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Background. Low bone mineral density (osteopenia) is encountered in children with acute lymphoblastic leukemia (ALL) before, during and after treatment. Prior experience with alendronate, an oral bisphosphonate, demonstrated high tolerability and evident clinical efficacy. However, concerns have been expressed about the long-term safety and utility of such agents in children. Procedure. Of 217 children with ALL treated on Dana Farber Cancer Institute protocols 69 received alendronate for a mean of 87 weeks after dual energy X ray absorptiometry (DXA). DXA was repeated following completion of alendronate, and again 5-9 years later in a subgroup of 32 children. Lumbar spine areal bone mineral (LS aBMD) Z scores were obtained and values corrected for height, age and weight (HAW) were calculated for subjects 3-18 years of age. Results. Almost 80% (N=172) of the children remain in continuous complete remission at a mean of 14.5 years from diagnosis. Of those who receive alendronate, which was almost uniformly well tolerated, 7/69 (10.3%) relapsed compared to 19/89 (21.3%) who did not receive the drug. The mean unmodified LS aBMD Z score rose from -1.78 to -0.47. This gain was statistically significant for both unmodified (p

The normal interrelationship of body composition with bone health is less clear in the context of disease. Survivors of acute lymphoblastic leukemia (ALL) exhibit sarcopenic obesity and osteopenia. The impact of body composition on bone health in such survivors was examined.Survivors of ALL (N=74),10 years from diagnosis, underwent dual-energy radiograph absorptiometry and peripheral quantitative computed tomography.Whole-body bone mineral content (WB BMC) Z scores were greater in males than females, but WB BMC indices (WB BMC/height 2 ) were comparable (0.74±0.125 and 0.72±0.069, respectively). WB BMC index (I) and fat-free mass index correlated significantly with trabecular bone mineral density, only in males. Fat mass index and appendicular lean mass index showed no such correlations. WB BMCI and fat-free mass index also correlated, again predominantly in males, with measures of strength in both trabecular and cortical bone. WB BMCI also correlated strongly with trabecular number, thickness, and hole size, also only in males.The results point to the need for enhancing muscle mass, measured by appendicular lean mass index, while reducing fat mass and maintaining good bone mineralization in long-term survivors of ALL to ensure the integrity of healthy bones.

Exposure to sub-optimal maternal vitamin D status during pregnancy has been linked to inadequate in utero bone growth with potential for post-natal deficits, but reported findings are inconsistent. Possible reasons include measurement error in assessing bone length/height, or lack of adjustment for confounding variables such as maternal/infant diet, physical activity and season of birth. The objective of this study was to determine the maternal and child factors associated with bone length traits in children at 3 years of age as part of a longitudinal follow-up of a pregnancy cohort.Mother-child dyads enrolled in the Family Atherosclerosis Monitoring In early Life study were included. Maternal serum 25-hydroxyvitamin D (25(OH)D) concentration was measured by liquid chromatography tandem mass spectrometry (LC-MS/MS). Anthropometry, physical activity by questionnaire and dietary assessment by food frequency questionnaire were completed for mothers during pregnancy (27-40 weeks gestation) and for children at 3 years with diet by 3-day food records (Nutritionist Pro). Whole body bone mineral density in mother and child (n = 473) was measured by dual-energy absorptiometry (DXA) at the 3 year visit. A software program was developed using MATLAB to derive bone length measurements from whole body DXA images using 8 long bones of each child. Association between maternal and child variables with offspring bone length was assessed using unadjusted and adjusted multivariate linear regression analyses.In the final adjusted multivariate regression model, factors associated with child bone length were maternal height (p = 0.05), child birth length (p = 0.005) and child weight z-score at 3 years (p 0.001). No association was observed between maternal serum 25(OH)D concentrations in pregnancy (of which 77% were in normal range) and child bone length.In healthy Canadian mothers and their children, the factors associated with child bone length achieved at 3 years of age appear to be related to genetic traits rather than environmental exposures. Measures of the length of long bones in children using DXA scans may have provided a more accurate assessment of bone length than whole body height measures.

Background Loss of bone mineral is a common concomitant of the treatment of acute lymphoblastic leukemia (ALL) due mainly to chemotherapy, especially with corticosteroids. Osteopenia/osteoporosis may be encountered long into survivorship. Measurement of bone mineral density (BMD) by dual-energy X-ray absorptiometry is limited to two-dimensionality and cannot distinguish trabecular from cortical bone. Methods A sample of 74 subjects, ages 13.5-38.3 years more than 10 years from diagnosis, underwent peripheral quantitative computed tomography (pQCT) at metaphyseal (trabecular bone) and diaphyseal (cortical bone) sites in the radius and tibia. pQCT provides three-dimensional assessment of bone geometry, density, and architecture. Results Average values in multiple metrics were similar to those in healthy individuals, but deficits in both trabecular and cortical bones were revealed by lower Z scores using an ethnically comparable sample of healthy individuals. Connectivity, a measure of bone architecture and a surrogate measure of bone strength, was lower in females than males. Survivors of standard-risk ALL had greater connectivity in and more compact trabecular bone than high-risk survivors who had received more intensive osteotoxic chemotherapy. There were no statistically significant differences in any of the metrics at any of the sites between subjects who had or had not a history of fracture, cranial irradiation, or use of a bisphosphonate. Conclusions These long-term survivors of ALL have somewhat compromised bone health, but data in comparable healthy populations are limited. Longitudinal studies in larger and more ethnically diverse cohorts will provide greater insight into bone health in this vulnerable population.

