Clinical trial NCT03702816
Conditions: Alzheimer Disease Parkinson Disease Inflammation
Keywords: neuroinflammation
Sponsor: Aaron Ritter, MD
Start date: 2018-12-13; Completion date: 2019-09-29
Enrollment: 24 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The complex pathological cascades leading to both Alzheimer's disease (AD) and Parkinson's disease (PD) involve, at various points, inflammation. Since inflammation is a treatable symptom, understanding how and when it impacts the brain, and where specifically in the brain, would offer important guidance in the development of new treatments, sorely needed in both diseases.

Microglia play an important anti-inflammatory role, and produce a substance, mitochondrial translocator protein (TSPO), whose presence can be used as a marker of regional inflammation. GE180 is a newly developed PET ligand which binds to TSPO and hence can be used in imaging studies to analyze regional inflammation in living patients. In prior studies it has shown regional specificity in multiple sclerosis and brain injury. In the current study, the investigators will be using GE180 to analyze regional and global inflammation in the brains of patients with AD and PD at a single time point.

The results of the current study will provide enriched understanding of inflammation in these conditions, and potentially provide preliminary data to inform design of future interventional trials.

Detailed description:
This study will involve a cohort that is currently being established at the Cleveland Clinic Lou Ruvo Center for Brain Health. The cohort has been established under the NIH Center of Biomedical Research Excellence (COBRE) grant and involves annual collection of detailed neuropsychological testing and biomarkers (blood and neuroimaging) from all participants annually. Data are filed in a registry (CNTN). Participants include healthy controls, participants with PD (with and without mild cognitive impairment (MCI)) and patients with MCI (with or without positive florbetapir scan, which demonstrates underlying AD changes likely causing the cognitive impairment) and patients with AD. For the current study, we will focus on patients with MCI with associated underlying AD or PD.

Participants will undergo GE180 PET one time during the study. The approach to PET data collection and analysis will be similar to work done previously with an earlier generation ligand (Edison et al., 2008) and to other work with this tracer (Fan et al., 2016). Participants will complete ECGs and have their vitals taken prior to and immediately following injections. Briefly, the ligand will be injected, there will be a 90 minute uptake period, and scan acquisition will commence for 30 minutes, and will be collected in list mode and rebinned into 18 time frames post acquisition.

The total duration of the study visit will be around 4 hours, and the participants will receive $50 compensation for the visit.

Arms: arm 1: Alzheimer's Disease

GE180 PET Scan arm 2: Parkinson's Disease

GE180 PET Scan arm 3: Control Group

GE180 PET Scan arm 4: Mild Cognitive Impairment

GE180 PET Scan
Interventions: intervention 1: GE180 PET Scan
Intervention descriptions: intervention 1: GE180 PET Scan

Protocol documents:
Prot_SAP_000.pdf: 
Protocol: The Relationship between Neuropsychological Testing and MRI, PET and Blood Biomarkers in 
Neurodegenerative Disease (NIH): AIM 2 
 
Cleveland Clinic Lou Ruvo Center for Brain Health 
Neurological Institute 
Cleveland Clinic 
THE RELATIONSHIP BETWEEN NEUROPSYCHOLOGICAL TESTING 
AND MRI, PET AND BLOOD BIOMARKERS IN 
NEURODEGENERATIVE DISEASE (NIH): AIM 2 
 
 
 
 
 
 
 
Co-Principal Investigator: 
Sponsor-Investigator: 
Aaron Ritter, MD 
888 West Bonneville Avenue 
Las Vegas, NV, 89106 
702-483-6049 
rittera@ccf.org 
Co-Principal Investigator,  
Co-Investigator: 
Protocol version number: 
Jessica Caldwell, PhD 
Jeff Cummings, MD 
7 
 
Version date: 
1/3/2020 


Title: The Relationship between Neuropsychological Testing and MRI, PET and Blood Biomarkers in 
Neurodegenerative Disease (NIH): AIM 2 
 
 
Co-PIs: Aaron Ritter, MD and Jessica Caldwell, PhD 
 
 
 
2 
 
 
 
ABBREVIATIONS 
AD 
 
Alzheimer’s disease 
AE 
 
Adverse Event 
BAA 
 
Business Associate Agreement 
CNTN  
Center for Neurodegeneration and Translational Neuroscience 
COBRE 
Center of Biomedical Research Excellence 
DRS 
 
