Optimized sampling for high resolution multi-pinhole brain SPECT with stationary detectors.

Brain perfusion SPECT can be used in the diagnosis of various neurologic or psychiatric disorders, e.g. stroke, epilepsy, dementia and posttraumatic stress disorder. As traditional SPECT provides limited resolution and sensitivity, we recently proposed a high resolution focusing multi-pinhole clinical SPECT scanner dubbed G-SPECT-I (Beekman et al 2015, Eur. J. Nucl. Med. Mol. Imaging 42 S209). G-SPECT-I achieves data completeness in the scan region of interest (ROI) by making small translations of the patient bed while using projections from all bed positions together for image reconstruction. A strategy to restrict the number of bed translations is desired to minimize overhead time. Previously we presented optimized bed translation paths for focused partial brain imaging, while here we focus on whole brain imaging which is the common procedure in perfusion studies. Thus, a series of noise-free scans using a reduced number of bed positions were simulated and compared to an oversampled reference scan acquired with 128 bed positions. Noisy simulations were included to validate the utility of the optimized sequences in more realistic situations. Brain uptake ratios (BURs) and left-right Asymmetry Indices (AIs) in 51 selected regions of interest (ROIs) were calculated for assessment. Results show that images were barely affected by decreasing the number of bed positions from 128 down to 18 (mean deviation from the reference of only 2.2% and 1.5% for the BUR and AI, respectively) while slightly larger deviations (2.9% and 2.7%, respectively) were obtained when using 12 positions. For both 18- and 12-position sequences these deviations due to sampling were much smaller than those induced by noise (mean deviation of 6.5% and 8.6%, respectively). Given an associated total overhead for bed movement of half a minute (18 positions) or 20 s (12 positions), G-SPECT-I can be a clinical platform that brings new protocols for fast (dynamic) whole brain SPECT and motion correction into reach.

Optimized image acquisition for dopamine transporter imaging with ultra-high resolution clinical pinhole SPECT.

SPECT can be used to image dopamine transporter (DaT) availability in the human striatum, e.g. for diagnosis of Parkinson's disease (PD). As traditional SPECT provides limited resolution and sensitivity, we proposed a full ring focusing multi-pinhole SPECT system (G-SPECT-I (Beekman 2015 Eur. J. Nucl. Med. Mol. Imaging 42 S209)) which demonstrated a 2.5 mm reconstructed resolution in phantom scans. G-SPECT-I achieves data completeness in the scan region of interest by translating the patient bed with an xyz-stage and combining projections from all bed positions into image reconstruction using a scanning focus method (SFM). This paper aims to develop dedicated SFM parameters for performing a DaTscan with high effective sensitivity and appropriate sampling. To this end, the axial scanning length was restricted and transaxial bed trajectories with a reduced number of positions based on a convex hull data-completeness model were tested. Quantitative accuracy was assessed using full G-SPECT-I simulations of an Alderson phantom based on measured system matrices. For each sampling strategy, the specific binding ratio (SBR) and asymmetry index (AI) in the left and right striatum, as well as the Localized SBR (L-SBR) and the Localized AI (L-AI) in eight striatal sub-regions were calculated and compared to those of the reference scan which performs full brain oversampling using 112 bed positions. Results show that structures essential for PD diagnosis were visually and quantitatively barely affected even when using the lowest number of bed translations (i.e. 4). The maximum deviation from the reference was only 1.5%, 1.5%, 5.5% and 7.0% for the SBR, AI, L-SBR and L-AI, respectively, when 4 positions were used. Thus, it is possible to perform an accurate DaTscan with a confined axial scan region and a limited number of focused bed positions. This enables protocols for extremely fast dynamic SPECT scans with less than half-minute time frames, which can be useful for motion correction.

Influence of respiratory gating, image filtering, and animal positioning on high-resolution electrocardiography-gated murine cardiac single-photon emission computed tomography.

