Measurement of regional substrate utilization rates by emission tomography.

Emission tomography can be used to monitor, in vivo and regionally, the utilization of metabolic substrates labeled with positron-emitting radioisotopes produced by a cyclotron. The concept was validated by measuring brain glucose utilization with carbon--11-labeled glucose in rhesus monkeys.

Clot-selective coronary thrombolysis with tissue-type plasminogen activator.

Coronary thrombolysis, an intervention that can abort the sequelae of acute myocardial infarction, was accomplished within 10 minutes in dogs by intravenous administration of clot-selective, tissue-type plasminogen activator. In addition to inducing clot lysis, this promising fibrinolytic agent restored intermediary metabolism and nutritional myocardial blood flow, detectable noninvasively with positron tomography, without inducing a systemic fibrinolytic state.

The measure in vivo of regional cerebral oxygen utilization by means of oxyhemoglobin labeled with radioactive oxygen-15.

Regional cerebral oxygen utilization rate is measured in vivo by the following method:A small volume of blood with radioactive oxygen-15-tagged hemoglobin is rapidly injected into the internal carotid artery of the patient under study. The first injection is followed by the injection carried out under identical circumstances but with blood labeled with water-(15)O. After each injection, the distribution of the radioactive label in the brain is measured and recorded, as a function of time, by six collimated scintillation probes placed over the subject's head. The recording, subsequent to the first injection, reflects (a) the arrival of the labeled oxygen into the tissues, (b) its partial conversion into water of metabolism, and (c) the washout of labeled water from the brain. The ratio of the amount of labeled water formed to the amount of oxygen perfusing the tissues, which can be derived from the recording, is a measure of fractional oxygen utilization. The second injection provides a measure of blood flow by the interpretation of the washout of labeled water from brain tissues. The product, fractional oxygen utilization x blood flow x arterial oxygen content, gives a measure of oxygen utilization rate. Some aspects of the validity of this method are tested by the injection of a nondiffusible indicator, carboxyhemoglobin-(15)O. Regional cerebral oxygen utilization rates for a series of patients with cerebral pathology are reported.

Correlation between regional cerebral blood flow and oxidative metabolism. In vivo studies in man.

To test the hypothesis that regional cerebral blood flow (rCBF) is normally regulated by regional metabolic activity, rCBF and the regional cerebral metabolic rate for oxygen (rCMRO2) were compared in selected human subjects. In normal subjects and patients with chronic, stable diseases of brain, rCBF correlated well with rCMRO2. In one individual with mild dementia, rCBF and rCMRO2 were measured before and during exercise of the hand and forearm contralateral to the hemisphere studied. Appropriate parallel changes occurred in both rCBF and rCMRO2 during hand exercise. In patients with acute diseases affecting the hemisphere studied, however, the correlation between rCBF and rCMRO2 was unpredictable.

Temporal dependence of beneficial effects of coronary thrombolysis characterized by positron tomography.

To delineate beneficial effects of intracoronary thrombolysis on myocardial metabolism in vivo and their dependence on the interval after coronary occlusion prior to reperfusion, we studied 23 closed-chest dogs. Coronary occlusion was produced with a thrombogenic copper coil to performance of cardiac positron emission tomography with 11C-palmitate. Jeopardized zones were calculated by summation by myocardial regions exhibiting less than 50 percent of the peak left ventricular wall radioactivity, and residual metabolic activity within jeopardized zones quantified based on the average counts compared with average counts in normal myocardium. After tomography, streptokinase was infused into the coronary artery (4,000 units per minute), resulting in angiographically demonstrable restoration of patency. Repeat tomography performed 90 minutes after the initial study with a second injection of 11C-palmitate demonstrated reduction of jeopardized zones by 51 +/- 6.3 percent (SE) and by 21 +/- 1.8 (p less than 0.01 based on paired comparisons) when refusion was initiated 1 to 2 (in four dogs) or 2 to 4 (in six dogs) hours after occlusion. Metabolic activity in initially jeopardized regions increased by 111 +/- 24.3 percent and 61.8 +/- 12.6 (p less than 0.01 for each). When streptokinase was infused later after occlusion, significant salutary metabolic effects did not occur. These results indicate that positron tomography may be useful in the clinical delineation of the efficacy of thrombolytic therapy in restoring myocardial metabolism and underscore the marked dependence of such efficacy on the duration of the interval of ischemia prior to the onset of reperfusion.

