Denoising non-steady state dynamic PET data using a feed-forward neural network.

The quality of reconstructed dynamic PET images, as well as the statistical reliability of the estimated pharmacokinetic parameters is often compromised by high levels of statistical noise, particularly at the voxel level. Many denoising strategies have been proposed, both in the temporal and spatial domain, which substantially improve the signal to noise ratio of the reconstructed dynamic images. However, although most filtering approaches are fairly successful in reducing the spatio-temporal inter-voxel variability, they may also average out or completely eradicate the critically important temporal signature of a transient neurotransmitter activation response that may be present in a non-steady state dynamic PET study. In this work, we explore an approach towards temporal denoising of non-steady state dynamic PET images using an artificial neural network, which was trained to identify the temporal profile of a time-activity curve, while preserving any potential activation response. We evaluated the performance of a feed-forward perceptron neural network to improve the signal to noise ratio of dynamic [11C]raclopride activation studies and compared it with the widely used highly constrained back projection (HYPR) filter. Results on both simulated Geant4 Application for Tomographic Emission data of a realistic rat brain phantom and experimental animal data of a freely moving animal study showed that the proposed neural network can efficiently improve the noise characteristics of dynamic data in the temporal domain, while it can lead to a more reliable estimation of voxel-wise activation response in target region. In addition, improvements in signal-to-noise ratio achieved by denoising the dynamic data using the proposed neural network led to improved accuracy and precision of the estimated model parameters of the lp-ntPET model, compared to the HYPR filter. The performance of the proposed denoising approach strongly depends on the amount of noise in the dynamic PET data, with higher noise leading to substantially higher variability in the estimated parameters of the activation response. Overall, the feed-forward network led to a similar performance as the HYPR filter in terms of spatial denoising, but led to notable improvements in terms of temporal denoising, which in turn improved the estimation activation parameters.

Real-time 3D motion tracking for small animal brain PET.

High-resolution positron emission tomography (PET) imaging of conscious, unrestrained laboratory animals presents many challenges. Some form of motion correction will normally be necessary to avoid motion artefacts in the reconstruction. The aim of the current work was to develop and evaluate a motion tracking system potentially suitable for use in small animal PET. This system is based on the commercially available stereo-optical MicronTracker S60 which we have integrated with a Siemens Focus-220 microPET scanner. We present measured performance limits of the tracker and the technical details of our implementation, including calibration and synchronization of the system. A phantom study demonstrating motion tracking and correction was also performed. The system can be calibrated with sub-millimetre accuracy, and small lightweight markers can be constructed to provide accurate 3D motion data. A marked reduction in motion artefacts was demonstrated in the phantom study. The techniques and results described here represent a step towards a practical method for rigid-body motion correction in small animal PET. There is scope to achieve further improvements in the accuracy of synchronization and pose measurements in future work.

High-resolution imaging of the large non-human primate brain using microPET: a feasibility study.

The neuroanatomy and physiology of the baboon brain closely resembles that of the human brain and is well suited for evaluating promising new radioligands in non-human primates by PET and SPECT prior to their use in humans. These studies are commonly performed on clinical scanners with 5 mm spatial resolution at best, resulting in sub-optimal images for quantitative analysis. This study assessed the feasibility of using a microPET animal scanner to image the brains of large non-human primates, i.e. papio hamadryas (baboon) at high resolution. Factors affecting image accuracy, including scatter, attenuation and spatial resolution, were measured under conditions approximating a baboon brain and using different reconstruction strategies. Scatter fraction measured 32% at the centre of a 10 cm diameter phantom. Scatter correction increased image contrast by up to 21% but reduced the signal-to-noise ratio. Volume resolution was superior and more uniform using maximum a posteriori (MAP) reconstructed images (3.2-3.6 mm(3) FWHM from centre to 4 cm offset) compared to both 3D ordered subsets expectation maximization (OSEM) (5.6-8.3 mm(3)) and 3D reprojection (3DRP) (5.9-9.1 mm(3)). A pilot (18)F-2-fluoro-2-deoxy-d-glucose ([(18)F]FDG) scan was performed on a healthy female adult baboon. The pilot study demonstrated the ability to adequately resolve cortical and sub-cortical grey matter structures in the baboon brain and improved contrast when images were corrected for attenuation and scatter and reconstructed by MAP. We conclude that high resolution imaging of the baboon brain with microPET is feasible with appropriate choices of reconstruction strategy and corrections for degrading physical effects. Further work to develop suitable correction algorithms for high-resolution large primate imaging is warranted.

