SV2A & TSPO PET Imaging for HIV Neurocognitive Disorders

(ART Trial)

Overseen By Paige Ryall

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Yale University

Must be taking: Antiretrovirals

Must not be taking: Anticoagulants

Disqualifiers: Substance dependence, Neurological illness, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 3

70 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to understand how HIV affects the brain using advanced imaging techniques like PET scans and MRIs. It focuses on people living with HIV who have been on antiretroviral therapy and have controlled their viral load. The trial explores brain changes at the synapse level (where nerve cells communicate) and how these relate to brain function. Participants with HIV who have controlled their virus for more than a year and are willing to undergo specific scans and tests, including SV2A PET Imaging and TSPO PET Imaging, might be a good fit for this study. As a Phase 1, Phase 2 trial, this research seeks to understand how the treatment works in people and measure its effectiveness in an initial, smaller group.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are taking anticoagulants like Coumadin, Heparin, Pradaxa, or Xarelto, you may not be eligible to participate.

What prior data suggests that this PET imaging technique is safe for humans?

Research shows that both SV2A and TSPO PET imaging techniques are generally safe for people. Studies have found that SV2A PET imaging, which uses a special tracer called \[11C\]UCB-J, is well-tolerated by participants. This method has measured brain cell connections in people with HIV, and no significant side effects have been reported.

For TSPO PET imaging, research also supports its safety in humans. This technique uses a tracer called \[11C\]PBR28 to detect inflammation in the brain. Studies involving people with HIV have not identified any major safety issues or significant negative effects from this imaging.

Both imaging techniques involve a low dose of radiation, similar to that of a CT scan. So far, participants in various studies have not reported any serious problems related to these PET scans. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about the SV2A and TSPO PET imaging techniques for HIV Neurocognitive Disorders because they offer a new way to understand and measure brain changes in people with HIV. Unlike current treatments that mostly manage symptoms, these PET scans can measure synaptic density and inflammation in the brain, providing insights into the underlying causes of cognitive issues. The SV2A PET scan uses the radioactive tracer [11C] UCB-J to assess synaptic density, while the TSPO PET scan uses [11C] PBR28 to measure inflammation. This dual approach could lead to more targeted therapies in the future by identifying specific brain changes associated with HIV.

What evidence suggests that this trial's imaging techniques could be effective for evaluating HIV neurocognitive disorders?

Research has shown that SV2A PET imaging can effectively measure the number of connections between brain cells. In this trial, participants will undergo SV2A PET imaging to track these changes over time, potentially aiding in the development of future treatments. Studies have found that people with HIV have fewer of these connections, providing insight into how HIV affects the brain. Meanwhile, a subset of participants will also undergo TSPO PET imaging to measure brain inflammation in people with HIV. Research has found that people with HIV have higher levels of TSPO, indicating more brain inflammation. Understanding these changes can help clarify how HIV impacts brain health and thinking abilities. ^{1 2 4 6 7}

Who Is on the Research Team?

Serena Spudich, MD

Principal Investigator

Yale University

Are You a Good Fit for This Trial?

This trial is for adults with well-controlled HIV on antiretroviral therapy (ART) for at least a year, showing minimal viral presence in tests. Participants must consent to the study and women must test negative for pregnancy. It's not suitable for those who can't undergo MRI or PET scans, blood draws, or neuropsychological assessments.

Inclusion Criteria

HIV: For females, a negative urine or serum pregnancy (HCG) test at screening and on each scan day before initiation of any scan procedures

HIV: Willingness to participate in phlebotomy, NPT Assessments & Surveys, MRI, and PET

HIV: Voluntary, written, informed consent (signed and dated)

Exclusion Criteria

I have a history of serious brain or nerve conditions.

PLWH: Medical contraindications to participation in a magnetic resonance imaging procedure (e.g., ferromagnetic implants/foreign bodies, claustrophobia, cardiac pacemaker, prosthetic valve, otologic implant, etc.)

