# White matter hyperintensity-associated astrocytopathy in Alzheimers disease and vascular cognitive impairment A targeted histopathologic study using postmortem 7T MRI

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $769,974

## Abstract

PROJECT SUMMARY
Vascular disease is the largest single identifiable risk factor for dementia apart from age and the only one
potentially preventable. Alzheimer's Disease (AD) pathology proportionately decreases with age in those with
clinical dementia, implicating non-AD mechanisms as important determinants of older-onset dementia. These
mechanisms are likely vascular in nature, as “mixed vascular/AD” is more common than AD alone in older
individuals. The hallmark of vascular cognitive impairment (VCI) is subcortical white matter disease, visualized
on magnetic resonance imaging (MRI) as white matter hyperintensities (WMHs). WMHs are ubiquitous with
age, increase the risk of dementia, stroke, and death, and are increased in AD. Our research shows WM
damage extends beyond WMHs, within the immediately surrounding normal appearing white matter (NAWM).
Recent studies suggest an important role of WM astrocytic dysfunction (“astrocytopathy”) in VCI. Our
preliminary data support this association, and has identified changes in astrocyte phenotypes and increased
tau pathology in the grey matter (GM) of cortex overlying WMHs compared with GM overlying NAWM,
suggesting WMH-associated astrocytopathy contributes to both WM and GM dysfunction in both VCI and AD.
We hypothesize that regional chronic cerebral ischemia results in astrocytic changes within the GM and WM,
that alone and in combination with AD-associated pathologies potentiate CNS dysfunction and subsequent
cognitive impairment and dementia in the elderly, and that WMHs may serve as a biomarker for these
changes. We have developed a 7T postmortem MR protocol that allows for the identification and targeted
sampling of WMHs and surrounding normal appearing tissue for histopathological examination that includes a
detailed assessment of astrocytic changes, using brain tissue from a well-characterized cohort of Oregon
Alzheimer's Disease Center subjects who come to autopsy. In Aim 1, we will identify the features of WM
astrocytopathy associated with WMHs and areas in transition to becoming WMHs. In Aim 2, we will identify
these changes in GM, associate these with AD-specific pathologic changes, and determine their spatial
relationship to regional WMHs. In Aim 3, we will determine which regional WM and GM astrocyte abnormalities
found in Aims 1 and 2 are associated with dementia status and global cognition, controlling for standard
pathologies associated with neurodegenerative diseases, such as those of AD. We anticipate that the studies
in human tissue will produce new insights into the relationship between VCI and AD, and suggest specific
functions and functional losses of astrocytes in mediating these associations. We anticipate that treatments
aimed at astrocytic protection and recovery from hypoxic injury could suggest a new spectrum of possibilities
for therapeutic targets designed to prevent AD and related dementias.

## Key facts

- **NIH application ID:** 9856308
- **Project number:** 5R01AG056712-03
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Lisa C Silbert
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $769,974
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9856308

## Citation

> US National Institutes of Health, RePORTER application 9856308, White matter hyperintensity-associated astrocytopathy in Alzheimers disease and vascular cognitive impairment A targeted histopathologic study using postmortem 7T MRI (5R01AG056712-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9856308. Licensed CC0.

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