Almost 10 years of PET/MR attenuation correction: the effect on lesion quantification with PSMA: clinical evaluation on 200 prostate cancer patients.

PURPOSE: After a decade of PET/MR, the case of attenuation correction (AC) remains open. The initial four-compartment (air, water, fat, soft tissue) Dixon-based AC scheme has since been expanded with several features, the latest being MR field-of-view extension and a bone atlas. As this potentially changes quantification, we evaluated the impact of these features in PET AC in prostate cancer patients. METHODS: Two hundred prostate cancer patients were examined with either 18F- or 68Ga-prostate-specific membrane antigen (PSMA) PET/MR. Qualitative and quantitative analysis (SUVmean, SUVmax, correlation, and statistical significance) was performed on images reconstructed using different AC schemes: Dixon, Dixon+MLAA, Dixon+HUGE, and Dixon+HUGE+bones for 18F-PSMA data; Dixon and Dixon+bones for 68Ga-PSMA data. Uptakes were compared using linear regression against standard Dixon. RESULTS: High correlation and no visually perceivable differences between all evaluated methods (r > 0.996) were found. The mean relative difference in lesion uptake of 18F-PSMA and 68Ga-PSMA remained, respectively, within 4% and 3% in soft tissue, and within 10% and 9% in bones for all evaluated methods. Bone registration errors were detected, causing mean uptake change of 5% in affected lesions. CONCLUSIONS: Based on these results and the encountered bone atlas registration inaccuracy, we deduce that including bones and extending the MR field-of-view did not introduce clinically significant differences in PSMA diagnostic accuracy and tracer uptake quantification in prostate cancer pelvic lesions, facilitating the analysis of serial studies respectively. However, in the absence of ground truth data, we advise against atlas-based methods when comparing serial scans for bone lesions.

Aberrant striatal dopamine links topographically with cortico-thalamic dysconnectivity in schizophrenia.

Aberrant dopamine function in the dorsal striatum and aberrant intrinsic functional connectivity (iFC) between distinct cortical networks and thalamic nuclei are among the most consistent large-scale brain imaging findings in schizophrenia. A pathophysiological link between these two alterations is suggested by theoretical models based on striatal dopamine's topographic modulation of cortico-thalamic connectivity within cortico-basal-ganglia-thalamic circuits. We hypothesized that aberrant striatal dopamine links topographically with aberrant cortico-thalamic iFC, i.e. aberrant associative striatum dopamine is associated with aberrant iFC between the salience network and thalamus, and aberrant sensorimotor striatum dopamine with aberrant iFC between the auditory-sensorimotor network and thalamus. Nineteen patients with schizophrenia during remission of psychotic symptoms and 19 age- and sex-comparable control subjects underwent simultaneous fluorodihydroxyphenyl-l-alanine PET (18F-DOPA-PET) and resting state functional MRI (rs-fMRI). The influx constant kicer based on 18F-DOPA-PET was used to measure striatal dopamine synthesis capacity; correlation coefficients between rs-fMRI time series of cortical networks and thalamic regions of interest were used to measure iFC. In the salience network-centred system, patients had reduced associative striatum dopamine synthesis capacity, which correlated positively with decreased salience network-mediodorsal-thalamus iFC. This correlation was present in both patients and healthy controls. In the auditory-sensorimotor network-centred system, patients had reduced sensorimotor striatum dopamine synthesis capacity, which correlated positively with increased auditory-sensorimotor network-ventrolateral-thalamus iFC. This correlation was present in patients only. Results demonstrate that reduced striatal dopamine synthesis capacity links topographically with cortico-thalamic intrinsic dysconnectivity in schizophrenia. Data suggest that aberrant striatal dopamine and cortico-thalamic dysconnectivity are pathophysiologically related within dopamine-modulated cortico-basal ganglia-thalamic circuits in schizophrenia.

Reduced striatal dopamine synthesis capacity in patients with schizophrenia during remission of positive symptoms.

