Clinical trial NCT05446168
Conditions: Parkinson Disease
Keywords: short chain fatty acid butyrate tributyrin functional neuroimaging
Sponsor: Nicolaas Bohnen, MD, PhD
Start date: 2022-07-01; Completion date: 2023-09-26
Enrollment: 18 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Small exploratory open-label pilot study to assess the short-chain fatty acid (SCFA) prodrug tributyrin as a potential therapy for persons with Parkinson disease

Detailed description:
The overarching goal of this small exploratory open-label pilot study is to explore metabolic (glucose metabolism, butyrate) and cognition (MoCa) before and after open-label treatment with the short-chain fatty acid (SCFA) prodrug tributyrin in a small pilot study in PD and normal control older adults. Positive findings in this small exploratory pilot trial may support target engagement study of SCFA supplementation in normal adults and PD.

Arms: arm 1: Participants will take 500mg TID tributyrin supplement for 30 days +/- 7 days. arm 2: Participants will take 500mg TID tributyrin supplement for 30 days +/- 7 days.
Interventions: intervention 1: tributyrin
Intervention descriptions: intervention 1: Post-biotic short chain fatty acid dietary supplement. Participants will take 500mg TID tributyrin supplement for 30 days +/- 7 days.

Protocol documents:
Prot_SAP_001.pdf: 
Nicolaas Bohnen, MD, Ph.D. 
UM HUM #00211320 
PROTOCOL VERSION #: 1.6 
 
1 
 
Brain Small Chain Fatty Acid Metabolism in Parkinson Disease: Tributyrin Supplementation 
NCT05446168 
7/23/2024 
 
 


Nicolaas Bohnen, MD, Ph.D. 
UM HUM #00211320 
PROTOCOL VERSION #: 1.6 
 
2 
CLINICAL PROTOCOL 
 
STUDY TITLE 
Brain Small Chain Fatty Acid Metabolism in Parkinson Disease: Tributyrin Supplementation 
Study Agents:  Tributyrin; [11C]Butyrate; [18F]FDG 
 
University of Michigan IRB HUM #00211320 
 
Principal Investigator:  
Nicolaas I Bohnen, MD, PhD  
 
Professor, Department of Radiology 
Professor, Department of Neurology 
University of Michigan 
Ann Arbor, MI  
 
Institution: University of Michigan 
 
 


Nicolaas Bohnen, MD, Ph.D. 
UM HUM #00211320 
PROTOCOL VERSION #: 1.6 
 
3 
Brain Small Chain Fatty Acid Metabolism in Parkinson's Disease: Tributyrin supplementation 
 
Cognitive decline, progressing usually to dementia, is a common and disabling feature of Parkinson's 
disease (PD).  Progression to dementia generally reflects progressive cortical pathologies.  We and 
others showed that cognitive decline is accompanied by and heralded by deficits in regional 
neocortical glucose metabolism, demonstrated with [18F]fluorodeoxyglucose (FDG) PET imaging 1, 2.  
These deficits are widely believed to reflect synaptic loss.  Convergent imaging data, however, 
suggests relative preservation of neocortical synapses with abnormal neuronal glucose metabolism.  
Recent studies of PD and Alzheimer disease (AD) subjects with synaptic terminal SV2A PET ligands 
indicate preservation of cortical synaptic terminals at early to moderate disease stages.  The major 
alternative brain energy substrate is ketone bodies that are small chain fatty acids (SCFAs).  
Comparative studies of brain SCFA and glucose uptake in Mild Cognitive Impairment and early AD 
subjects indicates relative preservation of regional brain SFCA metabolism in subjects with abnormal 
regional glucose uptake, suggesting relative preservation of synapses.   
This accumulated PET data is broadly consistent with the concept that mitochondrial dysfunction is a 
major feature of, and likely pathogenetic mechanism in, PD.  Other data suggests relevant 
dysfunction of glucose uptake and metabolism mechanisms in PD.  One implication is that enhancing 
neuronal SCFA metabolism will circumvent abnormalities of glucose uptake and initial metabolism, 
enhancing-restoring neuronal mitochondrial function.  This would potentially provide symptomatic 
benefits and might be a disease-modifying therapy (Figure 1).  There are other good reasons to 
pursue SCFA therapy in PD.  SFCAs may be significant modulators of inflammatory, oxidative, and 
transcriptional regulatory processes linked to neurodegeneration in PD (Figure 1).  Recent 
experimental work suggests important links between mitochondrial dysfunction and pathogenic 
inflammatory mechanisms in PD.  SCFA therapy may address the brain-gut axis dysbiosis that seems 
to characterize PD.    
Capitalizing on our experience with PD clinical research and development 
of novel PET methods, we propose an integrated series of experiments to 
measure brain SCFA metabolism and to assess target engagement of 
SCFA therapy in older adults and in persons with Parkinson disease (PD).   
 
Aim 1: To explore [11C]butyrate PET and [18F]FDG PET glucose 
metabolism and clinical measures before and after open-label treatment 
with the SCFA prodrug tributyrin in a small pilot study in patients with PD 
(n=8) and normal control older adults (n=2). A separate subset of 10 participants may complete the 
study without the PET or brain imaging biomarkers but using the exploratory clinical or laboratory test 
battery only for explorative reasons. 
   
 
Hypothesis 2: [11C]butyrate PET and glucose metabolism may change in the brain, liver, heart and gut 
after approximately 30-day intervention with tributyrin 500 mg t.i.d. p.o. with meals in patients with PD 
and normal older adults.    
 
Exploratory hypothesis: Tributyrin supplementation may affect measures of cognition, autonomic, sleep 
metabolic, genetic, and other measures. 
 
Impact:  Positive findings in this small exploratory pilot trial may support future target engagement 
studies of SCFA supplementation in normal adults and PD.   
 


Nicolaas Bohnen, MD, Ph.D. 
UM HUM #00211320 
PROTOCOL VERSION #: 1.6 
 
4 
 
Background 
 
Ketogenic diet and SCFA interventions in neurodegeneration: 
The ketogenic diet based on preferential intake of predominant medium and long-chain fatty acids 
and minimization of carbohydrates has become a subject of recent research in metabolic and 
neurodegenerative disorders. Preliminary positive findings have been reported mainly from short-
duration studies. Despite the benefits of this diet, health care professionals still question its safety due 
to the elevated serum ketones it induces and the limited dietary fiber intake 6. To compound the 
controversy, patient compliance with the program is poor due to the restrictive nature of the diet and 
symptoms related to energy deficit and gastrointestinal adversity during the introductory and energy 
substrate transition phase of the diet. Another class of fatty acids, so-called short chain fatty acid 
(SFCA), has been extensively studied for their role in the gut microbiome. For example SCFAs, in 
particular n-butyric acid (BA), acetic acid and propionic acid, are naturally present in the colon as a 
bacterial product of dietary fiber fermentation. Renewed interest in SCFAs has also emerged because 
of their ability to alter gene expression through histone deacetylase (HDAC) inhibition. HDAC has 
become a drug target in cancer as well as non-oncological diseases. These carboxylic acids are also 
of interest for their effects in the brain including memory enhancement and neuroprotection in rodent 
experiments 8. Animal and human ingestion studies of prebiotic fibers associated with brain health, 
such as inulin and resistant potato starch, found selective increases in the production of colonic BA 
and acetic acid 10, 11.  Similarly, intermittent fasting in MPTP-induced Parkinson's disease mice 
resulted in higher butyric acid as well as increased levels of 
BDNF 13. Although blood (and brain) levels of BA and acetic 
acid are naturally low 14, a 11C-acetate PET study in rats found 
significantly increased uptake in the brain (as well as heart and 
liver) after 8 weeks of inulin fiber supplemented feeding, see 
Figure 1 15. Effects of BA on the brain may be direct or indirect. 
Indirect actions of butyrate are believed to involve the hormono–
neuro–immuno system. For example, increased SCFA 
production in the colon may result in vagal nerve-mediated 
changes in the hypothalamus and induce blood-brain barrier 
changes. The 'gut brain axis' represents bidirectional 
communication between the gastrointestinal system and the 
brain and is based on a complex system, including the vagus 
nerve, sympathetic nerves, humoral, endocrine, and immune 
links. These observations suggest that SCFA may play a role in 
the so-called 'gut-brain axis' 19 and that interventions promoting 
SCFA may benefit patients with neurodegenerative or neuro-
inflammatory disorders.  
SCFAs can also be administered orally where gastric and  
duodenal absorption will result in increased portal vein and 
systemic plasma levels that may affect brain functions. For 
example, a 18F-FDG PET study in pigs found that 3 weeks of 
oral ingestion of sodium butyrate triggered basal brain glucose metabolism changes in the nucleus 
accumbens and hippocampus with histological evidence of increased hippocampal granular cell layer 
volume and neurogenesis 21. Intra-peritoneal administration of sodium butyrate in 6-OHDA-lesioned 
rats resulted in significant attenuation of motor deficits and increased striatal dopamine levels 22. 
Figure 2: Brain, heart and liver uptake 
of 11C-acetate before and after 8 weeks 
of inulin fiber supplemented feeding in 
rats (Frost et al. 2014 Nature 
Communications) 
 