The potential of a diverging fan beam collimator for use in a multimodal SPECT-MR system has been investigated. Collimation was designed for use with a stationary ring of gamma camera modules each comprised of a 32 × 32 pixel CZT detector. The collimators provide a desired field of view (FOV) of 25.0 cm at the center of the bore. Eleven collimator designs were compared, yielding between 13 to 23 modules per ring. Each design was evaluated using reconstructed resolution and sensitivity metrics. The designs were simulated with the Monte Carlo software, GEANT4 Application for the Tomographic Emission (GATE) and tomographic reconstruction was performed with a maximum-likelihood expectation maximization (ML-EM) algorithm in MATLAB. The results showed that a practical SPECT/MR design using 18 detectors per ring with a 3.83 cm length collimator gave equivalent tomographic resolution to that of a clinical SPECT/CT system but with 7.0 times greater detection sensitivity compared to the conventional rotating dual-head camera. Resolution across the reconstructed 25 cm x 25 cm FOV did show slight non-uniformity, with resolution improving around the periphery of the FOV as much as two-fold. A smearing artifact was seen in the corners of the FOV likely due to undersampling within those regions. A reconstructed hot-rod resolution phantom matched the previous results, giving similar resolution performance. However, the simulation also showed that the system suffers from aliasing effects when reconstructing features of 7.9 mm or less. To further investigate how the design choices affected the tomographic resolution, parameters for collimator hole size, detector pixel size, and number of projection angles were explored. Both the reduction of hole size and pixel size each allowed for improved resolvability down to 7.9 mm and 6.4 mm respectively. Increasing the number of projection angles was found to remove smearing artifacts from the image, however it did not significantly change the resolution. The resolution is therefore believed to be limited by the 2.46 mm pixel size and associated pixel matched collimator. These are promising results that show that a diverging fan beam collimator could be a viable choice for a SPECT/MR system.

The first stage of testing towards the further development of a full-ring SPECT/MR system has been evaluated. Performance of the cadmium zinc telluride (CZT) detectors were found to be unaffected by the static magnetic field, however they were found to react unreliably during simultaneous imaging when the MR sequence repetition time (TR) was less than 400ms and were influenced significantly by the imaging gradients. In an effort to better understand this phenomenon, component testing was performed by subjecting the CZT detector modules and electronics to various gradient sequences in a stand-alone gradient testing apparatus. We exposed the modules to 31 unique gradient sequence shapes of varying power and duration, typical of those used in clinical MR devices while simultaneously operating the CZT modules in event readout mode. Results indicate that certain detector pixels were preferentially affected (typically around the periphery of the detector array), leading to induced currents in the detector material and significant increases in erroneous event rates during the gradient ramp-up and ramp-down phases. The shape of the gradient waveform was also seen to have an effect on the detector performance with higher slew rates leading to impaired performance. Hardware disabling of the most severely affected pixels led to some reduction in erroneous background events, however, it also resulted in reduced detector resolution and sensitivity. Subsequent work led to the development of a gradient triggering circuit to momentarily suspend CZT event detection during the MR gradient ramp up and ramp down intervals. Subsequent testing of this circuit in a clinical 3T MR was performed. When gradient triggering was enabled, erroneous event data was reduced to near zero levels and resultant images show no structural differences when compared to control acquisitions. During gradient application, the CZT modules are suspended, thus yielding a 60% drop in sensitivity due to the additional deadtime of the triggering. The produced MR image showed a reduction in SNR of 92%. Co-registration of the MR and gamma camera images was successfully performed, showing both the structural and activity makeup of the phantom.

Background The late effects of treatment for acute lymphoblastic leukemia (ALL) include disordered body composition, especially obesity. Less attention has been focused on the loss of skeletal muscle mass (SMM) and the combined morbidity of sarcopenic obesity. Methods A cross-sectional study of body composition was undertaken via dual-energy x-ray absorptiometry in 75 long-term survivors of ALL (more than 10 years after the diagnosis). Measures were obtained of the fat mass (FM), fat-free mass (equivalent to the lean body mass [LBM]), and whole-body bone mineral content. Health-related quality of life (HRQL) was measured with the Health Utilities Index. Results The sum of the FM, LBM, and whole-body bone mineral content matched the total body weight measured directly (r = 0.998). The appendicular lean mass (ALM) was derived from the LBM in all 4 limbs and accounted for approximately 75% of the SMM. According to the fat mass index (FMI; ie, FM/height2 ), 12% of females and 18% of males were frankly obese by World Health Organization criteria. The median FMI z score was + 0.40, whereas the median z score for the appendicular lean mass index (ALMI; ie, ALM/height2 ) was -0.40. Sarcopenic obesity, defined as a positive FMI z score with a negative ALMI z score, was present in 32 subjects (43%). There were statistically significant and clinically important differences in overall HRQL between subjects with and without sarcopenic obesity. Conclusions Sarcopenic obesity is prevalent in long-term survivors of ALL, and this places them in double jeopardy from excess body fat and inadequate SMM (eg, a combination of metabolic and frailty syndromes). It is associated with an adverse impact on overall HRQL. Cancer 2018;124:1225-31. © 2017 American Cancer Society.

Monte Carlo is an important and well established research tool used in emission tomography. While used extensively in research applications, these techniques are not typically implemented clinically due to their low detection efficiency and long acquisition times. In order to make this computational tool faster, the variance reduction technique known as convolution-based forced detection (CFD) has been implemented into the SIMIND MC code (CFD-SIMIND) by our group. Briefly, at each site of interaction within the object, photons are forced to travel in a direction perpendicular to the detector and are then convolved with a distance dependent blurring kernel specific to that collimator and photon energy. A similar CFD method has already been implemented as an option in the SIMIND Monte Carlo program. This study performs a comparison between a well established, non-VRT Monte Carlo program, GATE, with our accelerated CFD-SIMIND. The intent of this work is to establish if CFD-SIMIND can either replace or be used in conjunction with GATE in order to gain significant reduction in simulation times for low and medium energy isotopes. A number of simulation studies were performed using point sources in air and water, along with the 3D XCAT phantom and a rectangular sheet source for 99mTc with low and medium energy collimator and 111In with medium energy collimator. A comparison in the projection domain was then performed in terms of spatial resolution, sensitivity, image profiles and energy spectra. The study has shown percent differences of between 3–5 % in sensitivity between CFD-SIMIND and GATE with mean universal image quality index value of 0.994 ± 0.009 and spatial resolution within 0.2 mm of each other. CFD-SIMIND offers a significant reduction in simulation time by a factor of 5–6 orders of magnitude compared to GATE. This acceleration time is useful for many applications. This study also provides an objective tool that can help to determine if CFD-SIMIND can be used in place of GATE in order to achieve images of sufficient quality within a reduced time and at much lower computational cost.

