# Developing a validated biomarker of cortical neurodegeneration in Alzheimer's disease using high-gradient diffusion MRI

> **NIH NIH R21** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $250,500

## Abstract

SUMMARY
The pathological changes of Alzheimer’s disease (AD) develop long before the onset of symptoms, with the
gradual accumulation of amyloid and tau in the brain followed by neuronal loss. While macroscopic brain changes
such as hippocampal atrophy and cortical thinning are well-established as markers of symptomatic AD, the
predictive value of such structural imaging measures is limited prior to the onset of dementia. High-gradient
diffusion MRI has emerged as a sensitive tool for probing microstructural alterations throughout the whole brain
and holds great promise for capturing the earliest microscopic gray matter abnormalities present in AD, before
their overt manifestation on conventional MRI. With the recent introduction of commercially available high-
performance gradient systems for clinical research, further elucidation of these imaging findings across the AD
spectrum and systematic comparison against histopathology is timely and critical for gaining a better
understanding of neuronal degeneration and the pathogenic factors influencing disease progression. The goal
of this project is to leverage the sensitivity of high-gradient diffusion MRI to map alterations in gray matter
microstructure in patients with mild cognitive impairment (MCI)/AD and individuals at risk of developing AD. This
work will build on the hardware and acquisition advances that our group has worked on for over a decade as
part of the Human Connectome Project and BRAIN Initiative to push the limits of diffusion MRI for mapping brain
tissue microstructure in the living human brain. We propose to acquire advanced diffusion MRI measures on the
next-generation Connectome scanner to map cortical and white matter microstructure in MCI/AD patients from
the Massachusetts General Hospital Alzheimer’s Disease Research Center (MADRC) and individuals from the
Human Connectome Project-Lifespan/Aging (HCP-Aging) cohort. Aim 1 will assess the relationship between
cortical microstructural metrics obtained from high-gradient diffusion MRI and amyloid and tau PET uptake in
MCI/AD and cognitively healthy older adults. Aim 2 will validate diffusion MRI measures of cellular morphology
against histopathology performed in vulnerable regions of postmortem brain specimens obtained from patients
with pathology-proven AD. At the end of this project, we anticipate the development of a validated, multi-scale
advanced diffusion MRI protocol targeted for evaluating alterations in cortical microstructure in older adults of
differing AD pathology status, with clear measures that can be translated to large-scale AD studies. Such
information will inform the interpretation of diffusion imaging metrics acquired using commercially available MRI
scanner hardware and provide key information regarding the underlying disease evolution to aid in the
development of future neuroprotective therapies for AD.

## Key facts

- **NIH application ID:** 10823839
- **Project number:** 1R21AG085795-01
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Susie Yi Huang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $250,500
- **Award type:** 1
- **Project period:** 2024-02-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10823839

## Citation

> US National Institutes of Health, RePORTER application 10823839, Developing a validated biomarker of cortical neurodegeneration in Alzheimer's disease using high-gradient diffusion MRI (1R21AG085795-01). Retrieved via AI Analytics 2026-08-11 from https://api.ai-analytics.org/grant/nih/10823839. Licensed CC0.

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