I have a bleeding disorder or am currently on blood thinners.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Assessment

Participants undergo baseline PET and MRI scans to measure synaptic density and microglia levels

1 day

1 visit (in-person)

Longitudinal Monitoring

Participants are monitored for changes in synaptic density and microglia levels over 24 months

24 months

2 visits (in-person) at baseline and 24 months

Follow-up

Participants are monitored for safety and effectiveness after the main study period

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• SV2A PET
• TSPO PET

Trial Overview The study uses advanced PET imaging with [11C]UCB-J and [11C]PBR28 tracers to measure synaptic density and microglia function in the brain of HIV patients on ART. It aims to understand changes in brain structure related to HIV injury by correlating these measures with neurocognitive performance and lab results.

How Is the Trial Designed?

Group I: People living with treated suppressed HIV infection (PLWH) Experimental Treatment 2 Interventions

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.

Group II: HIV-Negative Control (HIV-) Experimental Treatment 1 Intervention

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.

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

National Institute of Mental Health (NIMH)

Collaborator

Trials

3,007

Recruited

2,852,000+

Published Research Related to This Trial

The study introduces a new selective ligand for the translocator protein (TSPO), named BBPA, which could help researchers investigate neuroinflammation in humans and animals.

BBPA is designed to be used with SPECT imaging, providing a potential tool for understanding the interactions between neurons and glial cells in the context of neuroinflammation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[99mTc-BBPA]: A possible SPECT agent to understand the role of 18-kDa translocator protein (PBR/TSPO) during neuro-glial interaction. Kumari, N., Kaul, A., Deepika, ., et al.[2022]

The new TSPO ligand, [18F]BS224, shows high affinity and selectivity for the translocator protein, making it effective for detecting neuroinflammation in various neurodegenerative diseases, regardless of the rs6971 polymorphism that affects other ligands.

In animal models, [18F]BS224 provided clear imaging of inflammatory lesions with a high signal-to-background ratio, indicating its potential as a reliable biomarker for neuroinflammatory conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiosynthesis and characterization of [18F]BS224: a next-generation TSPO PET ligand insensitive to the rs6971 polymorphism. Lee, SH., Denora, N., Laquintana, V., et al.[2022]

The study demonstrated that [(11)C]CB184 is safe for use in humans for PET imaging of the 18-kDa translocator protein (TSPO), with no acute toxicity observed at clinical doses and an acceptable radiation absorbed dose.

[(11)C]CB184 effectively visualizes TSPO distribution in the human brain, showing rapid uptake and clearance, which aligns with known TSPO patterns, indicating its potential for studying neuroinflammation in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical and first-in-man studies of [(11)C]CB184 for imaging the 18-kDa translocator protein by positron emission tomography. Toyohara, J., Sakata, M., Hatano, K., et al.[2017]

In a study involving 24 virologically suppressed individuals living with HIV (PLWH) and 13 HIV-negative controls, TSPO-PET imaging showed no significant differences in neuroinflammation levels between the two groups, suggesting that neuroinflammatory levels in PLWH are comparable to those in HIV-negative individuals.

While neuroinflammation may contribute to cognitive deficits in PLWH, the study found no significant association between TSPO-PET binding and cognitive performance or clinical measures of HIV, indicating that other factors may also play a role in cognitive impairment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of [11C]-PBR28 Binding Between Persons Living With HIV and HIV-Uninfected Individuals. Boerwinkle, AH., Strain, JF., Burdo, T., et al.[2022]

The new 18F-labeled SV2A PET imaging probe, [18F]SynVesT-2, shows promising fast binding kinetics and high specific binding signals in the brains of non-human primates, indicating its potential for effective imaging.

