title: Defining the ischemic penumbra using magnetic resonance oxygen metabolic index.
abstract: OBJECTIVE
  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 (CMRO2), 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.
authors.affiliation: From the Biomedical Research Imaging Center and Departments of Radiology (H.A., Y.C., W.L.), Biostatistics (H.Z.), and Neurology (W.J.P., W.L.), University of North Carolina at Chapel Hill; Department of Neurology (A.L.F., G.K., N.K., J.-M.L.), Department of Radiology (R.P., K.D.V., C.P.D., J.-M.L.), Department of Emergency Medicine (P.P.), and School of Medicine (A.L.F., G.K., N.K., J.-M.L., R.P., K.D.V., C.P.D., J.-M.L., A.M.S., P.P.), Washington University, St. Louis, MO; and Emergency Department, Barnes-Jewish Hospital, St. Louis, MO (J.W.).
authors.forename: Hongyu
authors.initials: H
authors.lastname: An
authors.affiliation: From the Biomedical Research Imaging Center and Departments of Radiology (H.A., Y.C., W.L.), Biostatistics (H.Z.), and Neurology (W.J.P., W.L.), University of North Carolina at Chapel Hill; Department of Neurology (A.L.F., G.K., N.K., J.-M.L.), Department of Radiology (R.P., K.D.V., C.P.D., J.-M.L.), Department of Emergency Medicine (P.P.), and School of Medicine (A.L.F., G.K., N.K., J.-M.L., R.P., K.D.V., C.P.D., J.-M.L., A.M.S., P.P.), Washington University, St. Louis, MO; and Emergency Department, Barnes-Jewish Hospital, St. Louis, MO (J.W.).
authors.forename: Andria L
authors.initials: AL
authors.lastname: Ford
authors.affiliation: From the Biomedical Research Imaging Center and Departments of Radiology (H.A., Y.C., W.L.), Biostatistics (H.Z.), and Neurology (W.J.P., W.L.), University of North Carolina at Chapel Hill; Department of Neurology (A.L.F., G.K., N.K., J.-M.L.), Department of Radiology (R.P., K.D.V., C.P.D., J.-M.L.), Department of Emergency Medicine (P.P.), and School of Medicine (A.L.F., G.K., N.K., J.-M.L., R.P., K.D.V., C.P.D., J.-M.L., A.M.S., P.P.), Washington University, St. Louis, MO; and Emergency Department, Barnes-Jewish Hospital, St. Louis, MO (J.W.).
authors.forename: Yasheng
authors.initials: Y
authors.lastname: Chen
authors.affiliation: From the Biomedical Research Imaging Center and Departments of Radiology (H.A., Y.C., W.L.), Biostatistics (H.Z.), and Neurology (W.J.P., W.L.), University of North Carolina at Chapel Hill; Department of Neurology (A.L.F., G.K., N.K., J.-M.L.), Department of Radiology (R.P., K.D.V., C.P.D., J.-M.L.), Department of Emergency Medicine (P.P.), and School of Medicine (A.L.F., G.K., N.K., J.-M.L., R.P., K.D.V., C.P.D., J.-M.L., A.M.S., P.P.), Washington University, St. Louis, MO; and Emergency Department, Barnes-Jewish Hospital, St. Louis, MO (J.W.).
authors.forename: Hongtu
authors.initials: H
authors.lastname: Zhu
authors.affiliation: From the Biomedical Research Imaging Center and Departments of Radiology (H.A., Y.C., W.L.), Biostatistics (H.Z.), and Neurology (W.J.P., W.L.), University of North Carolina at Chapel Hill; Department of Neurology (A.L.F., G.K., N.K., J.-M.L.), Department of Radiology (R.P., K.D.V., C.P.D., J.-M.L.), Department of Emergency Medicine (P.P.), and School of Medicine (A.L.F., G.K., N.K., J.-M.L., R.P., K.D.V., C.P.D., J.-M.L., A.M.S., P.P.), Washington University, St. Louis, MO; and Emergency Department, Barnes-Jewish Hospital, St. Louis, MO (J.W.).
authors.forename: Rosana
authors.initials: R
authors.lastname: Ponisio
authors.affiliation: From the Biomedical Research Imaging Center and Departments of Radiology (H.A., Y.C., W.L.), Biostatistics (H.Z.), and Neurology (W.J.P., W.L.), University of North Carolina at Chapel Hill; Department of Neurology (A.L.F., G.K., N.K., J.-M.L.), Department of Radiology (R.P., K.D.V., C.P.D., J.-M.L.), Department of Emergency Medicine (P.P.), and School of Medicine (A.L.F., G.K., N.K., J.-M.L., R.P., K.D.V., C.P.D., J.-M.L., A.M.S., P.P.), Washington University, St. Louis, MO; and Emergency Department, Barnes-Jewish Hospital, St. Louis, MO (J.W.).
