SV2A PET Imaging in Alzheimer's Disease
Phase: PHASE2
Conditions: Alzheimer Disease
Sponsor: University of Wisconsin, Madison

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SV2A PET Imaging in Alzheimer's Disease 
 
Principal Investigators: 
Barbara Bendlin, PhD 
Brad Christian, PhD 
Sterling Johnson, PhD 
 
Supported by: 
R01 AG062285 (MPI Bendlin, Christian, Johnson) 
 
 
Sponsor of IND: 
Brad Christian, PhD, University of Wisconsin-Madison holds the IND for MK6240 (IND# 134, 516) and 
for SV2A UCB-J (IND# 141177) 
 
Sterling Johnson, PhD, University of Wisconsin-Madison holds the IND for PiB (IND# 177, 114) 

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TABLE OF CONTENTS 
STUDY TEAM ROSTER ...................................................................................................................... 4 
1 
Study objectives ...................................................................................................................... 5 
1.1 
Primary Objectives ...................................................................................................................... 5 
2 
BACKGROUND and Study Context ............................................................................................ 6 
2.1 
Background ................................................................................................................................. 6 
3 
STUDY DESIGN ......................................................................................................................... 7 
4 
SELECTION AND ENROLLMENT OF PARTICIPANTS ..................................................................... 7 
4.1 
Inclusion Criteria ......................................................................................................................... 7 
4.2 
Exclusion Criteria......................................................................................................................... 7 
4.3 
Study Recruitment Plan and Enrollment Procedures ..................................................................... 9 
5 
STUDY PROCEDURES .............................................................................................................. 11 
5.1 
Schedule of Evaluations .............................................................................................................. 11 
5.2 
Description of Evaluations and Procedures .................................................................................. 11 
5.2.1 
Screening Evaluation ........................................................................................................................ 11 
5.2.2 
Consenting Procedure ...................................................................................................................... 11 
5.2.3 
MRI Protocol .................................................................................................................................... 12 
5.2.4 
PET Scans ......................................................................................................................................... 13 
5.2.5 
(Optional) Lumbar puncture (LP) ................................................................................................... 155 
5.2.6 
(Optional) FDG ............................................................................................................................... 166 
5.2.7 
Genetic Testing ................................................................................................................................ 16 
5.2.8 
Blood Labs ........................................................................................................................................ 17 
5.2.9 
Neuropsychological testing and assessments, physical and neurological exam .............................. 17 
5.2.10 Consensus Diagnosis (for those not in WRAP or ADRC) ................................................................... 17 
5.3 
Data collection from source study ............................................................................................... 18 
5.4 
Data Banking ........................................................................................................................... 199 
5.5 
Data Sharing .............................................................................................................................. 19 
6 
SAFETY Considerations ........................................................................................................... 20 
6.1 
PET Imaging ([C-11]UCB-J, [F-18]MK6240, [F-18]FDG, and [C-11]PiB radiotracers) ......................... 20 
6.2 
Risks related to disclosure of PET scan results to particpants ........................................................ 20 
6.3 
Adverse Events and Serious Adverse Events Monitoring .............................................................. 21 
6.4 
Follow-up for Adverse Events ..................................................................................................... 22 
7 
STATISTICAL CONSIDERATIONS .............................................................................................. 22 
7.1 
Sample Size Justification ............................................................................................................. 22 
8 
DATA COLLECTION ............................................................................................................... 232 
8.1 
Data Collection Forms ................................................................................................................ 22 
9 
PARTICIPANT RIGHTS AND CONFIDENTIALITY ......................................................................... 22 
9.1 
Institutional Review Board (IRB) Review ..................................................................................... 22 
9.2 
Informed Consent Forms ............................................................................................................ 22 
9.3 
Participant Confidentiality .......................................................................................................... 23 
9.4 
Study Discontinuation ................................................................................................................ 23 

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10 Data Safety Monitoring Plan (DSMP) .................................................................................... 243 
10.1 
Internal Audit and Data Safety Monitoring ................................................................................. 23 
11 Data management tools ....................................................................................................... 243 
11.1 
CoRRIE – CRM database............................................................................................................. 23 
11.2 
PANDA and PACS ...................................................................................................................... 24 
11.3 
BOOKED ................................................................................................................................... 24 
12 PRIVACY .............................................................................................................................. 255 
12.1 
Privacy and Data Storage ........................................................................................................... 25 
12.2 
CoRRIE ...................................................................................................................................... 25 
12.3 
Booked ..................................................................................................................................... 25 
12.4 
PANDA ..................................................................................................................................... 26 
12.5 
REDCap ..................................................................................................................................... 26 
12.6 
FreezerPro ................................................................................................................................. 27 
13 REFERENCES .......................................................................................................................... 28 

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STUDY TEAM ROSTER 
Principal Investigators (MPI): 
Barbara Bendlin, PhD (Contact PI) 
Sterling Johnson, PhD 
Brad Christian, PhD 
Wisconsin ADRC 
Clinical Sciences Center 
600 Highland Avenue, J5/Mezz, Madison, WI 53792 
608-265-2483 
email address: bbb@medicine.wisc.edu 
 
 
Other investigators: 
Charles Stone MD, Nathaniel Chin, MD, Cindy Carlsson, MD 
Sanjay Asthana MD 

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1 
STUDY OBJECTIVES 
Introduction: Synaptic loss is a major feature of symptomatic Alzheimer’s disease (AD) 1. 
Conversely, abundance of synapses may confer resilience to cognitive decline in the presence 
of AD pathology. The pathology-defining features of AD are amyloid plaques and 
neurofibrillary tangles and their presence and distribution can be spatially estimated in-vivo 
with amyloid and tau positron emission tomography (PET). Although these biomarkers can 
inform on the degree and location of pathology, they do not provide an indicator of their 
effect on collocated or extended in-network neural damage including synaptic density. 
Synaptic vesicle glycoprotein 2A (SV2A) is expressed ubiquitously in synapses and the 
capability of assessing SV2A in vivo may provide a direct indicator of synaptic health. Such 
information would be of high importance for staging the level of synaptic loss or conversely 
synaptic abundance in the AD continuum and may potentially improve prognostic precision. 
The PET radioligand [C-11]UCB-J is a marker of SV2A 2-4. The overarching goal of this project is 
to use [C-11]UCB-J to obtain spatial information on neuronal synapse abundance and inform 
upon disease progression. We propose to collect longitudinal amyloid, tau and SV2A PET in 
participants in the Wisconsin ADRC and WRAP across the clinical stages of AD 5, including 
cognitively unimpaired biomarker negative, unimpaired biomarker positive, mild cognitive 
impairment (MCI), and dementia due to AD. 
 
1.1 
Primary Objectives 
Specific Aim 1). Determine the extent to which [C-11]UCB-J provides unique information from 
MRI regarding neurodegeneration. Approach: We will recruit N=60 cognitively unimpaired 
participants, N=30 MCI participants, and N=30 participants with AD dementia to undergo PET 
imaging with [C-11]UCB-J. MRI will include anatomic and diffusion connectivity MRI. When 
available, ancillary cerebrospinal fluid (CSF) indicators of neurodegeneration and synapse 
function will be examined for relationships with UCB-J. 
Specific Aim 2). Determine the rate of synapse loss as reflected by [C-11]UCB-J signal across 
all participants. Rationale: Trajectories of synaptic loss are unknown in vivo. Approach: We will 
determine the longitudinal trajectories of regional synapse loss that are observed over time 
among participants who undergo repeat [C-11]UCB-J (separated by two years, same 
participants scanned for Aim 1). We will also examine trajectories by amyloid and tau load. 
Quantifying longitudinal synaptic loss is expected to eventually facilitate the identification of 
individuals who are progressing to dementia, as well as inform upon changes that are normal 
for age. 
Specific Aim 3). Determine the extent to which [C-11]UCB-J associates with cognitive decline. 
Rationale: We expect that lower baseline SV2A density and longitudinal decline in SV2A 
density in the medial temporal lobe will be associated with faster progression of cognitive 
decline. We will also test the extent to which harboring multiple pathologies (↑amyloid, 
↑tau, and ↓SV2A density) contributes to cognitive decline. Approach: We will examine core 
indices of cognitive status and continuous measures of cognitive function from the source 
cohorts and utilize mixed effects models to ascertain the effect of UCB-J amyloid and tau on 

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cognition. 
 
