Conditions: Mild Cognitive Impairment
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 11
Healthy volunteers: no

Brief summary:
The proposed study aims to use 11C-acetate position emission tomography/computed tomography (PET/CT) to preliminarily test and validate methods for imaging astrocyte activation as an early indicator of neuroinflammation in Alzheimer's disease (AD). 11C-Acetate PET/CT has been shown to quantify astrocyte activation in vivo, but no reports have evaluated its potential in AD. The investigators propose to test 11C-Acetate PET/CT as a marker for astrocyte activation associated with pathologic amyloid deposition in AD. The investigators will compare binding between subjects with early stage AD and healthy controls. Further, the investigators will investigate the correlation between amyloid and acetate binding. If the investigators find increased astrocyte activation in response to cerebral amyloid by showing a group difference in brain acetate uptake between disease and controls or a strong correlation between acetate and amyloid PET/CT binding. Validating neuroinflammation markers in AD ultimately may guide therapeutic modulation of beneficial and damaging neuroinflammation to slow disease progression, as well as providing new insights into AD pathophysiology.

Detailed description:

Arms:
arm 1: Patients with Mild Cognitive Impairment (MCI) (up to 14) will be recruited primarily from the Penn Memory Center (PMC). Clinical diagnostic criteria (described in further detail in Study Procedures section) will be used to identify subjects who are meet criteria for amnestic MCI. Participants will receive injection of radioactive tracer 11C-acetate and complete a PET/CT scan. arm 2: Normal control subjects in the same age range (up to 6) will be recruited from a current ongoing study investigating neuroinflammation in late life depression and healthy controls, from the control group in which all subjects receive MRI and lumbar puncture (LP) and from the PMC research cohort. Participants will receive injection of radioactive tracer 11C-acetate and complete a PET/CT scan.

Interventions: intervention 1: 11C-acetate
Intervention descriptions: intervention 1: Participants will receive injection of radioactive tracer 11C-acetate and complete a PET/CT scan.

Protocol document:
Prot_SAP_000.pdf: 
  
CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized in writing by the study 
sponsor 
CLINICAL RESEARCH PROTOCOL 
 
 
 
 
11C-ACETATE PET/CT IMAGING AS A MARKER OF AMYLOID-
INDUCED NEUROINFLAMMATION 
. 
 
 
 
Principal Investigator: 
Ilya Nasrallah, MD, PhD 
Assistant Professor of Radiology 
University of Pennsylvania 
Department of Radiology 
3400 Spruce Street 
Philadelphia, PA 19104 
215-615-8054 
 
 
Sub-Investigators: 
 
 
 
 
 
 
 
 
IND Sponsor: 
Yvette Sheline, MD, Psychiatry 
David Mankoff, MD, PhD, Radiology 
David Wolk, MD, Neurology/Penn Memory Center 
Jacob Dubroff, MD, PhD, Radiology 
Robert Doot, PhD, Radiology 
 
 
 
The Department of Radiology, University of Pennsylvania, 
School of Medicine 
 
 
Study Product: 
 
 
[11C]acetate 
 
Protocol Number: 
 
IRB # 824822 
 
IND Number: 
 
119, 179 
 
 
 
 
 
 
 
 
 
 
Current Protocol Version Date: 
October 27, 2017 
Previous Protocol Version date: 
August 31, 2017 
 
 


11C-Acetate PET/CT in neuroinflammation 
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CONFIDENTIAL 
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Table of Contents 
 
STUDY SUMMARY ...................................................................................................................................... 1 
1. 
BACKGROUND ................................................................................................................................... 3 
1.1. 
INVESTIGATIONAL AGENT ................................................................................................................ 3 
1.2. 
RATIONALE..................................................................................................................................... 4 
1.3. 
RISK/BENEFIT ASSESSMENT ............................................................................................................ 5 
2. 
STUDY OBJECTIVES ......................................................................................................................... 7 
2.1. 
PRIMARY OBJECTIVE ...................................................................................................................... 7 
2.2. 
SECONDARY OBJECTIVES ............................................................................................................... 7 
3. 
STUDY DESIGN ................................................................................................................................... 7 
4. 
PARTICIPANT SELECTION ................................................................................................................ 9 
4.1. 
INCLUSION CRITERIA FOR COHORT 1: AMNESTIC MCI ...................................................................... 9 
4.2. 
INCLUSION CRITERIA FOR COHORT 2: NORMAL CONTROL ................................................................. 9 
4.3. 
INCLUSION CRITERIA FOR COHORT 3 (COGNITIVELY NORMAL AMYLOID POSITIVE) .............................. 9 
4.4. 
EXCLUSION CRITERIA (FOR ALL COHORTS).................................................................................... 10 
4.5. 
SUBJECT RECRUITMENT AND SCREENING ...................................................................................... 10 
4.6. 
SUBJECT WITHDRAWAL ................................................................................................................ 11 
5. 
INVESTIGATIONAL AGENT ............................................................................................................. 12 
5.1. 
DESCRIPTION ............................................................................................................................... 12 
5.2. 
PREPARATION OF STUDY DRUG .................................................................................................... 12 
5.3. 
RECEIPT OF STUDY DRUG 11C-ACETATE ........................................................................................ 12 
5.4. 
STUDY DRUG ADMINISTRATION: 11C-ACETATE ................................................................................ 12 
6. 
STUDY PROCEDURES AND STUDY CALENDAR ......................................................................... 13 
6.1. 
INITIAL SCREENING AND BASELINE VISITS PRIOR TO 11C-ACETATE PET/CT SCAN.............................. 14 
6.2. 
DAY OF 11C-ACETATE PET/CT SCAN ............................................................................................. 17 
7. 
IMAGE INTERPRETATION ............................................................................................................... 18 
7.1. 
11C-ACETATE PET/CT IMAGE ANALYSIS ........................................................................................ 18 
7.2. 
MEASUREMENT OF EFFECT ........................................................................................................... 18 
8. 
STATISTICAL PLAN ......................................................................................................................... 19 
8.1. 
SAMPLE SIZE DETERMINATION ...................................................................................................... 19 
8.2. 
STATISTICAL METHODS ................................................................................................................. 19 
8.3. 
SUBJECT POPULATION(S) FOR ANALYSIS ....................................................................................... 19 
9. 
ADVERSE EVENTS ........................................................................................................................... 19 
9.1. 
DEFINITIONS ................................................................................................................................. 19 
9.2. 
RECORDING OF ADVERSE EVENTS ................................................................................................ 21 
9.3. 
REPORTING OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ................................................ 22 
9.3.1. 
Investigator Reporting: Notifying the Study Sponsor ................................................. 22 
9.3.2. 
Investigator Reporting: Notifying the Penn IRB .......................................................... 22 
9.3.3. 
SPONSOR REPORTING ............................................................................................................. 24 
Notifying the FDA ............................................................................................................................. 24 
9.4. 
MEDICAL MONITORING .................................................................................................................. 25 
10. 
DATA HANDLING AND RECORD KEEPING .......................................................................... 25 
10.1. 
CONFIDENTIALITY ......................................................................................................................... 25 
10.2. 
SOURCE DOCUMENTS ................................................................................................................... 26 
10.3. 
RECORDS RETENTION .................................................................................................................. 26 


11C-Acetate PET/CT in neuroinflammation 
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11. 
STUDY MONITORING, AUDITING, AND INSPECTING .......................................................... 26 
11.1. 
STUDY MONITORING DEFINITION ................................................................................................... 26 
11.2. 
STUDY MONITORING ..................................................................................................................... 27 
11.3. 
DOCUMENTATION OF THE MONITORING VISIT ................................................................................. 28 
11.4. 
AUDITING AND INSPECTING ........................................................................................................... 28 
12. 
ETHICAL CONSIDERATIONS .................................................................................................. 28 
13. 
SUBJECT STIPENDS OR PAYMENTS .................................................................................... 29 
14. 
REFERENCES ........................................................................................................................... 29 
 
 
 
 
 
 
 
 
 


11C-acetate PET/CT in neuroinflammation  
 
page 1 
CONFIDENTIAL 
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sponsor 
Study Summary  
 
Title 
11C-Acetate PET/CT Imaging as a Marker of Amyloid-Induced Neuroinflammation 
Short Title 
11C-Acetate PET/CT in neuroinflammation 
Protocol Number 
IRB #824822 
Study Design 
Subjects will be part of one of the following cohorts:  
 
– Cohort 1: Patients with Mild Cognitive Impairment (MCI) (up to 14) will 
be recruited primarily from the Penn Memory Center (PMC). Clinical 
diagnostic criteria (described in further detail in Study Procedures 
section) will be used to identify subjects who are meet criteria for 
amnestic MCI. 
– Cohort 2: Normal control subjects in the same age range (up to 6) will 
be recruited from a current ongoing study investigating 
neuroinflammation in late life depression and healthy controls, from the 
control group in which all subjects receive MRI and LP (IRB 819654) 
and from the PMC research cohort.  
– Cohort 3: Cognitively normal subjects with a positive Amyloid PET (up 
to 5) may be recruited through other ongoing studies or PMC research 
cohort 
 
Screening assessments may take place over several days and may include 
demographic information, neurocognitive testing, with focus on language and 
visuospatial/ visuoperceptual measures; if available within 6 months of the study 
entry these tests may not be repeated. Amyloid brain PET/CT scan (required for 
Cohort 1 and  Cohort 3 only ) will be completed within 6 months prior to the 11C-
Acetate PET/CT, these scans may be done as part of this research protocol or they 
may be completed as part of another research study or clinical care, the images 
and reports for these scans will be reviewed. If the Amyloid brain PET/CT is done 
as part of this research study it will be done according to standard clinical 
procedure, using the FDA approved amyloid radiotracer, 18F-Florbetaben 
(Neuraceq). 
 
If the subject does not have a Brain MRI that is deemed acceptable for use for this 
study within 6 months of 11C-Acetate PET/CT they will be asked to undergo a 
research Brain MRI after they have consented for this study.  
 
Positron emission tomography/Computed Tomography (PET/CT) imaging will be 
used to evaluate the brain using the investigational radiotracer 11C-Acetate. All 
patients will undergo a dynamic brain PET/CT scan approximately 60 minutes 
starting at the time of injection of 11C-Acetate.  
 