authors.forename: Gyanendra
authors.initials: G
authors.lastname: Kumar
authors.affiliation: From the Biomedical Research Imaging Center and Departments of Radiology (H.A., Y.C., W.L.), Biostatistics (H.Z.), and Neurology (W.J.P., W.L.), University of North Carolina at Chapel Hill; Department of Neurology (A.L.F., G.K., N.K., J.-M.L.), Department of Radiology (R.P., K.D.V., C.P.D., J.-M.L.), Department of Emergency Medicine (P.P.), and School of Medicine (A.L.F., G.K., N.K., J.-M.L., R.P., K.D.V., C.P.D., J.-M.L., A.M.S., P.P.), Washington University, St. Louis, MO; and Emergency Department, Barnes-Jewish Hospital, St. Louis, MO (J.W.).
authors.forename: Amirali Modir
authors.initials: AM
authors.lastname: Shanechi
authors.affiliation: From the Biomedical Research Imaging Center and Departments of Radiology (H.A., Y.C., W.L.), Biostatistics (H.Z.), and Neurology (W.J.P., W.L.), University of North Carolina at Chapel Hill; Department of Neurology (A.L.F., G.K., N.K., J.-M.L.), Department of Radiology (R.P., K.D.V., C.P.D., J.-M.L.), Department of Emergency Medicine (P.P.), and School of Medicine (A.L.F., G.K., N.K., J.-M.L., R.P., K.D.V., C.P.D., J.-M.L., A.M.S., P.P.), Washington University, St. Louis, MO; and Emergency Department, Barnes-Jewish Hospital, St. Louis, MO (J.W.).
authors.forename: Naim
authors.initials: N
authors.lastname: Khoury
authors.affiliation: From the Biomedical Research Imaging Center and Departments of Radiology (H.A., Y.C., W.L.), Biostatistics (H.Z.), and Neurology (W.J.P., W.L.), University of North Carolina at Chapel Hill; Department of Neurology (A.L.F., G.K., N.K., J.-M.L.), Department of Radiology (R.P., K.D.V., C.P.D., J.-M.L.), Department of Emergency Medicine (P.P.), and School of Medicine (A.L.F., G.K., N.K., J.-M.L., R.P., K.D.V., C.P.D., J.-M.L., A.M.S., P.P.), Washington University, St. Louis, MO; and Emergency Department, Barnes-Jewish Hospital, St. Louis, MO (J.W.).
authors.forename: Katie D
authors.initials: KD
authors.lastname: Vo
authors.affiliation: From the Biomedical Research Imaging Center and Departments of Radiology (H.A., Y.C., W.L.), Biostatistics (H.Z.), and Neurology (W.J.P., W.L.), University of North Carolina at Chapel Hill; Department of Neurology (A.L.F., G.K., N.K., J.-M.L.), Department of Radiology (R.P., K.D.V., C.P.D., J.-M.L.), Department of Emergency Medicine (P.P.), and School of Medicine (A.L.F., G.K., N.K., J.-M.L., R.P., K.D.V., C.P.D., J.-M.L., A.M.S., P.P.), Washington University, St. Louis, MO; and Emergency Department, Barnes-Jewish Hospital, St. Louis, MO (J.W.).
authors.forename: Jennifer
authors.initials: J
authors.lastname: Williams
authors.affiliation: From the Biomedical Research Imaging Center and Departments of Radiology (H.A., Y.C., W.L.), Biostatistics (H.Z.), and Neurology (W.J.P., W.L.), University of North Carolina at Chapel Hill; Department of Neurology (A.L.F., G.K., N.K., J.-M.L.), Department of Radiology (R.P., K.D.V., C.P.D., J.-M.L.), Department of Emergency Medicine (P.P.), and School of Medicine (A.L.F., G.K., N.K., J.-M.L., R.P., K.D.V., C.P.D., J.-M.L., A.M.S., P.P.), Washington University, St. Louis, MO; and Emergency Department, Barnes-Jewish Hospital, St. Louis, MO (J.W.).
