Improving the accuracy of perfusion imaging in acute ischemic stroke

The basic premise underlying acute stroke therapy is to salvage some portion of the ischemic region from evolving into infarction, thereby partially or even completely maintaining brain function and improving outcome. The concept of preserving ischemic brain with timely intervention(s) and preventing infarction implies that salvageable tissue is present for a period of time after ischemic stroke onset and directly relates to the proposal of Astrup and colleagues in 1981 of the ischemic penumbra. As proposed by Astrup and colleagues, the ischemic penumbra was defined as a region of reduced cerebral blood flow (CBF) with absent electrical activity but preserved ion homeostasis and transmembrane electrical potentials. Many subsequent definitions for the ischemic penumbra were proposed, but the most clinically relevant ones are potentially reversible ischemic tissue by Hakim and the target of acute stroke therapy by Fisher. The ischemic penumbra concept envisions not only potentially salvageable or at-risk ischemic tissue but also nonviable tissue also identified as the ischemic core. Initial imaging of at-risk and nonviable ischemic tissue was obtained with positron emission tomography (PET) studies that provide quantitative measurements of CBF, the metabolic rate of oxygen (CMRO2), and the rate of oxygen extraction by brain tissue. With PET, penumbral ischemic tissue is characterized by an increase in oxygen extraction fraction (OEF) with reduced CBF and CMRO2, whereas the ischemic core has very low CBF levels and CMRO2 with poor OEF. 5 The CBF levels in the ischemic core were identified to be <12ml/100g/ min, and in the penumbral region the levels were 12 to 25ml/100g/min. A third ischemic tissue type, oligemic or not at-risk tissue, was also identified by PET and is defined as a region with reduced CBF, increased OEF, and normal CMRO2 . PET studies have substantial precision for distinguishing these 3 ischemic regions, but are not practical for clinical acute stroke imaging, because PET scanners are not readily available, and the imaging and data processing time required is too lengthy. With the advent of diffusion/perfusion MRI in the 1990s, hope arose that a clinically available imaging modality with a relatively rapid acquisition and data processing time in experienced hands could be useful for identification of the ischemic penumbra. On diffusionweighted magnetic resonance imaging (MRI) (diffusionweighted imaging; DWI), regions of hyperintensity are readily identified and represent ischemic tissue where ion homeostasis has been lost and cytotoxic edema has occurred. This DWI hyperintense region provides an approximation of the ischemic core, but it must be acknowledged that DWI hyperintensity can be partially reversed with early reperfusion. Recent data from both the EPITHET and DEFUSE studies indicate that the amount of DWI reversal is typically very small and unlikely to be clinically relevant. Therefore, the acute DWI lesion appears to provide a very good surrogate for acute irreversible tissue injury. The fact that DWI lesion can integrate the degree of injury over time provides a distinct advantage over CBF values that may fluctuate dynamically. For example, a single snapshot of brain perfusion does not provide information regarding the intensity and duration of the blood flow disturbance that occurred during the previous few hours. Bolus contrast perfusion MRI (perfusion-weighted imaging; PWI) provides a qualitative picture of the brain’s microcirculation. Regions of PWI abnormality that are normal on DWI, the PWI/DWI mismatch, can approximate the ischemic penumbra. A key unresolved issue has been how to optimally identify and quantify the PWI abnormality, and multiple different parameters including CBF, mean transit time, time to peak, and Tmax (time-to-maximum of the residue function) maps have been used, as discussed by Dani et al in this issue of Annals of Neurology. Furthermore, it has become clear that a method for quantitative thresholding of perfusion maps is extremely important, because mild disturbances in perfusion, even if persistent, do not result in brain infarction. Recent PET studies have demonstrated that when optimal parameters and thresholds are employed, PWI can provide high sensitivity and specificity for identification of PET-determined penumbral flow. For example, in a recent study that imaged acute stroke patients with both PWI and PET, a receiver operating characteristic analysis yielded an area under the curve of 0.95 for detection of PET-confirmed CBF