Cardiac parameters obtained from single-photon emission computed tomographic (SPECT) images can be affected by respiratory motion, image filtering, and animal positioning. We investigated the influence of these factors on ultra-high-resolution murine myocardial perfusion SPECT. Five mice were injected with 99m technetium (99mTc)-tetrofosmin, and each was scanned in supine and prone positions in a U-SPECT-II scanner with respiratory and electrocardiographic (ECG) gating. ECG-gated SPECT images were created without applying respiratory motion correction or with two different respiratory motion correction strategies. The images were filtered with a range of three-dimensional gaussian kernels, after which end-diastolic volumes (EDVs), end-systolic volumes (ESVs), and left ventricular ejection fractions were calculated. No significant differences in the measured cardiac parameters were detected when any strategy to reduce or correct for respiratory motion was applied, whereas big differences (> 5%) in EDV and ESV were found with regard to different positioning of animals. A linear relationship (p < .001) was found between the EDV or ESV and the kernel size of the gaussian filter. In short, respiratory gating did not significantly affect the cardiac parameters of mice obtained with ultra-high-resolution SPECT, whereas the position of the animals and the image filters should be the same in a comparative study with multiple scans to avoid systematic differences in measured cardiac parameters.

Three-dimensional histologic validation of high-resolution SPECT of antibody distributions within xenografts.

UNLABELLED: Longitudinal imaging of intratumoral distributions of antibodies in vivo in mouse cancer models is of great importance for developing cancer therapies. In this study, multipinhole SPECT with sub-half-millimeter resolution was tested for exploring intratumoral distributions of radiolabeled antibodies directed toward the epidermal growth factor receptor (EGFr) and compared with full 3-dimensional target expression assessed by immunohistochemistry. METHODS: (111)In-labeled zalutumumab, a human monoclonal human EGFr-targeting antibody, was administered at a nonsaturating dose to 3 mice with xenografted A431 tumors exhibiting high EGFr expression. Total-body and focused in vivo tumor SPECT was performed at 0 and 48 h after injection and compared both visually and quantitatively with full 3-dimensional immunohistochemical staining for EGFr target expression. RESULTS: SPECT at 48 h after injection showed that activity was predominantly concentrated in the tumor (10.5% ± 1.3% of the total-body activity; average concentration, 30.1% ± 4.6% of the injected dose per cubic centimeter). (111)In-labeled EGFr-targeting antibodies were distributed heterogeneously throughout the tumor. Some hot spots were observed near the tumor rim. Immunohistochemistry indicated that the antibody distributions obtained by SPECT were morphologically similar to those obtained for ex vivo EGFr target expression. Regions showing low SPECT activity were necrotic or virtually negative for EGFr target expression. A good correlation (r = 0.86, P < 0.0001) was found between the percentage of regions showing low activity on SPECT and the percentage of necrotic tissue on immunohistochemistry. CONCLUSION: Multipinhole SPECT enables high-resolution visualization and quantification of the heterogeneity of (111)In-zalutumumab concentrations in vivo.

VECTor: a preclinical imaging system for simultaneous submillimeter SPECT and PET.

UNLABELLED: Today, PET and SPECT tracers cannot be imaged simultaneously at high resolutions but require 2 separate imaging systems. This paper introduces a Versatile Emission Computed Tomography system (VECTor) for radionuclides that enables simultaneous submillimeter imaging of single-photon and positron-emitting radiolabeled molecules. METHODS: γ-photons produced both by electron-positron annihilation and by single-photon emitters are projected onto the same detectors by means of a novel cylindric high-energy collimator containing 162 narrow pinholes that are grouped in clusters. This collimator is placed in an existing SPECT system (U-SPECT-II) with 3 large-field-of-view γ-detectors. From the acquired projections, PET and SPECT images are obtained using statistical image reconstruction that corrects for energy-dependent system blurring. RESULTS: For PET tracers, the tomographic resolution obtained with a Jaszczak hot rod phantom was less than 0.8 mm, and 0.5-mm resolution images of SPECT tracers were acquired simultaneously. SPECT images were barely degraded by the simultaneous presence of a PET tracer, even when the activity concentration of the PET tracer exceeded that of the SPECT tracer by up to a factor of 2.5. Furthermore, we simultaneously acquired fully registered 3- and 4-dimensional multiple functional images from living mice that, in the past, could be obtained only sequentially. CONCLUSION: High-resolution complementary information about tissue function contained in SPECT and PET tracer distributions can now be obtained simultaneously using a fully integrated imaging device. These combined unique capabilities pave the way for new perspectives in imaging the biologic systems of rodents.

Fast spiral SPECT with stationary γ-cameras and focusing pinholes.

