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Neurology Today:
doi: 10.1097/01.NT.0000388907.49858.4e
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Brain Choline Concentration Found to be Early Marker of Ischemia and Infarct Expression

Fallik, Dawn

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When a patient has a stroke, doctors use diffusion and perfusion-weighted MRI to detect brain infarction. The challenge is predicting what areas of the brain may be affected.

But now a new study focuses on metabolic imaging, hoping to be able to pinpoint areas of the brain on the verge of infarction with the ultimate goal of returning blood flow to that area and saving the tissue.

The small study, published in the Sept. 7 issue of Neurology, found that levels of choline were elevated in peri-ischemic normal-appearing brains that became infarcted by three to seven days. Stroke experts, who were not involved in the study, said it was an interesting and promising move in using metabolic imaging as a predictive measure.

“It's an early phase study and it's intriguing,” said Ralph Sacco, MD, chairman of neurology at the University of Miami. “It's surprising that they didn't see more changes, but it's a step in the right direction.”

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STUDY METHODS, RESULTS

The research team, led by Joanna M. Wardlaw, MD, professor of applied neuroimaging at the University of Edinburgh and director of its Brain Imaging Research Centre, used proton MR spectroscopy (1HMRS) to see if they could measure changes earlier than would be visible on diffusion tensor imaging (DTI.)

The goal was to identify “tissue at risk,” the investigators wrote. …“Currently there is no reliable, sensitive and specific method for early on-invasive determination of tissue at risk: the mismatch between diffusion- and perfusion-weighted imaging (DWI/PWI mismatch) is still being evaluated, and there are no CSF or blood markers that diagnose stroke or predict prognosis.”

The researchers performed multi-voxel proton MR spectroscopy (1HMRS) on 31 patients within four to 26 hours after onset of acute ischemic stroke, and DTI at three to seven days. They compared concentrations of lactate, N-acetyl aspartate, choline, and creatine in normal-appearing voxels that became infarcted (“infarct expansion”) with normal-appearing voxels around the infarct that remained healthy (“non-expansion”) on follow-up DTI.

On follow-up, they determined that the mean brain choline concentration in “healthy-looking” voxels that eventually became infarcted increased by .48 units for each change in expansion category from non-expansion to partial to complete expansion.

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A SIGNATURE FOR ‘ISCHEMIC PENUMBRA?’

In an accompanying editorial, doctors questioned whether the rise in choline could be a signature for “ischemic penumbra,” the area of the brain that lays between dead tissue caused by lack of blow flow and normal-tissue brain.

“How do we predict who is going to benefit from acute stroke therapy? Are there biochemical changes that we can detect with non-invasive imaging that will predict whether that part of the brain will go on to infarction?” asked Lawrence R. Wechsler, MD, co-author of the editorial and director of the University of Pittsburgh Medical Center (UPMC) Stroke Institute. “All these things are being examined, but none are established as definitive predictors of what's going to happen.”

Dr. Wechsler said the higher amounts of choline made sense, as the chemical is an integral part of cell membrane structure and involved in the metabolic process that leads to the structural integrity and viability of cells.

Dr. Sacco agreed. He noted that choline measurements have been used as a predictive measure in brain tumors, but people have not applied those metabolic standards to stroke, in part because of logistical time issues.

The surprise, Dr. Wechsler said, was that lactate did not turn out to be a predictive measure. “This is only half the formula,” he added. “The second half is to make this a clinically useful technique.”

Joseph Broderick, MD, professor and chairman of the University of Cincinnati's neurology department, said the choline increase was interesting, but the next step would be to find whether the increase tells neurologists whether the brain tissue was salvageable or not.

DR. JOSEPH BRODERICK...
DR. JOSEPH BRODERICK...
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“When you do MR imaging, there are a lot of different approaches to look at in how the molecules move in the brain,” he said. “You're looking at how easily the molecules move and if their movement is restricted or changes, there's a signal change that shows as a bright area.

“But that generation does not always indicate the pieces of the brain that are dead or are about to die. Diffusion weight is not an absolute marker — some areas might be saved, but a number might go on to be dead tissue.”

One of the obstacles mentioned by the study authors was the time factor. The mean time of imaging from stroke onset was 16.3 hours, and four patients were imaged within two hours.

In the study, obtaining the 1HMRS data did not take longer than 10 minutes, according to the authors. But their approach needed specialist off-line image processing. Eventually, they said they hope with routine practice, doctors would be able to see results within a reasonable time after MRI.

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FUTURE PROSPECTS

All the doctors interviewed for this article said that while the 1HMRS imaging might not be doable in all clinical situations, that technology was changing rapidly and they could see a day when metabolic imaging was part of standard stroke analysis.

“Right now it's not something that every community hospital with an MRI scanner can easily do,” said Dr. Wechsler, “but it could get to the point where automated software can do this.”

There are many next steps and questions that arise from the study, Dr. Broderick said. What's the level or cutoff for choline elevation? How can doctors use the measurement to determine whether brain tissue is salvageable or not? Does it change the time window for treatment? And if it's alive, is this an area that would be amenable to tPA? To immediate reperfusion? Would it be better to cool the brain down?

“Even if it is feasible to see if metabolic levels can be measured accurately how could that help make decisions about what the brain is going to do?” Dr. Broderick said.

At the end of the day, Dr. Wechsler said, while 40 to 50 percent of patients have good outcomes from stroke incidents, that means 50 to 60 percent do not. “Can we do better than that?” he asked. “That's what we're looking for — how can we predict those patients who are likely to do well if we treat them.”

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ARTICLE IN BRIEF

Investigators found the elevated measures of choline, as measured by proton MR spectroscopy, served as a biomarker for ischemia and infracted tissue three to seven days post-stroke.

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REFERENCES:

Baraszewski B, Thomas RGR, Wardlaw JM, et al. Brain choline concentration: early quantitative marker of ischemia and infarct expansion? Neurology 2010; 75:850-856.
Barber PH, Wechsler LR. The ischemic penumbra: From celestial body to imaging technology. Neurology 2010; 75:844-845.

©2010 American Academy of Neurology

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