Joanne Markham

Noninvasive quantitation of myocardial blood flow in human subjects with oxygen-15-labeled water and positron emission tomography

Noninvasive measurement of myocardial blood flow in absolute terms (i.e., milliliters per gram per min) has been difficult to accomplish despite the intrinsically quantitative power of positron emission tomography because of the nonphysiologic nature of tracers that have been employed conventionally as well as the limited spatial resolution of currently available instruments. It was previously demonstrated that myocardial blood flow in animals can be quantitated accurately with the diffusible tracer oxygen-15-labeled water (H2(15)O) when the arterial input function and myocardial radiotracer concentration were measured directly. To extend the approach for completely noninvasive measurement of blood flow, a parameter estimation procedure was developed whereby effects of limited tomographic spatial resolution and cardiac motion were compensated for within the operational flow model. In validation studies in 18 dogs, myocardial blood flow measured with positron emission tomography after intravenously administered H2(15)O correlated closely with flow measured with concomitantly administered radiolabeled microspheres over the range of 0.29 to 5.04 ml/g per min (r = 0.95). Although regional ischemia was clearly identifiable tomographically, absolute flow could not be determined accurately in ischemic regions in four dogs because of poor count statistics related to wall thinning. Subsequently, myocardial blood flow was measured in 11 normal human subjects. Flow was homogeneous throughout the myocardium, averaged 0.90 +/- 0.22 ml/g per min at rest and increased to 3.55 +/- 1.15 ml/g per min after intravenous administration of dipyridamole. Therefore, positron emission tomography with H2 15O and the approach developed permits noninvasive measurement of myocardial blood flow in absolute terms in humans and should facilitate objective assessment of interventions designed to enhance nutritive perfusion.

Quantification of regional myocardial blood flow in vivo with H215O.

Using H215O (half-life = 2.1 min) we demonstrated that a modification of the tissue autoradiographic approach permitted quantitation of myocardial blood flow in open-chest dogs by direct assay of myocardial tissue and that noninvasive estimation with positron-emission tomography (PET) delineated relative myocardial blood flow in intact dogs. In open-chest anesthetized dogs, the single-pass extraction fraction of H215O averaged 96 +/- 5% at flows of 80 to 100 ml/100 g/min. This high extraction fraction did not differ significantly over the range of 12 to 238 ml/100 g/min. Myocardial blood flow calculated after a 60 sec intravenous infusion of H215O and direct analysis of tissue correlated well with results obtained with microspheres (r = .94, n = 9 dogs). Subsequently the approach was adapted for preliminary use with PET. Estimation of myocardial content of radiolabeled H2O after intravenous infusion of 20 to 30 mCi of H215O was corrected for vascular pool radioactivity with the use of tomographic data obtained after administration of C15O by inhalation to label red blood cells. Tomograms obtained in vivo in six dogs with either normal or reduced regional blood flow correlated closely with the tomographically detectable distribution of 68Ga-labeled microspheres (r = .93) and with postmortem microsphere distribution (r = .95). The technique accurately reflects myocardial blood flow. With the use of PET, rapid sequential noninvasive estimation of relative regional myocardial blood flow has been demonstrated that should ultimately permit improved objective assessment of nutritional blood flow in patients in response to medical and surgical interventions designed to augment perfusion.

Strategies for in vivo Measurement of Receptor Binding Using Positron Emission Tomography

Dopaminergic ligands labeled with positron-emitting radionuclides have been synthesized for quantitative evaluation of dopaminergic binding in vivo. Two different methods, the explicit method and an operationally simplified ratio method, have been proposed for analysis of these positron emission tomographic (PET) data. The basis for both methods is the same three-compartment model. The two methods differ in the assumptions necessary for practical implementation. We have compared these two approaches using PET data obtained in our laboratory. Sequential scans and serial arterial blood samples from a baboon following intravenous injection of [18F]spiroperidol were collected. Application of the two methods to the same data yielded different values for corresponding parameters. Values calculated by the ratio method for the specific rate constant describing receptor binding varied depending upon the time after tracer injection, thus demonstrating an internal inconsistency in this approach. Tracer metabolism markedly affected the binding measurements calculated with either method and thus cannot be ignored. Our results indicate that the adoption of simplifying assumptions for operational convenience can lead to substantial errors and must be done with caution. Alternatively, we present simple new analytical solutions of the tracer conservation equations describing the complete, unsimplified three-compartment model that vastly reduce the computations necessary to implement the explicit method.

