Kenneth B. Larson

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.

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.

In vivo determination of cerebral blood volume with radioactive oxygen-15 in the monkey.

A method for the in vivo determination of cerebral blood volume was tested in 15 adult rhesus monkeys. The technique utilized external residue detection and required the serial measurement of two mean transit times, namely, that of an intravascular tracer, CI5O-hemoglobin, and that of a diffusible tracer, H215O. In computing the mean transit time for the intravascular tracer, the conventional Hamilton extrapolation of the downslope of the recording obtained for the washout of the tracer from the brain subsequent to an intracarotid bolus injection was found to be inadequate, yielding a mean transit time that systematically underestimated that parameter. Alternatively, the use of a power law extrapolation, as proposed by Huang, allowed a more accurate prediction of the vascular mean transit time. The preliminary studies testing the method predicted that the relationship between cerebral blood volume (CBV) and cerebral blood flow (CBF) was adequately represented by the equation CBV = 0.80CBF038, with a correlation coefficient of r = 0.90 for the cerebral blood flow range of 16 to 134 ml/100 g min−1 with a normocapnic cerebral blood volume of 3.5 ml/100 g perfused brain tissue (arterial Pco2 = 37 torr, CBF = 50 ml/100 g min−).

The interpretation of mean transit time measurements for multiphase tissue systems

Abstract A model-independent proof of the central-volume principle for multiphase tissue systems is presented. This derivation emphasizes the transport processes which occur within the system, and the physical constraints which the system must satisfy for valid application of the principle. These constraints include: (i) the fluid flowing into the system must be equivalentlylabelled; (ii) the system under study must be part of a larger system which has no diffusive inlets or outlets. The derivation shows that the definition of the volume of distribution and the choice of appropriate partition coefficients for evaluation of this quantity, are independent of any assumption concerning tracer equilibrium between phases as a whole. A less restrictive definition of equivalent labelling also results from the proof. The relationship between the mean transit times measured by global residue detection and by “snapshot” outflow detection is derived. If diffusion of tracer across the boundaries of the monitored system is significant compared to convective transport, then these two transit times will not have identical values. The conditions under which valid measurements of regional, i.e. local, physiological variables can be performed by residue detection are also discussed, and it is shown that regional residue-detection measurements may be used to assess variations in anatomical structure throughout a larger region. However, the use of the height/area method for calculating regional perfusion can lead to error when tracer enters the detector field by diffusion, as opposed to convection, or when a significant amount of diffusion occurs before tracer enters the observed region.

Estimation of infarct size from serum MB creatine phosphokinase activity: Applications and limitations

Results of enzymatic estimates of infarct size have been verified under defined experimental conditions, and close correlations have been obtained between enzymatically and morphologically estimated infarct size in patients. Nevertheless, to provide a basis for improved enzymatic estimates we explored several aspects of the original model. The first order disappearance rate of creatine phosphokinase (CPK) was verified by observed high correlation coefficients of the logarithm of CPK versus time after myocardial infarction in patients or intravenous injection of purified myocardial CPK in dogs. Selected hemodynamic interventions simulating derangements accompanying myocardial infarction including acceleration of heart rate, diminution of cardiac output and reduction of renal or hepatic perfusion in conscious dogs did not markedly alter CPK disappearance. To exclude contributions from noncardiac CPK to enzymatic estimates we performed studies with the MB CPK isoenzyme. Under standard assay conditions, MB CPK was found virtually exclusively in myocardium. Serial serum MB CPK curves paralleled those of total CPK from patients with uncomplicated infarction. Similar MB curves were obtained even in patients whose noncardiac CPK values distorted the total CPK curve after intramuscular injections. The correlation coefficient between infarct size estimated from total CPK and MB CPK was 0.97 in 12 patients with hemodynamically uncomplicated infarction. Thus, hemodynamic perturbations associated with infarction are unlikely to affect CPK disappearance and hence should not lead to spurious enzymatic estimates of infarct size. Furthermore, improved enzymatic estimates can be obtained by quantitative assay of MB CPK, a more specific myocardial marker, avoiding spurious estimates due to contributions from noncardiac enzyme.