Nicolaas Bohnen, MD, Ph.D. 
UM HUM #00211320 
PROTOCOL VERSION #: 1.6 
 
5 
Moreover, sodium butyrate treatment attenuated oxidative stress and neuro-inflammatory markers. 
These effects occur concurrently with increased global H3 histone acetylation and BDNF levels 22.  
BA and its prodrug tributyrin are naturally present in butter. In spite of its promise, systemic butyrate 
supplementation suffers from several limitations as butyrate is metabolized rapidly as soon as it 
enters the colonocyte via its active transport system 24 and resulting plasma (or brain) concentrations 
are very low. Tributyrin, a stable and rapidly absorbed prodrug of butyric acid offers several 
advantages compared to butyrate. Tributyrin is a neutral short-chain fatty acid triglyceride that is likely 
to overcome the pharmacokinetic drawbacks of natural butyrate as a drug 25. Because it is rapidly 
absorbed and chemically stable in plasma, tributyrin diffuses through biological membranes and is 
metabolized by intracellular lipases, releasing therapeutically effective butyrate over time directly into 
the cell. Compared with butyrate, tributyrin has more favorable pharmacokinetics 25, 26 and is well 
tolerated 27. Liquid tributyrin filled into gelatin capsules and administered orally resulted in millimolar 
concentrations of butyrate both in plasma and inside the cell 27. Unlike BA, tributyrin is lipophilic with a 
plasma half-life of 40 minutes making it a preferred choice for systemic oral administration. 
Overall strategy 
 
Overview  
The overarching goal of this small exploratory open-label pilot study is to explore [11C]butyrate PET   
and [18F]FDG PET glucose metabolism and clinical measures before and after open-label treatment 
with the SCFA prodrug tributyrin in a small pilot study in PD (n=8) and normal control older adults 
(n=2). Positive findings in this small exploratory pilot trial may support target engagement study of 
SCFA supplementation in normal adults and PD. PET and/or MRI Imaging protocols will be optional 
for a separate subset of 10 participants may also complete the study based on clinical or laboratory 
test battery alone for the exploratory hypothesis. 
 
Timetable: This study, to be conducted over a 2-year period, will include a net total of n=20 subjects 
(NC, n=4; PD, n=16; total net; n=20; gross n=32 to allow for attrition). Details of the enrollment and 
major test procedures are listed in table 1 below. 
 
Milestone of recruitment success are net completion of 9 persons for year 1. 
 
Table 1: Study enrollment & main 
assessments 
NC 
PD 
TOTAL 
Baseline  [11C]butyrate PET and [18F]FDG 
PET-CT & brain MRI  with baseline clinical 
assessment 
NC=2 
PD=8 
 
n=10 
Post-intervention  [11C]butyrate PET and 
[18F]FDG PET-CT & MRI  
NC=2 
PD=8 
n=10 
30-day (± 7) tributyrin intervention with 
pre/post clinical assessments) 
NC=4 
PD=16 
n=20 
Exploratory clinical and laboratory test battery 
pre and post the tributyrin supplement 
intervention 
NC=4 
PD=16 
N=20 
Total subject net  recruitment aims 1 & 2 
NC=4 
 
PD=16 
n=20* 
*Net recruitment n=20; gross recruitment to account for attrition n=32 


Nicolaas Bohnen, MD, Ph.D. 
UM HUM #00211320 
PROTOCOL VERSION #: 1.6 
 
6 
 
Design: Exploratory open-label tributyrin supplementation pilot study.  
 
Methods: After obtaining informed consent and screening for study eligibility, study participants will 
undergo the baseline clinical assessment and imaging protocol (separate days). For patients with PD 
the motor component of the test battery will be performed in the dopaminergic medication 'off' state in 
the morning after overnight withholding of their dopaminergic medications in the PD, i.e., temporarily 
postponing the morning dose until the motor exam has completed.  The remainder of the test battery 
will be performed in the medication 'on' state. Participants will also complete some testing in a fasted 
state. For participants who were not consented prior to baseline, study staff will obtain a waiver of 
consent during screening call for fasting and withholding dopaminergic medications prior to their visit. 
Qualified personnel who have been trained in the use of the instruments and have undergone inter-
rater reliability evaluations will perform the assessments.  
 
There will be a total of 5 visits for this pilot study. The first two visits will consist of the initial general 
clinical assessment (e.g., vital signs, vital capacity lung/breath holding tests) and optional imaging split 
over 2 days (no specific sequence or preset time interval).  At visit 1 participants will be instructed to 
wear physical activity and sleep trackers (called ActivPal a sensor will be put on the upper leg and a 
ring called Oura ring, which will be worn at a finger) for 1 week prior to visit 2. Participants will also wear 
a continuous glucose monitor during the same time. After the participants complete the 1 week of 
physical activity, sleep and glucose monitoring they will return for visit 3, where a limited repeat clinical 
test battery will be administered. At visit 3 the participant will also be instructed to start the 
approximately 30 day supplementation of tributyrin. The physical activity and sleep trackers and the 
continuous glucose monitor will also be worn during the last week of the tributyrin supplementation 
period. At the end of the approximately 30-day tributyrin supplementation the participants will return for 
visits 4 (repeat clinical assessment) and 5 (repeat optional imaging) again split over 2 days. There is 
no pre-set sequence which assessment (clinical or imaging) comes first. Blood and/or saliva tests will 
be collected for assessments of genetic variables (e.g. ApoE). Blood assessment will also be used for 
metabolomics. Blood continuous glucose data will be collected blinded to the participant. 
 
Details for the schedule of activities for the tributyrin supplement intervention study are shown below 
(Table 2). 
 
 
Table 2 Schedule 
of activities 
Visit 1* / 
Visit 2*: 
Baseline 
assessm
ent 
(clinical) 
 
Visit 1* / Visit 
2* 
Baseline 
assessment 
(imaging – 
OPTIONAL) 
At-home 
wearable 
sensor 
use (1 
week ± 3 
days) 
Visit 3 
Pre- 
intervention  
assessment 
At-home 
4 (± 1) week 
Tributyrin 
(500 mg tid 
po) 
intervention 
Visit 4* / Visit 
5* 
Post- 
intervention 
clinical 
assessment 
(while on 
tributyrin) 
Visit 4* / Visit 
5* 
Post- 
intervention 
imaging 
assessment 
(while on 
tributyrin, 
OPTIONAL) 
Approximate time 
commitment 
4-6 
hours 
3-6 hours 
- 
4-5 hours 
- 
4-6 hours 
3- 6 hours  
Test location 
Domino
s 
Farms 
UM hospital 
Home 
Dominos 
Farms 
Home 
Dominos 
Farms 
UM hospital 
Informed Consent 
(or prior 
eConsent) 
X 
 
 
 
 
 
 
Eligibility 
X 
 
 
 
 
 
 


Nicolaas Bohnen, MD, Ph.D. 
UM HUM #00211320 
PROTOCOL VERSION #: 1.6 
 
7 
OPTIONAL  
[11C]butyrate, 
[18F]FDG 
PET-CT 1.2 
(brain/body)* 
 
X 
 
 
 
 
X (after 
taking 
tributyrin) 
In case of  
[11C]butyrate PET, 
obtain vital signs 
pre- & post 
injection of tracer 
 
X 
 
 
 
 
X 
OPTIONAL MRI 
brain* 
 
X 
 
 
 
 
X 
DEXA Bone 
Density Scan 
X 
 
 
 
 
X 
 
Blood/saliva/urine 
sample collection1 
X 
 
 
 
 
X 
 
Continuous 
glucose monitor  
for 7±3 days 
 
 
X 
 
X (last 7 
days) 
X 
 
Sleep tracking ring 
 
 
 
X 
X 
X 
X 
 
Activity tracker for 
7±3 days 
 
 
X 
 
X (last 7 
days) 
 
 
Motor MDS 
UPDRS2 
X 
 
 
X 
 
X 
 
Balance test 
MiniBESTest 
(sensored)2 
X 
 
 
X 
 
X 
 
Pegboard testing2 
X 
 
 
X 
 
X 
 
Foot Tapping2 
X 
 
 
X 
 
X 
 
Finger Tapping2 
X 
 
 
X 
 
X 
 
Electronic Gait 
Mat/sensored 
walk2 
X 
 
 
X 
 
X 
 
Beck Depression 
Inventory II scale 
X 
 
 
X 
 
X 
 
Spielberger Trait 
Anxiety Scale 
X 
 
 
X 
 
X 
 
Sleepiness scales 
X 
 
 
 
 
X 
 
 MoCa, 
PDCRS (limited 
cognition) 
X 
 
 
X (optional) 
 
X 
 
Cognitive test 
battery 
X 
 
 
X (optional) 
 
X 
 
PCFRS functional 
scale 
X 
 
 
 
 
X 
 
Quality of life 
scale PDQ-39 
X 
 
 
 
 
X 
 
Adverse event 
assessment 
X 
 
 
X 
 
X 
 
Phone Call/Email 
Drug monitoring 
 
 
 
 
X 
 
 
Drug 
accountability 
 
 
 
X 
 
X 
X 
Pregnancy test in 
women of 
 
X 
 
X 
 
 
X 


Nicolaas Bohnen, MD, Ph.D. 
UM HUM #00211320 
PROTOCOL VERSION #: 1.6 
 
8 
childbearing 
potential 
(within 48 
hours of 
PET) 
(within 48 
hours of 
PET) 
Note 
1: Fasting in morning 
2: Dopaminergic off state in PD  
*Visits 1-2 and 4-5. There is no pre-set sequence which assessment (clinical or imaging) comes first. 
 
