CHERENCUBE: concept definition and implementation challenges of a Cherenkov-based detector block for PET.

PURPOSE: A new concept for a depth-of-interaction (DOI) capable time-of-flight (TOF) PET detector is defined, based only on the detection of Cherenkov photons. The proposed "CHERENCUBE" consists of a cubic Cherenkov radiator with position-sensitive photodetectors covering each crystal face. By means of the spatial distribution of the detected photons and their time of arrival, the point of interaction of the gamma-ray in the crystal can be determined. This study analyzes through theoretical calculations and Monte Carlo simulations the potential advantages of the concept toward reaching a Cherenkov-only detector for TOF-PET with DOI capability. Furthermore, an algorithm for the DOI estimation is presented and the requirements for a practical implementation of the proposed concept are defined. METHODS: The Monte Carlo simulations consisted of a cubic crystal with one photodetector coupled to each one of the faces of the cube. The sensitive area of the detector matched exactly the crystal size, which was varied in 1 mm steps between 1 × 1 × 1 mm(3) and 10 × 10 × 10 mm(3). For each size, five independent simulations of ten thousand 511 keV gamma-rays were triggered at a fixed distance of 10 mm. The crystal chosen was PbWO4. Its scintillation properties were simulated, but only Cherenkov photons were analyzed. Photodetectors were simulated having perfect photodetection efficiency and infinite time resolution. For every generated particle, the analysis considered its creation process, parent and daughter particles, energy, origin coordinates, trajectory, and time and position of detection. The DOI determination is based on the distribution of the emission time of all photons per event. These values are calculated as a function of the coordinates of detection and origin for every photon. The common origin is estimated by finding the distribution with the most similar emission time-points. RESULTS: Detection efficiency increases with crystal size from 8.2% (1 × 1 × 1 mm(3)) to 58.6% (10 × 10 × 10 mm(3)) and decreases applying a photon detection threshold of 5/10/20 photons to 6.3%/4.3%/0.7% and 49.3%/30.4%/2.8%, respectively. The detection rate in the six photodetectors is uniform due to the nearly isotropic cone emission. Most cones originated after a photoelectric effect interaction, with two dominating peaks for the kinetic energy of the electron at 422.99 and 441.47 keV. The detection distance between same-event photons defines the spatial resolution of the detector required for individual photon recognition, with 20% of the detected photons having their closest neighbor within a distance of 5% of the length of the cube. Same-event photons are detected within a time window whose width is determined by the crystal size, with values of 30 and 150 ps for a 1 × 1 × 1 mm(3) and a 10 × 10 × 10 mm(3) cube, respectively. The DOI reconstruction has an accuracy of approximately 23% of the length of the cube, with an average value of 2.2 mm for a 10 × 10 × 10 mm(3) CHERENCUBE. CONCLUSIONS: The proposed concept requires a detector with high photodetection efficiency. The structure of the sensitive surface of the detector should be a two dimensional array of microcells, able to provide individual detection coordinates and time stamps. The microcell size determines the ability to recognize individual photons, influencing detection efficiency. The 3D DOI recognition relies on the accuracy of the time stamps and detection coordinates, without the need for a recognition of the projected patterns of photons. The refractive index of the material defines a detector intrinsic energy-based rejection of scattered PET events at the cost of reduced sensitivity.

Impact of flexible body surface coil and patient table on PET quantification and image quality in integrated PET/MR.