While there is consistent evidence for increased presynaptic dopamine synthesis capacity in the striatum of patients with schizophrenia during psychosis, it is unclear whether this also holds for patients during psychotic remission. This study investigates whether striatal dopamine synthesis capacity is altered in patients with schizophrenia during symptomatic remission of positive symptoms, and whether potential alterations relate to symptoms other than positive, such as cognitive difficulties. Twenty-three patients with schizophrenia in symptomatic remission of positive symptoms according to Andreasen, and 24 healthy controls underwent 18F-DOPA-PET and behavioural-cognitive assessment. Imaging data were analysed with voxel-wise Patlak modelling with cerebellum as reference region, resulting in the influx constant kicer reflecting dopamine synthesis capacity. For the whole striatum and its subdivisions (i.e. limbic, associative, and sensorimotor), averaged regional kicer values were calculated, compared across groups, and correlated with behavioural-cognitive scores, including a mediation analysis. Patients had negative symptoms (Positive and Negative Syndrome Scale-negative 14.13 ± 5.91) and cognitive difficulties, i.e. they performed worse than controls in Trail-Making-Test-B (TMT-B; P = 0.01). Furthermore, kicer was reduced in patients for whole striatum (P = 0.004) and associative (P = 0.002) and sensorimotor subdivisions (P = 0.007). In patients, whole striatum kicer was negatively correlated with TMT-B (rho = -0.42, P = 0.04; i.e. the lower striatal kicer, the worse the cognitive performance). Mediation analysis showed that striatal kicer mediated the group difference in TMT-B. Results demonstrate that patients with schizophrenia in symptomatic remission of positive symptoms have decreased striatal dopamine synthesis capacity, which mediates the disorder's impact on cognitive difficulties. Data suggest that striatal dopamine dysfunction contributes to cognitive difficulties in schizophrenia.

A multi-centre evaluation of eleven clinically feasible brain PET/MRI attenuation correction techniques using a large cohort of patients.

AIM: To accurately quantify the radioactivity concentration measured by PET, emission data need to be corrected for photon attenuation; however, the MRI signal cannot easily be converted into attenuation values, making attenuation correction (AC) in PET/MRI challenging. In order to further improve the current vendor-implemented MR-AC methods for absolute quantification, a number of prototype methods have been proposed in the literature. These can be categorized into three types: template/atlas-based, segmentation-based, and reconstruction-based. These proposed methods in general demonstrated improvements compared to vendor-implemented AC, and many studies report deviations in PET uptake after AC of only a few percent from a gold standard CT-AC. Using a unified quantitative evaluation with identical metrics, subject cohort, and common CT-based reference, the aims of this study were to evaluate a selection of novel methods proposed in the literature, and identify the ones suitable for clinical use. METHODS: In total, 11 AC methods were evaluated: two vendor-implemented (MR-ACDIXON and MR-ACUTE), five based on template/atlas information (MR-ACSEGBONE (Koesters et al., 2016), MR-ACONTARIO (Anazodo et al., 2014), MR-ACBOSTON (Izquierdo-Garcia et al., 2014), MR-ACUCL (Burgos et al., 2014), and MR-ACMAXPROB (Merida et al., 2015)), one based on simultaneous reconstruction of attenuation and emission (MR-ACMLAA (Benoit et al., 2015)), and three based on image-segmentation (MR-ACMUNICH (Cabello et al., 2015), MR-ACCAR-RiDR (Juttukonda et al., 2015), and MR-ACRESOLUTE (Ladefoged et al., 2015)). We selected 359 subjects who were scanned using one of the following radiotracers: [18F]FDG (210), [11C]PiB (51), and [18F]florbetapir (98). The comparison to AC with a gold standard CT was performed both globally and regionally, with a special focus on robustness and outlier analysis. RESULTS: The average performance in PET tracer uptake was within ±5% of CT for all of the proposed methods, with the average±SD global percentage bias in PET FDG uptake for each method being: MR-ACDIXON (-11.3±3.5)%, MR-ACUTE (-5.7±2.0)%, MR-ACONTARIO (-4.3±3.6)%, MR-ACMUNICH (3.7±2.1)%, MR-ACMLAA (-1.9±2.6)%, MR-ACSEGBONE (-1.7±3.6)%, MR-ACUCL (0.8±1.2)%, MR-ACCAR-RiDR (-0.4±1.9)%, MR-ACMAXPROB (-0.4±1.6)%, MR-ACBOSTON (-0.3±1.8)%, and MR-ACRESOLUTE (0.3±1.7)%, ordered by average bias. The overall best performing methods (MR-ACBOSTON, MR-ACMAXPROB, MR-ACRESOLUTE and MR-ACUCL, ordered alphabetically) showed regional average errors within ±3% of PET with CT-AC in all regions of the brain with FDG, and the same four methods, as well as MR-ACCAR-RiDR, showed that for 95% of the patients, 95% of brain voxels had an uptake that deviated by less than 15% from the reference. Comparable performance was obtained with PiB and florbetapir. CONCLUSIONS: All of the proposed novel methods have an average global performance within likely acceptable limits (±5% of CT-based reference), and the main difference among the methods was found in the robustness, outlier analysis, and clinical feasibility. Overall, the best performing methods were MR-ACBOSTON, MR-ACMAXPROB, MR-ACRESOLUTE and MR-ACUCL, ordered alphabetically. These methods all minimized the number of outliers, standard deviation, and average global and local error. The methods MR-ACMUNICH and MR-ACCAR-RiDR were both within acceptable quantitative limits, so these methods should be considered if processing time is a factor. The method MR-ACSEGBONE also demonstrates promising results, and performs well within the likely acceptable quantitative limits. For clinical routine scans where processing time can be a key factor, this vendor-provided solution currently outperforms most methods. With the performance of the methods presented here, it may be concluded that the challenge of improving the accuracy of MR-AC in adult brains with normal anatomy has been solved to a quantitatively acceptable degree, which is smaller than the quantification reproducibility in PET imaging.

