# Genetic Architecture of Cerebral Edema after Stroke

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2022 · $475,501

## Abstract

PROJECT SUMMARY
Cerebral edema is a major contributor to neurological deterioration and the leading cause of in-hospital death
after stroke. This pathologic water accumulation results in an increase in brain volume that can be measured
after most hemispheric strokes. This brain swelling not only raises the risk of cerebral herniation but also impairs
stroke recovery as much as infarct growth does. However, the key biologic factors and molecular mechanisms
that mediate formation of cerebral edema remain poorly defined. This knowledge gap has hindered development
of targeted interventions to mitigate the consequences of edema in conditions as diverse as brain trauma,
tumors, and hemorrhagic as well as ischemic strokes. There is significant variability between patients, with some
exhibiting malignant edema and others with none to mild swelling despite similar stroke sizes and severities. The
central objective of this proposal is to integrate imaging with genetics to identify key biologic pathways and
mediators implicated in cerebral edema. We will acquire serial CT scans from 3,506 patients in an NINDS-funded
stroke genetics study (GENISIS) and 1,000 being enrolled in an ERA-NET NEURON-funded study (iBioStroke).
We will apply automated analysis pipelines to obtain quantitative multi-dimensional measurements of edema
severity. Our primary biomarker is the displacement of cerebrospinal fluid (ΔCSF) that serves as a surrogate for
the volume of swelling that has developed after stroke. However, we will also measure hemispheric CSF ratio
and lesional water uptake as additional edema phenotypes. We will model edema formation (in relation to time
from stroke onset) to evaluate the degree to which biologic factors, such as age, sex, glucose, blood pressure,
and renal function, influence edema formation. Our central hypothesis is that inter-patient variability in edema
formation can be linked to both targetable clinical factors such as hyperglycemia and informative genetic
differences. Our preliminary data has suggested that ΔCSF has a significant heritable component. Specific Aim
1 seeks to quantify the relationship of key clinical factors, such as hyperglycemia and blood pressure, to edema
formation. We will leverage genomic data to further dissect which factors are causative in edema formation,
using Mendelian randomization. We will also quantify the impact of edema and hemorrhagic transformation on
stroke recovery. Specific Aim 2 will identify genes and pathways associated with cerebral edema after stroke. It
will employ genome-wide association (GWAS) approaches with multiple edema phenotypes in this large cohort.
We will further prioritize genes and pathways using functional annotation tools. Specific Aim 3 will dissect shared
versus edema-specific injury mechanisms by analyzing edema in relation to traits such as hemorrhagic
transformation, white matter injury and small-vessel disease. It will leverage large existing datasets to boost the
power of gene...

## Key facts

- **NIH application ID:** 10446825
- **Project number:** 1R01NS121218-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Rajat Raj Dhar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $475,501
- **Award type:** 1
- **Project period:** 2022-07-15 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10446825

## Citation

> US National Institutes of Health, RePORTER application 10446825, Genetic Architecture of Cerebral Edema after Stroke (1R01NS121218-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10446825. Licensed CC0.

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