 
Details of the neuropsychological test battery is shown in Table 3. 
 
Outcome measures:  
 
Primary outcome measures:  
• 
[11C]butyrate uptake 
• 
Change in average blood glucose 
metabolism measured by continuous 
glucose meter 
Exploratory outcome measures: 
• 
[18F]FDG PET glucose metabolism 
• 
Cognition dependent mobility 
functions: postural sway (iSWAY), 
Timed Up and Go test (iTUG) 
measured using Mobility Lab modules 
(APDM, Inc., Portland, OR) 28-30 
• 
Dynamic balance using the Mini-
BESTest 31 
• 
Spatiotemporal gait measurements 
using Protokinetics Zeno™ Walkway 
(Protokinetics LLC, Havertown, PA) 
• 
Remainder of the clinical and laboratory test battery 
 
 
 
Tributyrin intervention aim: BA and its prodrug tributyrin are naturally present in butter. In spite of its 
promise, systemic butyrate supplementation suffers from several limitations as butyrate is 
metabolized rapidly as soon as it enters the colonocyte via its active transport system 24 and resulting 
plasma (or brain) concentrations are very low. Tributyrin is a stable and rapidly absorbed prodrug of 
butyric acid offers several advantages compared to butyrate. Tributyrin is a neutral short-chain fatty 
acid triglyceride that is likely to overcome the pharmacokinetic drawbacks of natural butyrate as a 
drug 25. Because it is rapidly absorbed and chemically stable in plasma, tributyrin diffuses through 
biological membranes and is metabolized by intracellular lipases, releasing therapeutically effective 
butyrate over time directly into the cell. Compared with butyrate, tributyrin has more favorable 
pharmacokinetics 25, 26 and is well tolerated 27. Liquid tributyrin filled into gelatin capsules and 
administered orally resulted in millimolar concentrations of butyrate both in plasma and inside the cell 
27. Unlike BA, tributyrin is lipophilic with a plasma half-life of 40 minutes making it a preferred choice 
for systemic oral administration. Tributyrin is available over-the-counter as a supplement for patients 
with inflammatory bowel disease. Healus complete biotic butyrate supplement (500 mg tributyrin per 
Table 3: Neuropsychological characterization 
Overall mental status 
Montreal Cognitive Assessment Scale 3 
PD-Cognitive Rating Scale 4  
Intelligence 
WAIS-IV: Information5 
Attention & Cognitive 
Control 
n-back test (OPTIONAL) 7, Stroop Color Word 
Interference Test 9 
WAIS-IV: Digit Span (5)  
WAIS-III: Digit Symbol-Coding 5 
Language 
Boston Naming Test (30 item) 12 
Controlled Oral Word Association Test (Phonemic & 
Semantic) 
Learning & Memory 
California Verbal Learning Test – II 16 
 
Visuospatial/Construction 
Clock drawing 17 
Benton Judgment of Line Orientation 18 
Executive/Working 
Memory 
D-KEFS: Color Word Test, Verbal Fluency Test, Trail 
Making Test, Sorting Test 20 
WAIS-IV Matrix Reasoning, Digit Backwards 5 
Information processing 
speed 
D-KEFS: Trail Making Test 20 
WAIS-III: Digit Symbol-Coding 5, 23 
Reaction time  
 


Nicolaas Bohnen, MD, Ph.D. 
UM HUM #00211320 
PROTOCOL VERSION #: 1.6 
 
9 
capsule) will be used as 1 capsule tid with meals (total of 1.5 g of tributyrin per day). If the patient 
cannot tolerate tributyrin we will lower the dose to one bid and if this is not tolerated than to once per 
day (e.g. at evening) and if this is not tolerated we will withdraw the study participant from the study. 
The participant will be asked to complete a daily drug diary while taking tributyrin. All supplement 
bottles will be returned at the end of the study for a drug accountability check. 
Magnetic resonance imaging (MRI) will be performed on a 3 Tesla Philips Achieva system (Philips, 
Best, The Netherlands). A 3D inversion recovery-prepared turbo-field-echo was performed in the 
sagittal 
plane 
using 
TR/TE/TI=9.8/4.6/1041ms; 
turbo 
factor=200; 
single 
average; 
FOV=240x200x160mm; acquired Matrix = 240x200x160 slices and reconstructed to 1mm isotropic 
resolution. Resting-state fMRI scans will serve as a secondary outcome measure and be acquired using 
a 32-channel head coil and multi-band sequence 32, with nominal parameters: (TR/TE/FA = 720/34/52, 
2mm isotropic resolution, 72 slices). Data are collected with eyes fixated on a cross for 10 minutes 33. 
Pre-processing follows our standard pipeline that includes physiologic noise reduction and thorough 
motion correction 34, 35.  Graph theory analysis will be used to identify the most highly connected nodes 
following published methods. Briefly, ROIs will be represented as nodes and pairwise correlations, 
based upon the mean time series for each ROI, will serve as weights over corresponding edges, 
thresholded by FDR correction, p<0.05 34, 35. Change from baseline will serve as the primary measure 
of interest. 
 
PET imaging will be performed in 3D imaging mode on a Biograph 6 TruePoint PET/CT scanner 
(Siemens Molecular Imaging, Inc., Knoxville, TN), which acquire 63 transaxial slices (slice thickness: 
2.4 mm) over a 15.2 cm axial field-of-view. The i.v. injection dose for [11C]butyrate PET is 18 mCi and 
for [18F]FDG is 5 mCi.  Vital signs will be obtained pre- and post-[11C]butyrate injection. Images will be 
corrected for scatter and motion. The PET imaging frames will be spatially coregistered within subjects 
with a rigid-body transformation to reduce the effects of subject motion during the imaging session 36. 
Statistical parametric mapping (SPM) software (SPM12; Wellcome Trust Centre for Neuroimaging, 
University College, London, England [https://www.fil.ion.ucl.ac.uk/spm/software/spm12/] will be used 
for PET-MRI registration using the cropped T1-weighted MR volumetric scan. Freesurfer software 
(http://surfer.nmr.mgh.harvard.edu) will be used to define cortical and subcortical volumes-of-interest 
(VOI).  
 
MRI-based PET partial volume correction: We will use the Müller-Gärtner partial volume correction 
technique, which is based on the assumption that white matter uptake is homogeneous and uses 
gray matter (GM), white matter (WM) and cerebrospinal fluid (CSF) to correct the partial volume effect 
in GM tissues 37. Using the segmented images and the assumed PET resolution, the method 
calculates the spill-out from WM to GM and subsequently subtracts it from the GM. Similarly, it also 
calculates the spill-out from the GM to the surrounding tissues and compensates for the difference to 
the GM. The result is a grey matter image with corrected activity values in all voxels.  
 
Statistical analysis 
We will use mixed linear modeling to assess for changes in butyrate and glucose metabolism before 
and after the tributyrin supplementation.  
 
As a post hoc and only exploratory analyses we will regress differences in with tributyrin-induced 
changes of the various clinical and laboratory outcome measures.  
 


Nicolaas Bohnen, MD, Ph.D. 
UM HUM #00211320 
PROTOCOL VERSION #: 1.6 
 
10
Sample size estimation: This experiment is a first in human study of this drug for treatment of glucose 
changes in a neurodegenerative condition. There is a preliminary experiment of this safe drug 
conducted in high-fat fed mice that we base our same size justification off that showed mice receiving 
tributyrin showed a reduction in glucose levels compared to a comparator arm of approximately 13% 
with a standard deviation of 9% (PMID 22621868). If estimate a similar effect size in our cohort, 
estimating a mean plasma glucose of 110mg/dl at baseline, using a power of 0.8 and a two-sided 
alpha of 0.05 for our primary analysis that will compare pre and post tributyrin, we arrive at a total 
sample size of 20.  
 
