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Nanoparticles are ultrafine particulate matter having considerable potential for treatment of central nervous system (CNS) disorders. Despite their tiny size, the blood-brain barrier (BBB) restricts their access to the CNS. Their direct cerebrospinal fluid (CSF) administration bypasses the BBB endothelium, but still fails to give adequate brain uptake. We present a novel approach for efficient CNS delivery of 111In-radiolabelled gold nanoparticles (AuNPs; 10–15 nm) via intra-cisterna magna administration, with tracking by SPECT imaging. To accelerate CSF brain influx, we administered AuNPs intracisternally in conjunction with systemic hypertonic saline, which dramatically increased the parenchymal AuNP uptake, especially in deep brain regions. AuNPs entered the CNS along periarterial spaces as visualized by MRI of gadolinium-labelled AuNPs and were cleared from brain within 24 h and excreted through the kidneys. Thus, the glymphatic-assisted perivascular network augment by systemic hypertonic saline is a pathway for highly efficient brain-wide distribution of small AuNPs.

Implant infections caused by Staphylococcus aureus are difficult to treat due to biofilm formation, which complicates surgical and antibiotic treatment. We introduce an alternative approach using monoclonal antibodies (mAbs) targeting S. aureus and provide evidence of the specificity and biodistribution of S.-aureus-targeting antibodies in a mouse implant infection model. The monoclonal antibody 4497-IgG1 targeting wall teichoic acid in S. aureus was labeled with indium-111 using CHX-A”-DTPA as a chelator. Single Photon Emission Computed Tomography/computed tomographyscans were performed at 24, 72 and 120 h after administration of the 111In-4497 mAb in Balb/cAnNCrl mice with a subcutaneous implant that was pre-colonized with S. aureus biofilm. The biodistribution of this labelled antibody over various organs was visualized and quantified using SPECT/CT imaging, and was compared to the uptake at the target tissue with the implanted infection. Uptake of the 111In-4497 mAbs at the infected implant gradually increased from 8.34 %ID/cm3 at 24 h to 9.22 %ID/cm3 at 120 h. Uptake at the heart/blood pool decreased over time from 11.60 to 7.58 %ID/cm3, whereas the uptake in the other organs decreased from 7.26 to less than 4.66 %ID/cm3 at 120 h. The effective half-life of 111In-4497 mAbs was determined to be 59 h. In conclusion, 111In-4497 mAbs were found to specifically detect S. aureus and its biofilm with excellent and prolonged accumulation at the site of the colonized implant. Therefore, it has the potential to serve as a drug delivery system for the diagnostic and bactericidal treatment of biofilm.

Microscopic nuclear imaging down to spatial resolutions of a few hundred microns can already be achieved using low-energy gamma emitters (e.g. 125I, ∼30 keV) and a basic single micro-pinhole gamma camera. This has been applied to in vivo mouse thyroid imaging, for example. For clinically used radionuclides such as 99mTc, this approach fails due to penetration of the higher-energy gamma photons through the pinhole edges. To overcome these resolution degradation effects, we propose a new imaging approach: scanning focus nuclear microscopy (SFNM). We assess SFNM using Monte Carlo simulations for clinically used isotopes. SFNM is based on the use of a 2D scanning stage with a focused multi-pinhole collimator containing 42 pinholes with narrow pinhole aperture opening angles to reduce photon penetration. All projections of different positions are used to iteratively reconstruct a three-dimensional image from which synthetic planar images are generated. SFNM imaging was tested using a digital Derenzo resolution phantom and a mouse ankle joint phantom containing 99mTc (140 keV). The planar images were compared with those obtained using a single-pinhole collimator, either with matched pinhole diameter or with matched sensitivity. The simulation results showed an achievable 99mTc image resolution of 0.04 mm and detailed 99mTc bone images of a mouse ankle with SFNM. SFNM has strong advantages over single-pinhole imaging in terms of spatial resolution.

