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NEWS FROM THE AMERICAN NEUROLOGICAL ASSOCIATION ANNUAL MEETING: Researchers Move Closer to Identifying Early Biomarkers of Ischemic Penumbra in Acute Stroke

Laino, Charlene

doi: 10.1097/01.NT.0000423166.77711.2e
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MRI IN PATIENT WITH ACUTE ISCHEMIC STROKE (from left to right): diffusion weighted imaging (DWI) for the infarction area; perfusion weighted imaging (PWI) for the total hypoperfusion area; and mismatch, or ischemic penumbra, that represents the salvageable brain tissue (area in grey), obtained by subtracting DWI from PWI

MRI IN PATIENT WITH ACUTE ISCHEMIC STROKE (from left to right): diffusion weighted imaging (DWI) for the infarction area; perfusion weighted imaging (PWI) for the total hypoperfusion area; and mismatch, or ischemic penumbra, that represents the salvageable brain tissue (area in grey), obtained by subtracting DWI from PWI

Investigators reported that two biomarkers of oxidative stress — F2-isoprostane and a measurement of the total plasma antioxidant capacity —were associated with imaging evidence of mismatch in patients with acute ischemic stroke.

BOSTON—Elevated plasma levels of two biomarkers of oxidative stress are associated with radiographic evidence of mismatch in patients with acute ischemic stroke, Boston researchers reported at the American Neurological Association annual meeting here in October.

Mismatch is a measurement of the salvageable brain tissue in patients with ischemic stroke — the so-called ischemic penumbra, said investigator Svetlana Lorenzano, MD, PhD, a fellow in the department of neurology at Massachusetts General Hospital.

Currently, MRI is the best method available for measuring mismatch, she said. It is calculated by subtracting diffusion — the area already infracted and no longer salvageable as seen on diffusion-weighted MRI — from perfusion, a general measure of blood flow in the brain region affected by the ischemic process after an artery occlusion.

However, criteria for mismatch definition are not yet standardized or agreed upon, and MRI is not widely available, said Dr. Lorenzano, who performed the work under the guidance of principal investigator Karen L. Furie, MD, who recently joined Brown University as chair of the department of neurology at the Warren Alpert Medical School.

The new study, which was funded by the NIH, is a first step toward identifying “practical, less expensive and time-consuming biomarkers of salvageable brain tissue,” she said.

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Over a period of three years, the researchers prospectively measured plasma levels of F2-isoprostane P (F2-isoP), a marker of oxidative stress-induced damage to lipids within the cell membranes in 526 patients in two large academic hospitals in Boston.

They also performed the Oxygen Radical Absorbance Capacity (ORAC) assay, a measurement of the total plasma antioxidant capacity that has been developed as method for studying oxidative stress. “Theoretically, if you have a higher antioxidant capacity, there is a greater chance to have brain tissue saved,” Dr. Lorenzano said.

Since mitochondrial DNA is more susceptible to oxidative stress than nuclear DNA, they further measured the urine level of a biomarker of oxidative DNA damage, 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-OHdG). Plasma inflammatory and tissue damage biomarkers, such as high sensitivity C reactive protein (hs-CRP) and matrix metalloproteinase (MMP) 2 and 9, were also measured.

Patients also had MRI scans, with mismatch volume defined as baseline perfusion volume minus baseline diffusion volume (DWIv). Percentage mismatch volume was calculated, and the standard percentage mismatch cut-off of greater than 20 percent was used to identify patients with enough salvageable brain tissue to be treated.

“If there is less than 20 percent brain tissue that can be salvaged, the probability that a patient will benefit is low,” said Dr. Lorenzano.

Of 489 patients with definite diagnosis of ischemic stroke, 216 (44.2 percent) had both biomarkers and a baseline DWI/PWI study. Mismatch greater than 20 percent was found in 153 (70.8 percent) patients.

Results showed that patients with greater than 20 percent mismatch were significantly more likely to have higher levels of baseline F2-isoP and ORAC than patients with no or less mismatch.

There was no significant association between any of the other biomarkers and mismatch.

In multivariate analysis, F2-isoP emerged as an independent predictor of greater than 20 percent mismatch, independent of other confounding variables like baseline infarct volume (diffusion MRI volume), age, neurological severity, and IV t-PA.

“This is a first step,” Dr. Lorenzano. “We have shown a correlation.”

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While the work is a long way from being ready for clinical use, the ability to predict the area of ischemic penumbra would be useful for several reasons, Dr. Lorenzano continued. It would allow the selection of patients that are most likely to benefit from reperfusion therapy. And it could extend the therapeutic window for thrombolytic therapy with IV recombinant tissue-type plasminogen activator (rt-PA), the only pharmacological revascularization treatment that has been demonstrated to be effective in acute ischemic stroke, she said.