PAOPA, a potent analog of Prolyl-Leucyl-Glycinamide, has shown therapeutic potential at the preclinical stage for dopaminergic related illnesses, including animal models of schizophrenia, Parkinson’s disease and haloperidol-induced extrapyramidal movement disorders. PAOPA’s unique allosteric mechanism and dopamine D2 receptor specificity provide a unique composition of properties for the development of potential therapeutics for neuropsychiatric illnesses. We sought to investigate PAOPA’s therapeutic prospects across the spectrum of schizophrenia-like symptoms represented in the established phencyclidine-induced rat model of schizophrenia, (5 mg/kg PCP twice daily for seven days, followed by 7 days of drug withdrawal). PAOPA was assessed for its effect on brain metabolic activity and across a battery of behavioural tests including, hyperlocomotion, social withdrawal, sensorimotor gating, and novel object recognition. PAOPA showed therapeutic efficacy in behavioural paradigms representing the negative (social withdrawal) and cognitive-like (novel object recognition) symptoms of schizophrenia. Interestingly, some behavioural indices associated with the positive symptoms of schizophrenia that were ameliorated in PAOPA’s prior examination in the amphetamine-sensitized model of schizophrenia were not ameliorated in the PCP model; suggesting that the deficits induced by amphetamine and PCP—while phenotypically similar—are mechanistically different and that PAOPA’s effects are restricted to certain mechanisms and systems. These studies provide insight on the potential use of PAOPA for the safe and effective treatment of schizophrenia.

Three-dimensional (3D) mode imaging is the current standard for positron emission tomography-computed tomography (PET-CT) systems. Dynamic imaging for quantification of myocardial blood flow (MBF) with short-lived tracers, such as Rb-82-chloride (Rb-82), requires accuracy to be maintained over a wide range of isotope activities and scanner count-rates. We propose new performance standard measurements to characterize the dynamic range of PET systems for accurate quantitative imaging. Methods: 1100-3000 MBq of Rb-82 or N-13-ammonia was injected into the heart wall insert of an anthropomorphic torso phantom. A decaying isotope scan was performed over 5 half-lives on 9 different 3D PET-CT systems and 1 3D/two-dimensional (2D) PET-only system. Dynamic images (28x15s) were reconstructed using iterative algorithms with all corrections enabled. Dynamic range was defined as the maximum activity in the myocardial wall with

The modelling of the projection operator in tomographic imaging is of critical importance especially when working with algebraic methods of image reconstruction. This paper proposes a distance-driven projection method which is targeted to single-pinhole single-photon emission computed tomograghy (SPECT) imaging since it accounts for the finite size of the pinhole, and the possible tilting of the detector surface in addition to other collimator-specific factors such as geometric sensitivity. The accuracy and execution time of the proposed method is evaluated by comparing to a ray-driven approach where the pinhole is sub-sampled with various sampling schemes. A point-source phantom whose projections were generated using OpenGATE was first used to compare the resolution of reconstructed images with each method using the full width at half maximum (FWHM). Furthermore, a high-activity Mini Deluxe Phantom (Data Spectrum Corp., Durham, NC, USA) SPECT resolution phantom was scanned using a Gamma Medica X-SPECT system and the signal-to-noise ratio (SNR) and structural similarity of reconstructed images was compared at various projection counts. Based on the reconstructed point-source phantom, the proposed distance-driven approach results in a lower FWHM than the ray-driven approach even when using a smaller detector resolution. Furthermore, based on the Mini Deluxe Phantom, it is shown that the distance-driven approach has consistently higher SNR and structural similarity compared to the ray-driven approach as the counts in measured projections deteriorates.

Simultaneous multi-isotope Single Photon Emission Computed Tomography (SPECT) imaging has a number of applications in cardiac, brain, and cancer imaging. The major concern however, is the significant crosstalk contamination due to photon scatter between the different isotopes. The current study focuses on a method of crosstalk compensation between two isotopes in simultaneous dual isotope SPECT acquisition applied to cancer imaging using $^{99m}$ Tc and $^{111}$ In. We have developed an iterative image reconstruction technique that simulates the photon down-scatter from one isotope into the acquisition window of a second isotope. Our approach uses an accelerated Monte Carlo (MC) technique for the forward projection step in an iterative reconstruction algorithm. The MC estimated scatter contamination of a radionuclide contained in a given projection view is then used to compensate for the photon contamination in the acquisition window of other nuclide. We use a modified ordered subset-expectation maximization (OS-EM) algorithm named simultaneous ordered subset-expectation maximization (Sim-OSEM), to perform this step. We have undertaken a number of simulation tests and phantom studies to verify this approach. The proposed reconstruction technique was also evaluated by reconstruction of experimentally acquired phantom data. Reconstruction using Sim-OSEM showed very promising results in terms of contrast recovery and uniformity of object background compared to alternative reconstruction methods implementing alternative scatter correction schemes (i.e., triple energy window or separately acquired projection data). In this study the evaluation is based on the quality of reconstructed images and activity estimated using Sim-OSEM. In order to quantitate the possible improvement in spatial resolution and signal to noise ratio (SNR) observed in this study, further simulation and experimental studies are required.

The activation and expansion of brown adipose tissue (BAT) has emerged as a promising strategy to counter obesity and the metabolic syndrome by increasing energy expenditure. The subsequent testing and validation of novel agents that augment BAT necessitates accurate pre-clinical measurements in rodents regarding the capacity for BAT-derived thermogenesis. We present a novel method to measure BAT thermogenesis using infrared imaging following β3-adrenoreceptor stimulation in mice. We show that the increased body surface temperature observed using this method is due solely to uncoupling protein-1 (UCP1)-mediated thermogenesis and that this technique is able to discern differences in BAT activity in mice acclimated to 23 °C or thermoneutrality (30 °C). These findings represent the first standardized method utilizing infrared imaging to specifically detect UCP1 activity in vivo.

Using psychophysical studies, the authors have evaluated the effectiveness of various strategies for compensating for physical degradations in SPECT imaging. The particular application was Ga-67-citrate imaging of mediastinal tumors, which was chosen because Ga-67 is a particularly challenging radionuclide for imaging. The test strategies included compensations for nonuniform attenuation, distance-dependent spatial resolution, and scatter applied in various combinations as part of iterative reconstructions with the rescaled block iterative-expectation maximization (RBI-EM) algorithm. The authors also evaluated filtered backprojection reconstructions. Strategies were compared on the basis of human-observer studies of lesion localization and detection accuracy using the localization receiver operating characteristics (LROC) paradigm. These studies involved hybrid images which were obtained by adding the projections of Monte Carlo-simulated lesions to disease-free clinical projection data. The background variability in these images can provide a more realistic assessment of the relative utility of reconstruction strategies than images from anthropomorphic digital phantoms. The clinical datasets were obtained using a GE-VG dual-detector SPECT system with CT-estimated attenuation maps. After determining a target lesion contrast, they conducted pilot LROC studies to obtain a near-optimal set of reconstruction parameters for each strategy, and then conducted the strategy comparison study. The results indicate improved detection accuracy with RBI-EM as more compensations are applied within the reconstruction. The relative rankings of the test strategies agreed in most cases with those of previous studies that employed simulated projections of digital anthropomorphic phantoms, thus confirming the findings of those studies.

