Rigid-body transformation of list-mode projection data for respiratory motion correction in cardiac PET.

High-resolution cardiac PET imaging with emphasis on quantification would benefit from eliminating the problem of respiratory movement during data acquisition. Respiratory gating on the basis of list-mode data has been employed previously as one approach to reduce motion effects. However, it results in poor count statistics with degradation of image quality. This work reports on the implementation of a technique to correct for respiratory motion in the area of the heart at no extra cost for count statistics and with the potential to maintain ECG gating, based on rigid-body transformations on list-mode data event-by-event. A motion-corrected data set is obtained by assigning, after pre-correction for detector efficiency and photon attenuation, individual lines-of-response to new detector pairs with consideration of respiratory motion. Parameters of respiratory motion are obtained from a series of gated image sets by means of image registration. Respiration is recorded simultaneously with the list-mode data using an inductive respiration monitor with an elasticized belt at chest level. The accuracy of the technique was assessed with point-source data showing a good correlation between measured and true transformations. The technique was applied on phantom data with simulated respiratory motion, showing successful recovery of tracer distribution and contrast on the motion-corrected images, and on patient data with C15O and 18FDG. Quantitative assessment of preliminary C15O patient data showed improvement in the recovery coefficient at the centre of the left ventricle.

GATE: a simulation toolkit for PET and SPECT.

Monte Carlo simulation is an essential tool in emission tomography that can assist in the design of new medical imaging devices, the optimization of acquisition protocols and the development or assessment of image reconstruction algorithms and correction techniques. GATE, the Geant4 Application for Tomographic Emission, encapsulates the Geant4 libraries to achieve a modular, versatile, scripted simulation toolkit adapted to the field of nuclear medicine. In particular, GATE allows the description of time-dependent phenomena such as source or detector movement, and source decay kinetics. This feature makes it possible to simulate time curves under realistic acquisition conditions and to test dynamic reconstruction algorithms. This paper gives a detailed description of the design and development of GATE by the OpenGATE collaboration, whose continuing objective is to improve, document and validate GATE by simulating commercially available imaging systems for PET and SPECT. Large effort is also invested in the ability and the flexibility to model novel detection systems or systems still under design. A public release of GATE licensed under the GNU Lesser General Public License can be downloaded at http:/www-lphe.epfl.ch/GATE/. Two benchmarks developed for PET and SPECT to test the installation of GATE and to serve as a tutorial for the users are presented. Extensive validation of the GATE simulation platform has been started, comparing simulations and measurements on commercially available acquisition systems. References to those results are listed. The future prospects towards the gridification of GATE and its extension to other domains such as dosimetry are also discussed.

The effect of the nitric oxide donor glyceryl trinitrate on global and regional cerebral blood flow in man.

Despite their potential use as cerebral vasodilatory agents there are few studies of the effect of nitric oxide (NO) donors on the cerebral circulation in non-anaesthetised man. We determined the effect of the NO donor glyceryl trinitrate (GTN) at clinically relevant doses on global and regional cerebral blood flow (CBF) in healthy non-anaesthetised volunteers, using H(2)(15)O PET, ultrasonic colour velocity flow imaging of carotid artery flow, and transcranial Doppler (TCD) of middle cerebral artery velocities (MCAv). Three rates of GTN infusion (0.1, 0.4, 1.0 microg/kg/min) were used. There was no significant change in common or internal carotid artery flow following GTN administration although a dose dependent fall in MCAv post GTN was observed. There was no significant change in either global or regional CBF following GTN. Thus intravenous GTN at therapeutic doses in awake humans does not alter global or regional CBF. However it does produce basal cerebral artery vasodilatation as evidenced by a fall in MCAv in the absence of a change in internal carotid artery flow.

Histochemical correlates of (15)O-water-perfusable tissue fraction in experimental canine studies of old myocardial infarction.

