In vivo quantitation of regional myocardial blood flow by positron-emission computed tomography.
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Biomedical subjects
Publications and source records attributed to M E Phelps.
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Positron computed tomography (PCT) and F-18 2-fluorodeoxyglucose (FDG) were used to study the living human brain in coronal and transverse sections. Scans taken at 1-cm intervals in both directions clearly delineated the cerebral substructures (e.g., cortical areas, basal ganglia, internal capsule, and cerebellum). A compartmental model was used to calculate local cerebral metabolic rates for glucose from the images. Values agreed well with previous global and local human values and demonstrated metabolic symmetry of the left and right hemispheres at rest. Baseline anatomic maps such as these are a necessary prelude to the study of human brain metabolism in stimulated and pathologic states.
Positron computed tomography was used to investigate changes in the local cerebral metabolic rate for glucose (LCMRGlc) of the visual cortex. Progressive increases in LCMRGlc were found from eyes-closed control to stimulation with white light, alternating black/white checkerboard pattern, and a complex visual scene of a park, with the associative visual cortex increasing at a faster rate than the primary visual cortex as the visual scene complexity increased. A graded decrease in LCMRGlc of the visual cortex was found with a stepwise deletion of spontaneous cell firing at the retinal, geniculate and cortical level due to lesions. Left/right metabolic symmetry of the visual cortex during monocular stimulation confirms 50% crossing of the human visual system. Neonatal blindness showed no apparent degeneration of the visual cortex and was equivalent to eyes-closed controls. The interictal state of a patient with visual seizures demonstrated a hypometabolic visual cortex with a 2.5-fold increase in metabolism during an ictal visual hallucination.
A new method for attenuation correction in positron computed tomography (PCT) has been developed, and it can improve the quality of PCT images. The method requires a short transmission scan by the PCT system. Then boundaries between tissues with significantly different attenuation coefficients are determined from the transmission image by edge-finding techniques. Attenuation correction factors(ACF) are then calculated using these boundaries and the average attenuation coefficients within the enclosed regions. The method has been tested on computer-simulated data, on scans of phantoms, and on patient studies, and has been found effective in reducing the random noise in transmission measurements and in providing more accurate ACFs than the method using geometric attenuation correction. As a result, transmission scan times can be shortened, inconvenience to patients is reduced, and PCT images are improved.
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Positron emission computed tomography is a new technique of potential value for the noninvasive measurement of myocardial blood flow, mechanical function and, in particular, metabolism. The capability of this new study method is attributable to the technologic innovations of the imaging device and the availability of radioactive tracers that are specific for blood flow and metabolism. The device permits recording of cross-sectional images of the left ventricular myocardium that quantitatively reflect regional tracer tissue concentrations. Use of tracer kinetic models with this new technique permits measurements of regional glucose and fatty acid metabolism of the heart. Positron emission tomography is already an important new tool for investigative studies of cardiac physiology and pathophysiology; its clinical utility remains to be defined.
By means of emission computed tomography (ECT), we used 18F-fluorodeoxyglucose (18FDG) and 13N-ammonia (13NH3) as indicators of abnormalities in local cerebral glucose utilization (LCMRglc) and relative perfusion, respectively. The ECAT positron tomograph was used to scan normal control subject and 10 stroke patients at various times during recovery. In normal subjects, mean CMRglc was 5.28 +/- 0.76 mg per 100 gm tissue per minute (mean +/- SD; N = 8). In patients with stroke, mean CMRglc in the contralateral hemisphere was moderately decreased during the first week, profoundly depressed in irreversible coma, and normal after clinical recovery. Quantification was restricted by incomplete understanding of tracer behavior in diseased brain, but relative local distributions of 18FDG and 13NH3 trapping qualitatively reflected the increases and decreases as well as coupling and uncoupling expected for local alterations in glucose utilization and perfusion in stroke. Early after cerebrovascular occlusion there was a greater decrease in local trapping of 13NH3, than 18FDG within the infarct, probably because of increased anaerobic glycolysis. Otherwise, 18FDG was a more sensitive indicator of cerebral dysfunction than was 13NH3. Hypometabolism, due to deactivation or minimal damage, was demonstrated with the 18FDG scan in deep structures and broad zones of cerebral cortex that appeared normal on x-ray computed tomography and technetium 99m pertechnetate scans. In its present state of development, the 18FDG ECT method should aid in defining the location and extent of altered brain in studies of disordered function after stroke. With improved knowledge of tracer behaviour in diseased brain, the method has promise for mapping the response to therapeutic intervention and increasing our understanding of how the human brain responds to stroke.