Photomultiplier tube (PMT)-based scintillation cameras are predominant in molecular imaging but have the drawback that position estimation is severely degraded near the edges (dead edge effect). This leads to sensitivity losses and can cause severe problems in applications like molecular breast imaging and in certain SPECT devices. Using smaller light sensors or semiconductor detectors can solve this issue but leads to increased costs. Here we present a gamma detector based on standard PMTs with a novel light-guide-PMT geometry that strongly reduces dead edges. In our design, a monolithic NaI(Tl) scintillator is read out by square PMTs placed in a staggered arrangement. At the edge of the scintillator we inserted additional light-guides to emulate half-size PMTs. Detector performance was assessed for 99m Tc imaging; an average spatial resolution of 3.6 mm was measured over the whole detector, degrading to 4.0 mm within 30 mm to the critical edge. The dead edge of the scintillator is

A variety of polymer micelles are designed for the delivery of chemotherapeutic drugs to tumors. Although the promise of these nanocarriers is very high, in the clinic the effectivity is rather limited. Determining the in vivo fate of the micelles can greatly help to improve this treatment. Here, a simple and fast chelator-free method for radiolabeling of polymer micelles composed of different block copolymers is presented, which can allow evaluating the behavior of the nanocarriers in vivo using noninvasive nuclear imaging techniques (e.g., single photon computed tomography, SPECT). The radiolabeling method consists of adding the radioisotope ions, i.e., 111In(III), resulting in a high radiolabeling efficiencies up to 90%. The results suggest that the radiolabeling efficiency depends on two important factors: the properties of the hydrophobic block in the block copolymer composing the micelle core, and the speciation of the radiometal salts. The formation of metal hydroxides and their precipitation in the core of the micelles appears to be a key factor for high stability. Moreover, the method can be applied to radiolabel the micelles in the presence of chemotherapeutic drugs. Finally, a SPECT study shows that the radiolabeled samples are stable in vivo without any evident loss of 111In(III).

Implant-associated Staphylococcus aureus infections are difficult to treat because of biofilm formation. Bacteria in a biofilm are often insensitive to antibiotics and host immunity. Monoclonal antibodies (mAbs) could provide an alternative approach to improve the diagnosis and potential treatment of biofilm-related infections. Here, we show that mAbs targeting common surface components of S. aureus can recognize clinically relevant biofilm types. The mAbs were also shown to bind a collection of clinical isolates derived from different biofilm-associated infections (endocarditis, prosthetic joint, catheter). We identify two groups of antibodies: one group that uniquely binds S. aureus in biofilm state and one that recognizes S. aureus in both biofilm and planktonic state. Furthermore, we show that a mAb recognizing wall teichoic acid (clone 4497) specifically localizes to a subcutaneously implanted pre-colonized catheter in mice. In conclusion, we demonstrate the capacity of several human mAbs to detect S. aureus biofilms in vitro and in vivo.

Molecular imaging & biology : MIB 21(6), 1034-1043 (2019). doi:10.1007/s11307-019-01339-0, Published by Elsevier Science, Amsterdam [u.a.]

SPECT imaging with

Implant-associated Staphylococcus aureus infections are difficult to treat because of biofilm formation. Bacteria in a biofilm are often insensitive to antibiotics and host immunity. Monoclonal antibodies (mAbs) could provide an alternative approach to improve the diagnosis and potential treatment of biofilm-related infections. Here, we show that mAbs targeting common surface components of S. aureus can recognize clinically relevant biofilm types. The mAbs were also shown to bind a collection of clinical isolates derived from different biofilm-associated infections (endocarditis, prosthetic joint, catheter). We identify two groups of antibodies: one group that uniquely binds S. aureus in biofilm state and one that recognizes S. aureus in both biofilm and planktonic state. Furthermore, we show that a mAb recognizing wall teichoic acid (clone 4497) specifically localizes to a subcutaneously implanted pre-colonized catheter in mice. In conclusion, we demonstrate the capacity of several human mAbs to detect S. aureus biofilms in vitro and in vivo.

Background Calcification and inflammation are atherosclerotic plaque compositional biomarkers that have both been linked to stroke risk. The aim of this study was to evaluate their co-existing prevalence in human carotid plaques with respect to plaque phenotype to determine the value of hybrid imaging for the detection of these biomarkers. Methods Human carotid plaque segments, obtained from endarterectomy, were incubated in [111In]In-DOTA-butylamino-NorBIRT ([111In]In-Danbirt), targeting Leukocyte Function-associated Antigen-1 (LFA-1) on leukocytes. By performing SPECT/CT, both inflammation from DANBIRT uptake and calcification from CT imaging were assessed. Plaque phenotype was classified using histology. Results On a total plaque level, comparable levels of calcification volume existed with different degrees of inflammation and vice versa. On a segment level, an inverse relationship between calcification volume and inflammation was evident in highly calcified segments, which classify as fibrocalcific, stable plaque segments. In contrast, segments with little or no calcification presented with a moderate to high degree of inflammation, often coinciding with the more dangerous fibrous cap atheroma phenotype. Conclusion Calcification imaging alone can only accurately identify highly calcified, stable, fibrocalcific plaques. To identify high-risk plaques, with little or no calcification, hybrid imaging of calcification and inflammation could provide diagnostic benefit.