Rigid motion correction of dual opposed planar projections in single photon imaging.

Awake and/or freely moving small animal single photon emission imaging allows the continuous study of molecules exhibiting slow kinetics without the need to restrain or anaesthetise the animals. Estimating motion free projections in freely moving small animal planar imaging can be considered as a limited angle tomography problem, except that we wish to estimate the 2D planar projections rather than the 3D volume, where the angular sampling in all three axes depends on the rotational motion of the animal. In this study, we hypothesise that the motion corrected planar projections estimated by reconstructing an estimate of the 3D volume using an iterative motion compensating reconstruction algorithm and integrating it along the projection path, will closely match the true, motion-less, planar distribution regardless of the object motion. We tested this hypothesis for the case of rigid motion using Monte-Carlo simulations and experimental phantom data based on a dual opposed detector system, where object motion was modelled with 6 degrees of freedom. In addition, we investigated the quantitative accuracy of the regional activity extracted from the geometric mean of opposing motion corrected planar projections. Results showed that it is feasible to estimate qualitatively accurate motion-corrected projections for a wide range of motions around all 3 axes. Errors in the geometric mean estimates of regional activity were relatively small and within 10% of expected true values. In addition, quantitative regional errors were dependent on the observed motion, as well as on the surrounding activity of overlapping organs. We conclude that both qualitatively and quantitatively accurate motion-free projections of the tracer distribution in a rigidly moving object can be estimated from dual opposed detectors using a correction approach within an iterative reconstruction framework and we expect this approach can be extended to the case of non-rigid motion.

In vivo evidence for microglial activation in neurodegenerative dementia.

Evidence from numerous neuropathological observations and in vivo clinical imaging studies suggests a prominent role of activated microglia, the main effector cell of the brain's innate immune system, in Alzheimer's disease and other neurodegenerative diseases. Though the comprehensive molecular definition of the microglial activation process is still incomplete, the de novo expression of 'peripheral benzodiazepine-binding sites (PBBS)' by activated but not resting microglia has been established as a useful descriptor of functional state changes in microglia. As microglial transformation to an activated state is closely linked to progressive changes in brain disease, the detection of activated microglia can provide information about disease distribution and rate of disease progression. Positron emission tomography (PET) and [(11)C](R)-PK11195, a specific ligand of the PBBS, have been used to study systematically microglial activation in vivo. Significant microglial activation is present in the brains of patients with neurodegenerative dementia even at early and possibly preclinical stages of the disease with a spatial distribution reflecting different clinical phenotypes. We review some of the posited functions of activated microglia in the pathophysiology of dementia and speculate on the relationship between increased regional [(11)C](R)-PK11195 signals and the ensuing changes in brain volume. Finally, we provide a brief outlook on the development of new radioligands for the PBBS.

Instrumentation and methodology for quantitative pre-clinical imaging studies.

Radiotracer imaging studies performed on animals have the potential to play a major role in pharmaceutical development, pharmacology studies and basic biochemistry research. Recent developments in instrumentation and imaging methodology make it possible to image and quantify the kinetics of radiolabelled pharmaceuticals in a wide range of animal models from rodents to non-human primates. This article reviews the developments which have led to the current state-of-the-art, including advances in detector technologies, image reconstruction and tracer kinetic modelling. The practical issues specific to animal imaging studies are also discussed. With appropriate instrumentation and rigorous methodology, quantitative pre-clinical imaging has an important role to play in drug development.

Attenuation correction using count-limited transmission data in positron emission tomography.

Poisson noise in transmission data can have a significant influence on the statistical uncertainty of PET measurements, particularly at low transmission count rates. In this paper, we investigate the effect of transmission data processing on noise and quantitative accuracy of reconstructed PET images. Differences in spatial resolution between emission and transmission measurements due to transmission data smoothing are shown to have a significant influence on quantitative accuracy and can lead to artifacts in the reconstructed image. In addition, the noise suppression of this technique is insufficient to greatly reduce transmission scan times. Based on these findings, improved strategies for processing count-limited transmission data have been developed, including a method using segmentation of attenuation images. Using this method, accurate attenuation correction can be performed using transmission scan times as low as 2 min without increasing noise in reconstructed PET images.