Dementia Rating Scale 
eCRF  
Electronic Case Report Form 
FDA 
 
Food and Drug Administration 
GE180 
(S)-N,N-diethyl-9-(2-[18F]fluoroethyl)-5-methoxy-2,3,4,9-tetrahydro-1H-
carbazole-4-carboxamide ([18F]GEH120714) also known as Flutriciclamide 
(18F-GE180) an experimental PET tracer 
ICMJE 
International Committee of Medical Journal Editors 
IRB 
 
Institutional Review Board 
MCI 
 
Mild cognitive impairment 
MoCA  
Montreal Cognitive Assessment 
MRI 
 
Magnetic Resonance Imaging 
MTA  
Material Transfer Agreement 
PD 
 
Parkinson’s disease 
PET 
 
Positron Emission Tomography 
SAE 
 
Serious Adverse Event 
TSPO  
Translocator Protein 
UNLV  
University of Nevada, Las Vegas 
UP 
 
Unantcipated Problems 
 
 


Title: The Relationship between Neuropsychological Testing and MRI, PET and Blood Biomarkers in 
Neurodegenerative Disease (NIH): AIM 2 
 
 
Co-PIs: Aaron Ritter, MD and Jessica Caldwell, PhD 
 
 
 
3 
 
Table of contents 
1. Background and Significance 
1.1 Purpose ...........................................................................................................................6 
2. Study Objectives .....................................................................................................................6 
3. Study Design ...........................................................................................................................6 
4. Population ...............................................................................................................................7 
4.1. Inclusion/Exclusion criteria ..........................................................................................7 
4.2 Subject recruitment ........................................................................................................7 
4.3 Subject screening ...........................................................................................................7 
5. Study Procedures ....................................................................................................................8 
4.1 
Recruitment at CNTN Study Visit ...........................................................................8 
4.2 
Consent Visit ............................................................................................................8 
4.3 
PET...........................................................................................................................8 
6. Data analysis ...........................................................................................................................8 
7. Study Drug ..............................................................................................................................9 
7.1 Investigational Agent .....................................................................................................9 
7.2 Preclinical data ...............................................................................................................9 
7.3 Clinical data to date .....................................................................................................10 
7.4 Dose rationale ..............................................................................................................10 
7.5 Preparation and Administration of Study Drug ...........................................................11 
7.6 Receipt of Drug and Storage ........................................................................................11 
8. Data management..................................................................................................................11 
8.1 Records Retention ........................................................................................................11 
9. Safety Monitoring .................................................................................................................12 
9.1. Ethical considerations .................................................................................................12 
9.2. Privacy ........................................................................................................................13 
9.3. Adverse Events and Data Monitoring Committee (DMC) .........................................13 
9.4. Informed consent procedures ......................................................................................13 
10. Publication of study protocol and results ............................................................................14 
11. Study Monitoring, Auditing and Inspecting .......................................................................14 
11.1 Study Monitoring Plan ...............................................................................................14 
11.2 Auditing and Inspecting .............................................................................................14 
12. Study Finances ....................................................................................................................14 
12.1 Funding Source ..........................................................................................................14 


Title: The Relationship between Neuropsychological Testing and MRI, PET and Blood Biomarkers in 
Neurodegenerative Disease (NIH): AIM 2 
 
 
Co-PIs: Aaron Ritter, MD and Jessica Caldwell, PhD 
 
 
 
4 
 
12.2 Conflict of Interest .....................................................................................................14 
12.3 Subject Stipends or Payments ....................................................................................15 
14. References ...........................................................................................................................15 
 
  
 


Title: The Relationship between Neuropsychological Testing and MRI, PET and Blood Biomarkers in 
Neurodegenerative Disease (NIH): AIM 2 
 
 
Co-PIs: Aaron Ritter, MD and Jessica Caldwell, PhD 
 
 
 