Despite improvements in small animal PET instruments, many tracers cannot be imaged at sufficiently high resolutions due to positron range, while multi-tracer PET is hampered by the fact that all annihilation photons have equal energies. Here we realize multi-isotope and sub-mm resolution PET of isotopes with several mm positron range by utilizing prompt gamma photons that are commonly neglected. A PET-SPECT-CT scanner (VECTor/CT, MILabs, The Netherlands) equipped with a high-energy cluster-pinhole collimator was used to image 124I and a mix of 124I and 18F in phantoms and mice. In addition to positrons (mean range 3.4 mm) 124I emits large amounts of 603 keV prompt gammas that—aided by excellent energy discrimination of NaI—were selected to reconstruct 124I images that are unaffected by positron range. Photons detected in the 511 keV window were used to reconstruct 18F images. Images were reconstructed iteratively using an energy dependent matrix for each isotope. Correction of 18F images for contamination with 124I annihilation photons was performed by Monte Carlo based range modelling and scaling of the 124I prompt gamma image before subtracting it from the 18F image. Additionally, prompt gamma imaging was tested for 89Zr that emits very high-energy prompts (909 keV). In Derenzo resolution phantoms 0.75 mm rods were clearly discernable for 124I, 89Zr and for simultaneously acquired 124I and 18F imaging. Image quantification in phantoms with reservoirs filled with both 124I and 18F showed excellent separation of isotopes and high quantitative accuracy. Mouse imaging showed uptake of 124I in tiny thyroid parts and simultaneously injected 18F-NaF in bone structures. The ability to obtain PET images at sub-mm resolution both for isotopes with several mm positron range and for multi-isotope PET adds to many other unique capabilities of VECTor’s clustered pinhole imaging, including simultaneous sub-mm PET-SPECT and theranostic high energy SPECT.

SPECT imaging with 123I-FP-CIT is used for diagnosis of neurodegenerative disorders like Parkinson’s disease. Attenuation correction (AC) can be useful for quantitative analysis of 123I-FP-CIT SPECT. Ideally, AC would be performed based on attenuation maps ( μ -maps) derived from perfectly registered CT scans. Such μ -maps, however, are most times not available and possible errors in image registration can induce quantitative inaccuracies in AC corrected SPECT images. Earlier, we showed that a convolutional neural network (CNN) based approach allows to estimate SPECT-aligned μ -maps for full brain perfusion imaging using only emission data. Here we investigate the feasibility of similar CNN methods for axially focused 123I-FP-CIT scans. We tested our approach on a high-resolution multi-pinhole prototype clinical SPECT system in a Monte Carlo simulation study. Three CNNs that estimate μ -maps in a voxel-wise, patch-wise and image-wise manner were investigated. As the added value of AC on clinical 123I-FP-CIT scans is still debatable, the impact of AC was also reported to check in which cases CNN based AC could be beneficial. AC using the ground truth μ -maps (GT-AC) and CNN estimated μ -maps (CNN-AC) were compared with the case when no AC was done (No-AC). Results show that the effect of using GT-AC versus CNN-AC or No-AC on striatal shape and symmetry is minimal. Specific binding ratios (SBRs) from localized regions show a deviation from GT-AC ≤ 2.5% for all three CNN-ACs while No-AC systematically underestimates SBRs by 13.1%. A strong correlation ( r ≥ 0.99) was obtained between GT-AC based SBRs and SBRs from CNN-ACs and No-AC. Absolute quantification (in kBq ml−1) shows a deviation from GT-AC within 2.2% for all three CNN-ACs and of 71.7% for No-AC. To conclude, all three CNNs show comparable performance in accurate μ -map estimation and 123I-FP-CIT quantification. CNN-estimated μ -map can be a promising substitute for CT-based μ -map.