UNLABELLED: A method has been proposed to quantitate the myocardial water-perfusable tissue fraction (PTF) in the area of hypoperfused asynergic segments using (15)O-water (H2(15)O) and PET. This study investigated the histochemical correlates of PTF (and perfusable tissue index, PTI) in a canine model of old myocardial infarction. METHODS: Myocardial infarction was produced in 12 mongrel dogs, and PET was performed 1 mo later, providing quantitative parametric images of PTF, regional myocardial blood flow (MBF), and extravascular density from H2(15)O, (15)O-carbon monoxide, and transmission datasets. At the end of scanning, the myocardium was sectioned, and the PET images were compared directly with the corresponding myocardial sections. RESULTS: The distribution of tissue necrosis identified by histochemical staining corresponded well with the defect in PTF but not in MBF. PTF agreed with the equilibrium images of myocardial H2(15)O distribution, obtained after injection of a large bolus of H2(15)O. The defect surface area identified on PTF agreed well quantitatively with the morphometric estimates of the surface area of myocardial infarction. PTI agreed with the absolute proportion of histochemically defined normal myocardium (0.87 +/- 0.09 and 0.83 +/- 0.08, respectively; P < 0.01). Both PTF and PTI decreased significantly in segments of myocardial infarction and showed a significant difference between the transmural and nontransmural myocardial infarction. CONCLUSION: The absolute mass and proportion of histochemically defined noninfarcted tissue may be quantitated with PTF and PTI in the area of myocardial infarction segments.

Physical characteristics of the ECAT EXACT3D positron tomograph.

The 'EXACT3D' positron tomograph, which is now in routine clinical research use, was developed with the aim of achieving unprecedented sensitivity, high spatial and temporal resolution and simplicity of design using proven detector technology. It consists of six rings of standard detector blocks (CTI/Siemens EXACT HR+) with 4.39 mm x 4.05 mm x 30 mm elements, giving an axial field of view (FOV) of 23.4 cm. This extended FOV and the absence of interplane septa and retractable transmission rod sources has allowed greatly simplified gantry and detector cassette design. Operation in exclusive 3D mode requires an alternative to the conventional coincidence method for transmission scanning, and a single photon approach using a hydraulically driven 137Cs point source has been implemented. The tomograph has no other moving parts. A single time frame of data without any compression is very large (> 300 Mbyte) and two approaches are employed to overcome this difficulty: (a) adjacent sinograms can be summed automatically into different combinations and (b) listmode (event-by-event) acquisition has been instituted, which is both storage efficient (particularly for acquisition of sparse data sets) and maximizes temporal resolution. The high-speed I/O and computing hardware can maintain a sustained acquisition rate of about 4 million coincidence events per second. A disadvantage of the large axial FOV in 3D is the increased sensitivity to activity outside the coincidence FOV. However, this can be minimized by additional side shielding. The mean spatial resolution is 4.8 +/- 0.2 mm FWHM (transaxial, 1 cm off-axis) and 5.6 +/- 0.5 mm (axial, on-axis). Its absolute efficiency is 5.8% for a line source in air (just spanning the axial FOV) and 10% for a central point source (with thresholds of 350-650 keV). For a uniform 20 cm diameter cylinder, the efficiency is 69 kcps kBq(-1) ml(-1) (after subtraction of a scatter fraction of 42%). Sensitivity relative to the EXACT HR+ (with four rings of blocks) is 2.5 (3D) and 12 (2D) times respectively. The rate of random events in blood flow studies in the brain and body, using 15O-labelled water, can be controlled by limiting the administered dose and inserting additional side shielding.

The effect of the nitric oxide synthase inhibitor L-NMMA on basal CBF and vasoneuronal coupling in man: a PET study.

Nitric oxide (NO) regulates basal CBF. In a number of animal models NO has been implicated in the mediation of the regional changes in CBF (rCBF) that accompany neuronal activation (vasoneuronal coupling). However, some results in animal models have failed to confirm this finding, and the validity of extrapolation to man from animal data is uncertain. To determine the contribution of NO to basal global CBF and activation-induced changes in rCBF, the authors have performed quantitative H2(15)O positron emission tomography (PET) studies before and after administration of the non-isoform-specific NO synthase inhibitor, N(G)-monomethyl-L-arginine (L-NMMA), in 10 healthy male volunteers. Learning a novel sequence of finger movements was used as a paradigm to induce regional frontal cortex activation. The effect of NO synthase inhibition on the magnitude and pattern of activation was determined. Resting global CBF fell from 33.3 +/- 5.3 mL x 100 g(-1) x min(-1) at rest before L-NMMA, to 26.5 +/- 7.7 mL x 100 g(-1) x min(-1) after L-NMMA (P = 0.001). This fall was reversed by L-arginine administration. Learning sequential finger movements induced increases in rCBF in the left motor, right prefrontal, and bilateral premotor cortices. After NO synthase inhibition with L-NMMA, there was no change in this pattern of activation and no reduction in the magnitude of rCBF responses at the foci of maximal stimulation before and after L-NMMA. These findings confirm that NO production contributes to basal CBF regulation in man, but show that systemic NO synthase inhibition with L-NMMA does not impair regional vasoneuronal coupling.