5 
 
1. Background and Significance 
This is a research study that will evaluate imaging characteristics of a PET tracer named GE180  
that indicates regional neuroinflammation in cognitively normal older adults, patients with mild 
cognitive impairment, and those with Parkinson’s (PD) or Alzheimer’s disease (AD). All 
participants will be part of a registry from the Center for Neurodegeneration and Translational 
Neuroscience (CNTN), which provides a well characterized pool of participants with the 
aforementioned diagnoses. 
Inflammation has been shown to be part of the early pathogenic mechanism of AD1 and PD2, and 
represents an important potential target for therapy. These two diseases have distinct patterns of 
cognitive dysfunction, especially early in the disease course. In AD, amyloid depositions occur 
early in the disease process and by the time clinical symptoms are evident, are diffuse in the brain, 
while the spread of tau pathology in the brain occurs in a predictable topography, with spread from 
the medial temporal regions early in the disease to the association cortices of the frontal and 
parietal lobes as the disease progresses. This topographical distribution is closely associated with 
specific cognitive changes, which can be tracked with neuropsychological tests. The spread of 
disease-specific proteins in PD is less well understood, but there are particular cognitive 
trajectories that can be followed. Inflammation has also been shown to play a role in these 
disorders. If inflammation is a common element which can be visualized and quantified regionally, 
and is associated with particular cognitive dysfunction, then this would (a) demonstrate a target of 
therapy which may not be disease specific and (b) identify a way to measure the impact of any 
intervention. 
Microglia are the central nervous system’s phagocytes, and are distributed throughout the brain. 
They are very active and, in addition to an anti-inflammatory role, they have a role in plasticity 
and remodeling of synapses3. GE180 is an experimental PET tracer that binds to a mitochondrial 
translocator protein (TSPO), which is produced by microglia and is a putative biomarker for 
inflammation. TSPO is minimally expressed in the CNS in humans when healthy, but dramatic 
increases are apparent in response to neuronal damage and inflammation4. There have been some 
human studies with GE180 already5 and it is similar to an earlier experimental tracer 11C-(R)-
PK11195 which has been tested more exhaustively over the last 20 years6. GE180 has been found 
to be superior to 11C-(R)-PK11195 due to stronger signal to noise ratio and different 
pharmacokinetic properties including longer half-life7. Animal studies have shown GE180 to 
detect both AD-related and age-related changes in mice8. Several studies are currently underway 
in the UK, Canada and the USA using GE180 in disorders including AD and PD. To our 
knowledge, none of these studies uses as in depth cognitive profiling as will be used in the current 
study. 
Early research with a more primitive PET tracer 11C-(R)-PK11195 revealed that AD patterns of 
inflammation were suggestive of regional change and associated with reduced cognition as 
assessed using a nonspecific measure9 . In PD, two different patterns emerged, one being more 
general, the other more specific to certain cortical regions. This early research did not take 
advantage of neuropsychological methods which might elucidate the specific cognitive change 


Title: The Relationship between Neuropsychological Testing and MRI, PET and Blood Biomarkers in 
Neurodegenerative Disease (NIH): AIM 2 
 
 
Co-PIs: Aaron Ritter, MD and Jessica Caldwell, PhD 
 
 
 
6 
 
seen in these two diseases. By applying these methods, we hope to gain a far deeper understanding 
of the relationship between microglial activation and cognition across these two diseases.   
1.1 Purpose  
The purpose of the study is to assess the relationship between (a) overall and (b) regional 
inflammation with (a) overall and (b) domain-specific cognitive function in AD and PD. If we 
demonstrate a correlation between regional uptake of GE180 and specific cognitive profiles, 
further research will be warranted to investigate whether therapeutically driven reduction in 
inflammation also leads to improvement in cognition.  
 
2. Study Objectives 
The overall objective is to establish the relationship between regional microglial activation and  
neuropsychology test scores in patients with diagnoses of Alzheimer’s disease and Parkinson’s 
disease.  
 
We will test the hypothesis that regional enhancements in microglial activation would be reflected 
in neuropsychological test scores: The degree of memory impairment would be related to medial 
temporal lobe microglial activation, visuospatial impairment would relate to more posterior 
activation, executive dysfunction would relate to frontal activation. We will also test the hypothesis 
that higher levels of global inflammation will be associated with more severe cognitive 
impairment, especially in patients with mild cognitive impairment.   
 
3. Study Design 
This study will involve a cohort that is currently being established at the Cleveland Clinic Lou 
Ruvo Center for Brain Health. The cohort has been established under the NIH Center of 
Biomedical Research Excellence (COBRE) grant and involves annual collection of detailed 
neuropsychological and biomarkers (blood and neuroimaging) from all participants annually. Data 
are filed in a registry (CNTN). Under a data sharing agreement, all neuropsychological, blood 
screening, MRI, and PET data from CNTN will be available to Dr. Ritter (who is also a Clinical 
Core Leader on the COBRE project). Participants include healthy participants, participants with 
PD (with and without mild cognitive impairment (MCI)) and patients with MCI (with or without 
positive florbetapir scan, which demonstrates underlying AD changes likely causing the cognitive 
impairment) and patients with AD. For the current study, we will focus on patients with MCI with 
associated underlying AD or PD.   
 
