HIV Associated Neurocognitive DisorderPhase 1/2ARTNCT05586581
SV2A & TSPO PET Imaging Measures to Reveal Mechanisms of HIV Neuropathogenesis During Antiretroviral Therapy
A Phase 1/2 study testing SV2A PET and TSPO PET in people with HIV Associated Neurocognitive Disorder and HIV Dementia, run by Yale University at 1 site in United States.
Trial summary
The purpose of this study is to longitudinally characterize and evaluate changes in synaptic density in the brain using novel positron-emission tomography (PET) scans; magnetic resonance imaging (MRI), and clinical laboratory markers associated with HIV-related injury in the central nervous system. Read more about this study
- Who is it for?
- Ages 18 to 80 yearsHealthy volunteers can take part
- Conditions the study is for
- HIV Associated Neurocognitive Disorder, HIV Dementia, HIV Encephalitis
- What is being tested?
- SV2A PET and TSPO PET
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 70 participants
- Where
- 1 siteUnited States
- Study dates
- 17 May 2023to Dec 2030
- Phase
- Phase 1/2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
PLWH Inclusion Criteria:
- Voluntary, written, informed consent (signed and dated)
- For females, a negative urine or serum pregnancy (HCG) test at screening and on each scan day before initiation of any scan procedures.
- HIV infection on cART with documented viral suppression for at least one year. Plasma viral suppression will be defined as no more than one viral load
- Test above 20 HIV RNA cps/mL in the year prior to screening and no HIV RNA tests above 200 cps/mL in the same span.
- Willingness to participate in MRI, PET, phlebotomy, and Neuropsychological Testing (NPT) Assessments \& Surveys.
PLWH Exclusion Criteria:
- Active substance dependence (e.g., heroin, alcohol, cocaine, sedative hypnotics, methamphetamine) as determined by the standardized Behavioral Assessments.
- A history of significant non-HIV related neurological illness (e.g., cerebrovascular, seizures, traumatic brain injury).
- Medical contraindications to the administration of radioactivity (e.g., prior radiation exposure within the past year from research, or from workplace exposure, that in combination with the planned scans would exceed the FDA limit for annual radiation exposure).
- Medical contraindications to participation in a magnetic resonance imaging procedure (e.g., ferromagnetic implants/foreign bodies, claustrophobia, cardiac pacemaker, prosthetic valve, otologic implant, etc.).
- History of a bleeding disorder, low platelet count, or are currently taking anticoagulants (such as Coumadin, Heparin, Pradaxa, Xarelto).
HIV - Inclusion Criteria:
- Voluntary, written, informed consent (signed and dated)
- For females, a negative urine or serum pregnancy (HCG) test at screening and on each scan day before initiation of any scan procedures.
- Willingness to participate in phlebotomy, NPT Assessments \& Surveys, MRI, and PET.
- Physically healthy by medical history, physical, neurological, and laboratory examinations, as judged by the principal investigator.
- Have a negative test for HIV on file within the last three months or willing to have an HIV test in the current study.
HIV- Exclusion Criteria:
- Active substance dependence (e.g., heroin, alcohol, cocaine, sedative hypnotics, methamphetamine) as determined by the standardized Behavioral Assessments.
- A history of significant neurological illness (e.g., cerebrovascular, seizures, traumatic brain injury).
- Medical contraindications to the administration of radioactivity (e.g., prior radiation exposure within the past year, from research, or from workplace exposure, that in combination with the planned scans would exceed the FDA limit for annual radiation exposure)
- Medical contraindications to participation in a magnetic resonance imaging procedure (e.g., ferromagnetic implants/foreign bodies, claustrophobia, cardiac pacemaker, prosthetic valve, otologic implant, etc.
