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GW Investigator Finds Promising Blood Gene Expression Associated With Salvageable Brain Tissue in Stroke

When a person has a stroke, a small core of tissue is permanently damaged, while there is a larger surrounding area of brain tissue, called penumbra, at risk but still salvageable. In a preliminary study published in the Annals of Clinical and Translational Neurology, George Washington University (GW) investigator Zurab Nadareishvili, MD, PhD, and his colleagues from the National Institute of Neurological Disorders and Stroke at NIH, found that blood biomarkers may detect the presence of salvageable brain tissue during stroke.

The penumbra is not functioning tissue, but it is still alive, explained Nadareishvili, a neurologist at the Virginia Hospital Center and associate professor of neurology at the GW School of Medicine and Health Sciences. However, if blood flow is restored to the area through thrombolytic therapy, which is a clotbuster medication, or catheter based clot retrieval, known as thrombectomy, that area can start functioning again.

The repair of salvageable brain tissue after stroke with thrombectomy is time dependent; before 2018 treatment was effective only within six hours, but not necessarily after that time window. However, starting last year, new imaging technology is allowing for identification of penumbral tissue up to 24 hours after a stroke.

“We questioned whether it would be possible to find biomarkers of salvageable brain tissue in the blood using new powerful next-generation sequencing,” Nadareishvili said. “That technology allows analysis of roughly 25,000 gene expressions, while special software can analyze their interaction in the blood to identify pathways involved.”

Salvageable brain tissue was measured using MRI in 23 patients with acute stroke. With the help of next-generation sequencing, investigators found 34 genes differently expressed in association with penumbra. The genes mostly represented pathways related to inflammation and neuroprotection, Nadareishvili noted.

They also looked at whether there were upstream regulators of these changes in gene expression. According to Nadareishvili, the analysis showed that lipopolysaccharide, or LPS, was an upstream regulator of described changes in gene expression. LPS is the major component of the outer membrane of Gram-negative bacteria and during infection that activates the immune system. In experimental animal models of stroke LPS exacerbates brain damage though its interaction with toll-like receptor-4 (TLR-4), which results in the initiation of the inflammatory process. Thus, inhibition of this pathway may have neuroprotective effects on preservation of penumbra, he said.

The results of the study — the possibility of detecting the molecular signature of the salvageable brain tissue in the blood of patient with acute stroke — could lead to advancements in the development of a blood test to identify penumbra, Nadareishvili said.

That test potentially could then be implemented by EMS personnel to detect salvageable brain tissue in stroke patients before they even get to the hospital, he added. In addition, validation of observed findings in a larger study will help better the understanding of neuroprotective mechanisms, which may allow development of new treatment of acute stroke.

The study, “Molecular signature of penumbra in acute ischemic stroke: A pilot transcriptomics study,” was published in Annals of Clinical and Translational Neurology in March 2019 and is available at https://onlinelibrary.wiley.com/doi/full/10.1002/acn3.757