Participants will undergo GE180 PET. Our approach to PET data collection and analysis will be 
similar to work done previously with an earlier generation ligand 10 and to other work with this 
tracer5. We will complete ECGs prior to and immediately following injections. Briefly, the ligand 
will be injected, scan acquisition will then begin and will be collected in list mode and rebinned 
into 18 time frames post acquisition.   
 


Title: The Relationship between Neuropsychological Testing and MRI, PET and Blood Biomarkers in 
Neurodegenerative Disease (NIH): AIM 2 
 
 
Co-PIs: Aaron Ritter, MD and Jessica Caldwell, PhD 
 
 
 
7 
 
The total duration of the study will be around 2 hours, and the participants will receive $50 
compensation for the visit.  
 
4. Population 
A total of 70 participants will be recruited from the CNTN cohort. Specifically, we will recruit 10 
healthy participants, 20 MCI (10 of whom will be florbetapir positive, and 10 florbetapir negative), 
20 AD patients and 20 PD patients, 10 of whom will be cognitively intact and the other 10 will 
meet criteria for MCI. Participants will be age matched and they will be extracted from the larger 
CNTN cohort which stratifies to race based on the Nevada data from the 2014 US Census.  
4.1. Inclusion/Exclusion criteria 
Inclusion criteria 
1. Be enrolled in CNTN 
2. Aged 55 to 90 
3. Available study partners 
 
4. For MCI patients, fit criteria based in Movement Disorders Task Force or NIA 
 
Exclusion criteria 
1. Significant neurological disorders other than AD or PD; 
2. Unstable medical conditions 
3. History of major psychiatric diseases 
4. MRI evidence of infarction or other focal lesion or multiple lacunes  
5. Clinically significant abnormalities in B12 or TSH 
6. Identified as having a common polymorphism (rs6971) in the TSPO gene which has been 
shown to reduce binding affinity of tracers similar to GE18011. This testing will be done as 
part of their CNTN participation.   
In addition, subjects must answer questions in regards to their history of radiation exposure over 
the past year (past 12 months to day of screening). If their radiation exceeds half of the 
recommended amount (any amount greater than 25 mSv), they may not participate at the present 
time. However, assuming they are eligible against all other inclusion/exclusion criteria, they may 
be eligible for a scan in the future once their 12 month exposure is less than half of the 
recommended amount.  
4.2 Subject recruitment 
All participants will be recruited via the CNTN cohort. 
4.3 Subject screening  
All subjects who are part of the CNTN will be eligible for participation in the current study, other 
than those carrying a known genetic polymorphism, TSPO rs6971 polymorphism which impacts 
binding of GE180 and other TSPO binding agents, which occurs in approximately 10% of the 


Title: The Relationship between Neuropsychological Testing and MRI, PET and Blood Biomarkers in 
Neurodegenerative Disease (NIH): AIM 2 
 
 
Co-PIs: Aaron Ritter, MD and Jessica Caldwell, PhD 
 
 
 
8 
 
population. We will not recruit patients with this polymorphism. Since they will have already been 
followed in CNTN we will have this data prior to recruitment.  
 
5. Study Procedures 
The below procedures will be completed on all participants: 
4.1 Recruitment at CNTN Study Visit 
The CNTN has been collecting data since mid-2016. We will recruit participants as they come for 
their follow-up visit. Suitable participants will be made available for the study by the CNTN staff 
if they agree for data to be shared with this study. At that point, study staff will contact the potential 
participant and conduct a brief screen over the telephone or in person, explaining the content of 
the current sub-study. If the potential participant demonstrates interest and willingness to continue, 
they will be asked to come in to discuss informed consent at their next CNTN visit.  We will recruit 
patients into each cohort from the CNTN, at which point they will already have been characterized 
with neurology, neuropsychology and neuroimaging (amyloid PET and MRI) as well as having 
blood work completed. CNTN participants will be invited to recruit in the current study at their 
CNTN visit. 
4.2 Consent Visit 
This could potentially happen on the same day as the CNTN visit, in order to reduce the number 
of study visits. Participants will be given time to review the materials with their study partner, and 
then with the coordinator who will allow them to ask any questions they may have. Once fully 
informed written consent is obtained by both the patient and their study partner, the baseline 
GE180 PET visit will be scheduled.   
4.3 PET 
The participants will come for their visit, have their vitals and ECG taken, and will have fresh 
blood samples drawn. GE180 will then be injected and the scan will be performed. They will then 
have a secondary ECG. After this they will be free to leave. They will receive a wellness phone 
call from the study coordinator 48-72 hours later. The coordinator will stop making attempts to 
reach the participant after three unanswered calls.   
6. Data analysis 
Study size determination was completed using another previously published study 12 that used an 
earlier generation microglial ligand. Based on binding potentials in the same region (anterior 
cingulate cortex) we calculated that at a significance level of .05, and in order to attain a correlation 
of r=.8 we would require 10 subjects for 90% power in analyses of microglial activation from each 
of the regions of interest and the key cognitive outcome measures.  Given that we are using a 
different ligand and will be looking at more regions, we have increased the number so we can be 
confident in our results. It is important to note that sample size calculations based on neuroimaging 