Some subjects may be asked to undergo an optional cerebrospinal fluid (CSF) 
collection by lumbar puncture (LP) for additional research testing. Subjects have 
already undergone CSF collection clinically or as part of another study will not be 
asked to repeat these procedures. 
Study Center(s) 
University of Pennsylvania 
Objectives 
Primary Objective 
• 
Evaluate whether 11C-acetate uptake is increased in amyloid positive 
Mild Cognitive Impairment (MCI) subjects compared to amyloid 
negative healthy controls 


11C-Acetate PET/CT in neuroinflammation 
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CONFIDENTIAL 
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Secondary Objectives 
• 
Correlate 11C-acetate uptake to areas of greater amyloid plaque 
burden quantified on Amyloid PET/CT  
• 
Compare 11C-acetate in areas of mildly elevated PET SUVR to areas 
with high or sub-threshold amyloid burden 
• 
Correlate 11C-acetate uptake to levels of inflammatory markers in CSF 
Number of Subjects 
Up to 30 subjects may be enrolled, however, if a subject in the MCI cohort 
undergoes an Amyloid brain PET/CT scan as part of this study and it is deemed 
negative that subject will be considered non-evaluable and will be withdrawn from 
the study and replaced in the enrollment. The target enrollment is 25 evaluable 
subjects. 
Diagnosis and Main 
Inclusion Criteria 
Inclusion Criteria for Cohort 1: (amnestic MCI) 
1. Participants will be at least 55 years of age An Amyloid brain PET/CT is 
required. If a Amyloid brain PET/CT has been performed within 6 months 
of enrollment to this study and of adequate quality that scan may be used 
for the study analysis, subjects who do not have a Amyloid brain PET/CT 
will undergo an Amyloid brain PET/CT as a part of this study 
2. Mini-mental status examination (MMSE) score ≥ 24 at screening visit 
3. A brain MRI is required. If a brain MRI has been performed within 6 
months of 11C-Acetate PET/CT and of adequate quality that scan may be 
used for the study analysis, subjects who do not have a brain MRI will 
undergo a brain MRI as a part of this study 
4. Participants must identify a study partner who is willing to accompany the 
patient to study visits 
5. Participants must be informed of the investigational nature of this study 
and provide written informed consent in accordance with institutional and 
federal guidelines prior to study-specific procedures. If the patient is unable 
to provide informed consent, the patient’s legal representative may 
consent on behalf of the patient but the patient will be asked to confirm 
assent. 
 
Inclusion Criteria for Cohort 2 (Normal Control) 
1. Participants will be at least 55 years of age 
2. History of negative brain amyloid PET/CT scan within 6 months of study 
screening OR negative CSF analysis for AD biomarkers within 6 months of 
study screening 
3. Mini-mental status examination (MMSE) > 27 at screening visit 
4. A brain MRI is required. If a brain MRI has been performed within 6 
months of enrollment to this study and of adequate quality that scan may 
be used for the study analysis, subjects who do not have a brain MRI will 
undergo a brain MRI as a part of this study 
5. Participants must be informed of the investigational nature of this study 
and provide written informed consent in accordance with institutional and 
federal guidelines prior to study-specific procedures.  
 
Inclusion Criteria for Cohort 3 (Cognitively normal Amyloid positive) 
1. Participants will be at least 55 years of age 
2. History of positive brain amyloid PET/CT scan within 6 months of study 
screening  
3. Mini-mental status examination (MMSE) > 27 at screening visit 


11C-Acetate PET/CT in neuroinflammation 
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CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized by the study sponsor 
4. A brain MRI is required. If a brain MRI has been performed within 6 
months of enrollment to this study and of adequate quality that scan may 
be used for the study analysis, subjects who do not have a brain MRI will 
undergo a brain MRI as a part of this study 
5. Participants must be informed of the investigational nature of this study 
and provide written informed consent in accordance with institutional and 
federal guidelines prior to study-specific procedures.  
 
Exclusion Criteria (for both cohorts) 
1. Inability to tolerate or contraindication to imaging procedures (PET/CT or 
MRI) in the opinion of an investigator or treating physician 
2. History of stroke or other neurological disease that in the opinion of the 
investigator might interfere with evaluation of the 11C-Acetate scan 
3. Any medical or psychological conditions that, in the opinion of the 
investigator, would compromise the subject’s safety or successful 
participation in the study. 
 
Study Product 
[11C]Acetate 
Statistical 
Methodology 
Several methods for acetate binding quantification will be tested and compared; 
optimal quantification will be the simplest model that shows strong correlations 
between acetate binding and amyloid SUVR. 11C-Acetate binding and amyloid 
SUVR will be analyzed using PMOD for modeling and static uptake estimates and 
Statistical Parametric Mapping using T1 MRI for co-registration and template-
based regional segmentation. We will compare and correlate amyloid and acetate 
quantification using both Pearson’s correlation and non-parametric Spearman’s 
correlation.  
 
The expected positive correlation between acetate binding and CSF cytokine levels 
will be evaluated. Global, regional and voxel based correlations will be performed 
between acetate uptake and amyloid PET SUVR from MCI subjects. Acetate 
binding in voxels with amyloid SUVR below, between 100-125%, or above 125% of 
previously validated thresholds19,20 will also be compared. 
 
 
 
 
This document is a protocol for a human research study. This study is to be conducted 
according to US and international standards of Good Clinical Practice (FDA Title 21 part 312 
and International Conference on Harmonization guidelines), applicable government regulations 
and Institutional research policies and procedures.  
 
1. Background 
1.1. Investigational Agent  
 
11C-Acetate is a radiolabeled imaging agent that has been used for studying tumor cells, 
myocardial oxidative metabolism and also has been shown to quantify astrocyte 
activation with positron emission tomography (PET/CT). Acetate metabolism has long 
been linked to astrocyte activation1,2 brain metabolism is highly compartmentalized and 
acetate is actively taken up by astrocytes and used for energy metabolism and lipid 
synthesis. The latter mechanism accounts for trapping of radiolabel in 11C-Acetate 


11C-Acetate PET/CT in neuroinflammation 
Page 4 
 
CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized by the study sponsor 
PET/CT3 which can be quantified by both static uptake measures and kinetic analysis. 
This approach has been used to demonstrate astrocyte activation in multiple sclerosis 4 
and alcoholism 5. Acetate PET/CT allows quantification of astrocyte activation without 
perturbing brain metabolism due to the tracer doses used for PET/CT, operating well 
below physiologic substrate concentrations.  
 
This proposed protocol will test 11C-Acetate PET/CT as a marker for astrocyte activation 
associated with pathologic amyloid deposition in AD. Validating neuroinflammation 
markers in AD ultimately may guide therapeutic modulation of beneficial and damaging 
inflammatory responses to slow disease progression, as well as providing new insights 
into AD pathophysiology.   
1.2. Rationale 
 
Alzheimer disease (AD), the most common neurodegenerative cause of dementia, 
affects millions of Americans with prevalence that will dramatically increase as the 
population ages. AD is associated with two abnormal protein aggregates: amyloid 
plaques and tau neurofibrillary tangles, which spread across the brain as the disease 
progresses, however the precise mechanism of pathogenesis remains unknown. A likely 
precipitant or accelerant of AD neurodegeneration is neuroinflammation6. Glia, including 
astrocytes, which have myriad functions to support neuron and brain function, are 
mediators of neuroinflammation. Prior studies suggest that inflammation may have 
beneficial and detrimental effects on the brain. Astrocytes were noted to be increased in 
AD in the original observations by Alois Alzheimer, and subsequently demonstrated to 
be both associated with amyloid plaque and displaying ability to degrade them7,8. Thus, 
reactive astrocytosis may be in part beneficial. However, chemokine-induced 
inflammation, which induces activation of microglia, the macrophages of the CNS, also 
causes neuronal damage. 
 
 
Efforts to image neuroinflammation in AD have recently intensified9 10,11. Based on the 
precedent of amyloid PET/CT, which profoundly increased our understanding of the 
biology of AD, and the emergence of tau PET/CT, such efforts are likely to provide 
critical understanding of the link between proteinopathy and neuroinflammation in AD 
pathophysiology. Much effort thus far has investigated the Translocator protein (TSPO), 
expressed by microglia9,10 11,12, including showing an inflammatory response the pre-
dementia Mild Cognitive Impairment (MCI) phase of AD13. However, targeting microglia 
does not investigate the full spectrum of neuroinflammation, particularly the potentially 
beneficial astrocyte response.  
 
Our proposed study aims to use 11C-acetate PET/CT to preliminarily test and validate 
methods for imaging astrocyte activation as an early indicator of neuroinflammation in 
AD. 11C-Acetate PET/CT has been shown to quantify astrocyte activation in vivo, but no 
reports have evaluated its potential in AD. We propose to test 11C-Acetate PET/CT as a 
marker for astrocyte activation associated with pathologic amyloid deposition in AD. We 
will compare binding between subjects with early stage AD and cognitively normal 
subjects with positive Amyloid PET and healthy controls. Further, we will investigate the 
correlation between amyloid and acetate binding. If we find increased astrocyte 
activation in response to cerebral amyloid by showing a group difference in brain acetate 
uptake between disease and controls or a strong correlation between acetate and 
amyloid PET/CT binding. Validating neuroinflammation markers in AD ultimately may 


11C-Acetate PET/CT in neuroinflammation 
Page 5 
 
CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized by the study sponsor 
guide therapeutic modulation of beneficial and damaging neuroinflammation to slow 
disease progression, as well as providing new insights into AD pathophysiology.  
 
1.3. Risk/Benefit assessment 
 
11C-acetate is an investigational imaging drug, which has been extensively used in 
oncologic, cardiac and brain PET/CT imaging with no evidence of pharmacological 
effect.  No adverse events have been reported in a number of published studies of 
human experience for 11C-acetate at doses similar to what will be used for this study.  
The prescribed dose of 11C-acetate will be approximately 20 mCi, with an expected 
range of the injected dose for most studies of 15 - 25 mCi at the time of injection.  
In the unlikely circumstance that a participant has an AE, the principal investigator will 
determine the severity of the AE and the relationship of the event to radiotracer 
administration and decide the course of action for the study subject, usually with the aid 
of treating physicians.   
 
 
Risk/Benefit 
 
 
11C-Acetate 
Participants will undergo one 11C-acetate scan in this study. 11C-acetate is a positron 
emitting radiopharmaceutical. As such, it poses an intrinsic radiation exposure risk. 
However, when administered in low tracer doses as a PET imaging agent, as described 
in this protocol, this risk is felt to be small. The organ and total body doses associated 
with 11C-acetate PET/CT imaging are felt to be comparable to those associated with 
other widely used clinical nuclear medicine procedures.  
 
