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Objective  Accurate identification of the ischemic penumbra, the therapeutic target in acute clinical stroke, is of critical importance to identify patients who might benefit from reperfusion therapies beyond the established time windows. Therefore, we aimed to validate magnetic resonance imaging (MRI) mismatch–based penumbra detection against full quantitative positron emission tomography ( 15 O‐PET), the gold standard for penumbra detection in acute ischemic stroke.    Methods  Ten patients (group A) with acute and subacute ischemic stroke underwent perfusion‐weighted (PW)/diffusion‐weighted MRI and consecutive full quantitative  15 O‐PET within 48 hours of stroke onset. Penumbra as defined by  15 O‐PET cerebral blood flow (CBF), oxygen extraction fraction, and oxygen metabolism was used to validate a wide range of established PW measures (eg, time‐to‐maximum [Tmax]) to optimize penumbral tissue detection. Validation was carried out using a voxel‐based receiver‐operating‐characteristic curve analysis. The same validation based on penumbra as defined by quantitative  15 O‐PET CBF was performed for comparative reasons in 23 patients measured within 48 hours of stroke onset (group B).    Results  The PW map Tmax (area‐under‐the‐curve = 0.88) performed best in detecting penumbral tissue up to 48 hours after stroke onset. The optimal threshold to discriminate penumbra from oligemia was Tmax >5.6 seconds with a sensitivity and specificity of >80%.    Interpretation  The performance of the best PW measure Tmax to detect the upper penumbral flow threshold in ischemic stroke is excellent. Tmax >5.6 seconds–based penumbra detection is reliable to guide treatment decisions up to 48 hours after stroke onset and might help to expand reperfusion treatment beyond the current time windows.  ANN NEUROL 2019;85:875–886.

Penumbra detection in acute stroke with perfusion magnetic resonance imaging: Validation with 15 O‐positron emission tomography