Repeat studies in animal models of acute focal ischemia can be compared to incidental studies in the course of ischemic stroke in order to shed light on the development of changes causing ischemic infarcts or recovery of critically perfused tissue. Positron emission tomography (PET) studies of regional cerebral blood flow, cerebral metabolic rate for oxygen, oxygen extraction fraction (OEF), cerebral metabolic rate of glucose and flumazenil (FMZ) binding in the cat middle cerebral artery occlusion (MCAO) model and in patients with acute ischemic hemispheric stroke were reviewed. After permanent MCAO, the development of ‘misery-perfused’ penumbral tissue and its centrifugal conversion into necrosis could be demonstrated, resembling focal pathophysiological changes in patients with ischemic attacks. In the experimental model and in vascular insults in humans, a chance of recovery existed if collateral perfusion developed spontaneously within the first hours. In transient MCAO, reperfusion was only effective in preventing infarction when it was initiated as long as misery perfusion persisted; in these cases tissue was salvaged and large infarcts did not develop. In the other instances when oxygen metabolism broke down, and an increased OEF was no longer seen, reperfusion even at levels above preocclusion had no effect, and large space-occupying infarcts developed. These experimental findings are comparable to the variable outcome after thrombolytic therapy; if reperfusion is achieved within the therapeutic window of tissue viability, large infarcts are prevented and complete or partial recovery can be achieved. In the experimental model of focal ischemia and in human stroke, FMZ can be utilized as a marker of neuronal integrity. If FMZ binding in the cortex is decreased below 4 times the mean value of white matter in the acute stage, permanent infarcts were observed on late CT/MRI; this irreversible damage could not be prevented by thrombolytic therapy. These results demonstrated that PET studies in suitable ischemia models in cats can help to explain various courses and diverging outcomes of acute ischemic stroke. Comparable findings from experimental ischemia and human stroke may affect the selection of appropriate therapeutic strategies.

Keywords:
Focal ischemia, Penumbra, Early damage, Neuronal integrity, Multitracer PET, Animal model, Ischemic stroke, Reperfusion, Thrombolytic therapy
1.
Comar D, Mazière M, Godot JM, Berger G, Soussaline F, Menini C, Arfel G, Naquet R: Visualization of 11C-flunitrazepam displacement in the brain of the live baboon. Nature 1979;280:329–331.
2.
Ehrin E, Farde L, De Paulis T, Eriksson L, Greitz T, Johnström P, Litton JE, Nilsson JLG, Sedvall G, Stone-Elander S, Ögren S-O: Preparation of 11C-labelled raclopride, a new potent dopamine receptor antagonist: Preliminary PET studies of cerebral dopamine receptors in the monkey. Int J Appl Radiat Isot 1985;36:269–273.
3.
Fowler JS, Arnett CD, Wolf AP, Shiue DY, MacGregor RR, Halldin C, Langström B, Wagner HN Jr: A direct comparison of the brain uptake and plasma clearance of N-[11C]methylspiroperidol and [18F]N-methylspiroperidol in baboon using PET. Int J Rad Appl Instrum B 1986;13:281–284.
4.
Moerlein SM, Stöcklin G, Pawlik G, Wienhard K, Heiss W-D: Regional cerebral pharmacokinetics of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine as examined by positron emission tomography in a baboon is altered by tranylcypromine. Neurosci Lett 1986;66:205–309.
5.
van Lingen A, Ziegler S, Cherry SR, Green MV (eds): High Resolution Imaging in Small Animals with PET, MR and Other Modalities. Proceedings of the Amsterdam Meeting, Sept 27–29, 1999, Academisch Ziekenhuis Vrije Universiteit, Amsterdam.
6.
Wienhard K, Dahlbom M, Eriksson L, Michel Ch, Bruckbauer T, Pietrzyk U, Heiss W-D: The ECAT EXACT HR: Performance of a new high resolution positron scanner. J Comput Assist Tomogr 1994;18:110–118.
7.
Graf R, Kataoka K, Rosner G, Heiss W-D: Cortical deafferentation in cat focal ischemia: Disturbance and recovery of sensory functions in cortical areas with different degrees of cerebral blood flow reduction. J Cereb Blood Flow Metab 1986;6:566–573.
8.
Baron JC, Frackowiak RSJ, Herholz K, Jones T, Lammertsma AA, Mazoyer B, Wienhard K: Use of PET methods for measurement of cerebral energy metabolism and hemodynamics in cerebrovascular disease. J Cereb Blood Flow Metab 1989;9:723–742.
9.
Frackowiak RSJ, Lenzi GL, Jones T, Heather JD: Quantitative measurement of regional cerebral blood flow and oxygen metabolism in man using 15O and positron emission tomography: Theory, procedure, and normal values. J Comput Assist Tomogr 1980;4:727–736.
10.
Herscovitch P, Markham J, Raichle ME: Brain blood flow measured with intravenous H215O. 1. Theory and error analysis. J Nucl Med 1983;24:782–789.
11.
Reivich M, Kuhl D, Wolf A, Greenberg J, Phelps M, Ido T, Casella V, Fowler J, Hoffman E, Alavi A, Som P, Sokoloff L: The [18F]fluorodeoxyglucose method for the measurement of local cerebral glucose utilization in man. Circ Res 1979;44:127–137.
12.