- History of a bleeding disorder or are currently taking anticoagulants (such as Coumadin, Heparin, Pradaxa, Xarelto
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
Yale School of Medicne, Neuro ID Research Program
New Haven, Connecticut, 06510
Allison Nelson, RN, (475) 434-4324, allison.nelson@yale.edu
NeuroID@yale.edu
About this study
Official title: PET Imaging of Synaptic Density Combined With Neuroimmunologic Measures to Reveal Mechanisms of HIV Neuropathogenesis During ART
The purpose of this study is to longitudinally characterize and evaluate changes in synaptic density in the brain using novel positron-emission tomography (PET) scans; magnetic resonance imaging (MRI), and clinical laboratory markers associated with HIV-related injury in the central nervous system. This study will test hypotheses relating to the presence and mechanisms of aberrant brain structure at the synaptic level in living humans with virologically controlled HIV on antiretroviral therapy. To evaluate associations between PET imaging radiotracers [11C]UCB-J, a ligand for presynaptic vesicle protein 2A (SV2A), a vesicle membrane protein expressed in synapses, and PET [11C]PBR28 a measure of microglia function in the brain, the Yale PET center has developed an advanced approach of combining multiple distinct ligands in coordinated same-day PET imaging. Additionally, the study will evaluate the associations of this novel synaptic density marker with well-established clinical measures of neurocognitive performance and laboratory measures of blood and cerebrospinal fluid (CSF).
Read the detailed description
The HIV PET plus study builds upon the compelling preliminary findings of the investigators HIV PET pilot study (Yale Internal Review Board (IRB) #2000024620) that brain SV2A PET successfully identifies regions of reduced synaptic density, including a hippocampal-frontostriatal neural circuit that is relevant to central nervous system (CNS) dysfunction in PLWH on ART
The primary aims of this study are as follows:
Aim 1. To evaluate cross-sectional differences and 24-month longitudinal changes in synaptic density in PLWH on suppressive ART relative to matched HIV-negative (HIV-) controls. Synaptic density will be measured with SV2A PET scans acquired at baseline and two years in 40 PLWH on ART and in 30 HIV-, matched for age, gender, ethnicity, and history of substance use.
Hypotheses: (1a) Synaptic density in a hippocampal-frontostriatal neural circuit will be reduced in PLWH relative to matched HIV-; (1b) Synaptic density in this circuit will decline at a greater rate in PLWH relative to HIV-.
Aim 2. To determine, in PLWH on ART, the extent to which microglia levels impact synaptic density. Microglia levels will be measured with TSPO PET scans concurrently acquired with SV2A PET scans in a subset of 20 PLWH from Aim 1 at baseline, followed by repeat SV2A PET scans at 24 months.
Hypotheses: (2a) Greater microglia levels in a hippocampal-frontostriatal circuit will be associated with decreased synaptic density in this circuit; and (2b) Greater microglial levels at baseline will be a longitudinal predictor of a greater decline in synaptic density in this neural circuit over 24 months.
Aim 3. To determine the role of synaptic density in mediating the relation between microglia level, laboratory biomarkers of inflammation and neuronal injury, and neurocognitive functioning in PLWH. Blood, cerebrospinal fluid, and neurocognitive measures will be acquired in 40 PLWH on ART at baseline and 2 years with SV2A PET. The investigators will use parallel processing statistical approaches to examine multimodal longitudinal associations between baseline microglial activation, and changes in synaptic density, laboratory biomarkers and neurocognitive functioning to understand the molecular neuropathogenesis of CNS impairment in PLWH on ART.
Hypothesis: (3) In PWLH on ART, greater hippocampal-frontostriatal microglial activation at baseline will be associated with greater 24-month reductions in synaptic density, which will in turn be associated with greater reductions in neurocognitive functioning, particularly on measures of learning and memory.
- Being tested
- SV2A PET, TSPO PET
- Keywords
- Human immunodeficiency virus, Positron-Emission Tomography Imaging, Magnetic Resonance Imaging, Cerebrospinal Fluid, SV2A PET, TSPO PET, Neuro-immune dysfunction, Neuro-Inflammation, Biomarkers of inflammation, Neuronal Injury, Neurocognitive functioning, Hippocampus, Microglia, Neuropathogenesis, antiretroviral therapy
- Medical subject headings
- AIDS Dementia Complex, Acquired Immunodeficiency Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
SV2A PETDrug
Also called [11C]UCB-J, [11C]APP311
SV2A PET scan with radiotracer [11C]UCB-J for imaging synaptic density in the brain
TSPO PETDrug
Also called [11C]PBR28
TSPO PET scan with radiotracer [11C]PBR28 for imaging of neuroimmune status
| Study group | Role | What they receive |
|---|---|---|
| People living with treated suppressed HIV infection (PLWH) | Experimental | 40 PLWH participants will be scanned using anatomical magnetic resonance imaging (MRI) and undergo two SV2A (11C-UCB-J) PET scans with arterial sampling and full radio metabolite analysis to obtain measures of synaptic density at baseline and 24 months (2 years). For each SV2A PET, up to 20 millicurie (mCi) of [11C], UCB-J will be administered by an intravenous line (IV) with a scan duration of up to 120 minutes.