Experience with fully 3D PET and implications for future high-resolution 3D tomographs.

The aim of this paper is to report on experience with 3D positron emission tomography (PET) in our institute where we have three 3D scanners, of which two operate exclusively in 3D mode (ECAT ART, EXACT 3D). Fully 3D PET requires attention to a number of factors which are not as problematic in 2D PET. Firstly, 3D tomographs designed for whole-body acquisition suffer from a large single-photon field of view, extending well beyond the coincidence field of view. Single photons from outside the coincidence field of view increase the dead time and random coincidence rates, and contribute scattered events. For brain studies, we have extended the lead side shielding at the ends of the tomograph to mitigate against these effects, and this has dramatically improved the count rate performance. This approach is not as effective for whole-body scanning. In addition, operating in 3D without septa necessitates new approaches to transmission scanning, as measurements using positron emitters such as 68Ge/68Ga have the unfavourable characteristics of high dead time and high scatter. Both of our fully 3D scanners use 137Cs for single-photon transmission measurements, although the data are treated differently. On the ECAT ART, a combination of physical and electronic collimation effectively reduces transmission scatter to acceptable levels. On the EXACT 3D physical collimation is not as readily implemented and therefore segmentation and reassignment of the histogrammed attenuation (mu) values is employed to produce unbiased attenuation correction factors in 3D. Many of the lessons learnt with these BGO (bismuth germanate) based tomographs will be applicable to the next generation of systems using faster detectors such as lutetium oxyorthosilicate (LSO).

The effect of activity outside the direct field of view in a 3D-only whole-body positron tomograph.

The ECAT EXACT3D (CTI/Siemens 966) 3D-only PET tomograph has unprecedented sensitivity due to the large BGO (bismuth germanate) detector volume. However, the consequences of a large (23.4 cm) axial field-of-view (FOV) and the need for a patient port diameter to accommodate body scanning make the device more sensitive to photons arising from activity outside the direct (coincidence) FOV. This leads to relatively higher deadtime and an increased registration of random and scatter (true) coincidences. The purpose of this study is to determine the influence of activity outside the FOV on (i) noise-equivalent counts (NEC) and (ii) the performance of a 'model-based' scatter correction algorithm, and to investigate the effect of side shielding additional to that supplied with the tomograph. Annular shielding designed for brain scanning increased the NEC for blood flow (H[2]15O) measurement (integrated over 120 s) by up to 25%. For 11C tracer studies, the increase is less than 5% over 120 min. Purpose-built additional body shielding, made to conform to the shape of a volunteer, reduced the randoms count rate in a heart blood flow measurement (H[2]15O) by about 30%. After scatter correction the discrepancy between ROI count ratios for compartments within the 20 cm diameter 'Utah' phantom differed by less than 5% from true (sampled) activity concentration ratios. This was so with or without activity outside the FOV and with or without additional side shielding. Count rate performance is thus improved by extra shielding but more improvement is seen in head than in body scanning. Measurement of heart blood flow using bolus injections of H(2)15O would benefit from the use of detectors with lower deadtime and superior timing resolution such as LSO (lutetium oxyorthosilicate).

Three-dimensional performance of a small-diameter positron emission tomograph.

