Stroke 2013 July-9


David sherman lecture 2012: the role of positron emission tomography for translational research in stroke.

Stroke. 2012 Sep;43(9):2520-5.

Heiss WD.

Max Planck Institute for Neurological Research, Gleueler Str 50, 50931 Köln, Germany.


The concept of the ischemic penumbra was formulated 30 years ago based on experiments in animal models showing functional impairment and electrophysiological 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 “penumbra”, and restitution of flow above the functional threshold was able to reverse the deficits without permanent damage. However, in further experiments the dependency of the development of irreversible lesions on the interaction of severity and duration of critically reduced blood flow was established, proofing that the lower the flow the shorter the time for efficient reperfusion. Therefore, infarction develops from the core of ischemia to the areas of less severe hypoperfusion. The propagation of irreversible tissue damage is characterised by a complex cascade of interconnected electrophysiological, molecular, metabolic and perfusional disturbances. Waves of depolarisations, the peri-infarct spreading depression like depolarisations, inducing activation of ion pumps and liberation of excitatory transmitters have dramatic consequences as drastically increased metabolic demand cannot be satisfied in regions with critically reduced blood.

The translation of the experimental concept as the basis for efficient treatment of stroke requires non-invasive 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 (PET) allows the quantification of regional cerebral blood flow, the regional metabolic rate for oxygen and the regional oxygen extraction fraction. By these variables a clear definition of irreversible tissue damage and of critically perfused but potentially salvageable tissue (i.e. the penumbra) can be achieved in animal models and stroke patients. Additionally, further tracers can be used for early detection of irreversible tissue damage, e.g. by the central benzodiazepine receptor ligand flumazenil. However, PET is a research tool and its complex logistics limit clinical routine applications. As a widely applicable clinical tool perfusion/diffusion weighted magnetic resonance imaging (PW/DW-MRI) is used, and the “mismatch” between the PW- and the DW-abnormalities served as an indicator of the penumbra. However, comparative studies of PW/DW-MRI and PET pointed to an overestimation of the core of irreversible infarction as well as of the penumbra by MRI modalities. Some of these discrepancies can be explained by unselective application of relative perfusion thresholds, which might be improved by more complex analytical procedures. Heterogeneity of the MRI signatures used for the definition of the mismatch are also responsible for disappointing results in the application of PW/DW-MRI for the selection of patients for clinical trials. As long as a validation of the mismatch selection paradigm is lacking its use as a surrogate marker of outcome is limited.

PMID: 22895998


Wolf-Dieter Heiss-11


Figure 1: a: Activity of a single neuron during graded ischemia before, during and after reversible MCA occlusion; b: Recovery of neuronal function after a limited period of ischemia; c: Diagram of CBF thresholds required for the preservation of function and morphology of brain tissue. The activity of individual neurons is blocked when flow decreases below a certain threshold (dashed line) and returns when flow is raised again above this threshold. The fate of a single cell depends on the duration for which CBF is impaired below a certain level. The solid line separates structurally damaged from functionally impaired, but morphologically intact tissue, the “penumbra”. The dashed line distinguishes viable from functionally impaired tissue.(modified from Heiss and Rosner 1983).


Wolf-Dieter Heiss-22

Figure 2:

Sequential PET images of CBF, CMRO2 and OEF of MCA occlusion in cats compared to images of patients after stroke: Left columns: In the left cat, the progressive decrease of CMRO2 and the reduction of OEF predict infarction and cannot benefit from reperfusion. Only if OEF is increased until start of reperfusion it can be salvaged (right cat). Middle columns: In the patient the areas with preserved OEF are not infarcted and can survive in spontaneous course (posterior part of ischemic cortex in left, anterior part in right patient as indicated  on late MRI and CT). Right columns: In patients receiving rTPA treatment measurements of CMRO2 and OEF are nor feasible, but flow determinations show the effect. If reperfusion occurs early enough and before tissue damage, tissue can be salvaged (left patient). If reperfusion is achieved too late, tissue cannot be salvaged despite hyperperfusion in some parts (right patient).


Wolf-Dieter Heiss-33

Figure 3:

a, b: Volumetric comparison of TTP (MRI) and OEF (PET) images in 2 patients measured in the chronic phase of stroke. In both patients a TTP delay of > 4 seconds indicates a considerable mismatch volume (red contour on TTP images). The mismatch volumes were 473 cm3 for patient a and 199.7 cm3 for patient b. However, only patient b had a corresponding volume of penumbra (260 cm3). c: Volumes of penumbra (black) and mismatch defined by TTP > 4 (gray) in 13 patients: all 13 patients showed mismatch, only 8 patients showed penumbra, which comprised 1 – 75% of the mismatch volume. (modified from Sobesky et al Stroke 2005)

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