Rainer Wagner

Progressive Derangement of Periinfarct Viable Tissue in Ischemic Stroke

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.

Dynamic Penumbra Demonstrated by Sequential Multitracer PET after Middle Cerebral Artery Occlusion in Cats

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]fluorodeoxyglucose 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 ∼40% of control values immediately on arterial occlusion. It 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 ∼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.

Regional Kinetic Constants and Cerebral Metabolic Rate for Glucose in Normal Human Volunteers Determined by Dynamic Positron Emission Tomography of [18F]-2-Fluoro-2-Deoxy-D-Glucose

Using dynamic [18F]fluorodeoxyglucose (FDG) positron emission tomography with a high-resolution, seven-slice positron camera, the kinetic constants of the original three-compartment model of Sokoloff and co-workers (1977) were determined in 43 distinct topographic brain regions of seven healthy male volunteers aged 28–38 years. Regional averages of the cerebral metabolic rate for glucose (CMRglu) were calculated both from individually fitted rate constants (CMRglukinetic) and from activity maps recorded 30–40 min after FDG injection, employing a four-parameter operational equation with standard rate constants from the literature (CMRgluautoradiographic). Metabolic rates and kinetic constants varied significantly among regions and subjects, but not between hemispheres. k1 ranged between 0.0485 ± 0.00778 min−1 in the oval center and 0.0990 ± 0.01347 min−1 in the primary visual cortex. k2 ranged from 0.1198 ± 0.01533 min−1 in the temporal white matter to 0.1472 ± 0.01817 min−1 in the cerebellar dentate nucleus. k3 was lowest (0.0386 ± 0.01482 min−1) in temporal white matter and highest (0.0823 ± 0.02552 min−1) in the caudate nucleus. Maximum likelihood cluster analysis revealed four homogeneous groups of brain regions according to their respective kinetic constants: (1) white matter and mixed brainstem structures; (2) cerebellar gray matter and hippocampal formations; (3) basal ganglia and frontolateral and primary visual cortex; and (4) other cerebral cortex and thalamus. Across the entire brain, k1 and k2 were positively correlated (r = 0.79); k1 and k3 showed some correlation (r = 0.59); but no significant linear association was found between k2 and k3. A strong correlation with CMRglu could be demonstrated for k1 (r = 0.88) and k3 (r = 0.90), but k2 was loosely correlated (r = 0.56). CMRglu kinetic ranged from 17.0 ± 2.45 μmol/100 g/min in the occipital white matter to 41.1 ± 5.62 μmol/100 g/min in the frontolateral cortex. In most regions the mean values of CMRglu kinetic did not differ significantly from CMRglu autoradiographic. With few exceptions, however, within-region variance was significantly less for CMRglu kinetic than for CMRglu autoradiographic, suggesting greater individual reliability of results obtained by the kinetic approach.

Estimation of Local Cerebral Glucose Utilization by Positron Emission Tomography of [18F]2-Fluoro-2-deoxy-D-glucose: A Critical Appraisal of Optimization Procedures

Various approaches estimating local cerebral glucose utilization by positron emission tomography of labeled deoxyglucose are compared. Autoradiographic methods that predict the glucose utilization rate from a single scan are unreliable in pathologic tissue because of abnormal values of the model rate constants. A normalization procedure using the ratio of measured tissue activity to activity calculated with standard rate constants is proposed to readjust the values of the rate constants. Reliable estimates of metabolic rates can be obtained from dynamic recordings of tracer uptake. In the graphic approach, metabolic rate can be derived from the slope of a segment of a transformed uptake curve, which becomes linear at 15–20 min after intravenous tracer injection, with an accuracy comparable with that in complete dynamic studies. However, by recording and analyzing full-length uptake curves, in addition to metabolic rate, the model rate constants can be determined regionally. The physiological significance of those parameters is demonstrated in crossed cerebellar deactivation in 30 patients with supratentorial infarcts. Mild hypometabolism both within the ischemic lesion and in the morphologically intact cerebellum is accompanied by a reduction of the phosphorylation rate only. Severe metabolic depression, by contrast, affects both cerebellar transport and phosphorylation processes, whereas in the cerebrum, only the rate constant k1 is significantly correlated with the degree of metabolic disturbance.