To date approximately 3,450 humans have been studied with 11C-acetate in published 
literature. There have been no reported AEs associated with the administration of 11C-
acetate and no adverse reactions are expected as a result of the IV injection of 11C-
acetate. We will continue to monitor this information as the study progresses, including 
reviewing current literature and our in-house monitoring of this study. 
 
There is potential with intravenous injections, including 11C-Acetate, for allergic 
reactions. The dose will be delivered intravenously by skilled clinical professionals, and 
subjects will be monitored for any signs or symptoms of allergic reaction by trained 
personnel during the PET procedure. Symptoms of an allergic reaction could include 
itching, rashes, shortness of breath, low blood pressure or wheezing.  
 
[18F]florbetaben  
[18F]florbetaben injection (Neuraceq) is an FDA approved radiopharmaceutical for 
imaging individuals with cognitive impairment and this agent has been used extensively 
in humans with no evidence of pharmacological effect. In this study we will administer 
approximately 8.1 mCi (± 20%) of [18F]florbetaben according to the standard procedures 
used for clinical amyloid PET/CT scans at the University of Pennsylvania.  
 
IV Placement 
Venous cannulation is a routine clinical procedure that carries minimal risks when 
performed by trained personnel.  It is possible that bruising, dizziness or fainting could 
occur in some subjects.  There is a risk of phlebitis or infection, which is very remote.    


11C-Acetate PET/CT in neuroinflammation 
Page 6 
 
CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized by the study sponsor 
 
PET/CT scan procedure 
The PET/CT scan takes place in a small, enclosed space and therefore can be 
uncomfortable for some people with claustrophobia or musculoskeletal disorders (such 
as arthritis). Subjects will be made as comfortable as possible and staff will be available 
throughout the imaging to address any discomfort. 
 
A standard clinical report for 11C-acetate PET/CT scans will not be part of the subject’s 
medical record, the images will be reviewed by trained radiology readers designated by 
the study PI for the purposes of this study.  If there is a potentially clinically important 
finding that is incidentally discovered on this exam, it will be reported to a treating 
physician and may result in additional testing that will not be covered by the study 
budget. Images from the research scan will be stored on PACS. 
 
 
 
Brain MRI 
Subjects may undergo a research brain MRI if they have not undergone one within 6 
months prior to study enrollment. The greatest risk for MRI is a magnetic object flying 
through the air toward the magnet and hitting the subject. Some of the pulse sequences 
and/or RF coils are not FDA approved but are considered to pose no more than minimal 
risk. There is no known health risk associated with exposure to magnetic fields during an 
MRI. There are minimal risks from the loud noise associated with the MRI scanner and 
from discomfort of lying on a hard surface. Implanted medical devices and metallic 
foreign fragments inside the body may pose a risk is subjects were to enter the MRI 
magnet room. Potential participants will be screened to be sure they do not have an 
medical contraindications for MRI.  
 
There is a slight risk of anxiety due to claustrophobia. Any participant who experiences 
anxiety when placed on the MRI scanner will be removed from the scanner, offered 
reassurance from the technologist or study staff and offered the option of continuing or 
terminating the scan. If the participant decides that the anxiety  associated with the MRI 
is uncomfortable for them and they wish to terminate the exam at any point, then the 
examination will be ended at that point. There will be no attempt to coerce the 
participants to complete exams that they are not comfortable with.  
 
Incidental Findings: It is possible that during the course of the research study, the 
research staff may notice an unexpected finding(s). Should this occur, the finding(s) will 
be considered by the appropriate personnel and the PI will determine if the patient 
should be informed. These possible finding(s) may or may not be significant and may 
lead to anxiety about a condition and to further work-up by the subject’s physician. 
 
 
Lumbar Puncture (Optional) 
Lumbar puncture (LP) may be associated with pain during the performance of the 
procedure.  This is usually temporary and confined to the lower back. Headache may 
occur in about 5% of elderly people who undergo a LP. Less commonly, in about 1-4% 
of participants, a persistent low pressure headache may develop, probably due to a 
leakage of CSF. Lower rates of post-LP headaches have been noted in elderly patients. 
If a post-LP headaches persists it may need additional treatment, e.g. with fluids and 
analgesics. Uncommonly, a blood patch (injection of some of the participant's blood to 
patch the CSF leak) may be needed. Potential but rare risks of lumbar puncture include 


11C-Acetate PET/CT in neuroinflammation 
Page 7 
 
CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized by the study sponsor 
infection, damage to nerves in the back, and bleeding into the CSF space. The risk of 
these is much less than 1%.  
 
No psychological, social or legal risk is expected. While loss of confidentiality is possible, 
it is felt to be very unlikely due to the small number of professionals involved in the study 
with knowledge of this information. All clinicians and research staff involved are well 
trained in HIPAA practices. 
 
There is no anticipated benefit to study subjects as a result of their participation in this 
study. There is a potential benefit to general society if 11C-acetate PET/CT proves to be 
a useful imaging agent for evaluating amyloid-induced neuroinflammation. 
2. Study Objectives 
2.1. Primary Objective 
• 
Evaluate whether 11C-acetate uptake is increased in amyloid positive Mild Cognitive 
Impairment (MCI) subjects compared to amyloid negative healthy controls 
2.2. Secondary Objectives 
• 
Correlate 11C-acetate uptake to areas of greater amyloid plaque burden quantified on 
Amyloid PET/CT  
• 
Compare 11C-acetate in areas of mildly elevated PET SUVR to areas with high or 
sub-threshold amyloid burden 
• 
Correlate 11C-acetate uptake to levels of inflammatory markers in CSF 
      
3. Study Design 
 
Subjects will be part of one of the following cohorts:  
 
– Cohort 1:Patients with Mild Cognitive Impairment (MCI) (up to 14) will be recruited 
primarily from the Penn Memory Center (PMC). Clinical diagnostic criteria (described 
in further detail in Study Procedures section) will be used to identify subjects who are 
meet criteria for amnestic MCI. 
– Cohort 2: Normal control subjects in the same age range (up to 6) will be recruited 
from a current ongoing study investigating neuroinflammation in late life depression 
and healthy controls, from the control group in which all subjects receive MRI and LP 
(IRB 819654) and from the PMC research cohort.  
– Cohort 3: Cognitively normal subjects with a positive Amyloid PET (up to 5) may be 
recruited through other ongoing studies or PMC research cohort 
 
 
Screening assessments may take place over several days and may include demographic 
information, neurocognitive testing, with focus on language and visuospatial/ 
visuoperceptual measures; if available within 6 months of the study entry these tests may 
not be repeated. Amyloid brain PET/CT scan isrequired for Cohort 1 and Cohort 3 only, 
subjects in Cohort 2 may have an Amyloid PET that has been done as part of standard care 
or another study but this is not required for entry into Cohort 2- In order to reduce costs, 
subjects may be recruited from other studies that perform amyloid PET/CT (typically with 
18F-florbetaben or 18F-florbetapir) or have this test performed clinically. The CMS coverage 


11C-Acetate PET/CT in neuroinflammation 
Page 8 
 
CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized by the study sponsor 
with evidence development IDEAS amyloid PET/CT study starts recruitment February 
2016, providing Medicare reimbursement for clinical amyloid PET/CT scans for the first 
time; Penn will be a site for this study and we anticipate that many MCI patients being 
considered for this experimental 11C-Acetate imaging protocol will qualify to undergo clinical 
Amyloid PET/CT as part of the IDEAS trial (IRB # 824052). Amyloid PET/CT scans should 
be completed within 6 months prior to the 11C-Acetate PET/CT. If a subject has not 
undergone an Amyloid brain PET/CT as part of IDEAS or clinically then they will be asked 
to undergo a research Amyloid brain scan after they have consented for this study. If it is 
done as part of this research study the FDA approved radiotracer [18F]Florbetaben 
(Neuraceq) will be used according to the standard Penn imaging procedure. When 
available, an Amyloid brain PET/CT scan will be reviewed by an investigator or designee 
prior to scheduling the 11C-Acetate PET/CT scan. For Cohort 1, if the Amyloid PET/CT scan 
is deemed to be negative then the subject will be considered non-evaluable and will be 
withdrawn from the study. Cognitively normal subjects will be assigned to Cohort 2 
(negative amyloid PET) or 3 (positive amyloid PET); cognitively normal subjects can also be 
included in Cohort 2 with negative CSF biomarkers.  Non-evaluable subjects will be 
replaced in the study enrollment total.  
 
If the subject has undergone a brain MRI within 6 months of 11C-Acetate PET/CT it may 
meet the study requirements for MRI imaging; the scan will be reviewed by a study 
physician to determine whether it can be used for the purposes of this study. If the subject 
does not have a Brain MRI that is deemed acceptable within 6 months of 11C-Acetate 
PET/CT they will be asked to undergo a research Brain MRI after they have consented for 
this study.  
 
Subjects who qualify for the study will undergo an 11C-Acetate PET/CT imaging session 
after completing the screening requirements. Patients that meet the eligibility criteria will be 
approached about study participation regardless of race or ethnic background. 
 
Positron emission tomography/Computed Tomography (PET/CT) imaging will be used to 
evaluate the brain using the investigational radiotracer 11C-Acetate. Imaging will be 
performed using a dedicated PET/CT scanner (Philips Medical Systems, Netherlands). The 
protocol will be performed under the regulatory approval of the IRB and FDA IND that is 
held by the University of Pennsylvania, Department of Radiology.  All patients will undergo 
a dynamic brain PET/CT scan including approximately 60 minutes of imaging starting at the 
time of injection of 11C-Acetate. All images will be reconstructed using standard 
reconstruction techniques. Standardized uptake value ratio (SUVr), the ratio of regional to 
reference uptake, will be calculated with cerebellum as reference. The cerebellum does not 
show amyloid accumulation until very advanced stages of AD. 
 
Some subjects may be asked to undergo an optional cerebrospinal fluid (CSF) collection by 
lumbar puncture (LP) for additional research testing. Subjects have already undergone CSF 
collection clinically or as part of another study will not be asked to repeat these procedures. 
 
We anticipate enrolling up to 25 participants total (14 in Cohort 1 MCI cohort, 6 in Cohort 2 
normal control cohort, 5 in Cohort 3 cognitively normal amyloid positive) who meet eligibility 
requirements for this study. Accrual will likely occur over approximately 2 years. 
 