Title: The Relationship between Neuropsychological Testing and MRI, PET and Blood Biomarkers in 
Neurodegenerative Disease (NIH): AIM 2 
 
 
Co-PIs: Aaron Ritter, MD and Jessica Caldwell, PhD 
 
 
 
9 
 
data are limited, but the numbers proposed here are similar to or in excess of other studies using 
and novel PET ligands 10, thus we predict that the group sizes will be sufficient. 
Data Analysis will be conducted by the study team under the direction of the Principal Investigator.  
Image analysis will be conducted using parametric analytic technique in SPM12, combining 
GE180 results with the participants’ own MRIs. This will allow us to compare individuals in each 
disease group with an averaged image of controls. In addition, we will be able to extract uptake 
values in regions of interest to compare across groups and in relation to test scores. This approach 
is being used by colleagues at another site that is currently studying GE180 in older adults.  
Microglial activation data from each of the region of interest (ROI), in addition to overall cortical 
load, will be extracted. It will be represented statistically as a function of cortical thickness in that 
region. These data will be used in two analytic steps: the first using measures of overall cognitive 
function (assessed with the Dementia Rating Scale (DRS) and Montreal Cognitive Assessment 
(MoCA)), and the second using key cognitive outcome measures specific to the domains of 
memory, visuospatial function, language and executive functioning. These measures are all 
collected as part of the CNTN.  We will use a linear regression model to assess whether regional 
microglial activation predicts cognitive performance.  We will also complete repeated measures 
analyses to assess whether there is a change in microglial activation between time points and, if 
so, if this relates to changes in the cognitive measures.  
6.1 Predicted outcome: At baseline, we expect to find overall cortical load of GE180 uptake to 
predict summary scores on the DRS and MoCA, and for regional loads to predict specific cognitive 
domains. In PD-MCI we expect more cortical enhancement than in the PD-NCI subjects. Specific 
expectations across disease states include that hippocampal and temporal cortex load will be 
related to memory, frontal cortex load to executive ability, parietal load to visuospatial ability.  We 
also expect baseline levels of microglia to predict future decline in cognition but there will not be 
an increase in microglial activation over time.  This final expectation is based on data collected 
with the earlier generation microglial ligands, but change over time is yet to be explored in humans 
with GE180. 
7. Study Drug 
7.1 Investigational Agent 
GE180 is a PET imaging agent which was developed as a non-invasive in vivo probe of 
neuroinflammation. The mechanism of action is based on its high affinity for TSPO and high 
selectivity, with little binding to other receptors, transporters and channels. TSPO is elevated in 
response to neuronal damage and inflammation, such as occurs in neurodegenerative disease. In 
vitro studies support GE180’s high affinity to TSPO and high selectivity, with little binding to 
other receptors, transporters and channels.   
7.2 Preclinical data 
Nonclinical pharmacology data of GE180 supports its potential use to visualize TSPO in vivo.  In 
preclinical models of stroke and inflammation, GE180 has been shown to be effective in detecting 


Title: The Relationship between Neuropsychological Testing and MRI, PET and Blood Biomarkers in 
Neurodegenerative Disease (NIH): AIM 2 
 
 
Co-PIs: Aaron Ritter, MD and Jessica Caldwell, PhD 
 
 
 
