Early Predictive Biomarkers for Lesion After Transient Cerebral Ischemia

Abstract

Background and Purpose-Despite the improving imaging techniques, it remains challenging to predict the outcome early after transient cerebral ischemia. The aim of this study was thus to identify early metabolic biomarkers for outcome prediction. Methods-We modeled transient ischemic attacks and strokes in mice. Using high-field MR spectroscopy, we correlated early changes in the neurochemical profile of the ischemic striatum with histopathologic alterations at a later time point. Results-A significant increase in glutamine was measured between 3 hours and 8 hours after all ischemic events followed by reperfusion independently of the outcome and can thus be considered as an indicator of recent transient ischemia.On the other hand, a reduction of the score obtained by summing the concentrations of N-acetyl aspartate, glutamate, and taurine was a good predictor of an irreversible lesion as early as 3 hours after ischemia. Conclusions-We identified biomarkers of reversible and irreversible ischemic damage, which can be used in an early predictive evaluation of stroke outcome. (Stroke. 2011;42:799-805.)Key Words: biological markers Ⅲ magnetic resonance spectroscopy Ⅲ middle cerebral artery occlusion Ⅲ transient ischemic attack Ⅲ stroke T he course of ischemic episodes is very variable and it is difficult to predict the outcome of an individual patient early after ischemia and particularly early after reperfusion. A better prediction of the outcome at early time points would greatly facilitate clinical decisions. Moreover, this would help to distinguish transient ischemic attacks (TIAs) from stroke, refine patient selection for neuroprotection trials, and eventually help to identify patients more likely to benefit from future neuroprotective approaches.Several cerebral imaging techniques are available for the diagnosis and management of patients with stroke. 1 At late time points, the established lesion can be visualized both by T2-weighted images and CT. At early time points, before reperfusion, perfusion CT or perfusion-weighted MR images are used to measure perfusion and allow an estimation of damaged tissue and tissue at risk. 2 Diffusion-weighted MR images (DWI), and to some extent diffusion tensor imaging, monitor disturbances of ion homeostasis, water distribution, and tissue microstructure. The apparent diffusion coefficient (ADC) measured from DWI decreases immediately after the onset of ischemia and its decrease is proportional to the severity of ischemia. 3 A combination of DWI and perfusionweighted MR imaging techniques is used to detect tissue at risk where perfusion is decreased but water diffusion is still normal. 3 These techniques convey a good spatial resolution, are highly sensitive, and give information on the localization and extent of the lesion, but the estimation of the severity of ischemia is not very reliable insomuch as DWI hyperintensities are often reversible. 4 Moreover, detection of only half of the TIAs is possible even when using a combination of DWI and perfusion-weighted imaging. 5 S...

Longitudinal neurochemical modifications in the aging mouse brain measured in vivo by 1H magnetic resonance spectroscopy

“…An independent noninvasive measure of both and also their ratio at high-magnetic field strength may provide a more specific marker to indicate neuronal function and dysfunction (as glutamate and glutamine are mostly located in neurons and glia, respectively). For example, impaired neurotransmission and excitotoxicity after an ischemic insult lead to transient glutamate decrease and glutamine accumulation (Berthet et al, 2011;Lei et al, 2009). In line with this idea, disturbed glutamatergic neurotransmission in schizophrenia leads to altered levels of glutamine, glutamate, and most notably of Gln/Glu, as observed in translational and clinical 1 H MRS studies (Bustillo et al, 2009;Hashimoto et al, 2005;Lutkenhoff et al, 2008;Shirayama et al, 2010;Tayoshi et al, 2009).…”

“…This supports the use of the neurochemical profile as region-and time-specific biomarker and, indeed, its noninvasive detection by magnetic resonance spectroscopy (MRS) has emerged as an important research tool in translational neuroscience. Neurochemical profiling has thus been successfully used to reliably probe brain biochemical modifications upon disease and/or treatment monitoring in mice (Berthet et al, 2011;Zacharoff et al 2012), rats Rao et al, 2011), or humans (Bustillo et al, 2009;Seaquist et al, 2005). Each neuropathology has different etiology, is region specific and occurs with most prominence at a particular age range.…”

The neurochemical profile quantified by in vivo 1H NMR spectroscopy

“…Sibtain et al, 2007) and to decrease in neuropathological conditions, correlating with the degree of degeneration in humans (Bruhn et al, 1989;Gideon et al, 1992Gideon et al, , 1994Horská et al, 2009;Kantarci, 2007) and rodents (e.g. Berthet et al, 2011;Lei et al, 2009;Tkáč et al, 2007). In addition, after transient ischemia and brain injury without neuronal death, NAA levels are able to recover (Brulatout et al, 1996;De Stefano et al, 1995), suggesting it as a marker of neuronal functionality rather than neuronal density.…”

Infarct Volume Prediction by Early Magnetic Resonance Imaging in a Murine Stroke Model Depends on Ischemia Duration and Time of Imaging

“…[17][18][19][20][21] Full recovery of ADC at 3 hours after MCAO onset has been reported for MCAO duration of 8 to 30 minutes in rats and mice. [22][23][24] Of note, this does not reflect complete tissue recovery, as MR spectroscopy may still detect significant changes in neurochemical profiles. 22,25 The initial as well as the secondary decline of ADC has been shown to be associated with ATP depletion but not secondary deterioration of perfusion in rats.…”

“…[22][23][24] Of note, this does not reflect complete tissue recovery, as MR spectroscopy may still detect significant changes in neurochemical profiles. 22,25 The initial as well as the secondary decline of ADC has been shown to be associated with ATP depletion but not secondary deterioration of perfusion in rats. 26 Our CBF data at 6 hours after reperfusion (Figure 3; Figure II in the online-only Data Supplement) confirm this notion for mice.…”