# Assessing Diffusion MRI Metrics for Detecting Changes of Synaptic Density in Alzheimer's Disease

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $776,084

## Abstract

Project Abstract
Synaptic structure and function are the keys to several neurodegenerative disorders, including Alzheimer’s
disease (AD). Specifically, dysfunctional synapses and dysregulated synaptic plasticity in the hippocampus
are responsible for early memory and cognitive decline in AD. Invasive tools, such as electrophysiological or
immunohistochemical techniques, have been for decades to study synaptic morphology and density in animal
models or human postmortem brain samples. Nevertheless, it has been challenging to study synaptic
structure in living humans. The goals of the proposed research are: (1) to characterize the ability of in vivo
diffusion MRI techniques to detect alterations of axodendritic synapse density in a mouse model of Alzheimer’s
disease and (2) to assess the translational utility of such diffusion metrics for future in vivo human brain
studies.
A recent milestone in radiopharmaceutical development enables the possibility of studying synaptic vesicle
glycoprotein 2A (SV2A) in vivo via PET imaging. PET imaging with the 11C-UCB-J tracer has shown a
reduction of SV2A binding in mild cognitive impairment and AD patients. Despite its molecular accuracy, PET
imaging suffers from disadvantages including high cost, low spatial resolution, and ionizing radiation exposure.
On the other hand, MRI is a safe, non-invasive, and non-irradiating imaging technique that provides at least a
5-fold better spatial resolution. The modern advancement in diffusion MRI provides metrics that reflect neurite
density (i.e., axons and dendrites) via compartment modeling of intracellular volume fraction. Using in vivo
diffusion compartment-modeling imaging on the human brain, our laboratory demonstrated a significant
decrease in intra-neurite volume fraction in white-matter areas consequent to mild traumatic brain injury,
normal aging, and mild cognitive decline. We have also demonstrated decreased intra-neurite volume fraction
in the human hippocampal subfields associated with poor performance in cognitive and verbal learning
assessments across the clinical AD continuum.
Cumulatively, our and others’ results in human studies suggest these advanced diffusion metrics are sensitive
to brain degenerations and associated with cognitive and memory declines, which are thought to be caused by
dysfunctional and dysregulated synapses. Nevertheless, there has not been direct evidence nor detailed
characterization connecting these advanced diffusion metrics and synaptic density. The proposed research
aims to address this knowledge gap.

## Key facts

- **NIH application ID:** 10929466
- **Project number:** 5R01AG083951-02
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Yu-Chien Wu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $776,084
- **Award type:** 5
- **Project period:** 2023-09-15 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10929466

## Citation

> US National Institutes of Health, RePORTER application 10929466, Assessing Diffusion MRI Metrics for Detecting Changes of Synaptic Density in Alzheimer's Disease (5R01AG083951-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10929466. Licensed CC0.

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