Defining the Ischemic Penumbra Using Magnetic Resonance Oxygen Metabolic Index

Background and Purpose Imaging the ischemic penumbra during hyperacute stroke has been actively investigated because of its potential to individualize therapeutic opportunities beyond populationdefined time-windows. The ischemic penumbra was defined by Astrup as a zone of nonfunctioning but viable tissue that may recover its function if blood flow can be restored, for example, by therapeutic intervention. This concept originated from electrophysiological studies in primates, which revealed 2 cerebral blood flow (CBF) thresholds: a lower threshold of ion-pump failure that was associated with tissue infarction, and an upper threshold denoted by electric failure, but was associated with preserved tissue structure. The initial use of CBF thresholds to define the penumbra was problematic because the threshold delineating the ischemic core changed with increasing duration of ischemia. Subsequent positron emission tomography (PET) studies in animal models and in patients with stroke demonstrated that as CBF dropped in the affected region, oxygen extraction fraction (OEF) increased in attempt to maintain tissue-level metabolism or cerebral metabolic rate of oxygen utilization (CMRO 2 =CBF×OEF×arterial oxygen content). Despite elevation of OEF in the peri-infarct Background and Purpose—Penumbral biomarkers promise to individualize treatment windows in acute ischemic stroke. We used a novel magnetic resonance imaging approach that measures oxygen metabolic index (OMI), a parameter closely related to positron emission tomography–derived cerebral metabolic rate of oxygen utilization (CMRO 2 ), to derive a pair of ischemic thresholds: (1) an irreversible-injury threshold that differentiates ischemic core from penumbra and (2) a reversible-injury threshold that differentiates penumbra from tissue not-at-risk for infarction. Methods—Forty patients with acute ischemic stroke underwent magnetic resonance imaging at 3 time points after stroke onset: <4.5 hours (for OMI threshold derivation), 6 hours (to determine reperfusion status), and 1 month (for infarct probability determination). A dynamic susceptibility contrast method measured cerebral blood flow, and an asymmetrical spin echo sequence measured oxygen extraction fraction, to derive OMI (OMI=cerebral blood flow×oxygen extraction fraction). Putative ischemic threshold pairs were iteratively tested using a computation-intensive method to derive infarct probabilities in 3 tissue groups defined by the thresholds (core, penumbra, and not-at-risk tissue). An optimal threshold pair was chosen based on its ability to predict infarction in the core, reperfusion-dependent survival in the penumbra, and survival in not-at-risk tissue. The predictive abilities of the thresholds were then tested within the same cohort using a 10-fold cross-validation method. Results—The optimal OMI ischemic thresholds were found to be 0.28 and 0.42 of normal values in the contralateral hemisphere. Using the 10-fold cross-validation method, median infarct probabilities were 90.6% for core, 89.7% for nonreperfused penumbra, 9.95% for reperfused penumbra, and 6.28% for not-at-risk tissue. Conclusions—OMI thresholds, derived using voxel-based, reperfusion-dependent infarct probabilities, delineated the ischemic penumbra with high predictive ability. These thresholds will require confirmation in an independent patient sample. (Stroke. 2015;46:00-00. DOI: 10.1161/STROKEAHA.114.008154.)