Validation of MRI Determination of the Penumbra by PET Measurements in Ischemic Stroke

Abstract

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 noninvasive methods with which regional flow and energy metabolism can be repeatedly investigated to demonstrate penumbra tissue, which can benefit from therapeutic interventions. PET 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, PET is a research tool, and its complex logistics limit clinical routine applications. Perfusion-weighted or diffusion-weighted MRI is a widely applicable clinical tool, and the "mismatch" between perfusion-weighted and diffusion-weighted abnormalities serves as an indicator of the penumbra. However, comparative studies of perfusion-weighted or diffusionweighted MRI and PET have indicated overestimation of the core of irreversible infarction as well as of the penumbra by the MRI modalities. Some of these discrepancies can be explained by the nonselective application of relative perfusion thresholds, which might be improved by more complex analytic procedures. The heterogeneity of the MRI signatures used for the definition of the mismatch are also responsible for disappointing results in the application of perfusion-weighted or diffusion-weighted MRI to the selection of patients for clinical trials. As long as validation of the mismatch selection paradigm is lacking, the use of this paradigm as a surrogate marker of outcome is limited. ENERGY REQUIREMENTS OF BRAIN TISSUEBecause the energy demand of nervous tissue is very high, sufficient blood supply to the brain must be maintained consistently. The oxygen consumption of the brain is involved almost entirely in the oxidative metabolism of glucose which, in normal physiologic conditions, is the almost exclusive substrate for the energy metabolism of the brain (1). The glucose metabolized in neuronal cell bodies is used mainly to support cellular vegetative and hou...

Oxygen metabolism MRI – A comparison with perfusion imaging in a rat model of MCA branch occlusion and reperfusion

“…We also examined effects of M2CAO and reperfusion on the absolute levels of OEF and CMRO 2 in severely ischemic but still viable tissue. These regions were outlined in CBF maps as tissue with normal perfusion but CBF levels of 12-22ml/100 g/min which is consistent with levels attributed to the penumbra (132). Healthy contralateral regions were used as controls.…”

Stem Cell-Induced Biobridges as Possible Tools to Aid Neuroreconstruction after CNS Injury

“…Formation of a biobridge is a novel mechanism which describes how cell grafts can engage in injury-specific migration between neurogenic and non-neurogenic sites whereby normal cellular motility is restricted. Both in vitro and in vivo results have shown that transplantation of SB623 cells can improve the histopathological and behavioral deficits associated not only with TBI, but also with stroke, spinal cord injury, and Parkinson's disease (Wang et al, 1996; Tang et al, 1998; Chiang et al, 2001; Failor et al, 2010; Rinholm et al, 2011; Xiong et al, 2011; Merson and Bourne, 2014; Buono et al, 2015; Ranasinghe et al, 2015; Heiss and Zaro-Weber, 2017). …”

“…Thus, a more in-depth understanding of the concept of the stem cell-paved biobridge in neurodegenerative diseases potentially amendable by this therapeutic action, including ischemic stroke, hypoxic-ischemic encephalopathy (HIE), and cerebral palsy (CP) among others, may yield important therapeutic benefits (Tajiri et al, 2014). These disorders are each characterized, in part, by sites of cellular degeneration, separated from neurogenic areas of the brain that could otherwise facilitate the recovery of severe damaged cells (Failor et al, 2010; Rinholm et al, 2011; Xiong et al, 2011; Tajiri et al, 2013; Merson and Bourne, 2014; Tajiri et al, 2014; Duncan et al, 2015; Ranasinghe et al, 2015; Heiss and Zaro-Weber, 2017). …”

“…Minutes after infarction, areas with the largest decrease of blood flow are irreversibly damaged resulting in the formation of the necrotic core. Areas that are less damaged and still able to maintain metabolic functions are termed ischemic penumbra which surrounds the necrotic core (Taylor et al, 2008; Broughton et al, 2009; Tajiri et al, 2013, 2014; Duncan et al, 2015; Heiss and Zaro-Weber, 2017). Total or partial circulation blockade within the CNS results in cerebral ischemic injury which instigates deprivation of glucose and oxygen resulting in the activation of complex pathological pathways and neuronal cell death (Xiong et al, 2011; Merson and Bourne, 2014; An et al, 2015; Duncan et al, 2015; Bivard et al, 2016).…”

In vivo electron paramagnetic resonance oximetry and applications in the brain

“…PET imaging measures O 2 by detecting positron emitting radionuclides of a hypoxia biomarker, and has been used extensively and noninvasively in various in vivo brain and ischemic stroke studies 495051525354. Disadvantages to PET imaging is availability and the cost of cyclotrons needed to produce short-lived radionuclides, various interferences in the interpretation of PET imaging data, and PET measures O 2 consumption but not tissue pO 2 .…”