UNLABELLED: Small-animal SPECT systems with stationary detectors and focusing multiple pinholes can achieve excellent resolution-sensitivity trade-offs. These systems are able to perform fast total-body scans by shifting the animal bed through the collimator using an automated xyz stage. However, so far, a large number of highly overlapping central fields of view have been used, at the cost of overhead time needed for animal repositioning and long image reconstruction times due to high numbers of projection views. METHODS: To improve temporal resolution and reduce image reconstruction time for such scans, we have developed and tested spiral trajectories (STs) of the animal bed requiring fewer steps. In addition, we tested multiplane trajectories (MPTs) of the animal bed, which is the standard acquisition method of the U-SPECT-II system that is used in this study. Neither MPTs nor STs require rotation of the animal. Computer simulations and physical phantom experiments were performed for a wide range of numbers of bed positions. Furthermore, we tested STs in vivo for fast dynamic mouse scans. RESULTS: We found that STs require less than half the number of bed positions of MPTs to achieve sufficient sampling. The reduced number of bed positions made it possible to perform a dynamic total-body bone scan and a dynamic hepatobiliary scan with time resolutions of 60 s and 15 s, respectively. CONCLUSION: STs open up new possibilities for high throughput and fast dynamic radio-molecular imaging.

Murine cardiac images obtained with focusing pinhole SPECT are barely influenced by extra-cardiac activity.

Ultra-high-resolution SPECT images can be obtained with focused multipinhole collimators. Here we investigate the influence of unwanted high tracer uptake outside the scan volume on reconstructed tracer distributions inside the scan volume, for (99m)Tc-tetrofosmin myocardial perfusion scanning in mice. Simulated projections of a digital mouse phantom (MOBY) in a focusing multipinhole SPECT system (U-SPECT-II, MILabs, The Netherlands) were generated. With this system differently sized user-defined scan volumes can be selected, by translating the animal in 3D through the focusing collimators. Scan volume selections were set to (i) a minimal volume containing just the heart, acquired without translating the animal during scanning, (ii) a slightly larger scan volume as is typically applied for the heart, requiring only small XYZ translations during scanning, (iii) same as (ii), but extended further transaxially, and (iv) same as (ii), but extended transaxially to cover the full thorax width (gold standard). Despite an overall negative bias that is significant for the minimal scan volume, all selected volumes resulted in visually similar images. Quantitative differences in the reconstructed myocardium between gold standard and the results from the smaller scan volume selections were small; the 17 standardized myocardial segments of a bull's eye plot, normalized to the myocardial mean of the gold standard, deviated on average 6.0%, 2.5% and 1.9% for respectively the minimal, the typical and the extended scan volume, while maximum absolute deviations were respectively 18.6%, 9.0% and 5.2%. Averaged over ten low-count noisy simulations, the mean absolute deviations were respectively 7.9%, 3.2% and 1.9%. In low-count noisy simulations, the mean and maximum absolute deviations for the minimal scan volume could be reduced to respectively 4.2% and 12.5% by performing a short survey scan of the exterior activity and focusing the remaining scan time at the organ of interest. We conclude that reconstructed tracer distribution in the myocardium can be influenced by activity in surrounding organs when a too narrow scan volume is used. With slightly larger scan volumes this problem is adequately suppressed. This approach produced a smaller mean deviation and may be more effective than employing a narrow scan volume with an additional survey scan.

Targeted multi-pinhole SPECT.

PURPOSE: Small-animal single photon emission computed tomography (SPECT) with focused multi-pinhole collimation geometries allows scanning modes in which large amounts of photons can be collected from specific volumes of interest. Here we present new tools that improve targeted imaging of specific organs and tumours, and validate the effects of improved targeting of the pinhole focus. METHODS: A SPECT system with 75 pinholes and stationary detectors was used (U-SPECT-II). An XYZ stage automatically translates the animal bed with a specific sequence in order to scan a selected volume of interest. Prior to stepping the animal through the collimator, integrated webcams acquire images of the animal. Using sliders, the user designates the desired volume to be scanned (e.g. a xenograft or specific organ) on these optical images. Optionally projections of an atlas are overlaid semiautomatically to locate specific organs. In order to assess the effects of more targeted imaging, scans of a resolution phantom and a mouse myocardial phantom, as well as in vivo mouse cardiac and tumour scans, were acquired with increased levels of targeting. Differences were evaluated in terms of count yield, hot rod visibility and contrast-to-noise ratio. RESULTS: By restricting focused SPECT scans to a 1.13-ml resolution phantom, count yield was increased by a factor 3.6, and visibility of small structures was significantly enhanced. At equal noise levels, the small-lesion contrast measured in the myocardial phantom was increased by 42%. Noise in in vivo images of a tumour and the mouse heart was significantly reduced. CONCLUSION: Targeted pinhole SPECT improves images and can be used to shorten scan times. Scan planning with optical cameras provides an effective tool to exploit this principle without the necessity for additional X-ray CT imaging.