Comparison between MRI-based attenuation correction methods for brain PET in dementia patients.

INTRODUCTION: The combination of Positron Emission Tomography (PET) with magnetic resonance imaging (MRI) in hybrid PET/MRI scanners offers a number of advantages in investigating brain structure and function. A critical step of PET data reconstruction is attenuation correction (AC). Accounting for bone in attenuation maps (µ-map) was shown to be important in brain PET studies. While there are a number of MRI-based AC methods, no systematic comparison between them has been performed so far. The aim of this work was to study the different performance obtained by some of the recent methods presented in the literature. To perform such a comparison, we focused on [18F]-Fluorodeoxyglucose-PET/MRI neurodegenerative dementing disorders, which are known to exhibit reduced levels of glucose metabolism in certain brain regions. METHODS: Four novel methods were used to calculate µ-maps from MRI data of 15 patients with Alzheimer's dementia (AD). The methods cover two atlas-based methods, a segmentation method, and a hybrid template/segmentation method. Additionally, the Dixon-based and a UTE-based method, offered by a vendor, were included in the comparison. Performance was assessed at three levels: tissue identification accuracy in the µ-map, quantitative accuracy of reconstructed PET data in specific brain regions, and precision in diagnostic images at identifying hypometabolic areas. RESULTS: Quantitative regional errors of -20--10 % were obtained using the vendor's AC methods, whereas the novel methods produced errors in a margin of ±5 %. The obtained precision at identifying areas with abnormally low levels of glucose uptake, potentially regions affected by AD, were 62.9 and 79.5 % for the two vendor AC methods, the former ignoring bone and the latter including bone information. The precision increased to 87.5-93.3 % in average for the four new methods, exhibiting similar performances. CONCLUSION: We confirm that the AC methods based on the Dixon and UTE sequences provided by the vendor are inferior to alternative techniques. As a novel finding, there was no substantial difference between the recently proposed atlas-based, template-based and segmentation-based methods.

Energy-based scatter estimation in clinical PET.