Recently, the initial 2D physical characterization of a small-diameter positron emission tomograph, designed specifically for scanning of small laboratory animals, was reported. The physical characteristics of the tomograph operating in 3D mode have now been measured and compared to those obtained in 2D mode. In 3D, the transaxial resolution was measured as 2.4 +/- 0.1 mm full width at half maximum (FWHM) and 6.7 +/- 1.1 mm full width at tenth maximum (FWTM) at the centre of the transaxial field of view (FOV). These values degraded to 4.5 +/- 0.3 mm (tangential) and 6.6 +/- 0.3 mm (radial) FWHM and 10.6 +/- 1.6 mm (tangential) and 11.2 +/- 2.1 mm (radial) FWTM, respectively, at a distance of 40 mm from the centre of the transaxial FOV. The axial resolution was measured as 4.6 +/- 0.1 mm FWHM and 15.0 +/- 0.5 mm FWTM at the centre of the transaxial FOV, increasing to 5.0 +/- 0.1 mm FWHM and 18.8 +/- 3.7 mm FWTM at a radial distance of 40 mm from the centre of the transaxial FOV. These resolutions are similar to those obtained for the tomograph operating in 2D mode. The sensitivity of the tomograph operating in 3D was 4.31 x 10(4) counts s-1 MBq-1 at 250-850 keV compared to 0.995 x 10(4) counts s-1 MBQ-1 in 2D at the same energy thresholds. In this energy window the noise equivalent count rate peaked at 4.1 x 10(4) counts s-1, compared to 1.03 x 10(4) counts s-1 in 2D. A scatter fraction of 30.2% at 250-850 keV was measured for a 18F line source centered in a 60 mm diameter water filled phantom in 3D, compared to 31.0% in 2D for the same scanning geometry and energy thresholds. A comparison was made between 2D and 3D kinetic analyses for a group of five anaesthetized rats scanned using [11C] SCH 23390, a marker of dopamine D1 receptors. The integrity of the results was maintained between 2D and 3D data sets, though in 3D there was a significant reduction in the standard error of the fitted parameter. The results demonstrate that, with regard to sensitivity, there are significant gains in the physical performance of this tomograph when operating in 3D compared to 2D mode and that the quantification of PET studies of small animals using the 3D data reflects this.

Quantitative blood flow measurement of skeletal muscle using oxygen-15-water and PET.

UNLABELLED: The aim of the present study was to evaluate quantitation of muscle blood flow using [15O]H2O and PET. METHODS: The autoradiographic (ARG) and the steady-state methods using PET were used to measure femoral muscle blood flow. A simulation study was performed to examine the errors due to contamination of radioactivity in the blood content in muscle tissue, statistical noise and delay and the dispersion of the input curve in the ARG method. Five separate paired muscle blood flow examinations were carried out for comparison of the ARG and the steady-state techniques, including measurement of muscle blood volume in each subject. To obtain the normal range for resting muscle blood flow, additional measurements with the ARG method were performed in 16 normal subjects. RESULTS: When the integration time in ARG was increased to 200-300 sec, the errors due to arterial blood volume, statistical noise, delay and dispersion of the input curve were significantly reduced. Muscle blood flow values in the ARG (200 sec) and the steady-state studies were in good agreement, and each provided an estimated accuracy of 5%. Resting muscle blood flow averaged 3.12 +/- 1.55 ml/min.100 g muscle (range 1.43-6.72 ml/min.100 g muscle, n = 18). CONCLUSION: The ARG and the steady-state methods provided consistent blood flow values for skeletal muscle when a long tissue integration time (> or = 200 sec) was applied in the ARG study. Based on the lower effective radiation dose and the shorter total scan duration, the ARG method is favored over the steady-state method in the measurement of muscle blood flow.

ECAT ART - a continuously rotating PET camera: performance characteristics, initial clinical studies, and installation considerations in a nuclear medicine department.