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This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized by the study sponsor 
4. Participant Selection  
4.1. Inclusion Criteria for Cohort 1: Amnestic MCI  
4.1.1. Participants will be at least 55 years of age 
4.1.2. An Amyloid brain PET/CT is required. If a Amyloid brain PET/CT has been 
performed within 6 months of enrollment to this study and of adequate quality that 
scan may be used for the study analysis, subjects who do not have a Amyloid brain 
PET/CT will undergo an Amyloid brain PET/CT as a part of this study 
4.1.3. Mini-mental status examination (MMSE) score ≥ 24 at screening visit 
4.1.4. A brain MRI is required. If a brain MRI has been performed within 6 months of 
11C-Acetate PET/CT and of adequate quality that scan may be used for the study 
analysis, subjects who do not have a brain MRI will undergo a brain MRI as a part 
of this study 
4.1.5. Participants must identify a study partner who is willing to accompany the patient 
to study visits 
4.1.6. Participants must be informed of the investigational nature of this study and 
provide written informed consent in accordance with institutional and federal 
guidelines prior to study-specific procedures. If the patient is unable to provide 
informed consent, the patient’s legal representative may consent on behalf of the 
patient but the patient will be asked to confirm assent. 
 
4.2. Inclusion Criteria for Cohort 2: Normal Control  
4.2.1. Participants will be at least 55 years of age 
4.2.2. History of negative brain amyloid PET/CT scan within 6 months of study 
screening OR negative CSF analysis within 6 months of study screening 
4.2.3. Mini-mental status examination (MMSE) > 27 at screening visit 
4.2.4. A brain MRI is required. If a brain MRI has been performed within 6 months of 
enrollment to this study and of adequate quality that scan may be used for the 
study analysis, subjects who do not have a brain MRI will undergo a brain MRI as a 
part of this study 
4.2.5. Participants must be informed of the investigational nature of this study and 
provide written informed consent in accordance with institutional and federal 
guidelines prior to study-specific procedures.  
 
4.3. Inclusion Criteria for Cohort 3 (Cognitively normal Amyloid positive) 
4.3.1. Participants will be at least 55 years of age 
4.3.2. History of positive brain amyloid PET/CT scan within 6 months of study screening  
4.3.3. Mini-mental status examination (MMSE) > 27 at screening visit 
4.3.4. A brain MRI is required. If a brain MRI has been performed within 6 months of 
enrollment to this study and of adequate quality that scan may be used for the 
study analysis, subjects who do not have a brain MRI will undergo a brain MRI as a 
part of this study 
4.3.5. Participants must be informed of the investigational nature of this study and 
provide written informed consent in accordance with institutional and federal 
guidelines prior to study-specific procedures.  
 
 


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This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized by the study sponsor 
4.4. Exclusion Criteria (for both cohorts) 
4.4.1. Inability to tolerate or contraindication to imaging procedures (PET/CT or MRI) in 
the opinion of an investigator or treating physician 
4.4.2. History of stroke or other neurological disease that in the opinion of the 
investigator might interfere with evaluation of the 11C-Acetate scan 
4.4.3. Any medical or psychological conditions that, in the opinion of the investigator, 
would compromise the subject’s safety or successful participation in the study. 
 
All individuals will be told that their choice regarding study participation will in no way 
change their access to clinical care.  This should negate any undue influence or 
coercion.  
 
4.5. Subject Recruitment and Screening 
 
For the amnestic MCI cohort, potential subjects, or their legally authorized 
representative (as appropriate), will be allowed to read a written informed consent form. 
The principal investigator or designee will explain all study procedures, risks, and 
alternative therapies. The subject and legally authorized representative will have an 
opportunity to have all questions answered by a physician. The subject will then sign 
and date the informed consent form, indicating willingness to participate in the study.  
 
Subjects with neurodegenerative diseases are potentially a vulnerable population with 
compromised mental capacity. Investigators should take extra care to evaluate a 
patient’s ability to give consent. If the subject is capable of giving informed consent then 
the subject should sign on the consent line of the informed consent form. The 
designated study partner should sign as well, indicating that they have witnessed the 
subject’s consent, and further agree to participate as a study partner.  
 
If the subject is not capable of giving consent, consent may be given by a legally 
authorized representative. However, it is expected that all subjects entering this study 
should at least have the capacity to understand that they are engaging in a research 
study and should affirm that they do not object to participating, by signing on the Subject 
Assent line of the consent form. If the legally authorized representative is also the 
designated study partner they should sign the study partner line of the consent form as 
well, indicating that they have witnessed the subject’s assent, and further agree to 
participate as a study partner.  
 
All informed consent forms must be approved by the appropriate Institutional Review 
Board (IRB). In some cases a verbal consent discussion will be carried out by phone 
prior to scheduling of Amyloid or 11C-Acetate PET/CT scans. Healthy volunteers will be 
contacted by phone to discuss the study. For candidates for the MCI  cohort a verbal 
consent discussion by phone will only occur if both the patient and the study partner are 
available for the discussion. No study related procedures shall be performed prior to 
completion of the informed consent process, and signing of the consent form. A copy of 
the signed informed consent should be given to the patient and/or their legally 
authorized representative for their records.  
 
Patients may be receiving care at the Penn Memory Center, Frontotemporal Lobar 
Degeneration Center, or another clinic of the University of Pennsylvania Health System. 


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CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized by the study sponsor 
Age matched normal control cohort candidates will be recruited from a current ongoing 
study investigating neuroinflammation in late life depression and healthy controls, in 
which all subjects receive MRI and LP (IRB 819654) and from the PMC research cohort. 
Patients who meet the study inclusion criteria for this imaging protocol will be 
approached by study personnel for recruitment into this study. The patient will be 
consented by a physician or research personnel.  
 
All patients being considered for the study and eligible for screening must sign an 
informed consent for the study prior to any study specific procedures. Following 
completion of the pretreatment assessments and confirmation of eligibility, patients may 
undergo the 11C-Acetate PET/CT scan.  
 
A two-part consent process will be used for this study and the consent for administration 
of the investigational drugs will be discussed again with the patient on the day of the 
PET/CT scan and documented on a supplemental consent form by a delegated Nuclear 
Medicine Authorized User prior to administration of any study drugs. 
4.6. Subject Withdrawal 
 
The criteria for enrollment must be followed explicitly.  If a subject who does not meet 
enrollment criteria is inadvertently enrolled, that subject should be discontinued from the 
study.  A subject may voluntarily discontinue participation in this study at any time.  The 
investigator may also, at his or her discretion, discontinue the subject from participating 
in this study at any time.  If a subject is prematurely discontinued from participation in the 
study for any reason, at any time, at either the investigator’s discretion or the subject’s 
request, an effort must be made to document the reason(s) why a subject fails to return 
to the study clinic for necessary visits or is discontinued from the study.  The primary 
reason for discontinuing participation in the study may include, but is not limited to, one 
of the following: 
 
• 
Withdrawal of consent for imaging protocol by patient 
• 
Noncompliance with protocol, e.g., the patient fails to appear at one or more 
imaging procedures 
• 
Development of an intercurrent illness, injury, or medical condition likely to 
interfere with subject safety, the overall assessment, or the required 
administration of study medication 
• 
Development of any condition for which the investigator feels study withdrawal is 
justified. 
• 
Termination of the study  
 
Follow –up information may be obtained for subjects who discontinue the study if 
possible.  
 
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety, 
behavioral, or administrative reasons. If the subject withdraws from the study, and also 
withdraws consent for disclosure of future information, no further evaluations should be 
performed, and no additional data should be collected. The sponsor may retain and 
continue to use any data collected before such withdrawal of consent. 


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This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized by the study sponsor 
5. Investigational Agent 
5.1. Description 
 
11C-Acetate is a radiolabeled imaging agent that has been used for studying tumor cells, 
myocardial oxidative metabolism and also has been shown to quantify astrocyte 
activation with positron emission tomography (PET/CT). Acetate metabolism has long 
been linked to astrocyte activation 1,2; brain metabolism is highly compartmentalized and 
acetate is actively taken up by astrocytes and used for energy metabolism and lipid 
synthesis. The latter mechanism accounts for trapping of radiolabel in 11C-Acetate 
PET/CT3 which can be quantified by both static uptake measures and kinetic analysis. 
This approach has been used to demonstrate astrocyte activation in multiple sclerosis 4 
and alcoholism5. 11C-Acetate PET/CT allows quantification of astrocyte activation without 
perturbing brain metabolism due to the tracer doses used for PET/CT, operating well 
below physiologic substrate concentrations.  
 
This proposed protocol will test 11C-Acetate PET/CT as a marker for astrocyte activation 
associated with pathologic amyloid deposition in AD. Validating neuroinflammation 
markers in AD ultimately may guide therapeutic modulation of beneficial and damaging 
inflammatory responses to slow disease progression, as well as providing new insights 
into AD pathophysiology.   
 