BACKGROUND: Scatter correction (SC) is essential in PET for accurate quantitative imaging. The state-of-the-art SC method is single-scatter simulation (SSS). Although this method is usually robust and accurate, it can fail in some situations, for example when there is motion between the CT and PET scans in PET/CT. Therefore, it is of interest to consider other SC methods. PURPOSE: In this work, an energy-based scatter estimation (EBS) method is described in detail, tested in phantoms and patients, and compared to SSS. METHODS: This version of EBS was developed for list-mode data from Biograph Vision-600 PET/CT scanner. EBS is based on digitized 2D energy histograms in each bin of a coarsely sampled PET sinogram, either with or without time of flight (TOF). The histograms are modeled as a noisy realization of a linear combination of nine basis functions whose parameters were derived from a measurement of the 511-keV photopeak spectrum as well as Monte-Carlo simulations of the scattering process. EBS uses an iterative expectation maximization approach to determine the coefficients in the linear combination, and from this estimates the scatter. The investigation was restricted to 18 F-based PET data in which the acquired number of counts was similar to the levels seen in oncological whole-body PET/CT scans. To evaluate the performance, phantom scans were used that involved the NEMA NU2-2018 protocol, a slab phantom, an NU 2-1994 phantom, a cardiac phantom in an anthropomorphic chest phantom, and a uniformly-filled torso phantom with a bladder phantom slightly outside the axial field of view. Contrast recovery (CR) and other parameters were evaluated in images reconstructed with SSS and EBS. Furthermore, FDG PET scans of seven lung cancer patients were used in the evaluation. Standardized uptake values (SUV) based on SSS and EBS were compared in 27 lesions. RESULTS: EBS and SSS images were visually similar in all cases except the torso + bladder phantom, where the EBS was much closer to the expected uniform image. The NU2-2018 analysis indicated a 2% scatter residual in EBS images compared to 3% with SSS, and 10% higher background variability, which is a surrogate for image noise. The cardiac phantom scan showed that CR was 98.2% with EBS and 99.6% with SSS, and that the SSS sinogram had values greater than the net-true emission sinogram, indicating a slight overcorrection in the case of SSS. In the lesion SUV comparison in patient scans, EBS correlated strongly (R2  = 0.9973) with SSS, and SUV based on EBS were systematically 0.1 SUV lower. In the case of the torso + bladder phantom portion, the SSS image of the torso + bladder phantom was 299% times hotter than expected in one area, due to scatter estimation error, compared to 16% colder with EBS. CONCLUSIONS: In evaluating clinically relevant parameters such as SUV in focal lesions, EBS and SSS give almost the same results. In phantoms, some scatter figures of merit were slightly improved by use of EBS, though an image variability figure of merit was slightly degraded. In typical oncological whole-body PET/CT, EBS may be a suitable replacement for SSS, especially when SSS fails due to technical problems during the scan.

PET digitization chain for Monte Carlo simulation in GATE.

Objective. We introduce a versatile methodology for the accurate modelling of PET imaging systems via Monte Carlo simulations, using the Geant4 application for tomographic emission (GATE) platform. Accurate Monte Carlo modelling involves the incorporation of a complete analytical signal processing chain, called the digitizer in GATE, to emulate the different count rates encountered in actual positron emission tomography (PET) systems.Approach. The proposed approach consists of two steps: (1) modelling the digitizer to replicate the detection chain of real systems, covering all available parameters, whether publicly accessible or supplied by manufacturers; (2) estimating the remaining parameters, i.e. background noise level, detection efficiency, and pile-up, using optimisation techniques based on experimental single and prompt event rates. We show that this two-step optimisation reproduces the other experimental count rates (true, scatter, and random), without the need for additional adjustments. This method has been applied and validated with experimental data derived from the NEMA count losses test for three state-of-the-art SiPM-based time-of-flight (TOF)-PET systems: Philips Vereos, Siemens Biograph Vision 600 and GE Discovery MI 4-ring.Main results. The results show good agreement between experiments and simulations for the three PET systems, with absolute relative discrepancies below 3%, 6%, 6%, 7% and 12% for prompt, random, true, scatter and noise equivalent count rates, respectively, within the 0-10 kBq·ml-1activity concentration range typically observed in whole-body18F scans.Significance. Overall, the proposed digitizer optimisation method was shown to be effective in reproducing count rates and NECR for three of the latest generation SiPM-based TOF-PET imaging systems. The proposed methodology could be applied to other PET scanners.

Device-Less Data-Driven Cardiac and Respiratory Gating Using LAFOV PET Histo Images.