The use of multi-pinhole collimation has enabled ultra-high-resolution imaging of SPECT and PET tracers in small animals. Key for obtaining high-quality images is the use of statistical iterative image reconstruction with accurate energy-dependent photon transport modelling through collimator and detector. This can be incorporated in a system matrix that contains the probabilities that a photon emitted from a certain voxel is detected at a specific detector pixel. Here we introduce a fast Monte-Carlo based (FMC-based) matrix generation method for pinhole imaging that is easy to apply to various radionuclides. The method is based on accelerated point source simulations combined with model-based interpolation to straightforwardly change or combine photon energies of the radionuclide of interest. The proposed method was evaluated for a VECTor PET-SPECT system with (i) a HE-UHR-M collimator and (ii) an EXIRAD-3D 3D autoradiography collimator. Both experimental scans with 99mTc, 111In, and 123I, and simulated scans with 67Ga and 90Y were performed for evaluation. FMC was compared with two currently used approaches, one based on a set of point source measurements with 99mTc (dubbed traditional method), and the other based on an energy-dependent ray-tracing simulation (ray-tracing method). The reconstruction results show better image quality when using FMC-based matrices than when applying the traditional or ray-tracing matrices in various cases. FMC-based matrices generalise better than the traditional matrices when imaging radionuclides with energies deviating too much from the energy used in the calibration and are computationally more efficient for very-high-resolution imaging than the ray-tracing matrices. In addition, FMC has the advantage of easily combining energies in a single matrix which is relevant when imaging radionuclides with multiple photopeak energies (e.g. 67Ga and 111In) or with a continuous energy spectrum (e.g. 90Y). To conclude, FMC is an efficient, accurate, and versatile tool for creating system matrices for ultra-high-resolution pinhole SPECT.

Single photon emission computed tomography (SPECT) and SPECT-CT are widely used in clinical practice, mostly based on rotation of planar gamma cameras. Tomographic images are reconstructed mainly using iterative algorithms that permit use of flexible geometry and can easily incorporate various corrections. There are several recent advances in instrumentation that include the use of solid state detectors and specialized collimators with improved performance in terms of spatial resolution and/or energy resolution. Compact systems can be constructed that are well suited to organ-specific application with advantages over conventional rotating cameras. With appropriate correction for attenuation and scatter, as well as the effects of motion and limited resolution, absolute quantification of activity concentration is possible. This is particularly important in the increasingly important area of theranostics where radiation dose to target organs or tissues at risk can be estimated.

Purpose Atherosclerotic plaque development and progression signifies a complex inflammatory disease mediated by a multitude of proinflammatory leukocyte subsets. Using single photon emission computed tomography (SPECT) coupled with computed tomography (CT), this study tested a new dual-isotope acquisition protocol to assess each radiotracer’s capability to identify plaque phenotype and inflammation levels pertaining to leukocytes expressing leukocyte function-associated antigen-1 (LFA-1) and the leukocyte subset of proinflammatory macrophages expressing somatostatin receptor subtype-2 (SST2). Individual radiotracer uptake was quantified and the presence of corresponding immunohistological cell markers was assessed. Methods Human symptomatic carotid plaque segments were obtained from endarterectomy. Segments were incubated in dual-isotope radiotracers [111In]In-DOTA-butylamino-NorBIRT ([111In]In-Danbirt) and [99mTc]Tc-[N0–14,Asp0,Tyr3]-octreotate ([99mTc]Tc-Demotate 2) before scanning with SPECT/CT. Plaque phenotype was classified as pathological intimal thickening, fibrous cap atheroma or fibrocalcific using histology sections based on distinct morphological characteristics. Plaque segments were subsequently immuno-stained with LFA-1 and SST2 and quantified in terms of positive area fraction and compared against the corresponding SPECT images. Results Focal uptake of co-localising dual-radiotracers identified the heterogeneous distribution of inflamed regions in the plaques which co-localised with positive immuno-stained regions of LFA-1 and SST2. [111In]In-Danbirt and [99mTc]Tc-Demotate 2 uptake demonstrated a significant positive correlation (r = 0.651; p = 0.001). Fibrous cap atheroma plaque phenotype correlated with the highest [111In]In-Danbirt and [99mTc]Tc-Demotate 2 uptake compared with fibrocalcific plaques and pathological intimal thickening phenotypes, in line with the immunohistological analyses. Conclusion A dual-isotope acquisition protocol permits the imaging of multiple leukocyte subsets and the pro-inflammatory macrophages simultaneously in atherosclerotic plaque tissue. [111In]In-Danbirt may have added value for assessing the total inflammation levels in atherosclerotic plaques in addition to classifying plaque phenotype.

Single photon emission computed tomography (SPECT) is an important imaging modality for various applications in nuclear medicine. The use of multi-pinhole (MPH) collimators can provide superior resolution-sensitivity trade-off when imaging small field-of-view compared to conventional parallel-hole and fan-beam collimators. Besides the very successful application in small animal imaging, there has been a resurgence of the use of MPH collimators for clinical cardiac and brain studies, as well as other small field-of-view applications. This article reviews the basic principles of MPH collimators and introduces currently available and proposed clinical MPH SPECT systems.