AIM: The surface coils of the Biograph mMR integrated PET/MR system were optimised for PET, but are otherwise unaccounted for. The patient table is still more massive than those of PET/CT devices. The goal was to assess those hardware effects on quantification, count statistics, image quality and scan time both with phantoms and in patients and to investigate their clinical relevance. PATIENTS, MATERIAL, METHODS: PET phantom data were acquired with and without the patient table. Image noise was expressed as relative standard deviation and compared to a state-of-the-art PET/CT scanner. Protocols of the phantom/patient study regarding the surface coils were similar. Thoraces/abdomens of 11 patients were scanned with and without a coil (1 BP, 4 min). Mean uptake and standard deviation in a cubical VOI were derived and expressed as SUV. RESULTS: The patient table reduced the number of true coincidences (trues) by 19% (PET/MR) and by 11% (PET/CT). The scan duration for the mMR had to be increased by approximately 30% to achieve a noise level comparable to that of the PET/CT. Decreased SUVs with coil observed in the phantom were confirmed by the patient study. By removing the coil, the mean liver SUV increased by (6 ± 2)%. With (+3 ± 14)%, the average change was similar in lesions, but exceeded 20% in almost one fifth of them. The number of trues grew by (6 ± 1)% for the patients and by 7% for the phantom. CONCLUSION: Due to the additional attenuation caused by MR hardware, PET scan durations would have to be increased compared to current PET/CTs to provide similar image noise levels. The effect of the coils is mostly in the order of statistical fluctuations. In tumour lesions, it is more pronounced and shows a larger variability. Therefore, coils should be included in the attenuation correction to ensure accurate quantification and thus comparability across PET/MR and PET/CT scanners and within patient populations.

Respiratory gated [18F]FDG PET/CT for target volume delineation in stereotactic radiation treatment of liver metastases.

PURPOSE: The use of 4D-[(18)F]fluorodeoxyglucose (FDG) PET/CT in combination with respiratory gated magnet resonance imaging (MRI) in target volume definition for stereotactic radiation of liver metastases was investigated. METHODS AND MATERIALS: A total of 18 patients received respiration gated FDG-PET/CT and MRI. Data were fused using a rigid co-registration algorithm. The quality of the co-registration was rated on a scale from 1 (excellent) to 5 (poor) for co-registration of MRI with gated PET and ungated PET. Gross tumor volume (GTV) was delineated in CT (GTV (CT)), MRI (GTV(MRI)), and PET (GTV(PET)). MRI- and PET-based GTVs were defined by three observers each. Interobserver variability was calculated for all patients as well as for subgroups with and without previous treatment of liver metastases. All GTVs were compared for all patients and separately for patients with previous local therapy. In addition, a semiautomatic segmentation algorithm was applied on the PET images. RESULTS: Co-registration between MR and PET images was rated with 3.3 in average when non-gated PET was used and improved significantly (p < 0.01) to 2.1 using gated PET. The average GTV(CT) was 51.5 ml, GTV(MRI) 51.8 ml, and the average GTV(PET) 48.1 ml. Volumes delineated in MRI were 9.9% larger compared to those delineated in CT. Volumes delineated in PET were 13.8% larger than in MRI. The differences between the GTVs were more pronounced in patients with previous treatment. The GTVs defined in MRI showed an interobserver variability of 47.9% (84.1% with previous treatment and 26.2% without previous treatment). The PET-defined GTVs showed an interobserver variability of 21% regardless of previous treatment. Semiautomatic segmentation did not provide satisfying results. CONCLUSION: FDG-PET can distinguish vital tumor tissue and scar tissue, and therefore alters the GTV especially in patients with previous local treatment. In addition, it reduces the interobserver variability significantly compared to MRI. However, respiratory gated PET is necessary for good co-registration of PET and MRI.

Preliminary study of the detectability of coronary plaque with PET.

The evaluation of coronary plaque vulnerability could be of great diagnostic value in cardiology. Positron emission tomography (PET) is a good candidate due to its ability to quantify micromolar concentrations of targeted drugs. However, the detectability of sub-voxel targets such as coronary plaque is limited by partial volume effects and by cardiorespiratory motion. The goal of this paper is to investigate the impact of these factors in the detectability of plaque uptake. Radioactive markers were implanted on the epicardium of a pig and in vivo scans were performed. This was complemented with phantom measurements to determine the minimum detectable uptake as a function of background activity. Simulations were used to evaluate the effect of cardiorespiratory motion on the reconstructed lesions. Despite cardiorespiratory motion of up to 7 mm, the markers were detectable in the in vivo scans even after the injection of background. A lower limit of 250 Bq was found for a target to be detectable. Motion reduced the contrast of the reconstructed lesions to 23% of their static counterpart. Respiratory gating improved this to 49% of the static value. The results suggest that coronary plaque evaluation with PET is possible, provided that sufficient plaque-to-myocardium uptake contrast (50 to 100) can be achieved. This requirement increases exponentially for lesions with uptake below 250 Bq. The described experiments provide a means of estimating the minimum uptake and contrast required to ensure the detectability of plaque lesions.

