Translation of experimental concepts to clinical stroke

Experimental research has advanced our knowledge about brain physiology and the pathophysiology of brain disorders, but the transfer of this knowledge into clinical application is difficult and often lags behind. One of the reasons is the differences between the brains of experimental animals and man with respect to evolutionary state (non-gyrencephalic vs. gyrencephalic), anatomy (amount of gray vs. white matter), relative size, cellular density, blood supply and metabolism (see Table 1.1); additionally, experimental models in animals cannot be easily compared to complex human diseases often affecting multimorbid patients. The other problem arises from the investigative procedures, which cannot be equally applied in animals and patients. This is especially true when pathophysiological changes obtained by invasive procedures in animals, e.g. by analysis of tissue samples, by autoradiography or by histology, should be related to the course of a disease, but cannot be assessed repeatedly and regionally. To facilitate the transfer of knowledge from experimental neuroscience to

clinical neurology it is necessary to develop methods which can be equally applied in patients and animal models, and which are not invasive and can be performed repeatedly without affecting or harming the object. To this task of transferring experimental results into clinical application, functional imaging modalities are successfully applied.

Positron emission tomography (PET) is still the only method allowing quantitative determination of various physiological variables in the brain and was applied extensively for studies in patients with acute, subacute or chronic stages of ischemic stroke (review in Heiss [61]). The introduction of scanners with high resolution (2.5 to 5 mm for human, 1 mm for animal application) made PET a tool for studying animal models and to compare repeat examinations of various variables from experiments to the course of disease in humans. The regional decrease of cerebral blood flow (CBF) can be directly observed in PET as in other studies (SPECT, PW-MRI, PCT). However, even in early PET studies [90] preserved glucose consumption was observed in regions with decreased flow in the first hours after the ictus. In the 1980s, PET with oxygen-15 tracers became the gold standard for the evaluation of pathophysiological changes in early ischemic stroke [91]. The quantitative measurement of CBF, CMRO2, OEF and CBV permitted the independent assessment of perfusion and energy metabolism, and demonstrated the uncoupling of these usually closely related variables. These studies provided data on flow and metabolic variables predicting final infarction on late CTs (rCBF less than 12ml/(100g min), CMRO2 less than 65 mmol/ (100gmin)). Relatively preserved CMRO2 indicated maintained neuronal function in regions with severely reduced CBF; this pattern was coined "misery perfusion" and served as a definition for the penumbra, which is characterized by increased oxygen extraction fraction (up to more than 80% from the normal 40-50%). Late CT or MRI often showed these regions as morphologically intact.

Sequential PET studies of CBF, CMRO2 and CMRGlc before and repeatedly up to 24 hours after MCA occlusion in cats could demonstrate the development and growth of irreversible ischemic damage. Immediately after MCA occlusion CBF within the supplied territory dropped, but CMRO2 was less diminished and was preserved at an intermediate level. As a consequence, OEF was increased, indicating misery perfusion, i.e. penumbra tissue. With time,

OEF was decreased, a process which started in the center and developed centrifugally to the borderline of the ischemic territory, indicating the conversion into irreversible damage and the growth of the MCA infarct. In experiments with transient MCA occlusion it could be demonstrated that an infarct did not develop when reperfusion was initiated to tissue with increased OEF. Comparable to patients with early thrombolysis, reperfusion could salvage ischemic tissue in the condition of "penumbra" (Figure 1.10). Similar results were obtained in ischemia models of baboons.

In conclusion, PET permits the definition of various tissue compartments within an ischemic territory: irreversible damage by decreased flow and oxygen consumption below critical thresholds; misery perfusion, i.e. penumbra, by decreased flow, but preserved oxygen utilization above a critical threshold, expressed by increased OEF; luxury perfusion by flow increased above the metabolic demand; anaerobic glycolysis by a change in the ratio between glucose metabolism and oxygen utilization. However, PET has severe disadvantages limiting its routine application in patients with stroke: it is a complex methodology, requires multitracer application, and quantitative analysis necessitates arterial blood sampling.

Positron emission tomography (PET) is the only quantitative method to reliably identify irreversible tissue damage and penumbra.

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