The expansion of scientific knowledge and technology over the past decades did not result in an increased rate of drug discoveries for respiratory diseases. Despite the identification of numerous targets and lead compounds, few new therapeutic molecules have reached patient care. It is generally acknowledged that the large cost of drug development is mainly because of the high failure rate during clinical testing. Animal models of respiratory disorders used for experimental proof-of-principle and efficacy studies are often criticized because of inherent limitations, one of them being the tool-box used for the assessment of outcomes. Noninvasive imaging is a novel approach which might help to reverse this trend. Different imaging modalities can be combined and molecular, functional and anatomical events can be assessed quantitatively. Compounds with potential beneficial effects can be radiolabeled and proof-of-principle experiments can be addressed to ensure that the drug meets the area with pathology at sufficient concentrations. This method will also help to further characterize different animal models of respiratory disease calling researchers attention to the inherent limitations of each respective model, thus preventing subsequent futile use. Furthermore, preclinical trials can be performed longitudinally in animals in which the pathology has been quantitatively assessed before drug administration. The obvious benefit from a drug discovery perspective is that this approach is a vigorous test for any new drug or indication and probably will facilitate more ‘earlier and better failures’. This review is focusing on multiple components of assessing respiratory diseases with noninvasive small animal imaging tools and how they can be adapted for drug discovery.

In volumetric CT imaging of small animals, the breathing motion of the lungs during the image acquisition process results in inconsistent projection data being acquired. When reconstructed, these inconsistent data may produce images with reduced spatial resolution and image contrast. In order to minimize these effects, various approaches have been utilized to capture the respiratory signal of the animals under study and to only obtain CT data at specific moments in the respiratory cycle. These approaches typically utilize hardware-based physiological monitoring equipment in order to record the respiratory signal and either prospectively or retrospectively correlate this signal with acquired CT projection data. In this work, a new method of CT respiratory gating is described that does not rely on external physiological monitoring. Rather, determination of the respiratory phase of the animal is performed by postprocessing the acquired projection data. With this approach, any CT projection data can be respiratory gated with minimal effort. Validation of the method has been performed using a dynamic phantom and accuracy in tidal volumes determined to be within 16%. Rats and mice have been scanned and processed using the proposed method and compared to physiological-based measurement. With the proposed method, image quality is significantly improved in addition to providing quantitative information regarding tidal lung volumes.

In pelvic bone SPECT using Tc-99m labeled compounds, physical effects such as nonhomogeneous attenuation and the accumulation of activity into the bladder during the data acquisition process can often result in data inconsistencies. With filtered backprojection (FBP) reconstruction, this may result in streak artifacts. Various methods for attenuation compensation can be employed to account for some of these streaks, but if the rate of uptake of tracer in to the bladder is sufficient, the resultant streaks may be significant enough to impair lesion detection. We have investigated various reconstruction methods in an effort to reduce these artifacts. In order to assess the impact of inconsistent bladder activities on the detection of pelvic lesions, SPECT imaging was simulated using the Zubal voxelized phantom, for cases of both a static bladder activity and a changing activity distribution. Reconstructions were performed using FBP, ordered subset-expectation maximization (OSEM) and dynamic expectation maximization (dEM) and was assessed for lesion detectability using a channelized, nonprewhitening (CNPW) numerical observer model. This observer model was used to optimize reconstruction strategies for a human LROC observer study. The human LROC observer study was performed in order to assess the various reconstruction methods in terms of lesion detectability. Three human observers were used in this test. The results of this test indicate that FBP performs significantly worse than static OSEM iterative reconstruction with attenuation correction when assessed using the area under the LROC curve (maximal ALROC=0.47 for FBP versus 0.71 for OSEM). Visually, the dEM algorithm produces images with slightly reduced streak artifacts compared to OSEM, but this improvement was not reflected in significantly improved ALROC values. In fact, when assessed using human LROC methodology, detectability actually decreased slightly when using dEM (maximal ALROC=0.71 for OSEM versus 0.66 for dEM), although this reduction was not determined to be statistically significant. It is possible that the slightly reduced performance of the dEM algorithm may be due, in part, to not performing an optimization in the number of reconstruction iterations as was performed for the OSEM method

A number of factors impact the accuracy of activity quantitation in planar and single photon emission computed tomographic (SPECT) imaging. Two important such factors are attenuation and scattering in the medium containing the activity. The first removes photons which otherwise would have been included in the images, and the second adds events to the images from photons which would not have otherwise been imaged. A number of methods have been developed to compensate for these biases to activity quantitation. This review will briefly introduce planar quantitation which is commonly used for dosimetric purposes, and then present a slightly more detailed overview of SPECT quantitation which is arguably more accurate. It will conclude by cautioning users of commercial reconstruction software to validate it for quantitation before using it for dosimetric purposes.

During /sup 67/Ga citrate SPECT imaging, photon downscatter will occur from higher energy photons into lower energy acquisition windows thus possibly adversely affecting reconstructed image quality. With these additional scattered photons present in projection data, the effect of using more complex reconstruction strategies such as three-dimensional detector response compensation (3-D DRC) and attenuation correction (AC) is unclear. Using a combination of numerical channelized hotelling observers (CHO) and human localization receiver operating characteristics (LROC) studies it has been found that maximum lesion detectability occurs when projection data is reconstructed using two iterations of the rescaled block iterative (RBI) algorithm with both 3-D DRC and patient specific AC, followed by a postreconstruction low-pass 3-D Gaussian filtering with a FWHM of /spl ap/1 cm. These parameters deviate from optimal reconstruction parameters for primary photon-only projection data which finds that maximum lesion detection occurs after 4 RBI iterations with the same 3-D DRC, AC, and postfiltering. As expected, it is also observed that decreased tumor detectability results when scattered photons are present in /sup 67/Ga projection data compared to primary photon only reconstructions (reducing maximum A/sub L/ from 0.79 to 0.58). This decrease has been found to be statistically significant in both human LROC and numerical observer studies, suggesting the need for scatter compensation during /sup 67/Ga citrate imaging.