10 
 
inflammation in animal brains7,13.  Specifically, in mouse models of normal aging and AD, Liu 
and colleagues found a clear association between GE180 uptake and amyloid plaques, as well as 
immunohistochemical co-localization of GE180 and other microglia markers. They also showed 
an age-dependent elevation in whole brain uptake consistent with the notion that both aging and 
AD pathogenesis involve increased inflammation8.  
7.3 Clinical data to date 
Human studies of early inflammatory markers were hampered by reduced binding affinity14 and 
difficulty distinguishing the signal from noise related to uptake in the endothelial cells of the blood 
brain barrier and venous signal15. It was hoped that GE180 would counteract these problems and 
enhance the visualization of neuroinflammation in humans. Several clinical studies are currently 
underway. The first publication of human research has been focused on methodology5. Fan et al 
used 15 healthy adults aged 50-85 years. Their study was used to optimize scan length and to 
investigate the feasibility of generating parametric maps using graphical analysis. Results from 
their study have been incorporated into the design of the current study.   
7.4 Dose rationale  
GE180 is an intravenously administered diagnostic radiopharmaceutical used for PET. It is 
formulated as a clear, colorless aqueous solution containing NMT 10.0% v/v ethanol in phosphate 
buffered saline (PBS) with a pH of 6 – 8. It contains 90 – 110% of the labelled amount of 18F 
expressed as MBq/mL. There are no preservatives. It is manufactured to GMP standards and is 
supplied in a sterile endotoxin-free 10 mL glass vial. Study participants will receive a standard 
dose of 185MBq with maximum radioactivity dose of 270 MBq in a maximum volume of 10 mL 
(bolus) of GE180, containing not more than 2 μg/mL GEH120714 (20 μg for a 10 mL dose).This 
is consistent with other sites using the tracer.  


Title: The Relationship between Neuropsychological Testing and MRI, PET and Blood Biomarkers in 
Neurodegenerative Disease (NIH): AIM 2 
 
 
Co-PIs: Aaron Ritter, MD and Jessica Caldwell, PhD 
 
 
 
11 
 
7.5 Preparation and Administration of Study Drug 
GE180 will be manufactured as a radiolabeled drug product by Banner Health in Phoenix, Arizona, 
a health center that also specializes in the manufacturing and distribution of radiopharmaceuticals, 
with individual unit dosing through its own radiopharmacies and cyclotron-based PET 
manufacturing facilities. Using a GE FASTLab synthesizer with disposable cassettes 
(manufactured by GE Healthcare AS in Oslo, Norway), Banner will produce individual doses. 
Individual doses will be delivered to the Cleveland Clinic via Banner immediately after 
production. Administration will be similar to that already performed in humans. We will 
administer 185 MBq by bolus intravenous injection (in 20 seconds) immediately before the PET. 
All scanning will be completed on the PET scanner. An initial CT will be acquired for patient 
position and for attenuation correction of the PET images. The tracer will be injected and dynamic 
emission PET images will be acquired over 30 minutes 90 minutes post injection as shown to be 
optimal GE. The imaging protocol will be as follows: 
 
Method: Iterative: OSEM-3D (do NOT use TrueX or ToF reconstruction) 4 iterations; 24 subsets 
Grid: 400 × 400 × 81 (or 109 for TrueV model) 
Zoom: 2.0 (results in voxel size of ~1.018 mm)  
Smoothing Filter: NONE (All-pass or ‘0.0’)  
Match CT: ‘Off’ or ‘No’ (results in PET slice thickness of ~2.027 mm)  
All corrections ‘On’ 
 Images will then be corrected for attenuation, random and scattered emissions based on the 3D.  
7.6 Receipt of Drug and Storage 
Doses will be requested from Banner Health one week prior to need. Details of drug ordering, 
receipt and use will be kept on a log onsite and completed by designated study staff. These staff 
will verify that the dose is delivered intact, to the best of their ability. Any apparent discrepancies 
will be reported to the PI and Banner Health immediately, and the dose will not be used.  
GE180 will be stored upright in a lead shielded container at 15 – 30oC.  
8. Data management 
All participants will be assigned a unique study-specific ID when enrolled. Data will be housed in 
a Part 11 compliant database being created with OpenClinica. This same database will also house 
all COBRE data which will be available to Dr. Ritter his role as Core Leader on that grant-
sponsored project. Data will be entered by Dr. Ritter or his delegate, and both will be trained in 
the handling sensitive patient data. 
8.1 Records Retention 
Records will be retained for at least 6 years following the termination of the study. Records will 
be retained digitally on secure servers and paper documents will be secured in locked cabinets with 
access limited to study staff.  