 
Pitfalls, problems and alternative strategies 
 
Ineligibility and attrition rate: 
 
Protection of Human Subjects 
 
i) Human Subjects 
Description of subject populations:  
i) 
Healthy control persons, M/F, age 45 years and over without a history of neurological or 
psychiatric disease or significant GI disease or uncontrolled medical comorbidity will be 
recruited (net n=4).  
ii) 
PD (net n=16) Diagnosis of PD in PD participants (M/F, age 45 years and over) will based 
on the United Kingdom Parkinson's Disease Society Brain Bank Diagnostic Research Criteria 
(patients with clinically significant dementia will be excluded (i.e., fails informed assent 
screening criteria and has significant evidence of iADL functions, such as ability to take own 
medications while administering the pre-consent screening questionnaire).  
 
Exclusion criteria: 
1. Exclusion: (a) subjects with contra-indications to MR imaging, including pacemakers or severe 
claustrophobia (for participants undergoing imaging); (b) Evidence of large vessel stroke or mass 
lesion on MRI; (c) Regular use of anti-cholinergic, benzodiazepines or neuroleptic drugs, (d) history of 
significant GI disease, (e) significant metabolic or uncontrolled medical cormorbidity, (f) poorly 
controlled diabetes, (g) pregnancy or breast feeding, (h) dementia requiring informed assent, (i) 
suicidal ideation. 
  
Recruitment: Subjects will be recruited from the University of Michigan Movement Disorder clinics, UM 
research studies website, and/or advertisement/flyers. 
 
ii) Sources of Materials: 
 
Information gathered specifically for this research project includes test results from clinical test scales, 
psychometric cognitive measures, neurobehavioral rating scales, clinical motor data, questionnaires,  
and data derived from the butyrate and FDG PET and from brain  MRI. 
 
iii) Potential Risks: 
 


Nicolaas Bohnen, MD, Ph.D. 
UM HUM #00211320 
PROTOCOL VERSION #: 1.6 
 
11
Confidentiality of Research Information:  The research data to be collected from subjects will consist of 
confidential information relating to clinical, motor, cognitive, neurobehavioral and neuro-imaging 
functions.  These research data are not intended for entry into the subjects’ clinical medical records.  
However, the data remain potentially discoverable. This may lead to violation of privacy and 
embarrassment of the subject. 
 
Clinical Testing: Risks in regard to the clinical assessment are limited to fatigue, frustration, discomfort, 
and momentary embarrassment that may occur when one experiences difficulty performing a task or 
learning a new skill.  
 
Risks associated with clinical, neuropsychological and behavioral testing: This study involves cognitive 
tests and questionnaires. The cognitive tests are not harmful but some people find them frustrating and 
concerning. Risks in regard to the neuropsychological and behavioral assessment are limited to fatigue, 
frustration and momentary embarrassment that may occur when one experiences difficulty performing 
a task or learning a new skill. Some people may be uncomfortable/embarrassed disclosing personal 
information or become a little nervous about memory testing, and may experience discomfort or 
become tired. Study team members are very well experienced in the assessment of older individuals 
and persons with dementia, understanding the need for breaks, gentle reassurance, or reinforcement. 
All assessments will be stopped if requested by the participant.   
 
MRI scan: There is a substantial risk to persons who have metallic objects inside their bodies, as the 
magnet in the MR scanner can cause these to move. Consequently, participants with pacemakers or 
metallic objects located in the eye, ear, brain or blood vessel walls will be excluded. Participants who 
developed claustrophobic anxiety during scanning found that this fear dissipated within 15 min while 
remaining in the scanner, or as necessary, after exiting the scanner. There also is the potential that 
imaging could reveal a previously unrecognized but pre-existing abnormality. Many such abnormalities 
are not clinically significant, but they may cause anxiety or require further investigation by a personal 
physician. If one of the investigators identifies such an abnormality, they will contact the personal 
physician, who will arrange for appropriate care. 
 
PET-CT scans & venipuncture: Insertion of a catheter for intravenous injection of the PET 
radiopharmaceutical may be commonly associated with slight pain or bruising at the puncture site and 
rare chance of infection. Participation in this research study will involve low level exposure to radiation 
associated with the PET, CT and DEXA scans.  
 
Certified staff will be in attendance at all times during the study.  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, the participant will be exposed to radiation from the two [11C]butyrate 
PET, the two [18F]FDG PET-CT and two DEXA scans. The risks associated with the amount of 
radiation exposure participants receive in this study are considered very rare and comparable to 
every day radiation exposure risks.  
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. The maximum radiation exposure (assuming a 
person will complete all 4 PET scans) a participant will receive from the CT, [11C]butyrate PET and 
[18F]FDG PET scans is equivalent to a uniform whole body dose of 21.2 mSv, which is approximately 
42.4% of the annual radiation exposure (50 mSv) permitted to radiation workers by federal 
regulations. The participant will be instructed to use the bathroom and urinate as soon as possible 


Nicolaas Bohnen, MD, Ph.D. 
UM HUM #00211320 
PROTOCOL VERSION #: 1.6 
 
12
after the PET scans to minimize bladder exposure. The radiation the participant will be exposed to 
from each DXA scan is 0.0310 mSv, which is significantly less than 1% of the permitted annual 
radiation exposure.  
 
There is no known minimum level of radiation exposure that is recognized as being totally free of the 
risk of causing genetic defects (cellular abnormalities) or cancer.  However, the risk associated with 
the amount of radiation exposure that you will receive from this study is considered to be low. The risk 
of a side effect from this level of radiation exposure is very rare. The risk from radiation exposure of 
this amount is considered to be similar to other everyday risks, such as driving a car. 
 
No PET 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 scanning session, and urine sampling may be performed on subjects at baseline and post-
interventions as an additional screening measure. 
 
Risks associated with tributryin: The risks to participants are very minimal. Although tributyrin is taken 
for symptoms of irritable or inflammatory bowel disease it is possible that nausea or indigestion may 
occur.  However, these gastrointestinal side effects are both rare and mild. Tributyrin is received 
GRAS (Generally Regarded As Safe) certification from the FDA, is commercially available in the 
United States and prior work has shown that the dosing regimen proposed in this study has been 
found to be safe and generally well-tolerated.  
 
Data Study Monitoring Plan (DSMP): Drs. Bohnen and Albin will act as the Data Safety Monitoring 
Plan members for this study. All adverse events and other study related events will be discussed at 
monthly investigator meetings. Study team will document any adverse events specifically related to 
study participation (imaging, clinical visit, at-home supplement and/or device usage, etc.). Adverse 
events will be classified according to standard criteria and reported to the IRBMED (relevant 
University of Michigan IRB) according to standard guidelines. Serious adverse events will be reported 
within 24 hours. 
For risk of suicidality (if participants select answer responses 2 or 3 for question 9 on the Beck 
Depression Inventor, i.e. 'I would like to kill myself' (answer 2) or 'I would like to kill myself if I had a 
chance' (answer 3) then the staff will hand out the UM Depression brochure, refer to the contact 
information and also inform Dr. Bohnen or Dr. Albin who will discuss this with the participant. The face 
to face conversation with the physicians must occur during that visit and must not be deferred. There 
must be a safety plan in place before the patient can leave the building. 
 
 
References 
 
1. 
Albin RL, Minoshima S, D'Amato CJ, Frey KA, Kuhl DE, Sima AAF. Fluoro-deoxyglucose positron emission 
tomography in diffuse Lewy body disease. Neurology. 1996;47:462-6. 
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Bohnen NI, Koeppe RA, Minoshima S, Giordani B, Albin RL, Frey KA, Kuhl DE. Cerebral glucose metabolic features 
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10.2967/jnumed.111.089946. PubMed PMID: 21571793. 
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Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I, Cummings JL, Chertkow H. The 
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Nicolaas Bohnen, MD, Ph.D. 
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PROTOCOL VERSION #: 1.6 
 