Evaluation of the attenuation properties of MR equipment for its use in a whole-body PET/MR scanner.

The combination of magnetic resonance imaging (MR) and positron emission tomography (PET) scanners can provide a powerful tool for clinical diagnosis and investigation. Among the challenges of developing a combined scanner, obtaining attenuation maps for PET reconstruction is of critical importance. This requires accounting for the presence of MR hardware in the field of view. The attenuation introduced by this hardware cannot be obtained from MR data. We propose the creation of attenuation models of MR hardware, to be registered into the MR-based attenuation map prior to PET reconstruction. Two steps were followed to assess the viability of this method. First, transmission and emission measurements were performed on MR components (RF coils and medical probes). The severity of the artifacts in the reconstructed PET images was evaluated. Secondly, a high-exposure computed tomography (CT) scan was used to obtain a model of a head coil. This model was registered into the attenuation map of PET/CT scans of a uniform phantom fitted with the coil. The resulting PET images were compared to the PET/CT reconstruction in the absence of coils. The artifacts introduced by misregistration of the model were studied. The transmission scans revealed 17% count loss due to the presence of head and neck coils in the field of view. Important sources of attenuation were found in the lock, signal cables and connectors. However, the worst source of attenuation was the casing between both coils. None of the measured medical probes introduced a significant amount of attenuation. Concerning the attenuation model of the head coil, reconstructed PET images with model-based correction were comparable to the reference PET/CT reconstruction. However, inaccuracies greater than 1-2 mm in the axial positioning of the model led to important artifacts. In conclusion, the results show that model-based attenuation correction is possible. Using a high-exposure scan to create an attenuation model of the coils has been proved feasible. However, adequate registration of the model is mandatory.

Effect of inter-crystal scatter on estimation methods for random coincidences and subsequent correction.

Random coincidences can contribute substantially to the background in positron emission tomography (PET). Several estimation methods are being used for correcting them. The goal of this study was to investigate the validity of techniques for random coincidence estimation, with various low-energy thresholds (LETs). Simulated singles list-mode data of the MADPET-II small animal PET scanner were used as input. The simulations have been performed using the GATE simulation toolkit. Several sources with different geometries have been employed. We evaluated the number of random events using three methods: delayed window (DW), singles rate (SR) and time histogram fitting (TH). Since the GATE simulations allow random and true coincidences to be distinguished, a comparison between the number of random coincidences estimated using the standard methods and the number obtained using GATE was performed. An overestimation in the number of random events was observed using the DW and SR methods. This overestimation decreases for LETs higher than 255 keV. It is additionally reduced when the single events which have undergone a Compton interaction in crystals before being detected are removed from the data. These two observations lead us to infer that the overestimation is due to inter-crystal scatter. The effect of this mismatch in the reconstructed images is important for quantification because it leads to an underestimation of activity. This was shown using a hot-cold-background source with 3.7 MBq total activity in the background region and a 1.59 MBq total activity in the hot region. For both 200 keV and 400 keV LET, an overestimation of random coincidences for the DW and SR methods was observed, resulting in approximately 1.5% or more (at 200 keV LET: 1.7% for DW and 7% for SR) and less than 1% (at 400 keV LET: both methods) underestimation of activity within the background region. In almost all cases, images obtained by compensating for random events in the reconstruction algorithm were better in terms of quantification than the images made with precorrected data.

Standardised uptake values from PET/CT images: comparison with conventional attenuation-corrected PET.

