# Inflammation and delayed cognitive dysfunction after stroke

> **NIH NIH R56** · UNIVERSITY OF ARIZONA · 2022 · $627,236

## Abstract

PROJECT SUMMARY
Decades of research have shown a strong association between cerebrovascular disease, including stroke, and
subsequent cognitive impairment and dementia. However, vascular contributions to cognitive impairment and
dementia (VCID) are still unclear. Following stroke, there is a chronic inflammatory response that intensifies post-
stroke injury, and in animal models, causes delayed cognitive impairment. As such, the chronic inflammatory
response to stroke is a potential VCID. We recently demonstrated that at the molecular level, the chronic
inflammatory response to stroke strongly resembles that seen in atherosclerosis. In that regard, it is known that
overwhelmed lipid processing within myeloid cells is a driver of atherosclerosis, features of which are
dysregulated lipid metabolism within macrophages and production of high concentrations of neurotoxic cytokines
and degradative enzymes. Lipids are principal structural components of myelin and are therefore major
constituents of the human brain. Consequently, our overarching hypothesis is that following stroke, infiltrating
macrophages and resident microglia become overwhelmed by the sheer volume of cholesterol and other lipids
derived from the breakdown of myelin and cell membranes and, as a result, cause the chronic inflammatory
response described above. We propose that the permeation of cytokines and degradative enzymes produced
within the infarct into neighboring brain regions is the principal cause of the encephalomalacia, or “softening,”
that occurs to the tissue that surrounds chronic stroke infarcts. Thus, treatments that help phagocytic cells
process the large amounts of lipid debris generated by the breakdown of brain tissue may temper the chronic
inflammatory response to stroke and protect the surrounding brain tissue, thereby promoting healthier healing of
the brain and improving recovery. In cases where the infarct is located within or adjacent to a brain region
important for cognition, such treatments may even prevent dementia. Therefore, the goals of this proposal are
to identify the pro-inflammatory lipid species generated, and pathways triggered, by the break-down of the lipid
component of the brain following stroke (Aim 1); define the individual roles of pro-inflammatory lipid sensors in
driving the chronic inflammatory response to stroke (Aim 2); and determine whether lipid removal and immune
cell transcriptional reprogramming within the area of chronic inflammation can improve recovery from stroke and
prevent delayed cognitive impairment (Aim 3).

## Key facts

- **NIH application ID:** 10626672
- **Project number:** 1R56NS122710-01A1
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Kristian Paul Doyle
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $627,236
- **Award type:** 1
- **Project period:** 2022-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10626672

## Citation

> US National Institutes of Health, RePORTER application 10626672, Inflammation and delayed cognitive dysfunction after stroke (1R56NS122710-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10626672. Licensed CC0.

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