# Pathological mechanisms of white matter hyperintensities

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2022 · $688,667

## Abstract

SUMMARY
This project applies advanced in vivo imaging to determine the pathological mechanisms of white matter
hyperintensities (WMHs) and their contribution to cognitive decline in older adults at risk of Alzheimer's disease
(AD). WMHs are bright patches on T2- MRI but do not inform the pathology underlying their appearance. Our
work is innovative because it utilizes, for the first time, non-invasive methods to quantify axon and myelin
rarefaction, fluid retention, WMHs-associated cortical atrophy, and blood-brain barrier dysfunction as in vivo
drivers of WMHs formation. We will also test typical pathological markers of WMHs, i.e., hypoperfusion and
compromised vascular reactivity. All imaging measurements will be validated against well-established CSF
markers. Our scientific premise is that different locations of WMHs (deep vs. periventricular) correspond to
distinct mechanisms (vascular vs. neurodegenerative) and cognitive profiles. Thus, our work will allow the use
of pathological drivers of WMHs to develop targeted strategies to stop their growth and ameliorate associated
cognitive decline in the future. In Aim 1, we will test the hypothesis that vascular pathology predominates in deep
WMHs by measuring cortical cerebral blood flow, vascular reactivity, and blood-brain barrier dysfunction. We will
use specialized arterial spin labeling and a hypercapnic functional MRI approach for these measurements. We
will validate measurements with CSF markers of vascular injury (e-selectin), inflammation (adhesion molecules,
VCAM/ICAM), and blood-brain barrier permeability (albumin extravasation). In Aim 2, we will test the hypothesis
that neurodegenerative pathology predominates in periventricular WMHs by measuring axon rarefaction,
demyelination, and fluid retention using advanced diffusion imaging and myelin water fraction imaging. Validation
markers will be CSF levels of tau and myelin basic protein. In independent ex vivo samples of donor brain tissue,
we will quantify vascular pathology using smooth muscle actin and albumin immunohistochemical stains in the
two WMHs. We will also quantify axon and myelin density in the WMHs and normal-appearing white matter and
perform neuron counting in gray matter using an array of stains. Postmortem MRI will be used to identify WMHs
on donor brains. The quantitative neuropathology will serve as an independent validation of our hypotheses
regarding WMHs location and mechanisms. In Aim 3, we will test the hypothesis that deep WMHs interrupt
discrete short-range association fibers and striatal fibers, causing specific cognitive deficits, especially those
related to processing speed. Periventricular WMHs, on the other hand, interrupt long-range association tracts
causing global cognitive impairment. We will use mediation analysis to explain whether the two types of WMHs
influence the relationship between the different imaging markers and distinct cognitive symptoms. The proposal
takes advantage of the Cores and affi...

## Key facts

- **NIH application ID:** 10476503
- **Project number:** 5R01AG069960-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Swati Rane Levendovszky
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $688,667
- **Award type:** 5
- **Project period:** 2021-09-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10476503

## Citation

> US National Institutes of Health, RePORTER application 10476503, Pathological mechanisms of white matter hyperintensities (5R01AG069960-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10476503. Licensed CC0.

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