Correction and characterization of scattered events in three-dimensional PET using scanners with retractable septa.

Large sensitivity increases are realized in positron emission tomography when the interplane septa are removed and all lines of response acquired. Unfortunately, three-dimensional acquisition results in a large increase in scatter fraction which prevents accurate quantitation. By acquiring short two-dimensional scans prior to three-dimensional ones, scatter distributions can be estimated from differences between lines of response common to both datasets. This initial scatter distribution can be further modified to approximate scatter in the entire three-dimensional dataset. The method was validated with phantom measurements in which absolute activity concentrations were known in all compartments. Following scatter correction, a four-compartment phantom that was nonuniform in activity and density, both axially and transaxially, gave activity concentrations of 0.45 +/- 0.02, 0.31 +/- 0.02, 0.01 +/- 0.01 and 0.01 +/- 0.01 microCi/cc for compartments containing 0.43, 0.29, 0.0 (air) and 0.0 (water) microCi/cc, respectively. Thus, scatter distributions for complex sources can be estimated from image data without lengthy Monte-Carlo simulations. When activity distributions vary slowly with time, this method can be used to correct for scatter in three-dimensional patient studies.

Validation of postinjection transmission measurements for attenuation correction in neurological FDG-PET studies.

UNLABELLED: Accurate estimation of local cerebral metabolic rate of glucose utilization (LCMRGlu) with PET requires a separate measurement of photon attenuation using a transmission source that extends study duration. The feasibility of postinjection transmission, (PIT) scanning has been demonstrated but not previously validated in humans. METHODS: Preinjection and postinjection transmission scans were performed in 26 patients undergoing routine [18F]fluorodeoxyglucose (FDG) neurological PET. The PIT data were processed with two methods: One estimated emission contamination using an independent emission scan (PITind); the other estimated the contamination directly from the PIT scan, using simultaneously acquired emission data for subtraction (PITsim). These methods were compared with measured attenuation correction (AC) using preinjection transmission data (ACpre) and calculated AC (ACcalc). After reconstruction, image data were reformatted to fit a standard brain atlas to facilitate analysis of the region of interest and to allow subtraction of datasets averaged over all subjects. RESULTS: The ratios of LCMRGlu values with respect to those obtained by the ACpre method ranged from 0.98 to 1.06 (mean +/- s.d., 1.01 +/- 0.02) for PITind, from 0.96 to 1.04 (mean 0.99 +/- 0.02) for PITsim and from 0.77 to 1.12 (mean 0.96 +/- 0.07) for ACcalc. Both PIT methods agreed well with the ACpre method, whereas ACcalc gave rise to appreciable bias in structures near thick bone or sinuses. CONCLUSION: Accurate quantitative estimates of LCMRGlu can be obtained using PIT measurements. The PIT methods shorten study duration and increase patient throughput. The PITsim method has the further advantage that it is not affected by tracer redistribution and can therefore be applied to tracers with relatively rapid kinetics in vivo.

A transmission-dependent method for scatter correction in SPECT.

UNLABELLED: A method of scatter compensation has been developed that incorporates planar transmission measurements in the estimation of photopeak scatter in SPECT. METHODS: The scatter distribution is first estimated by convolving the planar projections with a monoexponential scatter function. The number of scattered events that subsequently reach the detector as a proportion of total events (i.e., scatter fraction) is then determined for each point in the projections based on narrow-beam transmission values, obtained using an external source. The assumptions of the method were tested using 99mTc and 201Tl point and line sources. The quantitative and qualitative impact of transmission-dependent scatter correction was assessed in realistic phantom experiments simulating blood-pool, lung and myocardial perfusion studies. RESULTS: The method accurately predicts the scatter distribution from 99mTc and 201Tl line sources in a phantom with variable density. Reconstructed counts are artificially enhanced in regions of high tissue density when scattered events are not removed from the projections prior to attenuation correction. Using convolution-subtraction with a constant scatter fraction (k = 0.4), scatter is underestimated in the heart and overestimated in the lungs, whereas transmission-dependent scatter correction enables activity to be quantified with > or = 95% accuracy in heart and lung regions. CONCLUSION: We conclude that incorporating transmission data enables accurate scatter compensation in objects with nonuniform density.

