Sixteen patients were studied by multitracer positron emission tomography (PET) within 6-48 (mean of 23) h of onset of a hemispheric ischemic stroke and again 13-25 (mean of 15.6) days later. Cerebral blood flow (CBF), cerebral blood volume (CBV), cerebral metabolic rate of oxygen (CMRO2), oxygen extraction fraction (OEF), and cerebral metabolic rate of glucose (CMRglc) were measured each time by standard methods, and the sets of brain slices obtained at the two studies were matched using a three-dimensional alignment procedure. On matched brain slices, regions of interest (ROIs) for infarct and peri-infarct tissue, contralateral mirror regions, and major brain structures were outlined. In the core of infarction, blood flow and metabolism were significantly lower than in the corresponding contralateral regions at the first study, and did not change during the observation period. In the peri-infarct tissue, CMRO2 was moderately decreased at the first measurement; over time, the CMRO2 deteriorated progressively while flow did not change. When peri-infarct regions were selected on the basis of increased OEF (25 +/- 29.8% above corresponding contralateral regions) on the early scans, the CBF was significantly decreased (23 +/- 6.6%) while the CMRO2 showed only a slight difference from the mirror region. Within the observation period, the CBF improved but the CMRO2, OEF, and CMRglc deteriorated. Only in a few regions with increased OEF and slightly impaired CMRO2 was metabolism preserved close to normal values. These data from repeat PET studies in reproducibly defined tissue compartments furnish evidence of viable tissue in the border zone of ischemia up to 48 h after stroke. While this viable peri-infarct tissue exhibits some potential for effective treatment of ischemic stroke, therapeutic routines available today cannot prevent subsequent metabolic derangement and progression to necrosis. Multitracer PET studies identifying viable tissue could be of value in the development of effective treatment of ischemic stroke.

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The microPET R4 scanner is a dedicated positron emission tomograph (PET) for studies of rodents. A number of scanner parameters such as spatial resolution, sensitivity, scatter, and count rate performance were determined in this work, which showed that the microPET R4 is a suitable PET scanner for small animals like mice and rats. In the center of the field of view (FOV) a maximal sensitivity of 43.66 cps/kBq for a centered point source was calculated from a measurement with a germanium-68 line source within an energy widow of 250-750 keV. A spatial resolution of 1.85 mm full-width at half-maximum (FWHM) in the axial direction and 1.66 mm FWHM in the transaxial direction was measured in the center with a 1-mm-diameter sodium-22 point source. Within the inner 20 mm of the FOV the volumetric resolution is better than 15.6 micro l, corresponding to a linear resolution of less than 2.5 mm in all three dimensions. Images of a high-resolution phantom and from mice and rat studies illustrate the good performance of the scanner. A maximal noise equivalent count rate (NECR) was reached at 174 kcps for a mouse phantom and at 93 kcps for a rat phantom (energy window 250-750 keV). Scatter fractions were measured between 0.30 and 0.42 for an energy window of 250-750 keV and phantom diameters similar to mice and rats. A comparison with the microPET P4 model for primates illustrates the gain in sensitivity due to a smaller detector ring diameter but also the changes in NECR.

Experimental models of focal cerebral ischemia have provided important data on early circulatory and biochemical changes, but typically their correspondence with metabolic and hemodynamic findings in stroke patients has been poor. To fill the gap between experimental studies at early time points and rather late clinical studies, we repeatedly measured CBF, CMRO2, oxygen extraction fraction (OEF), cerebral blood volume (CBV), and CMRglc in six cats before and up to 24 h after permanent middle cerebral artery (MCA) occlusion (MCAO), using the 15O steady state and [18F]fluorodeoxy-glucose methods and a high-resolution positron emission tomography (PET) scanner. Likewise, three sham-operated control cats were studied during the same period. Final infarct size was determined on serial histologic sections. In the areas of final glucose metabolic depression that were slightly larger than the histologic infarcts, mean CBF dropped to approximately 40% of control values immediately on arterial occlusion. If further decreased to < 20% during the course of the experiment. This progressive ischemia was most conspicuous in border zones. CMRO2 fell to a lesser degree (55%), eventually reaching approximately 25% of its control level. At early stages, OEF increased mainly in the center of ischemia. With time, areas of increased OEF moved from the center to the periphery of the MCA territory. Concurrently, progressive secondary decreases in OEF in conjunction with further reductions of CBF and CMRO2 indicated the development of central necrosis. The findings are highly suggestive of a dynamic penumbra. In five cats with complete MCA infarcts, CBF decreased and OEF increased in the contralateral hemisphere after 24 h, suggesting whole-brain damage. This effect may be explained by the widespread brain edema found histologically in addition to the nonspecific CBF reductions and OEF elevations observed also in the sham-operated controls after 1 day in the experimental condition. In one cat, cortical OEF increased only transiently. Normal CMRO2 and CMRglc were eventually restored, and the final infarct was small. This study demonstrates that acute regional pathophysiologic changes can be repeatedly assessed by multivariate PET in cats. Viable tissue can be detected up to several hours after MCA occlusion, and the transition of misery-perfused regions into necrosis or preserved tissue can be followed over time. The present results support the concept of a dynamic penumbra, in which for up to 24 h tissue damage spreads progressively from the center to the periphery of ischemia. Sequential high-resolution PET provides insight into the dynamics of regional pathophysiology and may thus further the development of rational therapeutic strategies.