August 1, 2012 — Researchers are making headway in finding a marker of blood-brain barrier (BBB) disruption that may distinguish an ischemic stroke from a transient ischemic attack (TIA) or an intracerebral hemorrhage, and may help to determine its severity.
A new proof-of-concept study shows that plasma concentrations of precursor fragments of the neuropeptide enkephalin (proenkephalin A, or PENK-A) are elevated in patients with acute stroke compared with those with TIA and nonischemic events.
Elevated PENK-A levels correlated with stroke severity and with brain lesion size, and they predicted mortality and more severe functional disability.
"Our data are intriguing and may help to advance the use of biomarkers in the clinical evaluation of stroke patients," lead author Wolfram Doehner, MD, PhD, from the Center for Stroke Research, in Berlin, Germany, told Medscape Medical News. "There is clearly an unmet need to establish biomarker-guided prognostic and functional evaluations for patients with stroke."
The new report was published in the July 24 issue of Journal of the American College of Cardiology.
This study included 189 patients who presented to the emergency department of the University Hospital Tübingen, in Germany, with symptoms of acute stroke, from whom blood was drawn within an hour, and who underwent computed tomography (CT) scanning within 90 minutes of admission.
Researchers measured plasma concentrations of PENK-A and precursor fragments of another bioactive neuropeptide — protachykinin A (PTA). As mature neuropeptides, both are involved in nociception and immune stimulation and have been implicated in the pathophysiology of Parkinson's disease, Alzheimer's disease, and severe head injury, he said.
Although the mature neuropeptides are degraded within minutes, their precursor fragments are much more stable and represent neuropeptide synthesis in stoichiometric relations. "They are therefore well suited as biomarkers and may be suitable for measurement in clinical settings," said Dr. Doehner.
A reliable biomarker could help assess BBB damage in patients arriving to the emergency department with a suspected stroke. It is believed that acute BBB changes are regulated by mast cells through release of inflammatory and vasoactive mediators.
The normal range of PENK-A is 41.8 to 131 pmol/L, and for PTA, the normal range is 30.8 to 179.2 pmol/L. Normal ranges are not dependent on age or sex.
At 3 months, researchers assessed clinical outcomes using chart analyses and a structured telephone interview, along with functional outcomes using the Modified Rankin Scale (mRS). They adjusted for age, sex, risk factors, and several clinical parameters, including arterial hypertension, diabetes mellitus, hyperlipidemia, family history of coronary artery disease, smoking, and medication use.
Of 189 patients assessed, 65.6% presented with a stroke, 8.5% with a TIA, and 25.9% with a nonischemic event.
Concentrations of PENK-A were significantly elevated in patients with stroke compared with patients with TIA and those with nonischemic events.
Table. PENK-A Levels by Diagnosis
|Group||Median, pmol/L||Interquartile Range|
|Stroke||123.8||93 - 160.5|
|TIA||114.5||85.3 - 138.8|
|Nonischemic events||102.8||76.4 - 137.6|
PENK-A, proenkephalin A; TIA, transient ischemic attack.
The PENK-A concentration increased in parallel to increasing severity of stroke, as defined by National Institutes of Health Stroke Scale (NIHSS) classes (P = .002). These associations were not seen with PTA.
PENK-A levels were also significantly elevated in the 24 patients who died during follow-up compared with survivors (146.6 pmol/L vs 112.1 pmol/L), and in the 34 patients who had a recurrent stroke or myocardial infarction (MI) (140.7 pmol/L vs 112.0 pmol/L). For these outcomes, no significant differences were noted for PTA.
After adjustments for age, NIHSS class, and brain lesion size, PENK-A remained significantly predictive of total mortality (hazard ratio [HR], 4.52; 95% confidence interval [CI], 1.1 - 19.0; P = .03) and of the composite endpoint of all-cause mortality, stroke recurrence, and nonfatal MI (HR, 6.65; 95% CI, 1.8 - 24.9; P = .005).
Patients in the highest quartile of PENK-A (greater than 153 pmol/L) had a 3-fold higher risk for mortality and a more than 2-fold higher risk for the composite endpoint compared with those in the lower 3 quartiles.
As for functional outcome, those with the highest quartile of PENK-A had significantly increased risk for developing moderate to higher full functional disability (mRS score of 3 or greater). After adjustment for age and brain lesion size, the highest quartile remained a significant predictor of impaired functional outcome (odds ratio [OR], 2.67; 95% CI, 1.4 - 6.25; P = .02).
Because this was a single-center study involving a relatively small number of patients, the results should be confirmed in larger and multicenter studies, said Dr. Doehner. "Further work is needed to uncover the exact role of PENK-A in the setting of acute stroke."
Because stroke is a leading cause of death and disability, identifying ischemic stroke in the emergency department is hugely important for initiating appropriate therapy as quickly as possible, said Dr. Doehner. Although several candidates for prognostic biomarkers are being investigated, no validated markers are currently in clinical use.
"Unfortunately, we are severely running behind in the use of biomarkers for stroke evaluation compared to acute cardiac events," where biomarkers are being used in clinical decision making, commented Dr. Doehner. "There may be several reasons to explain this, such as the complexity of the pathophysiology of stroke as compared to myocardial infarction."
Too Many Limitations?
Reached for comment on this study, Kerstin Bettermann, MD, PhD, associate professor of neurology at Penn State University, in Hershey, Pennsylvania, applauded the researchers for trying to find a biomarker for stroke but suggested that PENK-A might not be the one, at least not by itself. Dr. Bettermann has published on the topic of stroke biomarkers.
This study had too many design limitations, she told Medscape Medical News. For example, to make diagnoses, the study used CT, which is "not a very reliable reference" because it can miss things, she said.
Another limitation was that the study used just one measurement. "We don't know how this marker develops over time, and the measurement could depend on when you look at it," said Dr. Bettermann.
There was also a "lot of overlap" in interquartile ranges for patients with TIA and those with stroke.
Another drawback, according to Dr. Bettermann, is that the PENK-A marker is not specific for diseases of the brain, which is a "big disadvantage."
Although she found the outcome measures and inclusion of the subgroups "very appropriate," overall Dr. Bettermann thought that the study left a lot of questions unanswered. "This research is moving in the right direction," she said. "We absolutely need this, there's no question. But a lot of additional work needs to be done."
Dr. Doehner received support from the German Ministry of Education and Research, the Verein der Freunde und Förderer der Berliner Charité, and the European Commission. Full disclosures are available on the Journal's Web site. Dr. Bettermann has disclosed no relevant financial relationships.
J Am Coll Cardiol. 2012;60:346-354. Abstract
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