Clinical trial NCT03581305
Conditions: Depression HIV Infections HIV-Associated Cognitive Motor Complex
Keywords: 11C-DASB 18F-Fluoro-L-dopa HIV Depression Positron Emission Tomography (PET)
Sponsor: National Institutes of Health Clinical Center (CC)
Start date: 2018-11-20; Completion date: 2022-04-06
Enrollment: 46 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Background:

Human immunodeficiency virus (HIV) infection is a serious disease with no cure. Some people with HIV have depression and other mood problems. They can have problems with thinking and memory. Researchers think 2 chemicals in the brain may cause those problems. The chemicals are serotonin and dopamine. The researchers want to take images to learn more about those chemicals in HIV patients.

Objective:

To learn how HIV affects serotonin and dopamine in the brain.

Eligibility:

Adults ages 18-70 with HIV who have been on antiretroviral treatment for at least 1 year

Healthy adults ages 18-70

All participants must be already enrolled in protocol 13-N-0149.

Design:

* Participants will be screened with a urine drug test. The results could be shared with insurance companies.
* Participants who could be pregnant will have a pregnancy test.
* Participants may have a physical exam and blood tests.
* Participants will have 1 or 2 positron emission tomography (PET) scans. A needle will guide a thin plastic tube (catheter) into an arm vein. A radioactive drug will be injected into the plastic tube. This is a tracer that helps researchers understand the PET images.
* Participants who have the dopamine scan will have to fast for 4-6 hours before the scan. They will take a pill to help direct the tracer to the brain one hour before the scan.
* Each scan will last about 1.5 hours.
* Participants will be asked to drink a lot of fluids and empty their bladder frequently for the rest of the day after each scan.

Detailed description:
Background: An extensive body of literature points towards neuronal brain injury in human immunodeficiency virus positive (HIV-positive) subjects despite virological suppression of the virus in the periphery under the effect of antiretroviral therapies (ART). Existing evidence suggests that the central nervous system (CNS) could be an important reservoir for human immunodeficiency virus (HIV) regardless of cumulative time on treatment. This results in progressive neurocognitive dysfunction despite optimal treatment and peripheral control of the infection. Even though structural imaging studies have described abnormalities in optimally-treated HIV-positive subject population, there has been only a few attempts at deciphering the cellular levels of brain damage in those subjects using in vivo molecular imaging biomarkers. As part of CNS involvement, specific neurotransmitter systems including the dopaminergic and serotonergic systems are thought to be affected by the infection with distinct neurological, cognitive and psychological manifestations, even in optimally-treated subjects.

Objective: This protocol aims at identifying aspects of dopaminergic and serotonergic dysfunction in optimally-treated HIV-positive subjects using high resolution positron emission tomography (PET) of the brain and radioligands targeted against the dopaminergic (18F-FDOPA) and serotonergic (11C-DASB) systems.

Study population: We will identify 25 eligible HIV-infected individuals and 50 eligible HIV-negative (HIV-) individuals for the dopaminergic arm, and 20 HIV-infected individuals and 20 HIV-negative individuals for the serotonergic arm. Subjects will be selected from IRB approved NIH protocols, self-referred or will be referred form outside providers/institutions and those who meet eligibility criteria will be offered enrollment in our study.

Design: Subjects will undergo either a one-time 18F-FDOPA PET scan or a one-time 11C-DASB PET scan or both, if eligible. HIV-positive subjects and HIV-negative individuals will be included in the study.

Outcome Measures: Influx constant (Ki) for 18F-FDOPA PET and Binding potential relative to

non-displaceable binding (BPND) values for 11C-DASB PET

Arms: arm 1: 25 eligible HIV-infected individuals and 50 eligible HIV-negative (HIV-) individuals for the dopaminergic arm.

Dopaminergic arm:

Group A: HIV-positive subjects with or without co- morbidities; Group B: HIV-negative subjects with co-morbidities; Group C: HIV-negative subjects without co-morbidities arm 2: 20 HIV-infected individuals and 20 HIV-negative individuals for the serotonergic arm

Serotonergic arm:

Group D: HIV-positive subjects with or without co-morbidities; Group E: HIV-negative subjects with or without co-morbidities
Interventions: intervention 1: 18F-FDOPA intervention 2: 11C-DASB
Intervention descriptions: intervention 1: High resolution positron emission tomography (PET) of the brain and radioligands targeted against the dopaminergic (18F-FDOPA) system. intervention 2: High resolution positron emission tomography (PET) of the brain and radioligands targeted against the serotonergic (11C-DASB) system.

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Title: PET Imaging of the Dopaminergic and Serotonergic Systems in Treated 
HIV Positive Subjects 
 
Protocol Number: 18CC0117 
 
ClinicalTrials.gov Identifier: NCT03581305 
 
Version Date: 04/26/2022 


1
Protocol Number: 18CC0117
Version Date: 04/26/2022
Protocol Title: PET Imaging of the Dopaminergic and Serotonergic Systems in Treated 
HIV Positive Subjects
Abbreviated Title: Brain PET in Treated HIV 
Protocol Number: 18CC0117
Version Date: 04/26/2022 
Principal Investigator:
Dima Hammoud, MD
Radiology & Imaging Sciences Department, CC
Building 10, Room. 1C368 
10 Center Dr.
Bethesda MD 20814
Phone: 301-402-3041
Email: hammoudd@cc.nih.gov
Investigational Agents:
Drug Name:
18F-FDOPA
IND Number:
35513
Sponsor:
NIH CC
Manufacturer:
CC PET Department
 
      


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Protocol Number: 18CC0117
Version Date: 04/26/2022
Précis:
Background: An extensive body of literature points towards neuronal brain injury in 
human immunodeficiency virus positive (HIV-positive) subjects despite virological 
suppression of the virus in the periphery under the effect of antiretroviral therapies 
(ART). Existing evidence suggests that the central nervous system (CNS) could be an 
important reservoir for human immunodeficiency virus (HIV) regardless of cumulative 
time on treatment. This results in progressive neurocognitive dysfunction despite optimal 
treatment and peripheral control of the infection. Even though structural imaging studies 
have described abnormalities in optimally-treated HIV-positive subject population, there 
has been only a few attempts at deciphering the cellular levels of brain damage in those 
subjects using in vivo molecular imaging biomarkers. As part of CNS involvement, 
specific neurotransmitter systems including the dopaminergic and serotonergic systems 
are thought to be affected by the infection with distinct neurological, cognitive and 
psychological manifestations, even in optimally-treated subjects. 
Objective: This protocol aims at identifying aspects of dopaminergic and serotonergic 
dysfunction in optimally-treated HIV-positive subjects using high resolution positron 
emission tomography (PET) of the brain and radioligands targeted against the 
dopaminergic (18F-FDOPA) and serotonergic (11C-DASB) systems. 
Study population: We will identify 25 eligible HIV-infected individuals and 50 eligible 
HIV-negative (HIV-) individuals for the dopaminergic arm, and 20 HIV-infected 
individuals and 20 HIV-negative individuals for the serotonergic arm. Subjects will be 
selected from IRB approved NIH protocols, self-referred or will be referred form outside 
providers/institutions and those who meet eligibility criteria will be offered enrollment in 
our study. 
Design: Subjects will undergo either a one-time 18F-FDOPA PET scan or a one-time 
11C-DASB PET scan or both, if eligible. HIV-positive subjects and HIV-negative 
individuals will be included in the study.
Outcome Measures: Influx constant (Ki) for 18F-FDOPA PET and Binding potential 
relative to non-displaceable binding (BPND) values for 11C-DASB PET


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Protocol Number: 18CC0117
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Table of Contents
Précis:.........................................................................................................................................................2
Table of Contents....................................................................................................................................3
List of Abbreviations.............................................................................................................................5
1
Introduction and Background..................................................................................................6
1.1
Background information:.......................................................................................................................6
1.2
Dopaminergic System Involvement:..................................................................................................6
1.3
Serotonergic System Involvement ......................................................................................................7
1.4
Summary of Relevant Preliminary Studies:....................................................................................8
1.5
Rationale: ......................................................................................................................................................8
2
Study Objectives............................................................................................................................9
2.1
Primary Objectives ....................................................................................................................................9
2.2
Secondary Objectives................................................................................................................................9
3
Subjects ............................................................................................................................................9
3.1
Description of study population: All Subjects (Groups A-E):...................................................9
3.2
Inclusion criteria........................................................................................................................................9
3.2.1
All Subjects (Groups A-E): .....................................................................................................10
3.2.2
All HIV-positive Subjects with or without co-morbidities (Groups A 
[dopaminergic arm, n=25)] and Group D [serotonergic arm, n=20]) .........................10
3.2.3
HIV-negative Subjects WITH Co-morbidities (Group B, n=25)........................10
3.2.4
HIV-negative Subjects WITHOUT co-morbidities (Group C, n=25)...............10
3.2.5
HIV-negative Subjects with or without co-morbidities (Group E, n=20)...11
3.3
Exclusion criteria.....................................................................................................................................11
3.3.1
All Subjects (Groups A-E): .....................................................................................................11
3.3.2
Additional Exclusion Criteria for the Dopaminergic Arm (Groups A, B and 
C):
12
4
Study Design and Methods......................................................................................................12
4.1
Study overview..........................................................................................................................................12
4.2
Recruitment...............................................................................................................................................12
4.3
Schedule of Activities (SOA)................................................................................................................13
4.4
Screening.....................................................................................................................................................13
4.4.1
Screening activities performed prior to obtaining informed consent...................13
4.4.2
Screening activities performed after a consent for screening has been signed 14
4.5
Study Procedures.....................................................................................................................................15
4.5.1
Clinical Evaluations......................................................................................................................15
4.5.2
Laboratory Evaluations..............................................................................................................15
4.5.3
Neuropsychological Testing.....................................................................................................16
4.5.4
Imaging Studies .............................................................................................................................18
4.6
End of participation ...............................................................................................................................19
5
Management of Data and Samples........................................................................................20
5.1
Storage.........................................................................................................................................................20
5.2
Data and sample sharing plan...........................................................................................................20
6
Additional Considerations ......................................................................................................20
6.1
Research with investigational drugs or devices............................................................................20
6.2
Gene therapy..............................................................................................................................................20
7
Risks and Discomforts..............................................................................................................20
7.1
Potential Risks ..........................................................................................................................................20


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8
Subject Safety Monitoring .......................................................................................................22
8.1
Parameters to be monitored ..............................................................................................................22
8.2
Criteria for stopping procedures in an individual.....................................................................23
8.3
Criteria for individual subject withdrawal ..................................................................................23
9
Outcome Measures ....................................................................................................................23
9.1
Primary outcome measure..................................................................................................................23
9.2
Secondary outcome measures ...........................................................................................................23
10
Statistical Analysis.....................................................................................................................23
10.1
Statistical considerations for the FDOPA study .........................................................................23
10.2
Statistical Considerations for the DASB Study ...........................................................................24
10.2.1
Data analysis:.............................................................................................................................25
10.2.2
Interpretation of 18F-FDOPA and 11C-DASB PET Imaging............................26
11
Human Subjects Protection ....................................................................................................26
11.1
Subject selection.......................................................................................................................................26
11.2
Justification for exclusion of children.............................................................................................26
11.3
Justification for exclusion of subjects over 70 years: ...............................................................26
11.4
Justification for exclusion of non-English speakers..................................................................26
11.5
Justification for inclusion or exclusion of other vulnerable subjects ................................26
11.6
Justification for Inclusion of Neurocognitively Impaired Subjects ....................................26
11.7
Protection of Human subjects/protection of vulnerable subjects (employees)...........26
12
Anticipated Benefit....................................................................................................................27
13
Consent Documents and Process..........................................................................................27
13.1
Designation of those obtaining consent ........................................................................................27
13.2
Consent procedures ................................................................................................................................27
13.2.1
Considerations for Consent of NIH staff, or family members of study team .28
13.3
Consent documents.................................................................................................................................28
14
Data and Safety Monitoring ....................................................................................................28
14.1
Data and safety monitor ......................................................................................................................28
14.2
Data and safety monitoring plan .....................................................................................................28
14.3
Criteria for stopping the study or suspending enrollment or procedures......................28
15
Quality Assurance (QA)............................................................................................................28
15.1
Quality assurance monitor..................................................................................................................28
15.2
Quality assurance plan..........................................................................................................................29
16
FDA and NIH Reporting............................................................................................................29
16.1
Definition of reportable events..........................................................................................................29
16.2
Expedited reporting ...............................................................................................................................29
16.3
IRB Requirements for PI Reporting at Continuing Review ...................................................29
16.4
Clinical Director Reporting.................................................................................................................29
16.5
For FDA-Regulated Research associated with IND # 35513 (18F-DOPA) .....................29
17
Alternatives to Participation..................................................................................................29
18
Privacy ...........................................................................................................................................30
19
Confidentiality.............................................................................................................................30
19.1
For research data and investigator medical records ..............................................................30
20
Conflict of Interest .....................................................................................................................30
21
Technology Transfer.................................................................................................................31
22
Research and Travel Compensation....................................................................................31