A subset of PLWH (n=20) will participate in TSPO (11C-PBR28) PET scans on the same day as the baseline SV2A PET scan. For a TSPO PET, up to 20 mCi of [11C], PBR28 will be administered by an intravenous line (IV) with a scan duration of up to 120 minutes. Receives: Drug: SV2A PET; Drug: TSPO PET |
| HIV-Negative Control (HIV-) | Experimental | 30 HIV-Negative Control (HIV-) participants will be scanned using anatomical magnetic resonance imaging (MRI) and undergo two SV2A (11C-UCB-J) PET scans with arterial sampling and full radio metabolite analysis to obtain measures of synaptic density at baseline and 24 months (2 years). For each SV2A PET, up to 20 mCi of [11C], UCB-J will be administered by an intravenous line (IV) with a scan duration of up to 120 minutes.
A subset of will participate in TSPO (11C-PBR28) PET scans on the same day as the baseline SV2A PET scan. For a TSPO PET, up to 20 mCi of [11C], PBR28 will be administered by an intravenous line (IV) with a scan duration of up to 120 minutes. Receives: Drug: SV2A PET |
What is being measured
The primary outcome is the main question the study is designed to answer.
The primary outcome measure for 11C-UCB-J will be the binding potential of 11C-UCB-J, specifically non-displaceable binding potential (BPND), the ratio of the specifically bound radioligand to that of nondisplaceable radioligand in tissue.
Preliminary data from the investigators' pilot study revealed SV2A PET imaging with radiotracer 11C-UCB-J identified regions of reduced synaptic density in suppressed PLWH compared to matched HIV-negative controls.
PET and MRI imaging data will be processed for quantification of 11C-UCB-J imaging data in a larger group of suppressed PLWH compared to matched HIV-negative controls to test-retest reproducibility of 11C-UCB-J.
Measured: Through study completion date, an average of 5 years.
Change in cross-sectional differences and 24-month longitudinal changes in synaptic density in PLWH on suppressive ART relative to matched HIV-negative controls
Baseline and 24 Month PET and MRI imaging data will be processed for a linear mixed-effects model (LMM) to compare changes in hippocampal-frontostriatal 11C-UCB-J BPND between PLWH and healthy controls.
Measured: Baseline and 24 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Oct 2022
- Study start17 May 2023
- Primary completionDec 2028 (estimated)
- Study completionDec 2030 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for HIV Associated Neurocognitive DisorderStudies of the same condition, open and under way.
- More trials run by Yale UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Basic science
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Model description
- In this study, people living with treated suppressed HIV infection (PLWH) and matched HIV-negative controls will be scanned using anatomical magnetic resonance imaging (MRI) and PET. All participants will receive two SV2A PET scans (baseline and 2 years). A subset of PLWH participants will be asked to complete a TSPO PET scan on the same day as the baseline SV2A PET scan. Participants will undergo phlebotomy and medical/mental health and substance use histories for eligibility, and may also complete an ECG, blood tests, an optional lumbar puncture, neurocognitive testing \& behavioral/mood questionnaires.