External detection of early microvascular dysfunction after no-flow ischemia followed by reperfusion in isolated rabbit hearts.

To define relationships better between the duration of severe ischemia and microvas-cular functional integrity with an approach potentially applicable to studies in vivo, the effects of 30 and 60 minutes of global, no-flow ischemia on the coronary vascularure of isolated, perfused rabbit hearts were determined. Residue-detection data, analyzed with a two-compartment model, were used to estimate indices of microvascular function, including the mean-transit time (BSA) of radiolabeled bovine serum albumin (125I-BSA), vascular into extravascular space clearance, and vascular and extravascular space volumes. It was shown that the Central Volume Principle of tracer kinetics does not hold when transport of label between vascular and extravascular spaces takes place convectively by solvent drag, and a more general expression for ?BSA was derived and applied. Left ventricular end-diastolic pressure and left ventricular developed pressure were monitored with an isovolumic balloon. Aortic perfusion pressure, left ventricular end-diastolic pressure, left ventricular developed pressure and vascular space volume remained constant, while mean transit time, vascular into extravascular space clearance and extravascular space volumes increased gradually during 3-hour control perfusions. Perfusion pressure, mean transit time and extravascular space clearance increased significantly with reperfusion after 30 minutes of ischemia even though left ventricular end-diastolic and left ventricular-developed pressures returned to control levels. Vascular space volumes increased minimally, whereas extravascular space volumes increased S-fold during reperfusion. These changes in 126I-BSA washout and permeation across endothelium with reperfusion after no-flow ischemia indicate that compromised vascular integrity is an early manifestation of ischemia with functional consequences that persist even after ischemia sufficiently brief to permit restoration of left ventricular performance.

Increased ischemia-reperfusion injury to the heart associated with short-term, diet-induced hypercholesterolemia in rabbits.

The effects of increased dietary cholesterol content on coronary vascular hemodynamics and endothelial cell transport function were assessed in isolated rabbit hearts during 3.5 hours of reperfusion after 30 minutes of global, no-flow ischemia. In control hearts from rabbits fed normal chow, perfusion pressure, left ventricular end-diastolic pressure, maximum +dP/dt, and the rate of intravascular clearance of radiolabelled albumin remained constant during 5 hours of continuous perfusion, while the mean transit time of radiolabelled albumin increased 1.6 X baseline. In ischemic hearts from rabbits fed normal chow, perfusion pressure increased 59% during reperfusion while left ventricular end-diastolic pressure and maximum +dP/dt returned toward control levels. The rate of intravascular clearance of radiolabelled albumin decreased 36%, and the mean transit time of albumin increased approximately 3 X baseline. Ischemia-reperfusion injury to the cardiac vasculature and musculature was markedly increased in hearts of rabbits fed chow supplemented with 2% cholesterol for 2-3 weeks compared to rabbits fed the same diet for a longer duration (5-16 weeks) or rabbits fed normal chow. Prior to ischemia, permeation of the coronary vasculature by albumin was increased twofold in rabbits fed cholesterol for 2-3 weeks while myocyte contractile function was normal relative to chow-fed controls or the group fed cholesterol for 5-16 weeks. These effects of acute cholesterol feeding precede occlusive atherosclerotic coronary artery disease and occur at plasma cholesterol concentrations one third of those in rabbits fed cholesterol for the longer duration.(ABSTRACT TRUNCATED AT 250 WORDS)

Measurement of Regional Cerebral Blood Flow with Positron Emission Tomography: A Comparison of [15O]Water to [11C]Butanol with Distributed-Parameter and Compartmental Models