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23
References....................................................................................................................................32
List of Abbreviations 
11C-DASB
11C-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile
18F-FDOPA
18F-3,4-dihydroxy-6-18F-fluoro-l-phenylalanine
AIDS
acquired immune deficiency syndrome
ACC
American College of Cardiology
AE
adverse event
AHA
American Heart Association
ART
antiretroviral therapy
ASCVD 
atherosclerotic cardiovascular disease
BBB
blood-brain barrier
BLD
below level of detection
CNS
central nervous system
CSF
Cerebrospinal fluid
DAT
dopamine reuptake transporter
FDA
Food and Drug Administration
FDG-PET
fluorodeoxyglucose-positron emission tomograph
HAART
highly active antiretroviral therapy
HAND
HIV-associated neurocognitive disorders
HC
healthy controls
HCV
hepatitis C virus
HBV
hepatitis B virus
HIV
human immunodeficiency virus
HRRT
high resolution research tomograph
IND
Investigational New Drug
IRB
Institutional Review Board
MRI
magnetic resonance imaging
MAO
Monoamine oxidase 
NIH
National Institutes of Health
OSEM
ordered-subsets expectation maximum 
PBMCs
peripheral blood mononuclear cells
PET
positron emission tomography
PI
Principal Investigator
ROS
reactive oxygen species 
SAE
serious adverse event
SERT
serotonin transporter
SIV
Simian immunodeficiency virus
SLE
systemic lupus erythematosus
SSRIs
selective serotonin reuptake inhibitors
SUVmean
mean standardized uptake value
Tat
transactivator of transcription
Tg rat
HIV-1 transgenic rat


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TH
tyrosine hydroxylase
1
 Introduction and Background
1.1
Background information:
Similar to what has been recently described in simian immunodeficiency virus (SIV) 
infected monkeys 1, it is our hypothesis that the central nervous system (CNS) harbors 
latent HIV provirus despite long-term viral suppression by ART. HIV DNA, measured by 
quantitative and droplet digital PCR, was identified in > 50% of brain tissues obtained 
from subjects with low or undetectable viral load in the periphery prior to death 2. In the 
setting of appropriate viral suppression, HIV reservoirs in the brain include latently 
infected cells such as perivascular macrophages, microglial cells, and astrocytes 3. 
Integrated HIV provirus within those cells results in the production of HIV viral proteins 
as has been shown with detectable levels of transactivator of transcription (Tat) in the 
cerebrospinal fluid (CSF) of those subjects 4. In theory, the incomplete penetration of 
antiretroviral drugs across the blood-brain barrier (BBB) allows for low level production 
of those viral proteins which results in a subtle but continuous pattern of brain injury and 
neurotoxicity, eventually leading to cognitive and/or psychiatric dysfunction despite 
peripheral control of the infection. 
An extensive body of literature points towards neuronal brain injury in HIV positive 
subjects despite virological suppression of the virus in the periphery under the effect of 
antiretroviral therapies (ART). Even though structural imaging studies have described 
abnormalities in optimally-treated HIV-positive population, there has been only a few 
attempts at deciphering the cellular levels of brain damage in those subjects using in vivo 
molecular imaging biomarkers of specific neurotransmitter systems. Two systems that are 
known to be affected by HIV are the dopaminergic and serotonergic systems.
1.2
Dopaminergic System Involvement: 
Dopaminergic dysfunction manifested as parkinsonian symptomatology is one of the 
facets of HIV-associated neurocognitive disorders (HAND) 5-8. In fact, HIV infection is 
associated with especially marked vulnerability of the dopaminergic system to the effect 
of the virus which seems to target the basal ganglia resulting in loss of dopaminergic 
neurons 9. The mechanism of neurotoxicity involving the dopaminergic system is thought 
to be related to the neurotoxic effects of viral proteins, namely Tat and envelope 
glycoprotein 120 (gp120). The neurotoxicity of Tat was shown in primary hippocampal 
rat cell cultures in which Tat 1-72 triggered mitochondrial depolarization, increased 
intracellular production of reactive oxygen species (ROS) and protein oxidation, and 
caused neuronal degeneration 10. Similarly, the neurotoxic effect of gp120 was 
demonstrated in mesencephalic neuronal/glial culture model, with gp120-induced 
reduced function (decreased dopamine uptake), morphological changes, and reduced 
viability of the dopaminergic neurons 11. In another study, gp120 produced loss of 
nigrostriatal neurons, as shown both by histochemical analysis of brain sections for 
apoptosis and biochemical determination of dopamine concentration 12.
In vivo, dopaminergic loss was documented in SIV infected monkeys, found to have 
decreased neuronal number and neuronal density in the globus pallidus and substantia 
nigra compared to controls 13. Dopamine defects actually seem to precede neurologic 


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deficits in SIV-infected monkeys, thus implicating dysfunction of the dopaminergic 
system in the etiopathogenesis of HIV dementia 14. Similarly, in brain sections of subjects 
with known history of HIV encephalitis, striatal dopaminergic markers were abnormal: 
decreased presynaptic tyrosine hydroxylase (TH) protein and phosphorylated TH, 
increased presynaptic dopamine reuptake transporter (DAT), decreased postsynaptic 
dopamine receptor type 2 (D2R) and increased postsynaptic dopamine receptor type 3 
(D3R) 15. More interestingly, even in treated HIV-positive subjects, postmortem 
specimen revealed significant decrease in dopamine in the caudate nucleus, putamen, 
globus pallidus, and substantia nigra 16.
The neurotoxicity of HIV viral proteins is also synergistic with abuse drugs such as 
methamphetamine and cocaine that also act on the dopaminergic system 9,17,18. Drug 
abuse in this subject population is a common problem and as such can severely increase 
dopaminergic dysfunction in already predisposed individuals. Considering the poor 
penetration of the BBB by a large number of highly active antiretroviral therapy 
(HAART) drugs, and taking into account the high prevalence of drug abuse in HIV-
positive subjects, it appears that the need for neuroprotective agents in this subject 
population is great. The endpoints in studies of neuroprotective approaches however are 
variable and not easily quantifiable which results in uncertainty about the efficacy of the 
drugs 19,20. Having a quantifiable secondary endpoint in these situations can significantly 
improve the power of the study and might provide prognostic information not otherwise 
available through current clinical endpoints. One such quantitative technique is positron 
emission tomography (PET) of the dopaminergic system.
In the literature, only two studies have been performed using PET targeting different 
components of the dopaminergic system. In the first study, PET imaging of DAT in HIV 
subjects with associated dementia (but not those without dementia) showed significantly 
lower DAT availability in putamen (P = 0.009) and ventral striatum (P = 0.03) compared 
with seronegative controls. Higher plasma viral load in the HIV dementia subjects also 
correlated with lower DAT in the caudate and putamen 21. In the second study, HIV-
positive subjects with (HIV-positive Coc) and without history of cocaine dependence had 
lower DAT in putamen while only HIV-positive Coc showed lower DAT in caudate 
compared to HIV-negative controls 22. Some of the subjects in those studies however 
were still viremic. To our knowledge, there has been no evaluation yet of presynaptic 
dopamine metabolism in the setting of HIV and no evaluation of optimally treated 
subjects with any dopaminergic ligand.
1.3
Serotonergic System Involvement
Depression remains an important facet of HAND 23-26, despite significant advances in 
treatment of peripheral disease and control of the infection. There is however limited 
literature about the contribution of the serotonergic system to depressive disorders in 
HIV. Using real-time (RT)-PCR, the levels of serotonin transporter (SERT) mRNA in the 
peripheral blood mononuclear cells (PBMCs) of SHIV infected rhesus macaques was 
significantly reduced in comparison to control animals, suggesting SERT expression 
might be affected in HIV/acquired immune deficiency syndrome (AIDS) 27. Tryptophan 
metabolism dysregulation is also suspected to play a role in HIV-1 associated depression 
28,29. One PET study targeting SERT in the setting of HIV depression showed lower 11C-
DASB (a PET ligand that specifically targets SERT in the brain) binding in HIV-positive 
subjects compared to healthy controls (HC), however with depressed subjects showing 
higher 11C-DASB uptake compared to non-depressed subjects 30. No other cross-


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sectional or longitudinal PET studies have been performed to confirm this observation. 
All the findings above suggest a possible role for dysregulated serotonergic transmission 
in HIV-associated depression. 
1.4
Summary of Relevant Preliminary Studies:
In our human studies using fluorodeoxyglucose positron emission tomography (FDG-
PET) scanning, there was generalized hypometabolism in the HIV-positive subjects 
compared to age-matched HC. We found statistically significant lower whole brain 
maximum standardized uptake value (SUVmax) values in HIV-positive compared to HC 
but not to HIV-negative (HIV-) subjects with similar co-morbidities to the HIV-positive 
group. Among regions, mean standardized uptake (SUVmean) values in the thalamus, 
caudate and cerebellum were significantly lower than HC but not compared to HIV-
negative subjects. Among the relative SUVmean measurements however, only the 
thalamic values were significantly lower in HIV-positive compared to both HC and to 
HIV-negative subjects. Using a mixed-effect statistical model, the most predictive 
clinical variables for thalamic relative SUVmean values was study group (HIV status), 
cardiovascular disease risk and prior drug use. Considering the HIV-positive group 
separately, cardiovascular disease risk predicted most of the other SUV values. Our 
findings suggest an HIV specific effect on hypometabolism in the brain that is separate 
from the associated co-morbidities. 
Along the same lines, we have also evaluated HIV-1 transgenic (Tg) rats in our lab, 
looking for dopaminergic dysfunction. Along with decreased D2/D3R expression on 
PET, an interesting observation we made was significantly decreased TH staining. This 
suggested to us that there is a strong element of presynaptic dopaminergic loss in those 
animals which might be even greater than the postsynaptic deficit31. We then proceeded 
to evaluate DAT using a specific PET ligand (18F-FP-CMT). Decreased DAT expression 
in older Tg rats was seen, suggesting both pre and post synaptic dopaminergic deficits in 
this animal model of treated HIV-positive subjects32.
Preliminary results in SIV infected monkeys: we have recently imaged SIV infected 
monkeys at baseline, before inoculation and at multiple time points after inoculation. Out 
of seven monkeys, six animals demonstrated a consistent trend of increased 11C-DASB 
binding especially in areas with high binding such as the midbrain and thalamus. This 
could reflect upregulation (increased expression) of SERT under the effect of SIV 
infection or could reflect increased affinity of the receptor. The first possibility is the 
more likely one since no allosteric modifications that would change receptor affinity have 
been described yet for SERT. 
1.5
Rationale:
One issue of neurocognitive dysfunction in optimally-treated and virologically-controlled 
subjects is the magnitude of actual brain damage, and how much of it is related to HIV 
versus other commonly encountered co-morbidities in this subject population such as 
drug abuse, alcohol abuse, and co-infections (e.g. hepatitis C virus [HCV]). FDG-PET 
scans showed evidence of hypometabolism in the HIV-positive subjects however 
hypometabolism in some brain regions was also seen in HIV-negative individuals with 
co-morbidities. A few regions like the thalamus and caudate, however, demonstrated a 
more severe involvement in the HIV-positive group compared to the healthy and HIV-
negative individuals with co-morbidities suggesting a definite role for HIV in the 
neuropathology. To better understand the effect of HIV on various neurotransmitter 


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systems beyond the effect of co-morbidities, a detailed evaluation of those systems 
becomes necessary. Although this has been attempted previously using different ligands, 
the current proposal will be the first to assess the pre-synaptic dopaminergic and 
serotonergic systems in a homogenous, very well characterized, optimally-treated HIV-
positive subject population. 
2
Study Objectives 
2.1
Primary Objectives
To understand the pathophysiology of dopaminergic and serotonergic involvement in 
chronically infected and virologically controlled HIV-positive subjects compared to HIV-
negative subjects using high resolution PET scanning with 18F-FDOPA and 11C-DASB.
2.2
Secondary Objectives

To distinguish dopaminergic neurotransmitter damage related to HIV versus co-
morbidities.

To correlate 11C-DASB binding in the brain with depressive symptomatology in 
optimally-treated HIV-positive subjects.