13
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Wechsler D. Wechsler Adult Intelligence Scale-Third Edition. San Antonio, TX: Psychological Corporation; 1997. 
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Cavaleri F, Bashar E. Potential Synergies of beta-Hydroxybutyrate and Butyrate on the Modulation of 
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Reolon GK, Maurmann N, Werenicz A, Garcia VA, Schroder N, Wood MA, Roesler R. Posttraining systemic 
administration of the histone deacetylase inhibitor sodium butyrate ameliorates aging-related memory decline in rats. 
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Matt SM, Allen JM, Lawson MA, Mailing LJ, Woods JA, Johnson RW. Butyrate and Dietary Soluble Fiber Improve 
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Baxter NT, Schmidt AW, Venkataraman A, Kim KS, Waldron C, Schmidt TM. Dynamics of Human Gut Microbiota 
and Short-Chain Fatty Acids in Response to Dietary Interventions with Three Fermentable Fibers. MBio. 2019;10(1). Epub 
2019/01/31. doi: 10.1128/mBio.02566-18. PubMed PMID: 30696735; PMCID: PMC6355990. 
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Saxton J, Ratcliff G, Munro CA, Coffey EC, Becker JT, Fried L, Kuller L. Normative data on the Boston Naming Test 
and two equivalent 30-item short forms. Clin Neuropsychol. 2000;14:526-34. 
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Zhou ZL, Jia XB, Sun MF, Zhu YL, Qiao CM, Zhang BP, Zhao LP, Yang Q, Cui C, Chen X, Shen YQ. Neuroprotection 
of Fasting Mimicking Diet on MPTP-Induced Parkinson's Disease Mice via Gut Microbiota and Metabolites. 
Neurotherapeutics. 2019;16(3):741-60. Epub 2019/03/01. doi: 10.1007/s13311-019-00719-2. PubMed PMID: 30815845. 
14. 
Kim SW, Hooker JM, Otto N, Win K, Muench L, Shea C, Carter P, King P, Reid AE, Volkow ND, Fowler JS. Whole-
body pharmacokinetics of HDAC inhibitor drugs, butyric acid, valproic acid and 4-phenylbutyric acid measured with 
carbon-11 labeled analogs by PET. Nucl Med Biol. 2013;40(7):912-8. Epub 2013/08/03. doi: 
10.1016/j.nucmedbio.2013.06.007. PubMed PMID: 23906667; PMCID: PMC3769509. 
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Frost G, Sleeth ML, Sahuri-Arisoylu M, Lizarbe B, Cerdan S, Brody L, Anastasovska J, Ghourab S, Hankir M, Zhang 
S, Carling D, Swann JR, Gibson G, Viardot A, Morrison D, Louise Thomas E, Bell JD. The short-chain fatty acid acetate 
reduces appetite via a central homeostatic mechanism. Nat Commun. 2014;5:3611. Epub 2014/05/02. doi: 
10.1038/ncomms4611. PubMed PMID: 24781306; PMCID: PMC4015327. 
16. 
Delis DC, Kramer JH, Kaplan E, Ober BA. California Verbal Learning Test Manual, Adult Version. Second ed. San 
Antonio: The Psychological Corporation; 2000. 
17. 
Freedman M, Leach L, Kaplan E, Winocur G, Shulman KI, Delis DC. Clock drawing: A neuropsychological analysis. 
New York: Oxford University Press; 1994. 
18. 
Benton AL, Hamsher K, Varney NR, Spreen O. Contributions to Neuropsychological Assessment. New York: 
Oxford University Press; 1983. 
19. 
Agusti A, Garcia-Pardo MP, Lopez-Almela I, Campillo I, Maes M, Romani-Perez M, Sanz Y. Interplay Between the 
Gut-Brain Axis, Obesity and Cognitive Function. Front Neurosci. 2018;12:155. Epub 2018/04/05. doi: 
10.3389/fnins.2018.00155. PubMed PMID: 29615850; PMCID: PMC5864897. 
20. 
Delis DC, Kaplan E, Kramer JH. Delis-Kaplan Executive Function System (D-KEFS): Examiner's manual. San 
Antonio, TX: The Psychological Corporation; 2001. 
21. 
Val-Laillet D, Guerin S, Coquery N, Nogret I, Formal M, Rome V, Le Normand L, Meurice P, Randuineau G, 
Guilloteau P, Malbert CH, Parnet P, Lalles JP, Segain JP. Oral sodium butyrate impacts brain metabolism and 
hippocampal neurogenesis, with limited effects on gut anatomy and function in pigs. Faseb j. 2018;32(4):2160-71. Epub 
2017/12/16. doi: 10.1096/fj.201700547RR. PubMed PMID: 29242276. 


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PROTOCOL VERSION #: 1.6 
 
14
22. 
Sharma S, Taliyan R, Singh S. Beneficial effects of sodium butyrate in 6-OHDA induced neurotoxicity and 
behavioral abnormalities: Modulation of histone deacetylase activity. Behav Brain Res. 2015;291:306-14. Epub 
2015/06/07. doi: 10.1016/j.bbr.2015.05.052. PubMed PMID: 26048426. 
23. 
Chriett S, Dabek A, Wojtala M, Vidal H, Balcerczyk A, Pirola L. Prominent action of butyrate over beta-
hydroxybutyrate as histone deacetylase inhibitor, transcriptional modulator and anti-inflammatory molecule. Sci Rep. 
2019;9(1):742. Epub 2019/01/27. doi: 10.1038/s41598-018-36941-9. PubMed PMID: 30679586; PMCID: PMC6346118. 
24. 
Stein J, Zores M, Schroder O. Short-chain fatty acid (SCFA) uptake into Caco-2 cells by a pH-dependent and 
carrier mediated transport mechanism. Eur J Nutr. 2000;39(3):121-5. Epub 2000/08/05. PubMed PMID: 10918994. 
25. 
Schroder C, Eckert K, Maurer HR. Tributyrin induces growth inhibitory and differentiating effects on HT-29 colon 
cancer cells in vitro. Int J Oncol. 1998;13(6):1335-40. Epub 1998/11/24. doi: 10.3892/ijo.13.6.1335. PubMed PMID: 
9824654. 
26. 
Egorin MJ, Yuan ZM, Sentz DL, Plaisance K, Eiseman JL. Plasma pharmacokinetics of butyrate after intravenous 
administration of sodium butyrate or oral administration of tributyrin or sodium butyrate to mice and rats. Cancer 
Chemother Pharmacol. 1999;43(6):445-53. Epub 1999/05/13. doi: 10.1007/s002800050922. PubMed PMID: 10321503. 
27. 
Conley BA, Egorin MJ, Tait N, Rosen DM, Sausville EA, Dover G, Fram RJ, Van Echo DA. Phase I study of the orally 
administered butyrate prodrug, tributyrin, in patients with solid tumors. Clin Cancer Res. 1998;4(3):629-34. Epub 
1998/05/14. PubMed PMID: 9533530. 
28. 
Salarian A, Horak FB, Zampieri C, Carlson-Kuhta P, Nutt JG, Aminian K. iTUG, a sensitive and reliable measure of 
mobility. IEEE Trans Neural Syst Rehabil Eng. 2010;18(3):303-10. Epub 2010/04/15. doi: 10.1109/TNSRE.2010.2047606. 
PubMed PMID: 20388604; PMCID: 2922011. 
29. 
Mancini M, Salarian A, Carlson-Kuhta P, Zampieri C, King L, Chiari L, Horak FB. ISway: a sensitive, valid and 
reliable measure of postural control. J Neuroeng Rehabil. 2012;9:59. Epub 2012/08/24. doi: 10.1186/1743-0003-9-59 
1743-0003-9-59 [pii]. PubMed PMID: 22913719; PMCID: 3481400. 
30. 
Mancini M, Fling BW, Gendreau A, Lapidus J, Horak FB, Chung K, Nutt JG. Effect of augmenting cholinergic 
function on gait and balance. BMC Neurol. 2015;15(1):264. doi: 10.1186/s12883-015-0523-x. PubMed PMID: 26697847; 
PMCID: 4690312. 
31. 
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):323-31. Epub 2010/05/13. doi: 
10.2340/16501977-0537. PubMed PMID: 20461334; PMCID: 3228839. 
32. 
Feinberg DA, Setsompop K. Ultra-fast MRI of the human brain with simultaneous multi-slice imaging. J Magn 
Reson. 2013;229:90-100. Epub 2013/03/12. doi: 10.1016/j.jmr.2013.02.002. PubMed PMID: 23473893; PMCID: 
PMC3793016. 
33. 
Patriat R, Molloy EK, Meier TB, Kirk GR, Nair VA, Meyerand ME, Prabhakaran V, Birn RM. The effect of resting 
condition on resting-state fMRI reliability and consistency: a comparison between resting with eyes open, closed, and 
fixated. Neuroimage. 2013;78:463-73. Epub 2013/04/20. doi: 10.1016/j.neuroimage.2013.04.013. PubMed PMID: 
23597935; PMCID: PMC4003890. 
34. 
Roy CW, Seed M, Kingdom JC, Macgowan CK. Motion compensated cine CMR of the fetal heart using radial 
undersampling and compressed sensing. J Cardiovasc Magn Reson. 2017;19(1):29. Epub 2017/03/21. doi: 
10.1186/s12968-017-0346-6. PubMed PMID: 28316282; PMCID: PMC5357808. 
35. 
Hillary FG, Medaglia JD, Gates KM, Molenaar PC, Good DC. Examining network dynamics after traumatic brain 
injury using the extended unified SEM approach. Brain Imaging Behav. 2014;8(3):435-45. Epub 2012/11/10. doi: 
10.1007/s11682-012-9205-0. PubMed PMID: 23138853. 
36. 
Minoshima S, Koeppe RA, Fessler JA, Mintun MA, Berger KL, Taylor SF, Kuhl DE. Integrated and automated data 
analysis method for neuronal activation studying using O15 water PET. In: Uemura K, Lassen NA, Jones T, Kanno I, editors. 
Quantification of brain function to tracer kinetics and image analysis in brain PET. Tokyo: Excerpta Medica; 1993. p. 409-
18. 
37. 
Muller-Gartner H, Links J, Prince J, Bryan R, McVeigh E, Leal J, Davatzikos C, Frost J. Measurement of radiotracer 
concentration in brain gray matter using positron emission tomography:  MRI based correction of partial volume effects. 
J Cereb Blood Flow Metab. 1992;12:571-83. 