A scanning line source for simultaneous emission and transmission measurements in SPECT.

A scanning collimated line source for simultaneously acquiring emission and transmission data from a gamma camera has been developed. The line source is microprocessor-controlled and incorporates hardware to electronically window the spatial gamma camera signals in order to separate the emission signals of the subject from transmission signals from the line source. The device improves upon the previously described emission-transmission scanning technique using a flood source in three ways: (1) it overcomes the limitation that the transmission radionuclide must have a lower energy than the emission radionuclide; (2) it provides narrow-beam (scatter free) attenuation measurements of the subject being examined; and (3) it reduces the radiation exposure to staff. Attenuation coefficients for an elliptocal water-filled phantom were measured to be mu = 0.15 +/- 0.01 cm-1. The technique has been validated in phantom and human studies using a range of radionuclide combinations and imaging geometries and gives equivalent results using separate and simultaneous acquisitions.

Simultaneous emission and transmission measurements for attenuation correction in whole-body PET.

UNLABELLED: We describe a methodology for measuring and correcting for attenuation in whole-body PET using simultaneous emission and transmission (SET) measurements. METHODS: The main components of the methodology are: (a) sinogram windowing of low activity (< or = 50 MBq) rotating 68Ge/Ga rod sources, (b) segmented attenuation correction (SAC) and (c) maximum likelihood reconstruction using the ordered subsets EM (OS-EM) algorithm. The methods were implemented on a whole-body positron emission tomograph. Quantitative accuracy and the signal-to-noise ratio (SNR) were measured for a thorax-tumor phantom as functions of acquisition time (range: 2-20 min per position). RESULTS: When a typical rod source activity (200 MBq 68Ge/Ga) was used, emission SNR was 60% lower in simultaneous than in separate measurements. The difference was only 14% when the rods contained 45 MBq 68Ge/Ga. The SNR was further improved by SAC in conjunction with OS-EM reconstruction and the relative gain increased with increasing acquisition time. Quantitative estimates of tumor, liver and lung radioactivity agreed with values obtained from a separate high count measurement to within 8%, independent of acquisition time. CONCLUSION: Attenuation correction of whole-body PET images is feasible using SET measurements. There is good quantitative agreement with conventional methods and increased noise is offset by the use of SAC and OS-EM reconstruction.

Pharmacokinetic assessment of novel anti-cancer drugs using spectral analysis and positron emission tomography: a feasibility study.

PURPOSE: The aim of this study was to investigate the feasibility of evaluating the pharmacokinetics of radiolabeled anti-cancer drugs using spectral analysis, a non-compartmental tracer kinetic modeling technique, and positron emission tomography (PET). METHODS: Dynamic PET studies were performed on patients receiving tracer doses of 5-fluorouracil (5-[18F]-FU) and two developmental drugs [11C]-temozolomide and [11C]-acridine carboxamide. Spectral analysis was then used to (a) determine individual and group average pharmacokinetics, (b) predict tumour handling in response to different drug administration regimens, and (c) produce functional parametric images describing regional pharmacokinetics. RESULTS: Spectral analysis could distinguish tumour kinetics from normal tissue kinetics in an individual [11C]-temozolomide study and demonstrated a markedly greater volume of distribution (VD) in glioma than in normal brain, although there was no appreciable difference in mean residence time. Analysis of pooled acridine carboxamide data (n = 22) revealed a relatively large VD (and prolonged retention) in the liver and spleen and a markedly lower VD (and initial uptake) in the brain. Continuous infusion of 5-[18F]-FU was predicted to achieve a concentration in colorectal metastases in liver approximately 10 times that achieved in plasma at 10 h after commencement of the infusion. CONCLUSIONS: We conclude that spectral analysis provides important pharmacokinetic information about radiolabeled anti-cancer drugs with relatively few model assumptions.

The influence of tomograph sensitivity on kinetic parameter estimation in positron emission tomography imaging studies of the rat brain.