Specific Aim 4). Determine factors which impact synapse loss. Rationale: Several risk factors 
for cognitive decline and dementia have been identified including potentially modifiable 
factors such as insulin resistance and vascular risk factors. Approach: We will determine cross- 
sectional and longitudinal trajectories of regional synapse loss in relation to risk factors 
for cognitive decline and dementia. In order to determine insulin resistance, we will perform 
blood draw and assess fasting glucose and insulin values to determine the Homeostatic Model 
Assessment of Insulin Resistance (HOMA-IR). The impact of potentially modifiable risk factors 
on synapse loss in vivo is currently unknown. This aim will address this gap in knowledge, 
results which may translate to strategies for reducing dementia risk. 
 
2 
BACKGROUND AND STUDY CONTEXT 
2.1 
Background 
A critical gap in the field is the ability to predict with greater certainty who with AD pathology 
will progress to symptoms, and when. This project will focus on synaptic degeneration as an 
early marker of neurodegeneration and will address important as yet unanswered questions 
regarding the temporal occurrence of synaptic decline in relation to amyloid and tau 
pathology. There are clear implications of such new knowledge from this project in concepts 
relating to brain resiliency as embodied by synapse health, and to improved accuracy of 
cognitive prognosis. 
Synapse loss in AD. Synaptic loss is a key feature of AD, associated with progression from 
healthy cognition to dementia, and preceding neuronal degeneration 6-8. Even early in the 
disease, synapse density is reduced by up to 30%8. Neurogranin, a postsynaptic protein 
primarily localized to the cortex, hippocampus, and amygdala, has been used as a 
cerebrospinal (CSF) biomarker of synapse loss in AD. Using CSF neurogranin, several in vivo 
studies indicate that synapse loss is a feature of dementia and prodromal AD. CSF neurogranin 
levels are elevated in patients with AD and MCI compared to controls 9-11 and this elevation 
appears specific to AD compared to other neurodegenerative diseases 12. Moreover, higher 
CSF neurogranin levels predict conversion from MCI to AD and correlate with a greater rate of 
cognitive decline in MCI 13,14 and older controls 15. While CSF biomarkers may inform upon 
development of AD pathology, they do not provide regional information concerning brain 
areas affected by disease. Regional information obtained in vivo will be especially important 
given mixed literature16-19, and limitations in regional sampling imposed by the logistics of 
post-mortem examination. Imaging measures, such as PET, can inform upon specific regions 
affected by disease, as well as the heterogeneity of disease progression. The temporal 
relationship between the development of amyloid and tau pathology and synapse loss in AD is 
unknown. This project will begin to address this gap in knowledge. 
 
PET imaging of synapses. PET imaging of synapses is a newly developed methodology but 
expected to lead to substantial gains in knowledge of the progression of AD. Development of 
synapse imaging was born out of a medicinal chemistry program to identify antiepileptic drugs 

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with increased affinity at synaptic vesicle glycoprotein 2A (SV2A) which is expressed in 
synaptic vesicles throughout the brain. Research focused on developing PET ligands with high 
SV2A affinity and desirable absorption, distribution, metabolism, and excretion properties led 
to the development of several compounds with favorable in vivo imaging characteristics 3. Of 
these, [C-11]UCB-J is the most recently developed and demonstrates high brain uptake, fast 
kinetics, rapid metabolism, and is safe for multiple administrations3,20. 
 
3 
STUDY DESIGN 
Design: Participants will be recruited to participate in this longitudinal imaging protocol and 
be scanned with [C-11]UCBJ (synapse abundance), [F-18]MK6240 (tau tangles), [C-11]PiB 
(fibrillar amyloid). Additionally, participants will undergo an MRI (if one has not been done in 
the last 12 months), have genetic testing (if not already done with ADRC/WRAP), and 
plasma/serum will be collection for storage. Participants will, also, have the option of 
completing a lumbar puncture and FDG PET scan. Procedures occurring at baseline may be 
repeated approximately 24 months later. See table 1 in section 5: Study procedures. 
 
Patient groups: We will study approximately 120 participants who all fit within two broad 
cognitive groups: 1) cognitively unimpaired, or 2) with cognitive impairment spanning the MCI 
to mild dementia clinical stages due to presumed underlying AD etiology. 
 
Study Location: The entire study including subject recruitment, imaging and analysis will take 
place at the University of Wisconsin-Madison medical campus including the following sites: 
• Waisman Center Laboratory for Brain Imaging and Behavior: where PET and MRI imaging 
will occur as well as analysis. 
• Wisconsin Institute for Medical Research WIMR: where MRI may occur and backup PET 
scanners are located. 
• Alzheimer’s Disease Research Center (ADRC) Imaging Core in the CSC J5/Mezz; K6/3 and 
K6/4 areas of the CSC. At the ADRC Imaging Core, the images will be backed up, 
maintained, and analyzed. 
• Clinical Research Unit: where blood draws and lumbar punctures will be performed. 
• Virtual visits for completing questionnaires, the consent addendum, disclosure, and 
optional disclosure follow up visits, if applicable, may occur via phone call or UW approved 
HIPAA compliant video conferencing software, in addition to UW locations. 
• Dr. Pryzbelski’s clinic: where biomarker disclosure visits may occur 
Enrollment Window and Study Duration: Recruitment and enrollment will require as much as 
2.5 years. Applicable longitudinal imaging may occur about 104 weeks plus/minus 16 weeks 
after baseline imaging. 
 
4 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
4.1 
Inclusion Criteria 
Cognitively unimpaired adults: 
• Age: Between 55 and 89 

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• Normal Cognition: Results of most recent testing with the source cohort indicate the 
participant is cognitively unimpaired as judged by consensus or expert review 
• General health: Good general health with no conditions/medications affecting cognition or 
imaging 
• Commitment to imaging: Willing to undergo [C-11]UCB-J, [C-11]PIB, [F-18]MK6240 PET 
scans 
• An adequate MRI exam within 12 months prior to baseline. An MRI will be performed if 
not already available. 
Mild Dementia and amnestic Mild Cognitive Impairment 
• Age: 50 years or older 
• Abnormal cognitive status of MCI or dementia as judged by consensus or expert review 
using NIA-AA 2018 criteria5 
• MCIs must be affected in the memory domain but may also have other affected domains 
• Commitment to imaging: Willing to undergo [C-11]UCB-J, [C-11]PIB, [F-18]MK6240 PET 
scans. An adequate MRI exam within 12 months prior to baseline. This MRI exam will 
come from ADRC/WRAP studies. Clinical MRI's (ones obtained outside of our research 
program) will not be adequate. An MRI will be performed if not already available from 
within the research program. 
 
4.2 
Exclusion Criteria 
Candidates meeting any exclusion criteria at screening are not eligible for inclusion: 
• For women: pregnant, lactating or breastfeeding or intention to become pregnant 
• Evidence of unstable or untreated clinically significant gastrointestinal, cardiovascular, 
hepatic, renal, hematological, neoplastic, endocrine, alternative neurological, 
immunodeficiency, pulmonary, or other disorder or disease. Stable, treated chronic 
medical conditions like hypertension, hypercholesterolemia, diabetes mellitus, non- 
metastatic dermatologic or prostatic cancer, etc. are acceptable as long as they do not, in 
the study investigator’s opinion, contribute to cognitive dysfunction or limit participation 
in study procedures. 
• Any illness or other consideration that makes it unlikely that the subject will be able to 
complete the 24-month study 
• Current or prior history (within past 5 years) of significant alcohol or substance abuse as 
determined by the investigator 
• Psychiatric disorders that may interfere with the study including current major Axis I DSM- 
V disorders including but not limited to severe Major depression, current or history of 
bipolar I disorder, or schizophrenia 
• Current use of the anti-seizure medication Levetiracetam, also known as Keppra, Spritam 
or Roweepra 
• Lack of decisional capacity at the time of informed consent 
• MRI exclusion criteria include: 