In this paper, we investigate the use of a numerical observer to optimize ordered-subset expectation maximization (OSEM) reconstructions for the detection of coronary artery disease (CAD). The parameters optimized were the iteration number and the full-width at half-maximum of three-dimensional Gaussian postfiltering. The numerical observer employed in the optimization was the channelized Hotelling observer (CHO). The CHO had been used previously to rank tumor detection accuracy for different reconstruction strategies in Ga-67 images, showing good agreement with the rankings of human observers. The intent of this paper was to determine if this CHO could also be employed for the detection of CAD. Results indicate that when grayscale (quantized) images are used, the CHO optimization results correlate well with human observers. On the other hand, when the CHO was used with floating-point images, it provided very good detection performance even when the images were excessively filtered. This result was at odds with the human-observer performance which showed a decrease in detection accuracy with highly smoothed images. This reflects the need to better model the detection task of the human observers who usually view and rank grayscale images and by appropriately modeling the image noise that quantization introduces, we show that the CHO can better match human-observer detection performance.

Scatter can be a confounding problem in the detection of perfusion defects in myocardial perfusion imaging. The goal of this investigation was to compare practical methods of scatter compensation representing different classes of compensation strategies. The methods investigated were: (1) modification of the energy window; (2) use of effective values of attenuation coefficients; (3) estimating the scatter distribution from energy spectrum information; and (4) estimating the scatter distribution in the spatial domain using the attenuation maps and scatter kernels. Monte Carlo simulated projections from two MCAT source distributions were used to investigate the impact of the various methods on residual scatter and myocardial uniformity. The investigation showed that each of the methods reduce the scatter significantly; however, the spatial domain method gave the least variation with the different source distributions and the best uniformity.

There has been significant interest in the use of semiconductor detectors such as cadmium zinc telluride (CZT) for SPECT/MRI and PET/MRI due to their ability to operate in high magnetic fields. However, the effect of these materials on magnetic field homogeneity must be considered when designing an MR-compatible gamma camera. Field maps were generated for several materials considered for an MR-compatible gamma camera to determine the extent of the shift in magnetic field. The materials used were CZT, Al, carbon fiber, printed circuit boards, thermoelectric cooler, Pb and a composite material consisting largely of tungsten. A lipid phantom filled with a mixture of 50% canola oil and 50% water (∼9 cm × ∼9 cm × 6 cm) was imaged with and without the materials placed adjacent to the phantom/foot ankle coil. Data were acquired with the materials individually and as a combined system with and without power. MRI phase images, at TE = 5 and 8 ms (using a 3T MRI), were used to calculate magnetic field (B0) homogeneity. Tungsten and the thermoelectric cooler resulted in a significant B0 shift near the boundary of the phantom where the materials were placed, whereas the aluminum had the least effect on the field homogeneity. Based on a linear approximation, the material with the largest effect on the magnetic field, tungsten, would need to be placed approximately 0.6 cm outside of the RF receiver coil, making it 3.4 cm in total from the phantom to have negligible effect on the field homogeneity. There was negligible effect on magnetic field homogeneity when high or low voltage power were supplied to the CZT detector system.

Monte Carlo is an important and well established research tool in emission tomography. While used extensively in research applications, Monte Carlo techniques are not typically implemented clinically due to is its low detection efficiency and resultant long acquisition times. In order to make this notoriously slow computational tool faster, variance reduction techniques known as convolution based forced detection (CFD) have previously been implemented into SIMIND MC code (CFD-SIMIND) by our group. In this method, at each interaction site within the object, photons are forced to travel in a direction perpendicular to the detector and are convolved with a Gaussian blurring kernel based on the collimator response. This study focuses on the feasibility of using CFD-SIMIND in the absence of septal penetration and collimator scatter modeling for low and medium energy isotopes. In this study, the results of CFD-SIMIND have been compared with GATE Monte Carlo in order to validate the CFD-SIMIND results.

Dynamic SPECT (dSPECT) is an image reconstruction method capable of determining three dimensional regional estimates of physiological kinetic rates while still maintaining the simple acquisition protocol of a single, slow camera rotation. Through the use of inequality constraints in a least squares optimization routine, the authors are able to determine both the rate of tracer uptake and subsequent tracer washout over the acquisition time of the SPECT scan. Simulations modelling different camera acquisition geometries and with variable dual exponential kinetic parameters and model complexity (e.g., statistical noise, object attenuation) were performed. It was found that kinetic parameters were accurate to within 50% of the true values for the case of fast uptake and slow washout for a single head acquisition and improved to within 95% when acquired with a triple head camera. Experimental phantom tests corroborated these results and are shown to have an accuracy of about 90%. A preliminary patient study of renal dynamics has also been performed and compared with conventional planar dynamic imaging. Results from this study indicate that the dSPECT reconstruction method is able to determine kinetic information with accuracy comparable to that of conventional planar dynamic imaging methods while providing additional three dimensional time behaviour information.

Radionuclide imaging is now widely used whenever functional information is required. We present a new approach to dynamic SPECT imaging (dSPECT method) that uses a single slow rotation of a conventional camera and allows us to reconstruct a series of 3D images corresponding to the radiotracer distribution in the body at various times. Using simulations of various camera configurations and acquisition protocols, we have shown that this method is able to reconstruct washout half-lives with an accuracy greater than 90% when used with triple-head SPECT cameras. Accuracy decreases when using fewer camera heads, but dual-head geometries still give an accuracy greater than 80% for short and 90% for long half-lives and about 50-75% for single-head systems. Dynamic phantom experiments have yielded similar results. Presence of attenuation and background activity does not affect the accuracy of the dSPECT reconstructions. In all situations investigated satisfactory dynamic images were produced. A preliminary normal volunteer study measuring renal function was performed. The reconstructed dynamic images may be presented as a three-dimensional movie showing movement of the tracer through the kidneys and the measurement of the regional renal function can be performed. The time-activity curves determined from this dSPECT data are very similar to those obtained from dynamic planar scans.