We investigated the influence of tomograph sensitivity on reliability of parameter estimation in positron emission tomography studies of the rat brain. The kinetics of two tracers in rat striatum and cerebellum were simulated. A typical injected dose of 10 MBq and a reduced dose of 1 MBq were assumed. Kinetic parameters were estimated using a region of interest (ROI) analysis and two pixel-by-pixel analyses. Striatal binding potential was estimated as a function of effective tomograph sensitivity (S(eff)) using a simplified reference tissue model. A S(eff) value of > or =1% was required to ensure reliable parameter estimation for ROI analysis and a S(eff) of 3-6% was required for pixel-by-pixel analysis. We conclude that effective tomograph sensitivity of 3% may be an appropriate design goal for rat brain imaging.

In vivo imaging of nicotinic receptor upregulation following chronic (-)-nicotine treatment in baboon using SPECT.

To quantify changes in neuronal nAChR binding in vivo, quantitative dynamic SPECT studies were performed with 5-[(123)I]-iodo-A-85380 in baboons pre and post chronic treatment with (-)-nicotine or saline control. Infusion of (-)-nicotine at a dose of 2.0 mg/kg/24h for 14 days resulted in plasma (-)-nicotine levels of 27.3 ng/mL. This is equivalent to that found in an average human smoker (20 cigarettes a day). In the baboon brain the regional distribution of 5-[(123)I]-iodo-A-85380 was consistent with the known densities of nAChRs (thalamus > frontal cortex > cerebellum). Changes in nAChR binding were estimated from the volume of distribution (V(d) ) and binding potential (BP) derived from 3-compartment model fits. In the (-)-nicotine treated animal V(d) was significantly increased in the thalamus (52%) and cerebellum (50%) seven days post cessation of (-)-nicotine treatment, suggesting upregulation of nAChRs. The observed 33% increase in the frontal cortex failed to reach significance. A significant increase in BP was seen in the thalamus. In the saline control animal no changes were observed in V(d) or BP under any experimental conditions. In this preliminary study, we have demonstrated for the first time in vivo upregulation of neuronal nAChR binding following chronic (-)-nicotine treatment.

A convolution-subtraction scatter correction method for 3D PET.

3D acquisition and reconstruction in positron emission tomography (PET) produce data with improved signal-to-noise ratios compared with conventional 2D slice-oriented methods. However, the sensitivity increase is accompanied by an increase in the number of scattered photons and random coincidences detected. This paper presents a scatter correction technique for 3D PET data where an estimate of the scattered photon distribution is subtracted from the data before reconstruction. The scatter distribution is estimated by iteratively convolving the photopeak projections with a mono-exponential kernel. The method accounts for the 3D acquisition geometry and nature of scatter by performing the scatter estimation on 2D projections. The assumptions of the method have been investigated by measuring the variation in the scatter fraction and the scatter function at different positions in a cylinder. Both parameters were found to vary by up to 50% from the centre to the edge of a large water-filled cylinder. Despite this, in a uniform cylinder containing water with different concentrations of radioactivity, scatter was reduced from 25% in a non-radioactive region to less than 5% using the convolution-subtraction method. In addition, the relative concentration of a cylinder containing an increased concentration, which was underestimated by almost 50% without scatter correction, was within 5% of the true concentration after correction.

Accelerated EM reconstruction in total-body PET: potential for improving tumour detectability.

Total-body positron emission tomography (PET) is a useful diagnostic tool for evaluating malignant disease. However, tumour detection is limited by image artefacts due to the lack of attenuation correction and noise. Attenuation correction may be possible using transmission data acquired after or simultaneously with emission data. Despite the elimination of attenuation artefacts, however, tumour detection is still hampered by noise, which is amplified during image reconstruction by filtered backprojection (FBP). We have investigated, as an alternative to FBP, an accelerated expectation maximization (EM) algorithm for its potential to improve tumour detectability in total-body PET. Signal to noise ratio (SNR), calculated for a tumour with respect to the surrounding background, is used as a figure of merit. A software tumour phantom, with conditions typical of those encountered in a total-body PET study using simultaneous acquisition, is used to optimize and compare various reconstruction approaches. Accelerated EM reconstruction followed by two-dimensional filtering is shown to yield significantly higher SNR than FBP for a range of tumour sizes, concentrations and counting statistics (deltaSNR = 6.3 +/- 3.9, p < 0.001). The methods developed are illustrated by examples derived from physical phantom and patient data.