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o Findings from previous MRIs within the ADRC/WRAP research program that may be 
responsible for neurologic status of the subject such as significant evidence of 
cerebrovascular disease with multiple infarcts, infectious disease, space-occupying 
lesion, normal pressure hydrocephalus, CNS trauma, or any other structural 
abnormality that may impact cognition or image analysis, as judged by the investigator 
o MRI-incompatible implants or devices such as certain cardiac pacemakers or 
defibrillators, insulin pumps, cochlear implants, metallic ocular foreign body, 
implanted neural stimulators, CNS aneurysm clips, and other medical implants that 
have not been certified for MRI, or history of claustrophobia in MRI that prevents 
completion of MRI protocol 
• Lumbar puncture exclusion criteria include: 
o Previous lumbar spine surgery 
o Taking blood-thinning anti-platelet medications 
o Taking immunosuppressive medications 
o Being treated or were recently treated for an infection or virus within the last 2 to 3 
months 
 
4.3 
Study Recruitment Plan and Enrollment Procedures 
• Participants may already be in the ADRC clinical core cohort (2015-0030), the WRAP 
cohort (2016-0634), or other relevant ADRC-linked studies. Participants may have had an 
applicable MRI with the ADRC, WRAP, or appropriate linked study. When this is the case, 
we will accept the prior MRI instead of repeating to alleviate subject burden. When 
participants consent to the ADRC clinical core study and WRAP, they agree to be contacted 
about participation in other studies associated with the Alzheimer's Disease Research 
Center or WRAP. Participants may, also, be recruited from the ADRC Registry (2016-0735), 
UW memory clinics, the community, and social media. Subjects will be invited to 
participate via letter, phone, or in-person discussions around the time of their baseline or 
regularly scheduled visit. IRB-approved informational materials may be used. 
• For participants already in an ADRC-linked study, we will conduct database queries and 
screens for participants who meet criteria for controls or patient groups. 
 
• From this general pool, case records will be examined further for eligibility criteria and 
availability of usable MRI. 
o Data reviewed from source protocol records may include memory diagnosis, age, visit 
date(s), sex, race, education level, parental family history of Alzheimer's disease, 
cognitive test results that indicate dementia or MCI, cognitive test results on memory 
and executive function such as list learning, story learning, digit symbol tests, and trails 
tests. Data reviewed may include prior brain imaging and cerebrospinal fluid test 
results that indicate possible risk for dementia, genetic test results such as APOE allele 
carrier status, and other medical history that may affect eligibility for MRI and PET 
imaging such as metal-containing implants, significant neurologic disease or significant 
medical illness. 

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• Candidates who are ostensibly eligible on the record review may be recruited into the 
study in the following ways: 
1. If the participant is not due for an in-person ADRC-linked study in the near future: 
Participants will first be sent a letter in the mail to introduce them to the study. This 
letter will be followed up with a phone call. The screening questionnaire will be 
completed if the participant agrees, and then a study visit will be scheduled in which 
the participant will go over the consent form with a study coordinator. 
 
2. If the participant has an upcoming ADRC-linked study visit: 
The participant will be approached for recruitment at their study visit. They will be 
given a study Information Sheet and will go through the screening questionnaire if 
they agree. If participant would like to take more time to consider, a PET coordinator 
will contact them at a later date. 
 
3. If the participant has an upcoming ADRC or WRAP study visit: 
Participants will be sent a reminder letter in the mail for their upcoming appointment, 
and the letter may include information about this PET scan study opportunity and that 
they will receive more information at their study visit with either WRAP or ADRC. 
Participant may also be approached for recruitment at their WRAP or ADRC study visit. 
 
• Reasons for non-participation of eligible unscreened candidates will be logged. 
 
• Interested candidates will be screened for eligibility using a screening form, either over 
the phone or in person. If all eligibility criteria are met, the participant proceeds to the 
scheduling of a research visit. A screening log will be kept to record reasons for screen 
failures. 
 
• Women of childbearing potential will have a urine pregnancy test within 24 hours prior to 
undergoing each PET scan. The test must be negative to proceed with the scan. 
• Informed consent will be required prior to procedures. Only individuals with capacity to 
consent will be included. Our center has procedures built into the IRB approved 
consenting process to ensure participants have capacity to consent. 
• Exceptions to eligibility criteria are rare but may occur at the discretion of the principal 
investigators. For example, exceptions may be made related to a participant’s potentially 
confounding data. Exceptions will not be made related to a participant’s safety. 

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5 
STUDY PROCEDURES 
5.1 
Schedule of 
Evaluations 
See Table 1. 
Completion of study 
procedures at 
baseline and 
potential follow-up 
visits will take 1-4 
days depending on 
procedures due and 
the schedules of 
participants, staff, 
and facilities. 
5.2 
Description of 
Evaluations and 
Procedures 
5.2.1 Screening Evaluation 
Screening 
assessment: After 
appropriate subjects 
are identified who 
meet study criteria, 
they will be 
contacted by phone 
or mail by trained 
study coordinators 
and invited to 
participate. A 
screening discussion 
will be completed on 
the phone or in 
person. The 
screening is done to 
determine whether 
the participant continues to meet all study inclusion and none of the exclusion criteria and 
assess eligibility for MRI if applicable. 
5.2.2 Consenting Procedure 
Before any study procedures are performed, informed consent will be obtained. A single 
consent form and process will be used. The study coordinator or one of the study 
Table 1. Overview of study design and timeline 
Screening by Staff 
Baseline 
24 months 
Prior to baseline 
0 weeks (day 0) 
104 weeks (±16 weeks) 
Medical history, 
medication review, 
eligibility determination 
Review of medical/surgical 
history, medications, allergies, 
family history 
Review of medical/surgical 
history, medications, allergies, 
family history 
MRI (if not available within 12 
months) 
MRI (T1, T2, DTI) 
[11C]PiB PET 
[11C]PiB PET 
[18F]MK-6240 PET 
[18F]MK-6240 PET 
[11C]UCB-J PET 
[11C]UCB-J PET 
[18F]FDG PET (optional) 
[18F]FDG PET (optional) 
Lumbar puncture (optional) 
Lumbar puncture (optional) 
CDR interviews and NPI-Q, GDS, 
FAS, IQCODE questionnaires (if 
not done with ADRC/WRAP) 
CDR interviews and NPI-Q, GDS, 
FAS, IQCODE questionnaires (if 
not done with ADRC/WRAP) 
Diabetes questionnaire 
Diabetes questionnaire 
Genetic testing (if not done with 
ADRC/WRAP) 
Genetic testing (if not done with 
ADRC/WRAP) 
Blood draw: 
1. Plasma and Serum: all 
participants 
2. Glucose and insulin: all 
participants unless performed 
by parent study (ADRC or 
WRAP) in last 6 months 
3. Whole blood for ApoE: only 
community/clinic participants 
Blood draw: 
1. Plasma and Serum: all 
participants 
2. Glucose and insulin: all 
participants unless performed 
by parent study (ADRC or 
WRAP) in last 6 months 
3. Whole blood for ApoE: only 
community/clinic participants 
Physical and Neurological Exam 
(community/clinic participants or 
those participating in LP) 
Physical and Neurological Exam 
(community/clinic participants or 
those participating in LP) 
Neuropsychological testing 
(community/clinic participants): 
MoCA, Craft Story (recall 
immediate & delayed, Benson 
Complex Figure Copy (immediate 
& delayed), Number Span test 
(Forward & Backwards), Category 
Fluency (Animals & Vegetables), 
Trails Making Test (A & B), MINT 
(Multilingual Naming test), Verbal 
Fluency: Phonemic Test (F,L & C), 
RAVLT– Version 2 (Immediate, 
Delayed & Recognition tasks), 
WAIS-R Digit Symbol 
Neuropsychological testing 
(community/clinic participants): 
MoCA, Craft Story (recall 
immediate & delayed, Benson 
Complex Figure Copy (immediate 
& delayed), Number Span test 
(Forward & Backwards), Category 
Fluency (Animals & Vegetables), 
Trails Making Test (A & B), MINT 
(Multilingual Naming test), Verbal 
Fluency: Phonemic Test (F,L & C), 
RAVLT– Version 2 (Immediate, 
Delayed & Recognition tasks), 
WAIS-R Digit Symbol 
Disclosure of PET scan results (if 
consented) 
Disclosure of PET scan results (if 
consented) 

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investigators will obtain written informed consent, and the original document is stored in 
each participant’s study binder/folder. The coordinator will review the consent form with 
participants at the study visit in person. Once review is complete, an assessor will either 
provide a capacity assessment in person or via phone/internet. Consent and capacity will 
therefore take place at the same time. 
 