Introduction: Autoradiography is an established technique for high-resolution imaging of radiolabelled molecules in biological tissue slices. Unfortunately, creating a 3D image from a set of these 2D images is extremely time-consuming and error-prone. MicroSPECT systems provide such 3D images but have a low resolution. Here we present EXIRAD-3D, a fast automated method as an alternative for 3D autoradiography from coupes based on ultra-high resolution microSPECT technology. Methods: EXIRAD-3D uses a very small bore focusing multi-pinhole collimator mounted in a SPECT system with stationary detectors (U-SPECT/CT, MILabs B.V. The Netherlands) using a sample holder with integrated tissue cooling to avoid activity leaking or tissue deformation during the scan. The system performance was experimentally evaluated using various phantoms and tissue samples of animals in vivo injected with technetium-99m and iodine-123. Results: The reconstructed spatial resolution obtained with a Derenzo hot rod phantom was 120 μm (or 1.7 nl). The voxel values of a syringe phantom image appear to be uniform and scale linearly with activity. Uptake in tiny details of the mouse knee joint, thyroid, and kidney could be clearly visualized. Conclusion: EXIRAD-3D opens up the possibility for fast and quantitative 3D imaging of radiolabelled molecules at a resolution far better than in vivo microSPECT and saves tremendous amounts of work compared to obtaining 3D data from a set of 2D autoradiographs. Advances in knowledge and implications for patient care: EXIRAD-3D offers superior image resolution over microSPECT, and it can be a very efficient alternative for autoradiography in pharmaceutical and biological studies.

We recently developed a dedicated focusing multi-pinhole collimator for a stationary SPECT system that offers down to 120 µm (or 1.7 nL) spatial resolution SPECT images of cryo-cooled tissue samples (EXIRAD-3D). This collimator is suitable for imaging isotopes that are often used in small animal and diagnostic SPECT such as 125I (27 keV), 201Tl (71 keV), 99mTc (140 keV), and 111In (171 and 245 keV). The goal of the present work is to develop high-resolution pinhole imaging of tissue samples containing isotopes with high-energy photon emissions, for example, therapeutic alpha and beta emitters that co-emit high energy gammas (e.g. 213Bi (440 keV) and 131I (364 keV)) or 511 keV annihilation photons from PET isotopes. To this end, we optimise and evaluate a new high energy small-bore multi-pinhole collimator through simulations. The collimator-geometry was first optimised by simulating a Derenzo phantom scan with a biologically realistic activity concentration of 18F at two system sensitivities (0.30% and 0.60%) by varying pinhole placements. Subsequently, the wall thickness was selected based on reconstructions of a Derenzo phantom and a uniform phantom. The obtained collimators were then evaluated for 131I (364 keV), 213Bi (440 keV), 64Cu (511 keV), and 124I (511 + 603 keV) with biologically realistic activity concentrations, and also for some high activity concentrations of 18F, using digital resolution, mouse knee joint, and xenograft phantoms. Our results show that placing pinhole centres at a distance of 8 mm from the collimator inner wall yields good image quality, while a wall thickness of 43 mm resulted in sufficient shielding. The collimators offer resolutions down to 0.35 mm, 0.6 mm, 0.5 mm, 0.6 mm, and 0.5 mm when imaging 131I, 213Bi, 18F, 64Cu, and 124I, respectively, contained in tissue samples at biologically achievable activity concentrations.

Today, versatile emission computed tomography (VECTor) technology using dedicated high-energy collimation enables simultaneous positron emission tomography (PET) and single photon emission computed tomography (SPECT) down to 0.6 mm and 0.4 mm resolution in mice, respectively. We recently showed that for optimal resolution and quantitative accuracy of PET images the long tails of the 511 keV point spread functions (PSFs) need to be fully modelled during image reconstruction. This, however, leads to very time consuming reconstructions and thus significant acceleration in reconstruction speed is highly desirable. To this end we propose and validate a combined dual-matrix dual-voxel (DM-DV) approach: for the forward projection the slowly varying PSF tails are modelled on a three times rougher voxel grid than the central parts of the PSFs, while in the backprojection only parts of the PSF tails are included. DM-DV reconstruction is implemented in pixel-based ordered subsets expectation maximization (POSEM) and in a recently proposed accelerated pixel-based similarity-regulated ordered subsets expectation maximization (SROSEM). Both a visual assessment and a quantitative contrast-noise analysis confirm that images of a hot-rod phantom are practically identical when reconstructed with standard POSEM, DM-DV-POSEM or DM-DV-SROSEM. However, compared to POSEM, DM-DV-POSEM can reach the same contrast 5.0 times faster, while with DM-DV-SROSEM this acceleration factor increases to 11.5. Furthermore, mouse cardiac and bone images reconstructed with DM-DV-SROSEM are visually almost indistinguishable from POSEM reconstructed images but typically need an order of magnitude less reconstruction time.