Background: The outstanding capabilities of modern Positron Emission Tomography (PET) to highlight small tumor lesions and provide pathological function assessment are at peril from image quality degradation caused by respiratory and cardiac motion. However, the advent of the long axial field-of-view (LAFOV) scanners with increased sensitivity, alongside the precise time-of-flight (TOF) of modern PET systems, enables the acquisition of ultrafast time resolution images, which can be used for estimating and correcting the cyclic motion. Methods: 0.25 s so-called [18F]FDG PET histo image series were generated in the scope of for detecting respiratory and cardiac frequency estimates applicable for performing device-less data-driven gated image reconstructions. The frequencies of the cardiac and respiratory motion were estimated for 18 patients using Short Time Fourier Transform (STFT) with 20 s and 30 s window segments, respectively. Results: The Fourier analysis provided time points usable as input to the gated reconstruction based on eight equally spaced time gates. The cardiac investigations showed estimates in accordance with the measured pulse oximeter references (p = 0.97) and a mean absolute difference of 0.4 ± 0.3 beats per minute (bpm). The respiratory frequencies were within the expected range of 10-20 respirations per minute (rpm) in 16 out of 18 patients. Using this setup, the analysis of three patients with visible lung tumors showed an increase in tumor SUVmax and a decrease in tumor volume compared to the non-gated reconstructed image. Conclusions: The method can provide signals that were applicable for gated reconstruction of both cardiac and respiratory motion, providing a potential increased diagnostic accuracy.

Positron range in combination with point-spread-function correction: an evaluation of different implementations for [124I]-PET imaging.

AIM: To evaluate the effect of combining positron range correction (PRC) with point-spread-function (PSF) correction and to compare different methods of implementation into iterative image reconstruction for 124I-PET imaging. MATERIALS AND METHODS: Uniform PR blurring kernels of 124I were generated using the GATE (GEANT4) framework in various material environments (lung, water, and bone) and matched to a 3D matrix. The kernels size was set to 11 × 11 × 11 based on the maximum PR in water and the voxel size of the PET system. PET image reconstruction was performed using the standard OSEM algorithm, OSEM with PRC implemented before the forward projection (OSEM+PRC simplified) and OSEM with PRC implemented in both forward- and back-projection steps (full implementation) (OSEM+PRC). Reconstructions were repeated with resolution recovery, point-spread function (PSF) included. The methods and kernel variation were validated using different phantoms filled with 124I acquired on a Siemens mCT PET/CT system. The data was evaluated for contrast recovery and image noise. RESULTS: Contrast recovery improved by 2-10% and 4-37% with OSEM+PRC simplified and OSEM+PRC, respectively, depending on the sphere size of the NEMA IQ phantom. Including PSF in the reconstructions further improved contrast by 4-19% and 3-16% with the PSF+PRC simplified and PSF+PRC, respectively. The benefit of PRC was more pronounced within low-density material. OSEM-PRC and OSEM-PSF as well as OSEM-PSF+PRC in its full- and simplified implementation showed comparable noise and convergence. OSEM-PRC simplified showed comparably faster convergence but at the cost of increased image noise. CONCLUSIONS: The combination of the PSF and PRC leads to increased contrast recovery with reduced image noise compared to stand-alone PSF or PRC reconstruction. For OSEM-PRC reconstructions, a full implementation in the reconstruction is necessary to handle image noise. For the combination of PRC with PSF, a simplified PRC implementation can be used to reduce reconstruction times.

Implementation of a Spatially-Variant and Tissue-Dependent Positron Range Correction for PET/CT Imaging.

Aim: To develop and evaluate a new approach for spatially variant and tissue-dependent positron range (PR) correction (PRC) during the iterative PET image reconstruction. Materials and Methods: The PR distributions of three radionuclides (18F, 68Ga, and 124I) were simulated using the GATE (GEANT4) framework in different material compositions (lung, water, and bone). For every radionuclide, the uniform PR kernel was created by mapping the simulated 3D PR point cloud to a 3D matrix with its size defined by the maximum PR in lung (18F) or water (68Ga and 124I) and the PET voxel size. The spatially variant kernels were composed from the uniform PR kernels by analyzing the material composition of the surrounding medium for each voxel before implementation as tissue-dependent, point-spread functions into the iterative image reconstruction. The proposed PRC method was evaluated using the NEMA image quality phantom (18F, 68Ga, and 124I); two unique PR phantoms were scanned and evaluated following OSEM reconstruction with and without PRC using different metrics, such as contrast recovery, contrast-to-noise ratio, image noise and the resolution evaluated in terms of full width at half maximum (FWHM). Results: The effect of PRC on 18F-imaging was negligible. In contrast, PRC improved image contrast for the 10-mm sphere of the NEMA image quality phantom filled with 68Ga and 124I by 33 and 24%, respectively. While the effect of PRC was less noticeable for the larger spheres, contrast recovery still improved by 5%. The spatial resolution was improved by 26% for 124I (FWHM of 4.9 vs. 3.7 mm). Conclusion: For high energy positron-emitting radionuclides, the proposed PRC method helped recover image contrast with reduced noise levels and with improved spatial resolution. As such, the PRC approach proposed here can help improve the quality of PET data in clinical practice and research.