Participants who would like to know their amyloid result will also complete the consent 
addendum for disclosure of PET scan results. The consent addendum may be completed in 
conjunction with the main informed consent or after initial study consent and visits if they 
would like more time to consider the option or would like to opt in after previously opting out 
of disclosure in the informed consent. The consent addendum may be conducted in-person, 
via phone call, or via UW approved HIPAA compliant video conferencing software. If the 
consent addendum is not completed in person, participants will be instructed to electronically 
sign the document via an FDA Part 11 compliant software. If the participant is unable to 
electronically sign the consent, the participant will be instructed to mail the signed consent to 
the study team. In instances of remote consent, in which the study is not able to witness the 
signing of the consent, the study team will verify the identity of the signer by confirming 
personal information such as date of birth and current address. Capacity assessment will be 
completed by study clinician or nurse practitioner for individuals with dementia, as applicable, 
before a participant with dementia consents to disclosure of results with the consent 
addendum. If the capacity assessment indicates that the participant lacks decision-making 
capacity at this point, the participant’s assent and surrogate consent may be obtained. 
 
5.2.3 MRI Protocol 
If the participant otherwise meets all inclusion and no exclusion criteria, the MRI will be 
performed if a suitable scan is not available from approximately the prior 12 months to 
baseline from an affiliated study. If participants report a possible history of metal in their eyes 
or a history of working with metal (grinding, welding, etc.), they will receive an orbital x-ray to 
ensure eligibility for MRI. This procedure includes a T1-weighted anatomic volume, a T2- 
weighted fluid attenuated inversion recovery (FLAIR) scan, and diffusion imaging. These 
sequences do not take the place of a clinical MRI examination. If clinically significant 
abnormalities are found, the participant is excluded and referred for further clinical follow-up. 
 
The MRI exams will be performed using a 3T MRI scanner at the Waisman Center or WIMR. 
The scan duration is typically 60 minutes and no longer than 75 minutes and consists of 
established as well as innovative locally developed scan sequences. Participants are asked to 
fast 4 hours prior to MRI. 
The MRI procedure is considered complete if a T1-weighted volume, FLAIR, and DWI scan are 
successfully acquired. When feasible, additional scans will be acquired. The additional 
sequences will make it possible to conduct exploratory comparisons. Sequences may include: 

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T1w Brain Volume: This sequence provides high-resolution volume and region quantification. 
This sequence is required and used for quantifying the PET images. 
T2 Fluid attenuated inversion recovery (FLAIR): This is a 3D volume acquisition and is 
sensitive to ischemic disease and other pathology. This scan will be used to quantify white 
matter hyper-intensity lesion burden. 
 
Diffusion Imaging: A diffusion-weighted may be performed used for whole brain advanced 
DTI studies. Diffusion encoding will be performed using multiple shells and multiple directs 
requisite for NODDI and advanced DTI modeling of white matter tracts. 
 
Other non-required MRI sequences: Additional sequences from the ADRC/WRAP standard 
protocol may be used to maintain continuity with prior and future MRIs with the program. 
These are performed when time schedule and tolerability permit and will be used to conduct 
exploratory analyses. 
Quantitative T1 Mapping with MPNRAGE: This is a locally developed anatomical sequence for 
detailed T1-mapping and tissue segmentation. This is a non-standard sequence conducted in 
Research mode. 
 
Pseudo-continuous arterial spin labeling (pCASL): This provides a perfusion weighted scan 
used to assess flow and aspects of neurovascular function. 
 
4D flow: We will use a novel high-resolution flow-sensitive MRI approach to quantify 
macroscopic CBF in all extracranial and intracranial arteries in a single acquisition. The method 
developed at UW uses radial undersampling and significantly reduces otherwise prohibitively 
long scan times for a vascular examination uses no exogenous contrast agent. The method 
allows for coverage of the entire brain, providing high spatial resolution and flow dynamics 
within an approximately 7-minute exam. This is a non-standard sequence conducted in 
Research mode. 
5.2.4 PET Scans 
PIB: The synthesis and PET scanning with [C-11]PiB will be consistent with the methods 
described in the drug IND. A target dose of 8-15 mCi +/- 10% of PiB bolus is injected over ~30 
second infusion with the participant positioned in the scanner. A 70 minute dynamic PET scan 
will be initiated with the injection of radiotracer. An alternative abbreviated imaging session 
of 50-70 minutes post-injection may be used if the participant is unable to complete a full 70 
minute scanning procedure. If an acceptable PiB scan conducted with our research program is 
available within approximately 12 months of baseline, this scan will not be repeated. 
MK6240: The synthesis and PET scanning with [F-18]MK6240 will be consistent with the 
methods described in the drug IND. A target dose of 5-10 mCi +/- 10% of MK6240 bolus is 
injected over ~30 second infusion. Uptake occurs at rest for approximately 70 minutes 

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followed by imaging across the interval of approximately 70 to 110 minutes from time of 
injection (thus, approximately 40 minutes of imaging). A 20-minute frame within this window 
will be considered sufficient for a successful scan. If an acceptable tau scan conducted with 
our research program is available within approximately 12 months of baseline, this scan will 
not be repeated. 
 
UCB-J: The synthesis and PET scanning with [C-11]UCB-J will be consistent with the methods 
described in the drug IND. A target dose of 5-15 mCi +/- 10% of UCB-J bolus is injected over 
~30 second infusion with the participant positioned in the scanner. A 70 minute dynamic PET 
scan will be initiated with the injection of radiotracer. An alternative abbreviated imaging 
session of 40-70 minutes post-injection may be used if the participant is unable to complete a 
full 70 minute scanning procedure. If an acceptable UCB-J scan conducted with our research 
program is available within approximately 12 months of baseline, this scan will not be 
repeated. 
 
If there is any tracer synthesis failure, we will reschedule the visit to a later date. 
 
PET Scanner: PET imaging may be collected using either a PET scanner or a PET/CT scanner, 
depending on scanner availability. Participants are positioned headfirst and supine with the 
canthomeatal line parallel to the in-plane field of view. The CT or a transmission scan is 
acquired for attenuation correction. 
 
It is possible that this scan will need to be repeated (whether a chemistry issue arose, there 
was a problem with the scan itself, etc.). An additional CT transmission scan contributes a 
radiation dose of 0.2mCv, which is less than 1% of the dose received from the entire protocol. 
 
Blood pressure: A participant’s blood pressure will be taken before and after each PET scan 
they participate in. 
Disclosure of Biomarker findings to participants: Amyloid PET scan results may provide 
important helpful information pertinent to a person’s diagnosis, clinical care, and personal 
planning goals. Results of amyloid PET may be disclosed to participants who consent to this 
and who want to know their results by a trained clinician with expertise in 
dementia/geriatrics. Study staff will contact participants to determine their interest in 
learning their amyloid results with a phone call and follow up with a letter, if needed. The 
study staff will provide and review an educational pamphlet and/or educational PowerPoint 
slides. They will also conduct psychological screening assessments and a pre-disclosure semi- 
structured interview to gauge the emotional readiness of the participant to receive these 
results and to ensure safety after disclosure of results which may include the following: PHQ-4 
(Patient Health Questionnaire – 4), C-SSRS (Columbia-Suicide Severity Rating Scale), 
Alzheimer’s Disease Suicide Questionnaire, and INI-AD (Impact of NeuroImaging in 
Alzheimer’s Disease; completed post-disclosure). If the psychological screening assessments 

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exceed set thresholds, the study team will determine if the participant will either be excluded 
from disclosure or re-screened at a later date by a clinician prior to disclosure. 
These assessments are only applicable for disclosure of PET scan results to participants. If 
during any of the participant interactions (whether in person, by phone, or video 
conferencing) the participant expresses concerns, hopelessness, or suicidal ideation, the study 
coordinator will involve relevant clinical expertise to address participant concerns and issues. 
Follow up will be initiated by the clinical team when warranted. Participants that exceed set 
thresholds or do not have emotional readiness at clinician’s discretion will be excluded from 
the disclosure procedure. Participants will be made aware that a study coordinator or clinician 
will provide a follow-up phone call approximately 24-72 hours post-disclosure to follow up 
and address any further questions or concerns. Any concerns will be immediately followed up 
by a study clinician. Participants may be provided with referrals for mental health treatment 
or encouraged to follow-up with their primary care provider. We are equipped to handle 
potential negative effects from disclosing amyloid status; however, we anticipate that, similar 
to other studies, any negative effects will be mild and temporary. 
The disclosure of PET results occurs within approximately 12 months of PET scanning visits or 
consenting to the disclosure process. The disclosure will be completed in-person or via UW 
approved HIPAA compliant video conferencing software by an experienced clinician, 
practitioner, or social worker within the ADRC research program. This role will be documented 
in the delegation of duties log. Standardized talking points will be followed for the disclosure, 
and the participant will be offered support including clinical referrals as needed, a follow-up 
letter reiterating the results, and any recommendations, and informing the participant’s 
physician if requested. Participants will be offered optional supportive follow up visits, 
including a session to discuss lifestyle/risk reduction and/or a session to review community 
resources and referrals, and participants will be provided with an optional satisfaction 
measure for quality improvement purposes. 
 