Altered regional myocardial metabolism in congestive cardiomyopathy detected by positron tomography.

The present study was performed to determine whether positron emission tomography performed after intravenous injection of 11C-palmitate permits detection and characterization of congestive cardiomyopathy. Positron emission tomography was performed after the intravenous injection of 11C-palmitate in 13 normal subjects, 17 patients with congestive cardiomyopathy, and six patients with initial transmural myocardial infarction (defined electrocardiographically). Regionally depressed accumulation of 11C-palmitate was assessed, characterized, and quantified in seven parallel transaxial reconstructions in each patient. Normal subjects exhibited homogeneous accumulation of 11C-palmitate within the left ventricular myocardium, with smooth transitions in regional content of radioactivity. Patients with cardiomyopathy exhibited marked spatial heterogeneity of the accumulation of palmitate throughout the myocardium, easily distinguishable from that in normal subjects and distinct from that observed in patients with transmural infarction, in whom discrete regions of depressed accumulation of palmitate were observed with residual viable myocardium accumulating palmitate homogeneously. Patients with cardiomyopathy exhibited a larger number of discrete noncontiguous regions of accumulation of palmitate within the myocardium than either control subjects or patients with transmural infarction (17.4 +/- 0.6 [SEM] versus 11.8 +/- 0.7 versus 10.3 +/- 0.6, p less than 0.005). Similarly, regions of accumulation of palmitate were irregularly shaped in patients with cardiomyopathy, with a longer normalized perimeter than either control subjects or patients with transmural infarction (2.0 +/- 0.05 versus 1.8 +/- 0.06 versus 1.9 +/- 0.09, p less than 0.05). Regional abnormalities of the accumulation of 11C-palmitate could not be explained by regional differences in left ventricular wall motion or myocardial perfusion. Thus, marked heterogeneity of regional myocardial accumulation of 11C-palmitate is detectable and quantifiable in patients with congestive cardiomyopathy by positron emission tomography and may be particularly valuable for early detection and characterization of cardiomyopathy.

Determination of radionuclide concentrations with positron CT scanning (PETT): concise communication.

A series of experiments was undertaken to evaluate the response of a positron emission transverse tomograph (PETT) to measured radionuclide concentrations similar to those encountered in human studies. The correlation between the response of the imaging system (mean PETT number/min), and the concentration of the radioactivity producing the output data, was linear with a computed sensitivity of 2720 PETT number/min, per micronCi/ml, per picture element, for a radionuclide (100% beta+) contained in either of two phantoms and imaged with a reduction of 1.5 cm. It was concluded that the output data are essentially independent of the imaged object's physical dimensions for the range of 18-28-cm diam and faithfully reflect the regional radioactivity concentration within the object, provided valid attenuation correction is achieved and the sampled area is not compromised by the imaging system's limitations of spatial resolution.

A spheroid positron emission tomograph for brain imaging: a feasibility study.

UNLABELLED: It has been long recognized that the primary advantage of imaging the brain with a positron emission tomography using GSO scintillation detectors placed on a spheroid surface is the large solid angle of acceptance for annihilation radiation, which results in improved system sensitivity and image signal-to-noise ratio. In the present study, we investigated spheroid system geometry, detector design and contribution of scattered coincidences. METHODS: Scintillation detector distribution on a spheroidal surface was investigated by approximating the surface by polygons. Finding a suitable crystal for this purpose led to the development of an experimental GSO block-type detector. The fraction of scattered coincidences was experimentally evaluated using phantoms and detector pairs in conjunction with a testing platform, and the relationship between scattered fraction and phantom volume was obtained. RESULTS: Spheroid geometry was best implemented with a polyhedron consisting of a series of consecutive rings formed by trapezoids. An experimental block-type detector with 36 GSO scintillators and four 14-mm-diameter photomultiplier tubes, together with custom electronics, yielded a spatial resolution of 3.4 mm FWHM and an energy resolution of 18% FWHM. Using nearly "ideal" scintillation detectors with a 350-keV threshold, we found the scatter fraction to be 0.32 for a 20-cm uniform phantom, 0.22 for a 15-cm phantom and closely proportional to the square root of the phantom volume. CONCLUSION: For cerebral studies, a spheroid PET using GSO scintillators has several advantages: optimized geometry for sensitivity, a dead-time fivefold smaller than an equivalent BGO system, and appreciably better light output for improved energy resolution and detector identification. The construction of such a system is within the capabilities of present technology.