5.2. Preparation of Study Drug 
 
The manufacturing of 11C-acetate will occur in the Cyclotron Facility of the Department of 
Radiology at the University of Pennsylvania.  This facility manufactures USP compliant 
radiolabeled compounds for human use on a daily basis.  The drug manufacturing will be 
fully documented and controlled by a set of Standard Operating Procedures (SOPs) 
prepared and maintained by the University of Pennsylvania Cyclotron.   
5.3. Receipt of Study Drug 11C-acetate 
 
11C-acetate will be delivered to the Nuclear Medicine Division of the University of 
Pennsylvania Medical Center by a trained Cyclotron team member in single dose vials 
according to the standard procedures outlined by the Cyclotron Facility.  Once the drug 
has been delivered to the Nuclear Medicine Division all standard hospital procedures will 
apply for handling, processing, and destruction of any residual amounts if applicable. As 
11C-acetate is a short-lived radiotracer with a half-life of approximately 20 minutes it will 
be synthesized for same day use; 11C-acetate will not be stored. The remaining activity 
in the vials that exists will be stored only until the activity decays to an undetectable 
level.  All vials will be disposed of according to the standard procedures set forth by the 
hospital and overseen by Nuclear Medicine staff. 
5.4. Study Drug Administration: 11C-acetate 
 
The 11C-acetate dose will be drawn and measured by the dose calibrator in the imaging 
facility and administered by IV injection to the patient under the direct supervision of a 
Nuclear Medicine Authorized User.  The prescribed dose of 11C-acetate will be 
approximately 20 mCi, with an expected range of the injected dose for most 


11C-Acetate PET/CT in neuroinflammation 
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CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized by the study sponsor 
studies of 15 - 25 mCi at the time of injection, a lesser dose may be injected if, in the 
opinion of a Nuclear Medicine Authorized User complete imaging data could be 
generated.  In the dose of 11C-acetate, only a small fraction of the acetate molecules are 
radioactive. 11C-acetate is administered to subjects by intravenous injection.  The 
injection or imaging procedure will be terminated in any patient who exhibits 
anaphylaxis, significant dyspnea or chest pain. For additional study drug information 
refer to the Investigator’s Brochure for 11C-acetate. 
6. Study Procedures and Study Calendar 
 
 
STUDY CALENDAR 
1 Patients that have a Brain MRI scan previously performed within 6 months of study enrollment 
may not need to repeat this scan, images will be reviewed by a physician to determine if the MRI 
can be used for the purposes of the study, this may occur prior to consent and enrollment in this 
study.   
2 Many patients will be recruited from other studies that perform Amyloid PET/CT scans (typically 
using 18F-florbetaben or 18F-florbetapir) the amyloid PET/CT scan should be performed within 6 
months of study enrollment. If a subject has not undergone an Amyloid brain PET/CT as part of 
IDEAS or clinically then they will be asked to undergo a research Amyloid brain scan after they 
have consented for this study. If it is done as part of this research study the FDA approved 
radiotracer [18F]Florbetaben (Neuraceq) will be used according to the standard Penn imaging 
procedure. Only Cohort 1 and Cohort 3 patients will be required to have an Amyloid PET/CT 
scan. Scan results will be reviewed prior to scheduling the 11C-Acetate PET/CT scan. 
3 Mini Mental State Exam 
4 Optional: Patients who have previously had CSF stored or tested will not be asked to repeat 
these procedures. Timing of this will vary depending on if the patient has already had this done as 
part of clinical care or another study. If it is being performed prior to the imaging, lumbar puncture 
should occur a minimum of 48 hours prior to the 11C-Acetate PET/CT scan. 
5 Neuropsychological test battery will include the following tests:  
a. Trail Making Test A and B 
b. Category Fluency 
c. 30-item Boston Naming Test 
d. Rey Auditory Verbal Learning Test (AVLT) - for episodic memory 
e. Digit-symbol – for processing speed, executive functioning 
f. 
Lexical fluency (F words in 1 min). 
g. Pfeffer Functional Activities Questionnaire (FAQ) 
h. Geriatric Depression Scale (GDS) 
i. 
Optional: ADAS-cog, if time permits 
   
Screening 
Assessments8 
Baseline 
Assessments   
Day of 11C-Acetate 
PET/CT scan 
Informed Consent 
X 
 
 
Demographics 
X 
 
 
Brain MRI1 
X 
 
 
Amyloid PET/CT scan2 
X 
 
 
MMSE3 
X 
 
 
Lumbar Puncture4 
X 
X 
 
Neuropsychological test battery5 
 
X 
 
Pfeffer Functional Activities 
Questionnaire (FAQ) 
 
X 
 
11C-acetate PET/CT scan 
 
 
X 
Venous blood sampling6 
 
 
X 
Adverse Event Evaluation7 
 
 
X 


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CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized by the study sponsor 
6 Venous blood samples will be taken during the 11C-Acetate PET/CT imaging session in order to 
measure radioactive counts in the blood. If a second IV line is not able to be successfully 
accessed or an investigator does not think the patient can tolerate a second IV for blood draws 
this may be omitted.  
7 Follow up may occur by telephone or in person, depending on the subject’s schedule. Follow up 
should take place the next available business day (i.e. not a weekend or a holiday). The AE 
monitoring period is 10 hours following 11C-acetate injection 
8 Screening assessments may be performed over multiple days 
6.1. Initial screening and baseline visits prior to 11C-acetate PET/CT scan  
 
The investigator will provide for the protection of the subjects by following all applicable 
regulations.  These regulations are available upon request from the sponsor.  The 
sponsor and IRB must review the informed consent form used during the informed 
consent process, and it must be available for inspection.   
 
Before any procedures specified in this protocol are performed, a subject must: 
 
• 
Be informed of all pertinent aspects of the study and all elements of informed 
consent.  
• 
Be given time to ask questions and time to consider the decision to participate. 
• 
Voluntarily agree to participate in the study.  
• 
Sign and date an IRB/IEC-approved informed consent form. 
 
Potential subjects for Cohort 1 will be identified by treating physicians at Penn Memory 
Center or their referral clinics within the University of Pennsylvania Health System.  
Potential subjects will be approached by their treating physician about participation in the 
study. If the patient is interested in participation they will be contacted by one of the 
investigators and/or study staff for recruitment. The research team will review the study 
and obtain consent after subjects have adequate opportunity to discuss the study and 
have all questions answered.  
 
Potential subjects for Cohort 2 and Cohort 3 may be recruited from the subject 
population of a current study investigating neuroinflammation in late life depression and 
health controls (IRB 819654) from the healthy control group and from the PMC research 
cohort. Subjects in that ongoing study all receive MRI and LP and would be evaluated 
for additional eligibility criteria for this imaging protocol and will be approached by study 
personnel about participation.   
 
Screening may take place over several days. All screening assessments should be 
performed prior to the 11C-Acetate PET/CT imaging session. 
 
Screening assessments include:   
 
1. Demographics (age, gender, race, ethnicity) 
2. Medical history (may be taken from medical record review) 
3. Concomitant medications recorded 
4. Mini Mental State Exam (MMSE) 
5. Brain MRI including standard clinical sequences and volumetric MRI. Patients 
that have a Brain MRI scan that was performed within 6 months of study 
enrollment may not need to repeat this scan; images will be reviewed by a 


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CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized by the study sponsor 
physician to determine if the MRI can be used for the purposes of the study, this 
may occur prior to consent and enrollment in this study. 
6. Amyloid brain PET/CT scan (required for Cohort 1 and Cohort 3) - In order to 
reduce costs, subjects may be recruited from other studies that perform amyloid 
PET/CT (typically using 18F-florbetaben or 18F-florbetapir. The CMS coverage 
with evidence development IDEAS amyloid PET/CT study starts recruitment 
February 2016, providing Medicare reimbursement for clinical amyloid PET/CT 
scans for the first time; Penn will be a site for this study and we anticipate that 
many patients being considered for this experimental 11C-Acetate imaging 
protocol will qualify to undergo clinical Amyloid PET/CT as part of the IDEAS 
registration trial (IRB 824052). Amyloid PET/CT scans should be completed 
within 6 months of study enrollment. If a subject has not undergone an Amyloid 
brain PET/CT as part of IDEAS or clinically then they will be asked to undergo a 
research Amyloid brain scan after they have consented for this study. If it is done 
as part of this research study the FDA approved radiotracer [18F]florbetaben 
(Neuraceq) will be used according to the standard Penn imaging procedure. For 
Cohort 1 and Cohort 3, the Amyloid brain PET/CT scan will be reviewed by an 
investigator or designee prior to scheduling the 11C-Acetate PET/CT scan, for 
subjects in Cohort 2 if an Amyloid PET is available it will be reviewed, however, it 
is not required for participation in Cohort 2.. If the Amyloid PET/CT scan is 
deemed to be negative then the subject will be considered non-evaluable and will 
be withdrawn from the study. Non-evaluable subjects will be replaced in the 
study enrollment total. 
 
Baseline assessments: may be performed the same day as screening assessments or 
on a separate day within 90 days of the 11C-Acetate PET/CT, including the day of that 
study. 
 
Amyloid brain PET/CT scan (if performed as a research scan for this study) 
 
The following procedures will be done on the day of the [18F]florbetaben PET/CT scan 
• 
Weight and height will be recorded 
 
Injection of [18F]florbetaben 
 
The patient will be made comfortable in a preparatory room, one intravenous line (IV) will 
be placed, usually one in the arm or hand. Patients will receive approximately 8.1 mCi (± 
20%) of [18F]florbetaben intravenously by trained nuclear medicine staff, a lesser dose 
may be injected if, in the opinion of a Nuclear Medicine Authorized User complete 
imaging data could be generated.  
 
Patients will be escorted to the scanner room and positioned in the PET/CT scanner with 
arms by the side. According to standard procedures used for clinical amyloid PET/CT 
scans at the Hospital of the University of Pennsylvania, an approximately 15 minute 
static brain PET scan will be obtained starting at approximately 90 minutes post-
injection. A low-dose brain CT scan will be acquired according to standard PET/CT 
imaging procedures; this CT is used for attenuation correction in PET scan processing. 
The CT can be performed either before or after the PET transmission scan. There are no 
separate diagnostic CT scans performed as part of this research.  
 
 


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This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized by the study sponsor 
Brain MRI 
 
If the subject has undergone a brain MRI within 6 months of study entry it may meet the 
study requirements for MRI imaging; the scan will be reviewed by a study physician to 
determine whether it can be used for the purposes of this study. If the subject does not 
have a Brain MRI that is deemed acceptable within 6 months of study enrollment they 
will be asked to undergo a research Brain MRI after they have consented for this study. 
Prior to the brain MRI they will be asked to complete an MRI safety form which is a 
standard assessment form, created by the Department of Radiology at the Hospital of 
the University of Pennsylvania to assess history of specific prosthesis, surgical implants, 
and other MRI contraindications. The greatest risk is a magnetic object flying through the 
air toward the magnet and hitting the subject. Some of the pulse sequences and/or RF 
coils are not FDA approved but are considered to pose no more than minimal risk. There 
is no known health risk associated with exposure to magnetic fields during an MRI. 
There are minimal risks from the loud noise associated with the MRI scanner and from 
discomfort of lying on a hard surface. Implanted medical devices and metallic foreign 
fragments inside the body may pose a risk is subjects were to enter the MRI magnet 
room.  
 
Incidental Findings: It is possible that during the course of the research study, the 
research staff may notice an unexpected finding(s). Should this occur, the finding(s) will 
be considered by the appropriate personnel and the PI will determine if the patient 
should be informed of these findings. These possible finding(s) may or may not be 
significant and may lead to anxiety about a condition and to further work-up by the 
subject’s physician. 
 