PURPOSE: In PET/CT, CT-derived attenuation factors may influence standardised uptake values (SUVs) in tumour lesions and organs when compared with stand-alone PET. Therefore, we compared PET/CT-derived SUVs intra-individually in various organs and tumour lesions with stand-alone PET-derived SUVs. METHODS: Thirty-five patients with known or suspected cancer were prospectively included. Sixteen patients underwent FDG PET using an ECAT HR+scanner, and subsequently a second scan using a Biograph Sensation 16PET/CT scanner. Nineteen patients were scanned in the reverse order. All images were reconstructed with an iterative algorithm (OSEM). Suspected lesions were grouped as paradiaphragmatic versus distant from the diaphragm. Mean and maximum SUVs were also calculated for brain, lung, liver, spleen and vertebral bone. The attenuation coefficients (mu values) used for correction of emission data (bone, soft tissue, lung) in the two data sets were determined. A body phantom containing six hot spheres and one cold cylinder was measured using the same protocol as in patients. RESULTS: Forty-six lesions were identified. There was a significant correlation of maximum and mean SUVs derived from PET and PET/CT for 14 paradiaphragmatic lesions (r=0.97 respectively; p<0.001 respectively) and for 32 lesions located distant from the diaphragm (r=0.87 and r=0.89 respectively; p<0.001 respectively). No significant differences were observed in the SUVs calculated with PET and PET/CT in the lesions or in the organs. In the phantom, radioactivity concentration in spheres calculated from PET and from PET/CT correlated significantly (r=0.99; p<0.001). CONCLUSION: SUVs of cancer lesions and normal organs were comparable between PET and PET/CT, supporting the usefulness of PET/CT-derived SUVs for quantification of tumour metabolism.

PET/CT Biograph Sensation 16. Performance improvement using faster electronics.

AIM: The new PET/CT Biograph Sensation 16 (BS16) tomographs have faster detector electronics which allow a reduced timing coincidence window and an increased lower energy threshold (from 350 to 400 keV). This paper evaluates the performance of the BS16 PET scanner before and after the Pico-3D electronics upgrade. METHODS: Four NEMA NU 2-2001 protocols, (i) spatial resolution, (ii) scatter fraction, count losses and random measurement, (iii) sensitivity, and (iv) image quality, have been performed. RESULTS: A considerable change in both PET count-rate performance and image quality is observed after electronics upgrade. The new scatter fraction obtained using Pico-3D electronics showed a 14% decrease compared to that obtained with the previous electronics. At the typical patient background activity (5.3 kBq/ml), the new scatter fraction was approximately 0.42. The noise equivalent count-rate (R(NEC)) performance was also improved. The value at which the R(NEC) curve peaked, increased from 3.7 x 10(4) s(-1) at 14 kBq/ml to 6.4 x 10(4) s(-1) at 21 kBq/ml (2R-NEC rate). Likewise, the peak true count-rate value increased from 1.9 x 10(5) s(-1) at 22 kBq/ml to 3.4 x 10(5) s(-1) at 33 kBq/ml. An average increase of 45% in contrast was observed for hot spheres when using AW-OSEM (4ix8s) as the reconstruction algorithm. For cold spheres, the average increase was 12%. CONCLUSION: The performance of the PET scanners in the BS16 tomographs is improved by the optimization of the signal processing. The narrower energy and timing coincidence windows lead to a considerable increase of signal- to-noise ratio. The existing combination of fast detectors and adapted electronics in the BS16 tomographs allow imaging protocols with reduced acquisition time, providing higher patient throughput.

A true singles list-mode data acquisition system for a small animal PET scanner with independent crystal readout.

We present a unique data acquisition system designed to read out signals from the MADPET-II small animal LSO-APD PET tomograph. The scanner consists of 36 independent detector modules arranged in a dual-radial layer ring (phi 71 mm). Each module contains a 4 x 8 array of optically isolated, 2 x 2 mm LSO crystals, coupled one-to-one to a 32 channel APD. To take full advantage of the detector geometry, signals from each crystal are individually processed without any data reduction. This is realized using custom designed mixed-signal ASICs for analogue signal processing, and FPGAs to control the digitization of analogue signals and subsequent multiplexing. Analogue to digital converters (ADCs) digitize the signal peak height, time to digital converters (TDCs) time stamp each event relative to a system clock and two 32 bit words containing the energy, time and position information for each singles event are multiplexed through three FIFO stages before being written to disk via gigabit Ethernet. Every singles event is processed and stored in list-mode format, and coincidences are sorted post-acquisition in software. The 1152 channel data acquisition system was designed to be able to handle sustained data rates of up to 11 520 000 cps without loss (10 000 cps/channel). The timing resolution of the TDC was measured to be 1 ns FWHM. In addition to describing the data acquisition system, performance measurements made using a 128-channel detector prototype will be presented.