Nicolaas Bohnen, MD, Ph.D. 
UM HUM #00211320 
PROTOCOL VERSION #: 1.6 
 
15
 

ICF_000.pdf: 
Study ID: HUM00211320   IRB: IRBMED   Date Approved: 3/9/2023   Expiration Date: 3/8/2024 
Consent Subtitle: _______ 
Page 1 of 21 
Consent Version: ____Oct 2022____ 
 
Brain Small Chain Fatty Acid Metabolism in Parkinson Disease: Tributyrin 
Supplementation (BUTTER) 
 
NCT05446168 
 
3/9/2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Study ID: HUM00211320   IRB: IRBMED   Date Approved: 3/9/2023   Expiration Date: 3/8/2024 
Consent Subtitle: _______ 
Page 2 of 21 
Consent Version: ____Oct 2022____ 
UNIVERSITY OF MICHIGAN 
CONSENT TO BE PART OF A RESEARCH STUDY 
  
1.  KEY INFORMATION ABOUT THE RESEARCHERS AND THIS STUDY   
1.1 Study title: Brain Small Chain Fatty Acid Metabolism in Parkinson Disease: Tributyrin supplementation   
1.2 Company or agency sponsoring the study: Farmer 
Family Foundation 
1.3 Principal Investigator: Nicolaas Bohnen, MD, PhD, University of Michigan, Departments of Radiology and 
Neurology, Functional Neuroimaging, Cognitive & Mobility Laboratory 
Study Coordinator: Alexis Griggs, BA, and Robert Vangel, BSc, University of Michigan, Department of Radiology, 
Functional Neuroimaging, Cognitive & Mobility Laboratory 
1.4 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.   
The investigators want to learn whether the intake of tributyrin, a small chain fatty acid that is naturally present 
in butter, may affect glucose uptake in the brain or body. The investigators also want to explore how the intake 
of the tributyrin supplement may affect cognitive (thinking), motor or other clinical functions. Clinical, motor, 
cognitive testing will be performed before and after the treatment with the approximately 30day tributyrin 
supplement. Optional brain and body glucose and butyrate PET imaging and optional brain MRI will be 
performed before and at the end of an approximately 30-day period where you will take the tributyrin 
supplement. Physical activity, sleep, and glucose levels will be monitored for a week prior to the start of the 
tributyrin supplement intake and during the last week of the supplement intake. Sleep will also be monitored 
throughout your time taking the tributyrin supplement. Physical activity and sleep will be monitored using 
wearable sensor. A glucose monitor will also be worn during the same period. If you are a person with 


Study ID: HUM00211320   IRB: IRBMED   Date Approved: 3/9/2023   Expiration Date: 3/8/2024 
Consent Subtitle: _______ 
Page 3 of 21 
Consent Version: ____Oct 2022____ 
Parkinson's disease the investigators may ask you to hold your Parkinson's disease medications in the morning 
of the imaging or clinical assessments.  
2. PURPOSE OF THIS STUDY 
2.1 Study purpose:  
This research is studying an over-the-counter supplement called tributyrin (a prodrug of butyric acid also 
known as butter acid) in older persons people or people with Parkinson's disease to learn about its safety and 
its effect on your body and brain as a treatment for Parkinson's disease or other age-related brain conditions 
that may affect cognitive or thinking functions.  This study will examine the relationship between uptake of 
glucose (sugar) in the brain and body as determined by the use of optional radiolabel PET tracer of glucose. 
Optional PET imaging is used to take pictures of the brain while you are lying in a camera following the 
intravenous injection of the radiolabeled tracer. The images will show how much glucose and/or butyrate is 
used by the brain or body.  Optional brain MRI and optional genetic analysis will also be performed before and 
after using the tributyrin supplement. 
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? 
Men and women without or with Parkinson’s disease or normal adults who are at least 45 years of age, can 
participate in this study. Participants should be willing and able to comply with study requirements. Subjects 
with other neurological (including seizures), psychiatric, or unstable medical conditions may be excluded. 
Subjects with poorly controlled diabetes will be excluded. Persons taking particular medications that might 
interfere with the research will also be excluded. In addition, subjects 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, as well as subjects with any contraindication for Positron Emission 
Tomography (PET) imaging, including significant prior participation in research procedures involving ionizing 
radiation will not be able to complete the optional imaging portion of this study. Patients who take 
benzodiazepine drugs, such as diazepam, lorazepam or clonazepam regularly are not eligible for this study. 
Pregnant or breastfeeding women are also not eligible for this study. 
3.2 How many people are expected to take part in this study? 
Up to 32 people are expected to participate in this study. We will target a minimum of 16 persons with 
Parkinson's disease and 4 normal older adults. 
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. There will be a total of 5 visits for this study. Your first 
two visits will consist of the initial clinical assessment and (optional) imaging split over 2 days. After visit 1 you 
will be instructed to wear physical activity and sleep trackers (called ActivPal a physical activity sensor will be 
put on your upper leg and a sleep tracker ring called Oura ring, which you will wear at a finger) for 1 week prior 
to visit 3. You will also wear a continuous glucose monitor during the same time. After you complete the 1 
week of physical activity, sleep and glucose monitoring, you will return for visit 3, where the clinical 


Study ID: HUM00211320   IRB: IRBMED   Date Approved: 3/9/2023   Expiration Date: 3/8/2024 
Consent Subtitle: _______ 
Page 4 of 21 
Consent Version: ____Oct 2022____ 
assessments will be repeated. At visit 3 you will also be instructed to start the approximately 30-day 
supplementation of tributyrin. You will additionally wear the Oura ring for the duration of the supplement 
regimen. The physical activity and sleep trackers and the continuous glucose monitor will also be worn during 
the last week of the tributyrin supplementation. You will return then for visits 4 (repeat clinical assessment) 
and 5 (repeat optional imaging) split over 2 days. There is no pre-set sequence which assessment (clinical or 
imaging) comes first. 
The table below provides specific details about these visits: 
Table 2 Schedule of 
activities 
Visit 1* / 
Visit 2*: 
Baseline 
assessme 
nt 
(clinical) 
Visit 1* / 
Visit  
2* 
Baseline 
assessment  
(imaging –  
OPTIONAL) 
At-home 
wearable  
sensor 
use  
(7 days ± 3 
days) 
Visit 3 
Preintervention 
assessment 
At-home 
30 (± 7) days 
Tributyrin  
(500 mg tid 
po)  
intervention 
Visit 4*/ Visit  
5* 
Postintervention 
clinical 
assessment 
(while on 
tributyrin) 
Visit 4* / Visit  
5* 
Postintervention 
imaging 
assessment 
(while on 
tributyrin,  
OPTIONAL) 
Approximate time 
commitment 
4-6 hours 
3-6 hours 
- 
4-5 hours 
- 
4-6 hours 
3- 6 hours  
Test location 
Domino’s 
Farms 
UM 
hospital 
Home 
Domino’s 
Farms 
Home 
Domino’s 
Farms 
UM hospital 
Informed Consent 
(or prior eConsent) 
X 
 
 
 
 
 
 
Eligibility 
X 
 
 
 
 
 
 
OPTIONAL  
[11C]butyrate,  
[18F]FDG 
PET-CT 1.2 
(brain/body)* 
 
X 
 
 
 
 
X (while taking 
tributyrin) 
In case of   
[11C]butyrate PET, 
obtain vital signs 
pre- & post 
injection of tracer 
 
X 
 
 
 
 
X 
OPTIONAL MRI 
brain* 
 
X 
 
 
 
 
X 
DEXA Bone Density 
Scan 
X 
 
 
 
 
X 
 
Blood/saliva/urine 
sample collection1 
(optional) 
X 
 
 
 
 
X 
 
Continuous 
glucose monitor 
for 7±3 days 
 
 
X 
 
X (last 7 
days) 
X 
 
Sleep tracking ring 
 
 
X 
X 
X 
X 
 


Study ID: HUM00211320   IRB: IRBMED   Date Approved: 3/9/2023   Expiration Date: 3/8/2024 
Consent Subtitle: _______ 
Page 5 of 21 
Consent Version: ____Oct 2022____ 
Activity tracker for 
7±3 days 
 
 
X 
 
X (last 7 
days) 
 
 
Motor MDS UPDRS2 
X 
 
 
X 
 
X 
 
Balance test  
MiniBESTest  
(sensored)2 
X 
 
 
X 
 
X 
 
Pegboard testing2 
X 
 
 
X 
 
X 
 
Foot Tapping2 
X 
 
 
X 
 
X 
 
Finger Tapping2 
X 
 
 
X 
 
X 
 
Electronic Gait  
Mat/sensored 
walk2 
X 
 
 
X 
 
X 
 
Beck Depression 
Inventory II scale 
X 
 
 
X 
 
X 
 
Spielberger Trait 
Anxiety Scale 
X 
 
 
X 
 
X 
 
Sleepiness scales 
X 
 
 
 