Due to the recent progress of anti-amyloid therapies, participants with a diagnosis of MCI or 
dementia and with a positive amyloid PET scan may now receive those results at anytime. PET 
result disclosure may occur with participants who received their PET scan under the ADRC, 
WRAP, an ADRC-affiliated study, or a WRAP-affiliated study when disclosure under the 
protocol conducting the scan isn’t feasible (e.g. the protocol is in data analysis) 
 
5.2.5 (Optional) Lumbar puncture (LP) 
Participants who agree to this procedure will have cerebrospinal fluid (CSF) acquired via LP at 
baseline (if no sample from the past 18 months is available) and at the end of the potential 2- 
year follow-up (if no sample from the past 18 months is available). An experienced clinician 
will collect CSF on all willing and eligible participants according to well-established procedures 
and the infrastructure of the ADRC. The procedure will be done in the Clinical Research Unit 
(CRU) after a 4 hour fast. Though, exceptions to the fasting requirement may be made on a 
case-by-case basis in consultation with a study clinician or PI. 

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All CSF collection is completed according to the guidelines put forth in the “Biospecimens Best 
Practice Guidelines for the ADCs” published by the National Alzheimer’s Coordinating Center 
(NACC) and available on their website. CSF collection occurs at approximately the same time 
at each visit to help control for diurnal variability. LPs will be performed using Sprotte spinal 
needles, drip method and/or gentle extraction technique. Participants are placed in the sitting 
position and asked to maximally flex their knees, hips, back, and neck. The skin over the L3-L4 
or L4-L5 vertebrae is prepped. 1% lidocaine is used as a local anesthetic, followed by insertion 
of a spinal needle with an introducer into the L3-L4 or L4-L5 interspace using sterile technique. 
Approximately 25 mL of CSF will be collected using sterile polypropylene collection tubes. 
Fresh CSF will be analyzed on the Roche analyzer in-house, and the remainder of the extracted 
CSF will be aliquoted, frozen, and stored as usual for future assays. 
 
Vitals will be taken at any CRU visit. 
CSF samples may be sent to Dr. Henrik Zetterberg—an internationally recognized leader in CSF 
biomarker analysis—at his laboratory at the Sahlgrenska Hospital Goteborg University in 
Sweden as a fee-for-service analysis. (APOE genotyping will not be shared outside). All 
samples will be coded with a unique identifier to keep the laboratory blinded to factors such 
as subject identity or group. 
 
CSF samples will also be released to the University of Bristol, Dementia Research Group, 
Bristol, England (Dr. Scott Miners). Dr. Miner’s lab will be running new assays to look at 
Alzheimer’s disease and vascular markers. 
 
CSF samples, along with plasma and serum, may also be sent to the Center for Biomedical 
Research, Ulm, Germany (Dr. Patrick Oeckl) for measurement of markers related to Synapses. 
Samples will be coded with a unique identifier to keep the laboratory blinded to factors such 
as subject identity or group. 
 
5.2.6 (Optional) FDG 
Participants are studied after an approximately 4hr fast (water is allowed). The blood sugar 
will be tested (via finger puncture) before an FDG PET scan. Following the 5 mCi (± 20%) 
injection with [F-18]FDG compound, participants rest in a quiet room. Imaging begins 
approximately 30 minutes post injection and takes place over an interval of 30 minutes. Our 
team has obtained PET images for several NIH funded protocols (including the Alzheimer’s 
Disease Neuroimaging Initiative), and thus we are experts in obtaining both of these scans. 
Amyloid, tau and synaptic density PET images will not typically be clinically evaluated as the 
clinical relevance of a positive scan is yet unknown. Approximately 30% of cognitively healthy 
individuals are amyloid positive, and the diagnostic relevance of a positive scan is yet to be 
determined. FDG-PET scans will not typically be evaluated by a clinician because the clinical 
utility of this scan in a healthy participant is not known. FDG is an FDA approved tracer; 
however, this is being used outside of its clinical labeling indications as it is being used for 
research purposes only. 

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5.2.7 Genetic Testing 
Genetic testing (for the APOE gene) will be conducted on participants who have not had this 
testing with the ADRC. The result of this test will not be shared back with the participant. 
Blood will be drawn from subjects for the purpose of genotyping various SNP sequences, 
including Apolipoprotein E (ApoE), at their baseline visit only (who do not have this 
information on file). Genotyping will be performed on batches of stored samples of DNA 
extracted from buffy coat derived from blood collected at baseline. Buffy coat and DNA not 
used for genotyping will be stored for future use. Results of this genotyping will not be 
reported to subjects, nor will it be included in their medical records, as the results of this 
genotyping do not yet aid the participant in future treatment options. 
5.2.8 Blood Labs 
Blood plasma and serum will be collected from all participants to be stored for future research 
to look at markers for AD risk factors. Additionally, fasting glucose and fasting insulin will be 
tested if not already completed by the WRAP/ADRC study the same day. Blood will still be 
drawn if the participant is not fasting. Both procedures will be done at baseline and the 
potential follow-up to allow for the analysis of changes that occur over time. This procedure 
will be done at CRU. 
 
5.2.9 Neuropsychological testing and assessments, physical and neurological exam 
Participants who have not undergone neuropsychological testing or physical/neuro exams 
with the WADRC or WRAP or participant, such as those who are recruited from the memory 
clinic or community, will be required to do so with this study at baseline and the potential 
follow up visit. The neuropsychological testing will consist of a multidimensional set of brief 
measures assessing cognitive, emotional status that can be used as a “common currency” 
across diverse study designs and settings. These will be supplemented by measures that are 
consistent with other national studies of AD, such as the NIH-funded Alzheimer's Disease 
Neuroimaging Initiative (ADNI). Participants will also complete: MoCA, Craft Story (recall 
immediate & delayed), Benson Complex Figure Copy (immediate & delayed), Number Span 
test (Forward & Backwards), Category Fluency (Animals & Vegetables), Trails Making Test (A 
& B), MINT (Multilingual Naming test), Verbal Fluency: Phonemic Test (F,L &C), RAVLT– 
Version 2 (immediate, delayed & recognition tasks ), and WAIS-R Digit Symbol. 
 
For completion of certain assessments, such as the Clinical Dementia Rating [CDR] Scale and 
IQCode, a family member or a friend will be asked to provide information via the telephone. 
 
All tests will be given by trained personnel and will be standardized for reliable 
administration. In some cases, the tests may be audio-recorded to make sure we accurately 
document the participant’s responses. 
 
Physical and neurological exams will be completed by ADRC clinicians. Information on family 
history, medical/surgical history, medications, and allergies will be collected from participants 

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from the community, memory clinic, or those without current information with WRAP or 
ADRC. Participants will be provided forms at a visit. Forms can be completed at a visit, after a 
visit by phone, or at home then returned by mail. 
 