Integrity of Neurocognitive Networks in Dementing Disorders as Measured with Simultaneous PET/Functional MRI.

Functional MRI (fMRI) studies have reported altered integrity of large-scale neurocognitive networks (NCNs) in dementing disorders. However, findings on the specificity of these alterations in patients with Alzheimer disease (AD) and behavioral-variant frontotemporal dementia (bvFTD) are still limited. Recently, NCNs have been successfully captured using PET with 18F-FDG. Methods: Network integrity was measured in 72 individuals (38 male) with mild AD or bvFTD, and in healthy controls, using a simultaneous resting-state fMRI and 18F-FDG PET. Indices of network integrity were calculated for each subject, network, and imaging modality. Results: In either modality, independent-component analysis revealed 4 major NCNs: anterior default-mode network (DMN), posterior DMN, salience network, and right central executive network (CEN). In fMRI data, the integrity of the posterior DMN was found to be significantly reduced in both patient groups relative to controls. In the AD group the anterior DMN and CEN appeared to be additionally affected. In PET data, only the integrity of the posterior DMN in patients with AD was reduced, whereas 3 remaining networks appeared to be affected only in patients with bvFTD. In a logistic regression analysis, the integrity of the anterior DMN as measured with PET alone accurately differentiated between the patient groups. A correlation between indices of 2 imaging modalities was low overall. Conclusion: FMRI and 18F-FDG PET capture partly different aspects of network integrity. A higher disease specificity for NCNs as derived from PET data supports metabolic connectivity imaging as a promising diagnostic tool.

Impact of non-uniform attenuation correction in a dynamic [18F]-FDOPA brain PET/MRI study.

BACKGROUND: PET (positron emission tomography) biokinetic modelling relies on accurate quantitative data. One of the main corrections required in PET imaging to obtain high quantitative accuracy is tissue attenuation correction (AC). Incorrect non-uniform PET-AC may result in local bias in the emission images, and thus in relative activity distributions and time activity curves for different regions. MRI (magnetic resonance imaging)-based AC is an active area of research in PET/MRI neuroimaging, where several groups developed in the last few years different methods to calculate accurate attenuation (µ-)maps. Some AC methods have been evaluated for different PET radioisotopes and pathologies. However, AC in PET/MRI has scantly been investigated in dynamic PET studies where the aim is to get quantitative kinetic parameters, rather than semi-quantitative parameters from static PET studies. In this work, we investigated the impact of AC accuracy in PET image absolute quantification and, more importantly, in the slope of the Patlak analysis based on the simplified reference tissue model, from a dynamic [18F]-fluorodopa (FDOPA) PET/MRI study. In the study, we considered the two AC methods provided by the vendor and an in-house AC method based on the dual ultrashort time echo MRI sequence, using as reference a multi-atlas-based AC method based on a T1-weighted MRI sequence. RESULTS: Non-uniform bias in absolute PET quantification across the brain, from - 20% near the skull to - 10% in the central region, was observed using the two vendor's µ-maps. The AC method developed in-house showed a - 5% and 1% bias, respectively. Our study resulted in a 5-9% overestimation of the PET kinetic parameters with the vendor-provided µ-maps, while our in-house-developed AC method showed < 2% overestimation compared to the atlas-based AC method, using the cerebellar cortex as reference region. The overestimation obtained using the occipital pole as reference region resulted in a 7-10% with the vendor-provided µ-maps, while our in-house-developed AC method showed < 6% overestimation. CONCLUSIONS: PET kinetic analyses based on a reference region are especially sensitive to the non-uniform bias in PET quantification from AC inaccuracies in brain PET/MRI. Depending on the position of the reference region and the bias with respect to the analysed region, kinetic analyses suffer different levels of bias. Considering bone in the µ-map can potentially result in larger errors, compared to the absence of bone, when non-uniformities in PET quantification are introduced.

Advances in PET/MR instrumentation and image reconstruction.