 
X 
 
 MoCa, 
PDCRS (limited 
cognition) 
X 
 
 
X (optional) 
 
X 
 
Cognitive test 
battery 
X 
 
 
X (optional) 
 
X 
 
PCFRS functional 
scale 
X 
 
 
 
 
X 
 
Quality of life scale  
PDQ-39 
X 
 
 
 
 
X 
 
Adverse event 
assessment 
X 
 
 
X 
 
X 
 
Phone Call / Email 
Drug monitoring 
 
 
 
 
X 
 
 
Drug accountability 
 
 
 
X 
 
X 
X 
Pregnancy test in 
women of 
childbearing 
potential 
 
X 
(within 48 
hours of 
PET) 
 
X 
 
 
X 
(within 48 
hours of PET) 
Note 
1: Fasting in morning 
2: Dopaminergic off state in people with Parkinson   
*Visits 1-2 and 4-5. There is no pre-set sequence which assessment (clinical or imaging) comes first. There may be a time 
interval of up to one month between Visits 1 and Visits 3, depending on scheduling 


Study ID: HUM00211320   IRB: IRBMED   Date Approved: 3/9/2023   Expiration Date: 3/8/2024 
Consent Subtitle: _______ 
Page 6 of 21 
Consent Version: ____Oct 2022____ 
If you are a person with Parkinson's disease and taking anti-Parkinson medications, i.e., you will be asked to 
withhold taking certain dopaminergic medications, such as Sinemet (levodopa) or Mirapex (pramipexole), on 
the morning of your testing visits at our testing site at Domino’s Farms. You also will need to withhold your 
dopaminergic medications prior to the PET scans. After completion of the clinical motor testing and the scan 
you can take the morning dose. You will also be asked to refrain from eating breakfast on the mornings of 
baseline and post-intervention testing and imaging visits.  
Clinical test days (Visits 1, 3 and 4) 
General 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. 
In addition, we will ask you for some general demographic and clinical information. Bone density and body 
tissue mass will be assessed with a DXA scanner. 
Motor 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). We will place small sensors at your 
wrist, ankles, and around your chest to measure your body movements while you perform different balance 
and gait tasks. Some of the walking may be tested while walking on an electronic gait mat. If you are a person 
with Parkinson's disease and who is taking Parkinson's medication these assessments will be performed while 
you are “off” your dopaminergic medications (withholding the morning dose prior to motor testing in the 
morning). After motor testing has completed (after about 1 hour) you can take your anti-parkinsonian 
medication. 
Cognitive and behavioral tests:  The cognitive 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. 
Genetic analysis: We are interested in investigating whether some genes may affect the clinical disease 
presentation. To this end, we are collecting saliva and/or a blood sample to analyze a sample of your DNA. If 
you decline to participate in the genetic 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 UM Human genetics 
lab or the UM Functional Neuroimaging, Cognitive & Mobility lab. Researchers will analyze the genetic samples 
for known variants in the DNA sequence. We will not be sharing the results with you. 
Samples: Blood and/or urine samples will be collected for analysis and may be used for analysis of gene 
expression (see above) and/or metabolic/inflammatory markers. We will collect approximately 80 mL or 5 
tablespoons of blood and approximately 20mL of urine. 
Optional Imaging (days 2 or 5)  
MRI scan:  MRI scans allow the investigators to visualize all the structures in the brain in great 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. 


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_________ (Initials) I agree to take part in the optional MRI scan of the brain. 
PET scans: The PET scans will allow the investigators to “see” the uptake of butyric acid and/or glucose in the 
brain and body. To establish this, in two separate sessions, a radiotracer will be injected into your vein through 
an i.v. (intravenous line or plastic “tube” inserted in an arm vein). If you choose to participate in the optional 
imaging, you will have the option of participating in one or both PET scans. 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 tracer will be injected as you lie on a table, which will move into a hollow machine resembling an 
X-ray scanner (CT or CAT). Images of your brain and upper abdomen/lower chest will be obtained over a period 
of 60 to 90 minutes. Women of childbearing potential will be required to provide a urine sample for a urine 
pregnancy test within 48 hours prior to the PET scan. If you are a person with Parkinson’s disease and who is on 
Parkinson’s medication you will be asked to withhold taking your dopaminergic medications, such as Sinemet 
(levodopa) or Mirapex (pramipexole), on the morning of your testing. You can resume these after completion of 
the PET scans. The PET scanning will be obtained after fasting for at least 6 hours. For imaging in the morning 
this will mean fasting after midnight.  
__________ (Initials) I agree to take part in the optional Butyrate PET scan. 
__________ (Initials) I agree to take part in the optional glucose PET scan. 
Testing at home 
Assessment of daily life activity and sleep: You will be asked to wear an activity monitor for a week 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 were 
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). You will also wear a ring called Oura ring to track your sleep before 
and throughout your time taking the tributyrin supplement. The 1-week activity monitoring will be repeated 
during the last week of the approximately 30-day tributyrin supplement intake. 
Continuous glucose monitor: The continuous glucose monitor will be worn at your lower abdomen. The 
continuous glucose monitor will be inserted using an automatic applicator that you put over the skin and press 
a button. The inserted sensor filament will be covered by a water-resistant cover so you can take a bath, 
shower or swim if you want. The sensor is contained in a bandaid and can be removed the same way as 
removing a regular bandaid. 
30 days (± 7) tributyrin supplementation 
Tributyrin is a triglyceride (fatty acid) that is naturally present in butter. Once absorbed tributyrin is broken 
down in three butyric acid (butyrate) molecules. Tributyrin has been determined to be Generally Recognized as 
Safe (GRAS) for use as a food ingredient in the US by the FDA. Tributyrin is available over-the-counter as a 
supplement. You will take 500 mg capsule three times per day by mouth (total of 1.5 grams per day). This daily 
dosage is equivalent to the amount of tributyrin that is naturally present in approximately two tablespoons of 
butter. 


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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.  
If you are a woman who is sexually active and have not yet gone through menopause, you will need to assure 
the study team that you will avoid pregnancy through using abstinence or an effective family planning method. 
We will administer a pregnancy test prior to taking the study medication. This will usually be performed at the 
time of the PET scans before starting the study medication.  
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. 
We will also contact you during the study to monitor how things are going.  
Please bring back any left-over capsules at the end of the study and hand them to the research staff. 
Some assessments throughout this protocol may be performed remotely using Zoom for Health at U of M. 
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 in Ann Arbor. PET and MRI imaging will take place at the 
University of Michigan Health System Hospital (University Hospital). 
There will be a total of 5 study visits (or 3 study visits for participants who choose not to participate in the 
optional imaging visits) as listed in the schedule of activities table above. The table also contains information 
about the approximate time commitment per study. If all the study procedures cannot be completed in one 
visit, you may be asked to return to complete the procedures or, if possible, to conduct them by phone. The 
table also lists information about the 1 week physical activity, sleep and continuous glucose monitoring. 
4.3 When will my participation in the study be over?  
The study will be over after you have completed all study visits and have returned the left-over tributyrin 
capsules to the study team. 
4.4 What will happen with my information and/or biospecimens used in this study? 
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.  
_________ (initials) I consent to having my coded research data (i.e. data without my name included) shared 
with researchers and data-repositories inside or outside of the University of Michigan. I understand that if I 


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withdraw my permission, a reasonable effort will be made by the investigators to remove the research data or 
prevent it from being used; however, this may not always be possible. 
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? 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); Very Rare 
- occurring in less than 0.1% of people (fewer than 1 in 1,000 persons). 
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 PET and 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. 
- 
If you are a person with Parkinson's disease taking Parkinson's medications there is an infrequent 
chance that you may develop "freezing" symptoms when you do not take your dopaminergic 
medication, which is caused by stiffening of your muscles making movements more difficult. You may 
require additional assistance from your caretaker during this time. 
Any risk of adverse effects will be minimized by careful supervision during test procedures that are being 
conducted when are withdrawn of your dopaminergic medications. You will be instructed to resume taking your 
dopaminergic medications after the completion of the testing. If the withdrawal of medication is intolerable, 
you may resume taking medication and withdraw from this study at any time. 