“We could individualize therapy, treating beyond the approved therapeutic window of 3.0 hours in the US and 4.5 hours in Europe,” she explained. “If we know there is still salvageable tissue, we might say, ‘go for it with tPA,’” even if six or seven hours have passed, she said.

If the tissue is already dead, on the other hand, treatment would be futile and would only expose the patient to unnecessary adverse events and cost, Dr. Lorenzano said.

The work may also offer new insights into the pathophysiology of cerebral ischemia in the human brain, she said, noting that much of the current understanding comes from studies of rat brains.



And in centers where MRI is not available, a blood test could help in the differential diagnosis of acute ischemic stroke, much like testing for the biomarker troponin aids in the diagnosis of myocardial infarction, Dr. Lorenzano said.

Finally, biomarkers can be targets for novel therapies such as neuroprotectant agents, she said, noting that none are currently available.

The researchers chose to look for biomarkers of oxidative stress, as it is one of the earliest and most important responses in the biochemical cascade set off by an acute cerebral ischemic injury, Dr. Lorenzano said. Experimental studies have demonstrated that there is an increase in oxidative stress biomarkers in the early phase of acute ischemic stroke, she said.

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Other researchers had mixed reactions. Larry B. Goldstein, MD, professor of medicine (neurology) and director of the Duke Stroke Center at Duke University Medical Center, said that while the researchers did show a correlation between two biomarkers of oxidative stress and the area of penumbra, there is no standard or agreed-upon definition of mismatch using MRI.

“These MRI measurements are probably as good a gold standard as we have, but they are still controversial,” he said.

Additionally, should the study be validated, some of the researchers' proposed uses for the biomarkers are farfetched, Dr. Goldstein said.

“Saying here is a serum biomarker that identifies patients who have a certain area of penumbra is quite different than having a blood biomarker like troponin that can be used ‘in differential diagnosis,’” Dr. Goldstein said.

He noted that several teams of researchers are working on panels of biomarkers that might be used for diagnosis of acute ischemic stroke. One team reported in 2010 in the journal Stroke that they had identified and replicated a gene expression profile that discriminated ischemic stroke from relevant control groups.

Other researchers reported in Stroke in 2009 that they tested a biomarker panel that included MMP9 and showed a sensitivity of 86 percent for detecting all stroke and a sensitivity of 94 percent for detecting hemorrhagic stroke, he noted. The researchers concluded that, “Although the diagnostic accuracy of the current panel is clearly imperfect, this study demonstrates the feasibility of incorporating a biomarker based point-of-care algorithm with readily available clinical data to aid in the early evaluation and management of patients at high risk for cerebral ischemia.”

Daniel T. Lackland, PhD, professor of epidemiology in the department of neurosciences at the Medical University of South Carolina, was a bit more enthused about the research.

“They performed a kind of cross-sectional assessment and found an association between certain biomarkers and ischemic penumbra,” he said.

As the researchers acknowledged, the work next needs to be validated and in a different population, Dr. Lackland said. “It is doubtful that patients at the two medical centers studied share some unique factor that explains the association, but it needs to be ruled out,” Dr. Lackland said.





Once the results are replicated, “we need a study, perhaps using frozen samples at first, to determine just how well these biomarkers predict penumbra — the sensitivity and the specificity,” he said.

But if all the research pans out, “it would be great to have biomarkers that tell us who has not had a stroke, or that predict the risk of having a stroke,” Dr. Lackland said.

Peter Sandercock, DM, professor of medical neurology and honorary consultant neurologist and director of Edinburgh Neuroscience at Western General Hospital in Edinburgh, is less sanguine about the prospects. “All these [substances] get into the blood too late to be of any help. Plus, the really useful stuff never leaves the brain due to the blood-brain barrier,” he said.

“Any of these blood markers are going to have low sensitivity and specificity for predicting stroke,” he continued. “It's totally different that with MI [myocardial infarction], where the heart muscle is damaged and substances go into surrounding blood rather immediately.”

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• Stamova B, Xu H, Sharp FR, et al. Gene expression profiling of blood for the prediction of ischemic stroke. Stroke 2010;41:2171–2177.
    • Laskowitz, DT, Kasner SE, Jach EC, et al, for the BRAIN Study Group. Clinical usefulness of a biomarker-based diagnostic test for acute stroke: the Biomarker Rapid Assessment in Ischemic Injury (BRAIN) study. Stroke 2009;40:77–85.
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