Absolute quantitative total-body small-animal SPECT with focusing pinholes.

PURPOSE: In pinhole SPECT, attenuation of the photon flux on trajectories between source and pinholes affects quantitative accuracy of reconstructed images. Previously we introduced iterative methods that compensate for image degrading effects of detector and pinhole blurring, pinhole sensitivity and scatter for multi-pinhole SPECT. The aim of this paper is (1) to investigate the accuracy of the Chang algorithm in rodents and (2) to present a practical Chang-based method using body outline contours obtained with optical cameras. METHODS: Here we develop and experimentally validate a practical method for attenuation correction based on a Chang first-order method. This approach has the advantage that it is employed after, and therefore independently from, iterative reconstruction. Therefore, no new system matrix has to be calculated for each specific animal. Experiments with phantoms and animals were performed with a high-resolution focusing multi-pinhole SPECT system (U-SPECT-II, MILabs, The Netherlands). This SPECT system provides three additional optical camera images of the animal for each SPECT scan from which the animal contour can be estimated. RESULTS: Phantom experiments demonstrated that an average quantification error of -18.7% was reduced to -1.7% when both window-based scatter correction and Chang correction based on the body outline from optical images were applied. Without scatter and attenuation correction, quantification errors in a sacrificed rat containing sources with known activity ranged from -23.6 to -9.3%. These errors were reduced to values between -6.3 and +4.3% (with an average magnitude of 2.1%) after applying scatter and Chang attenuation correction. CONCLUSION: We conclude that the modified Chang correction based on body contour combined with window-based scatter correction is a practical method for obtaining small-animal SPECT images with high quantitative accuracy.

Pixel-based subsets for rapid multi-pinhole SPECT reconstruction.

Block-iterative image reconstruction methods, such as ordered subset expectation maximization (OSEM), are commonly used to accelerate image reconstruction. In OSEM, the speed-up factor over maximum likelihood expectation maximization (MLEM) is approximately equal to the number of subsets in which the projection data are divided. Traditionally, each subset consists of a couple of projection views, and the more subsets are used, the more the solution deviates from MLEM solutions. We found for multi-pinhole single photon emission computed tomography (SPECT) that even moderate acceleration factors in OSEM lead to inaccurate reconstructions. Therefore, we introduce pixel-based ordered subset expectation maximization (POSEM), which is based on an alternative subset choice. Pixels in each subset are spread out regularly over projections and are spatially separated as much as possible. We validated POSEM for data acquired with a focusing multi-pinhole SPECT system. Performance was compared with traditional OSEM and MLEM for a rat total body bone scan, a gated mouse myocardial perfusion scan and a Defrise phantom scan. We found that POSEM can be operated at acceleration factors that are often an order of magnitude higher than in traditional OSEM.

U-SPECT-II: An Ultra-High-Resolution Device for Molecular Small-Animal Imaging.

UNLABELLED: We present a new rodent SPECT system (U-SPECT-II) that enables molecular imaging of murine organs down to resolutions of less than half a millimeter and high-resolution total-body imaging. METHODS: The U-SPECT-II is based on a triangular stationary detector set-up, an XYZ stage that moves the animal during scanning, and interchangeable cylindric collimators (each containing 75 pinhole apertures) for both mouse and rat imaging. A novel graphical user interface incorporating preselection of the field of view with the aid of optical images of the animal focuses the pinholes to the area of interest, thereby maximizing sensitivity for the task at hand. Images are obtained from list-mode data using statistical reconstruction that takes system blurring into account to increase resolution. RESULTS: For (99m)Tc, resolutions determined with capillary phantoms were smaller than 0.35 and 0.45 mm using the mouse collimator with 0.35- and 0.6-mm pinholes, respectively, and less than 0.8 mm using the rat collimator with 1.0-mm pinholes. Peak geometric sensitivity is 0.07% and 0.18% for the mouse collimator with 0.35- and 0.6-mm pinholes, respectively, and 0.09% for the rat collimator. Resolution with (111)In, compared with that with (99m)Tc, was barely degraded, and resolution with (125)I was degraded by about 10%, with some additional distortion. In vivo, kidney, tumor, and bone images illustrated that U-SPECT-II could be used for novel applications in the study of dynamic biologic systems and radiopharmaceuticals at the suborgan level. CONCLUSION: Images and movies obtained with U-SPECT-II provide high-resolution radiomolecule visualization in rodents. Discrimination of molecule concentrations between adjacent volumes of about 0.04 microL in mice and 0.5 microL in rats with U-SPECT-II is readily possible.