Feasibility of time-of-flight reconstruction in positron emission tomography.

A feasibility study was carried out to determine whether image quality can be improved by the use of time-of-flight (TOF) information in positron emission tomography (PET). The experiment used two fast cesium fluoride detectors followed by constant-fraction discriminators for coincidence-timing resolutions of 600 to 800 psec full width at half maximum, depending on the energy discrimination level. A point source was scanned to study the spatial response of the point spread function with and without the TOF information for nonfiltered back-projected data. Back-projected images of a simplified chest phantom, 42 cm in diameter and filled with relative activity concentrations of 1.0, and 5, are presented for the unfiltered data to demonstrate the improvement in image quality obtained with the use of TOF. Filtered and reconstructed images of this phantom are also presented to show the relative differences in the images obtained with PET and TOF-PET techniques for similar filter functions.

Design and performance characteristics of a whole-body positron transaxial tomograph.

A whole-body positron-emission transaxial tomograph (PETT III) is described in detail and evaluated in terms of resolution, accuracy, and efficiency. The PETT III utilizes annihilation coincidence detection to provide spatial resolution; high sensitivity is achieved by using 48 Nal(tl) detectors set in a hexagonal array with a multiple-coincidence logic. The assumptions and approximations made in the reconstruction and their effect on image quality are discussed. Phantom studies shows the depth-independent resolution and response of PETT III, as well as its ability to recover activity distribution quantitatively in the cross section measured. Images obtained with patients and normal volunteers show the potential clinical utility of PETT III.

Application of annihilation coincidence detection to transaxial reconstruction tomography.

A study was carried out to investigate the use of annihilation coincidence detection (ACD) in emmision transaxial reconstruction tomography. The ACD was evaluated in terms of spatial resolution and sensitivity with depth, detection efficiency, effect of pulse-height analysis on resolution and efficiency, correction for attenuation, and cold spot contrast. A prototype positron emission transaxial tomograph (PETT) consisting of a hexagonal array of 24 Nal (Tl) detectors employing ACD was constructed. A fast Fourier transform algorithm was employed to generate the reconstructed image. Computer simulations and phantom and animal studies were carried out to demonstrate that this approach yields tomographic radionuclide images that have high resolution and contrast (hot and cold spot) and that are independent of activity above and below the plane examined. The ACD yields a quantitative nuclear medicine imaging device with high detection efficiency. Comparisons are presented between the ACD and the scintillation camera and scanner. Discussion of the possible applications of the PETT in nuclear medicine is included.

Effect of positron range on spatial resolution.

The effect of beta+ range on spatial resolution of imaging systems employing the detection of 511-keV annihilation radiation was determined by measuring the variation in the line-spread functions (LSFs) of positron-emitting radionuclides of 64Cu, 11C, and 15O as compared with the 514-keV gamma-ray emitter 85Sr. These radionuclides have maximum beta+ energies of 0.656, 0.960, and 1.72 MeV, respectively. The LSFs were measured in a tissue-equivalent phantom with high-resolution (approximately 2.4 mm FWHM) and low-resolution (approximately 8.8 mm FWHM) straightbore collimators coupled to a NaI(Tl) detector. Theoretical LSFs for the beta+ ranges were also calculated and convolved with the 85Sr LSF to yield the predicted LSFs for 11C and 15O. The high-resolution study showed a 0% and 2.3% increase in the full-width half-maximum (FWHM) and full-width tenth-maximum (FWO.1M) for the low-energy beta+ of 64Cu and a 37% (FWHM) and 52% (FWO.1M) increase for the high energy beta+ of 15O as compared with 85Sr. However, when the system resolution was decreased to 8.8 mm FWHM, the 64Cu showed no change at FWHM or FWO.1M and the 15O showed a 2.3% (FWHM) and 7.8% (FWO.1M) relative to 85Sr. The predicted LSFs were in good agreement with the experimental. These data indicate that the effect of beta+ range on spatial resolution is minimal unless the beta+ energy is larger than or equal to 1.5 MeV and the system resolution is on the order of a few millimeters.