5.2.10 Consensus Diagnosis (for those not in WRAP or ADRC) 
After each study visit, our expert clinician(s) and research staff will meet to review the 
information we collect about the participants and give their opinion about their diagnostic 
status. In this meeting, all data will be reviewed from all participants including those with 
Alzheimer’s disease, mild cognitive impairment, and the healthy older controls. Participants’ 
diagnostic status will be reviewed after every study visit since cognitive function might 
change year after year. No matter the cognitive status, if the memory tests performed in 
this study reveal something unexpected that is of clinical concern, a study team clinician, 
with expertise in diagnosing memory disorders, will contact the participant by phone to 
discuss the results and refer them for clinical evaluation. 
5.3 
Data collection from source study 
This study recruits from WRAP, ADRC, the ADRC Registry, UW memory clinics, linked studies, 
and the community. Relevant information from those sources will be obtained for analysis 
under this protocol. Data collected will be both retrospective and prospective. Information to 
be collected includes the following: 
 
• Cognitive data including all relevant psychometric assessments and alpha-numeric results 
from serial cognitive assessments. Cognitive test results may indicate dementia or MCI. 
Data collected also includes cognitive test results on global cognitive tests, memory, and 
executive function such as list learning, story learning, digit symbol tests, and trails tests. 
Rationale: Using these collected data will facilitate analysis of relationships between 
disease burden and the presumed cognitive effects. 
 
• Clinical data including diagnostic consensus conference summaries. Primary diagnoses 
(such as MCI or dementia due to AD) and any relevant secondary diagnoses (such as 
vascular disease) would be captured. Rationale: Diagnosis is a main grouping variable. 
 
• CSF lab test results if participants have provided CSF. We will access the results of those 
tests. Values will include AD-related assays such as tau and amyloid, inflammation assays 
such as YKL40, neurodegeneration assays such as neurogranin and neurofilament light, 
and other proteins that are relevant to synapse loss, aging, and Alzheimer’s. Rationale: 
These assays are used to cross-validate the molecular PET scans. 
 
• Prior imaging such as existing MRI, PIB and MK6240 images. They will be utilized in 
analyses. Rationale: Reduce participant burden, minimize exposure to procedures and 
radiation (e.g., repeating an MRI or PET scan) when existing data is already available, and 
evaluate longitudinal change in amyloid and tau burden. 

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• Questionnaire data including previously and prospectively collected self-report and 
informant report data from ADRC and WRAP, such as symptom checklists and surveys 
such as clinical dementia rating, quick dementia rating scale, informant questionnaire on 
cognitive decline in the elderly (IQCODE) and independent activities of daily living (IADL). 
May also include survey results such as sleep surveys, diet surveys, and physical or 
cognitive activity surveys. Rationale: These questionnaires provide support for diagnostic 
groups and provide an index of symptom severity and resiliency. 
 
• Genetics including APOE genetic status. Rationale: APOE4 is a risk factor for AD and will be 
analyzed as a predictive marker. 
5.3.1 Visit Sharing 
Participants in this study are also eligible to enroll in LEAD, ALERTT, LIFE, PREDICT3 and the 
ADRC/WRAP PET Study. To reduce participant burden, visits may be shared with other 
studies. In other words, participants may complete more than one study during a single visit. 
Subjects who enroll in Synapse and ALERTT, PREDICT3, ADRC/WRAP PET Study, LEAD, LIFE, 
ADRC, or WRAP may undergo shared study visits, in which the relevant collected information 
will be analyzed in both studies. The synchronization of study visits will be handled by each 
protocol’s primary study coordinator. PET imaging data will be shared amongst studies to 
reduce the PET imaging burden placed on participants. We will not repeat a PET scanning 
procedure if a participant has recently had a tau or amyloid PET scan with another study. 
Participant comfort is assessed at regular intervals. The results of lab tests will be shared 
across protocols. This will reduce subject burden. Only data and samples approved for 
collection under the other study’s protocol will be transferred from this study. Likewise, only 
data and samples approved for collection under this protocol will be transferred from the 
aforementioned studies. Study coordinators of the other protocol will be listed as key 
personnel on this study. Participants will be enrolled and consented for all studies that are 
conducted at the shared visit. Study staff from those protocols will already have access to this 
study’s code-name links. As a step to protect confidentiality, data and samples will be labeled 
with study ID numbers and not names. 
 
5.4 
Data Banking: 
Data banking is a required component of the study; participants must agree to data banking at 
the time of consent. Participants may request to have their data withdrawn from the bank, 
and then, study personnel will remove their data from the bank and will discontinue using it 
for further research. Data collected from this study will be stored on Department of Medicine 
computer servers that are password-protected. Banked data is coded with a subject ID. Only 
approved study personnel have access to the key linking subject ID and identifiable subject 
information. Unless staff are listed as key personnel on this study, they will not be given 
access to the code linking subject identity with subject ID. 

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5.5 
Data Sharing: 
Banked images and their meta-data from this study will be managed by the ADRC imaging 
core. Images may be uploaded to the National Alzheimer’s Coordinating Center or other NIH- 
specified repository. The images will be shared back with the ADRC UP protocol (2013-0178), 
the ALERTT study (2018-1348), the ADRC, and WRAP to address the major specific aims of this 
project. Once the data is shared with the ADRC UP protocol, the data may be used to address 
future unspecified research. Other investigators who wish to use these data may contact Dr. 
Bendlin, and she will collaborate with Dr. Christian and Dr. Johnson to decide how the data 
from this study are shared. Investigators from other departments within UW, institutions 
outside UW, and private companies may contact Dr. Bendlin and request the data. Only coded 
data are shared with researchers that are not listed as key personnel on the projects. The 
multi-PIs (Bendlin, Christian, Johnson) hold ultimate responsibility for data sharing oversight 
and will review all requests. 
 
Coded images and AE data pertaining to MK6240 will also be sent to Cerveau Technologies, 
Inc., the provider of the MK6240 drug precursor. Cerveau will use these data for image quality 
assurance and drug safety profile tracking. Cerveau maintains safety data for all sites using the 
MK6240 drug and is responsible for Investigational Drug Brochure updates. In addition to 
images, Cerveau will have access to brain MR images, unique subject identifiers, amyloid 
images and status, cognitive metrics consisting of MMSE, ADAS-COG and CDR, weight/height, 
scan time, MK6240 dose, scan date, clinical diagnosis, demographic information, and smoking 
status. 
 
Cerveau will provide secure storage of the study data described above, be responsible for 
transferring MRI and PET images, perform Image data quality control, and ensure consistent 
image acquisition and transfer via an electronic image submission system. The electronic 
image submission system is in compliance with 21 CFR Part 11, electronic records, electronic 
signatures and predicate rules. Compliance is achieved through a combination of SOP 
adherence and a structured validation system. Security of this system includes the use of 
passwords that limit user access according to their job responsibilities. Throughout the study, 
an image data back-up will be performed on data storage systems. Off-site image data back- 
up will also be performed. Other electronic data (electronic CRFs, audit trails, database 
contents, electronic documents, etc.) will be stored on a dedicated database server and saved 
daily throughout the study. Access to the data at the clinical site is restricted to authorized 
personnel only. 
 
6 
SAFETY CONSIDERATIONS 
6.1 
PET Imaging ([C-11]PiB, [F-18]MK6240, [C-11]UCB-J, and [F-18]FDG radiotracers) 
Radiation exposure: PET Imaging ([C-11]PiB, [F-18]MK6240, [C-11]UCB-J, and [F-18]FDG 
radiotracers) involves exposure to small amounts of ionizing radiation, which has no known or 
expected harmful effects. The possibility exists for a rare reaction to any of the substances or 
procedures to which the subject is exposed. 

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People who live in the US receive on average a total of 6.4 mSv per year. 50% (3.2 mSv) comes 
from natural background sources (e.g., food we eat, air we breathe) and 50% (3.2 mSv) from 
human sources (e.g., dental and medical exams). 
 