authors.forename: Colin P
authors.initials: CP
authors.lastname: Derdeyn
authors.affiliation: From the Biomedical Research Imaging Center and Departments of Radiology (H.A., Y.C., W.L.), Biostatistics (H.Z.), and Neurology (W.J.P., W.L.), University of North Carolina at Chapel Hill; Department of Neurology (A.L.F., G.K., N.K., J.-M.L.), Department of Radiology (R.P., K.D.V., C.P.D., J.-M.L.), Department of Emergency Medicine (P.P.), and School of Medicine (A.L.F., G.K., N.K., J.-M.L., R.P., K.D.V., C.P.D., J.-M.L., A.M.S., P.P.), Washington University, St. Louis, MO; and Emergency Department, Barnes-Jewish Hospital, St. Louis, MO (J.W.).
authors.forename: Michael N
authors.initials: MN
authors.lastname: Diringer
authors.affiliation: From the Biomedical Research Imaging Center and Departments of Radiology (H.A., Y.C., W.L.), Biostatistics (H.Z.), and Neurology (W.J.P., W.L.), University of North Carolina at Chapel Hill; Department of Neurology (A.L.F., G.K., N.K., J.-M.L.), Department of Radiology (R.P., K.D.V., C.P.D., J.-M.L.), Department of Emergency Medicine (P.P.), and School of Medicine (A.L.F., G.K., N.K., J.-M.L., R.P., K.D.V., C.P.D., J.-M.L., A.M.S., P.P.), Washington University, St. Louis, MO; and Emergency Department, Barnes-Jewish Hospital, St. Louis, MO (J.W.).
authors.forename: Peter
authors.initials: P
authors.lastname: Panagos
authors.affiliation: From the Biomedical Research Imaging Center and Departments of Radiology (H.A., Y.C., W.L.), Biostatistics (H.Z.), and Neurology (W.J.P., W.L.), University of North Carolina at Chapel Hill; Department of Neurology (A.L.F., G.K., N.K., J.-M.L.), Department of Radiology (R.P., K.D.V., C.P.D., J.-M.L.), Department of Emergency Medicine (P.P.), and School of Medicine (A.L.F., G.K., N.K., J.-M.L., R.P., K.D.V., C.P.D., J.-M.L., A.M.S., P.P.), Washington University, St. Louis, MO; and Emergency Department, Barnes-Jewish Hospital, St. Louis, MO (J.W.).
authors.forename: William J
authors.initials: WJ
authors.lastname: Powers
authors.affiliation: From the Biomedical Research Imaging Center and Departments of Radiology (H.A., Y.C., W.L.), Biostatistics (H.Z.), and Neurology (W.J.P., W.L.), University of North Carolina at Chapel Hill; Department of Neurology (A.L.F., G.K., N.K., J.-M.L.), Department of Radiology (R.P., K.D.V., C.P.D., J.-M.L.), Department of Emergency Medicine (P.P.), and School of Medicine (A.L.F., G.K., N.K., J.-M.L., R.P., K.D.V., C.P.D., J.-M.L., A.M.S., P.P.), Washington University, St. Louis, MO; and Emergency Department, Barnes-Jewish Hospital, St. Louis, MO (J.W.). weili_lin@med.unc.edu leejm@neuro.wustl.edu.
authors.forename: Jin-Moo
authors.initials: JM
authors.lastname: Lee
authors.affiliation: From the Biomedical Research Imaging Center and Departments of Radiology (H.A., Y.C., W.L.), Biostatistics (H.Z.), and Neurology (W.J.P., W.L.), University of North Carolina at Chapel Hill; Department of Neurology (A.L.F., G.K., N.K., J.-M.L.), Department of Radiology (R.P., K.D.V., C.P.D., J.-M.L.), Department of Emergency Medicine (P.P.), and School of Medicine (A.L.F., G.K., N.K., J.-M.L., R.P., K.D.V., C.P.D., J.-M.L., A.M.S., P.P.), Washington University, St. Louis, MO; and Emergency Department, Barnes-Jewish Hospital, St. Louis, MO (J.W.). weili_lin@med.unc.edu leejm@neuro.wustl.edu.
authors.forename: Weili
authors.initials: W
authors.lastname: Lin
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D002545:Brain Ischemia / Q000175:diagnosis / Q000378:metabolism*; D002544:Cerebral Infarction / Q000175:diagnosis / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000502:physiology*; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D008875:Middle Aged; D010100:Oxygen / Q000378:metabolism*; D011379:Prognosis; D015203:Reproducibility of Results; D020521:Stroke / Q000175:diagnosis / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D010100:Oxygen
keywords: magnetic resonance imaging; reperfusion