To correlate in vivo uptake of 18F-FDOPA and 11C-DASB PET with duration of 
infection with HIV, the duration of HIV infection prior to the initiation of 
antiretroviral therapy (ART), and nadir CD4.
3
Subjects
3.1
Description of study population: All Subjects (Groups A-E):
Subjects will include chronically infected HIV-positive subjects with plasma HIV-RNA 
<100 copies/mm3 or below level of detection (BLD) for greater than one year () along 
with HIV-negative subjects with and without co-morbidities. 
Accrual Ceiling: 155
Dopaminergic arm: 35 HIV-positive and 60 HIV-negative subjects (total 95 subjects)
Serotonergic arm: 30 HIV-positive and 30 HIV-negative subjects (total 60 subjects)
Our target sample size is: 
Dopaminergic arm: 25 HIV-positive and 50 HIV-negative subjects (total 75 subjects)
Serotonergic arm: 20 HIV-positive and 20 HIV-negative subjects (total 40 subjects)
Any withdrawals/dropouts will be replaced. 
NIH employees may participate if eligible. Subordinates of investigators will not be 
allowed to participate.
3.2
Inclusion criteria 
Subject groups:
Dopaminergic arm: 
Group A: HIV-positive subjects with or without co- morbidities
Group B: HIV-negative subjects with co-morbidities
Group C: HIV-negative subjects without co-morbidities


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Serotonergic arm:
Group D: HIV-positive subjects with or without co-morbidities
Group E: HIV-negative subjects with or without co-morbidities
3.2.1
All Subjects (Groups A-E):
1. Men and women, 18-70 years of age
2. Ability to sign informed consent by the subject
3. Subjects may be enrolled in or have been discharged from IRB approved NIH 
protocols OR subjects may be referred from outside providers/institutions. 
4. Has the ability to be seen by an outside medical doctor who provides care.
3.2.2
All HIV-positive Subjects with or without co-morbidities (Groups A 
[dopaminergic arm, n=25)] and Group D [serotonergic arm, n=20])
1.
Known and documented HIV-1 infection
2.
Plasma HIV-RNA BLD (<100 copies/mm3) for greater than one year since the 
last available documented viral load measurement.
3.
At least one year of continuous ART prior to last documented suppressed viral 
load measurement and no history of ART modification or interruption since then.
3.2.3
HIV-negative Subjects WITH Co-morbidities (Group B, n=25)
1. HIV-antibody negative 
2. At least one or more of the following criteria: 
a.
Hypertension, as defined by treatment with medications for hypertension 
or with a systolic blood pressure at screening ≥140mm Hg.
b. Diabetes mellitus, as defined by HgbA1C ≥6.5% or known treatment for 
diabetes.
c.
Hepatitis C infection as documented by lab results of a positive Hepatitis 
C antibody and/or detectable Hepatitis C viral load. Subjects who 
responded to HCV treatment (SVR) will be included.
d. History of previous but not current drug abuse 
e.
History of previous but not current alcoholism (defined as alcohol intake 
that affect/affected the subject’s work or home life).
f.
Clinical atherosclerotic cardiovascular disease (ASCVD) (e.g. history of 
acute coronary syndromes, or myocardial infarction, stable or unstable 
angina, coronary or other arterial revascularization or peripheral arterial 
disease of atherosclerotic origin) and/or 10-year heart disease risk score 
(ASCVD risk score) >7.5% (7.5 % score is the threshold for starting statin 
therapy as per the 2013 American College of Cardiology [ACC] / 
American Heart Association [AHA] guidelines 33).
3.2.4
HIV-negative Subjects WITHOUT co-morbidities (Group C, n=25)
1. HIV-antibody negative
2. No history of any of the following:
a.
Hypertension, as defined by treatment with medications for hypertension 
or with a systolic blood pressure at screening ≥140mm Hg.
b. Diabetes mellitus, as defined HgbA1C ≥6.5% or treatment for diabetes.
c.
Hepatitis C infection as documented by lab results of positive Hepatitis C 
antibody and/or detectable Hepatitis C viral load. Subjects who responded 
to HCV treatment (SVR) will not be included.


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d. History of previous drug abuse. 
e.
History of previous alcoholism. Alcoholism is based on alcohol having 
affected the subject’s work or home life.
f.
Clinical ASCVD (e.g. history of acute coronary syndromes, or myocardial 
infarction, stable or unstable angina, coronary or other arterial 
revascularization or peripheral arterial disease of atherosclerotic origin) 
and/or 10-year heart disease risk score (ASCVD risk score) >7.5% (7.5 % 
score is the threshold for starting statin therapy as per the 2013 ACC/AHA 
guidelines 33).
g. Any other disease entities including chronic infections (e.g. Hepatitis B, 
Lyme disease), neurological diseases (e.g. Multiple sclerosis, vasculitis) or 
systemic diseases (e.g. Sjogren’s diseases, sarcoidosis, systemic lupus 
erythematosus [SLE]) that in the opinion of the investigator would be 
considered a significant co-morbidity. 
3.2.5
HIV-negative Subjects with or without co-morbidities (Group E, n=20)
1. HIV-antibody negative
3.3
Exclusion criteria 
3.3.1
All Subjects (Groups A-E):
1. Illness or other condition that, in the opinion of the PI, may interfere with study 
participation at the time of enrollment, including known history of significant 
intracranial structural damage such as previous stroke(s) or history of intracranial 
benign or malignant tumors.
2. Conditions other than HAND associated with cognitive impairment or dementia 
such as Alzheimer’s, Parkinson’s disease, head injury with loss of consciousness 
>30 minutes, or seizure disorders.
3. A positive screening result for psychiatric diseases that are known to affect the 
dopaminergic or serotonergic systems. 
4. Current substance abuse that would interfere with PET scan results at the 
investigators’ discretion 36-41.
5. Medications: use of any drug with known dopaminergic or serotonergic activity 
within 6 months prior to planned imaging date(s). 
6. Pregnant or Lactating women: Women of childbearing potential must have a 
negative serum or urine pregnancy test within 1 week prior to study entry. 
Pregnancy testing will also be performed in enrolled female participants prior to 
any radiation exposure.
7. Prior or planned/anticipated exposure to radiation due to clinical care or 
participation in other research protocols, which would exceed the recommended 
acceptable annual limit of radiation exposure once accounting for the requirements 
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3.3.2
Additional Exclusion Criteria for the Dopaminergic Arm (Groups A, B and 
C):
1. Use of any of the following drugs within 6 months from planned imaging date(s):
a)
Haloperidol (increased intracerebral dopamine turnover caused by 
haloperidol may result in increased accumulation of 18F-DOPA) 34 
b)
Monoamine oxidase (MAO) inhibitors (may result in increased 
accumulation of 18F-DOPA in the brain) 34 
c)
Reserpine (reserpine-induced depletion of the contents of intraneuronal 
vesicles may prevent retention of 18F-DOPA in the brain) 35 
d)
Carbidopa/LDOPA (LDOPA competes with 18F-DOPA for DOPA 
decarboxylase activity) 35-40)
2. Allergy to carbidopa
Note that HBV is not an exclusion criterion for groups A, B, D or E since it’s not known 
to have direct CNS pathology in the absence of advanced liver disease and cirrhosis.
4
Study Design and Methods
4.1
Study overview
Subjects will be recruited through protocol number 13-N-0149 (ALL HANDS protocol, 
PI Dr. Avindra Nath), other IRB-approved intramural NIH protocols, or through referrals 
from outside providers/institutions or self-referred. Participants will be evaluated for 
eligibility to one of the groups (A-E). Once consented and found eligible, subjects will 
undergo PET scanning using 18F-FDOPA and/or 11C-DASB. All the visits will be on 
outpatient basis unless a participant is inpatient at the Clinical Center for another 
protocol. There will be no follow-up visits after the completion of the PET scan(s). In 
case the planned scans cannot be done for any reason and the subject is still eligible and 
willing to participate, a second visit will be scheduled to complete the study procedures. 
4.2
Recruitment
Subjects will be recruited through protocol number 13-N-0149 (ALL HANDS protocol, 
PI Dr. Avindra Nath), through other IRB-approved intramural NIH protocols, through 
referrals from outside providers/institutions or through self-referral. 
We will send an IRB approved letter to the PIs of NIH protocols targeting HIV infected 
subjects (Appendix B) and ask for help in identifying potential subjects in their protocols 
who might be interested in our study. We will also include an IRB approved flyer 
describing our study to give to volunteers. If the subjects express interest, we will access 
their medical record at NIH to evaluate if they are potentially eligible. We will then 
proceed to contact them for more information as below. 
If we get referrals from outside providers/institutions or self-referred potential subjects 
contact us, we will conduct a phone interview and ask them to send us relevant medical 
records to evaluate if they satisfy the eligibility criteria. 
When a subject (either referred from an NIH protocol, from outside providers/institutions 
or self-referred) is evaluated and found to be potentially eligible based on the 
inclusion/exclusion criteria of one or more of the groups, he/she will be re-contacted 


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about participating in one or more of our PET studies. If the subject is at NIH, the 
investigators will explain the nature of the study with all the associated risks in person. If 
they are not at NIH, investigators will call the subject to explain the nature of the study 
with all the associated risks. If the subjects are still interested in participating, they will 
be asked to sign the informed consent document before any study procedures are 
conducted and they will be scheduled for screening procedures to evaluate if they are 
eligible. For NIH employees, there will be no direct solicitation of employees/staff by 
supervisors.  
4.3
Schedule of Activities (SOA)
Time Point a
Procedures
Screening
Visit 1
Visit 2
Informed consent
X
Demographics
X
Medical history
X
Physical exam and vital 
signs
X
Client Diagnostic 
Questionnaire (CDQ)
X
Laboratory Tests b
X
Urine toxicology screen c
X
X
Pregnancy test c
X
Neuropsychological testing d
X
MRI (Brain)
X
PET (18F-FDOPA and/or 
11C-DASB) e
X
Adverse event review and 
evaluation
X
a If not all procedures could be completed in one visit, they could be rescheduled to another day.
b HIV RNA Viral Load (only for groups A and D)), CBC/diff/platelets, hepatic panel, 
Hemoglobin A1c (if known history of Diabetes mellitus), fasting lipid profile, Acute Care 
Panel, Hep C antibody and HCV RNA Quant) (No need to be performed if its performed within 
3 month of planned PET scan)
c Urine toxicology and urine or serum pregnancy test will be performed 48 hours or less prior to 
the planned scan and must be checked before scanning.
d Neuropsychological test may include the following: WTAR; WAIS-III; TMT; HVLT-R; 
BVMT-R; WCST-64; COWAT; FAS and Animals; PASAT; Grooved Pegboard Test; Judgment 
of Line Orientation and Medical Symptom Validity Test. 
e The PET (18F-FDOPA and/or 11C-DASB) scanning will be performed either on the same day 
(one visit) or on two separate visits based on the subject’s preferences and scan time availability.
4.4
Screening
4.4.1
Screening activities performed prior to obtaining informed consent
Minimal risk activities that may be performed before the subject has signed a consent 
include the following: 
•
Email, written, in person or telephone communications with prospective 
subjects. 
•
Review of existing medical records to include H&P, laboratory studies, 
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•
Review of existing brain MRI images.
Since this study was approved before revised Common Rule that did not allow pre-
screening procedures without the consent, it is being requested that consent for pre-
screening procedures be waived
4.4.2
Screening activities performed after a consent for screening has been signed
The evaluations will be completed at the National Institutes of Health (NIH) Clinical 
Center. We will obtain informed consent before any screening procedures. The following 
procedures will be performed for screening purposes:

History and physical exam including vital signs (No need to be repeated if it has 
been performed at NIH within 3 month of planned PET scan)

Laboratory tests: HIV RNA Viral Load (only for groups A and D), 
CBC/diff/platelets, hepatic panel, Hemoglobin A1c (if known history of 
Diabetes mellitus), fasting lipid profile, Acute Care Panel, Hep C antibody and 
HCV RNA Quant). (No need to be repeated if performed at NIH within 3 month 
of planned PET scan)

MRI Brain (No need to be repeated if performed at NIH within one year of 
planned PET scan)

Client diagnostic test (CDQ) (No need to be repeated if performed at NIH within 
3 months of planned PET scan)
4.4.2.1
Client Diagnostic Test (CDQ)
Psychiatric disorders and substance use disorders will be assessed with the Client 
Diagnostic Questionnaire (CDQ) 41, a psychiatric screening tool that was adapted from 
the PRIME-MD 42a well-validated screening tool for assessing psychiatric disorders and 
substance use disorders in primary care settings. The CDQ was developed and validated 
for persons affected by HIV.  For the diagnosis of any disorder, the sensitivity, 
specificity, overall accuracy, and kappa coefficient of the CDQ were 91%, 78%, 85% and 
70%, respectively.  We will use the CDQ to screen for presence of major depressive 
disorder, other depressive disorder, panic disorder, generalized anxiety disorder, post-
traumatic stress disorder (PTSD), psychosis, alcohol abuse and substance abuse. If during 
the CDQ, we identify evidence of severe depression (“I would like to kill myself” or “I 
would kill myself if I had a chance”), a psychiatric consult will automatically be offered 
to the subject with the goal to assess his or her immediate safety.  The role of this 
psychiatry consult is only to assess and manage immediate safety concerns, and not to 
provide an ongoing mental health treatment.  However, in each case where the 
psychiatrist or psychologist, following the safety assessment, recommends mental health 
treatment, the participant will be advised to pursue the recommended treatment outside of 
the clinical center and according to her/his healthcare access plan.
4.4.2.2 MRI brain
Subjects will undergo a 3 tesla MRI scan of the brain for research purposes and to 
evaluate anatomical abnormalities.  This scan may also be used for localization of PET 
regions for other studies of HIV-HAND planning to use PET.  MRI scanning will be 
performed at the NIH Clinical Center or the NMR Center, and the procedure takes about 
1-2 hours.  Persons requiring more than oral lorazepam (or an equivalent) as sedation for 
MRI will be excluded from the protocol.  


