SV2A & TSPO PET Imaging for HIV Neurocognitive Disorders

(ART Trial)

Overseen By Alliosn Nelson, RN

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Yale University

Must be taking: Antiretrovirals

Must not be taking: Anticoagulants

Disqualifiers: Substance dependence, Neurological illness, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

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).

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 data supports the idea that SV2A & TSPO PET Imaging for HIV Neurocognitive Disorders is an effective treatment?

The available research shows that SV2A & TSPO PET Imaging can help identify brain changes in people with HIV, which might be linked to cognitive problems. For example, one study found that people with HIV had higher levels of certain brain markers compared to healthy individuals, suggesting brain inflammation. However, the research does not clearly show that this imaging is an effective treatment for improving symptoms. Instead, it seems more useful for understanding and monitoring the condition. There is no direct comparison to other treatments in the provided data, and the effectiveness of SV2A & TSPO PET Imaging as a treatment is not clearly supported by the available research. ^{1 2 3 4 5}

What safety data exists for SV2A & TSPO PET Imaging in HIV neurocognitive disorders?

The provided research does not directly address safety data for SV2A & TSPO PET Imaging in HIV neurocognitive disorders. However, it discusses the use of TSPO PET imaging in various contexts, including neurodegenerative and psychiatric disorders, and highlights challenges such as the rs6971 polymorphism affecting TSPO ligand binding. The studies focus on the application and effectiveness of TSPO PET imaging rather than specific safety outcomes. ^{1 2 5 6 7}

Is the treatment in the trial 'SV2A & TSPO PET Imaging for HIV Neurocognitive Disorders' a promising treatment?

The treatment in the trial uses PET imaging to study brain changes in people with HIV, focusing on a protein called TSPO. This approach helps identify brain areas affected by HIV, which can lead to better understanding and management of cognitive issues in these patients. It shows promise in improving how we monitor and potentially treat neurocognitive disorders in people with HIV. ^{1 2 3 5 8}

Research Team

Serena Spudich, MD

Principal Investigator

Yale University

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• SV2A PET (Imaging Agent)
• TSPO PET (Imaging Agent)

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Regional brain distribution of translocator protein using [(11)C]DPA-713 PET in individuals infected with HIV. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Pilot imaging of the colony stimulating factor 1 receptor in the brains of virally-suppressed individuals with HIV. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Comparison of [11C]-PBR28 Binding Between Persons Living With HIV and HIV-Uninfected Individuals. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Synthesis and Preclinical Evaluation of an 18F-Labeled Synaptic Vesicle Glycoprotein 2A PET Imaging Probe: [18F]SynVesT-2. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Tracing the History of the Human Translocator Protein to Recent Neurodegenerative and Psychiatric Imaging. [2022]

6. United States 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. [2022]

7. Germany pubmed.ncbi.nlm.nih.gov

Radiosynthesis and characterization of [18F]BS224: a next-generation TSPO PET ligand insensitive to the rs6971 polymorphism. [2022]

8. Japan 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. [2017]