Pinhole collimation is widely recognized for offering superior resolution-sensitivity trade-off in SPECT imaging of small subjects. The newly developed EXIRAD-3D autoradiography technique (MILabs B.V.) based on a highly focusing multi-pinhole collimator achieves micron-resolution SPECT for cryo-cooled tissue samples. For such high resolutions, the choice of pinhole material may have a significant impact on images. Therefore, this paper aims to compare the performance of EXIRAD-3D with lead, tungsten, gold, and depleted uranium pinhole collimators designed such that they achieve equal sensitivities. Performance in terms of resolution is characterized for several radioisotopes, namely 111In (171 keV and 245 keV), 99mTc (140 keV), 201Tl (71 keV), and 125I (27 keV). Using Monte Carlo simulation, point spread functions were generated and their profiles as well as their full-width-at-half-maximum and full-width-at-tenth-maximum were determined and evaluated for different materials and isotopes. Additionally, simulated reconstructions of a Derenzo resolution phantom, validated with experimental data, were judged by assessment of the resolvable rods as well as a contrast-to-noise ratio (CNR) analysis. Our results indicate that using materials with higher photon-stopping power yields images with better CNR for the studied isotopes with improvements ranging from 1.9% to 36.6%. Visual assessment on the reconstructed images suggests that for EXIRAD-3D, the tungsten collimator is generally a good choice for a wide range of SPECT isotopes. For relatively high-energy isotopes such as 111In, using gold inserts can be beneficial.

In clinical brain SPECT, correction for photon attenuation in the patient is essential to obtain images which provide quantitative information on the regional activity concentration per unit volume (kBq. ml − 1 ). This correction generally requires an attenuation map ( μ map) denoting the attenuation coefficient at each voxel which is often derived from a CT or MRI scan. However, such an additional scan is not always available and the method may suffer from registration errors. Therefore, we propose a SPECT-only-based strategy for μ map estimation that we apply to a stationary multi-pinhole clinical SPECT system (G-SPECT-I) for 99mTc-HMPAO brain perfusion imaging. The method is based on the use of a convolutional neural network (CNN) and was validated with Monte Carlo simulated scans. Data acquired in list mode was used to employ the energy information of both primary and scattered photons to obtain information about the tissue attenuation as much as possible. Multiple SPECT reconstructions were performed from different energy windows over a large energy range. Locally extracted 4D SPECT patches (three spatial plus one energy dimension) were used as input for the CNN which was trained to predict the attenuation coefficient of the corresponding central voxel of the patch. Results show that Attenuation Correction using the Ground Truth μ maps (GT-AC) or using the CNN estimated μ maps (CNN-AC) achieve comparable accuracy. This was confirmed by a visual assessment as well as a quantitative comparison; the mean deviation from the GT-AC when using the CNN-AC is within 1.8% for the standardized uptake values in all brain regions. Therefore, our results indicate that a CNN-based method can be an automatic and accurate tool for SPECT attenuation correction that is independent of attenuation data from other imaging modalities or human interpretations about head contours.

Planar molecular breast imaging (MBI) is rapidly gaining in popularity in diagnostic oncology. To add 3D capabilities, we introduce a novel molecular breast tomosynthesis (MBT) scanner concept based on multi-pinhole collimation. In our design, the patient lies prone with the pendant breast lightly compressed between transparent plates. Integrated webcams view the breast through these plates and allow the operator to designate the scan volume (e.g. a whole breast or a suspected region). The breast is then scanned by translating focusing multi-pinhole plates and NaI(Tl) gamma detectors together in a sequence that optimizes count yield from the volume-of-interest. With simulations, we compared MBT with existing planar MBI. In a breast phantom containing different lesions, MBT improved tumour-to-background contrast-to-noise ratio (CNR) over planar MBI by 12% and 111% for 4.0 and 6.0 mm lesions respectively in case of whole breast scanning. For the same lesions, much larger CNR improvements of 92% and 241% over planar MBI were found in a scan that focused on a breast region containing several lesions. MBT resolved 3.0 mm rods in a Derenzo resolution phantom in the transverse plane compared to 2.5 mm rods distinguished by planar MBI. While planar MBI cannot provide depth information, MBT offered 4.0 mm depth resolution. Our simulations indicate that besides offering 3D localization of increased tracer uptake, multi-pinhole MBT can significantly increase tumour-to-background CNR compared to planar MBI. These properties could be promising for better estimating the position, extend and shape of lesions and distinguishing between single and multiple lesions.