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The imaging protocol may include:
2. Basic anatomical imaging sequences, including but not limited to PD/T2-
weighted images as well as unenhanced T1, T2*, and FLAIR images.   
3. Diffusion weighted imaging.
4. 3D T1weighted images, which will be used for co-registration with the PET. 
Interpretation of imaging studies: All structural MR images of the brain will be 
interpreted qualitatively by the neuroradiologist on call as soon as possible after the 
completion of the scan.  During scanning, the images will be monitored for quality (e.g., 
motion artifacts degrading the images) and repeated as needed.  Coregistration of 3D T1 
weighted images with the PET images will be performed later on a specialized 
workstation connected to the PACS system in Radiology/nuclear medicine.  The MRI 
imaging will be used to rule out major acute abnormalities that need immediate clinical 
attention, or subacute/chronic conditions that require further medical care.  This 
information will be shared with the subject and his/her primary doctor.  If needed, the 
subject will also be referred to his/her primary doctor for further evaluations and 
treatment.  If the subject does not have insurance or primary care physician, the study 
team will assist him/her in finding medical care.
MRI scans are performed on FDA-approved scanners with FDA-approved 
radiofrequency coils and FDA-approved pulse sequences, and their use conforms to the 
corresponding FDA labels. Acquisition parameters may be modified within the permitted 
range. These studies may involve software modifications as allowed under 21 CFR 
812.2(b)(4), which stipulates that any modification “is not for the purpose of determining 
safety or effectiveness and does not put subjects at risk.” All research pulse sequences 
will not conform to the FDA’s Criteria for Significant Risk Investigations of Magnetic 
Resonance Diagnostic Devices.
We use MR Image Reconstruction and Analysis Software, this software is 
provided/developed by Pmod (Zurich, Switzerland). We use Pmod to reconstruct MRI 
imaging and co-register MRI to PET scans acquired in this study. This software is used 
for research purposes only and not intended for use for clinical diagnosis or direct clinical 
efficacy testing. We classify the software as an NSR device under this protocol. For the 
purposes of this protocol, research post processing software is exempt from the IDE 
regulations under 21 CFR 812.2(c) because it is noninvasive, does not require an invasive 
sampling procedure that presents significant risk, and does not by design or intention 
introduce energy into a subject.
4.5
Study Procedures
4.5.1
Clinical Evaluations
An interim medical history (including antiretroviral adherence) and assessment of vital 
signs will be performed within 48 hours of the scan. If in the assessment of the 
investigator, there are interim findings that could impact selection group criteria (e.g. 
change in medications or new symptoms), additional screening lab work may be ordered 
and scanning will be not be performed until the results are back. Abnormal results will be 
communicated to subjects.


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4.5.2
Laboratory Evaluations
For all subjects: A urine toxicology screen will be performed 48 hours or less prior to the 
planned scan date, and will be checked before scanning.
For women of childbearing potential: A human chorionic gonadotropin (β-hCG) test with 
a sensitivity of 25-50 mIU/mL using urine or serum will be performed 48 hours or less 
prior to the planned scan and must be confirmed as negative before scanning. 
Both the urine pregnancy and toxicology screening results are required prior to 
proceeding to the PET scan. 
All the laboratory tests performed under this protocol are solely for research purposes.
4.5.3
Neuropsychological Testing
All subjects who enroll will undergo neuropsychological testing to evaluate for presence 
and severity of cognitive impairment (see Appendix A).
Tests will be administered by an experienced neuropsychologist or trained 
psychometrician under the supervision of a neuropsychologist.  These tests will be 
administered to establish an initial baseline of neuropsychological functioning and 
diagnostic classification.  This battery of tests is consistent with instruments used in other 
HIV related studies assessing cognitive functioning, both inside and outside of the NIH 
(i.e., it is largely consistent with the CHARTER battery 43, but includes a few additional 
instruments).  The battery provides a thorough evaluation of the major domains of 
cognitive functioning.  
Neuropsychological testing results will be accepted if performed within one year of 
enrollment and if consistent with the NIH group of tests. If testing was performed outside 
of NIH, subjects will need to arrange for copies of the raw data to be sent to the NIH 
protocol neuropsychologist prior to initial visit so the validity of the testing and the scores 
can be verified. For subjects enrolled in other NIH studies the data can be made available 
across protocols with the subject’s consent. 
Brief Description of Neuropsychological Tests
The primary purpose of our neuropsychological battery is for classification of HAND and 
not for outcome scores, per se.  The HAND classifications that we will use for this study 
to estimate the prevalence of HAND will remain consistent throughout the course of the 
study.  We will also explore in this study how other classification methods will compare 
against the gold standard HAND diagnosis, but this will not be a primary outcome 
measure of this study.  Nevertheless, the primary measures we will look at to make such 
classification will include demographically corrected T-scores for the following:
1. Wechsler Test of Adult Reading (WTAR) (The Psychological Corporation, 2001 
#31) is a test of word-reading used to estimate premorbid intelligence. (Scoring:  this 
test is administered to estimate IQ and is not used for classification, per se.) 
2. Wechsler Adult Intelligence Scale – Third Edition (WAIS-III) subtests 44 
including Coding, Symbol Search and Letter-Number Sequencing will be 
administered.  They measure aspects of working memory and information processing 
speed.  (Scoring:  Digit Symbol/Coding, Symbol Search, and Letter-Number 
Sequencing: number correct or number correct minus errors, as specified in the test 
manual.) 
3. Trail Making Test (TMT) Parts A and B 45 is a test of visual attention and task 
switching that require visual scanning, number and letter sequencing, and visual 


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motor speed.  The test requires the individual to connect the dots of 25 consecutive 
targets (numbers only in Trail A and then numbers and letters in Trail B) on sheets of 
paper.  (Scoring:  completion time.) 
4. Hopkins Verbal Learning Test-Revised (HVLT-R) 46 is a list-learning task 
assessing immediate and delayed recall as well as recognition.  (Scoring: total recall 
and delayed recall.)
5. Brief Visual Memory Test-Revised (BVMT-R) 47 is a test of visual memory 
assessing immediate and delayed recall.  (Scoring:  total recall and delayed recall.)
6. Wisconsin Card Sort Test (WCST-64) 48 is an objective measure of executive 
dysfunction, emphasizing abstract reasoning, ability to use feedback to shift cognitive 
sets, and goal-directed behavior in response to changing contingencies.  (Scoring:  
total errors and perseverative errors.)
7. Controlled Oral Word Association Test (COWAT; FAS and Animals) 49 measure 
language and executive functioning test by evaluating the spontaneous production of 
words beginning with a given letter or of a given class within a limited amount of 
time.  (Scoring:  number of words generated and semantic fluency.) 
8. Paced Auditory Serial Addition Test (PASAT) 50 is a measure of cognitive function 
that specifically assesses auditory information processing speed and flexibility, 
calculation ability, and working memory.  (Scoring:  number correct.) 
9. Grooved Pegboard Test 51 is an assessment of bilateral fine motor manual dexterity.  
(Scoring:  speed for dominant and non -dominant hands.
10. Judgment of Line Orientation 52 is a test of visuospatial abilities.  (Scoring:  
number correct.)
11. Medical Symptom Validity Test 53 is a memory-based test of symptom validity.
In addition to this list of tests, we will be screening for depression using the Beck 
Depression Inventory - II 54.  A high score on the BDI-II will not preclude participation in 
the protocol, but will be taken into consideration when attempting to classify HAND.  
When BDI-II item 9 is endorsed at level 2 or 3 (“I would like to kill myself” or “I would 
kill myself if I had a chance”), a psychiatric consult will automatically be offered to the 
subject with the goal to assess his or her immediate safety.  If item 9 is endorsed at level 
1, a determination will be made by the study psychologist or psychiatrist whether offering 
a full psychiatry consult is necessary.  The role of this psychiatry consult is only to assess 
and manage immediate safety concerns, and not to provide an ongoing mental health 
treatment.  However, in each case where the psychiatrist or psychologist, following the 
safety assessment, recommends mental health treatment, the participant will be advised to 
pursue the recommended treatment outside of the clinical center and according to her/his 
healthcare access plan.
We will also assess subjects’ level of functional disability through questionnaire and/or 
tasks. Texas Functional Living Scale (Cullum, Weiner, and Saine, 2009), Patient’s 
Assessment of Own Functioning (PAOFI; Chelune, Heaton, and Lehman, 1986), and the 
Lawton Activities of Daily Living (Self and Other).  Additional clinical 
neuropsychological measures as described in Lezak, Howieson, and Loring 55 and/or 
Strauss, Sherman, and Spreen 56 or other similar neuropsychological test compendia may 
be administered as the situation warrants, such as to rule out other primary or secondary 
diagnoses, follow up on interesting leads for future research, and/or for more in depth 
description of subjects.  Examples of additional measures include: subtests from the 


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Delis-Kaplan Executive Function System 57, California Verbal Learning Test-II 58, and 
the Wechsler Memory Scale-III 59.
As part of the neuropsychological testing we will be using the Clinical Trials Survey 
System (CTSS).  Portions of this testing will be administered on a computer after the 
participant has signed informed consent.  The forms used may include Activities of Daily 
Living, Neurobehavioral Medical Screen, Employment Questionnaire, and Patient’s 
Assessment of Own Functioning.  
4.5.4
Imaging Studies
The imaging studies in this protocol include radiation exposure and are performed solely 
for research purposes. Each PET scan will be completed over the course of one visit 
based on scheduling and participant convenience. We will scan subjects on the CPS/CTI 
high resolution research tomograph (HRRT), head-only camera.
Both the 18F-FDOPA and 11C-DASB PET scans may be completed by each participant 
if eligible, however each scan will be performed only once (this is a cross-sectional only 
PET study and there will be no longitudinal scans). If a participant is found to be eligible 
for both PET studies, the scanning will be performed either on the same day (one visit) or 
on two separate visits based on the subject’s preferences and scan time availability. If 
performed on the same day, the 11C-DASB scan will be performed first (in the morning) 
and the 18F-DOPA will be performed after at least seven half-lives of the isotope (11C 
half-life = 20 minutes) which is equivalent to 140 minutes after injection of 11C-DASB. 
4.5.4.1
18F-DOPA PET Procedure
18F-DOPA is a Radioactive Research Drug (regulated under 21 CFR 361). The drug will 
be used under the approved Investigational New Drug (IND) No 35513. The sponsor of 
the IND is the NIH clinical Center and the authorized representative of the sponsor is Dr. 
Peter Herscovitch, PET department.
Subjects will be asked to fast for 4-6 hours prior to scanning. The exact time to begin 
fasting will be determined based on the planned FDOPA scan time. If the patient is 
diabetic and taking oral medications or long acting insulin, we will ask him/her not to 
make any changes. If they are taking short acting insulin before meals, we will ask them 
not to take their dose until after the scan. We will make an effort to schedule them for an 
early scan to avoid long fasting. The maximum number of hours fasting will be seven and 
a half hours (including scanning time of 90 minutes). If we suspect the patient to be 
hypoglycemic at any point, we will check blood sugar level by finger stick. 
Upon presentation to the PET department at the NIH Clinical Center, subjects will 
receive 200 mg of carbidopa orally (to reduce peripheral metabolism of FDOPA and 
increase tracer availability in the brain) one hour prior to the injection of labeled 18F-
DOPA. 18F-DOPA is metabolized peripherally. Carbidopa inhibits peripheral DOPA 
decarboxylase and increases delivery of 18F-DOPA to the brain, improving image quality 
60. It is widely used for this purpose in conjunction with 18F-DOPA scanning. This dose 
(200 mg) is higher than the clinical dose (12.5-25 mg TID) however there has been no 
reported issues or side effects although it has been used in hundreds of PET studies at and 
outside NIH. The maximum daily dosage for Sinemet (carbidopa/levodopa, 25/100) as 
approved by the Food and Drug Administration (FDA) is eight tablets, which 
corresponds to 200 mg of carbidopa. A recent study has even showed no side effects 
when subjects took the drugs at dosages above the 800 mg threshold 61.


