 
 
VUMC = Vanderbilt University Medical Center site 
RSB = Rock Steady Boxing site 
 
The Healthy cohort will complete only a single visit, for 10 minutes, in which they will complete the informed consent 
and the BEST, as well as asked about demographics, medical history, and exclusion/inclusion criteria. 
 
2 
STUDY DESIGN  
 
2.1 
OVERALL DESIGN 
 
For the PD cohort, participants will be recruited from Vanderbilt University Medical Center Neurology’s 
Behavioral and Cognitive and Movement Disorder Clinics by Drs. Claassen and Considine. We will 
prospectively enroll participants with idiopathic Parkinson’s disease (n=50; age range=55-80 years), 
equally distributed and matched for age and sex between groups with (n=25) and without (n=25) mild 

 
 
 
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cognitive impairment. These populations provide a cohort to evaluate the potential relationship 
between glymphatic flow and beta-amyloid burden, given the elevated risk of beta-amyloid 
accumulation associated with PD and MCI conditions. Patients will have medical and motor presentation 
indicated for the community-based exercise program. Those patients with clinically-defined MCI, will be 
without evidence of vascular cognitive impairment, primary mood disorder, or comorbid medical 
condition that could contribute to cognitive symptoms (e.g. pulmonary, hematologic, metabolic, or 
vitamin deficiency). Potential participants will undergo a neurological and neuropsychological 
examination (including cognitive exam and behavioral/symptom questionnaires) to characterize their 
medical and neurobehavioral status. They will then undergo baseline neuroimaging protocols, both MRI 
brain scan (DTI-ALPS) and PET/CT (C11PiB ) brain scan. Actigraph will be attached to the patient to 
continuously monitor motor activity. A background monitor of typing cadence will be activated on their 
computer to monitor for changes in fine motor control. The cohort will complete the same clinical and 
neuroimaging assessments after they participate in a 12-week community-based exercise intervention. 
Specifics about assessments and the exercise program are as follows. 
 
For the healthy cohort, participants will be recruited from the general population and a database of 
individuals who have elected to be contacted about future research or for this study through a contact 
form. They will be adults between the ages of 18 and 90 without neurological or psychiatric pathology (N 
= 75). Under the supervision of the clinical coordinator, the participants will be asked to complete the 
Brief Estimate of Seconds Task (BEST) in person or via Microsoft Teams. These data will aid in the creation 
of a normative reference group for the BEST, dependent on sex and age. Using data collected in both the 
PD and healthy cohorts, we will perform subsequent analyses to determine the relationship between PD 
BEST scores and clinical disease severity (UPDRS), neuroanatomical ROIs, and standard 
neuropsychometric cognitive measures. These findings will elucidate the origins and extent of time 
perception changes in PD 
 
2.2 
STUDY DESIGN SPECIFICS 
 
Clinical Assessments 
 
PD cohort 
All potential participants will undergo neurological and neuropsychological examination to determine 
eligibility, categorize MCI status, and provide quantification of neurocognitive functioning and 
neuropsychiatric symptomatology.  
 
Screening data (see inclusion/exclusion criteria) from eligible enrollees will be also used as part of 
clinical baseline assessment.  
 
Neurological examination will include the Unified Parkinson’s Disease Rating Scale III (UPDRS-III)56 and 
the Clinical Dementia Rating (CDR)57 scale. Vitals and a blood sample (10mL) will be collected as part of 
this examination. Medical history will include an inquiry as to whether the participant is actively dieting. 
 
The neuropsychological examination protocol will consist of a memory measure (i.e., the Hopkins Verbal 
Learning Test – Revised [HVLT-R]58, consisting of Learning, Recall, and Recognition subcomponents), 
executive functioning measures (i.e., Trail Making Test – A & B59, Verbal Fluency [FAS]60, Stroop61), and 
exploratory measures of cognitive-performance thought potentially sensitive to PD-related pathology 
(Brief Estimate of Seconds Test [BEST]62, Simon Task63). To evaluate sleep disturbance symptomatology, 

 
 
 
8 
PROMIS – Sleep Disturbance (SD) and Sleep-related Impairment (SRI) short forms will be administered64. 
To evaluate mood symptomatology, the Hospital Anxiety and Depression Scale (HADS)65 will be 
administered.  
 
Physical assessment is routinely completed at the first and last visit of the community-based exercise 
program, including rating/timing of ability to complete simple posture and gait tasks, as well as self-
reported difficulty with gait initiation.  UPDRS-III will also be administered at screening (on-drug), 
baseline assessment (off-drug), and follow-up assessment (off-drug) Additionally, between enrollment 
and competition, the patients will wear an actigraph to continuously measure motor activity.  
 