Title: The Relationship between Neuropsychological Testing and MRI, PET and Blood Biomarkers in 
Neurodegenerative Disease (NIH): AIM 2 
 
 
Co-PIs: Aaron Ritter, MD and Jessica Caldwell, PhD 
 
 
 
12 
 
 
8.2 Blood Samples Analyses 
Neuroinflammation is increasingly identified as a key driver of neurodegeneration. However, 
current studies typically use peripheral blood to identify evidence of neuroinflammatory processes. 
These have not been correlated with changes in the central nervous system.  
We will draw blood markers of inflammation to correlate with changes seen on GE180. 
Inflammatory markers will be collected, stored, and analyzed at UNLV by Jefferson Kinney, Ph.D 
who is covered under an existing Business Associate Agreement (BAA) with LRCBH.   
On the day of the scan, these samples will be picked up by a member of the UNLV team to be 
processed and stored. Samples will be picked up within two hours of blood draw. The de-linking 
of the sample from the participant’s PHI occurs at the time of collection at LRCBH. The identity 
of participants will not be shared with the UNLV team. The participant’s identification number 
will be affixed to the specimen tubes along with date of blood draw. LRCBH will maintain a 
database for tracking all samples into the CTRC that will include the following information: study 
ID number, date of collection, cohort, age, gender. All clinical data will be de-identified and study 
personnel outside Cleveland Clinic will not have access to the data key. Biospecimen management 
for sample receipt, processing, and analysis, has been approved by the UNLV Institutional Review 
Board and the stored specimens will be in accordance with the rules and procedures established 
by the UNLV IRB. 
Additional samples may be sent to other collaborators provided that an approved Material Transfer 
Agreement (MTA) is put into place between this institution/individual and LRCBH. The same de-
linking process as described above will be utilized in these cases. After the de-identified sample 
has left LRCBH, it is the responsibility of the outside institution/individual and their IRB to 
develop approved protocols and procedures detailing the usage and storage of these samples. 
9. Safety Monitoring 
PET brain imaging with GE180 entails no more than minimal risk per the Investigator Brochure.  
Monitoring of this study will occur through the Cleveland Clinic Coordinating Center for Clinical 
Research, the details of which are provided in the attached Monitoring Plan.  
A Data Monitoring Committee will not be used to review safety data involving adverse advents 
for this study as all study procedures can involve no more than minimal risk.  
9.1. Ethical considerations 
This study will 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. 
This protocol and any amendments will be submitted to the Cleveland Clinic Institutional Review Board 
(IRB), for formal approval of the study conduct. The study will be monitored according to the attached 


Title: The Relationship between Neuropsychological Testing and MRI, PET and Blood Biomarkers in 
Neurodegenerative Disease (NIH): AIM 2 
 
 
Co-PIs: Aaron Ritter, MD and Jessica Caldwell, PhD 
 
 
 
13 
 
Monitoring Plan. No study recruitment will take place until FDA IND approval has been obtained, and the 
IRB has approved the 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  
9.2. Privacy   
Patient data will be analyzed in a completely de-identified format in order to minimize any risk 
to patient privacy. Information about study subjects will be kept confidential and managed 
according to the Health Insurance Portability and Accountability Act of 1996 (HIPAA). Subjects 
or a legally acceptable surrogate will provide authorization that they have been informed 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 authorization for use of the PHI. 
 The HIPAA language is included as part of the informed consent form.   
Any electronic data will be maintained on secure servers behind the Cleveland Clinic firewall and 
on the OpenClinica database as outlined above. The database will be populated by the study 
research coordinator.   
The study CRFs have been constructed for this study. All data will be collected on the CRF and 
all missing data on the CRF will be explained. 
All documents will be retained for a minimum period of six years following completion of the 
study. 
9.3. Adverse Events and Data Monitoring Committee (DMC) 
Due to the minimal risk of the study procedures the likelihood of adverse events is very low. No 
data monitoring committee will be employed for the study. Adverse events (AE) will be evaluated 
by the P.I. and reported to the Cleveland Clinic IRB for review according to the AE reporting 
protocols set forth by the IRB. FDA guidelines will also be followed in reporting adverse events.  
Unanticipated problems (UP) will be reported as soon as they occur to the IRB.  
No clinical report will be generated from the testing completed as part of this study.  
9.4. Informed consent procedures 
After detailed explanation of the study and its potential risks, informed consent will be obtained 
by a member of the study team prior to commencement of scanning. The informed consent process 
will be documented in the research record. A copy of the signed informed consent form will be 
provided to the participant and the original signed form will be stored in the research record.  


Title: The Relationship between Neuropsychological Testing and MRI, PET and Blood Biomarkers in 
Neurodegenerative Disease (NIH): AIM 2 
 
 
Co-PIs: Aaron Ritter, MD and Jessica Caldwell, PhD 
 
 
 
14 
 
 
10. Publication of study protocol and results 
Upon study completion and finalization of the study report, the results of this study will be 
presented at appropriate scientific meetings and published. Publications will comply with the 
standards of the Cleveland Clinic Foundation and the International Committee of Medical Journal 
Editors (ICMJE) guidelines. 
The study will be registered on ClinicalTrials.Gov and results will be reported there. 
 