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- 
During the course of the study you may receive several blood draws, intravenous (iv) catheters, and 
injections for the PET radiotracer.  There is an infrequent risk of bruising, bleeding, infection, or 
soreness at the injection site. There is a very rare risk for infection. There is a rare risk that you may 
feel dizzy, lightheaded, or faint after an injection. 
Blood drawing, iv catheter insertions, and injections will be performed by a certified and experienced research 
technician or other health care professional who is also trained in blood borne pathogens control. Aseptic 
techniques will be used in accordance with University of Michigan guidelines. You can lie down if you feel dizzy, 
lightheaded or faint after an injection. 
- 
None of the test results, brain images, and procedures in this study will be reviewed or interpreted for 
making a medical diagnosis. For example, there is the potential that the MRI scan may reveal an 
abnormality that is already in your body, such as a cyst or tumor. Any result or abnormality that would 
be indicative of current or future disease will most likely not be discovered. 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. 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 an infrequent 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. 
- 
Risks associated with the dual-energy X-ray absorptiometry (DXA) scan are described below under the 
header “PET scans.” 
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. 


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Cognitive, 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. 
Tributyrin side-effects: 
Tributyrin is usually well tolerated. However, possible infrequent side-effects may include mild nausea, 
indigestion, feeling bloaty, heartburn, loose bowel movements, constipation, passing gas, headache, 
dizziness/lightheadedness, or sleep changes. There is a rare risk of allergy. Tributyrin may cause a butter-like 
odor. 
MRI scan: 
- 
There is an infrequent risk of finding an unexpected abnormality in the scan. We will discuss this with 
you and with your permission can also discuss it with your doctor. 
- 
There is an infrequent 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 a 
technician throughout the study, and you will be able let him/her know right away if you want to stop the study 
and get out of the scanner. At your request, you may be provided with a mild sedative; however, you must have 
made prior arrangements to be driven home by an accompanying adult. 
- 
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. 
- 
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. 


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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. The radiologist may order 
an X-ray to make sure there are no metallic fragments in your eyes or chest. 
PET scans: 
- 
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. 
The use of [11C]butyrate PET  is considered to be generally safe and effective as approved by the University of  
Michigan Radioactive Drug Research Committee in accordance with Food and Drug Administration regulations 
(21 CFR 361.1).  The use of [18F]FDG PET is considered to be generally safe.  Certified staff will be in attendance 
at all times during the study.  A physician will be available and an emergency cart is located in the PET Facility 
for treatment of any adverse reactions that may occur. 
During the course of this study, you will be exposed to radiation from the CT scan (embedded in the PET 
scanner) and the [11C]butyrate PET, [18F]FDG radiotracer PET, and two DEXA scans. The risks associated with the 
amount of radiation exposure participants receive in this study are considered very rare and comparable to 
every day radiation exposure risks. 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. 
The potential 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. The radiation exposure you will receive from the [11C]butyrate 
PET, and [18F]FDG PET scan is equivalent to a uniform whole body dose of 21.2 mSv, which is approximately 
42.4 % of the annual radiation exposure (50 mSv) permitted to radiation workers by federal regulations. This 
amount is approximately 7.1 times the average annual natural background radiation exposure, which is 3 mSv 
per year. You will be instructed to use the bathroom and urinate as soon as possible after the PET scans in order 
to minimize bladder exposure. The radiation you will be exposed to from each DXA scan is 0.0310 mSv, which is 
significantly less than 1% of the permitted annual radiation exposure. 
There is no known minimum level of radiation exposure that is recognized as being totally free of the risk of 
causing genetic defects (cellular abnormalities) or cancer.  However, the risk associated with the amount of 
radiation exposure that you will receive from this study is considered to be low. The risk of a side effect from 
this level of radiation exposure is very rare. The risk from radiation exposure of this amount is considered to be 
similar to other everyday risks, such as driving a car. 
 
- 
No PET 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 scanning session. 
Assessment of daily life and sleep activity: 
- 
There is a very rare risk of the movement monitor (actigraphy) detaching, which may result in 
tripping during the daily life monitoring of overall movement (actigraphy). It should be noted that the 
actigraphy device only measures overall movement. It does not record your geographical location or 


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specific activities that you were performing, nor can this be derived at a later point from the data 
that is stored in the actigraphy device. 
You will receive instruction for proper attachment of the actigraphy device. 
- 
Wearing the Oura ring sleep/physical activity tracker is not likely to pose significant risks. 
Like with every ring you may wear on a finger there is a small risk that the ring may feel tight or you may 
have difficulties removing it from the finger. You will be individually fitted for the ring to minimize the risk. 
Continuous glucose monitoring: 
- 
There is a small risk of pain when applying the sensor. You may occasionally feel a tinge of pain or 
discomfort when wearing the monitor. There is an infrequent risk of an allergic skin reaction or skin 
irritation to the covering tape. Signs of skin irritation will disappear once you remove the sensor. 
Genetic Analysis 
- 
It is possible that our genetic analysis may reveal a mutation of clinical relevance or unclear clinical 
significance. However, the genetic testing we will perform will not be utilized for clinical purposes 
(strictly for research purposes). The results of these tests will not be shared with you. 
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 potentially receive a benefit of better sleep or better bowel functions when taking tributyrin. 
Otherwise, you may not receive any personal benefits from being in this study. Participation in this study may 
provide important new insights into better treatment options of Parkinson’s disease. This may ultimately result 
in development of treatments for this disorder. 
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. 


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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 Parkinson disease. 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.  
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 researchers’ number listed in section 10.1. 
The study team has given you instructions about this research study. It is important that you follow these 
instructions carefully. If you get sick, have a medical complication, or are injured as a result of your being in the 
study, call Dr. Nicolaas Bohnen immediately, at 734-998-8400. The doctor will either treat you or send you to 
another doctor for treatment. You will get free medical care at the UMHS for any hospitalization or ER visit 
caused by the study drug, device, or procedure. The UMHS and the study doctor are responsible for 
determining whether your condition was the result of your participation in the study. The UMHS will pay for 
your hospitalization or ER visit only if the need for treatment has been caused by the study drug, device or 
procedure. This means that you or your health plan must pay for any treatment that is part of your usual 
medical care or that is related to a medical condition you had before participating in the study. It is not the 


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general policy of the federal funding agencies to compensate or provide medical treatment for human subjects 
in federally funded studies. 
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 and PET 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. 
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. 
8.2 Will I be paid or given anything for taking part in this study? 
You will receive $100 for each of the clinical testing visits (total of $300 for visits 1, 3 and 4)  
You will receive $50 per completed PET or MRI scan ( up to $150 for each of visit 2 or 5; combined total of 
$300). 
You will receive a total of $50 for each week of the physical activity, sleep and glucose monitoring; combined 
total of $100 for the two weeks. 
You will receive $100 for the completion of the approximate 30-day of tributyrin supplementation. 
Compensation for your time and effort after full study completion may total a maximum of $800. 
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. 


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If you receive payment of $600 or more for taking part in this study, the University of Michigan accounting 
department will collect your name, address, social security number, payment amount, and related information. 
For tax reporting purposes this information must be sent to the Internal Revenue Service (IRS). 
8.3 Who could profit or financially benefit from the study results? 
Researchers conducting the study, the University of Michigan, and other researchers that obtain your 
deidentified 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. 
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?  
The information below describes how your privacy and the confidentiality of your research records will be 
protected in this study. 
9.1 How will the researchers protect my privacy? 
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 locations 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 
Xrays for MRI screening purposes or a urine pregnancy test is ordered, the order requisition and test results 
may become part of your regular medical record. 
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 


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• 
Federal employees receiving care through the Federal Employees Health Benefits Plans 
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.  Information 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.) 
• 
All records relating to your condition, the treatment you have received, and your response to the 
treatment 
• 
Mental health care records (except psychotherapy notes not kept with your medical records) 
• 
Alcohol/substance abuse treatment records 
• 
Demographic information 
• 
Personal information 
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 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). 
 
• 
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.  


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


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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 Coordinators: Alexis Griggs and Robert Vangel 
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 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:  US Country Code: 001) 
Fax: 734-763-1234 e-mail: 
irbmed@umich.edu  
If you are concerned about a possible violation of your privacy or concerned about a study you may contact the 
University of Michigan Health System Compliance Help Line at 1-866-990-0111. 
When you call or write about a concern, please provide as much information as possible, including the name of 
the researcher, the IRBMED number (at the top of this form), and details about the problem.  This will help 
University officials to look into your concern.  When reporting a concern, you do not have to give your name 
unless you want to. 
11.  RECORD OF INFORMATION PROVIDED 
11.1 What documents will be given to me? 
Your signature in the next section means that you have received copies of all of the following documents: 
 This signed and dated informed consent document, “Consent to be Part of a Research Study”). (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 


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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. 
Legal Name: ________________________________________________________________________ 
Signature: _________________________________________________________________________ 
Date of Signature (mm/dd/yy): ________________________ 
Consent for Participating in Genetic Analysis 
This project involves optional participation in the genetic analysis.  I understand that it is my choice 
whether or not to take part in the genetic analysis.  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 genetic analysis. 
_____ Yes, I agree to take part in the optional genetic analysis. 
_____ No, I do not agree to take part in the optional genetic analysis. 
Legal Name: ________________________________________________________________________ 
Signature: _________________________________________________________________________ 
Date of Signature (mm/dd/yy): ________________________ 
  


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