Advances in fully three-dimensional (3D) image reconstruction techniques have permitted the development of a commercial, rotating, partial ring, fully 3D positron emission tomographic (PET) scanner, the ECAT ART. The system has less than one-half the number of bismuth germanate detectors compared with a full ring scanner with the equivalent field of view, resulting in reduced capital cost. The performance characteristics, implications for installation in a nuclear medicine department, and clinical utility of the scanner are presented in this report. The sensitivity (20 cm diameterx20 cm long cylindrical phantom, no scatter correction) is 11400 cps.kBq-1.ml-1. This compares with 5800 and 40500 cps.kBq-1.ml-1 in 2D and 3D respectively for the equivalent full ring scanner (ECAT EXACT). With an energy window of 350-650 keV the maximum noise equivalent count (NEC) rate was 27 kcps at a radioactivity concentration of approximately 15 kBq.ml-1 in the cylinder. Spatial resolution is approximately 6 mm full width at half maximum on axis degrading to just under 8 mm at a distance of 20 cm off axis. Installation and use within the nuclear medicine department does not appreciably increase background levels of radiation on gamma cameras in adjacent rooms and the dose rate to an operator in the same room is 2 microSv. h-1 for a typical fluorine-18 fluorodeoxyglucose (18F-FDG) study with an initial injected activity of 370 MBq. The scanner has been used for clinical imaging with18F-FDG for neurological and oncological applications. Its novel use for imaging iron-52 transferrin for localising erythropoietic activity demonstrates its sensitivity and resolution advantages over a conventional dual-headed gamma camera. The ECAT ART provides a viable alternative to conventional full ring PET scanners without compromising the performance required for clinical PET imaging.

The potential of high-resolution positron emission tomography to monitor striatal dopaminergic function in rat models of disease.

The use of a recently commissioned small-diameter, high-resolution positron emission tomography (PET) to obtain a measure of specific binding of 3 carbon-11 labelled ligands in rat striatum is described. Using cerebellum as a reference tissue, compartmental modelling was used to obtain individual estimates of striatal binding potential (defined as the ratio of rate constants to and from the specifically bound compartment) for [11C]raclopride (D2 receptors), [11C]SCH 23390 (D1 receptors) and [11C]RTI-121 (dopamine transporter). The coefficients of variation in control, anaesthetized rats were of the order of 10%. Using two models of human disease, namely striatal injection of ibotenic acid to produce postsynaptic cell loss as in Huntington's disease, and 6-hydroxydopamine injection into substantia nigra pars compacta to mimic dopaminergic terminal loss in Parkinson's disease, marked reductions in binding potential were observed for the corresponding pre- or postsynaptic markers. When the regions of interest are so small as to be of the order of the spatial resolution of the system, factor such as spill over and partial volume negate absolute quantification of tissue radioactivity. Nevertheless, the use of PET to monitor relative changes in dopaminergic integrity should be considered as a viable complement to established in vivo microdialysis and post mortem techniques.

Benzodiazepine site pharmacokinetic/pharmacodynamic quantification in man: direct measurement of drug occupancy and effects on the human brain in vivo.

To date, the study of the relationship between drug occupancy and action in the brain has had to rely on the use of either animal models or of indirect kinetic measures in man, e.g. serum concentrations of unbound drug (as a measure of "free" drug in brain). We describe the first set of experiments which directly measure agonist-induced changes in both pharmacodynamic effects and pharmacokinetic parameters simultaneously and which demonstrate the feasibility of these studies in man. Five healthy volunteers each had two PET scans using [11C]flumazenil (a radiolabelled benzodiazepine site antagonist) as part of a study investigating kinetic models and the relationship between occupancy and effect of benzodiazepine site ligands. In both studies the [11C]flumazenil was displaced from the brain by infusion of midazolam administered i.v. 30 min into the scan. In one study a higher dose of midazolam was administered than in the other (range 12.5-50 micrograms/kg). Time-activity curves of the concentration of radioligand were derived in 17 different brain regions using a stereotactic automatic method of region selection. We demonstrated that there are significant differences in an index of occupancy, induced by the two different doses of midazolam, both across brain regions and within subjects. There was a significant correlation between measured occupancy index change and pharmacodynamic effects as measured by the peak change in beta 1 spectral power on EEG. There was no significant correlation between dose administered and EEG changes; plasma concentrations of midazolam were correlated with the occupancy index and with the EEG measures. In addition, we have demonstrated that a non-regional total index of brain occupancy can be obtained by analysing the non-tomographic data obtained with the PET scanner (total radioactivity counts head curve) and that this index shows significant correlations both with the dose administered and with the pharmacodynamic measure. This last finding validates the use of other non-tomographic counting techniques (Malizia et al., 1995a) where an index of displacement can be obtained after the administration of less than 1% of the dose of radiation needed for a PET study. These studies are likely to be useful in human psychopharmacology, in particular in the assessment of tolerance and of putative changes in benzodiazepine sensitivity in anxiety disorders. The same principles can be applied to other ligand studies and will be useful to validate current PK/PD models.