System calibration and statistical image reconstruction for ultra-high resolution stationary pinhole SPECT.

For multipinhole single-photon emission computed tomography (SPECT), iterative reconstruction algorithms are preferred over analytical methods, because of the often complex multipinhole geometries and the ability of iterative algorithms to compensate for effects like spatially variant sensitivity and resolution. Ideally, such compensation methods are based on accurate knowledge of the position-dependent point spread functions (PSFs) specifying the response of the detectors to a point source at every position in the instrument. This paper describes a method for model-based generation of complete PSF lookup tables from a limited number of point-source measurements for stationary SPECT systems and its application to a submillimeter resolution stationary small-animal SPECT system containing 75 pinholes (U-SPECT-I). The method is based on the generalization over the entire object to be reconstructed, of a small number of properties of point-source responses which are obtained at a limited number of measurement positions. The full shape of measured point-source responses can almost be preserved in newly created PSF tables. We show that these PSFs can be used to obtain high-resolution SPECT reconstructions: the reconstructed resolutions judged by rod visibility in a micro-Derenzo phantom are 0.45 mm with 0.6-mm pinholes and below 0.35 mm with 0.3-mm pinholes. In addition, we show that different approximations, such as truncating the PSF kernel, with significant reduction of reconstruction time, can still lead to acceptable reconstructions.

Submillimeter total-body murine imaging with U-SPECT-I.

UNLABELLED: Recently, we launched a stationary SPECT system (U-SPECT-I) dedicated to small-animal imaging. A cylinder with 75 gold micropinhole apertures that focus on a mouse organ was used to maximize the detection yield of gamma-photons. Image resolutions of approximately 0.45 and 0.35 mm could be achieved with 0.6- and 0.3-mm pinholes, respectively. Here, we present a combined acquisition and reconstruction strategy that allowed us to perform full-body imaging with U-SPECT-I. METHODS: The bed was stepped in the axial and transaxial directions so that the pinholes collected photons from the entire animal (scanning focus method, or SFM). Next, a maximum-likelihood expectation maximization algorithm exploited all projections simultaneously to reconstruct the entire volume sampled. The memory required for image reconstruction was dramatically reduced by using the same transition submatrix for each of the bed positions. This use of the same submatrix was possible because the submatrix acted on subvolumes that were shifted during reconstruction to match the corresponding location of the focus. RESULTS: In all cases, SFM clearly improved on the method that involves stitching separate reconstructions of subvolumes obtained from the different bed positions. SFM suffered less from noise, streak artifacts, and improper background activity. In a mouse-sized phantom containing a capillary-resolution insert, sets of radioactively filled capillaries as small as 0.45 mm separated by 0.45 mm could be distinguished. Total-body mouse bone imaging using (99m)Tc-hydroxymethylene diphosphonate showed that uptake in very small structures, such as parts of the vertebral processes, could be distinguished. CONCLUSION: In addition to providing ultra-high-resolution images of mouse organs, focusing SPECT pinhole systems are also suitable for submillimeter-resolution total-body imaging of mice.

U-SPECT-I: a novel system for submillimeter-resolution tomography with radiolabeled molecules in mice.

UNLABELLED: A major advance in biomedical science and diagnosis was accomplished with the development of in vivo techniques to image radiolabeled molecules, but limited spatial resolution has slowed down applications to small experimental animals. Here, we present a SPECT system (U-SPECT-I) dedicated to radionuclide imaging of murine organs at a submillimeter resolution. METHODS: The high performance of U-SPECT-I is based on a static triangular detector setup, with a cylindric imaging cavity in the center and 75 gold micropinhole apertures in the cavity wall. The pinholes are focused on a small volume of interest such as the mouse heart or spine to maximize the detection yield of gamma-photons. Three-dimensional molecular distributions are iteratively estimated using the detector data and a statistical reconstruction algorithm that takes into account system blurring and data noise to increase resolution and reduce image noise. RESULTS: With 0.6-mm-diameter pinholes, the maximum fraction of detected photons emitted by a point source (peak sensitivity) is 0.22% for a 15%-wide energy window and remains higher than 0.12% in the central 12 mm of the central plane. In a resolution phantom, radioactively filled capillaries as small as 0.5 mm and separated by 0.5 mm can be distinguished clearly in reconstructions. Projection data needed for the reconstruction of cross sections of molecular distributions in mouse organs can readily be obtained without the need for any mechanical movements. Images of a mouse spine show 99mTc-hydroxymethylene diphosphonate uptake down to the level of tiny parts of vertebral processes. These are separated clearly from the vertebral and intervertebral foramina. Using another tracer, one can monitor myocardial perfusion in the left and right ventricular walls, even in structures as small as the papillary muscles. CONCLUSION: U-SPECT-I allows discrimination between molecular concentrations in adjacent volumes of as small as about 0.1 muL, which is significantly smaller than can be imaged by any existing SPECT or PET system. Our initial in vivo images of the mouse heart and spine show that U-SPECT-I can be used for novel applications in the study of dynamic biologic systems with a clear projection to clinical applications. The combination of high resolution and detection efficiency of U-SPECT-I opens up new possibilities for the suborgan-level study of radiotracers in mouse models.