Selective defect of in vivo glycolysis in early Huntington's disease striatum

Activity of complexes II, III, and IV of the mitochondrial electron transport system (ETS) is reduced in postmortem Huntingtons disease (HD) striatum, suggesting that reduced cerebral oxidative phosphorylation may be important in the pathogenesis of neuronal death. We investigated mitochondrial oxidative metabolism in vivo in the striatum of 20 participants with early, genetically proven HD and 15 age-matched normal controls by direct measurements of the molar ratio of cerebral oxygen metabolism to cerebral glucose metabolism (CMRO2/CMRglc) with positron emission tomography. There was a significant increase in striatal CMRO2/CMRglc in HD rather than the decrease characteristic of defects in mitochondrial oxidative metabolism (6.0 ± 1.6 vs. 5.1 ± 0.9, P = 0.04). CMRO2 was not different from controls (126 ± 37 vs. 134 ± 31 μmol 100 g−1 min−1, P = 0.49), whereas CMRglc was decreased (21.6 ± 6.1 vs. 26.4 ± 4.6 μmol 100 g−1 min−1, P = 0.01). Striatal volume was decreased as well (13.9 ± 3.5 vs. 17.6 ± 2.0 ml, P = 0.001). Increased striatal CMRO2/CMRglc with unchanged CMRO2 is inconsistent with a defect in mitochondrial oxidative phosphorylation due to reduced activity of the mitochondrial ETS. Because HD pathology was already manifest by striatal atrophy, deficient energy production due to a reduced activity of the mitochondrial ETS is not important in the mechanism of neuronal death in early HD. Because glycolytic metabolism is predominantly astrocytic, the selective reduction in striatal CMRglc raises the possibility that astrocyte dysfunction may be involved in the pathogenesis of HD.

Regional assessment of myocardial metabolic integrity in vivo by positron-emission tomography with 11C-labeled palmitate.

SUMMARYTo determine whether positron emission tomography (PET) after the combined administration of 11C-palmitate intravenously to image myocardium and 11CO by inhalation to image the cardiac blood pool with 11CO-hemoglobin provides quantitative delineation of the locus and extent of myocardial infarction, 28 patients with suspected myocardial infarction were studied. Twenty-one patients had electrocardiographically documented transmural infarction and in seven, the diagnosis of infarction was ultimately excluded based on enzymatic and electrocardiographic criteria. To assess reproducibility, four patients were studied on two occasions 1 month apart. Inferior and apical infarcts were readily localized with sagittal and coronal as opposed to transaxial reconstructions. Complete electrocardiographic and tomographic concordance was observed for the locus of all transmural infarcts. Reproducibility of tomographic estimates was within 10%. Tomographic estimation of the extent of infarction with 11C-palmitate in a subset of patients in whom right ventricular contributions to overall enzyme release could be exluded was facilitated by delineation of the endocardial border with the 11CO-hemoglobin cardiac blood pool image in the same plane. The correlation between enzymatic (serial plasma MB-CK method) and tomographic estimates of infarct size was close (r = 0.92). Thus, as has been shown in experimental animals, PET with 11C-palmitate permits quantification and localization of myocardial infarcts in patients.

Quantification of differences in frequency content of signal-averaged electrocardiograms in patients with compared to those without sustained ventricular tachycardia☆

To quantify differences in the frequency content of signal-averaged electrocardiograms between patients with and without sustained ventricular tachycardia (VT), the energy spectra of the terminal QRS and ST segments of signal-averaged orthogonal ECGs were computed in 3 groups of patients by squaring the magnitude of the fast-Fourier transformed data. The terminal 40 ms of the QRS complex and ST segment were analyzed as a single unit to enhance frequency resolution. Group I comprised 23 patients with documented, remote myocardial infarction who had manifested subsequent episodes of sustained VT; group II comprised 53 patients with previous, remote infarction without subsequent sustained VT; and group III comprised 11 normal subjects. The terminal QRS and ST segments from patients with sustained VT contained a 10- to 100-fold greater proportion of components in the 20- to 50-Hz range compared with corresponding electrocardiographic segments in patients without VT. There were no significant differences in the peak frequencies among patient groups. However, the relative contribution of the magnitudes of these peak frequencies to the overall maximum magnitude of the spectral plot differed significantly (p less than 0.0001). No frequencies above 50 Hz contributed substantially to the energy spectra of the terminal QRS and ST segments in any group. Thus, differences in the energy spectra do not result from differences in the frequencies of components, but are attributable instead to differences in the amplitudes of components within a relatively narrow range of frequencies. The quantitative approach developed should provide objective indexes for assessing effects of antiarrhythmic interventions on abnormalities recognizable by frequency-domain analysis and improve noninvasive definition of risk for development of sustained VT.

Tracer-kinetic models for measuring cerebral blood flow using externally detected radiotracers.