Neuropsychological testing 
 
Neuropsychological test battery will include standardly used tests including: 
j. 
Trail Making Test A and B 
k. Category Fluency 
l. 
30-item Boston Naming Test 
m. Rey Auditory Verbal Learning Test (AVLT) - for episodic memory 
n. Digit-symbol – for processing speed, executive functioning 
o. Lexical fluency (F words in 1 min). 
p. Pfeffer Functional Activities Questionnaire (FAQ) 
 
q. Geriatric Depression Scale (GDS) 
r. Optional: ADAS-cog, if time permits 
 
Optional: Cerebrospinal fluid (CSF) by Lumbar Puncture (LP).  
 
Some subjects may be asked to undergo an optional lumbar puncture to collect CSF. If 
subjects agree to the LP it will be performed by a qualified physician who is experienced 
in performing the procedure. Subjects, or their designated decision maker, will call the 
investigator to report any adverse events associated with the LP procedure. Patients 
who have previously had CSF collected and stored or tested will not be asked to repeat 
these procedures. If it is being performed prior to the imaging, lumbar puncture should 
occur a minimum of 48 hours prior to the 11C-Acetate PET/CT scan. 
 


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CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized by the study sponsor 
The following additional patient data may be self-reported by the patient or obtained from 
medical chart review:  demographics (including gender, date of birth and race).  
 
6.2. Day of 11C-acetate PET/CT scan 
   
Consent for administration of the investigational drugs will be discussed again with the 
patient on the day of the PET/CT scan and documented on a supplemental consent form 
by a delegated Nuclear Medicine Authorized User prior to administration of any study 
drugs. 
 
The following procedures will be done on the day of the 11C-acetate PET/CT scan 
• 
Weight and height will be recorded 
 
Injection of 11C-acetate. 
 
The patient will be made comfortable in a preparatory room, two intravenous lines (IVs) 
will be placed, usually one in each arm or hand. The location of the IV used for injection 
will be documented. Patients will be escorted to the scanner room and positioned in the 
PET/CT scanner with arms by the side. Patients will receive approximately 20 mCi of 
11C-acetate intravenously under the direct supervision of a Nuclear Medicine Authorized 
User (AU).The prescribed dose of 11C-acetate will be approximately 20 mCi, with an 
expected range of the injected dose for most studies of 15 to 25 mCi at the time 
of injection, a lesser dose may be injected if, in the opinion of a Nuclear Medicine 
Authorized User complete imaging data could be generated.  
 
Subjects will undergo a 60 minute dynamic brain PET/CT scan starting at approximately 
the same time as the injection of 11C-Acetate. A low-dose brain CT scan will be acquired 
according to standard PET/CT imaging procedures; this CT is used for attenuation 
correction in PET scan processing. The CT can be performed either before or after the 
PET transmission scan. There are no separate diagnostic CT scans performed as part of 
this research.  
 
Venous Blood Sampling: Subjects will have two intravenous (IV) lines placed prior to 
start of scanning, these will generally be placed one in each upper extremity, one IV will 
be used for injection of the tracer, the other IV will be used for collecting venous blood 
samples during the course of the scanning protocol. The side of the body used for 
injection will be documented. 
 
Venous Blood Sampling: Venous blood samples will be collected at approximately 2, 5, 
10, 20, 40 and 60 minutes post-injection to measure radioactive counts in the blood. The 
actual time of each blood draw will be recorded. Sampling may be reduced to fewer time 
points if experience from the first subjects indicates fewer time points will be sufficient for 
analysis. The total amount of blood drawn for venous sampling will be approximately 12 
mL (about 3 teaspoons). If a second IV line is not able to be successfully accessed or an 
investigator does not think the patient can tolerate a second IV for blood draws this may 
be omitted at the discretion of an investigator, this will be recorded in the CRF and will 
not be considered a protocol deviation.  
  
Adverse events that are grade 3 or higher will be recorded for the period up to 10 hours 
post injection of the radiotracer. Research personnel will conduct follow up by telephone 


11C-Acetate PET/CT in neuroinflammation 
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CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized by the study sponsor 
or in person, depending on the subject’s schedule. Follow up should take place the next 
available business day (i.e. not a weekend or a holiday).  
 
7. Image Interpretation 
7.1. 11C-acetate PET/CT Image Analysis 
 
The low dose CT from the 11C-Acetate PET/CT scans will be reviewed by a trained 
radiology reader designated by the principal investigator. Any findings that may affect 
the clinical course of the subject will be reported to the patient’s physician.  The 11C-
Acetate PET/CT data is not validated for clinical use; as such, results will not be 
reported. 
 
11C-Acetate PET/CT, Amyloid PET/CT and MRI images will be coregistered to allow 
template-based determination of regions of interest (ROI) on PET. We will obtain venous 
blood samples to calibrate an image-based arterial input function for the kinetic analysis. 
 
 
Standardized uptake value ratio (SUVr), the ratio of regional to reference uptake, will be 
calculated with cerebellum as reference for both the 11C-Acetate and the amyloid 
PET/CT images.  To account for atrophy, partial volume correction will be applied.  
Regional quantification will be performed using analysis software, such as Scenium 
(Siemens Medical Systems), PMOD (PMOD Technologies), or SPM (Wellcome Trust). 
Voxel based comparisons of PET/CT and MRI data may also be performed. We may 
also use graphical (Patlak) analysis, and with kinetic analysis using a two compartment 
model, which we have tested on other applications such as brain tumors 14 15 16. Plasma 
CO2 will be estimated from venous samples, which will each be divided into two aliquots, 
one into acidic and the other into basic solution. Radioactivity in each aliquot will be 
counted with the difference in counts between acidic and basic used to calculate plasma 
CO2, which will be used in kinetic analysis of acetate binding.  
 
Optimal quantification of acetate binding will be the simplest model that shows strong 
correlations between acetate binding and amyloid SUVR. Acetate binding and amyloid 
SUVR will be analyzed using PMOD17 for modeling and static uptake estimates and 
Statistical Parametric Mapping18 using T1 MRI for coregistration and template-based 
regional segmentation. We will compare and correlate amyloid and acetate quantification 
using both Pearson’s correlation and non-parametric Spearman’s correlation. 
7.2. Measurement of Effect 
 
This protocol is designed to develop relationships between parameters determined from 
an 11C-Acetate PET/CT imaging biomarker study and ones derived from amyloid 
PET/CT, MRI, laboratory biomarker assays, and neurocognitive testing.  
 
The primary analysis variables for the study are: 
•  11C-Acetate PET/CT SUVR regional quantification 
• Amyloid PET/CT SUVR 
• Statistical Parametric Mapping segmentation of MRI 
 
 
Secondary analysis variables are: 
• Levels of IL-6, IL-1 and TNFα in CSF 


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CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized by the study sponsor 
• Neurocognitive test results (tests detailed elsewhere in this document) 
 
8. Statistical Plan 
8.1. Sample Size Determination 
 
The primary objective will be to evaluate whether 11C-acetate uptake is increased in 
amyloid positive Mild Cognitive Impairment (MCI) subjects compared to amyloid 
negative healthy controls. With a sample size of 14 MCI and 6 normal controls, 
assuming 20% precision, we estimate we could detect a difference of 15%; with a 
smaller sample of 8 MCI subjects and 4 controls, we estimate that we could detect a 
difference of 30%, However, this is a pilot study which will allow us to determine 
feasibility and estimate sample size for a future larger study.  
8.2. Statistical Methods 
 
Optimal quantification will be the simplest model that shows strong correlations between 
acetate binding and amyloid SUVR. 11C-Acetate binding and amyloid SUVR will be 
analyzed using PMOD for modeling and static uptake estimates and Statistical 
Parametric Mapping using T1 MRI for coregistration and template-based regional 
segmentation. We will compare and correlate amyloid and acetate quantification using 
both Pearson’s correlation and non-parametric Spearman’s correlation.  
 
The expected positive correlation between acetate binding and CSF cytokine levels will 
be evaluated. Global, regional and voxel based correlations will be performed between 
acetate uptake and amyloid PET SUVR from MCI subjects and cognitively normal 
subjects with a positive Amyloid scan. Acetate binding in voxels with amyloid SUVR 
below, between 100-125%, or above 125% of previously validated thresholds19,20 will 
also be compared. 
8.3. Subject Population(s) for Analysis 
 
The primary analysis population will consist of age matched cohorts of amnestic MCI 
patients and normal controls. Patients will be recruited from the clinical practices of Penn 
Memory Center, Frontotemporal Lobar Degeneration Center, or other clinics of the 
University of Pennsylvania Health System. All subjects with an 11C-acetate PET/CT will 
contribute to the primary analysis.  
9. Adverse Events 
9.1. Definitions 
Adverse Events are classified as serious or non-serious.  
Adverse Events that do not meet the established criteria for Serious Adverse Events 
(see below) should be regarded as non-serious adverse events.  
 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a participant that does 
not necessarily have a causal relationship with the study procedure. It is any symptom, 
sign, illness or experience that develops or worsens in severity during the course of the 


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This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized by the study sponsor 
study procedure.  Intercurrent illnesses or injuries should be regarded as adverse 
events.  Abnormal results of diagnostic procedures are considered to be adverse events 
if the abnormality: 
• results in study withdrawal 
• Is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
 
Serious Adverse Event  
 A Serious Adverse Event (SAE) is any Adverse Event that is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Expected and Unexpected Adverse Events  
AEs may be expected or unexpected: 
  
• 
An expected AE is one that is described in the protocol, the ICF, or the 
investigator’s brochure.  
• 
An unexpected AE is one that has not been described in the protocol, the ICF, 
or the investigator’s brochure.  
 
Adverse Event Grading  
Grade denotes the severity of the AE.  
 
1 – Mild  
2 – Moderate  
3 – Severe  
4 – Life-threatening or disabling  
5 – Fatal 
 
Adverse Event Attribution  
Attribution is used to determine whether an AE is related to a study treatment or 
procedure.  
Attribution categories are:  
Definite: The AE is clearly related to a treatment or procedure  
Probable: The AE is likely related to a treatment or procedure  
Possible: The AE may be related to a treatment or procedure  
Unlikely: The AE is likely unrelated to a treatment or procedure  
Unrelated: The AE is clearly not related to a treatment or procedure 
 
 
Important Medical Events  
Important Medical Events are those events that may not be immediately life threatening, 
but are clearly of major clinical significance. They may jeopardize the subject’s health 
and may require medical intervention.  
 


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Preexisting Condition 
A preexisting condition is a condition that is present at the start of the study.  A 
preexisting condition should be recorded as an adverse event if the frequency, intensity, 
or the character of the condition worsens during the study period. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition.  At the end of the study, any new clinically significant findings/abnormalities 
that meet the definition of an adverse event must also be recorded and documented as 
an adverse event.  
 