The combination of positron emission tomography (PET) and MRI has attracted the attention of researchers in the past approximately 20 years in small-animal imaging and more recently in clinical research. The combination of PET/MRI allows researchers to explore clinical and research questions in a wide number of fields, some of which are briefly mentioned here. An important number of groups have developed different concepts to tackle the problems that PET instrumentation poses to the exposition of electromagnetic fields. We have described most of these research developments in preclinical and clinical experiments, including the few commercial scanners available. From the software perspective, an important number of algorithms have been developed to address the attenuation correction issue and to exploit the possibility that MRI provides for motion correction and quantitative image reconstruction, especially parametric modelling of radiopharmaceutical kinetics. In this work, we give an overview of some exemplar applications of simultaneous PET/MRI, together with technological hardware and software developments.

MR-compatibility assessment of MADPET4: a study of interferences between an SiPM-based PET insert and a 7 T MRI system.

Compromises in the design of a positron emission tomography (PET) insert for a magnetic resonance imaging (MRI) system should minimize the deterioration of image quality in both modalities, particularly when simultaneous demanding acquisitions are performed. In this work, the advantages of using individually read-out crystals with high-gain silicon photomultipliers (SiPMs) were studied with a small animal PET insert for a 7 T MRI system, in which the SiPM charge was transferred to outside the MRI scanner using coaxial cables. The interferences between the two systems were studied with three radio-frequency (RF) coil configurations. The effects of PET on the static magnetic field, flip angle distribution, RF noise, and image quality of various MRI sequences (gradient echo, spin echo, and echo planar imaging (EPI) at 1H frequency, and chemical shift imaging at 13C frequency) were investigated. The effects of fast-switching gradient fields and RF pulses on PET count rate were studied, while the PET insert and the readout electronics were not shielded. Operating the insert inside a 1H volume coil, used for RF transmission and reception, limited the MRI to T1-weighted imaging, due to coil detuning and RF attenuation, and resulted in significant PET count loss. Using a surface receive coil allowed all tested MR sequences to be used with the insert, with 45-59% signal-to-noise ratio (SNR) degradation, compared to without PET. With a 1H/13C volume coil inside the insert and shielded by a copper tube, the SNR degradation was limited to 23-30% with all tested sequences. The insert did not introduce any discernible distortions into images of two tested EPI sequences. Use of truncated sinc shaped RF excitation pulses and gradient field switching had negligible effects on PET count rate. However, PET count rate was substantially affected by high-power RF block pulses and temperature variations due to high gradient duty cycles.

Simultaneous characterization of tumor cellularity and the Warburg effect with PET, MRI and hyperpolarized 13C-MRSI.

Modern oncology aims at patient-specific therapy approaches, which triggered the development of biomedical imaging techniques to synergistically address tumor biology at the cellular and molecular level. PET/MR is a new hybrid modality that allows acquisition of high-resolution anatomic images and quantification of functional and metabolic information at the same time. Key steps of the Warburg effect-one of the hallmarks of tumors-can be measured non-invasively with this emerging technique. The aim of this study was to quantify and compare simultaneously imaged augmented glucose uptake and LDH activity in a subcutaneous breast cancer model in rats (MAT-B-III) and to study the effect of varying tumor cellularity on image-derived metabolic information. Methods: For this purpose, we established and validated a multimodal imaging workflow for a clinical PET/MR system including proton magnetic resonance (MR) imaging to acquire accurate morphologic information and diffusion-weighted imaging (DWI) to address tumor cellularity. Metabolic data were measured with dynamic [18F]FDG-PET and hyperpolarized (HP) 13C-pyruvate MR spectroscopic imaging (MRSI). We applied our workflow in a longitudinal study and analyzed the effect of growth dependent variations of cellular density on glycolytic parameters. Results: Tumors of similar cellularity with similar apparent diffusion coefficients (ADC) showed a significant positive correlation of FDG uptake and pyruvate-to-lactate exchange. Longitudinal DWI data indicated a decreasing tumor cellularity with tumor growth, while ADCs exhibited a significant inverse correlation with PET standard uptake values (SUV). Similar but not significant trends were observed with HP-13C-MRSI, but we found that partial volume effects and point spread function artifacts are major confounders for the quantification of 13C-data when the spatial resolution is limited and major blood vessels are close to the tumor. Nevertheless, analysis of longitudinal data with varying tumor cellularity further detected a positive correlation between quantitative PET and 13C-data. Conclusions: Our workflow allows the quantification of simultaneously acquired PET, MRSI and DWI data in rodents on a clinical PET/MR scanner. The correlations and findings suggest that a major portion of consumed glucose is metabolized by aerobic glycolysis in the investigated tumor model. Furthermore, we conclude that variations in cell density affect PET and 13C-data in a similar manner and correlations of longitudinal metabolic data appear to reflect both biochemical processes and tumor cellularity.