Linear dimension reduction of sequences of medical images: II. Direct sum decomposition.

Using unitary transformations together with a previously described statistical theory for optimal linear dimension reduction it is shown how pixels in a sequence of images can be decomposed into a sum of variates, covariates, and residual vectors, with all covariances equal to zero. It is demonstrated that this decomposition is optimal with respect to noise. In addition, it results in simplified and well conditioned equations for dimension reduction and elimination of covariates. The factor images are not degraded by subdivision of the time intervals. In contrast to traditional factor analysis, the factors can be measured directly or calculated based on physiological models. This procedure not only solves the rotation problem associated with factor analysis, but also eliminates the need for calculation of the principal components altogether. Examples are given of factor images of the heart, generated from a dynamic study using oxygen-15-labelled water and positron emission tomography. As a special application of the method, it is shown that the factor images may reveal any contamination of the blood curve derived from the original dynamic images with myocardial activity.

Aging effect on neutral amino acid transport at the blood-brain barrier measured with L-[2-18F]-fluorophenylalanine and PET.

UNLABELLED: Neutral amino acids (NAAs) are transported from the blood to the brain using the same carrier system in a competitive fashion. The purpose of this study is to establish a method for evaluating neutral amino acid transport at the blood-brain barrier (BBB) in humans and to examine the aging effect of amino acid transport. METHODS: A dynamic PET study with L-(2-18F)-fluorophenylalanine (18F-Phe) was performed in 14 normal volunteers (age 21-71 yr; mean +/- s.d., age range 48.0 +/- 17.1 yr). By using a two-compartment model analysis and a weighted integration technique, the influx rate constant K1, the efflux rate constant k2 and distribution volume Vd of 18F-Phe were estimated in various brain structures. RESULTS: The value of K1 was inversely correlated with plasma NAA concentration (r = -0.69, p < 0.01). The cerebellum showed the highest value of K1, while the white matter showed the lowest. There was no significant change in K1 during aging. The value of k2 was significantly increased with age. CONCLUSION: No decline of K1 during aging indicated that NAA transport from the blood to the brain is a limiting process of age in amino acid incorporation. Fluorine-18-Phe PET imaging is a feasible method to study NAA transport at the BBB in vivo in humans and can be applied to pathological conditions of the brain.

The design and physical characteristics of a small animal positron emission tomograph.

A small diameter positron emission tomography, designed specifically for small animal studies, was constructed from existing, commercially available, bismuth germanate (BGO) detectors and electronics. The scanner consists of 16 BGO detector blocks arranged to give a tomograph with a diameter of 115 mm and an axial field of view (FOV) of 50 mm. Each block is cut to produce eight (axial) by seven (radial) individual detector elements. The absence of interplane septa enables the acquisition of 3D data sets consisting of 64 sinograms. A 2D data set of 15 sinograms, consisting of eight direct and seven adjacent cross planes, can be extracted from the 3D data set. Images are reconstructed from the 2D sinograms using a conventional filtered backprojection algorithm. Two methods of normalization were investigated, based on either a rotating 68Ge rod source, or a uniform 68Ge plane source, with a uniform cylindrical 18F phantom. Attenuation of the emitted photons was estimated using a rotating 68Ge rod source. The transaxial resolution of the tomograph was measured as 2.3 mm full width at half maximum (FWHM) and 5.6 mm full width at tenth maximum (FWTM) at the centre of the FOV, degrading to 6.6 mm (radial) and 4.4 mm (tangential) FWHM and 10.4 mm (radial) and 14.4 mm (tangential) FWTM at 40.0 mm from the centre of the FOV. The axial slice width was 4.3 mm FWHM, 10.3 mm FWTM at the centre of the transaxial field of view and 4.4 mm FWHM, 10.6 mm FWTM at 20.0 mm from the centre of the FOV. A scatter fraction of 31.0% was measured at 250-850 keV, for an 18F line source centred in a 60 mm diameter, water-filled phantom, reducing to 20.4% and 13.8% as the lower energy discrimination was increased to 380 keV and 450 keV, respectively. The count rate performance was measured using a noise equivalent count rate method, and the linearity of the dead time correction was confirmed over the count rates encountered during routine scanning. In 2D mode, the absolute sensitivity of the tomograph was measured as 9948 counts s-1 MBq-1 at 250-850 keV, 8284 counts s-1 MBq-1 at 380-850 keV and 6280 counts s-1 MBq-1 at 450-850 keV.

