Tracking the Chemical Calling Card of a Killer Stroke

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Citations Brain Aneurysm Foundation Research Grant Awards

Newswise — Columbus, OH. It’s been described as a “thunderclap” headache. A sudden, blinding pain that’s so intense that almost anyone who experiences it usually finds themselves in an emergency room. The pain is the hallmark of a very rare, but unusually deadly type of stroke called a subarachnoid hemorrhage (SAH), the result of ruptured blood vessels leaking blood between the skull and brain and around the brain stem. These strokes –usually caused by blood vessel malformations or aneurysms – are fatal 50% of the time.

The danger however, doesn’t end there, according to Ciaran Powers, MD, PhD, a neurosurgeon at The Ohio State University Wexner Medical Center who specializes in treating patients with SAHs.

“Of those patients who survive the initial hemorrhage, 30% will go on to have a secondary stroke within two weeks of the initial event, which can cause further disability or death,” said Powers. “We don’t know exactly why these delayed strokes happen, or who will get them.”

Scientists know that the secondary strokes, called delayed cerebral ischemia (DCI), are caused by spasms in brain blood vessels that block blood flow. Physicians have therapies and surgery that can help SAH patients who have this delayed stroke, but Powers is looking for a way to stop DCIs before they can even happen.

“My goal is to decode the biological processes in the brain that trigger the DCIs. Then we can identify high-risk patients and step up our interventions, or if a patient is at less risk, we could get them out of the ICU and into a step down unit a little sooner,” said Powers.

65 year-old Eileen Marcon and her family are familiar with the agonizing time spent in the ICU waiting to see if a secondary stroke will strike. Last year, Marcon, was getting ready for bed when she says she felt a pop of fluid in her head. It was a ruptured aneurysm.

“There was no pain, but I knew immediately I had to get to a hospital,” she recalled.

Marcon remembers sitting in the ER waiting room, and then being in physical therapy - but has no recollection of the three weeks in between. Powers had stopped the bleed, but the hemorrhage wiped out her memories, which is common among SAH patients. While she was still in the ICU, Marcon's husband, a scientist, enrolled her in Powers’ study, recognizing the value of having a tool to predict secondary strokes.

To identify patients at risk for DCI, Powers is studying the quantities of micro-RNAs that are created in the hours and days after a hemorrhage to see if he can identify biomarkers that could help predict the delayed stroke. Micro-RNAs are tiny snippets of non-coding DNA that turn off the production of proteins created by genes, proteins that tell cells what to do.

“During a hemorrhage like this, one can only imagine the biochemical chaos taking place. Brain cells are dying from lack of oxygen, blood is mixing with spinal fluid, genes and cells are firing off all kinds of distress signals. Maybe some of the messages get mixed up and hurt instead of help,” said Powers.

In a small study, supported by Ohio State’s Center for Clinical and Translational Science (CCTS) Davis Bremer Pilot Award, Powers identified more than 140 micro-RNAs that are present in the spinal fluid of eight patients who had an SAH followed by DCI. He categorized the micro-RNAs into abundance patterns, compared them with normal controls, and then focused on a handful of micro-RNAs that literally leapt out of the pack.

“Some of these micro-RNAs shoot up immediately after a stroke and then level out, others start low and then go up. We found three micro-RNAs, all connected to dysfunctions in neurological remodeling and repair, that increase as much as 100-fold, so we have a compelling place to start looking,” says Powers.

The CCTS pilot study findings helped Powers secure a grant from the Brain Aneurysm Foundation and a Young Clinician Investigator Award from The Neurosurgery Research and Education Foundation (NREF) of the American Association of Neurosurgeons.

Powers is planning expand his study size and is partnering with another CCTS-funded stroke investigator who developed an animal model of ischemia in order to analyze micro-RNA released in brain tissues at the precise area around a blocked blood vessel. He still has blood samples from his pilot study participants to examine, as they may also contain other types of biomarkers that could help him predict post-SAH events.

The momentum behind the research is good news for Powers, who says that he has more questions now than when he started.

“Do these micro-RNAs have a mechanistic role in causing the delayed event, or are they simply biomarkers? Where are these micro-RNAs even coming from – the blood in spinal fluid or the brain itself? Just the answer to one of those questions would advance our knowledge of SAH dramatically.”

Today, Marcon has made a full recovery and didn’t sustain any long-term effects from the hemorrhage. She says she knows the ordeal was especially difficult for her husband and their five children who had to sit by her bedside knowing that one of these delayed strokes could strike at any time. Fortunately, it did not.

“It must have been hell for them, not knowing if I would be alive the next hour or the next day,” said Marcon. “Dr. Powers saved my life, so I was happy to participate in his study. If I could spare one person or one family the pain of not knowing, that would be just great.”

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The Ohio State University Center for Clinical and Translational Science (CCTS) is funded by the National Institutes of Health (NIH) Clinical and Translational Science Award (CTSA) program (UL1TR001070, KL2TR001068, TL1TR001069) The CTSA program is led by the NIH’s National Center for Advancing Translational Sciences (NCATS). The content of this release is solely the responsibility of the CCTS and does not necessarily represent the official views of the NIH.


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