To further our understanding of the best way to measure regional CBF with positron emission tomography (PET), we directly compared two candidate tracers ([15O]water and [11C]butanol, administered intravenously) and two popular implementations of the one-compartment (IC) model: the autoradiographic implementation representing a single PET measurement of tissue radioactivity over 1 min and a dynamic implementation representing a sequence of measurements of tissue radioactivity over 200 s. We also examined the feasibility of implementing a more realistic, and thus more complex, distributed-parameter (DP) model by assigning fixed values for all of its parameters other than CBF and tracer volume of distribution (Vd), a requirement imposed by the low temporal resolution and statistical quality of PET data. The studies were performed in three normal adult human subjects during paired rest and visual stimulation. In each subject seven regions of interest (ROIs) were selected, one of which was the primary visual cortex. The corresponding ROI were anatomically equivalent in the three subjects. Regional CBF, Vd, tracer arrival delay, and dispersion were estimated for the dynamic data curves. A total of 252 parameter sets were estimated. With [11C]butanol both implementations of the IC model provided similar results (r = 0.97). Flows estimated using the 1C models were lower (p < 0.01) with [15O]water than with [11C]butanol. In comparison with the IC model, the constrained version of the DP used in these studies performed inadequately, overestimating high flow and underestimating low flow with both tracers, possibly as the result of the necessity of assigning fixed values for all of its parameters other than CBF and Vd.

Measurement of relative blood flow, transit-time distributions and transport-model parameters by residue detection when radiotracer recirculates☆☆☆

Abstract The interpretation of tracer kinetic data obtained by external monitoring of radioactively-labeled indicators is generally based on mathematical models that ignore recirculation. An important limitation of these models is that they can be used successfully only in those situations in which the major portion of the response curves are obtainable prior to the onset of the first recirculation. A further complication that limits the usefulness of the models is due to interference from radiotracers carried by recirculation into adjacent perfused regions also within the field of view of the detector. In this paper, we develop a mathematical model applicable for measuring blood flow per unit volume and determining transit-time distributions by external monitoring when recirculation is not a late event and must be taken into consideration. Additionally, the model accounts for interfering recirculation of tracer to adjacent perfused regions in the field of view of the detector. Central to the model is the use of two injections of tracer: one upstream (arterial) and one downstream (venous) of the particular organ or region of interest. Thus, two residue curves are obtained. We develop equations indicating how to employ the two residue curves in order to determine the mean transit time of tracer through the vascular system of interest, as well as higher moments of the transit-time distribution if they are desired. These equations are natural generalizations of Zierlers residue-detection method in that they do not depend for their validity on any model of mass transport within the system of interest. The numerical calculations implied by our equations need not rely on curve-fitting of the data. In addition to mean flow per unit volume, our method can yield compartmental parameters if these are appropriate and desired.

Myocyte Contracture, Vascular Resistance, and Vascular Permeability After Global Ischemia in Isolated Hearts From Alloxan-Induced Diabetic Rabbits

Coronary vascular hemodynamics, albumin permeation, and myocyte contractility were assessed in isolated hearts from 6-mo alloxan-induced diabetic (ALX-D) rabbits during 3 h of reperfusion after 40 min of global no-flow ischemia. Residue-detection data, generated during the single passage of a bolus of 125I-labeled bovine serum albumin (125I-BSA) through the coronary vasculature, were used to estimate indices of vascular function, including the mean transit time of 125I-BSA, the fractional rate of intravascular clearance of 125I-BSA, and 125I-BSA permeation of coronary vessels. During reflow after ischemia in hearts from control rabbits, vascular resistance increased approximately three times that at baseline, left ventricular end-diastolic pressure (LVEDP) increased 8–10 times, and maximum +dP/dt recovered 0.4 times baseline, whereas the fractional rate of washout of intravascular 125I-BSA decreased to less than one-half of baseline values (was prolonged 2-fold), and albumin permeation and mean-transit time were increased 3 and 5 times baseline, respectively. In hearts from diabetic rabbits, vascular resistance was similar to the control group before ischemia but increased only one-third as much during reflow after ischemia. Increases in LVEDP during reflow were ∼50% lower than controls, and +dP/df recovered ∼2.5 times more than in control hearts. 125I-BSA permeation in diabetics was similar to controls before ischemia, but during reflow increased 6 times (∼2 times controls). Washout of intravascular 125I-BSA was prolonged ∼20% versus baseline during 3 h of reflow in hearts from diabetic rabbits. Thus, ALX-D in the rabbit delayed ischemia-reperfusion injury to myocytes and vascular smooth muscle cells while increasing vascular albumin permeation.