Ordered subsets expectation maximization (OS-EM) is widely used to accelerate image reconstruction in single photon emission computed tomography (SPECT). Speedup of OS-EM over maximum likelihood expectation maximization (ML-EM) is close to the number of subsets used. Although a high number of subsets can shorten reconstruction times significantly, it can also cause severe image artifacts such as improper erasure of reconstructed activity if projections contain few counts. We recently showed that such artifacts can be prevented by using a count-regulated OS-EM (CR-OS-EM) algorithm which automatically adapts the number of subsets for each voxel based on the estimated number of counts that the voxel contributed to the projections. While CR-OS-EM reached high speed-up over ML-EM in high-activity regions of images, speed in low-activity regions could still be very slow. In this work we propose similarity-regulated OS-EM (SR-OS-EM) as a much faster alternative to CR-OS-EM. SR-OS-EM also automatically and locally adapts the number of subsets, but it uses a different criterion for subset regulation: the number of subsets that is used for updating an individual voxel depends on how similar the reconstruction algorithm would update the estimated activity in that voxel with different subsets. Reconstructions of an image quality phantom and in vivo scans show that SR-OS-EM retains all of the favorable properties of CR-OS-EM, while reconstruction speed can be up to an order of magnitude higher in low-activity regions. Moreover our results suggest that SR-OS-EM can be operated with identical reconstruction parameters (including the number of iterations) for a wide range of count levels, which can be an additional advantage from a user perspective since users would only have to post-filter an image to present it at an appropriate noise level.

In recent years, breast imaging using radiolabelled molecules has attracted significant interest. Our group has proposed a multi-pinhole molecular breast tomosynthesis (MP-MBT) scanner to obtain 3D functional molecular breast images at high resolutions. After conducting extensive optimisation studies using simulations, we here present a first prototype of MP-MBT and evaluate its performance using physical phantoms. The MP-MBT design is based on two opposing gamma cameras that can image a lightly compressed pendant breast. Each gamma camera consists of a 250 × 150 mm2 detector equipped with a collimator with multiple pinholes focusing on a line. The NaI(Tl) gamma detector is a customised design with 3.5 mm intrinsic spatial resolution and high spatial linearity near the edges due to a novel light-guide geometry and the use of square PMTs. A volume-of-interest is scanned by translating the collimator and gamma detector together in a sequence that optimises count yield from the scan region. Derenzo phantom images showed that the system can reach 3.5 mm resolution for a clinically realistic 99mTc activity concentration in an 11-minute scan, while in breast phantoms the smallest spheres visible were 6 mm in diameter for the same scan time. To conclude, the experimental results of the novel MP-MBT scanner showed that the setup had sub-centimetre breast tumour detection capability which might facilitate 3D molecular breast cancer imaging in the future.

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.

Objective To evaluate the presence and localization of folate receptor expressing macrophages in the rat groove model of osteoarthritis and determine the suitability of a new folate conjugate with albumin-binding entity (cm09) for in vivo SPECT (single-photon emission computed tomography) analysis. Design In male Wistar rats, local cartilage damage was induced in addition to a standard ( n = 10) or high-fat diet ( n = 6). After 12 weeks, 111In labeled folate conjugates were administered, and SPECT/CT (computed tomography) imaging was performed after 24 hours. Subsequently, osteoarthritis severity and folate receptor expression were assessed using (immuno)-histological sections. Results In vivo SPECT/CT imaging of the new folate conjugate (cm09) was as useful as a folate conjugate without albumin-binding entity in the groove model of osteoarthritis with less renal accumulation. Induction of cartilage damage on a standard diet resulted in no effect on the amount of folate receptor expressing macrophages compared with the contralateral sham operated joints. In contrast, inducing cartilage damage in the high-fat diet group resulted in 28.4% increase of folate receptor expression as compared with the nondamaged control joints. Folate receptor expressing cells were predominantly present in the synovial lining and in subchondral bone as confirmed by immunohistochemistry. Conclusions Folate receptor expression, and thus macrophage activation, can clearly be demonstrated in vivo, in small animal models of osteoarthritis using the new 111In-folate conjugate with specific binding to the folate receptor. Increased macrophage activity only plays a role in the groove model of osteoarthritis when applied in a high-fat diet induced dysmetabolic condition, which is in line with the higher inflammatory state of that specific model.

