Journal of Cerebral Blood Flow & Metabolism (2009) 29, 217–219 & 2009 ISCBFM All rights reserved 0271-678X/09 $32.00 www.jcbfm.com
Commentary
Multimodal magnetic resonance imaging for assessing evolution of ischemic penumbra: a key translational medicine strategy to manage the risk of developing novel therapies for acute ischemic stroke Juan C Chavez1, Margaret M Zaleska2, Xinkang Wang1, Andrew Wood2, Orest Hurko1, Menelas N Pangalos2 and Giora Z Feuerstein1 1
Discovery Translational Medicine, Wyeth Research, Collegeville, Pennsylvania, USA; 2Discovery Neuroscience, Wyeth Research, Princeton, New Jersey, USA
The implicit aim of neuroprotection is to rescue neurons within distressed but still viable tissue, thereby promoting functional recovery upon neuronal salvage. The clinical failure of this approach suggests that previous efforts to develop stroke therapies lacked means to predict success or futility in pre-clinical and early clinical studies. A key translational medicine strategy that can improve predictability relies on imaging methodologies to map the spatiotemporal evolution of the ischemic penumbra. This could serve as a biomarker indicative of neuroprotective potential and could increase likelihood of success in clinical studies by allowing selection of patients who are most likely to respond to therapy. Journal of Cerebral Blood Flow & Metabolism (2009) 29, 217–219; doi:10.1038/jcbfm.2008.103; published online 3 September 2008 Keywords: focal ischemia; neuroprotection; penumbra; MR imaging; translational medicine
The basic concept of ischemic penumbra, tissue damaged but not dead yet, must be regarded as essential to research efforts aimed at developing neuroprotective strategies for the treatment of acute ischemic stroke. This concept emerged from the hypothesis that the tissue surrounding the infarct core remains viable but severely compromised because of metabolic, hemodynamic, and neurochemical alterations characteristic of the ischemic environment (Baron, 2005; Hossmann and Kleihues, 1973). In this region, endogenous protective mechanisms (i.e., local expression of survival factors) and residual collateral blood flow are only able to delay the otherwise inevitable cell death process leading to infarct growth (Baron, 2005; Fisher, 2004). This concept also implies the corollary hypothesis that the penumbra is a region of salvageable tissue that can be rescued if an effective intervention is in Correspondence: Dr JC Chavez, Discovery Translational Medicine, Wyeth Research, 500 Arcola Road S-2348, Collegeville, PA 19468, USA. E-mail:
[email protected] Received 18 June 2008; revised 29 July 2008; accepted 30 July 2008; published online 3 September 2008
place before irreversible damage occurs (Hossmann and Kleihues, 1973). The hope of neuroprotective strategies is the salvage of neurons and other brain cells within the area compromised by the ischemic event, yet sufficiently viable for eventual recovery within a critical time frame. In this context, previous efforts to develop an efficacious neuroprotective agent for ischemic stroke have been plagued by two fundamental gaps: (1) lack of information of the extent of salvageable tissue within the ischemic territory at a time of pharmacological intervention and (2) inability to monitor the spatial and temporal evolution of penumbra in response to any given treatment. From the translational medicine perspective, we can no longer afford to ignore these gaps that augment the risk of failure in future trials with neuroprotective agents. Although there is a growing consensus that quantification of penumbra will be essential for the design of future trials, there is no consensus yet on the precise method by which it should be measured (Wintermark et al, 2008). Reliable detection of the ischemic penumbra might be done by identification of brain regions with reduced cerebral blood flow that have an increased oxygen extraction fraction,
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distinguishing them from the ischemic core where oxygen extraction is greatly diminished or absent (Baron, 2005; Fisher, 2004). Such a task is not easy to accomplish and requires positron emission tomography using 15O as a tracer, a technology that is not practical for acute management of stroke (Ackerman et al, 1981). An alternative approach to penumbral imaging involves echoplanar magnetic resonance that is thought to identify infarcted and hypoperfused but still salvageable tissue by using diffusion weighted (DWI) and perfusion weighted imaging modalities, respectively (Wintermark et al, 2008). DWI measures alterations in the diffusion of water molecules that in the case of ischemia are manifested by hyperintense lesions reflecting a reduction in the apparent diffusion coefficient of water. These changes are primarily due to metabolic failure leading to disruption of ion homeostasis and cytotoxic edema. DWI lesions are believed to represent the non-viable ischemic core, although very early reversibility has been shown in animal models and occasionally in humans (Kidwell et al, 2003). In contrast, perfusion weighted makes use of the signal loss of flow that occurs during the dynamic tracking of the first pass of an intravenous paramagnetic contrast agent. A signal intensity–time curve is obtained from whole brain T2-weighted perfusion scans and used to generate maps of relative cerebral blood volume (CBV), mean transient time (MTT) and regional cerebral blood flow among other parameters. Conceptually, the mismatch between perfusion weighted and DWI signals should provide an index of the extent of penumbra at any time post-stroke and these parameters can also be used to monitor infarct growth over time. Although diffusionweighted image acquisition and generation of apparent diffusion coefficient maps are relatively straightforward procedures, perfusion-weighted data acquisition is a complex process and the parameters used to define perfusion lesions are variable and somewhat arbitrary (Kane et al, 2007). Emerging data from several trials and large observational cohorts suggest that magnetic resonance imaging (MRI)-based mismatch, despite varying definitions and standardization issues, does select patients with the potential to benefit from therapies. For instance, recent results from the Echo-Planar Imaging Thrombolytic Evaluation Trial (EPITHET) provided objective evidence on the use of mismatch in perfusion and diffusion-weighted MRI as a surrogate measure for the extent of the ischemic penumbra. Although echoplanar imaging of thrombolytic evaluation trial failed to demostrate significance for its primary end point related to attenuation of infarct volume growth, secondary analysis showed that response to thrombolysis was significantly associated with improved reperfusion in patients with significant mismatch and this in turn was associated with more favorable clinical outcome (Davis et al, 2008). Clearly, the penumbral Journal of Cerebral Blood Flow & Metabolism (2009) 29, 217–219
