# Multimodal neuroimaging assessments of synaptic integrity: Linking pathology and cognition (Project 3)

> **NIH NIH P01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $461,294

## Abstract

SUMMARY: PROJECT 3- SYNAPTIC FUNCTION
The proximal cause of cognitive impairment in Alzheimer’s disease (AD) is synaptic dysfunction and synaptic
loss. As summarized in Projects 1 and 4, there is consistent evidence that amyloid-beta (aβ) is associated with
cognitive decline, that aβ alone is not sufficient, and that rates of cognitive decline are considerably
heterogeneous . Consequently, assessment of synaptic integrity is pivotal for linking the deleterious effects of
AD and other age related pathology with resilience or susceptibility to cognitive decline. The goal of Project 3
is to explore and build upon our understanding and capacity to assess synaptic integrity within the AD
spectrum and beyond through innovative multimodal PET and MRI imaging and quantitation. In Aim 1, we will
extend and build upon our prior work with resting state functional connectivity, focusing on relating longitudinal
change in a composite measure of functional network connectivity to change in cognition, aβ, tau, or
modulating factors (Project 2). In Aim 2, we will extend and build upon our multimodal functional imaging
capabilities through inclusion and characterization of a proxy measure of relative blood flow derived from the
wash-in of the PiB tracer (
PiB-R1). In conjunction with FDG-PET and resting state functional connectivity MRI
(rs-fcMRI), we will evaluate whether
PiB-R1 is a useful proxy for FDG, if change in
PiB-R1 is an informative
measure for cognition, molecular pathology, or modulating factors, and whether PiB-R1 can control for flow
effects in other functional imaging modalities. In Aim 3, we will go beyond the available arsenal of functional
measures, with an exploratory investigation of a new synaptic imaging radioligand for TARPγ8, the regulatory
protein for AMPA receptors, that is highly expressed in hippocampus. This is a high risk, but potentially high
reward, aim that is an important step towards a more direct assessment of synaptic integrity. Utilizing a subset
of HABS participants, we will acquire TARPγ8-PET imaging and assess relationships between TARPγ8-PET
and measures hypothesized to be related to synaptic dysfunction (age, cognition, hippocampal volume, FDG,
and fMRI), as well as PET measures of Alzheimer’s disease molecular pathology. If successful, TARPγ8-PET
imaging will provide an opportunity to compare our functional imaging measures from Aims 1 and 2 to a more
direct synaptic assessment and allow us to better characterize the extent and manner in which current
functional imaging measures reflect synaptic integrity related to AMPA receptor signaling. By leveraging the
rich longitudinal characterization of the HABS cohort, including data collected during the first two grant cycles,
and the resources of the other projects and cores, Project 3 will focus on synaptic integrity as a means to
bridge the gap between pathological markers with heterogeneous time-dependent influences and cognitive
decline in order to provide a better unde...

## Key facts

- **NIH application ID:** 10144910
- **Project number:** 5P01AG036694-12
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Aaron P Schultz
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $461,294
- **Award type:** 5
- **Project period:** 2010-07-15 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10144910

## Citation

> US National Institutes of Health, RePORTER application 10144910, Multimodal neuroimaging assessments of synaptic integrity: Linking pathology and cognition (Project 3) (5P01AG036694-12). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10144910. Licensed CC0.

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