11. Study Monitoring, Auditing and Inspecting 
11.1 Study Monitoring Plan 
This study will be monitored under the Cleveland Clinic Coordinating Center for Clinical Research.  
Monitoring activities will be carried out according to the monitoring plan (see attached).  The 
investigator will allocate adequate time for such monitoring activities. The Investigator will also 
ensure that the monitor or other compliance or quality assurance reviewer is given access to all the 
above noted study-related documents and study related facilities (for example, PET scanning suite), 
and has adequate space to conduct the monitoring visit. 
11.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, the 
sponsor, government regulatory bodies, and Institutional compliance and quality assurance groups of 
all study related documents (for example, source documents, regulatory documents, data collection 
instruments, study data etc.). The investigator will ensure the capability for inspections of applicable 
study-related facilities (for example, PET scanning suite). Participation as an investigator in this 
study implies acceptance of potential inspection by government regulatory authorities and applicable 
Institutional compliance and quality assurance offices. 
 
12. Study Finances 
12.1 Funding Source 
This study is funded through a grant from the National Institute of General Medical Sciences grant 
number 5 P20 GM109025-02. 
12.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain) must have the conflict reviewed the by Conflict of Interest Committee with a 
Committee-sanctioned conflict management plan that has been reviewed and approved prior to 
participation in this study. All Cleveland Clinic investigators will follow the Institutional conflict of 
interest policy. Each Investigator will complete a Cleveland Clinic specific Financial Disclosure 
Form per Institution requirements. 


Title: The Relationship between Neuropsychological Testing and MRI, PET and Blood Biomarkers in 
Neurodegenerative Disease (NIH): AIM 2 
 
 
Co-PIs: Aaron Ritter, MD and Jessica Caldwell, PhD 
 
 
 
15 
 
12.3 Subject Stipends or Payments 
Subjects will be paid $50 compensation for the study visit. 
13. Publication Plan 
Dr. Ritter and Dr. Caldwell, Co-Principal Investigators, have primary responsibility for 
publication of the results of this study. It is the full intention of the investigators to publish the 
results of this study as soon as possible.  
 
 
14. References 
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comprehensive review of [11C]PK11195 challengers. Eur J Nucl Med Mol Imaging. 2008;35(12):2304-2319. 
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in a preclinical model of stroke. Eur J Nucl Med Mol Imaging. 2015;42(3):503-511. 
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Liu B, Le KX, Park MA, et al. In Vivo Detection of Age- and Disease-Related Increases in 
Neuroinflammation by 18F-GE180 TSPO MicroPET Imaging in Wild-Type and Alzheimer's Transgenic 
Mice. J Neurosci. 2015;35(47):15716-15730. 
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Calsolaro V, Edison P. Neuroinflammation in Alzheimer's disease: Current evidence and future directions. 
Alzheimers Dement. 2016;12(6):719-732. 
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Edison P, Archer HA, Gerhard A, et al. Microglia, amyloid, and cognition in Alzheimer's disease: An 
[11C](R)PK11195-PET and [11C]PIB-PET study. Neurobiology of disease. 2008;32(3):412-419. 
11. 
Owen DR, Yeo AJ, Gunn RN, et al. An 18-kDa translocator protein (TSPO) polymorphism explains 
differences in binding affinity of the PET radioligand PBR28. J Cereb Blood Flow Metab. 2012;32(1):1-5. 
12. 
Yokokura M, Mori N, Yagi S, et al. In vivo changes in microglial activation and amyloid deposits in brain 
regions with hypometabolism in Alzheimer's disease. European journal of nuclear medicine and molecular 
imaging. 2011;38(2):343-351. 
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Dickens AM, Vainio S, Marjamaki P, et al. Detection of microglial activation in an acute model of 
neuroinflammation using PET and radiotracers 11C-(R)-PK11195 and 18F-GE-180. J Nucl Med. 
2014;55(3):466-472. 
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Turkheimer FE, Rizzo G, Bloomfield PS, et al. The methodology of TSPO imaging with positron emission 
tomography. Biochem Soc Trans. 2015;43(4):586-592. 
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Rizzo G, Veronese M, Tonietto M, Zanotti-Fregonara P, Turkheimer FE, Bertoldo A. Kinetic modeling 
without accounting for the vascular component impairs the quantification of [(11)C]PBR28 brain PET data. 
J Cereb Blood Flow Metab. 2014;34(6):1060-1069.