Tomographic images of blood pool and perfusion in brain and heart.

A whole-body positron-emission transaxial tomograph (PETT III) was used to image the cross-sectional distribution of 13NH3 and 11CO-hemoglobin in the human brain and heart. Carotid and intravenous bolus injections of 13NH3 in the rhesus monkey had shown that 13NH3 is efficiently extracted by the brain and clears from it slowly (half-time, 40-50 min for carotid injections and 60-70 min for intravenous injections). The intravenous tomographic images in humans showed an excellent relationship between 13NH3 uptakes in the cortex, subcortical white matter, cerebellum, and brain stem and normal blood perfusion or flow in these structures. Cerebral lesions with high (metastasis) and low (stroke) blood flows showed correspondingly high and low uptakes of 13NH3. Large- and small-vascular structures of the brain were also clearly seen in 11CO-hemoglobin tomographic images. Normal myocardium and the ventricular chambers were well defined, and a transmural anterior myocardial infarct was clearly shown. The effective combination of positron transaxial tomography and compounds labeled with positron-emitters provides a safe new method for quantitatively imaging hemodynamic and physiologic functions of selected organs with good tomographic image quality.

Transaxial tomographic imaging of canine myocardium with 11C-palmitic acid.

Radiopharmaceuticals incorporated directly into the metabolic pathways in myocardium provide a useful means for evaluating such processes. Palmitic acid, a major physiologic substrate of myocardium, has a well-understood role in myocardial metabolism. Accordingly, 11C-palmitic acid was the substrate chosen for use in conjunction with positron emission transaxial tomography to obtain images of canine myocardium. This procedure provides high-contrast images of tranverse sections of the myocardium, with good target-to-nontarget ratios (in the image), over a period of 5 to 85 minutes. Clearance half-times for blood and myocardial tissue were found to be 4.8 and 330 min, respectively. In normal myocardium, images obtained with 11C-palmitic acid were those obtained with 13NH3 and 11CO-hemoglobin. In vivo images of hearts with myocardial infarcts showed a clear delineration of infarcts and normal tissue.

Carbon-11-labeled methylated polyamine analogs: uptake in prostate and tumor in animal models.

The polyamines putrescine, spermine, and spermidine were methylated by the addition of carbon-11-labeled formaledehyde followed by sodium borohydride. High labeling yields wrbon-11-labeled formaldehyde followed by sodium borohydride. High labeling yields were obtained and the final products were purified by simply boiling the solution. This decomposed the excess sodium borohydride and removed the volatile impurities. The final radiochemical purity of all the methylated compounds was above 85%. All three methyltated compounds accumulated in the prostates of male rats and the distribution of N-methyl-1,4-diaminobutane (the putrescine analog) was very similar to that previously obtained with tritiated putrescine. The uptake of the putrescine analog in both the prostate and in mouse tumor was slightly higher than that obtained with the other two analogs studied. Utilizing a positron transaxial tomographic scanner and the putrescine analog, we have been able to image the prostate gland of a dog.

The origins of positron emission tomography.

The development of positron emission tomography (PET) took place through the combination of the following recognitions: (1) a handful of short-lived, positron-emitting radionuclides, carbon-11, nitrogen-13, and oxygen-15, exhibit chemical properties that render them particularly suitable for the tracing of important physiological pathways, and (2) the radiation emitted as a result of the annihilation of positrons in matter exhibited physical properties that made it well-suited for nuclear medicine imaging, particularly for tomographic reconstruction. The scientific building blocks that were necessary for the structure of PET were contributed over a period of several decades by many investigators in physics, mathematics, chemistry, and fundamental biology.

Special characteristics and potential for dynamic function studies with PET.