Healthy cohort: 
All participants will be administered the Brief Estimate of Seconds Test (BEST) in person or via Microsoft 
Teams. 
 
Imaging 
 
PD cohort 
MRI. Participants will begin with MRI in the morning after their 16-hour dopaminergic washout the 
night/evening prior. Self-reported total sleep time the night prior will be recorded. They will be free to 
re-initiate therapy after MRI is complete. The following imaging and angiography sequences will be 
completed. We will apply our previously-reported 3T methods (16-channel neurovascular coil) with the 
below 50 min protocol: 
 
 Anatomical imaging. T1-weighted (MPRAGE; spatial resolution=1.0x1.0x1.0mm3; 3D turbo-gradient-
echo; TR/TE=8.2/3.7ms), and T2-weighted (FLAIR; spatial resolution=0.9x1.1x3.0mm3; turbo-inversion-
recovery; 
TR/TI/TE=11000/2800/120ms) 
imaging, 
and 
intracranial 
(spatial 
resolution 
= 
0.5x0.8x1.4mm3; 
3D 
gradient 
echo; 
TR/TE=23/3.5ms) 
and 
extracranial 
(spatial 
resolution=0.9x0.9x3.0mm3; 2D gradient echo; TR/TE=18.6/3.2ms) time-of-flight (TOF) MR 
angiography (MRA).  
 Microvascular hemodynamic compliance. A single-shot gradient echo echo-planar-imaging (EPI) scan 
(TE=30 ms), multiband-factor=3, isotropic spatial resolution=2 mm, SENSE-factor=2.5, and TR=1s will 
be acquired with whole-brain coverage. The scan will utilize a hypercapnic normoxic (5% CO2 / 21% O2 
/ 74% N2) stimulus. The stimulus will be administered through a tight-fitting non-rebreathing oxygen 
facemask from compressed gas cylinders (flow rate=12 L/min) with the following paradigm:  180s 
normocapnic normoxia / 90s hypercapnia repeated once, followed by 180s normocapnic normoxia. 
Heart and respiration rate, EtCO2, and FiO2 will be recorded.  
 CSF flow. 2D-Qflow measurements will be performed in the cerebral aqueduct (Fig. 7). Venc=12 cm/s, 
spatial resolution = 0.5x0.5x4 mm3, field-of-view = 200x200x4 mm3, and 30 frames per heart cycle. 
Scan durations vary with heart rate, but are generally 2-4 min. Reproducibility has been determined 
by repeating the flow measurements in six subjects (Fig. 7). Background correction will be performed 
with a method previously developed for quantification of blood flow velocity in small perforating 
arteries4.  
 Lymphangiography for lymph vessel visualization. 3D turbo-spin-echo with variable refocusing angle 
sweep=40-110°, 
driven 
equilibrium 
module, 
dynamic 
DANTE 
flip 
angle 
sweep=0–8°, 
TE=600/TR=2500ms, slices=80, spatial resolution=1x1x1mm3. We have shown that this method 
provides sensitivity to long T2 slow flow species, such as lymph, and we have evaluated this method 
for sensitivity to lateralizing lymphedema and MLD therapy26 (Figs. 3,4).  

 
 
 
9 
 S usc e pti bilit y w ei g ht e d i m a gi n g ( S WI) f or i d e ntific ati o n of m e d ull ar y v ei ns. W h ol e -br ai n 3 D t ur b o -
gr a di e nt -ec h o  ( T R/ T E 1/T E = 3 1/ 7. 2/ 6. 2  ms;  fli p  a n gl e = 1 7 °)  wit h  s p ati al  r es ol uti o n = 0. 6x 0. 6x 2  m m3 
(slic es = 1 3 0) will b e ac q uir e d wit h t h e s a m e slic e a n g ul ati o n as D TI.  
 Diff usi o n t e ns or i m a gi n g ( D TI) f or p eriv asc ul ar fl o w d et er mi n ati o n. W h ol e -br ai n 2 D s pi n ec h o E PI 
( T R/ T E = 1 0 0 0 0/ 6 0 ms) i n 3 2 dir ecti o ns ( 2 m m is otr o pic s p ati al r es ol uti o n) usi n g s e q u e nti al ac q uisiti o ns 
wit h b = 0 s/ m m 2, b = 1 0 0 0 s/ m m2, a n d b = 2 0 0 0 s/ m m2. 
 S pi n l a b eli n g f or c ervic al L N p erf usi o n. S pi n l a b eli n g will b e p erf or m e d wit h a n 1 1 -ms hy p ers ec a nt 
i nv ersi o n (l a b eli n g) pr e p uls e, f oll o w e d by a n i nv ersi o n ti m e r a n g e of 3 0 0 t o 2 4 0 0 ms i n 3 0 0 ms 
i ncr e m e nts, w hic h will e n a bl e bl o o d tr a nsit ti m e a n d p erf usi o n q u a ntific ati o n. Ot h er p ar a m et ers: 
l a b eli n g = S T A R; T E = 1 1 ms; s p ati al r es ol uti o n = 2x 2x 2 m m 3; av er a g es = 1 4. 
 