Qualitative [18F]FDG positron emission tomography in primary breast cancer: clinical relevance and practicability

Positron emission tomography (PET) using fluorine-18 2-deoxy-2-fluoro-d-glucose (FDG) is of potential value for the diagnosis of malignant tumours. The aim of this study was to evaluate the use of FDG PET in patients with breast tumours, appraising its applicability in visualising primary carcinomas and regional metastases in a clinical setting. Results of FDG PET were compared with those of mammography, breast ultrasonography and histology in 30 patients with inconclusive breast findings. For PET, transmission and emission images were taken in one or two scan positions, depending on the available time and the clinical status of patients. PET showed focal FDG uptake with high contrast in 21 of 23 primary carcinomas. In one patient, only PET correctly visualized multifocal disease (three foci, Ø 0.4–1 cm). The accuracy of PET in the detection of primary breast cancer was 90%, and in the detection of involved axillary lymph nodes, 94%. All metastases (lymph nodes, lungs, bones, soft tissues) covered by the field of view and demonstrated by other methods (X-ray, computed tomography, magnetic resonance imaging, bone scan) showed FDG uptake. In three patients, only PET initiated further diagnostic procedures. The results indicate that FDG PET can provide a rapid diagnostic study (45–60 min) and allows accurate tumour staging of several organ systems for primary tumour and metastases with a single imaging study in a routine clinical setting.

Repeat positron emission tomographic studies in transient middle cerebral artery occlusion in cats: residual perfusion and efficacy of postischemic reperfusion.

The wider clinical acceptance of thrombolytic therapy for ischemic stroke has focused more attention on experimental models of reversible focal ischemia. Such models enable the study of the effect of ischemia of various durations and of reperfusion on the development of infarctions. We used high-resolution positron emission tomography (PET) to assess cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2), oxygen extraction fraction (OEF), and cerebral metabolic rate of glucose (CMRglc) before, during, and up to 24 h after middle cerebral artery occlusion (MCAO) in cats. After determination of resting values, the MCA was occluded by a transorbital device. The MCA was reopened after 30 min in five, after 60 min in 11, and after 120 min in two cats. Whereas all cats survived 30-min MCAO, six died after 60-min and one after 120-min MCAO during 6–20 h of reperfusion. In those cats surviving the first day, infarct size was determined on serial histologic sections. The arterial occlusion immediately reduced CBF in the MCA territory to <40% of control, while CMRO2 was less affected, causing an increase in OEF. Whereas in the cats surviving 24 h of reperfusion after 60- and 120-min MCAO, OEF remained elevated throughout the ischemic episode, the initial OEF increase had already disappeared during the later period of ischemia in those cats that died during the reperfusion period. After 30-min MCAO, the reperfusion period was characterized by a transient reactive hyperemia and fast normalization of CBF, CMRO2, and CMRglc, and no or only small infarcts in the deep nuclei were found in histology. After 60- and 120-min MCAO, the extent of hyperperfusion was related to the severity of ischemia, decreased CMRO2 and CMRglc persisted, and cortical/subcortical infarcts of varying sizes developed. A clear difference was found in the flow/metabolic pattern between surviving and dying cats: In cats dying during the observation period, extended postischemic hyperperfusion accompanied large defects in CMRO2 and CMRglc, large infarcts developed, and intracranial pressure increased fatally. In those surviving the day after MCAO, increased OEF persisted over the ischemic episode, postischemic hyperperfusion was less severe and shorter, and the perfusional and metabolic defects as well as the final infarcts were smaller. These results stress the importance of the severity of ischemia for the further course after reperfusion and help to explain the diverging outcome after thrombolysis, where a relation between the residual flow and the effectiveness of reperfusion was also observed.

Regional cerebral glucose metabolism in man during wakefulness, sleep, and dreaming

Regional cerebral glucose metabolism was measured by positron emission tomography in 4 healthy male volunteers, both during wakefulness and sleep, using the 2-deoxy-D-[2-18F]glucose method. While 3 of the subjects did not report dreaming and, during sleep stages I-IV of variable duration, exhibited a non-selective decrease in metabolic rates averaging 12.6 +/- 4.73% (mean +/- S.D.) for the entire brain, the fourth volunteer who experienced an extended nightmare during his sleep examination showed a generalized increase in cerebral glucose utilization ranging from 2.1% in lentiform nucleus to 30.0% in the superior frontal cortex, with a weighted whole brain average of 16.4%. These findings suggest that energy metabolism in the human brain is generally depressed during slow-wave sleep as opposed to a--possibly differential--activation during dreaming.

