# PET IMAGING OF SYNAPTIC DENSITY COMBINED WITH NEUROIMMUNOLOGIC MEASURES TO REVEAL MECHANISMS OF HIV NEUROPATHOGENESIS DURING ART

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $1,103,962

## Abstract

Summary/Abstract
Widespread use of effective antiretroviral therapy (ART) in the past two decades has improved
the clinical manifestations and altered the pathology of neurologic disease in people living with
HIV (PLWH). However, in the context of this treatment that has successfully prolonged millions
of lives, new pressing questions have emerged regarding the etiology of persistent neurological
and cognitive impairment that frequently manifests in PLWH on ART. The human brain is a
complex and inaccessible organ that, to date, defies comprehensive understanding in the
context of homeostasis and disease. Thus, the hallmark neuropathologic finding of HIV
associated neurocognitive disorder (HAND), synaptodendritic injury, has thus far only been
possible to evaluate in post-mortem human autopsy brains and animal models of HIV. Our
group at Yale recently developed and validated a novel positron-emission tomography (PET)
radiotracer, [11C]UCB-J, a ligand for the presynaptic vesicular membrane protein synaptic
vesicular glycoprotein 2A (SV2A), to image synaptic density in the human brain. The premise of
this application is based on our ongoing pilot study which demonstrates that brain SV2A PET
successfully identifies regions of reduced synaptic density -- including in a hippocampal-
frontostriatal neural circuit that correlates with CNS dysfunction -- in PLWH on ART. In the
current proposal, we seek to measure synaptic density longitudinally over 24 months in a larger
group of PLWH on ART relative to a matched prospectively enrolled HIV-negative group. We
will combine this breakthrough imaging methodology of synaptic density with PET imaging of
neuroimmune status (using radioligand [11C]PBR28 targeting the 18-kDa translocator protein, or
TSPO, sensitive to microglia) to explore the premise that neuroimmune dysregulation during
ART mediates reduced synaptic density. Finally, we aim to longitudinally integrate these
measures with neurocognitive and laboratory assessments in parallel processing models that
allow us to dissect mechanisms and clinical outcomes of HAND. Our application is based on
robust and compelling preliminary data that demonstrates the utility of SV2A PET imaging in
identifying regions of reduced synaptic density in PLWH on ART. Our proposed project will
generate powerful clinical-translational support for potentially reversible brain alterations in
synaptic density, and their relation to microglia levels and clinical and biological measures in
PLWH. This program will set the stage for identification of therapeutic targets and provide a
biomarker for interventional studies aimed to improve HIV-related injury in the CNS.

## Key facts

- **NIH application ID:** 10263367
- **Project number:** 5R01MH125396-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** SERENA S SPUDICH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,103,962
- **Award type:** 5
- **Project period:** 2020-09-15 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10263367

## Citation

> US National Institutes of Health, RePORTER application 10263367, PET IMAGING OF SYNAPTIC DENSITY COMBINED WITH NEUROIMMUNOLOGIC MEASURES TO REVEAL MECHANISMS OF HIV NEUROPATHOGENESIS DURING ART (5R01MH125396-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10263367. Licensed CC0.

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