Sette G, Baron JC, Young AR, Miyazawa H, Tillet I, Barré L, Travère JM, Derlon JM, MacKenzie ET: In vivo mapping of brain benzodiazepine receptor changes by positron emission tomography after focal ischemia in the anesthetized baboon. Stroke 1993;24:2046–2058.
13.
Heiss W-D, Graf R, Wienhard K, Löttgen J, Saito R, Fujita T, Rosner G, Wagner R: Dynamic penumbra demonstrated by sequential multitracer PET after middle cerebral artery occlusion in cats. J Cereb Blood Flow Metab 1994;14:892–902.
14.
Reinoso-Suárez F: Topographischer Hirnatlas der Katze. Darmstadt, Merck, 1961.
15.
Heiss W-D, Huber M, Fink G, Herholz K, Pietrzyk U, Wagner R, Wienhard K: Progressive derangement of periinfarct viable tissue in ischemic stroke. J Cereb Blood Flow Metab 1992;12:193–203.
16.
Heiss W-D, Graf R, Löttgen J, Ohta K, Fujita T, Wagner R, Grond M, Wienhard K: Repeat positron emission tomographic studies in transient middle cerebral artery occlusion in cats: Residual perfusion and efficacy of postischemic reperfusion. J Cereb Blood Flow Metab 1997;17:388–400.
17.
Powers WJ, Press GA, Grubb RL Jr, Gado M, Raichle ME: The effect of hemodynamically significant carotid artery disease on the hemodynamic status of the cerebral circulation. Ann Intern Med 1987;106:27–35.
18.
Heiss W-D, Rosner G: Functional recovery of cortical neurons as related to degree and duration of ischemia. Ann Neurol 1983;14:294–301.
19.
The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group: Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995;333:1581–1587.
20.
Heiss W-D, Grond M, Thiel A, von Stockhausen H-M, Rudolf J, Ghaemi M, Löttgen J, Stenzel C, Pawlik G: Tissue at risk of infarction rescued by early reperfusion: A positron emission tomography study in systemic recombinant tissue plasminogen activator thrombolysis of acute stroke. J Cereb Blood Flow Metab 1998;18:1298–1307.
21.
Löttgen J, Pietrzyk U, Herholz K, Wienhard K, Heiss W-D: Estimation of ischemic cerebral blood flow using [15O]water and PET without arterial blood sampling; in Carson RE, Daube-Witherspoon ME, Herscovitch P (eds): Quantitative Functional Brain Imaging with Positron Emission Tomography. San Diego, Academic Press, 1998, pp 151–154.
22.
Heiss W-D, Graf R, Fujita T, Ohta K, Bauer B, Löttgen J, Wienhard K: Early detection of irreversibly damaged ischemic tissue by flumazenil positron emission tomography in cats. Stroke 1997;28:2045–2051.
23.
Heiss W-D, Grond M, Thiel A, Ghaemi M, Sobesky J, Rudolf J, Bauer B, Wienhard K: Permanent cortical damage detected by flumazenil positron emission tomography in acute stroke. Stroke 1998;29:454–461.
24.
Heiss W-D, Kracht L, Grond M, Rudolf J, Bauer B, Wienhard K, Pawlik G: Early [11C]flumazenil/H2O positron emission tomography predicts irreversible ischemic cortical damage in stroke patients receiving acute thrombolytic therapy. Stroke 2000;31:366–369.
25.
Siesjö BK: Pathophysiology and treatment of focal cerebral ischemia. Part II: Mechanisms of damage and treatment. J Neurosurg 1992;77:337–354.
26.
Choi D: Antagonizing excitotoxicity: A therapeutic strategy for stroke? Mt Sinai J Med 1998;65:133–138.
27.
Barone FC, Feuerstein GZ: Inflammatory mediators and stroke: New opportunities for novel therapeutics. J Cereb Blood Flow Metab 1999;19:819–834.
28.
Baird AE, Warach S: Magnetic resonance imaging of acute stroke. J Cereb Blood Flow Metab 1998;18:583–609.
29.
Hossmann K-A, Hoehn-Berlage M: Diffusion and perfusion MR imaging of cerebral ischemia. Cerebrovasc Brain Metab Rev 1995;7:187–217.
30.
Baron JC: Mapping the ischaemic penumbra with PET: Implications for acute stroke treatment. Cerebrovasc Dis 1999;9:193–201.
31.
Cherry SR, Shao Y, Silverman RW, Meadors K, Siegel S, Chatziioannou A, Young JW, Jones WF, Moyers JC, Newport D, Boutefnouchet A, Farquhar TH, Andreaco M, Paulus MJ, Binkley DM, Nutt R, Phelps ME: MicroPET: A high resolution PET scanner for imaging small animals. IEEE Trans Nucl Sci 1997;44:1161–1166.
32.
Tenjin H, Ueda S, Mizukawa N, Imahori Y, Hino A, Ohmori Y, Yasukochi K: Positron emission tomographic measurement of acute hemodynamic changes in primate middle cerebral artery occlusion. Neurol Med Chir (Tokyo) 1992;32:805–810.
33.
Pappata S, Fiorelli M, Rommel T, Hartmann A, Dettmers C, Yamaguchi T, Chabriat H, Poline JB, Crouzel C, DiGiamberardino L, Baron JC: PET study of changes in local brain hemodynamics and oxygen metabolism after unilateral middle cerebral artery occlusion in baboons. J Cereb Blood Flow Metab 1993;13:416–424.
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2001
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