Seventeen patients with partial epilepsy had electroencephalographic (EEG) monitoring concurrent with cerebral positron emission computed tomography (PECT) after 18F-fluorodeoxyglucose (18FDG) and 13N-ammonia (13NH3) were given intravenously as indicators of local cerebral glucose utilization (LCMRglc) and relative perfusion, respectively. In 12 of 15 patients who had unilateral or focal electrical abnormalities, interictal 18FDG scan patterns clearly showed localized regions of decreased (14 to 58%) LCMRglc that correlated anatomically with the eventual EEG localization. These hypometabolic zones appeared normal on x-ray computed tomography in all but 3 patients and were unchanged on 18FDG scans repeated on different days. In 5 of 6 patients who underwent anterior temporal lobectomy the interictal 18FDG scan correctly detected the pathologically confirmed lesion as a hypometabolic zone, and removal of the lesion site resulted in marked clinical improvement. In contrast, the ictal 18FDG scan patterns clearly showed foci of increased (82 to 130%) LCMRglc that correlated temporally and anatomically with ictal EEG spike foci and were within the zones of interictal hypometabolism (three studies in 2 patients). 13NH3 distributions paralleled 18FDG increases and decreases in abnormal zones, but 13NH3 differences were of lesser magnitude. When the relationship of 13NH3 uptake to local blood flow found in dog brain was applied as a correction to the patients' 13NH3 scan data, local alterations in perfusion and glucose utilization were usually matched in both the interictal and the ictal state. We conclude that the interictal 18FDG-PECT scan is useful in aiding localization of the dysfunctional cerebral zone most likely to be responsible for seizures in patients being considered for anterior temporal lobectomy. With further development, emission computed tomography may help in better categorizing the various forms of the disorder and in elucidating the basic mechanisms of epilepsy in humans.
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Eight subjects were taught to decrease their heart rates via biofeedback training. Four of these received contingently faded, beat-by-beat analogue feedback and contingent reinforcement each time their performance met a specified and adjusting criterion. The other four received continuous, beat-by-beat analogue feedback, but not the contingent reinforcement. Subjects in the two groups were yoked to ensure equal densities of reinforcement. Subjects in the first group were asked to decrease heart rates 15% from baseline and were then trained using only 75%, 50% and 25% of beat-by-beat feedback. It was hypothesized that the immediate reinforcement of appropriate behavior and the contingent fading (following mastery) of feedback would aid in the generalization of the response. Following completion of all criterion steps or 10 training sessions, whichever came first, all subjects were tested with no feedback and no contingent reinforcement. The group receiving contingently faded feedback training showed a significantly greater heart rate decrease in the training sessions and also the test session. These results were interpreted as indicating that biofeedback can be conceptualized as an operant conditioning paradigm, and that the use of operant techniques may help subjects produce clinically significant changes.
The utility and ultimate role of positron emission computed tomography in health care delivery is difficult to assess at present and needs to be defined in the future. It would seem that with improvements in instrumentation and physiologic indicators, and with the development of compact, reliable, and generator-like cyclotrons, "physiologic tomography" will become more widely applicable. Physiologic tomography of the heart undoubtedly represents an important new tool for investigative studies that will improve our understanding of cardiac physiology in health and disease. The quantiative aspects as well as simultaneous evaluation of more than one segment of myocardial performance, e.g., simultaneous study of mechanical function, blood flow, and metabolism and their interdependency, will provide new insights into myocardial physiology. Because many of the cardiovascular disorders may originate at the cellular or metabolic level, it is hoped that this technique will serve as a means for the early detection of cardiac disease, perhaps at a stage when it is still amenable to therapy.
