Article

NR2 Peptide Assay Detects Transient Ischemic Attack and Acute Ischemic Stroke


 

VIENNA—An in vitro assay that detects NR2 peptide, a brain-borne biomarker of neurotoxicity, correlated with early symptoms of multiple transient ischemic attack (TIA) and new acute ischemic lesions confirmed by radiologic findings, investigators reported at the 6th World Stroke Congress.

A Potential Biomarker for Stroke?
Currently, no simple, rapid blood biomarker test can detect acute cere­bral ischemia, differentiate cere­bral ischemia from stroke “mimics,” or predict near-term risk of recurrent TIA or stroke. For patients who present with stroke-like symptoms, use of a biomarker in conjunction with clinical assessment and brain imaging may provide greater diagnostic sensitivity and specificity.

It is well known that N-methyl-d-aspartate (NMDA) receptors are major excitatory neuroreceptors that regulate neuronal electrical signals. Substantial progress in understanding the mechanisms of stroke has been made based on findings of the effects of NMDA receptors on cerebral vascular regulation. NMDA receptors are localized on the surface of epithelia of microvessels that form the blood-brain barrier and control microvessel function. NR2 peptide fragments are rapidly cleaved from the NMDA receptors by thrombin-activated serine proteases due to a cerebral ischemic event. Once released into the bloodstream via the compromised blood-brain barrier within minutes of the onset, NR2 peptides remain detectable in the blood for at least three days after an event.

Increased NR2 peptide levels (> 1.0 ng/mL) have been associated with immediate risk of an acute stroke, whereas levels below 1.0 ng/mL characterize nonischemic events (eg, healthy controls and stroke mimics). This real-time evidence of neurotoxicity underlying cerebral ischemia led to the development of the Gold Dot magnetic-particle (MP)-ELISA test kit (CIS Biotech, Inc, Atlanta), which determines concentrations of NR2 peptide immunochemically in plasma samples.

Elevated NR2 Peptide Level Indicates Acute Ischemic Stroke
In a prospective blind study, Svetlana Dambinova, DSci, PhD, a Visiting Professor at Emory University in Atlanta, along with Joseph D. Weissman, MD, PhD, of DeKalb Medical Center in Decatur, Georgia, and colleagues used the Gold Dot MP-ELISA kit to assess plasma samples from 89 patients; 50 of whom were admitted within 48 hours of an acute ischemic stroke that was defined by imaging. Of these 50 patients, 82% had hypertension, 34% had diabetes, and 30% had both conditions. Mean age was 63. In a group of 30 controls who did not have a stroke (mean age, 57), one person had both preexisting conditions and 33% had controlled hypertension.

Significant differences in median NR2 peptide concentration levels were found between the acute cortical stroke group (4.91 ng/mL) and the control group (0.86 ng/mL). For stroke lesions greater than 2 cc, at a cutoff of 1.0 ng/mL, sensitivity was 98% and specificity was 94%. Elevated amounts of free NR2 peptide correlated with new lesion areas on diffusion-weighted imaging and MRI.

NR2 peptide levels in patients with TIA and ischemic stroke increased significantly. In contrast, patients with intracerebral hemorrhage (ICH) and cranial nerve palsies had levels lower than 0.7 ng/mL, while those with subarachnoid hemorrhage (SAH) had slightly elevated levels (1.11 ng/mL).

When an ROC curve was generated for NR2 peptide relative to neurologic and imaging data for the patients with TIA and ischemic stroke, compared with the control group (ie, those with ICH, SAH, and nerve palsies), the corresponding area under the curve was 0.91. The sensitivity and specificity of the NR2 peptide assay were 83% and 84%, respectively, for TIA/ische­mic stroke versus ICH, SAH, or stroke mimics.

Case Reports
The researchers also described two case reports. The first, an 82-year-old hypertensive patient with a one-month history of crescendo hemispheric TIA, presented following onset of transient left hemiparesis, at which time blood was drawn. NR2 peptide level was 9.1 ng/mL. The hemiparesis cleared completely within 30 minutes following blood draw. Several hours later, the patient had a permanent stroke (NR2 peptide level, 20.5 ng/mL). The NR2 peptide found to be elevated in this case is consistent with the fact that it is released early in the ischemic process when ischemia is still reversible. This is significant in that some previously studied biomarkers are released after relatively late stages of ischemia when cell death has already occurred.

The second case was a 26-year-old female who presented to the hospital with a one-week history of confusion, hemiparesis, altered mental status, and subcortical white matter changes on MRI. On presentation to the emergency department, her NR2 peptide level was greater than 50.0 ng/mL, and it remained high during the first week of hospitalization. Her hospitalization was remarkable for the angiographic demonstration of a vasculitis-like pattern affecting many cerebral vessels that was believed to be secondary to methamphetamine abuse. By the second day of admission (NIH Stroke Scale score, 20), the patient developed a large right hemispheric stroke with some bilateral involvement. The NR2 peptide level remained above the cutoff of 1.0 ng/mL during her second week of hospitalization. Diffusion-weighted imaging and MRI scans at 24 hours and at days 7, 30, and 60 revealed an ischemic lesion. This patient demonstrated a prolonged release of the NR2 peptide in association with amphetamine-associated vasculopathy.

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