Anger cameras based on monolithic NaI scintillators read out by an array of PMTs are predominant in planar gamma imaging and SPECT. However, position estimation of gamma interactions is usually severely degraded near the edges of the scintillator which can be extremely undesirable for applications like breast imaging. Here we propose a relatively cost-effective solution based on the use of scintillators with absorptive edges with an unconventional light-guide-PMT layout employing a maximum likelihood positioning algorithm. The basic design on which we aim to improve consists of a monolithic NaI(Tl) scintillator read out by 3 × 5 square PMTs (conventional layout, CL) that could be suitable for molecular breast imaging. To better detect gamma interactions near the crystal’s critical edge, we tried different set-ups: we replaced the 5 large PMTs near the edge by 11 smaller PMTs (small-sensor layout, SSL); we emulated rectangular PMTs along the critical edge by inserting a row of 5 rectangular light-guides that direct the light toward square PMTs placed behind (shifted layout, SL); we inserted rectangular light-guides alternatingly, such that the PMTs are in an interlocking pattern (alternating shifted layout, ASL). The performance of our designs was tested with Monte Carlo simulations. Results showed that SSL, SL, and ASL gave better spatial resolution near the critical edge than CL (3.4, 3.6, and 4.1 mm near the edge compared with 5.3 mm for CL), and thus resulted in a larger usable detector area. To conclude, for applications where small dead edges are crucial, our designs may be cost-effective solutions.

Pre- and intraoperative diagnostic techniques facilitating tumor staging are of paramount importance in colorectal cancer surgery. The urokinase receptor (uPAR) plays an important role in the development of cancer, tumor invasion, angiogenesis, and metastasis and over-expression is found in the majority of carcinomas. This study aims to develop the first clinically relevant anti-uPAR antibody-based imaging agent that combines nuclear (111In) and real-time near-infrared (NIR) fluorescent imaging (ZW800-1). Conjugation and binding capacities were investigated and validated in vitro using spectrophotometry and cell-based assays. In vivo, three human colorectal xenograft models were used including an orthotopic peritoneal carcinomatosis model to image small tumors. Nuclear and NIR fluorescent signals showed clear tumor delineation between 24h and 72h post-injection, with highest tumor-to-background ratios of 5.0 ± 1.3 at 72h using fluorescence and 4.2 ± 0.1 at 24h with radioactivity. 1-2 mm sized tumors could be clearly recognized by their fluorescent rim. This study showed the feasibility of an uPAR-recognizing multimodal agent to visualize tumors during image-guided resections using NIR fluorescence, whereas its nuclear component assisted in the pre-operative non-invasive recognition of tumors using SPECT imaging. This strategy can assist in surgical planning and subsequent precision surgery to reduce the number of incomplete resections.

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 (Tc-99m)-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

Objectives: SPECT with sub-MBq amounts of tracer or sub- second time resolution would enable a wide range of new imaging protocols such as screening tracers with initially low yield or labeling efficiency, imaging low receptor densities or even performing SPECT outside regular radiation laboratories. To this end we developed dedicated ultra-high-sensitivity pinhole SPECT. Methods: A cylindrical collimator with 54 focused 2.0 mm diameter conical pinholes was manufactured and mounted in a U- SPECT+ stationary SPECT system (MILabs, The Netherlands). The system matrix for image reconstruction was calculated via a hybrid method based on both 99mTc point source measurements and ray-tracing analytical modeling. SPECT image reconstruction was performed using Pixel-based OSEM. Performance was evaluated with phantoms, and low-dose bone, dynamic kidney and cardiac mouse scans. Results: The peak sensitivity reaches 1,3% (13080 cps/MBq). Reconstructed spatial resolution (rod visibility in a micro-Jaszczak phantom) was 0.85 mm. Even with only a quarter MBq of activity, 30 minutes bone SPECT scans provided surprisingly high levels of details. Dynamic dual-isotope kidney and 99mTc-sestamibi cardiac scans were acquired with a time-frame resolution down to 1 s. Conclusions: The high sensitivity achieved increases the range of mouse SPECT applications by enabling in vivo imaging with less than a MBq of tracer activity or down to one second frame dynamics.