Parametric image reconstruction using spectral analysis of PET projection data.

Spectral analysis is a general modelling approach that enables calculation of parametric images from reconstructed tracer kinetic data independent of an assumed compartmental structure. We investigated the validity of applying spectral analysis directly to projection data motivated by the advantages that: (i) the number of reconstructions is reduced by an order of magnitude and (ii) iterative reconstruction becomes practical which may improve signal-to-noise ratio (SNR). A dynamic software phantom with typical 2-[11C]thymidine kinetics was used to compare projection-based and image-based methods and to assess bias-variance trade-offs using iterative expectation maximization (EM) reconstruction. We found that the two approaches are not exactly equivalent due to properties of the non-negative least-squares algorithm. However, the differences are small (< 5%) and mainly affect parameters related to early and late time points on the impulse response function (K1 and, to a lesser extent, VD). The optimal number of EM iteration was 15-30 with up to a two-fold improvement in SNR over filtered back projection. We conclude that projection-based spectral analysis with EM reconstruction yields accurate parametric images with high SNR and has potential application to a wide range of positron emission tomography ligands.

Simultaneous estimation of physiological parameters and the input function--in vivo PET data.

Dynamic imaging with positron emission tomography (PET) is widely used for the in vivo measurement of regional cerebral metabolic rate for glucose (rCMRGlc) with [18F]fluorodeoxy-D-glucose (FDG) and is used for the clinical evaluation of neurological disease. However, in addition to the acquisition of dynamic images, continuous arterial blood sampling is the conventional method to obtain the tracer time-activity curve in blood (or plasma) for the numeric estimation of rCMRGlc in mg glucose/100-g tissue/min. The insertion of arterial lines and the subsequent collection and processing of multiple blood samples are impractical for clinical PET studies because it is invasive, has the remote, but real potential for producing limb ischemia, and it exposes personnel to additional radiation and risks associated with handling blood. In this paper, based on our previously proposed method for extracting kinetic parameters from dynamic PET images, we developed a modified version (post-estimation method) to improve the numerical identifiability of the parameter estimates when we deal with data obtained from clinical studies. We applied both methods to dynamic neurologic FDG PET studies in three adults. We found that the input function and parameter estimates obtained with our noninvasive methods agreed well with those estimated from the gold standard method of arterial blood sampling and that rCMRGlc estimates were highly correlated (r = 0.973). More importantly, no significant difference was found between rCMRGlc estimated by our methods and the gold standard method (P > 0.16). We suggest that our proposed noninvasive methods may offer an advance over existing methods.

Attenuation correction for freely moving small animal brain PET studies based on a virtual scanner geometry.

Attenuation correction in positron emission tomography brain imaging of freely moving animals is a very challenging problem since the torso of the animal is often within the field of view and introduces a non negligible attenuating factor that can degrade the quantitative accuracy of the reconstructed images. In the context of unrestrained small animal imaging, estimation of the attenuation correction factors without the need for a transmission scan is highly desirable. An attractive approach that avoids the need for a transmission scan involves the generation of the hull of the animal's head based on the reconstructed motion corrected emission images. However, this approach ignores the attenuation introduced by the animal's torso. In this work, we propose a virtual scanner geometry which moves in synchrony with the animal's head and discriminates between those events that traversed only the animal's head (and therefore can be accurately compensated for attenuation) and those that might have also traversed the animal's torso. For each recorded pose of the animal's head a new virtual scanner geometry is defined and therefore a new system matrix must be calculated leading to a time-varying system matrix. This new approach was evaluated on phantom data acquired on the microPET Focus 220 scanner using a custom-made phantom and step-wise motion. Results showed that when the animal's torso is within the FOV and not appropriately accounted for during attenuation correction it can lead to bias of up to 10% . Attenuation correction was more accurate when the virtual scanner was employed leading to improved quantitative estimates (bias < 2%), without the need to account for the attenuation introduced by the extraneous compartment. Although the proposed method requires increased computational resources, it can provide a reliable approach towards quantitatively accurate attenuation correction for freely moving animal studies.