# Microstructural changes in gray and white matter in aging and AD

> **NIH NIH R01** · STANFORD UNIVERSITY · 2023 · $765,438

## Abstract

PROJECT SUMMARY
Accumulating neuropathological and animal studies suggest that AD pathology impacts brain microstructure
years before clinical manifestation of the disease. Various processes involved including alterations in dendritic
arborization and spines, neurite morphology, synaptic density, and axonal transport and packing. Until recently,
the evaluation of these microstructural properties and their association with AD pathology has been mainly
limited to postmortem tissue. Recent advances in MRI techniques have provided us with the ability to measure
cortical and white matter microstructural properties such as neurite morphology and macromolecular tissue
content in human in vivo. In the proposed study, we will employ a set of advanced quantitative MRI sequences
and analytical approaches to measure changes in cortical and white matter neurite morphology and
macromolecular content in preclinical AD and will examine their association with cognitive outcomes, and
amyloid and tau pathology measured by PET. We have recently demonstrated the utility of these measures in
detecting alterations in cortical and white matter neurite and macromolecular content in a sample of healthy
older adults and patients with amnestic mild cognitive impairment. We have also tested the association
between these measures and AD pathology in a small sample of older adults with confirmed AD pathology.
Teaming up with experts in early AD characterization and AD pathology and leveraging Stanford ADRC PET-
MR and deep phenotyping resources, we will study the following aims on a sample of 120 older adults who
have a clinical consensus diagnosis of either cognitively normal controls (HC) or mild cognitive impairment
(MCI), and will be confirmed to be Aβ- or Aβ+ based on ADRC amyloid PET data. We will examine cross-
sectional and longitudinal changes in cortical microstructural properties including neurite density (NDI) and
orientation dispersion index (ODI) (Aim 1), and in white matter microstructural and macromolecular tissue
properties including NDI, ODI and macromolecular tissue volume (MTV) (Aim 2), along with their association
with cognitive outcomes and AD pathology identified by PET. Taking a network-neuroscience approach, we will
also examine connectome-level microstructural changes in preclinical AD and will test the utility of a multi-layer
network framework for integrating measures across modalities (microstructural, molecular, PET, cognition) to
capture the heterogeneity of AD. The proposed systematic investigation of microstructural and molecular
changes in cortical and white matter in preclinical AD and their association with AD pathology and cognitive
outcomes in a well-characterized preclinical AD sample can provide unique insight regarding AD development
in early stages of the disease and can significantly improve our mechanistic understanding of AD. The
outcomes also have the potential to inform development of experimental treatments, monitoring their
effe...

## Key facts

- **NIH application ID:** 10630116
- **Project number:** 5R01AG073362-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Hadi Hosseini
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $765,438
- **Award type:** 5
- **Project period:** 2022-06-01 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10630116

## Citation

> US National Institutes of Health, RePORTER application 10630116, Microstructural changes in gray and white matter in aging and AD (5R01AG073362-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10630116. Licensed CC0.

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