Inter-crystal scatter in a dual layer, high resolution LSO-APD positron emission tomograph.

Improving system efficiency without jeopardizing spatial resolution is one of the main problems of small animal PET scanners. In pursuit of this goal, the future LSO-APD-PET prototype MADPET-II will combine highly granulated detector modules with a dual layer structure. The individual readout of the LSO crystals allows separately handling multiple signals related to those photons scattering between different crystal units (inter-crystal scatter, ICS). The contribution of ICS events can significantly increase the system efficiency. Such coincidences are not characterized by a unique LOR. However, in order to minimize resolution degradation, it would be desirable to identify the primary path of the ICS events. Since ICS is geometry dependent, this work was aimed at investigating the effects of ICS in the performance of the dual layer prototype. Different recovery algorithms to select the primary crystal were implemented and developed, and applied to Monte Carlo simulated data. Some of these algorithms were based on the properties of Compton kinematics. For a centred point source and a 100 keV lower energy threshold, the absolute system efficiency was found to increase by 35% when including ICS events: from 1.8% without ICS events to 2.8% with ICS. Similarly, for a threshold of 200 keV, the contribution of ICS coincidences still represented approximately 20% of the total detected coincidences, leading to an absolute system efficiency of almost 2%. The mispositioning introduced by processing ICS coincidences only led to a moderate broadening of the axial line spread function (LSF), especially at the tails of the profile (FWTM). This effect was also noticeable in the transaxial plane. In presence of scattering media (water-filled cylinder), the resolution degradation was dominated by the contribution of object scatter. The reconstructed images from a simulated homogeneous cylinder filled with activity with a non-active rod at its centre were employed to estimate the impact of ICS on the image quality. In general, the use of ICS coincidences increased the signal-to-noise ratio (SNR) but worsened contrast. The effects of ICS on resolution could be reduced by employing a new identification scheme based on the maximum signal and the Compton kinematics. This method yielded the highest identification rate for the correct photon trajectory, even for a finite energy resolution of 15% (511 keV). This technique also increased the SNR by 17% to 30% and preserved the image contrast. In conclusion, by combining individual crystal readout, a low energy threshold and an appropriate recovery scheme, the processing of ICS coincidences significantly increases the system efficiency without any substantial deterioration of the image quality.

Quantification of [(18)F]FDG uptake in the normal liver using dynamic PET: impact and modeling of the dual hepatic blood supply.

UNLABELLED: For quantification of hepatic [(18)F]FDG uptake, the dual blood supply to the liver must be considered. In contrast to the arterial input, however, the portal venous blood supply to the liver cannot be monitored directly by PET because of the inaccessibility of the portal vein on PET scans. In this study, we investigated whether the dual hepatic input can be predicted from the measurable arterial input. Moreover, we assessed the effect of different input models on the rate constants of the standard 3-compartment model describing regional uptake of FDG. METHODS: Dynamic FDG PET scanning was performed on 5 foxhounds. Activity concentrations in blood from the aorta and the portal vein were measured simultaneously using external circuits. After image reconstruction, time--activity courses were determined from the aorta and the liver. The venous input was approximated by convolving the arterial input with a notional system function describing the dispersion of the arterial input on its way through the gastrointestinal tract. On the basis of these data, 5 different hepatic input models, which pertain to a single-input as well as a dual-input scenario, were statistically compared with regard to the adequacy of the model fits to liver data and to differences in the estimated rate constants. RESULTS: Portal venous input to the liver could be approximated by convolving the arterial input function with a system function. From this function, a mean transit time of 25 s was computed for FDG to pass through the gastrointestinal tract. According to the statistical analysis, dual-input models were superior to their single-input counterparts. However, differences in the rate constants estimated for the 5 input models were in the same order as interindividual variations within the different model groups. For the dephosphorylation rate constant, a consistent value of 0.05 +/- 0.01 min(-1) was found. CONCLUSION: Dual-input models proved to be superior to single-input models with respect to the adequacy of FDG model fits to normal liver data. However, the hepatic blood supply may be approximated by the arterial input function as well, especially for the evaluation of liver lesions mainly fed by the hepatic artery.