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Scanning procedure: Subjects will be positioned in the scanner and a swimming cap with 
small light reflectors will be put on their head. It is used to monitor the head position and 
movement during the scan; the information is used in the PET image reconstruction 
process to reduce any blurring of the PET images. Prior to the 18F-DOPA administration, 
a transmission scan will be obtained with a rotating Cs-137 source for attenuation 
correction. 
18F-DOPA administration – Approximately 10-12 mCi of 18F-DOPA will be brought by 
shielded carrier to the PET scanner. The radiopharmaceutical will be injected over a 
period of approximately 1-2 minutes using an FDA-approved infusion pump under the 
supervision of an authorized user of radiopharmaceuticals. Subsequently, dynamic PET 
imaging will be obtained in list mode for a total scan duration of 90 min.
After the completion of the scan, subjects will empty their bladder and will be instructed 
to drink plenty of fluids and void at approximately 2-hour intervals thereafter. 
4.5.4.2
11C-DASB PET Procedure
11C-DASB is a Radioactive Research Drug (Regulated under 21 CFR 361). The drug has 
been approved by the Radioactive Drug Research Committee (RDRC) at NIH (Rad 
Authorization No.: 2675). 11C-DASB use at NIH does not require an IND.
Scanning procedure: Subjects will be positioned in the scanner and a swimming cap with 
small light reflectors will be put on their head. It is used to monitor the head position and 
movement during the scan; the information is used in the PET image reconstruction 
process to reduce any blurring of the PET images. Prior to the 11C-DASB administration, 
a transmission scan will be obtained with a rotating Cs-137 source for attenuation 
correction. 
11C-DASB administration: Approximately 20 mCi of 11C-DASB will be brought by 
shielded carrier to the PET scanner. The radiopharmaceutical will be injected over a 
period of approximately 1-2 minutes using an FDA-approved infusion pump under the 
supervision of an authorized user of radiopharmaceuticals. Subsequently, dynamic PET 
imaging will be obtained in list mode for a total scan duration of 90 min. 
After the completion of the scan, subjects will empty their bladder and will be instructed 
to drink plenty of fluids and void at approximately 2-hour intervals thereafter. All 
procedures are solely for research purposes. Radiation will be used for research purposes 
only. There will be no “follow-up visits” done after completion of the PET scan(s). 
4.6
End of participation
Once protocol procedures have been completed, study participants will be considered off 
study, and patients can continue their participation in any other NIH protocols if they 
already are enrolled in those protocols. Subjects will be notified of new abnormal 
laboratory test results. Other laboratory results will be available to them per request, 
including via the patient portal. Because PET scans have low resolution and do not 
provide structural information like MRI, the scans will be reviewed for quality control in 
real time but not for incidental findings. No qualitative description of the findings will be 
provided to the subject.
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the 
following reasons:


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
Significant study intervention non-compliance 

If the participant meets an exclusion criterion (either newly developed or not 
previously recognized) that precludes further study participation

Death

Screen Failure
5
Management of Data and Samples
5.1
Storage
No blood or urine samples will be stored for this study. Test results and data from the 
imaging studies will be stored in the archives of the NIH PET department and will be 
accessible only by the investigator and investigator team using a pre-allocated user name 
and password. The raw data will also be stored in an NIH password protected research 
folder (\\ccruby\GROUPS\HammoudLab) only accessible by the principle investigator’s 
team. Only investigators or their designees will have access to the data. 
5.2
 Data and sample sharing plan
This protocol is not subject to the Genomic Data Sharing (GDS) policy. 
Blood and urine test results and imaging data may also be shared with collaborating 
laboratories at NIH or outside of NIH and/or submitted to NIH-designated repositories 
and databases if consent for sharing was obtained. Repositories receiving data from this 
protocol may be open-access or restricted access. 
Blood and urine test results and imaging data will be stripped of identifiers and may be 
coded (“de-identified”) or unlinked from an identifying code (“anonymized”). When 
coded data is shared, the key to the code will not be provided to collaborators, but will 
remain at NIH. Data and samples may be shared with investigators and institutions with 
an FWA or operating under the Declaration of Helsinki (DoH) and reported at the time of 
continuing review. Sharing with investigators without an FWA or not operating under the 
DoH will be submitted for prospective IRB approval. Submissions to NIH-sponsored or 
supported databases and repositories will be reported at the time of Continuing Review. 
Submission to non-NIH sponsored or supported databases and repositories will be 
submitted for prospective IRB approval.
Required approvals from the collaborating institution will be obtained and data will be 
transferred in accordance with NIH and federal regulations. 
6
Additional Considerations
6.1
Research with investigational drugs or devices
18F-DOPA is a Radioactive Research Drug (regulated under 21 CFR 361). The drug will 
be used under the approved Investigational New Drug (IND) No 35513. The sponsor of 
the IND is the NIH clinical Center and the authorized representative of the sponsor is Dr. 
Peter Herscovitch, PET department.
6.2
Gene therapy
There are no gene therapies used for this protocol. 
7
Risks and Discomforts
7.1
Potential Risks


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Potential risks from this study include those associated with: 1) Neuropsychological 
Testing, 2) MRI scanning 3) placement of venous lines, 4) PET scans, 5) radiation 
exposure from the PET ligands. 
Neuropsychological Testing
Subjects may be uncomfortable talking about how they feel.  Portions of the different tests 
may be somewhat challenging, and answering questions about memory, ability to learn and 
think, and mood may be difficult for some people.  The neuropsychological tests are not 
harmful, but may be frustrating or stressful.  We will only ask that they try their best and 
inform them that no one performs perfectly on these tasks.  If the subject gets tired or 
frustrated during the evaluation, they can ask for a break, they may choose not to answer 
every question, or they may choose to stop the testing all together.
Client Diagnostic Questionnaire
Subject may feel uncomfortable talking about their feelings and remembering past 
experiences that made them feel sad or scared. Subjects can choose to not answer questions 
if they don’t want to answer. Subjects can stop the questionnaire at any time.
MRI Scanning
The MRI images obtained are the same as routinely obtained scans for a variety of clinical 
and research reasons.  MRI uses powerful magnetic fields and electromagnetic radiation 
(radio waves).  Adverse Events associated with MRI are extremely rare, and have generally 
been associated with lapses in process, e.g. inadvertent presence of a metallic object within 
the suite.  Very rarely, accidents related to the RF coils have caused AEs.  The feeling of 
being isolated or confined in the scanner may cause some subjects to request that the 
procedure be stopped, and it may be expected that some subjects in this protocol will also 
be unable or unwilling to cooperate.  We hope to minimize these problems by carefully 
explaining the procedure and maintaining voice contact with the subject at all times.  The 
most likely complication is that a subject will be unable to hold still for the duration of the 
procedure.  This would result in the degradation of the quality of the image obtained, but it 
would not be dangerous to the subject.  All subjects will complete a detailed questionnaire 
for metal screening, which will address possible occupational or accidental exposure to 
metal slivers, shavings, shrapnel, etc.  Those with a history suggestive of such a problem 
will be excluded.  No subjects with surgically implanted metallic objects, which could 
affect the magnets used in the scanner, will be eligible to enter the study.
Once on the table, the patient’s head will be secured with cushions. The table will then be 
slowly moved into the scanner. The subject will be informed that the scan can be stopped at 
any time should he/she be too uncomfortable. There is no evidence that scanning at high 
magnetic field strengths is dangerous, but long-term effects are not known.
Venous catheter insertion: Venous catheter insertion can be associated with pain, 
bruising, infection, or clot formation. Using proper placement techniques will minimize 
these risks. 
PET scanning: There are no known physical hazards to subjects from being inside the 
PET scanner, which detects injected radioactivity within the body. Additionally, the 
scanning procedures are conducted in the presence of trained staff, should subjects 
experience any discomfort and require medical attention. Subjects can communicate with 
the staff while in the scanner and can withdraw from the study at any time, if they wish to 
do so. Occasionally subjects become anxious during the scanning procedure, in which case, 


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they can request the operator to stop the scanning and to be removed from the scanning 
bed.
18F-FDOPA: 18F-DOPA is a radioactive molecule used for dopaminergic imaging. 
After intravenous injection, 18F-DOPA is taken in organs proportionally to the levels of 
DOPA decarboxylase enzyme within those organs. Imaging begins 1 hour after 
administration of DOPA decarboxylase blocker, carbidopa. Carbidopa does not cross 
the BBB and thus only blocks enzyme activity in the periphery. This results in 
increased 18F-DOPA levels in the brain. Imaging begins at the same time as the 
administration of 18F-DOPA intravenously. The principal route of excretion of 18F-
DOPA is through the urinary system. There are no known side effects associated with 
18F-DOPA injection. The dose of 18F-DOPA administered is approximately 10-12 mCi 
per scan (per year). 
11C-DASB: 11C-DASB is a radioactive molecule targeted against SERT, and 
commonly used for serotonergic imaging. After intravenous injection, 11C-DASB is 
taken in organs proportionally to the levels of SERT. Imaging begins at the same time as 
the administration of 11C-DASB intravenously. The principal route of excretion of 11C-
DASB is through the urinary system. There are no known side effects associated with 
11C-DASB injection. The dose of 11C-DASB administered is approximately 20 mCi per 
scan (per year). 
Administration of Carbidopa: There are no reports of adverse events when carbidopa is 
given once at the dose used in this PET scan (200 mg).
Radiation Exposure Risks: PET scans require exposure to radiation. All tests requiring 
subject exposure to ionizing radiation are considered potentially hazardous. A detailed 
breakdown of the radiation exposure risks expected for the subjects enrolled in this protocol 
are included in the NIH 88-23(a) Application for Authorization to Use Radiation in 
Research Involving Human Subjects. The radiation received conforms to the NIH 
Radiation Safety Committee guidelines for subjects participating in research studies, 
defined as a 5 rem effective dose in 12 consecutive months. 
The total radiation exposure from the 18F-DOPA PET scan from this protocol in one year 
is 0.89 rem. The total radiation exposure from the 11C-DASB PET scan from this protocol 
in one year is 0.52 rem. If a subject is eligible and consents to participating in both 18F-
DOPA and 11C-DASB studies, the total radiation exposure from this protocol in one year 
is 1.41 rem. 
To minimize the risks of radiation, the subject’s medical records will be reviewed 
carefully and the subjects will be asked about any recent research radiation exposure 
inside and outside NIH to make sure the total yearly exposure would not exceed 5 rem 
effective dose in 12 consecutive months
8
Subject Safety Monitoring
8.1
Parameters to be monitored
Study personnel, overseen by the PI, will closely monitor participant safety during study 
procedures. If, during the course of interviewing, assessment and imaging procedures, 
study staff identifies a condition that should require immediate clinical intervention, all 
procedures will be immediately stopped and necessary steps will be taken. Parameters to 
be monitored for safety reasons include level of consciousness. Toxicity will be assessed 


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according to the most recent version of the NCI Common Terminology Criteria for 
Adverse Events (CTCAE v5.0).
8.2
Criteria for stopping procedures in an individual
A subject may be removed from study under the following conditions:
•
If a subject satisfies eligibility criteria at screening but in the interval between 
consent and scanning events happen and the eligibility criteria are no more 
met.
•
If the subject is unable to stay still in the PET scanner for the required study 
duration.
8.3
Criteria for individual subject withdrawal 
A subject may ask to be removed from the study at any time. 
A subject may be withdrawn from the study at the discretion of the principal investigator 
(PI).
9
Outcome Measures
9.1
Primary outcome measure

Influx constant (Ki) for 18F-FDOPA PET. 

Binding potential relative to non-displaceable binding (BPND) values 
for 11C-DASB PET.
9.2
Secondary outcome measures

Correlation of 18F-FDOPA with co-morbidities (e.g. Co-infections, 
atherosclerotic cardiovascular disease (ASCVD) risk scores, prior and 
current drug abuse).

Correlation of 11C-DASB with Neuropsychiatric evaluation (e.g. 
depressive and executive function/cognitive scores).

Correlation of 18F-FDOPA and 11C-DASB with HIV infection 
parameters (e.g. time since HIV diagnosis, duration of infection before 
treatment initiation, nadir CD4).
10 Statistical Analysis
10.1 Statistical considerations for the FDOPA study
Sample size for the FDOPA PET: There has been no previous imaging of FDOPA in 
HIV-positive subjects. Based on a paper 62 evaluating subjects with familial parkinsonism 
that were either symptomatic or asymptomatic, in comparison to healthy volunteers and 
subjects with Parkinson’s Disease, Ki mean values and standard deviations were reported 
as shown in Table 1 below:
Table 1 Ki mean values and standard deviations in subjects with familial 
Parkinsonism compared to healthy volunteers
 
 
caudate
putamen
Healthy controls
Avg
0.0113
0.01
 
SD
0.0017
0.0013
PD
Avg
0.0073
0.0039


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We believe the HIV-positive subjects will have similar results as the familial 
asymptomatic PD; while our subjects do not have PD symptoms, they are expected to 
have defective dopaminergic systems based on the FDG-PET findings. Hence we decided 
to use the asymptomatic PD data as reflective of the HIV-positive subject group. Since 
we found the caudate nucleus to be more affected in our subject population than the 
putamen, the means and standard deviations of Ki values in the HC and asymptomatic 
familial group were used to calculate the sample size needed for our study. For the 
second group (HIV-negative subjects), we assumed Ki values to be at a mid-point 
between HC (mean 0.0113, SD 0.0017) and HIV-positive subjects (familial 
asymptomatic mean 0.008833, SD 0.001358), with the mid-point value being 0.0100665 
(pooled SD 0.001539).
Sample size estimates were for a one-way analysis of variance (ANOVA) comparing the 
three groups while considering post-hoc pairwise comparisons, particularly between the 
HIV-positive subjects and the HIV-negative subjects with co-morbidities. Thus, we 
utilized a more cautious approach focused on being able to detect a difference between 
these two subject groups using the Ki estimates described above. Calculations yielded a 
sample size of 23 subjects per group, with alpha=0.05 and 80% power. Considering a 5-
10% drop-out rate resulted in a final sample size of 25 per group. Given the ANOVA 
comparison among three groups, an additional 25 HC would be needed for this study, for 
a total of 75 subjects equally balanced among the three groups. Subgroup analysis by sex, 
age, and ethnicity will be carried out during data analysis.
10.2 Statistical Considerations for the DASB Study
In our previous study we were able to show higher 11C-DASB uptake in depressed 
subjects compared to non-depressed subjects using a sample size of 9 each. From our 
recent animal data, the mean BPND before inoculation was 2.11 (0.51), while the mean 
values at the last time point was 2.69 (0.56). We expect the difference between pre- and 
post- inoculation monkeys (average SD of 0.53, differences in means of 0.56) to be the 
same in the two independent groups (HIV-positive vs HIV-negative, HC). 
Table 2. Numeric Results for Two-Sample T-Test Allowing Unequal Variance
Alternative Hypothesis: H1: δ = μ1 - μ2 ≠ 0
Target 
Power
Actual 
Power
N1
N2
N
μ1
μ2
δ
σ1
σ2
Alpha
0.80
0.81642
15
15
30
2.1
2.7
-0.6
0.5
0.6
0.050
 