Three 5'-phosphorodiamidate derivatives of 5-fluoro-2'-deoxyuridine (FdUrd), 5-fluoro-2'-deoxyuridine 5'-phosphorodiamidate (4a), 5'-phosphorodiimidazolidate (4b), and 5'-phosphorodimorpholidate (4c), were synthesized by aminolysis of 5-fluoro-2'-deoxyuridine 5'-phosphorodichloridate with the respective amine. In culture, these 5'-phosphorodiamidates inhibited the growth of murine leukemia (L5178Y) cells. 5-Fluoro-2'-deoxyuridine 5'-phosphorodiamidate (4a) was the most active derivative and, on a molar basis, produced a cytostatic effect comparable to that of FdUrd and 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUrd-5'-P). Compounds 4b and 4c were less active than 4a, with relative rates of activity 4a > 4b > 4c that corresponded to their rates of hydrolysis to FdUrd-5'-P. None of the 5'-phosphorodiamidates inhibited thymidylate synthetase of concentrations up to 1 mM.
Effect of insufficient transverse sampling on quantitative positron emission computed tomography (ECT) was investigated with computer simulation and measurements on parallel bar and line source phantoms. Aliasing artifacts were observed and were found to be dependent on both the configuration and the location of imaged objects. Images of parallel bar phantoms were found to have aliasing artifacts similar in characteristics to aliasing on one-dimensional signals. In line source images, aliasing effects were manifested as variations in amplitude and full width at half maximum resolution (FWHM) for sources at even slightly different locations in the field of view. It was found that employing sampling distances smaller than one-third of the intrinsic detector FWHM eliminated noticeable aliasing artifacts. Image resolution was also found to be affected by the sampling distance. For a sampling distance equal to one-half of the intrinsic detector FWHM, the imaging FWHM is about 10% worse than the intrinsic FWHM. Selection of sampling distance in noisy environments is discussed. Parallel bar phantoms are shown to have advantages over line sources in the evaluation of sampling and resolution performance of ECT scanners.
A method for the determination of local cerebral metabolic rates of glucose (LCMRGlc) in normal man is described. The method employs [18F]2-fluoro-2-deoxy-D-glucose (FDG) and emission-computed tomography (ECT). FDG was injected intravenously as a bolus. Radioactivities in separate brain regions were measured with ECT. Plasma FDG concentration following injection was measured from blood samples. A mathematical model that describes the kinetics of FDG transports was employed to determine the transport rate constants of FDG and to convert the radioactivity measurements to metabolic rates. The model has taken into account the possible dephosphorylation reaction from FDG-6-PO4 (FDG-6-P) to free FDG in brain tissues. Experiments were performed in 13 normal volunteers. The rate constants of FDG in man were found to be comparable to those of deoxyglucose in rat and in rhesus monkey. The average LCMRGlc in gray and in white matter were found to be 7.30 +/- 1.18 (SD) and 3.41 +/- 0.64 mg/min per 100 g brain tissue, respectively. The subject-to-subject variation of LCMRGlc as measured by the present method was comparable to those of other methods that measure whole-brain CMRGlc.
Local cerebral blood volume (CBV) was mapped in 10 normal subjects and in 30 patients after head injury. In normal subjects, the mean CBV was 4.34 ml/100 gm. The coefficient of variation was 12% for the group mean, and 3% for values obtained in duplicate studies of individuals. Patients with head injuries were divided into three groups according to the stage of their illness: acute illness, early recovery, and later recovery. Averages of mean CBV were within one standard deviation of normal. In contrast, consistent changes were found in serial studies of the mean CBV in the same patient. Compared to recovery values, levels of mean CBV measured soon after injury were reduced, largely at the expense of the gray-matter compartment. In five adults with predominantly unilateral lesions, there was an average early reduction in mean CBV and cerebral blood flow of 15% and 36%, respectively. In three children with diffuse brain swelling, there was an average early mean CBV reduction of 12%; a single child had early increased mean CBV at a time when intracranial pressure was high. Greater changes were seen in local CBV on individual sections. There were mixed zones of hypervolemia and hypovolemia in regions of infarction and intracerebral hematoma. Subdural hematomas had consistent medial margins of increased local CBV, representing dilated blood vessels of the underlying cortex. The presence and displacement of this hypervolemic zone were sensitive indicators of persistent subdural collection and mass effect, even when the collection was lucent to x-ray computed tomography.