Reappearance of cardiac presynaptic sympathetic nerve terminals in the transplanted heart: correlation between PET using (11)C-hydroxyephedrine and invasively measured norepinephrine release.

UNLABELLED: Previously, sympathetic reinnervation of the transplanted heart has been described using invasive catheterization techniques and noninvasive radionuclide imaging techniques. However, little is known about the agreement between these 2 methods. Thus, correlation between (11)C-hydroxyephedrine (HED) PET and invasively measured norepinephrine (NE) release was investigated in transplant recipients in this study. METHODS: Using PET and the catecholamine analog HED, 17 patients were studied between 2 mo and 13.6 y after transplantation. Based on results in completely denervated hearts, areas with HED retention >7%/min were defined as reinnervated. Additionally, transcardiac NE release induced by intravenous tyramine (55 microg/kg) was measured by coronary sinus and aortic catheterization within 1 wk of the PET study. NE levels between coronary sinus and aortic root, DeltaNE(CS-AO), were calculated at baseline and after tyramine administration. Differences of more than 3 SD of baseline (>163 pg/mL) were interpreted as reinnervation. RESULTS: HED retention indicated reinnervation in 10 patients. Maximal HED retention ranged from 4.3%/min to 16.4%/min. DeltaNE(CS-AO) 1 min after tyramine administration ranged between -10 pg/mL and 1157 pg/mL, and 8 patients were above the reinnervation threshold. Fisher's exact test demonstrated good agreement between results of PET and DeltaNE(CS-AO) measurements (P = 0.002). Maximal HED retention was also significantly correlated with NE release (r = 0.69; P = 0.001). CONCLUSION: Results of invasively measured NE release and noninvasive (11)C-HED PET are well correlated. This study further supports the usefulness of PET as a noninvasive approach for detection of reappearance of catecholamine uptake sites after heart transplantation.

A prototype high-resolution animal positron tomograph with avalanche photodiode arrays and LSO crystals.

To fully utilize positron emission tomography (PET) as a non-invasive tool for tissue characterization, dedicated instrumentation is being developed which is specially suited for imaging mice and rats. Semiconductor detectors, such as avalanche photodiodes (APDs), may offer an alternative to photomultiplier tubes for the readout of scintillation crystals. Since the scintillation characteristics of lutetium oxyorthosilicate (LSO) are well matched to APDs, the combination of LSO and APDs seems favourable, and the goal of this study was to build a positron tomograph with LSO-APD modules to prove the feasibility of such an approach. A prototype PET scanner based on APD readout of small, individual LSO crystals was developed for tracer studies in mice and rats. The tomograph consists of two sectors (86 mm distance), each comprising three LSO-APD modules, which can be rotated for the acquisition of complete projections. In each module, small LSO crystals (3.7 x 3.7 x 12 mm3) are individually coupled to one channel within matrices containing 2x8 square APDs (2.6 x 2.6 mm2 sensitive area per channel). The list-mode data are reconstructed with a penalized weighted least squares algorithm which includes the spatially dependent line spread function of the tomograph. Basic performance parameters were measured with phantoms and first experiments with rats and mice were conducted to introduce this methodology for biomedical imaging. The reconstructed field of view covers 68 mm, which is 80% of the total detector diameter. Image resolution was shown to be 2.4 mm within the whole reconstructed field of view. Using a lower energy threshold of 450 keV, the system sensitivity was 350 Hz/MBq for a line source in air in the centre of the field of view. In a water-filled cylinder of 4.6 cm diameter, the scatter fraction at the centre of the field of view was 16% (450 keV threshold). The count rate was linear up to 700 coincidence counts per second. In vivo studies of anaesthetized rats and mice showed the feasibility of in vivo imaging using this PET scanner. The first LSO-APD prototype tomograph has been successfully introduced for in vivo animal imaging. APD arrays in combination with LSO crystals offer new design possibilities for positron tomographs with finely granulated detector channels.