SD
0.0028
0.0013
Familial 
asymptomatic
Avg
0.008833
0.0067
 
SD
0.001358
0.000755
Familial symptomatic
Avg
0.0056
0.00414
 
SD
0.001765
0.001324


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0.81
0.81642
15
15
30
2.1
2.7
-0.6
0.5
0.6
0.050
0.82
0.84202
16
16
32
2.1
2.7
-0.6
0.5
0.6
0.050
0.83
0.84202
16
16
32
2.1
2.7
-0.6
0.5
0.6
0.050
0.84
0.84202
16
16
32
2.1
2.7
-0.6
0.5
0.6
0.050
0.85
0.86442
17
17
34
2.1
2.7
-0.6
0.5
0.6
0.050
0.86
0.86442
17
17
34
2.1
2.7
-0.6
0.5
0.6
0.050
0.87
0.88395
18
18
36
2.1
2.7
-0.6
0.5
0.6
0.050
0.88
0.88395
18
18
36
2.1
2.7
-0.6
0.5
0.6
0.050
0.89
0.90091
19
19
38
2.1
2.7
-0.6
0.5
0.6
0.050
0.90
0.90091
19
19
38
2.1
2.7
-0.6
0.5
0.6
0.050
Based on that assumption, 19 subjects are needed per group, at alpha = 0.05 and power at 
90%, with 5% dropout rate resulting in N= 20 per group. 
However, since monkey data might not accurately reflect human data, we are planning on 
reassessing our results after ten people in each group are recruited in order to re-estimate 
the accuracy of presumed variance and if deemed necessary increase the sample size 
accordingly. This would guarantee that the sample size calculation is based on the 
estimate of variance. We will not have an interim analysis. As part of the final data 
analysis, subgroup analysis by sex, age, and ethnicity will be carried out.
The total accrual ceiling for this protocol including 18F-DOPA and 11C-DASB studies is 
155 subjects.
10.2.1 Data analysis:
18F-DOPA: PET scans will be reconstructed in 22 frame protocol (3×20, 2×30, 2×60, 
3×120, 8×300 and 4×600 s) using the ordered-subsets expectation maximum (OSEM) 
algorithm, in a 31× 31-cm field of view and a 256×256 pixel matrix with a pixel size of 
1.2×1.2 mm. PET frames will be corrected for radioactive decay.
The attenuated and decay corrected scan will be registered to the same subject’s 
anatomical magnetic resonance imaging (MRI) scan (obtained under our protocol or 
other NIH approved protocols if applicable). The MRI scans will then get affine 
normalized to a brain MRI template and volumes of interest will be drawn on the 
template. The kinetic rate constant Ki for 18F-DOPA uptake will then be calculated using 
a linear fit based on the Patlak method 63 for the VOIs with a time activity curve in the 
occipital reference region as the input function. Ki values will then be compared across 
subject groups.
11C-DASB: dynamic PET imaging will be obtained in list mode for a total scan duration 
of 90 min. PET scans will be reconstructed in 22 frame protocol (3×20, 2×30, 2×60, 
3×120, 8×300 and 4×600 s) using the OSEM algorithm, in a 31× 31-cm field of view and 
a 256×256 pixel matrix with a pixel size of 1.2×1.2 mm. PET frames will be corrected for 
radioactive decay.
The attenuated and decay corrected scan will be registered to the same subject’s 
anatomical MRI scan (obtained under our protocol or other NIH approved protocols if 
applicable). The MRI scans will then get affine normalized to a brain MRI template 
(MNI) and volumes of interest will be drawn on the template. The binding potential 
values of 11C-DASB in various parts of the brain will then be calculated using 2-


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Protocol Number: 18CC0117
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parameter multilinear reference tissue parametric imaging method (MRTM2) using the 
cerebellum as a reference region. 
10.2.2 Interpretation of 18F-FDOPA and 11C-DASB PET Imaging 
Data analysis and interpretation will be done in a blinded manner. When the data is 
transferred from the PET server to the investigator’s server, one operator (co-
investigator) will make sure the images are de-identified and saved prior to detailed 
analysis. The same operator will eventually re-identify the data once the analysis is 
complete. 
11 Human Subjects Protection
11.1 Subject selection
Subject selection will be equitable among eligible patients. No population will be 
excluded from the study on the basis of race, ethnicity, sex, disability, nationality or 
religion.
11.2 Justification for exclusion of children 
Subjects younger than 18 years of age are excluded because of radiation risks to 
children/young adults and because the developing brain is not within the scope of this 
study.
11.3 Justification for exclusion of subjects over 70 years:
We are excluding subjects over 70 years of age because we want to avoid the potential 
influence of advanced age on the PET scans.
11.4 Justification for exclusion of non-English speakers 
Non-English-speaking participants are not eligible for enrollment in in our protocol 
because many of the neuropsychological subtests that are necessary to our study are only 
validated in English. 
11.5 Justification for inclusion or exclusion of other vulnerable subjects
Exclusion of Pregnant or Lactating Women: 
Women who are pregnant or lactating are not eligible to enter the study. The study 
requires exposure to radiation, which could pose a risk to the fetus. Lactating females are 
excluded due to exposure to the radioactive compound for PET scans, which may be 
excreted in the breast milk and could be potentially harmful to breast-fed infants.
11.6 Justification for Inclusion of Neurocognitively Impaired Subjects 
By definition, subjects with HAND are neurocognitively impaired. Because of the need 
to study this disorder, we must include subjects with neurocognitive impairment into this 
study. However, each such subject must have capacity to provide informed consent to 
participate. If subjects, at any point during the screening and study procedures, become 
decisionally impaired and lose their capacity to provide informed consent, they will be 
excluded.
11.7 Protection of Human subjects/protection of vulnerable subjects (employees)
NIH staff and family members of study team members may be enrolled in this study as 
this population meets the study entry criteria.  Neither participation nor refusal to 


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participate as a subject in the research will have an effect, either beneficial or adverse, on 
the participant’s employment or position at NIH.
Every effort will be made to protect participant information, but such information may be 
available in medical records and may be available to authorized users outside of the study 
team in both an identifiable an unidentifiable manner.
The NIH Information Sheet on NIH Staff Research Participation will be made available.  
Please see section 13.2.1 for consent of NIH Staff. 
12 Anticipated Benefit
There are no anticipated direct benefits to the participants but the measurements 
performed may add information about the subjects’ neurocognitive health status. This 
information may or may not help in the subjects’ medical management. 
This study will likely yield generalized knowledge that can ultimately impact our 
understanding of the human brain function and neurotransmitter involvement in HIV-1 
infection. 
13 Consent Documents and Process
13.1 Designation of those obtaining consent
Study investigators designated as able to obtain consent in study personnel page, will 
obtain informed consent. 
13.2 Consent procedures 
All volunteers will receive a verbal explanation in terms suited to their comprehension of 
the purposes, procedures and potential risks of the study and of their rights as research 
volunteers. Participants will have the opportunity to carefully review the written consent 
form and ask questions regarding this study prior to signing. The investigator obtaining 
consent will document the consent process in the participant’s medical record. A copy of 
the completed signed informed consent form will be provided to the participant.
Loss of consent capacity during participation is unlikely, so a durable power of attorney 
will not be required. If loss of consent capacity occurs during the study, the subject will 
be excluded/taken off study.
In most cases, it is clear whether subjects are competent to make their own decisions, and 
this can be judged by the evaluating physician. Occasionally, it is not so clear. In those 
cases, the subject is considered able to provide informed consent if he/she:
• Understands his or her situation/medical condition.
• Understands the risks associated with the research.
• Communicates a decision based on that understanding.
If after this assessment, there is still doubt about the subject’s competency to provide 
informed consent, we will consult the Clinical Center Capacity Assessment Team 
(ACAT) before enrolling the subject. Individuals who are unable to consent are not 
eligible for initial enrollment. 
The subjects will sign the informed consent document prior to undergoing any research 
procedures. The subjects may withdraw consent at any time throughout the course of the 
study. The rights and welfare of the subjects will be protected by emphasizing to the 


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subjects that the quality of their medical care will not be adversely affected if they 
decline to participate in this study.
Prior to the scheduled PET scans, subjects will undergo a focused short assessment to 
confirm no change in eligibility criteria and to rule out the possibility of pregnancy 
despite a negative pregnancy test.
13.2.1 Considerations for Consent of NIH staff, or family members of study team
Consent for NIH staff will be obtained as detailed above with following additional 
protections:
Consent from staff members will be obtained by an individual independent of the staff 
member’s team whenever possible.  Otherwise, the consent procedure will be 
independently monitored by the CC Department of Bioethics Consultation Service in 
order to minimize the risk of undue pressure on the staff member.
13.3 Consent documents
The attached consent form contains all required consent elements. We are attaching one 
unified consent form for both the DOPA and DASB studies (Unified consent all groups).
14 Data and Safety Monitoring
14.1 Data and safety monitor
This study’s monitoring will be conducted according to the Clinical Center Intramural 
Clinical Monitoring Guidelines. Monitoring will be done by the study team (PI and 
associate investigators) with reviews of study enrollment, data collection status, and 
regulatory obligations annually. 
14.2 Data and safety monitoring plan
Accrual and safety data will be monitored by the PI, who will provide oversight to the 
conduct of this study. The PI will continuously evaluate implementation of the protocol 
for any unusual or unpredicted complications that occur and will review the data for 
accuracy and completeness. The PI, in collaboration with associate investigators and 
clinic OP8 staff will review any cases associated with serious adverse outcomes and 
advise on whether any changes in the research plan are warranted. 
14.3  Criteria for stopping the study or suspending enrollment or procedures
If, in the judgment of the PI and Lead Associate Investigator, a specific study procedure 
is yielding frequent unexpected or adverse outcomes, that procedure will be suspended 
until a review can be undertaken in consultation with the IRB. Depending on that 
consultation, the procedure may be dropped from the protocol via an amendment, or 
specific language may be added to the protocol and consent forms to reflect the changing 
risk level.
15 Quality Assurance (QA)
15.1 Quality assurance monitor
The Principal Investigator will ensure that: 

the protocol is being correctly followed 

changes to the protocol have been approved by the IRB 


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
accurate, complete, and current records are being maintained and are secure 

subject withdrawal or study failure is noted in the records and 

informed consent has been correctly documented
15.2 Quality assurance plan
The NIH Clinical Center’s Quality Assurance Program will conduct study monitoring at 
least annually or more frequently as required for open studies unless studies are 
monitored by an outside organization or sponsor. Monitoring visits will include a review 
of subject consent documents and safety laboratory results and diagnostic test results will 
be monitored for accuracy and correct dating. All regulatory reports, reviews and 
amendments, adverse events and problem reports related to study, along with investigator 
credentials, training records, and the delegation of responsibility log will also be 
reviewed during monitoring visits. Any major findings will be summarized in writing and 
reported to the study PI. Any major findings mentioned in the monitoring report will be 
summarized in writing and reported to the IRB at the time of the continuing review.
16 FDA and NIH Reporting
16.1 Definition of reportable events
Please refer to definitions provided in Policy 801: Reporting Research Events.
16.2 Expedited reporting 
Please refer to the reporting requirements in Policy 801: Reporting Research Events.
16.3 IRB Requirements for PI Reporting at Continuing Review
Please refer to the reporting requirements in Policy 801: Reporting Research Events.
16.4 Clinical Director Reporting
Problems expeditiously reported to the IRB in iRIS will also be reported to the Clinical 
Director. A separate submission is not necessary, as reports in iRIS will be available to 
the Clinical Director.
16.5 For FDA-Regulated Research associated with IND # 35513 (18F-DOPA)
According to the requirements of 21 CFR 312.64(b), the PI will immediately report any 
SAE to the Sponsor whether or not considered drug related, including SAEs listed in the 
protocol or investigator brochure and must include an assessment of whether there is a 
reasonable possibility that the drug caused the event. The PI will record nonserious AEs 
and report them to the Sponsor representative according to the protocol. The sponsor will 
be responsible for reporting to the FDA. The Principal Investigator will also provide the 
Sponsor with a copy of the CC monitoring report for the clinical investigation on an 
annual basis. 
To avoid deviation reports for anticipated missed visits/procedures, anticipated deviations 
in the conduct of the protocol will not be reported to the IRB unless they occur at a rate 
greater than anticipated by the study team. 
17 Alternatives to Participation 
Subjects do not receive any treatment in this study or forego any treatment in order to 
participate in this study. The alternative, therefore, is not to participate.


