# Revealing tissue microstructure in the brain gray matter in Alzheimer's disease using in vivo high-gradient diffusion MRI

> **NIH NIH DP5** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $420,000

## Abstract

Project Summary/Abstract
Alzheimer’s disease (AD) accounts for about 70% of dementia cases, and the number of AD patients continues
to grow substantially due to the worldwide phenomenon of population aging, prompting the call for innovative
technologies that will enable the early identification of patients at risk and monitoring of disease progression and
therapeutic response. There is a known sequence of pathological alterations that develop in Alzheimer’s disease
(AD) long before frank cognitive decline, offering potential targets for early detection of disease onset with
subsequent interventions. While volumetric MRI changes are useful to assess the presence of
neurodegeneration, regional cortical volume loss is a relatively late structural marker of neurodegeneration in
AD. On the other hand, diffusion MRI (dMRI) is a non-invasive imaging technique sensitive to pathological
changes on the cellular level, at least three orders of magnitude below the nominal spatial resolution of
conventional MRI. So far, most AD studies using dMRI have largely focused on white matter changes. However,
on histopathology, AD is primarily a cortical disease. The ability to probe early microstructural changes in GM in
vivo would open the door to assessing disease onset and progression, facilitating the development of disease-
modifying therapy. This project will bridge the gap in understanding changes in GM tissue microstructure in AD
and mild cognitive impairment (MCI) using a combination of tools in multiple domains, such as biophysical
modeling, ex vivo and in vivo dMRI, and histological validation. We will address this multi-faceted research
challenge through the following aims: Aim 1: Establish time-dependent dMRI measurements to evaluate the
density of axonal varicosities, size of cell body (soma), and soma/neurite density using a high-gradient MRI
system. By leveraging the very strong diffusion gradients on the current and next-generation Connectome MRI
scanner, we will develop a novel technique for evaluating the tissue microstructure in healthy subjects, AD and
MCI patients. Aim 2: Validate in vivo and ex vivo dMRI measures of axonal and soma structure via Monte Carlo
simulations of diffusion and histological analysis in three-dimensional realistic substrates based on light and
electron microscopy, and micro-CT data. Aim 3: Assess the correlation of GM microstructural parameters with
cognitive dysfunction, amyloid and tau PET scans, and blood and cerebrospinal fluid protein biomarkers, such
as amyloid beta, total and phosphorylated tau (P-tau 181 and P-tau 217).
 In summary, building on our previous success in assessing white matter microstructure using dMRI, our
study in GM promises to provide reliable noninvasive imaging markers of neurodegeneration, facilitating our
understanding of the mechanisms underlying the progression of AD. Ultimately, the quantification of GM
microstructure will offer prognostic and confirmatory biomarkers for neurodegenerative...

## Key facts

- **NIH application ID:** 10254657
- **Project number:** 1DP5OD031854-01
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Hong Hsi Lee
- **Activity code:** DP5 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $420,000
- **Award type:** 1
- **Project period:** 2021-09-14 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10254657

## Citation

> US National Institutes of Health, RePORTER application 10254657, Revealing tissue microstructure in the brain gray matter in Alzheimer's disease using in vivo high-gradient diffusion MRI (1DP5OD031854-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10254657. Licensed CC0.

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