Techniques to estimate dynamic parameters from the data acquired during a single rotation of a standard (single, dual and triple head) SPECT camera are being investigated. The performance of the constrained linear least squares (C-LS) method is being assessed. This method uses a simple assumption that the activity within each pixel at a given projection angle is less than or equal to the activity seen at the prior angle. In simulations, we have used an analytical heart model with single and bi-exponential activity decrease, with and without background activity and statistical noise in the data. Studies using a single, a 90/spl deg/ dual and a 120/spl deg/ triple head camera were modeled with a total acquisition time of 20 min, performing rotation over 1800. These simulations were followed by experimental scans of our dynamic phantom used with and without attenuation and subsequently a preliminary study involving a human subject was performed. Dynamic images from simulations and phantom experiments reconstruct well with an accuracy of reconstructed half-lives for most reconstructions within a 20% error range. Some streaking artifacts which are evident in images corresponding to early reconstruction times subside upon incorporating further constraints and regularizations.

Background Functional imaging studies in schizophrenic patients have demonstrated metabolic brain abnormalities during cognitive tasks. This study aimed to 1) introduce a novel analysis of brain metabolic function in live animals to characterize the hypo- and hyperfrontality phenomena observed in schizophrenia and following NMDA antagonist exposure, and 2) identify a robust and representative MK-801 treatment regimen that effectively models brain metabolic abnormalities as well as a range of established behavioural abnormalities representative of schizophrenia. Methods The validity of the MK-801 animal model was examined across several established pre-clinical tests, and a novel assessment of brain metabolic function using PET/CT fused imaging. In the present study, MK-801 was administered acutely at 0.1 mg/kg and 0.5 mg/kg, and sub-chronically at 0.5 mg/kg daily for 7 days. Results Acute treatment at 0.5 mg/kg-disrupted facets of memory measured through performance in the 8-arm radial maze task and generated abnormalities in sensorimotor gating, social interaction and locomotor activity. Furthermore, this treatment regimen induced hyperfrontality (increased brain metabolic function in the prefrontal area) observed via PET/CT fused imaging in the live rat. Limitations While PET and CT fused imaging in the live rat offers a functional representation of metabolic function, more advanced PET/CT integration is required to analyze more discrete brain regions. Conclusion These findings provide insight on the effectiveness of the MK-801 pre-clinical model of schizophrenia and provide an optimal regimen to model schizophrenia. PET/CT fused imaging offers a highly translatable tool to assess hypo- and hyperfrontality in live animals.

Preclinical imaging allows pulmonary researchers to study lung disease and pulmonary drug delivery noninvasively and longitudinally in small animals. However, anatomically localizing a pathology or drug deposition to a particular lung region is not easily done. Thus, a detailed knowledge of the anatomical structure of small animal lungs is necessary for understanding disease progression and in addition would facilitate the analysis of the imaging data, mapping drug deposition and relating function to structure. In this study, contrast-enhanced micro-computed tomography (CT) of the lung produced high-resolution images that allowed for the characterization of the rodent airway and pulmonary vasculature. Contrast-enhanced micro-CT was used to visualize the airways and pulmonary vasculature in Sprague-Dawley rats (200–225 g) and BALB/c mice (20–25 g) postmortem. Segmented volumes from these images were processed to yield automated measurements of the airways and pulmonary vasculature. The diameters, lengths, and branching angles of the airway, arterial, and venous trees were measured and analyzed as a function of generation number and vessel diameter to establish rules that could be applied at all levels of tree hierarchy. In the rat, airway, arterial, and venous tress were measured down to the 20th, 16th, and 14th generation, respectively. In the mouse, airway, arterial, and venous trees were measured down to the 16th, 8th, and 7th generation, respectively. This structural information, catalogued in a rodent database, will increase our understanding of lung structure and will aid in future studies of the relationship between structure and function in animal models of disease.

The recent introduction of organ specific imaging systems such as the GE Discovery NM 530c has focused attention on using arrays of small cameras using single-pinhole collimators. While offering advantages in terms of the speed of data acquisition and detection sensitivity, cost issues arise with an increased number of detectors. The goal of this research is to minimize the number of detectors for data acquisition while preserving the resolution of the reconstructed images so that small structures of interest can be reconstructed reliably. The approach taken to solve this problem is to analyze the Fourier properties of a mathematical formulation of the single-pinhole transform in order to construct an optimal sampling lattice. The sampling lattice, in turn, dictates the distance between pinholes and the shift of the detector surface if required.

In simultaneous dual isotope breast SPECT studies using 1231 labelled Z-MIVE and 99mTc-sestamibi, 123I labelled ZMIVE not only detects the presence of estrogen receptor (ER) but also thought to complement 99mTc-sestamibi in differentiating between benign and malignant breast lesions for patients with breast cancer. The major concern in simultaneous 99mTc/123I SPECT is the significant crosstalk contamination between the different isotopes used. The current study focuses on a method of crosstalk compensation between two isotopes in simultaneous 99mTc/123I SPECT in case of Thallium activated Sodium Iodide (Nal(Tl)) detector (Energy resolution 9.8% at 140 keV) and Cadmium Zinc Telluride (CZT) detector (Energy resolution 5% 140 keV) respectively. Monte Carlo (MC), which is thought to offer the most realistic crosstalk and scatter compensation modelling, in typical implementations, has inherent long calculation times (often several hours or days) associated with it. This makes MC unsuitable for clinical applications. Our group has previously incorporated convolution based forced detection (CFD) into SIMIND Monte Carlo program which have made MC feasible to use in clinical time frames. We have developed an iterative MC-based image reconstruction technique that simulates the photon downscatter from one isotope into the acquisition window of a second isotope. The MC based estimation of scatter contamination contained in projection views is then used to compensate for the photon contamination during iterative reconstruction. We use a modified ordered subset-expectation maximization (OS-EM), named as simultaneous ordered subset-expectation maximization (Sim-OSEM), to perform this step. We have undertaken a number of simulation studies using our modelled breast phantom to verify this approach. Reconstruction using Sim-OSEM showed very promising results in terms of crosstalk and scatter compensation and uniformity of background. In our case images obtained using Sim-OSEM were comparable or even better than the images reconstructed from separately acquired projection data using analytical attenuation based reconstruction. This may be due to better small angle scatter compensation in case of Sim-OSEM as MC based forward projector was used.