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18 Privacy
All research activities will be conducted in as private a setting as possible.
19 Confidentiality
19.1 For research data and investigator medical records
All the imaging data and results of the laboratory studies will remain confidential. 
All records will be kept confidential to the extent provided by federal, state and local law. 
The study monitors and other authorized representatives of the Sponsor may inspect all 
documents and records required to be maintained by the Investigator, including but not 
limited to, medical records. Records will be kept locked and all computer entry and 
networking programs will be done with coded numbers only. Clinical information will 
not be released without written permission of the subject, except as necessary for 
monitoring by IRB, the FDA, the NINDS, the OHRP, or the sponsor’s designee.
For NIH employees, the PI will train study staff regarding obtaining and handling 
potentially sensitive and private information about co-workers through staff discussions 
and written branch/section procedures. 
Data from the imaging studies will be stored in the archives of the NIH PET department 
and will be accessible only by the investigator and investigator team using a pre-allocated 
user name and password. Raw and analyzed data will also be stored in a password-
protected computers in a password protected research folder 
(\\ccruby\GROUPS\HammoudLab ). Only investigators or their designees will have 
access to the data.
To further protect the privacy of study participants, a Certificate of Confidentiality has 
been issued by the National Institutes of Health (NIH).  This certificate protects 
identifiable research information from forced disclosure. It allows the investigator and 
others who have access to research records to refuse to disclose identifying information 
on research participation in any civil, criminal, administrative, legislative, or other 
proceeding, whether at the federal, state, or local level. By protecting researchers and 
institutions from being compelled to disclose information that would identify research 
participants, Certificates of Confidentiality help achieve the research objectives and 
promote participation in studies by helping assure confidentiality and privacy to 
participants.
20 Conflict of Interest
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons 
who have a role in the design, conduct, analysis, publication, or any aspect of this trial 
will be disclosed and managed. Furthermore, persons who have a perceived conflict of 
interest will be required to have such conflicts managed in a way that is appropriate to 
their participation in the design and conduct of this trial.  The study leadership in 
conjunction with the Clinical Center has established policies and procedures for all study 
group members to disclose all conflicts of interest and will establish a mechanism for the 
management of all reported dualities of interest.


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21 Technology Transfer
There are no technology transfer agreements for this protocol.
22 Research and Travel Compensation 
All participants will be compensated for research-related discomfort and inconveniences 
in accord with NIH guidelines (Table 3). 
Payment will be sent after each visit. Travel will not be provided or compensated for. 
No escort fee will be provided. Compensation will be prorated for parts completed if 
subjects do not complete the study. NIH employees or staff who participate during work 
hours must have permission from their supervisor. NIH employees or staff must either 
participate outside of work hours or take leave in order to receive compensation.
Table 3.
SUBJECT REIMBURSEMENT SCHEDULE: 
Inconvenience 
units
Pay for 
inconvenience 
Time 
(h)
Pay for 
time 
Total pay
MRI with movement 
restriction
11
110.00
2
30.00
140.00
Neurocognitive testing
10
100.00
4
50.00
150.00
Mental Health 
Questionnaire (CDQ)
1
10.00
1
20.00
30.00
PET 18F DOPA
15
150.00
3
40.00
190.00
PET 11C DASB
15
150.00
3
40.00
190.00
Antecubital venous 
catheter 18F DOPA
3
30.00
30.00
Antecubital venous 
catheter 11C DASB
3
30.00
30.00
Blood tests first visit
3
30.00
30.00
Blood tests second visit 
(if needed)
3
30.00
30.00
TOTAL:
Variable depending on optional procedures elected. Max 
compensation is $820


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23 References
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Gama, L. et al. Reactivation of simian immunodeficiency virus reservoirs in the 
brain of virally suppressed macaques. AIDS 31, 5-14, 
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2
Lamers, S. L. et al. HIV DNA Is Frequently Present within Pathologic Tissues 
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Nath, A. Eradication of human immunodeficiency virus from brain reservoirs. 
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Hersh, B. P., Rajendran, P. R. & Battinelli, D. Parkinsonism as the presenting 
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Mirsattari, S. M., Power, C. & Nath, A. Parkinsonism with HIV infection. 
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Nath, A. et al. Neurotoxicity and dysfunction of dopaminergic systems associated 
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Hu, S., Sheng, W. S., Lokensgard, J. R., Peterson, P. K. & Rock, R. B. 
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ICF_001.pdf: 
Protocol Title: PET Imaging of the Dopaminergic and Serotonergic Systems in Treated 
HIV Positive Subjects 
 
Protocol Number: 18CC0117 
 
ClinicalTrials.gov Identifier: NCT03581305 
 
Informed consent form: Version Date: 10/18/2021 
 


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 09/30/2021
Protocol Number: 18CC0117
Page 1 of 11
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR:  Dima Hammoud, M.D.
STUDY TITLE: PET Imaging of the Dopaminergic and Serotonergic Systems in Treated HIV    
Positive Subjects
STUDY SITE: Clinical Center
Cohort: Standard
Consent Version:  09/30/2021
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Principal Investigator: Dima Hammoud, MD, 301-402-3041, hammoudd@cc.nih.gov
Study Coordinator: Amanda Wiebold, RN, 301-594-5194, amanda.weibold@nih.gov
Study Coordinator: Tracy Cropper, RN, BSN, 301-402-6132, tcropper@nih.gov 
This consent form describes a research study and is designed to help you decide if you would like 
to be a part of the research study.  
You are being asked to take part in a research study at the National Institutes of Health (NIH). 
Members of the study team will talk with you about the information described in this document. 
Some people have personal, religious, or ethical beliefs that may limit the kinds of medical or 
research treatments they would want to receive (such as blood transfusions). Take the time needed 
to ask any questions and discuss this study with NIH staff, and with your family, friends, and 
personal health care providers. Taking part in research at the NIH is your choice.
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may change 
your mind and stop participating in the study at any time and for any reason. In either case, you 
will not lose any benefits to which you are otherwise entitled. However, to be seen at the NIH, you 
must be taking part in a study or are being considered for a study. If you do choose to leave the 
study, please inform your study team to ensure a safe withdrawal from the research.  
WHY IS THIS STUDY BEING DONE?
The purpose of this research is to learn how human immunodeficiency virus (HIV) affects two 
chemicals in the brain, serotonin and dopamine.
BACKGROUND
Serotonin is a brain chemical that is important in mood changes, mainly depression. We do not 
understand yet why some people with HIV have high levels of depression and other mood 
problems. The serotonin system in the brain may have a connection to those problems. Previous 
imaging research has shown the serotonin system to be different in HIV compared to healthy 
uninfected subjects, especially in HIV patients who are depressed. 
Dopamine is another brain chemical that is involved in movement, memory and thinking. We also 
do not understand yet why some people with HIV have some memory and thinking problems. The 
IRB NUMBER: 18CC0117
IRB APPROVAL DATE: 10/18/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 09/30/2021
Protocol Number: 18CC0117
Page 2 of 11
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
dopamine system in the brain may have a connection to those problems. Previous imaging research 
has shown the dopamine system to be especially sensitive to the effects of HIV in the brain.
In this study, we will look at serotonin and dopamine in the brain of people with HIV and compare 
the findings to those in people without HIV.  We will look at the serotonin system by positron 
emission tomography (PET) scan using a radioactive drug called 11C-DASB. We will look at the 
dopamine system by doing a PET scan using another radioactive drug called 18F-FDOPA. You 
may do one of those PET scans or both in this study.
STUDY POPULATION
As many as forty five people with HIV, and seventy people without HIV, will take part in this 
study.
PROCEDURES
Screening 
If we think you can be included in this study and you are willing and able to take part, you will be 
asked to come to the NIH for the screening.
1. Physical Exam, if needed
2. Blood testing, if needed.
3. MRI scan, if needed
4. Client Diagnostic Questionnaire, if needed
If you had a physical exam under protocol another NIH protocol less than three months before the 
day of the PET scan, you will not have a repeat the exam.
If you had blood tests under another NIH protocol less than three months before the day of the 
PET scan, you may or may not need to repeat those tests. Blood will be drawn through a needle in 
your arm. We will draw no more than two teaspoons of blood during the entire study.
Client Diagnostic Questionnaire
If needed, we will ask you about your current mental health and your mental health history. We 
will ask you about your mood. We will ask you if you have had scary past experiences and how 
they have affected you. We will ask you about your history of taking drugs for fun and how much 
alcohol you drink. These answers will be kept strictly confidential. (No need to be repeated if 
performed at NIH within 3 months of planned PET scan)
Neuroimaging with Brain MRI
If needed, we will obtain a Magnetic resonance imaging (MRI) scan on your brain. MRI uses a 
very strong magnet and radio waves to take pictures of your brain. The MR scanner is a large long 
metal tube. You will lie still on a table that slides into the MR tube. You will be in the MRI scanner 
for about 45 minutes. While in the scanner you will hear loud knocking noises, and you will be 
fitted with earplugs or earmuffs to muffle the sound. You will be able to communicate with the 
MR staff at all times during your scan, and you may ask to be moved out of the machine at anytime. 
An MRI from another NIH study might be acceptable as per the investigators’ discretion.  You 
may not need to repeat it for this study. 
IRB NUMBER: 18CC0117
IRB APPROVAL DATE: 10/18/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 09/30/2021
Protocol Number: 18CC0117
Page 3 of 11
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PET scan (either 18F-FDOPA or 11C-DASB)
After we complete screening procedures and you are found to be eligible for this study we will do 
PET scan (either 18F-FDOPA or 11C-DASB) for one visit. If you are eligible and decide to 
participate in both parts of this study (18F-FDOPA and 11C-DASB), you might have both scans 
on the same day or you might be asked to come for an additional visit.  The scanning will be done 
in the PET department at the Clinical Center.  Each visit will include:
1. Urine testing.
2. Blood testing, if needed.
3. Updated history and physical exam, if needed.
4. PET scan.
5. Neuropsychological testing, if needed 
Urine Testing:
To determine if you are eligible for this study, we will test your urine for illegal drugs (urine 
toxicology).  If your drug test is positive, you will be told and you might not be included in the 
study. The results of the drug testing will be in your NIH medical record. If you do not want this 
information in your medical record, you should not participate in this study.  Your medical record 
can only be released with your written agreement. However, insurance companies may require you 
to release these records and may not give you insurance if you refuse.
Pregnancy Testing:
The radioactive drug used in this study can harm a developing fetus. Participants who are 
physically able to become pregnant will have a pregnancy test before the PET scan. You will not 
be able to participate if the pregnancy test is positive.
The urine pregnancy and toxicology screening results are required prior to proceeding to the PET 
scan. Other test results are not required before initiating scan.
Blood Testing
If you had blood tests under another NIH protocol or this protocol less than three months before 
the day of the PET scan, you may or may not need to repeat those tests.
PET Scan: 
The PET scan gives information on brain chemistry and function. For the 18F-FDOPA PET scan, 
you will be asked to fast for 4-6 hours prior to the scan. If you are diabetic and taking oral 
medications or long acting insulin, we will ask you to take your medications as usual. If you take 
short acting insulin before meals, we will ask you to not take the insulin until your meal after the 
scan. If you feel your sugar is low at any point during the fasting period, we will check your blood 
sugar levels. The maximum fasting time will be seven and a half hours, which includes the time in 
the scanner. One hour before the scan begins you will receive one pill (carbidopa) which helps 
direct the 18F-FDOPA tracer to your brain. You can eat normally after the end of the scan.
For the 11C-DASB scan you will not be asked to fast. 
IRB NUMBER: 18CC0117
IRB APPROVAL DATE: 10/18/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 09/30/2021
Protocol Number: 18CC0117
Page 4 of 11
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
The PET scanner is shaped like a doughnut. You will lie on a bed that slides in and out of the 
scanner.  
You will have an intravenous (IV) catheter placed for either PET scan.A needle will be used to 
guide a thin plastic tube (catheter) into one of your arm veins. The needle will be removed, leaving 
only the catheter in the vein. The catheter will be taped to the skin to hold it in place.  The IV will 
be used to inject the 11C-DASB or 18F-DOPA tracers. The scan duration after either injection will 
be an hour and a half. 
Once the scan is over, we will ask you to empty your bladder and drink a lot of fluids. We will 
also ask you to empty your bladder every two hours thereafter for the rest of the day.
If you are eligible and you agree to participate in both studies, both scans might be done on the 
same day or on separate days:

If the scans are scheduled on the same day, we will ask you to fast for 4-6 hours before the 
second scan (18F-FDOPA). Your blood tests (if needed) and urine tests will be performed only 
once. You will have the first scan early in the day (11C-DASB). At the end of the first scan, 
we will ask you to empty your bladder. You can then take a break until one hour before the 
second scan. At that time, you will receive one pill (carbidopa) which helps direct the 18F-
FDOPA tracer to your brain. One hour later you will have the second scan (18F-FDOPA). At 
the end of the second scan, we will also ask you to empty your bladder again and every two 
hours thereafter for the rest of the day. You can eat normally after the end of the second scan.

