# Stanford Neurosurgery and Neurology Resident Research Education Program

> **NIH NIH R25** · STANFORD UNIVERSITY · 2022 · $9,697

## Abstract

Project Summary
Ischemic stroke is one of the leading causes of dementia, with 30-40% of stroke patients
developing significant dementia within 10 years. However, the mechanistic link between
ischemic injury and subsequent development of vascular dementia remains incompletely
understood. We do know that additional stroke-triggered mechanisms are contributing, as even
after controlling for stroke risk factors (age, hypertension, diabetes, myocardial infarction,
congestive heart failure, cerebral atrophy, white matter changes, and recurrent strokes), the
occurrence of cerebral infarction itself independently increases dementia risk.
Recent work from the Buckwalter lab demonstrated that ischemic injuries induce a persistent,
chronic inflammatory response in the CNS remote from the initial lesion site that is critical for
later development of cognitive decline. However, the source and identity of molecular antigens
that sustain the inflammatory response are not known. Immunostaining for innate and adaptive
immune cells after stroke show prominent localization where the white matter tracts have
undergone Wallerian axon degeneration. This raises the possibility that axonal proteins are the
major source of antigens that stimulate the neuro-inflammatory response, and that axonal
degeneration is a necessary step to trigger and maintain the chronic inflammatory state that
ultimately leads to development of post-stroke cognitive impairment.
Taking advantage of a mutant mouse strain that I previously identified to be resistant to axonal
degeneration following ischemic injuries, I will test the hypothesis that preventing axonal
degeneration is necessary to (1) attenuate the inflammatory response after stroke, and (2)
mitigate the development of post-stroke dementia. These genetic and animal disease models
provide powerful approaches to ask whether functional preservation of axons mitigates immune
cell infiltration and activation after stroke, and whether this subsequently prevents the
development of post-stroke dementia.
The proposed work will provide mechanistic insight into how ischemic injuries lead to vascular
dementia, and help uncover therapeutic targets to delay or attenuate the progression of a major
stroke-related comorbidity.

## Key facts

- **NIH application ID:** 10568764
- **Project number:** 3R25NS065741-12S1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Melanie Hayden Gephart
- **Activity code:** R25 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $9,697
- **Award type:** 3
- **Project period:** 2009-03-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10568764

## Citation

> US National Institutes of Health, RePORTER application 10568764, Stanford Neurosurgery and Neurology Resident Research Education Program (3R25NS065741-12S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10568764. Licensed CC0.

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