QT Dispersion Is Determined by the Extent of Viable Myocardium in Patients With Chronic Q-Wave Myocardial Infarction

BACKGROUND QT dispersion is lower in patients with successful thrombolysis after acute myocardial infarction, suggesting that QT dispersion may be determined by the extent of viable and scarred myocardium. METHODS AND RESULTS To test this hypothesis, QT dispersion was measured in a 12-lead resting ECG in 44 patients with chronic Q-wave myocardial infarction. To assess the extent of viable and scarred myocardium, all patients underwent F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET). In addition, all patients had revascularization of the infarct-related artery and repeated angiography 4 months later. QT dispersion was lower (53+/-20 versus 94+/-24 ms, P<.0001) in patients with evidence of a substantial amount of viable myocardium in the infarct region as demonstrated by PET (average FDG uptake > or = 50% of normalized, maximum FDG uptake) than in patients with only minimal residual viability. Average FDG uptake of the infarct region and FDG defect size were significantly related to QT dispersion (r=.64, P<.0001; r=.67, P<.0001), whereas ejection fraction was not (r<.1, P=NS). QT dispersion of < or = 70 ms had a sensitivity of 85% and a specificity of 82% to predict viable myocardium in the infarct region. QT dispersion was also lower in patients with improvement of left ventricular function 4 months after revascularization (54+/-21 versus 88+/-30 ms, P=.0003). QT dispersion of < or = 70 ms had a sensitivity of 83% and a specificity of 71% to predict improvement of left ventricular function. CONCLUSIONS QT dispersion is determined by the amount of viable myocardium in the infarct region and may serve as a novel, rapidly available marker of substantial viability in the infarct region of patients with chronic Q-wave myocardial infarction.

Production of 6-[18F]fluoro-l-DOPA and its metabolism in vivo—a critical review

This report critically appraises methods for the synthesis of 6-[18F]fluoro-L-3,4-dihydroxyphenylalanine (6-FDOPA) that are based on labelling by non-regioselective electrophilic fluorination, regioselective fluorodemetalation or nucleophilic substitution. Recommendations for the standardization of labelling procedures, the optimization of radiochemical yield and the assurance of product quality and safety are given. Studies of the metabolism of 6-FDOPA in vivo are also reviewed to emphasize the importance of the biochemical component of the development of this tracer for positron emission tomography (PET).

Improvement of myocardial blood flow to ischemic regions by angiotensin-converting enzyme inhibition with quinaprilat IV: a study using [15O] water dobutamine stress positron emission tomography.

OBJECTIVES This study was designed to analyze the effects of acute angiotensin-converting enzyme (ACE) inhibition on myocardial blood flow (MBF) in control and ischemic regions. BACKGROUND Although animal studies indicate an improvement of MBF to ischemic regions after ACE inhibition, this effect has not been conclusively demonstrated in patients with coronary artery disease. METHODS Myocardial blood flow was analyzed in ischemic and nonischemic regions of 10 symptomatic patients with coronary artery disease using repetitive [15O] water positron emission tomography at rest and during maximal dobutamine stress before and after ACE inhibition with quinaprilat 10 mg i.v. To exclude the possibility that repetitive ischemia may cause an increase in MBF, eight patients underwent the same protocol without quinaprilat (placebo patients). RESULTS Rate pressure product in control and quinaprilat patients was comparable. In placebo patients, repetitive dobutamine stress did not change MBF to ischemic regions (1.41 +/- 0.17 during the first stress vs. 1.39 +/- 0.19 ml/min/g during the second stress, p = 0.93). In contrast, MBF in ischemic regions increased significantly after acute ACE inhibition with quinaprilat during repetitive dobutamine stress (1.10 +/- 0.13 vs. 1.69 +/- 0.17 ml/min/g, p < 0.015). Dobutamine coronary reserve in ischemic regions remained unchanged in placebo patients (1.07 +/- 0.11 vs. 1.10 +/- 0.16, p = 0.92), but increased significantly after quinaprilat (0.97 +/- 0.10 vs. 1.44 +/- 0.14, p < 0.002). Total coronary resistance decreased after ACE inhibition (123 +/- 19 vs. 71 +/- 10 mm Hg x min x g/ml, p < 0.02). CONCLUSIONS Angiotensin-converting enzyme inhibition by quinaprilat significantly improves MBF to ischemic regions in patients with coronary artery disease.