Rapid calculation of regional cerebral blood flow and distribution volume using iodine-123-iodoamphetamine and dynamic SPECT.

UNLABELLED: Iodine-123-iodoamphetamine (IMP) is commonly used as a flow tracer for SPECT due to its large first-pass extraction fraction. Significant clearance from the brain, however, causes changes in distribution and underestimation of CBF values when a conventional microsphere model is applied to prolonged data acquisition. We have developed a rapid method to calculate CBF images in which clearance effects are taken into account. METHODS: A dynamic SPECT scan was obtained from five subjects (four patients with cerebral infarctions and one healthy volunteer) following intravenous injection of IMP lasting 1 min. The arterial input function was obtained by frequent blood sampling and measurement of the octanol extraction ratio. The dynamic images were weighted and integrated so that the look-up table procedures yielded values of CBF and distribution volume (Vd) simultaneously. RESULTS: Calculated values for CBF and Vd were consistent with those determined by nonlinear least squares fitting [CBF: Y = 1.03X-0.30 (ml/100 ml/min), r = 0.998, p < 0.001; Vd: Y = 0.99X-0.11 (ml/ml), r = 0.99, p < 0.001] and calculated CBF correlated significantly with CBF measured by PET [Y = 0.85X-0.15 (ml/100 ml/min), r = 0.92, p < 0.001]. CONCLUSION: This technique is valid for estimating CBF.

Deficits in cerebral glucose metabolism demonstrated by positron emission tomography in individuals at risk of familial Alzheimer's disease.

In order to establish whether positron emission tomography (PET) can identify metabolic changes in Alzheimer's disease at a presymptomatic stage, we have examined 24 asymptomatic at risk individuals from families with Alzheimer's disease. A significant reduction in global cerebral metabolic rate for glucose was found when compared with 16 age-matched controls. There was also a focal, parieto-temporal deficit similar to, although less extensive than, that found in 18 symptomatic individuals from familial Alzheimer's disease (FAD) pedigrees. Follow up of this cohort will establish whether these metabolic changes relate to a presymptomatic stage of the disease.

Benzodiazepine receptor quantification in vivo in humans using [11C]flumazenil and PET: application of the steady-state principle.

Carbon-11-labeled flumazenil combined with positron emission tomography (PET) was used to measure the concentration (Bmax) of the benzodiazepine (Bz) receptor in the brain and its equilibrium dissociation constant (KD) for flumazenil in five normal subjects. The steady-state approach was used injecting the tracer as a bolus of high specific activity. In each subject two studies were carried out. The first study was performed at essentially zero receptor occupancy, the tracer alone study. The second study was performed at a steady-state receptor occupancy of about 50%, achieved by a prolonged constant infusion of nonlabeled ("cold") flumazenil starting 2h before the bolus tracer injection and continuing until the end of scanning period. In this second study the free concentration of unmetabolized flumazenil in plasma water was measured in multiple blood samples. The observed tissue and plasma tracer curves, calibrated in the same units of radioactivity per millimeter, were analyzed in two ways: (a) by the noncompartmental (stochastic) approach making no assumptions regarding number of compartments in the tissue, and (b) by the single-compartment approach assuming rapid exchange (mixing) of tracer between all tissue compartments. The noncompartmental and the compartmental analyses gave essentially the same values for the distribution volume of the tracer, the parameter used for quantitation of the Bz receptor. As the compartmental approach could be applied to a shorter observation period (60 min instead of 120 min) it was preferred. The five subjects had a mean KD value of 12 nM/L of water and Bmax values of the grey matter ranging from 39 +/- 11 in thalamus to 120 +/- 14 nM/L of brain in occipital cortex. Most previous studies have been based on the pseudoequilibrium approach using the brain stem as a receptor-free reference region. This yields practically the same KD but lower Bmax values than the steady-state approach presented here.