This imaging technique could be valuable for diagnosing and monitoring various neuropsychiatric diseases, such as Alzheimer's and Parkinson's, by targeting the synaptic vesicle glycoprotein 2A (SV2A) which is crucial for neurotransmitter release.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synthesis and Preclinical Evaluation of an 18F-Labeled Synaptic Vesicle Glycoprotein 2A PET Imaging Probe: [18F]SynVesT-2. Cai, Z., Li, S., Zhang, W., et al.[2021]

A PET study using the TSPO-targeted radiotracer [(11)C]DPA-713 revealed that individuals with HIV show significantly higher glial cell activation in specific brain regions compared to healthy controls, indicating potential neuroinflammation related to cognitive deficits.

Even in neuro-asymptomatic HIV subjects, regional abnormalities in TSPO were observed, with increased activation in the frontal cortex linked to HIV-associated dementia, highlighting the importance of monitoring neuroinflammation in HIV management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regional brain distribution of translocator protein using [(11)C]DPA-713 PET in individuals infected with HIV. Coughlin, JM., Wang, Y., Ma, S., et al.[2022]

The 18 kDa translocator protein (TSPO) is a key marker for measuring glial activation in the brain, which is important for understanding neurodegenerative diseases like multiple sclerosis, Parkinson's disease, and amyotrophic lateral sclerosis.

Recent research has raised questions about interpreting TSPO expression in psychiatric disorders, suggesting that neuroinflammation may play a significant role, highlighting the need for further investigation in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tracing the History of the Human Translocator Protein to Recent Neurodegenerative and Psychiatric Imaging. Downer, OM., Marcus, REG., Zürcher, NR., et al.[2022]

In a study involving 16 virally-suppressed people with HIV (VS-PWH) and 15 HIV-uninfected individuals, the use of the radiotracer [11C]CPPC to image the colony stimulating factor 1 receptor (CSF1R) did not show significant differences in brain binding between the two groups, suggesting similar levels of neuroimmune activation.

Despite the lack of significant findings, there was a moderate effect size indicating a trend towards higher CSF1R binding in specific brain regions (striatum and parietal cortex) in VS-PWH, suggesting that larger studies may be needed to fully understand the neuroimmune mechanisms in treated HIV populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pilot imaging of the colony stimulating factor 1 receptor in the brains of virally-suppressed individuals with HIV. Rubin, LH., Du, Y., Sweeney, SE., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05586581

Study Details | NCT05586581 | SV2A & TSPO PET Imaging ... The purpose of this study is to longitudinally characterize and evaluate changes in synaptic density in the brain using novel positron-emission tomography ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8528400/

Preliminary In Vivo Evidence of Reduced Synaptic Density in ... We used novel PET imaging of SV2A to assess synaptic density in a cohort of older male, virologically suppressed HIV participants and demographically similar ...

3. frontiersin.org frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2024.1380561/full

SV2A PET imaging in human neurodegenerative diseases A recent nonhuman PET study with 18F-SDM-16 showed the highest SV2A uptake affinity and metabolic stability compared to other available SV2A PET ...

4. elischolar.library.yale.edu elischolar.library.yale.edu/cgi/viewcontent.cgi?article=4131&context=ymtdl

Pet Imaging Reveals Reduced Synaptic Density In People ... Measurement of synaptic density in living humans may allow better understanding of HIV neuropathogenesis and provide a dynamic biomarker for therapeutic studies ...

5. natap.org natap.org/2020/CROI/croi_130.htm

PET IMAGING OF SYNAPTIC DENSITY IN HIV Here we report initial results from a pilot positron emission tomography (PET) ... SV2A imaging may be a promising outcome measure for ...

6. natap.org natap.org/2020/CROI/croi_106.htm

PET IMAGING OF SYNAPTIC DENSITY IN HIV Here we report initial results from a pilot positron emission tomography (PET) study employing the novel ligand 11C-UCB-J for synaptic ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11064927/

SV2A PET imaging in human neurodegenerative diseases We discuss the evidence of the utility of SV2A PET tracers as tools for monitoring disease progression and predicting clinical outcomes and ...