Post-Study Adverse Event 
All unresolved adverse events should be followed by the investigator until the event is 
resolved or the subject is lost to follow-up.   
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if the 
Principal Investigator believes the abnormality is related to participation in the study. 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
recorded as a serious adverse event. The event should be reported if the Principal 
Investigator believes the hospitalization is related to participation in the study. 
 
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as 
the period from the initiation of any study procedures to the end of the study treatment 
follow-up. For this study, the study treatment follow-up is defined as 10 hours following 
the administration of the study radiotracer,11C-acetate. 
9.2. Recording of Adverse Events 
 
At each study visit session, the Principal Investigator or designee, must seek information 
from the subject in reference to any adverse events specific to imaging procedures or 
injection of 11C-acetate that may have occurred by specific questioning and as 
appropriate by examination.  Information on all adverse events should be recorded in as 
much detail as possible on a source document or the medical record and entered on the 
Adverse Event Log.  
 
All adverse events occurring during the AE reporting period of 10 hours post 11C-acetate 
injection will be recorded. The clinical course of each event should be followed until 
resolution, stabilization, or until it has been determined that the study treatment or 
participation is not the cause.  Serious adverse events that are still ongoing at the end of 
the study period must be followed up to determine the final outcome.  Any serious 
adverse event that occurs after the study period and is considered to be possibly related 
to the study imaging or study participation should be recorded and reported immediately.  
 
The PI should be contacted immediately to determine the reporting requirements for the 
event as outlined in the protocol. 
 


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The clinical course of each event should be followed until resolution, stabilization or until 
it has been determined that the investigational agent or study procedure is not the cause 
of the event.   
9.3. Reporting of Adverse Events and Serious Adverse Events 
 
It is the responsibility of the Principal Investigator to determine the grade, attribution and 
expectedness of the event and if the event is reportable according to the requirements 
outlined in the protocol. 
  
For this investigational agent the following criteria should be met to consider an adverse 
event reportable: 
 
•  The event occurred within 10 hours after the injection of the investigational agent, 
11C-acetate. 
• All unexpected events regardless of grade or attribution.  
• Expected events that are grade 3 or higher. 
• Expected events that are possibly, probably or defiantly related to the 
investigational agent. 
 
When reporting please supply a narrative with as much description of the event as 
possible (chart note is acceptable) along with the completed AE Log or CRF signed and 
dated by the Principal Investigator.  
 
The narrative should include: 
 
Protocol number and name 
Subject number  
Date of onset 
A detailed description of the event 
If the study procedure was discontinued 
 
9.3.1. Investigator Reporting: Notifying the Study Sponsor 
All reportable Adverse Events and Serious Adverse Events must be reported to 
the study sponsor (The Department of Radiology, IND Support Office) by email 
within 24 hours of the event. Please include the AE Log and narrative as 
mentioned above.   
 
If the event is considered serious the Principle Investigator must complete the 
Serious Adverse Event (SAE) form and fax or email to the study sponsor within 24 
hours.  All documentation will be kept on file at the study site.   
 
Significant new information on ongoing adverse events should be provided 
promptly to the study sponsor 
9.3.2. Investigator Reporting: Notifying the Penn IRB 
This section describes the requirements for safety reporting by investigators who 
are Penn faculty, affiliated with a Penn research site, or otherwise responsible for 
safety reporting to the Penn IRB. The University of Pennsylvania IRB (Penn IRB) 


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requires expedited reporting of those events related to study participation that are 
unforeseen and indicate that participants or others are at increased risk of harm.   
 
The Penn IRB requires Principal Investigators to submit AE and SAE reports 
within 10 working days from the time the investigator becomes aware of the event. 
 
 
The Penn IRB will not acknowledge safety reports or bulk adverse event 
submissions that do not meet the criteria outlined below: 
 
• The event occurred within 10 hours after the injection of the 
investigational agent. 
• All unexpected events regardless of grade or attribution.  
• Expected events that are grade 3 or higher. 
• Expected events that are possibly, probably or defiantly related to the 
investigational agent. 
 
Penn IRB Reporting Process 
Unanticipated problems posing risks to subjects or others as noted above will be 
reported to the Penn IRB using the form: “Unanticipated Problems Posing Risks to 
Subjects or Others Including Reportable Adverse Events” or as a written report of 
the event (including a description of the event with information regarding its 
fulfillment of the above criteria and follow-up/resolution). 
 
Copies of each report and documentation of IRB notification and receipt will be 
kept in the Clinical Investigator’s study file. 
 
                        Other Reportable Events to Penn IRB: 
                         For clinical drug trials, the following events are also reportable to the Penn IRB: 
• Any adverse event that would cause the sponsor to modify the 
investigators brochure, protocol or informed consent form, or would 
prompt other action by the IRB to assure protection of human subjects. 
• Information that indicates a change to the risks or potential benefits of 
the research, in terms of severity or frequency. For example:  
• 
An interim analysis indicates that participants have a lower rate of 
response to treatment than initially expected. 
• 
Safety monitoring indicates that a particular side effect is more 
severe, or more frequent than initially expected. 
• 
A paper is published from another study that shows that an arm of 
your research study is of no therapeutic value. 
• 
Change in FDA safety labeling or withdrawal from marketing of a drug, 
device, or biologic used in a research protocol. 
• 
Breach of confidentiality 
• 
Change to the protocol taken without prior IRB review to eliminate 
apparent immediate hazard to a research participant. 
• 
Incarceration of a participant when the research was not previously 
approved under Subpart C and the investigator believes it is in the best 
interest of the subject to remain on the study. 


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• 
Complaint of a participant when the complaint indicates unexpected risks 
or the complaint cannot be resolved by the research team. 
• 
Protocol violation (meaning an accidental or unintentional deviation from 
the IRB approved protocol) that in the opinion of the investigator placed 
one or more participants at increased risk, or affects the rights or welfare 
of subjects. 
9.3.3. Sponsor Reporting 
Notifying the FDA 
The study sponsor is required to report certain study events in an 
expedited fashion to the FDA.  These written notifications of adverse 
events are referred to as IND Safety Reports. The following describes the 
safety reporting requirements by timeline for reporting and associated type 
of event: 
 
• 
Within 7 calendar days 
Any study event that is: 
 Associated with the use of the study drug. 
 Unexpected.  
 Fatal or life-threatening.  
 
• 
Within 15 calendar days 
Any study event that is: 
1. associated with the use of the study drug, 
2. unexpected, and 
3. serious, but not fatal or life-threatening 
     -OR- 
– A previous adverse event that was not initially deemed reportable but is 
later found to fit the criteria for reporting (reporting within 15 calendar 
days from when event was deemed reportable). 
Any finding from tests in laboratory animals that:  
• Suggest a significant risk for human subjects including reports of 
mutagenicity, teratogenicity, or carcinogenicity. 
 
 
Notifying Participating Investigators 
 
            It is the responsibility of the study sponsor to notify all participating 
investigators, in a written IND safety report, of any adverse event 
associated with the use of the drug that is both serious and unexpected, 
as well as any finding from tests in laboratory animals that suggest a 
significant risk for human subjects.  Additionally, sponsors are also 
required to identify in IND safety reports all previous reports concerning 
similar adverse events and to analyze the significance of the current 
event in light of the previous reports. 
 
            Additional Sponsor Reporting Requirements 


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This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized by the study sponsor 
            Sponsors are also required to identify in IND safety reports all previous 
reports concerning similar adverse events and to analyze the significance 
of the current event in light of the previous reports. 
 
 
9.4. Medical Monitoring 
 
It is the responsibility of the Principal Investigator, Dr. Nasrallah, to oversee the safety of 
the study.  This safety monitoring will include careful assessment and appropriate 
reporting of adverse events as noted above, as well as the construction and 
implementation of a site data and safety-monitoring plan (see section 11 Auditing, 
Monitoring and Inspecting).  Medical monitoring will include a regular assessment of the 
number and type of serious adverse events. 
10. Data Handling and Record Keeping 
10.1. 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the 
following:  
• What protected health information (PHI) will be collected from subjects in this 
study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of 
subject authorization.  For subjects that have revoked authorization to collect or use PHI, 
attempts should be made to obtain permission to collect at least vital status (i.e. that the 
subject is alive). 
 
All research personnel associated with this study have completed the University of 
Pennsylvania human subjects training as well as HIPAA Compliance Training.  Trained 
staff will assess eligibility, introduce the study rationale, procedures, study risks, and 
collect the combined informed consent/HIPAA authorization form.  The study team will 
work to uphold the privacy of the participants in several ways.  Communications made 
among study staff regarding participants will use ID numbers whenever possible and 
minimize the use of patient name or other identifying information except when necessary 
for conduct of the study. Paper-based records will be kept in a secure location and only 
be accessible to personnel involved in the study. Computer-based files will only be made 
available to personnel involved in the study through the use of access privileges and 
passwords. Whenever feasible, identifiers will be removed from study-related 
information. In data analysis sets, we will use ID numbers and/or patient initials only.   
 
Precautions will be applied to protecting subject privacy and the protected health 
information detailed below: 
 
1. Name 


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This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized by the study sponsor 
2. Address 
3. Electronic mail addresses 
4. Telephone Number 
5. Date of Birth 
6. Medical Record Number 
7. Health Plan ID numbers 
8. Social Security Number 
9. Any other unique identifying number, characteristic or code 
10. Current and past medications or therapies 
11. Information from the tests and procedures described earlier in this document 
12. Previous procedure, diagnosis and treatment information from institutions other than Penn 
if it relates to study eligibility 
13. Emergency contact number, name, and relationship 
 
 
Data will be accessible to the study investigators, all study staff, Department of 
Radiology IND office representatives, Radiation Research Safety Committee members, 
UPenn IRB and Office of Clinical Research, and the FDA (if desired).   
 
10.2. 
Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  
Source data are contained in source documents.  Examples of these original documents, 
and data records include: hospital records, clinical and office charts, laboratory notes, 
memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after 
verification as being accurate and complete, microfiches, photographic negatives, 
microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at 
the laboratories, and at medico-technical departments involved in the clinical trial. 
10.3. 
Records Retention 
 
It is the investigator’s responsibility to retain study essential documents for at least 2 
years after the last approval of a marketing application in their country and until there are 
no pending or contemplated marketing applications in their country or at least 2 years 
have elapsed since the formal discontinuation of clinical development of the 
investigational product.  These documents should be retained for a longer period if 
required by an agreement with the sponsor.  In such an instance, it is the responsibility 
of the sponsor to inform the investigator/institution as to when these documents no 
longer need to be retained.  
 