- Masking
- None (open label)
- Enrolment
- 70 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Yale University
- Sponsor type
- University, hospital or other
- Collaborators
- National Institutes of Health (NIH), National Institute of Mental Health (NIMH)
- Responsible party
- Principal investigator, Serena Spudich, MD, Yale University
- Investigators
- Serena Spudich, MD, Principal investigator, Yale University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05586581
- Sponsor's protocol ID
- 2000033582
- Other IDs
- 5R01MH125396
- Acronym
- ART
- Status last verified
- Oct 2026
- First submitted
- 16 Oct 2022
- Last updated
- 14 Oct 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 14 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- PET Imaging of Synaptic Density Combined With Neuroimmunologic Measures to Reveal Mechanisms of HIV Neuropathogenesis During ART
- ClinicalTrials.gov ID
- NCT05586581
- Acronym / sponsor ID
- ART / 2000033582
- Keywords
- Human immunodeficiency virus, Positron-Emission Tomography Imaging, Magnetic Resonance Imaging, Cerebrospinal Fluid, SV2A PET, TSPO PET, Neuro-immune dysfunction, Neuro-Inflammation
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 70 participants (estimated)
- Lead sponsor
- Yale UniversityUniversity, hospital or other
- Collaborators
- National Institutes of Health (NIH), National Institute of Mental Health (NIMH)
- Study start
- 17 May 2023 (actual)
- Primary completion
- Dec 2028 (estimated)
- Study completion
- Dec 2030 (estimated)
- First posted
- 19 Oct 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study is to longitudinally characterize and evaluate changes in synaptic density in the brain using novel positron-emission tomography (PET) scans; magnetic resonance imaging (MRI), and clinical laboratory markers associated with HIV-related injury in the central nervous system. This study will test hypotheses relating to the presence and mechanisms of aberrant brain structure at the synaptic level in living humans with virologically controlled HIV on antiretroviral therapy. To evaluate associations between PET imaging radiotracers [11C]UCB-J, a ligand for presynaptic vesicle protein 2A (SV2A), a vesicle membrane protein expressed in synapses, and PET [11C]PBR28 a measure of microglia function in the brain, the Yale PET center has developed an advanced approach of combining multiple distinct ligands in coordinated same-day PET imaging. Additionally, the study will evaluate the associations of this novel synaptic density marker with well-established clinical measures of neurocognitive performance and laboratory measures of blood and cerebrospinal fluid (CSF).
Detailed description
The HIV PET plus study builds upon the compelling preliminary findings of the investigators HIV PET pilot study (Yale Internal Review Board (IRB) #2000024620) that brain SV2A PET successfully identifies regions of reduced synaptic density, including a hippocampal-frontostriatal neural circuit that is relevant to central nervous system (CNS) dysfunction in PLWH on ART
The primary aims of this study are as follows:
Aim 1. To evaluate cross-sectional differences and 24-month longitudinal changes in synaptic density in PLWH on suppressive ART relative to matched HIV-negative (HIV-) controls. Synaptic density will be measured with SV2A PET scans acquired at baseline and two years in 40 PLWH on ART and in 30 HIV-, matched for age, gender, ethnicity, and history of substance use.
Hypotheses: (1a) Synaptic density in a hippocampal-frontostriatal neural circuit will be reduced in PLWH relative to matched HIV-; (1b) Synaptic density in this circuit will decline at a greater rate in PLWH relative to HIV-.
Aim 2. To determine, in PLWH on ART, the extent to which microglia levels impact synaptic density. Microglia levels will be measured with TSPO PET scans concurrently acquired with SV2A PET scans in a subset of 20 PLWH from Aim 1 at baseline, followed by repeat SV2A PET scans at 24 months.
Hypotheses: (2a) Greater microglia levels in a hippocampal-frontostriatal circuit will be associated with decreased synaptic density in this circuit; and (2b) Greater microglial levels at baseline will be a longitudinal predictor of a greater decline in synaptic density in this neural circuit over 24 months.
Aim 3. To determine the role of synaptic density in mediating the relation between microglia level, laboratory biomarkers of inflammation and neuronal injury, and neurocognitive functioning in PLWH. Blood, cerebrospinal fluid, and neurocognitive measures will be acquired in 40 PLWH on ART at baseline and 2 years with SV2A PET. The investigators will use parallel processing statistical approaches to examine multimodal longitudinal associations between baseline microglial activation, and changes in synaptic density, laboratory biomarkers and neurocognitive functioning to understand the molecular neuropathogenesis of CNS impairment in PLWH on ART.
Hypothesis: (3) In PWLH on ART, greater hippocampal-frontostriatal microglial activation at baseline will be associated with greater 24-month reductions in synaptic density, which will in turn be associated with greater reductions in neurocognitive functioning, particularly on measures of learning and memory.