Noninvasive imaging of alpha(v)beta3 integrin expression using 18F-labeled RGD-containing glycopeptide and positron emission tomography.

The alpha(v)beta3 integrin is an important cell adhesion receptor involved in tumor-induced angiogenesis and tumor metastasis. Here we describe the 18F-labeling of the RGD-containing glycopeptide cyclo(-Arg-Gly-Asp-D-Phe-Lys(sugar amino acid)-) with 4-nitrophenyl 2-[18F]fluoropropionate and the evaluation of this compound in vitro and in tumor mouse models. Binding assays with isolated immobilized alpha(v)beta3, alpha(v)beta5, and alpha(IIb)beta3 as well as in vivo studies using alpha(v)beta3-positive and -negative murine and xenotransplanted human tumors demonstrated receptor-specific binding of the radiolabeled glycopeptide yielding high tumor:background ratios (e.g., 120 min postinjection: tumor:blood, 27.5; tumor:muscle, 10.2). First imaging results using a small animal positron emission tomograph suggest that this compound is suitable for noninvasive determination of the alpha(v)beta3 integrin status and therapy monitoring.

Non-invasive assessment of the effect of cardiac sympathetic innervation on metabolism of the human heart.

The role of cardiac sympathetic nerves in the regulation of myocardial metabolism is not well defined. Owing to the presence of incomplete reinnervation, heart transplant recipients provide a unique model to study the effects of efferent sympathetic innervation. Using this model, we sought to determine the influence of cardiac sympathetic signals on substrate utilisation and overall oxidative metabolism. In 21 transplant recipients, positron emission tomography was applied to determine sympathetic innervation with the noradrenaline analogue carbon11 hydroxyephedrine, oxidative metabolism with carbon11 acetate (n=14), and glucose utilisation with fluorine-18 fluorodeoxyglucose (n=7). The reinnervated area comprised 22% +/- 20% of the left ventricle. Oxidative metabolism was similar in denervated and reinnervated myocardium [0.06 +/- 0.01 vs 0.06 +/- 0.01/min for k(mono)], while glucose uptake was significantly higher in denervated myocardium (6.9 +/- 6.6 vs 6.0 +/- 6.2 micromol/min/100 g; P=0.03). Reinnervation mainly occurred in the territory of the left anterior descending artery, where retention of 11C-hydroxyephedrine (6.8 +/- 2.7%/min) was higher compared with territories of the left circumflex (4.1 +/- 1.7%/min; P<0.01) and right coronary (3.8 +/- 1.1%/min; P<0.01) arteries. Oxidative metabolism was similar in all three territories, but compared with the reinnervated territory of the left anterior descending artery (53% +/- 16% of maximum), relative FDG uptake was higher in territories of the left circumflex (76% +/- 6%, P<0.01) and right coronary (67% +/- 10%, P<0.05) arteries. Similar degrees of regional heterogeneity were not observed in normals. Thus, while overall energy production through oxidative metabolism remains unaffected, cardiac utilisation of glucose in the fasting state is increased in the absence of catecholamine uptake sites. Innervated myocardium, however, may preferentially utilise free fatty acids, suggesting a role for sympathetic tone in substrate utilisation.

Effect of thyroid hormones on cardiac function, geometry, and oxidative metabolism assessed noninvasively by positron emission tomography and magnetic resonance imaging.

Thyroid hormones influence cardiac performance directly and indirectly via changes in peripheral circulation. Little, however, is known about the effect on myocardial oxidative metabolism and its relation to cardiac function and geometry. Patients with a history of thyroidectomy for thyroid cancer present a unique model to investigate the cardiac effects of hypothyroidism. Ten patients without heart disease were investigated in the hypothyroid state and again 4-6 weeks later under euthyroid conditions. Myocardial oxidative metabolism was measured by positron emission tomography with [11C]acetate and the clearance constant k(mono). Cine magnetic resonance imaging was applied to determine left ventricular geometry. A stroke work index (SWI = stroke volume x systolic blood pressure/ventricular mass) was calculated. Then, to estimate myocardial efficiency, a work metabolic index [WMI = SWI x heart rate/k(mono)] was obtained. Compared to hormone replacement, systemic vascular resistance and left ventricular mass were significantly higher in hypothyroidism. Ejection fraction and SWI were significantly lower. Despite an additional reduction of k(mono), the WMI was significantly lower, too. In summary, cardiac oxygen consumption is reduced in hypothyroidism. This reduction is associated with increased peripheral resistance and reduced contractility. Estimates of cardiac work are more severely suppressed than those of oxidative metabolism, suggesting decreased efficiency. These findings may provide an explanation for development or worsening of heart failure in hypothyroid patients with preexisting heart disease.