This study consists of up to 8 PET scans including 4 at baseline and 4 at the potential 2-year 
follow up. The scans may take place on a PET/CT or just PET machine. The radiation dose 
calculations include the low dose CT procedure. 
C-11 PiB brain scan (2.9mSv at each of two scans = 6.8mSv) 
F-18 MK-6240 brain scan (12 mSv = 24 mSv) 
C-11 UCB-J brain scan (2.0 mSv at each of two scans = 4.0 mSv) 
F-18 FDG brain scan (4.2 mSv at each of two scans- 8.4 mSv) 
 
The four scans together = 42 mSv total potential exposure over the two-year study (baseline 
and potential follow-up). This is below the guidelines established in 21CFR §361.1 for 
occupational whole body (Annual Limit - 50 mSv) exposure. 
6.2 
Risks related to disclosure of PET scan results to participants 
Although several studies suggest minimal acute psychological consequences to disclosure of 
beta-amyloid results or other AD risk information, there is a risk of increased depression, 
anxiety, or potential for suicidality associated with learning beta-amyloid results. Additionally, 
there is a risk that participants will make decisions based on beta-amyloid results that impact 
other psychosocial outcomes (e.g., financial/retirement plans, long-term care plans) that will 
take longer to fully evaluate. There is a risk that beta-amyloid results will be shared by 
participants with individuals who are also impacted by the information regarding risk for 
development of AD, such as family members. If that happens, there could be consequences 
(emotional, stigma etc.) for both the participant and recipient of the information. It could 
affect relationships with family and friends, affect employment, or make it harder to get 
insurance or a job. Although we will not add study information to medical records, we will 
communicate results to providers at the participants’ request, and it is possible that 
participants could share the information with their healthcare providers who may add it to 
their medical record. Participants will be informed that this has the potential to impact long- 
term care insurance applications or other unforeseen consequences regarding medical care. 
We will ensure that a number of safeguards are in place to protect participants from any 
serious, negative effects of disclosure such as completing the psychological screening 
assessments to assess depressive symptoms, anxiety, and suicidality, the pre-disclosure 
questions, the post-disclosure questions, providing follow up, and offering optional follow-up 
support visits to discuss lifestyle/risk reduction and/or community resources and referrals. 
Participants that exceed set thresholds or do not have emotional readiness at the clinician’s 
discretion will be excluded from the disclosure procedure. 

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6.3 
Adverse Events and Serious Adverse Events Monitoring 
The PIs will be apprised of any adverse events and will report any SAEs experienced in the 
study to the IRB. Although no study related serious adverse events or significant trends have 
been reported in the combined experience of our institution and other institutions for either 
radioligand, we will examine AEs for study related trends. If needed, we would modify the 
consent form after consulting with the CTRC Research Subject Advocate and the IRB. 
 
Vitals are assessed prior to and after the PET scans. The participant is given the study team’s 
contact information so that they may report any adverse events that may occur within the 
next 24 hours. If any adverse events are discovered, a clinician will continue to follow up with 
the participant until resolved. 
 
An adverse event (AE) is any unfavorable and unintended diagnosis, symptom, sign (including 
an abnormal laboratory finding), syndrome, or disease which either occurs during the study 
(having been absent at baseline) or, if present at baseline, appears to worsen. Adverse events 
will be recorded regardless of their relationship to the study. 
A serious adverse event (SAE) is generally defined as any untoward medical occurrence that 
results in death, is life threatening, requires inpatient hospitalization or prolongation of 
existing hospitalization, results in persistent or significant disability/incapacity, or is a 
congenital anomaly. 
 
Participants will be advised to inform us of any adverse events following PET scans. 
 
6.4 
Follow-up for Adverse Events 
The investigator is obliged to follow subjects with AE’s until the events have subsided, the 
conditions are considered medically stable, or the participants are no longer available for 
follow up. Subjects who discontinue due to adverse events will be treated and followed 
according to established medical practice. 
7 
STATISTICAL CONSIDERATIONS 
7.1 
Sample Size Justification 
Approximately 120 participants will be enrolled. This will provide a sufficient number of cases 
to achieve the aims described above. 
Prospective power was estimated using MedCalc version 18.2.130. Assuming an AUC of 0.73 
for discriminating MCI and Control participants 31, and a correlation of 0.77 between synaptic 
density and cognition 32, with our proposed sample of NMCI=30 and NCtrl=60, we will have 80% 
power to detect a 10% improvement in AUC with [C-11]UCB-J. A sample of 30 participants 
with dementia due to AD will be imaged to obtain qualitative information concerning synapse 
density loss in phenotypic and biomarker confirmed disease. 

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8 
DATA COLLECTION 
8.1 
Data Collection Forms 
The study coordinator works with the participant at the study visit to collect all relevant data. 
Case report forms will be generated to record the data. CRFs and all participant specific data 
are stored hard copy in an individual binder/folder. 
 
9 
PARTICIPANT RIGHTS AND CONFIDENTIALITY 
9.1 
Institutional Review Board (IRB) Review 
This protocol and the informed consent document and any subsequent modifications will be 
reviewed and approved by the University of Wisconsin-Madison Health Sciences IRB. 
 
9.2 
Informed Consent Forms 
A signed consent form will be obtained from each participant. The consent form will describe 
the purpose of the study, the procedures to be followed, and the risks and benefits of 
participation. A copy will be given to each participant and this fact will be documented in the 
participant’s record. Only participants with cognitive capacity to provide consent will enroll in 
this study. 
 
This study enrolls participants with cognitive capacity, but it cannot be predicted in advance 
who will lose decision-making capacity over the course of the study. We need to enroll those 
who are at risk for losing capacity to determine if the synaptic density significantly varies or 
changes at this stage in the disease. The longitudinal study aims require collecting data on 
synapse density at time points two years apart. 
If the subject has lost capacity to consent during the study, we would request a surrogate to 
re-consent in their place. Surrogates may include a court appointed guardian or next of kin (in 
the order of priority): spouse, adult child (18 or older), parent, adult sibling, grandparent, or 
adult grandchild. If surrogate consent is required, the consent form will be modified to specify 
surrogate consent and instruct surrogates that their decisions should be based on what the 
surrogate believes would be desired by the subject. If that cannot be determined, the 
surrogate would decide based upon what s/he believes is in the subject’s best interest. 
 
9.3 
Participant Confidentiality 
Any data, forms, reports, PET images, and other records will be identified with minimum PHI 
necessary. A participant ADRC identification number (Participant ID, PID) is used to maintain 
confidentiality, and the key to the ID code is never released outside the study team. All 
records will be kept in a locked file cabinet. All computer entry and networking programs will 
be done using PIDs only. Identifying information will not be released without written 
permission of the participant, except as necessary for monitoring by IRB, the FDA, the NIA, 
and the OHRP. 
9.4 
Study Discontinuation 
The study may be discontinued by the IRB, the NIA, the OHRP, the FDA, or other government 

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agencies as part of their duties to ensure that research participants are protected. 
 
10 
DATA SAFETY MONITORING PLAN (DSMP) 
10.1 
Internal Audit and Data Safety Monitoring: 
Refer to the Study Monitoring Plan, which is a separate document, for the Data Safety 
Monitoring Plan. This observational cohort study does not meet the definition of a clinical 
trial, and an external DSMC is not required from a design standpoint. Further, the radioligand 
is delivered in tracer quantities and has no pharmacological effect. 
The Study Monitoring Plan describes the strategy, responsibilities, and quality management 
activities in place to ensure adequate protection of the rights, welfare, and safety of human 
subjects and the quality and integrity of the resulting data, in compliance with applicable laws, 
regulations, policies, and guidance. 
 
11 
DATA MANAGEMENT TOOLS 
11.1 
CoRRIE – CRM database 
Directly identifiable information and indirectly identifiable (identified by study ID number) 
information will be stored in CoRRIE. 
 
CoRRIE is a contact database that is used by all ADRC-linked studies. It is a web-based, 
electronic database for contact management that is password-protected and managed by 
DOM. 
In addition to storing the names of those who enroll in this study, the CoRRIE database will 
also help the staff to manage their contacts with participants. The database allows for the 
storage of participants’ relationship to our program by stating which studies in our program 
they are enrolled in or have been enrolled in the past. This allows staff to answer the phone 
call of someone with a memory disorder and be able to tell them when their next visit is and 
who they will be seeing. The database also allows us to track and assign activities that take 
place during the course of research (phone calls, letters, screenings). This helps to ensure that 
participants are not needlessly contacted and overall improves the customer service provided 
to our participants by the members of our research program. The purpose of storing this data 
is for programmatic cohesion in working with subjects with memory problems. It is important 
to know which subjects are enrolled in which studies so that we may provide appropriate 
coordination of their study visits. 
 
UNIVERSAL IDENTIFIER 
An internal ID number is generated by the ADRC CoRRIE database and will have “RMRaic00” 
added to it to create a unique participant identifier that will remain with the participant from 
study to study. This number will be used to label brain images collected in affiliated ADRC 
protocols. This will allow physicians who are reviewing the brain scans to look for brain 
changes over time. 