Design and simulation of a high-resolution stationary SPECT system for small animals.

Exciting new SPECT systems can be created by combining pinhole imaging with compact high-resolution gamma cameras. These new systems are able to solve the problem of the limited sensitivity-resolution trade-off that hampers contemporary small animal SPECT. The design presented here (U-SPECT-III) uses a set of detectors placed in a polygonal configuration and a cylindrical collimator that contains 135 pinholes arranged in nine rings. Each ring contains 15 gold pinhole apertures that focus on the centre of the cylinder. A non-overlapping projection is acquired via each pinhole. Consequently, when a mouse brain is placed in the central field-of-view, each voxel in the cerebrum can be observed via 130 to 135 different pinholes simultaneously. A method for high-resolution scintillation detection is described that eliminates the depth-of-interaction problem encountered with pinhole cameras, and is expected to provide intrinsic detector resolutions better than 150 microm. By means of simulations U-SPECT-III is compared to a simulated dual pinhole SPECT (DP-SPECT) system with a pixelated array consisting of 2.0 x 2.0 mm NaI crystals. Analytic calculations indicate that the proposed U-SPECT-III system yields an almost four times higher linear and about sixty times higher volumetric system resolution than DP-SPECT, when the systems are compared at matching system sensitivity. In addition, it should be possible to achieve a 15 up to 30 times higher sensitivity with U-SPECT-III when the systems are compared at equal resolution. Simulated images of a digital mouse-brain phantom show much more detail with U-SPECT-III than with DP-SPECT. In a resolution phantom, 0.3 mm diameter cold rods are clearly visible with U-SPECT-III, whereas with DP-SPECT the smallest visible rods are about 0.6-0.8 mm. Furthermore, with U-SPECT-III, the image deformations outside the central plane of reconstruction that hamper conventional pinhole SPECT are strongly suppressed. Simulation results indicate that future pinhole SPECT systems are likely to bring about significant improvements in radio-molecular imaging of small animals.

Monte Carlo-based down-scatter correction of SPECT attenuation maps.

Combined acquisition of transmission and emission data in single-photon emission computed tomography (SPECT) can be used for correction of non-uniform photon attenuation. However, down-scatter from a higher energy isotope (e.g. 99mTc) contaminates lower energy transmission data (e.g. 153Gd, 100 keV), resulting in underestimation of reconstructed attenuation coefficients. Window-based corrections are often not very accurate and increase noise in attenuation maps. We have developed a new correction scheme. It uses accurate scatter modelling to avoid noise amplification and does not require additional energy windows. The correction works as follows: Initially, an approximate attenuation map is reconstructed using down-scatter contaminated transmission data (step 1). An emission map is reconstructed based on the contaminated attenuation map (step 2). Based on this approximate 99mTc reconstruction and attenuation map, down-scatter in the 153Gd window is simulated using accelerated Monte Carlo simulation (step 3). This down-scatter estimate is used during reconstruction of a corrected attenuation map (step 4). Based on the corrected attenuation map, an improved 99mTc image is reconstructed (step 5). Steps 3-5 are repeated to incrementally improve the down-scatter estimate. The Monte Carlo simulator provides accurate down-scatter estimation with significantly less noise than down-scatter estimates acquired in an additional window. Errors in the reconstructed attenuation coefficients are reduced from ca. 40% to less than 5%. Furthermore, artefacts in 99mTc emission reconstructions are almost completely removed. These results are better than for window-based correction, both in simulation experiments and in physical phantom experiments. Monte Carlo down-scatter simulation in concert with statistical reconstruction provides accurate down-scatter correction of attenuation maps.