The possibility of utilizing the PET approach to the investigation of dynamic physiologic processes has not been limited so far by radiation exposure to the patient but rather considerations by the technical limitations of PET imaging devices. In the past few years, several PET designs have been optimized specifically for fast dynamic studies. The most recent of these designs incorporates cesium fluoride detectors to achieve high counting rate capabilities. At this time, the value of fast dynamic studies with PET can be only theorized but expectations for the modality rest on solid physiologic hypotheses. The incorporation of time-of-flight information into the PET reconstruction process promises to further enhance the capabilities of fast PET devices by the improvement of temporal resolution through signal-to-noise ratio increase. PET devices incorporating time-of-flight information are beyond the drawing board stage and are now under construction.

Basic principles of computed axial tomography.

Computer tomography (CT) is a radiological imaging method which yields transverse tomographic images reflecting with high accuracy the spatial distribution of x-ray attenuation in the part examined. The contrast resolution achieved by CT permits the visualization of soft tissue structure heretofore invisible with conventional radiographic procedure. The CT image is reconstructed by a computer applied algorithm, from a series of x-ray attenuation measurements obtained at different angles around the subject, by means of radiation detectors; The signal to noise ratio for these measurements is optimized by reducing the contribution of scattered radiation and of system noise. The CT principle of image reconstruction is also applicable in nuclear medicine imaging, with the goal of achieving contrast improvement and quantitative assessment of radionuclide distribution over conventional "projection" techniques. In this application, however, the attenuation of the radiation in the tissue interposed between the radionuclide and the detector must be taken into account to yield quantitatively accurate images. Furthermore, the variation of the field of view of the collimator as a function of distance contributes another unwanted variable to the reconstruction process. A mathematically rigorous tomographic reconstruction which would account for these variables is unavailable for gamma ray-emitting radionuclides, although approximate solutions of that problem have led to the satisfactory images of the head. Images of larger inhomogeneous organs are less quantitative. The detection of coincidence annihilation counting of positron-emitting radionuclides allows the accurate correction for the attenuation of that radiation in tissues and permits depth independent collimation which renders these radionuclide particularly suitable for their imaging by CT. A number of CT devices designed for the imaging of positron emitting radionuclides are yielding nuclear medicine images of quality and potential clinical usefulness unequaled by more conventional projection techniques.

Radioactive oxygen-15 in the study of cerebral blood flow, blood volume, and oxygen metabolism.

The short half-life of 15O led early observers to believe that it was unsuitable for use as a biological tracer. However, initial studies with this nuclide demonstrated its potential usefulness for in vivo, regional physiologic measurements. Subsequently, techniques were developed to measure cerebral blood flow (CBF), blood volume, and oxygen metabolism using intracarotid injection of 15O-labeled radiopharmaceuticals and highly collimated scintillation probes to record the time course of radioactivity in the brain. The development of positron emission tomography (PET) made possible the in vivo, noninvasive measurement of the absolute concentration of positron-emitting nuclides. A variety of tracer kinetic models were formulated to obtain physiologic measurements from tomographic images of the distribution of 15O-labeled radiopharmaceuticals in the brain. 15O-labeled carbon monoxide, administered by inhalation, binds to hemoglobin in RBCs, and therefore can be used as a intravascular tracer to measure regional cerebral blood volume (rCBV). Several strategies have been developed to measure regional CBF using 15O-labeled water as an inert, diffusible flow tracer. Regional cerebral oxygen metabolism is measured using scan data obtained following the inhalation of 15O-labeled oxygen; independent determinations of local blood flow and blood volume are also required for this measurement. The tracer kinetic models used to measure rCBV, blood flow, and oxygen metabolism will be described and their relative advantages and limitations discussed. Several examples of the use of 15O tracer methods will be reviewed to demonstrate their widespread applicability to the study of cerebral physiology and pathophysiology.

A new look at the cyclotron for making short-lived isotopes. 1966 -classical article-.

This reprint of an article that first appeared in Nucleonics in 1966 provides a unique perspective of the introduction of the cyclotron into clinical medicine and medical research. The cyclotron offers a potentially powerful tool to biomedical centers. With this accelerator one can produce a variety of short-lived nuclides that are unavailable from other sources.