P E T/ C T . A si n gl e a d mi nistr ati o n of a p pr oxi m at ely o n e -ti m e i ntr a v e n o us a d mi nistr ati o n of 5 5 5 M B q ( 1 5 ± 
1. 5 m Ci) C 1 1 Pi B , t h e n a 7 0 -mi n ut e  dy n a mic  P E T/ C T  ac q uisiti o n ( 4 x 1 5, 8 x 3 0, 9 x 6 0, 2 x 1 8 0, 1 0 x 3 0 0 
s ec o n d fr a m es fr a m es) will b e p erf or m e d. I m a g es will b e r ec o nstr uct e d usi n g a n or d er e d s u bs et Esti m at e  
al g orit h m ( 4 it er ati o ns, 1 6 s u bs ets, wit h a p ost -r ec o nstr ucti o n G a ussi a n filt er of 5 m m), a n d c orr ect e d 
f or sc att er a n d att e n u ati o n. I m a g es will b e c o-r e gist er e d t o t h e hi g h s p ati al r es ol uti o n T 1-w ei g ht e d 
i m a g e as w e h a v e p erf or m e d pr e vi o usl y a n d a m e a n c ortic al:c er e b ell ar S U Vr will b e c alc ul at e d as t h e 
pri m ar y p ar a m et er of i nt er est. F or ex pl or at ory ev al u ati o n, w e will als o r ec or d S U Vr i n bi -t e m p or al, bi-
occi pit al, bi -fr o nt al, a n d bi-p ari et al l o b e s. 
 
 
E x ercis e  
 
P D c o h ort  
P ati e nts will u n d er g o a n i niti al ev al u ati o n wit h C oll e e n Bri d g es, t h e R oc k St e a dy B oxi n g i nstr uct or. E ac h 
cl ass c o nsists of 6 0 mi n ut es of i nt e ns e a er o bic ex ercis e. Of n ot e, t his cl ass is s p ecific all y d esi g n e d f or 
p ati e nts wit h g ait, b al a nc e, a n d m ot or sy m pt o ms c o m m o n t o P ar ki ns o n’s dis e as e. I n di vi d u als wit h 
s y m pt o ms t h at pr ecl u d e s af e p artici p ati o n ar e scr e e n e d o ut as p art of t h e pr o gr a m’s r o uti n e i niti al 
e v al u ati o n. All c o m p o n e nts of t h e cl ass ar e n o n -c o nt act, a n d strictl y a er o bic i n n at ur e. T h e y will r ec e iv e 
2 0  cl ass cr e dits ( ov er t w o i nst all m e nts), as t h e pr o gr a m r ec o m m e n ds att e m pti n g t o att e n d r o u g hl y t wic e 
p er w e e k . As t his is a n o bs er v ati o n al st u dy, p artici p a nts will n ot b e excl u d e d b a se d o n t h eir att e n d a nc e, 
t h o u g h t his v ari a bl e will b e m o nit or e d  t o ai d i n a n al ys es a n d i nt er pr et ati o n. As n ot e d a b ov e, a fi n al 
p hysic al ev al u ati o n will als o b e c o n d uct e d o n t h eir l ast cl ass.  
 
F oll o w -u p  
 
P D c o h ort  
Cli nic al a n d n e ur oi m a gi n g ass ess m e nts will b e c o n d uct e d wit hi n 1 w e ek of c o m pl eti o n of t h e ex ercis e 
pr o gr a m.  
 
2. 3  
E N D O F S T U D Y D E FI NI TI O N  
 
P D c o h ort  

 
 
 
10 
A participant is considered to have completed the study if he or she has completed both baseline and 
follow-up assessment phases of the study, as well as attended at least 1 of the community-based 
exercise classes.  
 
The end of the study is defined as completion of the last visit or procedure shown in the SoA in the trial 
globally. 
 
Healthy cohort 
A participant is considered to have completed the study if they have completed the BEST. 
 
3 
STUDY DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL 
 
3.1 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
 
• 
Significant study intervention non-compliance or lost to follow-up 
• 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant 
• 
Disease progression which requires discontinuation of the study intervention 
• 
If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
• 
Participant unable to complete follow-up assessments. 
The reason for participant discontinuation or withdrawal from the study will be recorded.  
 
4 
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