SV2A & TSPO PET Imaging Measures to Reveal Mechanisms of HIV Neuropathogenesis During Antiretroviral Therapy

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).

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.

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