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The concept of the ischemic penumbra was formulated on the basis of animal experiments showing functional impairment and electrophysiologic disturbances with decreasing flow to the brain below defined values (the threshold for function) and irreversible tissue damage with blood supply further decreased (the threshold for infarction). The perfusion range between these thresholds was termed the "penumbra," and restitution of flow above the functional threshold was able to reverse the deficits without permanent damage. In further experiments, the dependency of the development of irreversible lesions on the interaction of the severity and the duration of critically reduced blood flow was established, proving that the lower the flow, the shorter the time for efficient reperfusion. As a consequence, infarction develops from the core of ischemia to the areas of less severe hypoperfusion. The translation of this experimental concept as the basis for the efficient treatment of stroke requires methods by which regional flow and energy metabolism can be repeatedly investigated to demonstrate penumbra tissue, which can benefit from therapeutic interventions. Positron emission tomography allows the quantification of regional cerebral blood flow, the regional oxygen extraction fraction, and the regional metabolic rate for oxygen. With these variables, clear definitions of irreversible tissue damage and of critically hypoperfused but potentially salvageable tissue (i.e. the penumbra) in stroke patients can be achieved. However, positron emission tomography is a research tool, and its complex logistics limit clinical routine applications. Perfusion-weighted or diffusion-weighted magnetic resonance imaging is a widely applicable clinical tool, and the "mismatch" between perfusion-weighted and diffusion-weighted abnormalities serves as an indicator of the penumbra. Also computed tomography angiography and computed tomography perfusion imaging can be used to detect areas suspicious of penumbra. The findings with both methods should be validated by positron emission tomography measurements. Several studies included the selection of patients for intravenous thrombolysis on the basis of a perfusion-weighted imaging-diffusion-weighted imaging mismatch or computed tomography perfusion studies. A meta-analysis of several mismatch-based thrombolysis studies of delayed treatment from the DIAS, DIAS-2, DEDAS, EPITHET, and DEFUSE trials revealed increased recanalization. However, this analysis did not confirm an improvement in clinical outcome with delayed thrombolysis. Randomized controlled trials that did enroll patients based on the presence of a target mismatch on multimodal imaging demonstrated a higher benefit of revascularization treatment by comparison with those who did not and demonstrated for the first time that revascularization treatment for occlusion of an internal carotid artery (ICA) or a proximal middle cerebral artery (MCA) was still beneficial from 6 to 24 h after onset among patients in whom the clinical examination and the multimodal brain imaging indicate a persistent penumbra. On this background, the yield of imaging for the selection of patients for a revascularization therapy will be discussed.

Perfusion-weighted (PW) magnetic resonance imaging (MRI) is used to detect penumbral tissue in acute stroke, but the selection of optimal PW-maps and thresholds for tissue at risk detection remains a matter of debate. We validated the performance of PW-maps with 15O-water-positron emission tomography (PET) in a large comparative PET-MR cohort of acute stroke patients. In acute and subacute stroke patients with back-to-back MRI and PET imaging, PW-maps were validated with 15O-water-PET. We pooled two different cerebral blood flow (CBF) PET-maps to define the critical flow (CF) threshold, (i) quantitative (q)CBF-PET with the CF threshold <20 ml/100 g/min and (ii) normalized non-quantitative (nq)CBF-PET with a CF threshold of <70% (corresponding to <20 ml/100 g/min according to a previously published normogram). A receiver operating characteristic (ROC) curve analysis was performed to specify the accuracy and the optimal critical flow threshold of each PW-map as defined by PET. In 53 patients, (stroke to imaging: 9.8 h; PET to MRI: 52 min) PW-time-to-maximum (Tmax) with a threshold >6.1 s (AUC = 0.94) and non-deconvolved PW-time-to-peak (TTP) >4.8 s (AUC = 0.93) showed the best performance to detect the CF threshold as defined by PET. PW-Tmax with a threshold >6.1 s and TTP with a threshold >4.8 s are the most predictive in detecting the CF threshold for MR-based mismatch definition.

In this study, we aimed to assess the detection of crossed cerebellar diaschisis (CCD) following stroke by perfusion-weighted magnetic resonance imaging (PW-MRI) in comparison with positron emission tomography (PET). Both PW-MRI and 15O-water-PET were performed in acute and subacute hemispheric stroke patients. The degree of CCD was defined by regions of interest placed in the cerebellar hemispheres ipsilateral (I) and contralateral (C) to the supratentorial lesion. An asymmetry index (AI=C/I) was calculated for PET-cerebral blood flow (CBF) and MRI-based maps of CBF, cerebral blood volume (CBV), mean transit time (MTT), and time to peak (TTP). The resulting AI values were compared by Bland-Altman (BA) plots and receiver operating characteristic analysis to detect the degree and presence of CCD. A total of 26 imaging procedures were performed (median age 57 years, 20/26 imaged within 48 hours after stroke). In BA plots, all four PW-MRI maps could not reliably reflect the degree of CCD. In receiver operating characteristic analysis for detection of CCD, PW-CBF performed poorly (accuracy 0.61), whereas CBV, MTT, and TTP failed (accuracy <0.60). On the basis of our findings, PW-MRI at 1.5 T is not suited to depict CCD after stroke.