selection hypothesis requires confirmation in an adequately powered trial that has a clinical primary end point, but the encouraging results from EPITHET offers a new hope that the mismatch approach could serve to image ischemic penumbra in real time, and hence be used to select patients who are more likely to respond to thrombolysis and perhaps to other types of therapeutic intervention. Although MR-based DWI and perfusion weighted are currently the most widely used imaging methods to assess salvageable tissue, the thresholds between viable and nonviable tissue cannot yet be assessed with reliable accuracy. More importantly, this approach cannot tell us whether the mismatch corresponds to a metabolically active and healthy tissue. An alternative approach for assessing the presence of salvageable penumbra is CT/CT perfusion that is more often used in clinical practice because of its practicality in terms of speed and cost. However, this approach also requires further refining of the thresholds to establish perfusion maps that could improve reproducibility and reliability of the mismatch assessment. Altogether, these uncertainties highlight the need for improved methodology for imaging salvageable tissue as this approach is likely to be an essential component of the path forward for evaluation and development of novel therapeutic agents for acute ischemic stroke. In a recent report, Santosh et al, described a novel approach for the identification of the ischemic penumbra utilizing an MRI technique (oxygen challenge), which detects differences in tissue oxygen extraction from changes in T2* signal intensity (Santosh et al, 2008). This approach provides an index of tissue metabolic capacity based on blood oxygen level dependent imaging and the T2* signal changes in brain associated with ventilating with 100% oxygen versus room air. This technique takes advantage of the different magnetic properties of oxyhaemoglobin (Hb-O2) and deoxyhaemoglobin (Hb) as well as the differences in the (Hb-O2)/(Hb) ratios in different tissue compartments. Because the T2* signal is affected by alterations in the blood (Hb-O2)/(Hb) ratio, T2* signal changes arising from the ‘oxygen challenge’ can provide information on levels of oxygen utilization in injured versus normal tissues. Utilizing this approach, Santosh et al, were able to determine the differential effect of high oxygen on T2* signal intensity on tissue within the ischemic core, penumbra, and contralateral normal hemisphere. The authors observed the greatest increase within penumbral tissue, as defined by diffusion/perfusion MRI mismatch and the least amount of signal increase in the ischemic core. In a second experiment, similar changes in T2* signal intensity were observed when tissue status was confirmed by histological analysis. The approach of using the diamagnetic and paramagnetic effects of high-flow oxygen induced effects on tissue oxygenation status and T2* signal intensity to identify ischemic core
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and penumbra is novel and could provide useful imaging information when used synergistically with diffusion/perfusion MRI. When the ischemic core and penumbra are identified by diffusion/perfusion MRI, it is widely acknowledged that the distinctions represent an approximation. Refining the accuracy in delineation of these areas could have substantial impact toward making better treatment decisions and identifying responders to thrombolysis or other therapies (Wintermark et al, 2008). The encouraging results from Santosh et al will need to be validated with whole brain arterial spinlabeling MRI perfusion and diffusion imaging as the current study was based on signal acquisition from only one arterial spin-labeling slice. Additional experiments to define the precise thresholds for distinguishing between core and penumbral tissue will have to be determined with whole brain imaging and a larger sample size. Replication of these results by other investigators will also be needed, as will extension to a thromboembolic stroke model. Combining MRI identification of the ischemic core and penumbra with recombinant tPA treatment will help to relate the identification of penumbral and core tissue to response to an effective treatment. In other words, does the identification of potentially salvageable ischemic tissue by adding the oxygen challenge effects on T2* imaging alone/or in addition to diffusion/perfusion MRI add to the predictive power of which ischemic tissue will respond to reperfusion therapy? Another potential concern related to this work is that arterial spin-labeling perfusion was used to define the perfusion abnormality on the mismatch. In clinical practice, arterial spin-labeling perfusion is not routinely performed and bolus contrast perfusion MRI is the current clinical method used to define mismatch (Donnan et al, 2008). Thus, it will be necessary to determine the mismatch with bolus contrast perfusion MRI and determine how the oxygen challenge imaging relates to core and penumbra determined by this clinically used approach to penumbral imaging. In conclusion, the results presented by Santosh et al are important and hold great promise for further refining and improving on MRI-based penumbral imaging. As the authors realize, this is a first step that will need to be extended with many additional studies in both animals and patients. In this regard, novel approaches for penumbral imaging will fill an important gap in the efforts to identify an effective stroke therapy. Clearly, the consistent and continued failure of drugs in stroke trials forces us to rethink
and modify our approaches if we are to have any chance of success in stroke intervention in the future.
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Journal of Cerebral Blood Flow & Metabolism (2009) 29, 217–219