Molecular breast imaging (MBI) is an imaging modality used as an adjuvant to mammography in women with dense breast tissue. In order to be useful for population screening, the radiation dose from MBI must be on par with the dose obtained from x-ray mammography. In an effort to reduce radiation dose while maintaining acceptable image quality, we are investigating the use of incorporating backscattered photons in order to improve image quality. Because backscattered photons simply undergo a 1800 scatter prior to detection, they yield the same spatial information as primary photons, but with reduced energy (90.4 keY for Tc-99m). We have performed Monte Carlo simulations of a Tc-99m source with a pixelated CZT based gamma camera to investigate the feasibility of backscatter imaging in an effort to reduce patient dose while maintaining image quality. Aspects of image quality was quantified through a comparison of the count sensitivity spatial resolution and contrast to noise ratio with and without backscatter photons using a clinical MBI system. Using a triple energy window scatter correction results in an increase in count sensitivity by up to 10%, minimal degradation in spatial resolution and an increase in contrast to noise ratio by up to 8%.

A Monte Carlo-based image reconstruction algorithm for SPECT has previously been developed utilizing an accelerated version of the SIMIND Monte Carlo program incorporating convolution-based forced detection. This program has been extended to also provide estimates of patient specific radiation dose by storing energy deposition information inside the object as part of the simulation process. Simulations have been performed with both simple and complex geometries and have been validated against GATE to ensure that the results are reproducible. In simple geometries, energy deposition values agree to within 10% between SIMIND and GATE. However, in higher density materials there is a large discrepancy between the dose estimates found in both programs. Future efforts include determining the source of these discrepancies.

Simultaneous multi-isotope SPECT imaging has a number of applications, for example, cardiac, brain and cancer imaging. The major concern in simultaneous multi-isotope is the significant crosstalk contamination between the different isotopes used. The current study focuses on a method of crosstalk compensation between two isotopes in simultaneous dual isotope SPECT acquisition applied to cancer imaging using 99mTc/111In. Monte Carlo (MC), which is thought to offer the most realistic crosstalk and scatter compensation modeling, in typical implementations, has inherent long calculation times (often several hours or days) associated with it. This makes MC unsuitable for clinical applications. We have previously incorporated convolution based forced detection into SIMIND Monte Carlo program which have made MC feasible to use in clinical time frames. In order to evaluate the accuracy of our accelerated MC program a number of point source simulation results were compared to experimentally acquired data in terms of spatial resolution and detector sensitivity. We have developed an iterative MC-based image reconstruction technique that simulates the photon downscatter from one isotope into the acquisition window of a second isotope. The MC based estimation of scatter contamination contained in projection views is then used to compensate for the photon contamination during iterative reconstruction. We use a modified ordered subset-expectation maximization (OS-EM), named as simultaneous ordered subset-expectation maximization (Sim-OSEM), to perform this step. We have undertaken a number of simulation tests and phantom studies to verify this approach. The proposed reconstruction technique also evaluated by reconstruction of experimentally acquired projection phantom data. Reconstruction using Sim-OSEM showed very promising results in terms of crosstalk and scatter compensation and uniformity of background compared to analytical attenuation based reconstruction after triple energy window (TEW) based scatter correction of projection data. In our case images obtained using Sim-OSEM showed better scatter compensation and more uniform background when compared to the images reconstructed for separately acquired projection data using analytical attenuation based reconstruction.

We have investigated the use of a tileable 4 × 4 array of SiPM pixels coupled with a CsI(Tl) crystal for use in a gamma camera. We have performed simulations of a number of geometries using both pixelated and monolithic scintillation crystals. Event positioning algorithms were also investigated as an alternative to conventional Anger logic positioning. Simulations have shown that by using multi-channel parallel electronics, we can adequately resolve intrinsic spatial resolution down to 1 mm, even in the presence of noise. Based on the results of these simulations, we have built a prototype SiPM system comprising of 16 detection channels coupled to either 2mm (6 × 6) or 3mm (4 × 4) discrete crystals. A charge sensitive preamplifier, pulse height detection circuit and a digital acquisition system make up our pulse processing components in our gamma camera system. With this system, we can adequately distinguish each crystal element in the array and have obtained an energy resolution of 30 ± 1% (FWHM) with Tc-99m (140 keV). In the presence of a magnetic field, we have seen no spatial distortion of the resultant image and have obtained an energy resolution of 31 ± 3%. Subsequent work will expand this prototype system to a larger array (16 × 16 SiPM pixels) and will include implementing a novel signal multiplexing scheme (256 to 32 channels).

Introduction This study used the dopamine transporter (DAT) probe, [ 123 I]-2β-carbomethoxy-3β-(4-fluorophenyl)- N -(3-iodo- E -allyl)nortropane ([ 123 I]altropane), to assess the DAT levels in the 6-hydroxydopamine rat model of Parkinson's disease. We sought to assess if the right to left [ 123 I]altropane striatal ratios correlated with dopamine content in the striatum and substantia nigra and with behavioural outcomes. Methods [ 123 I]altropane images taken pre- and postlesion were acquired before and after the transplantation of neural stem/progenitor cells. The images obtained using [ 123 I]altropane and single photon emission computed tomography (SPECT) were compared with specific behavioural tests and the dopamine content assessed by high-performance liquid chromatography. Results [ 123 I]altropane binding correlated with the content of dopamine in the striatum; however, [ 123 I]altropane binding did not correlate with the dopamine content in the substantia nigra. There was a significant correlation of altropane ratios with the cylinder test and the postural instability test, but not with amphetamine rotations. The low coefficient of determination ( r 2 ) for these correlations indicated that [ 123 I]altropane SPECT was not a good predictor of behavioural outcomes. Conclusion Our data reveal that [ 123 I]altropane predicts the integrity of the striatal dopamine nerve terminals, but does not predict the integrity of the nigrostriatal system. [ 123 I]altropane could be a useful marker to measure dopamine content in cell replacement therapies; however, it would not be able to evaluate outcomes for neuroprotective strategies.