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11.2 
PANDA and PACS 
Image data management tool: Image data are electronically transferred and stored on servers 
at the ADRC imaging core, and metadata is inserted into an imaging database called PANDA. 
Image headers by protocol do not contain identifying information. Additionally, each image is 
automatically inspected, and any PHI is removed. These resources are maintained by the 
Department of Medicine. Some derived numeric image data and cognitive and questionnaire 
data may be maintained in PANDA. User access is protocol specific such that only users 
authorized to see this study’s data will have access. 
 
MRI and PET images labeled with only study IDs as identifiers may also be uploaded to the 
Dept of Radiology PACS directly from the scanner for radiology over-reads. 
 
11.3 
BOOKED 
Directly identifiable information and indirectly identifiable (identified by study ID number) 
information will be stored in Booked. A participant scheduling web application, Booked, has 
been developed by extending the Booked (PHP) free, open source project. The Booked 
application can prevent double booking of staff and resources, provide email notification to 
staff when they are added to appointments, provide email notification if an appointment has 
been cancelled, and provide email reminders before an appointment starts. Staff can be 
linked to multiple roles in appointments. The calendar view can be filtered by resource, staff, 
and study participant. The appointments are color coded by appointment type and staff 
member. Booked reports can track cancelled appointments, cancellation reasons, 
appointment types, resource usage, staff hour totals, and staff appointment counts. Booked is 
limited to https ssl connections. Only users granted protocol specific permissions can log into 
Booked and view study participant information. It is also important to note that the Booked 
software is installed on the DOM production server in the DOM server room; therefore, all 
Booked data will be on the DOM server. Access to Booked via the web is limited to UW 
Networks. Booked is a free, open source project; therefore, there are no connections or 
relationships with the Booked software manufacturer. Participant Name, phone number and 
ADRC Registry ID (2016-0735) are identifiers used in Booked. Booked is an appointment 
scheduling application, so the participant’s name, phone, and Study ID are needed to identify 
the participant. These identifiers will only be visible to users who are on the protocols that the 
participant is enrolled in. 
12 
PRIVACY 
12.1 
Privacy and Data Storage 
Physical data will be kept in locked cabinets in our lab which has space at the UW Hospital. 
Other data will be kept on the Department of Medicine's secure server and at the Waisman 
Center server which comports with HIPAA security requirements. Only individuals in our labs 
will have access to these computers and any PHI. Any data shared with individuals outside of 
our lab (i.e., papers or presentations) will be coded or anonymized. Each subject will also have 
an individual study number to code their study data. Names are never entered at the scanner 
console, only study numbers. Study numbers are used on data collection forms. 

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Directly identifiable information and indirectly identifiable (identified by study ID number) 
information will be stored on CoRRIE and Booked. 
 
12.2 
CoRRIE 
CoRRIE refers to the ADRC Registry Protocol (2016-0735); however, it is also an electronic 
database/contact management system that stores information (inclusive of PHI) from the 
'First Contact Form' as described in 2016-0735 and tracks study participation. The electronic 
database is web-based, though only accessible within the DOM server, and is password- 
protected. Data are not stored in temporary files. Registered accounts must be approved by 
our research staff supervisors, and access/activity in the database will be monitored. Only 
those listed on the 2016-0735 protocol will be allowed access. 
12.3 
Booked 
Booked is a participant visit scheduling web application that has been developed by extending 
the Booked (PHP) free, open source project. Booked software has been installed on the DOM 
production server in the DOM server room. All Booked data will be on the DOM server. Access 
to Booked via the web is limited to UW DOM Networks. Booked is a free, open source project; 
therefore, there are no connections or relationships with the Booked software manufacturer, 
and data will not be stored online with the software manufacturer. Booked is limited to https 
ssl connections. Only users granted protocol specific permissions can log into Booked and 
view study participant information. Booked is an appointment scheduling application, so the 
participant’s name, phone number, and Registry ID are needed to identify the participant. 
These identifiers will only be visible to users who are on the protocols which the participant is 
enrolled in. The DOM IT department has been consulted with regard to HIPAA security 
requirements. 
12.4 
PANDA 
PANDA (PAN = Greek prefix meaning ‘all’; Data Archive) is a data and imaging management 
tool that has received IRB approval for use in other ADRC and WRAP linked protocols. Data 
and images are electronically transferred to PANDA, which is maintained by the ADRC imaging 
core. PANDA is a Ruby on Rails application using a MySQL backend database, which provides 
secure web interfaces to a repository of MRI, PET and project-specific variables including 
neuropsychology, lab results, questionnaires, and participant properties. Security of the 
database uses best practice guidelines. Viewing and editing data are separately granted 
permissions and are access-controlled at the project level. Editing of data will be locked to all 
but the DBA. In all cases, this also requires a user to be listed on the IRB-approved protocol 
(via ARROW study team list). For security, all login and query downloads are logged and 
traceable by user and date. Further, any logged query, including table fields and selection 
criteria, may be reconstructed at a later date for auditing if needed. The DBA has an interface 
to view the queries by user/time. As imaging data cannot be uploaded, it is the image 
metadata that are uploaded into the SQL database; the images themselves are stored on a 
secure DOM server in the imaging core as well as in Waisman Center brain imaging lab. Data 

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are transferred to database users using https downloads of queries in CSV text files that can 
subsequently be imported into statistical analysis software. 
12.5 
REDCap 
REDCap is an electronic data management system that will be used to capture, edit, manage, 
and export study data (inclusive of PHI) for analysis. REDCap is a mature, secure web 
application that can be used to collect virtually any type of data; it is specifically geared to 
support data capture for research studies. The REDCap Consortium is composed of 2,514 
active institutional partners in 116 countries who utilize and support REDCap in various ways. 
All communication between the clients and the REDCap application takes place via Hypertext 
Transfer Protocol over Secure Socket Layer or HTTPS. HTTPS provide the ability for normal 
web-based communication over an encrypted Secure Socket Layer (SSL) connection. This 
ensures that data passing between the client and REDCap is protected. 
The REDCap server is housed in a state-of-the-art data center managed by the UW SMPH 
network staff. The levels of security for the server are fivefold and include: 
1. Physical Security 
The server is located in a secure data center under control of UW School of 
Medicine and Public Health (SMPH) ITS. The server is in a dedicated computer 
machine room (passkey access only) containing emergency backup power, an 
uninterruptible power supply (UPS), and an automatic fire detection and 
suppression system. SMPH ITS does not have access to the DOM REDCap server. 
2. Access controls 
Data access is limited to DOM Faculty and staff-approved individuals. 
3. Domain access restrictions 
Access to DOM computing resources, including the DOM REDCap Server, is 
restricted to individuals with a login ID for the DOM Domain. Login IDs are issued 
only upon approval of the Administrator or Principal Investigator (Data Custodian). 
Login IDs are only issued upon confirmation that the individual has completed 
appropriate training. 
 
4. Authentication 
Password protection is used at the network level for all transactions that allow 
entry and editing of data, provide access to EPHI data, or administrative activities. 
5. Firewall 
The DOM REDCap server is located behind the UW-Madison SMPH firewall. The 
SMPH firewall does not allow outside access to the server itself. Outside access to 
the application is allowed through a combination of firewall rules, reverse proxy 
access, and directory level user authentication. 

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The REDCap database is backed up hourly, daily, weekly, and monthly. These backups are 
stored in an offsite datacenter. The files on the REDCap server are backed up daily and stored 
in an offsite datacenter. 
 
Within the REDCap software itself, there is an audit trail that includes all operations 
performed on the data. Viewing data or exporting data will trigger a record in the audit log. 
Each audit record includes the operation, date, time, and the user who performed the 
operation. 
At the server level, logs are compiled to track users who login to the server. The server is only 
accessed directly by administrators for administrative or maintenance purposes. Any failed 
login attempts are tracked in order to log potentially malicious activity. 
 
12.6 
FreezerPro 
FreezerPro is a sample management system created by Brooks Automation, Inc. that will link 
each participant’s study visits and their associated biological sample collection kits. The 
application and data will be hosted on the DOM server. Access to the web application is 
managed through DOM LDAP authentication and FreezerPro’s role-based authorization. 
Access to the system is encrypted via HTTPS/TLS secure handshake certificate, and it is not 
accessible from outside the DOM network. Registered accounts must be approved by our 
research staff supervisors, and access/activity in the database will be monitored by system- 
specific supervisors. Additionally, the database will be accessible to a limited number of users 
(coordinator, PI, and other laboratory personnel) with password protection. 
 
13 
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