Study design
- Primary purpose
- Basic science
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- In this study, people living with treated suppressed HIV infection (PLWH) and matched HIV-negative controls will be scanned using anatomical magnetic resonance imaging (MRI) and PET. All participants will receive two SV2A PET scans (baseline and 2 years). A subset of PLWH participants will be asked to complete a TSPO PET scan on the same day as the baseline SV2A PET scan. Participants will undergo phlebotomy and medical/mental health and substance use histories for eligibility, and may also complete an ECG, blood tests, an optional lumbar puncture, neurocognitive testing \& behavioral/mood questionnaires.
| Arm | Type | Receives |
|---|---|---|
| People living with treated suppressed HIV infection (PLWH) | Experimental | Drug: SV2A PET, Drug: TSPO PET40 PLWH participants will be scanned using anatomical magnetic resonance imaging (MRI) and undergo two SV2A (11C-UCB-J) PET scans with arterial sampling and full radio metabolite analysis to obtain measures of synaptic density at baseline and 24 months (2 years). For each SV2A PET, up to 20 millicurie (mCi) of [11C], UCB-J will be administered by an intravenous line (IV) with a scan duration of up to 120 minutes. A subset of PLWH (n=20) will participate in TSPO (11C-PBR28) PET scans on the same day as the baseline SV2A PET scan. For a TSPO PET, up to 20 mCi of [11C], PBR28 will be administered by an intravenous line (IV) with a scan duration of up to 120 minutes. |
| HIV-Negative Control (HIV-) | Experimental | Drug: SV2A PET30 HIV-Negative Control (HIV-) participants will be scanned using anatomical magnetic resonance imaging (MRI) and undergo two SV2A (11C-UCB-J) PET scans with arterial sampling and full radio metabolite analysis to obtain measures of synaptic density at baseline and 24 months (2 years). For each SV2A PET, up to 20 mCi of [11C], UCB-J will be administered by an intravenous line (IV) with a scan duration of up to 120 minutes. A subset of will participate in TSPO (11C-PBR28) PET scans on the same day as the baseline SV2A PET scan. For a TSPO PET, up to 20 mCi of [11C], PBR28 will be administered by an intravenous line (IV) with a scan duration of up to 120 minutes. |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| SV2A PETAlso: [11C]UCB-J, [11C]APP311SV2A PET scan with radiotracer [11C]UCB-J for imaging synaptic density in the brain | Drug | HIV-Negative Control (HIV-), People living with treated suppressed HIV infection (PLWH) |
| TSPO PETAlso: [11C]PBR28TSPO PET scan with radiotracer [11C]PBR28 for imaging of neuroimmune status | Drug | People living with treated suppressed HIV infection (PLWH) |
Primary outcome
The primary outcome measure for 11C-UCB-J will be the binding potential of 11C-UCB-J, specifically non-displaceable binding potential (BPND), the ratio of the specifically bound radioligand to that of nondisplaceable radioligand in tissue.
Time frame: Through study completion date, an average of 5 years.
Preliminary data from the investigators' pilot study revealed SV2A PET imaging with radiotracer 11C-UCB-J identified regions of reduced synaptic density in suppressed PLWH compared to matched HIV-negative controls. PET and MRI imaging data will be processed for quantification of 11C-UCB-J imaging data in a larger group of suppressed PLWH compared to matched HIV-negative controls to test-retest reproducibility of 11C-UCB-J.
Change in cross-sectional differences and 24-month longitudinal changes in synaptic density in PLWH on suppressive ART relative to matched HIV-negative controls
Time frame: Baseline and 24 months
Baseline and 24 Month PET and MRI imaging data will be processed for a linear mixed-effects model (LMM) to compare changes in hippocampal-frontostriatal 11C-UCB-J BPND between PLWH and healthy controls.
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Oct 2026.
- Individual participant dataSharing planned: No
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Serena Spudich, MD principal investigator
Yale University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing SV2A PET and TSPO PET in people with HIV Associated Neurocognitive Disorder and HIV Dementia, run by Yale University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 14 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Allison Nelson, RN ((475) 434-4324, allison.nelson@yale.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The primary outcome measure for 11C-UCB-J will be the binding potential of 11C-UCB-J, specifically non-displaceable binding potential (BPND), the ratio of the specifically bound radioligand to that of nondisplaceable radioligand in tissue. (time frame: Through study completion date, an average of 5 years.). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Oct 2026; AzTrials last refreshed its copy on 26 Oct 2026.