Hybrid LROC studies can be used to more realistically assess the impact of reconstruction strategies, compared to those constructed with digital phantoms. This is because hybrid data provides the background variability that is present in clinical imaging, as well as, control over critical imaging parameters, required to conduct meaningful tests. Hybrid data is obtained by adding Monte Carlo simulated lesions to disease free clinical projection data. Due to Ga-67 being a particularly challenging radionuclide for imaging, we use Ga- 67 hybrid SPECT data to study the effectiveness of the various correction strategies developed to account for degradations in SPECT imaging. Our data was obtained using GE-VG dual detector SPECT-CT camera. After determining a target lesion contrast we conduct pilot LROC studies to obtain a near-optimal set of reconstruction parameters for the different strategies individually. These near-optimal parameters are then used to reconstruct the final evaluation study sets. All LROC study results reported here were obtained employing human observers only. We use final LROC study results to assess the impact of attenuation compensation, scatter compensation and detector resolution compensation on data reconstructed with the RBI-EM algorithm. We also compare these with FBP reconstructions of the same dataset. Our experiment indicates an improvement in detection accuracy, as various degradations inherent in the image acquisition process are compensated for in the reconstruction process.

The ability of micro-computed tomography (CT) to noninvasively evaluate allergic pulmonary inflammation in an experimental model was investigated. In addition, two image segmentation methods and the value of respiratory gating were investigated in the context of this model. Brown Norway rats were exposed to one of four doses of house dust mite (HDM) extract (0, 0.15, 15 or 150 microg) delivered intratracheally every 24 h for 10 days. CT scanning was performed at baseline and after several longitudinal HDM exposures. Both thoracic- and lung-segmentation methods yielded similar results when standardisation practices were employed. While tissue histology correlated well with CT images, cell counts from bronchoalveolar lavage depicted greater inflammation than did density measures from CT images. Evidence from representative CT slices and transaxial density distribution indicated that inflammation was primarily associated with major airways and extended into the periphery from these focal points. Respiratory gating demonstrated that images of the inspiratory state provided greater contrast of inflammatory processes. Lastly, decreases in tidal volumes indicated significant mechanical respiratory changes in animals exposed to both 15 and 150 microg. In summary, CT image segmentation can extract pertinent data on in vivo allergic airway/lung inflammation. Furthermore, respiratory gating provides additional contrast and insight into these quantification practices.

In SPECT imaging, photon transport effects such as scatter, attenuation and septal penetration can negatively affect the quality of the reconstructed image and the accuracy of quantitation estimation. As such, it is useful to model these effects as carefully as possible during the image reconstruction process. Many of these effects can be included in Monte Carlo (MC) based image reconstruction using convolution-based forced detection (CFD). With CFD Monte Carlo (CFD-MC), often only the geometric response of the collimator is modeled, thereby making the assumption that the collimator materials are thick enough to completely absorb photons. However, in order to retain high collimator sensitivity and high spatial resolution, it is required that the septa be as thin as possible, thus resulting in a significant amount of septal penetration for high energy radionuclides. A method for modeling the effects of both collimator septal penetration and geometric response using ray tracing (RT) techniques has been performed and included into a CFD-MC program. Two look-up tables are pre-calculated based on the specific collimator parameters and radionuclides, and subsequently incorporated into the SIMIND MC program. One table consists of the cumulative septal thickness between any point on the collimator and the center location of the collimator. The other table presents the resultant collimator response for a point source at different distances from the collimator and for various energies. A series of RT simulations have been compared to experimental data for different radionuclides and collimators. Results of the RT technique matches experimental data of collimator response very well, producing correlation coefficients higher than 0.995. Reasonable values of the parameters in the lookup table and computation speed are discussed in order to achieve high accuracy while using minimal storage space for the look-up tables. In order to achieve noise-free projection images from MC, it is seen that the inclusion of the RT implementation for septal penetration increases the speed of the simulation by a factor of about 7,500 compared to the conventional SIMIND MC program.

Background Idiopathic pulmonary fibrosis (IPF) is a treatment resistant disease with poor prognosis. Numerous compounds have been demonstrated to efficiently prevent pulmonary fibrosis (PF) in animal models but only a few were successful when given to animals with established fibrosis. Major concerns of current PF models are spontaneous resolution and high variability of fibrosis, and the lack of assessment methods that can allow to monitor the effect of drugs in individual animals over time. We used a model of experimental PF in rats and compare parameters obtained in living animals with conventional assessment tools that require removal of the lungs. Methods PF was induced in rats by adenoviral gene transfer of transforming growth factor-beta. Morphological and functional changes were assessed for up to 56 days by micro-CT, lung compliance (measured via a mechanical ventilator) and VO2max and compared to histomorphometry and hydroxyproline content. Results Standard histological and collagen assessment confirmed the persistent fibrotic phenotype as described before. The histomorphological scores correlated both to radiological (r2 = 0.29, p < 0.01) and functional changes (r2 = 0.51, p < 0.0001). VO2max did not correlate with fibrosis. Conclusion The progression of pulmonary fibrosis can be reliably assessed and followed in living animals over time using invasive, non-terminal compliance measurements and micro-CT. This approach directly translates to the management of patients with IPF and allows to monitor therapeutic effects in drug intervention studies.

Monte Carlo (MC) is a well-utilized tool for simulating photon transport in single photon emission computed tomography (SPECT) due to its ability to accurately model physical processes of photon transport. As a consequence of this accuracy, it suffers from a relatively low detection efficiency and long computation time. One technique used to improve the speed of MC modeling is the effective and well-established variance reduction technique (VRT) known as forced detection (FD). With this method, photons are followed as they traverse the object under study but are then forced to travel in the direction of the detector surface, whereby they are detected at a single detector location. Another method, called convolution-based forced detection (CFD), is based on the fundamental idea of FD with the exception that detected photons are detected at multiple detector locations and determined with a distance-dependent blurring kernel. In order to further increase the speed of MC, a method named multiple projection convolution-based forced detection (MP-CFD) is presented. Rather than forcing photons to hit a single detector, the MP-CFD method follows the photon transport through the object but then, at each scatter site, forces the photon to interact with a number of detectors at a variety of angles surrounding the object. This way, it is possible to simulate all the projection images of a SPECT simulation in parallel, rather than as independent projections. The result of this is vastly improved simulation time as much of the computation load of simulating photon transport through the object is done only once for all projection angles.The results of the proposed MP-CFD method agrees well with the experimental data in measurements of point spread function (PSF), producing a correlation coefficient (r(2)) of 0.99 compared to experimental data. The speed of MP-CFD is shown to be about 60 times faster than a regular forced detection MC program with similar results.