Coronary microvascular reactivity to sympathetic stimulation in patients with idiopathic dilated cardiomyopathy.

UNLABELLED: The objective of this study was to assess noninvasively the microvascular reactivity to sympathetic stimulation in patients with idiopathic dilated cardiomyopathy (IDC) and in healthy volunteers, who underwent cardiac catheterization for exclusion of coronary artery disease. METHODS: Myocardial flow was quantified with 13N-ammonia PET and tracer kinetic modeling at rest and in response to cold pressor testing (CPT). Ten healthy volunteers (8 men, 2 women; mean age +/- SD, 50.7 +/- 15 y) and 10 matched patients (8 men, 2 women; mean age, 52.5 +/- 14 y) with IDC (mean left ventricular ejection fraction, 0.30 +/- 0.12) were included in the study. RESULTS: Myocardial perfusion at rest was not significantly different between the groups. However, myocardial vascular resistance (MVR) was significantly lower in IDC patients at rest than in healthy volunteers. In response to CPT a significant decrease in MVR was found in healthy volunteers (1.9 +/- 0.4 to 1.5 +/- 0.4 mm Hg x 100 g/mL; 22% decrease) but not in IDC patients (1.5 +/- 0.4 to 1.4 +/- 0.3 mm Hg x 100 g/mL; 9% decrease). Consequently, the increase of the myocardial blood flow in response to CPT was significantly lower (P < 0.008) in IDC patients (56 +/- 17 to 66 +/- 18 mL/100g/min; 20% increase) compared with healthy volunteers (52 +/- 12 to 80 +/- 30 mL/100 g/min; 52% increase), whereas both showed comparable hemodynamic reactions. CONCLUSION: The data indicate that CPT in combination with 13N PET imaging is a valuable noninvasive tool for assessment of coronary microvascular reaction to sympathetic stimulation in IDC patients. Lower coronary vascular resistance was found in IDC patients at rest compared with healthy volunteers, suggesting possible exhaustion of sympathetically induced dilation of the coronary microvasculature in IDC patients at rest. This mechanism may explain the impaired flow response to cold in IDC patients in the present study.

Reproducibility of metabolic measurements in malignant tumors using FDG PET.

UNLABELLED: PET using 18F-fluorodeoxyglucose (FDG) is increasingly applied to monitor the response of malignant tumors to radiotherapy and chemotherapy. The aim of this study was to assess the reproducibility of serial FDG PET measurements to define objective criteria for the evaluation of treatment-induced changes. METHODS: Sixteen patients participating in phase I studies of novel antineoplastic compounds were examined twice by FDG PET within 10 d while they were receiving no therapy. Standardized uptake values (SUVs), FDG net influx constants (Ki), glucose normalized SUVs (SUV(gluc)) and influx constants (K(i,gluc)) were determined for 50 separate lesions. The precision of repeated measurements was determined on a lesion-by-lesion and a patient-by-patient basis. RESULTS: None of the parameters showed a significant increase or decrease at the two examinations. The differences of repeated measurements were approximately normally distributed for all parameters with an SD of the mean percentage difference of about 10%. The 95% normal ranges for spontaneous fluctuations of SUV, SUV(gluc), Ki and K(i,gluc) were determined to be +/-0.91, +/-1.14, +/-0.52 mL/100 g/min and +/-0.64 mL/100 g/min, respectively. Analysis on a lesion-by-lesion basis yielded similar results. CONCLUSION: FDG PET provides several highly reproducible quantitative parameters of tumor glucose metabolism. Changes of a parameter that are outside the 95% normal range determined in this study may be used to define a metabolic response to therapy.