All tracer-kinetic models currently employed with positron-emission tomography (PET) are based on compartmental assumptions. Our first indication that a compartmental model might suffer from severe limitations in certain circumstances when used with PET occurred when we implemented the Kety tissue-autoradiography technique for measuring CBF and observed that the resulting CBF estimates, rather than remaining constant (to within predictable statistical uncertainty) as expected, fell with increasing scan duration T when T > 1 min. After ruling out other explanations, we concluded that a one-compartment model does not possess sufficient realism for adequately describing the movement of labeled water in brain. This article recounts our search for more realistic substitute models. We give our derivations and results for the residue-detection impulse responses for unit capillary-tissue systems of our two candidate distributed-parameter models. In a sequence of trials beginning with the simplest, we tested four progressively more detailed candidate models against data from appropriate residue-detection experiments. In these, we generated high-temporal-resolution counting-rate data reflecting the history of radiolabeled-water uptake and washout in the brains of rhesus monkeys. We describe our treatment of the data to yield model-independent empirical values of CBF and of other parameters. By substituting these into our trial-model functions, we were able to make direct comparisons of the model predictions with the experimental dynamic counting-rate histories, confirming that our reservations concerning the one-compartment model were well founded and obliging us to reject two others. We conclude that a two-barrier distributed-parameter has the potential of serving as a substitute for the Kety model in PET measurements of CBF in patients, especially when scan durations for T > 1 min are desired.

Noninvasive quantification of regional myocardial perfusion with rubidium-82 and positron emission tomography. Exploration of a mathematical model.

Positron emission tomography (PET) centers without cyclotrons use generator-produced rubidium-82 (82Rb) for assessment of myocardial perfusion. The aim of the present study was to determine whether myocardial blood flow could be assessed quantitatively with 82Rb and PET. Because the myocardial extraction fraction of 82Rb varies inversely and nonlinearly with flow and cannot be measured conveniently with PET, we used an experimentally derived mathematical function defining the relation between single-pass extraction fraction of 82Rb and flow to obviate the necessity of measuring the extraction fraction directly. Myocardial blood flow in absolute terms (ml/g/min) was estimated from dynamic PET scans after intravenous administration of 82Rb in intact dogs and compared with flows measured with radiolabeled microspheres. In 36 comparisons in 13 dogs studied at rest, or after coronary occlusion, reperfusion, or after coronary hyperemia induced with intravenous dipyridamole, over the flow range from 0.2 to 2.0 ml/g/min, estimates of perfusion with rubidium correlated well with flows measured concomitantly with microspheres, although there was a slight underestimation of flow with rubidium (flow by 82Rb = 0.92 x flow by microspheres-0.021, r = 0.83). In general, estimates of flow in ischemic regions were less reliable than estimates for regions with normal flow. Thus, although the relation between myocardial extraction and retention of 82Rb and flow can vary under a variety of physiological and pathophysiological conditions, this study demonstrates the ability to obtain quantitative estimates of myocardial blood flow with 82Rb and PET under carefully defined conditions without measuring the extraction fraction directly.

Photon time-of-flight-assisted positron emission tomography

In positron emission tomography (PET), the annihilation radiation is usually detected as a coincidence occurrence that localizes the position of the annihilation event to a straight line joining the detectors. The measure of the difference between the time of flight (TOF) of the annihilation photons between their inception and their detection permits the localization of the position of the annihilation event along the coincidence line. The incorporation of TOF information into the PET reconstruction process improves the signal-to-noise ratio in the image obtained. The utilization of scintillation detectors utilizing cesium fluoride scintillators, fast photomultiplier tubes, and fast timing circuits allows sub-nanosecond coincidence timing resolution needed for the effective use of TOF in PET. Mathematical considerations and pilot experiments show that with state-of-the-art electronic components and through the application of proper reconstruction algorithms, the combination of TOF and PET positional data improves severalfold the signal-to-noise ratio with respect to conventional PET image reconstruction at the cost of increasing the amount of data to be processed. The construction of a TOF-assisted PET device is within the capability of state-of-the-art technology.

Identification of patients with sustained ventricular tachycardia by frequency analysis of signal-averaged electrocardiograms despite the presence of bundle branch block.

Previously, we have demonstrated distinguishing features in the fast Fourier transform (FFT) of signal-averaged electrocardiograms (ECGs) obtained during sinus rhythm in the absence of bundle branch block that differentiate patients with from those without sustained ventricular tachycardia (VT). The ECGs during sinus rhythm from many patients with sustained VT, however, exhibit intraventricular conduction abnormalities. Accordingly, this study was performed to determine whether the presence of bundle branch block during sinus rhythm precluded accurate identification of patients with sustained VT. Studies were performed in 28 normal subjects (group I) and 141 patients with organic heart disease grouped according to clinical characteristics. Group II comprised 40 patients without VT in whom the QRS duration during sinus rhythm was less than 120 msec. Group III included 21 patients without VT in whom the QRS duration during sinus rhythm was 120 msec or greater. Group IV comprised 43 patients with sustained VT having ECGs during sinus rhythm with QRS durations less than 120 msec. Group V included 37 patients with sustained VT in whom the QRS duration during sinus rhythm was 120 msec or greater. FFTs of the terminal QRS and ST segment of signal-averaged X, Y, and Z ECGs were computed. Transformed data were expressed as an FFT magnitude and the relative contribution and peak magnitudes of 20 to 50 Hz frequencies determined after first demonstrating that this FFT method was more appropriate, when compared with the energy spectrum, for analyzing ECG signals having a broad range of ST segment durations.(ABSTRACT TRUNCATED AT 250 WORDS)