11. Study Monitoring, Auditing, and Inspecting 
11.1. 
Study Monitoring Definition 
Study Monitoring is the oversight of the progress of a research study and verifying 
that it is conducted, recorded, and reported in accordance with the protocol, standard 
operating procedures, Good Clinical Practice (GCP), and federal regulations. 


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This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized by the study sponsor 
Monitoring oversees protocol and regulatory compliance, participant’s welfare and 
safety.  Monitoring is a recurring observation of a study as it progresses. 
11.2. 
Study Monitoring 
 
The Study Sponsor is responsible for assigning staff to monitor the research study. 
The Study Monitor will conduct all monitoring activities in accordance with the Study 
Monitoring Plan. Study Monitors will review all required regulatory documents, subject 
charts and Case Report Forms (CRFs) for completion and accuracy.  
 
Study Monitoring Plan 
 
The Study Monitoring Plan will be prepared prior to activation of the study and will be 
implemented after accrual to the study. The frequency and intensity of monitoring 
activities depend on several factors, including risk to study subjects, complexity of the 
study protocol, and implications of the research findings. The higher the risk to 
subjects, the more frequently monitoring will be conducted. Other factors that may 
increase monitoring frequency include the projected enrollment number, the/ 
anticipated rate of subject accrual and protocol compliance. 
 
Study Monitoring Visits 
 
The Principal Investigator will allocate adequate time and space for monitoring 
activities.  The Principal Investigator will also ensure that the Study Monitor or other 
Compliance or Quality Assurance Reviewer is given access to all requested study-
related documents and facilities if necessary. 
 
Monitoring visits usually take place where the study is being conducted. There will be     
occasions where monitoring will take place in the IND Support office. 
 
Monitoring Visits are usually composed of Study Initiation Visit, Interim Visits and the 
Study Close-out Visit. Principal Investigators will be informed of upcoming Visits and 
will be given adequate time to prepare for a Monitoring Visit. 
 
Frequency of Visits 
 
Enrollment will be complete when up to 25 subjects are enrolled in the study. 
Monitoring visits will be conducted periodically throughout the study as described 
below:   
 
• The first monitoring visit will occur after the first subject from each 
cohort has completed their research imaging visit. 
 
• A second monitoring visit will be conducted when approximately 
5 subjects cohort 1 and 5 subjects from the Cohorts 2 and 3 have 
completed their research imaging visit.  3 subjects form Cohort 1 
will be evaluated and 2 subjects from Cohorts 2 and 3 will be 
evaluated. 
 


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This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized by the study sponsor 
• A third monitoring visit will be conducted after  all subjects have 
completed their research imaging visits. At this time 3 additional 
subjects from the  Cohort 1 will be evaluated.   
This visit may also serve as the close-out monitoring visit. 
 
Data Review 
 
The study Regulatory Binder, subject charts and Case Report Forms (CRFs) will 
be reviewed at each monitoring visit.   
 
11.3. 
Documentation of the Monitoring Visit 
 
All monitoring visit findings will be documented on the Monitor’s Report and a copy will 
be sent to the Principle Investigator. Any findings from the visit will require resolution 
within 30 working days 
 
11.4. 
Auditing and Inspecting 
 
The Principal Investigator will also permit study-related audits and inspections 
required by any University Compliance and/or Quality Assurance group, the EC/IRB 
and any government regulatory body including the FDA and according to their 
timeline.  
 
12. Ethical Considerations 
 
This study is to be conducted accordance with applicable US government regulations and 
international standards of Good Clinical Practice, and applicable institutional research 
policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent 
Ethics Committee (EC) or Institutional Review Board (IRB), in agreement with local legal 
prescriptions, for formal approval of the study conduct.  The decision of the EC/IRB 
concerning the conduct of the study will be made in writing to the investigator and a copy of 
this decision will be provided to the sponsor before commencement of this study.   
 
All subjects for this study will be provided a consent form describing this study and 
providing sufficient information for subjects to make an informed decision about their 
participation in this study.  This consent form will be submitted with the protocol for review 
and approval by the EC/IRB for the study.  The formal consent of a subject, using the 
EC/IRB-approved consent form, must be obtained before that subject undergoes any study 
procedure.  The consent form must be signed by the subject or legally acceptable 
surrogate, and the investigator or investigator-designated research professional obtaining 
the consent.  
 
Neither the complete nor any part of the results of the study carried out under this protocol, 
nor any of the information provided by the sponsor for the purposes of performing the study, 
will be published or passed on to any third party without the consent of the study sponsor.  


11C-Acetate PET/CT in neuroinflammation 
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CONFIDENTIAL 
This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized by the study sponsor 
Any investigator involved with this study is obligated to provide the sponsor with complete 
test results and all data derived from the study. 
 
13. Subject Stipends or Payments 
 
Subjects will receive $75 for completing the 11C-Acetate PET/CT scan appointment.  If the 
subject obtains an LP for the purpose of this study, they will receive an additional $50. If the 
patient completes the MRI as part of this study then they will receive an additional $50. The 
compensation will be mailed from the University’s Accounts Payable Department. All 
necessary information (e.g. W9 form) required by Accounts Payable will be collected at the 
study visits. We will provide parking vouchers for the day of the 11C-Acetate PET/CT scan 
appointment, the day of the Amyloid brain PET/CT scan (if completed for this study only) 
and the day of the Brain MRI (if completed only for this study).  
 
14. References 
 
1. 
Muir D, Berl S, Clarke DD. Acetate and fluoroacetate as possible markers for glial metabolism in 
vivo. Brain research. Aug 20 1986;380(2):336-340. 
2. 
Wyss MT, Weber B, Treyer V, et al. Stimulation-induced increases of astrocytic oxidative 
metabolism in rats and humans investigated with 1-11C-acetate. Journal of cerebral blood flow 
and metabolism : official journal of the International Society of Cerebral Blood Flow and 
Metabolism. Jan 2009;29(1):44-56. 
3. 
Wyss MT, Magistretti PJ, Buck A, Weber B. Labeled acetate as a marker of astrocytic 
metabolism. Journal of cerebral blood flow and metabolism : official journal of the International 
Society of Cerebral Blood Flow and Metabolism. Aug 2011;31(8):1668-1674. 
4. 
Takata K, Kato H, Shimosegawa E, et al. 11C-acetate PET imaging in patients with multiple 
sclerosis. PloS one. 2014;9(11):e111598. 
5. 
Volkow ND, Kim SW, Wang GJ, et al. Acute alcohol intoxication decreases glucose metabolism 
but increases acetate uptake in the human brain. NeuroImage. Jan 1 2013;64:277-283. 
6. 
Heneka MT, Carson MJ, El Khoury J, et al. Neuroinflammation in Alzheimer's disease. The 
Lancet. Neurology. Apr 2015;14(4):388-405. 
7. 
Wyss-Coray T, Loike JD, Brionne TC, et al. Adult mouse astrocytes degrade amyloid-beta in vitro 
and in situ. Nature medicine. Apr 2003;9(4):453-457. 
8. 
Serrano-Pozo A, Mielke ML, Gomez-Isla T, et al. Reactive glia not only associates with plaques 
but also parallels tangles in Alzheimer's disease. The American journal of pathology. Sep 
2011;179(3):1373-1384. 
9. 
Kreisl WC, Lyoo CH, McGwier M, et al. In vivo radioligand binding to translocator protein 
correlates with severity of Alzheimer's disease. Brain : a journal of neurology. Jul 2013;136(Pt 
7):2228-2238. 
10. 
Okello A, Edison P, Archer HA, et al. Microglial activation and amyloid deposition in mild cognitive 
impairment: a PET study. Neurology. Jan 6 2009;72(1):56-62. 
11. 
Schuitemaker A, Kropholler MA, Boellaard R, et al. Microglial activation in Alzheimer's disease: 
an (R)-[(1)(1)C]PK11195 positron emission tomography study. Neurobiology of aging. Jan 
2013;34(1):128-136. 
12. 
Varley J, Brooks DJ, Edison P. Imaging neuroinflammation in Alzheimer's disease and other 
dementias: Recent advances and future directions. Alzheimer's & dementia : the journal of the 
Alzheimer's Association. Sep 2015;11(9):1110-1120. 
13. 
Yasuno F, Kosaka J, Ota M, et al. Increased binding of peripheral benzodiazepine receptor in 
mild cognitive impairment-dementia converters measured by positron emission tomography with 
[(1)(1)C]DAA1106. Psychiatry research. Jul 30 2012;203(1):67-74. 
14. 
Spence AM, Mankoff DA, Muzi M. Positron emission tomography imaging of brain tumors. 
Neuroimaging clinics of North America. Nov 2003;13(4):717-739. 


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This material is the property of the University of Pennsylvania.  Do not disclose or use except as authorized by the study sponsor 
15. 
Yu EY, Muzi M, Hackenbracht JA, et al. C11-acetate and F-18 FDG PET for men with prostate 
cancer bone metastases: relative findings and response to therapy. Clinical nuclear medicine. 
Mar 2011;36(3):192-198. 
16. 
Mankoff DA, Shields AF, Graham MM, Link JM, Krohn KA. A graphical analysis method to 
estimate blood-to-tissue transfer constants for tracers with labeled metabolites. Journal of nuclear 
medicine : official publication, Society of Nuclear Medicine. Dec 1996;37(12):2049-2057. 
17. 
PMOD Technologies, Zurich, Switzerland: http://www.pmod.com. 
18. 
Wellcome Department of Imaging Neuroscience, University College London, United Kingdom: 
http://www.fil.ion.ucl.ac.uk/spm/. 
19. 
Joshi AD, Pontecorvo MJ, Lu M, Skovronsky DM, Mintun MA, Devous MD, Sr. A Semiautomated 
Method for Quantification of F 18 Florbetapir PET Images. Journal of nuclear medicine : official 
publication, Society of Nuclear Medicine. Nov 2015;56(11):1736-1741. 
20. 
Ong K, Villemagne VL, Bahar-Fuchs A, et al. (18)F-florbetaben Abeta imaging in mild cognitive 
impairment. Alzheimer's research & therapy. 2013;5(1):4.