If the scans are scheduled on separate days, you will then follow the instructions for each scan 
separately. You will only have to fast for the 18F-FDOPA scan. We may not repeat your blood 
studies if you had the required blood studies done as part of this protocol (18-CC-0117) or as 
part of 13-N-0149 (ALL HANDS protocol) within three months from the date of the second 
scan.
Neuropsychological Testing:
If needed, we will test your memory, attention, concentration, and thinking. We may ask you about 
how you feel. You will be interviewed, complete questionnaires, take pen and paper or 
computerized tests, and perform simple actions. The testing can take up to 4 hours.  If you have 
had these tests within one year, we might be able to use those results instead of repeating the tests. 
However, we may need to repeat some or all of the tests if the outside tests are different from ours 
or if your thinking has changed since the testing was done.
Your neuropsychological testing data will be entered into a research database. If other NIH 
investigators want to study your neuropsychological testing data, the NIH study team may send 
your results to them. The study team may share information such as your gender, age, health 
history, or ethnicity when necessary.
STORAGE AND SHARING OF SAMPLES AND DATA
A.
Your blood and urine test results, your imaging data and your neuropsychiatric data will 
be stored securely on the NIH campus. Your name and identifying information will not be on the 
test results and data.  The test results and data will either have a code that links to your identifying 
IRB NUMBER: 18CC0117
IRB APPROVAL DATE: 10/18/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 09/30/2021
Protocol Number: 18CC0117
Page 5 of 11
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
information or will be stored without a code linking them to you.  If they are coded, the key to the 
code will be kept at NIH in a separate, secure area and will not be shared.  
B.
Your blood and urine tests results, your imaging data and your neuropsychiatric data may 
be shared with others, including those not at NIH. Your data may be sent to a repository for storage 
and may be released for research purposes.  Some repositories restrict access to the samples and 
data they contain to researchers and projects they approve. Some repositories permit unrestricted 
access. The samples and data may be used for other research projects, including those not related 
to HIV.  If you do not want your samples and data used for other projects, you should not 
participate in this study. Research using data from this study may lead to new tests, drugs, or 
devices with commercial value. You will not receive any payment for any product developed from 
research using your data.
C.
If you withdraw from this research study before it is done, we will keep and continue to 
use samples and data that have already been collected. Your privacy will be protected as much as 
possible.
Banking and Sharing of Identified Samples or Data:
If you are enrolled in other studies, your imaging data and results from your blood, urine and 
neuropsychiatric tests may be shared with investigators of those studies.  The test results and 
imaging data may be shared with your name and identifying information.  Sharing these data and 
samples will help minimize your need to repeat procedures if data or samples are already collected.
RISKS, INCONVENIENCE AND DISCOMFORTS
History and Physical Examination:
There is minimal medical risk or discomfort from the physical exam.
Urine Sample:
There is minimal medical risk or discomfort from giving a urine sample
Intravenous Line:
You may have some discomfort and bruising from the needle insertion. Some people feel light-
headed or faint.  The risks of an intravenous catheter also include bleeding, infection, or 
inflammation of the skin and vein with pain and swelling. These will be treated if they occur.
Carbidopa administration prior to 18F-FDOPA scan:
There are no reports of adverse events when carbidopa is given once at the dose used in this PET 
scan (18F-FDOPA).
Radiation Safety:
This research study involves exposure to radiation from one PET scan with up to 20 millicuries of 
radioactive 11C-DASB. This radiation exposure is not required for your medical care and is for 
research purposes only. The amount of radiation you will receive in this study is 0.52 rem which 
is below the guideline of 5 rem per year allowed for research subjects by the NIH Radiation Safety 
Committee.  If you complete all the studies that require radiation in the referring protocol and 
participate in the other PET study in this protocol (18F-FDOPA), your maximum total radiation 
IRB NUMBER: 18CC0117
IRB APPROVAL DATE: 10/18/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 09/30/2021
Protocol Number: 18CC0117
Page 6 of 11
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
exposure will be 1.4 rem, which is also below the guideline of 5 rem per year allowed for research 
subjects by the NIH Radiation Safety Committee. The average person in the United States receives 
a radiation exposure of 0.3 rem per year from natural sources, such as the sun, outer space, and the 
earth's air and soil.  If you would like more information about radiation, please ask the investigator 
for a copy of the pamphlet, An Introduction to Radiation for NIH Research Subjects.
While there is no direct evidence that the amount of exposure received from participating in this 
study is harmful, there is indirect evidence it may not be completely safe.  There may be a very 
slight increase in the risk of cancer. 
Please tell your doctor if you have had any radiation exposure in the past year, either from other 
research studies or from medical tests or care, so we can make sure that you will not receive too 
much radiation. Radiation exposure includes x-rays taken in radiology departments, cardiac 
catheterization, and fluoroscopy as well as nuclear medicine scans in which radioactive materials 
were injected into your body. 
If you are pregnant or breast feeding, you may not participate in this research study.  It is best to 
avoid radiation exposure to unborn or nursing infants since they are more sensitive to radiation 
than adults.
Neuropsychiatric Testing
You may be uncomfortable talking about how you feel. Portions of the different tests may be 
somewhat challenging, and answering questions about memory, ability to learn and think, and
mood may be difficult for you. The neuropsychological tests are not harmful but may be frustrating 
or stressful. No one performs perfectly on these tasks we only ask that you try your best. If you 
get tired or frustrated during the evaluation, you can ask for a break, you may choose not to answer 
every question, or you may choose to stop the testing all together. 
Client Diagnostic Questionnaire
You may feel uncomfortable talking about your feelings and remembering past experiences that 
make you feel sad or scared. You can choose not to answer questions if you do not want to answer. 
You can stop the questionnaire at any time.
MRI scan
People are at risk for serious injury from the MR magnet if there is metal present. For this reason, 
all magnetic objects (for example, watches, coins, jewelry, and credit cards) must be removed 
before entering the MR scan room. You will not be able to have an MRI if you have a pacemaker 
or other implanted electrical device. This includes brain stimulators, some types of dental implants, 
aneurysm clips (metal clips on the wall of a large artery), metallic prostheses (including metal pins 
and rods, heart valves, and cochlear implants), implanted delivery pump, or shrapnel/metal 
fragments. You will be screened for these conditions before having any scan. If you are not sure if 
there is metal present in your body, discuss this with the research team. Those with back problems 
may have back pain or discomfort from lying in the scanner. The noise from the scanner can be 
loud enough to damage hearing, especially in people who already have hearing loss. Please discuss 
any hearing problems with the research team before the MRI. You will be fitted with hearing 
IRB NUMBER: 18CC0117
IRB APPROVAL DATE: 10/18/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 09/30/2021
Protocol Number: 18CC0117
Page 7 of 11
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
protection and if the hearing protection becomes loose during the scan, the radiology staff can help 
you. There are no known long-term risks of MR scans.
Once you are on the table, we will secure your head with cushions to prevent your head from 
moving. You can ask us to stop the scan at any time if you feel too uncomfortable. There is no 
evidence that scanning at high magnetic field strengths is dangerous, but we do not know if there 
are any long-term effects. Some people become anxious during an MR scan because of being in a 
small space. If you feel anxious, you can receive lorazepam or a similar medication and you will 
be monitored in the outpatient clinic until it has worn off and it is safe for you the leave. 
You will need to arrange for someone to drive you home or we will provide a taxi for you. Side 
effects of lorazepam include sleepiness, dizziness, weakness, unsteadiness, hallucinations, 
confusion, and rarely an allergic reaction causing rash, hives, or swelling.
It is not known if MR is completely safe for the developing fetus. Therefore, all women of 
childbearing potential will have a pregnancy test performed no more than 1 week before the MRI 
scan. The scan will not be done if the pregnancy test is positive.
Investigational use of MRI (machine, sequences and/or coils): We will be using the MRI for 
investigational research. This means that the way the MRI is generating the images may be 
different from what is normally done in a routine clinical scan. However, all studies done under 
this protocol will be performed within FDA safety guidelines. We also plan to use research coils 
(antennae). These are parts of the machine that help generate the image. This use of research tools 
in the MRI has not been approved by the FDA and is considered investigational. Additionally, 
some of the MR machines that we use are considered investigational (not yet approved by the FDA 
for this use) but are used within the FDA safety guidelines
Risks of Storage and Sharing of Samples and Data:
Even though we will remove information that could identify you from Blood and urine tests results 
and your imaging that are sent to repositories or shared, there is a very small chance that the blood 
and urine tests results and imaging data could be identified as yours.
ANTICIPATED BENEFITS
There is no direct benefit to you from participating in this research study. However, we hope to 
learn more about HIV.
RIGHT OF WITHDRAWAL AND CONDITIONS FOR EARLY WITHDRAWAL  
You may withdraw from the study at any time and for any reason without loss of benefits or 
privileges to which you are otherwise entitled. We can remove you from the study at any time if 
we believe that continuation is not in your best medical interest or if you are unable to comply 
with the requirements of the study.
RESULTS FROM THIS STUDY
The PET imaging information we obtain from this study will not provide information on your 
health. You will not receive any individual results from those scans. However, we will inform you 
of any abnormal test results we get from your blood and urine testing.
IRB NUMBER: 18CC0117
IRB APPROVAL DATE: 10/18/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 09/30/2021
Protocol Number: 18CC0117
Page 8 of 11
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
ALTERNATIVES TO PARTICIPATION OR TREATMENT
This study does not provide treatment and does not replace any therapy that your own doctor is 
giving you or your child. You may choose not to participate.
COMPENSATION, REIMBURSEMENT, AND PAYMENT
Will you receive compensation for participation in the study?
Some NIH Clinical Center studies offer compensation for participation in research. The amount 
of compensation, if any, is guided by NIH policies and guidelines.
You will receive compensation according to the table below for a maximum of $820.
Compensation will be prorated for parts completed if you do not complete the study.
Employees and staff who participate during work hours must have permission from their 
supervisor. NIH employees must either participate outside of work hours or take leave in order to 
receive compensation.
With few exceptions, study compensation is considered taxable income that is reportable to the 
Internal Review Service (IRS). A “Form 1099-Other Income” will be sent to you if your total 
payments for research participation are $600 or more in a calendar year. If you have unpaid debt 
to the federal government, please be aware that some or all of your compensation may be 
automatically reduced to repay that debt on your behalf.
This study does not offer reimbursement for, or payment of, travel, lodging or meals. 
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center. 
CONFLICT OF INTEREST (COI)
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a COI Guide.  You may ask your research team for a copy 
of the COI Guide or for more information.  Members of the research team who do not work for 
Pay for 
inconvenience 
Time 
(h)
Pay for time Total pay
PET scan (2 possible)
150.00
3
40.00
190.00
Antecubital venous 
catheter (with each scan)
30.00
30.00
Blood tests (2 possible)
30.00
30.00
MRI
110.00
2
30.00
140.00
Neurocognitive Testing
100.00
4
50.00
150.00
Mental Health 
Questionnaire
10.00
1
20.00
30.00
Total 
Variable depending on procedures performed. Max 
compensation is $820
IRB NUMBER: 18CC0117
IRB APPROVAL DATE: 10/18/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 09/30/2021
Protocol Number: 18CC0117
Page 9 of 11
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
NIH are expected to follow these guidelines or the guidelines of their home institution, but they 
do not need to report their personal finances to the NIH.
No NIH investigator involved in this study receives payments or other benefits from any company 
whose drug, product or device is being tested.
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY  
Will your medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be kept 
private.  However, we cannot guarantee total privacy.  Organizations that may look at and/or copy 
your medical records for research, quality assurance, and data analysis include:

The NIH and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people.

National Institutes of Health Intramural Institutional Review Board
When results of an NIH research study are reported in medical journals or at scientific meetings, 
the people who take part are not named and identified.  In most cases, the NIH will not release any 
information about your research involvement without your written permission.  However, if you 
sign a release of information form, for example, for an insurance company, the NIH will give the 
insurance company information from your medical record.  This information might affect (either 
favorably or unfavorably) the willingness of the insurance company to sell you insurance.
If we share your specimens or data with other researchers, in most circumstances we will remove 
your identifiers before sharing your specimens or data. You should be aware that there is a slight 
possibility that someone could figure out the information is about you. 
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act. 
Certificate of Confidentiality
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances.  
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.  
The Certificate does not protect your information when it:  
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
IRB NUMBER: 18CC0117
IRB APPROVAL DATE: 10/18/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 09/30/2021
Protocol Number: 18CC0117
Page 10 of 11
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA); 
3. is for other research;
4. is disclosed with your consent. 
The Certificate does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research. 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or 
others including, for example, child abuse and neglect, and by signing below you consent to those 
disclosures. Other permissions for release may be made by signing NIH forms, such as the Notice 
and Acknowledgement of Information Practices consent.
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical records we 
collect under the authority of the Public Health Service Act.  In some cases, the Privacy Act 
protections differ from the Certificate of Confidentiality.  For example, sometimes the Privacy Act 
allows release of information from your medical record without your permission, for example, if 
it is requested by Congress. Information may also be released for certain research purposes with 
due consideration and protection, to those engaged by the agency for research purposes, to certain 
federal and state agencies, for HIV partner notification, for infectious disease or abuse or neglect 
reporting, to tumor registries, for quality assessment and medical audits, or when the NIH is 
involved in a lawsuit.  However, NIH will only release information from your medical record if it 
is permitted by both the Certificate of Confidentiality and the Privacy Act.
POLICY REGARDING RESEARCH-RELATED INJURIES  
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation for 
research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.
PROBLEMS OR QUESTIONS
If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Dima 
Hammoud, MD, 301-402-3041. Other researchers you may call are: Bryan Smith, MD, 301-451-
4585 and Tracy Cropper, RN, BSN, 301-402-6132. You may also call the NIH Clinical Center 
Patient Representative at 301-496-2626, or the NIH Office of IRB Operations at 301-402-3713, if 
you have a research-related complaint or concern.
CONSENT DOCUMENT 
Please keep a copy of this document in case you want to read it again.
IRB NUMBER: 18CC0117
IRB APPROVAL DATE: 10/18/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 09/30/2021
Protocol Number: 18CC0117
Page 11 of 11
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Witness to the oral short-form consent process only: This section is only required if you are doing the oral 
short-consent process and this English consent form has been approved by the IRB for use as the basis of 
translation.
Witness:
Signature of Witness*
Print Name of Witness
Date
*NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER:
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.
IRB NUMBER: 18CC0117
IRB APPROVAL DATE: 10/18/2021