TRIMAGE: A dedicated trimodality (PET/MR/EEG) imaging tool for schizophrenia.

Simultaneous PET/MR/EEG (Positron Emission Tomography - Magnetic Resonance - Electroencephalography), a new tool for the investigation of neuronal networks in the human brain, is presented here within the framework of the European Union Project TRIMAGE. The trimodal, cost-effective PET/MR/EEG imaging tool makes use of cutting edge technology both in PET and in MR fields. A novel type of magnet (1.5T, non-cryogenic) has been built together with a PET scanner that makes use of the most advanced photodetectors (i.e., SiPM matrices), scintillators matrices (LYSO) and digital electronics. The combined PET/MR/EEG system is dedicated to brain imaging and has an inner diameter of 260 mm and an axial Field-of-View of 160 mm. It enables the acquisition and assessment of molecular metabolic information with high spatial and temporal resolution in a given brain simultaneously. The dopaminergic system and the glutamatergic system in schizophrenic patients are investigated via PET, the same physiological/pathophysiological conditions with regard to functional connectivity, via fMRI, and its electrophysiological signature via EEG. In addition to basic neuroscience questions addressing neurovascular-metabolic coupling, this new methodology lays the foundation for individual physiological and pathological fingerprints for a wide research field addressing healthy aging, gender effects, plasticity and different psychiatric and neurological diseases. The preliminary performances of two components of the imaging tool (PET and MR) are discussed. Initial results of the search of possible candidates for suitable schizophrenia biomarkers are also presented as obtained with PET/MR systems available to the collaboration.

Digital autoradiography using room temperature CCD and CMOS imaging technology.

CCD (charged coupled device) and CMOS imaging technologies can be applied to thin tissue autoradiography as potential imaging alternatives to using conventional film. In this work, we compare two particular devices: a CCD operating in slow scan mode and a CMOS-based active pixel sensor, operating at near video rates. Both imaging sensors have been operated at room temperature using direct irradiation with images produced from calibrated microscales and radiolabelled tissue samples. We also compare these digital image sensor technologies with the use of conventional film. We show comparative results obtained with (14)C calibrated microscales and (35)S radiolabelled tissue sections. We also present the first results of (3)H images produced under direct irradiation of a CCD sensor operating at room temperature. Compared to film, silicon-based imaging technologies exhibit enhanced sensitivity, dynamic range and linearity.

PET performance evaluation of MADPET4: a small animal PET insert for a 7 T MRI scanner.

MADPET4 is the first small animal PET insert with two layers of individually read out crystals in combination with silicon photomultiplier technology. It has a novel detector arrangement, in which all crystals face the center of field of view transaxially. In this work, the PET performance of MADPET4 was evaluated and compared to other preclinical PET scanners using the NEMA NU 4 measurements, followed by imaging a mouse-size hot-rod resolution phantom and two in vivo simultaneous PET/MRI scans in a 7 T MRI scanner. The insert had a peak sensitivity of 0.49%, using an energy threshold of 350 keV. A uniform transaxial resolution was obtained up to 15 mm radial offset from the axial center, using filtered back-projection with single-slice rebinning. The measured average radial and tangential resolutions (FWHM) were 1.38 mm and 1.39 mm, respectively. The 1.2 mm rods were separable in the hot-rod phantom using an iterative image reconstruction algorithm. The scatter fraction was 7.3% and peak noise equivalent count rate was 15.5 kcps at 65.1 MBq of activity. The FDG uptake in a mouse heart and brain were visible in the two in vivo simultaneous PET/MRI scans without applying image corrections. In conclusion, the insert demonstrated a good overall performance and can be used for small animal multi-modal research applications.

Simulation study of PET detector limitations using continuous crystals.

Continuous crystals can potentially obtain better intrinsic detector spatial resolution compared to pixelated crystals, additionally providing depth of interaction (DoI) information from the light distribution. To achieve high performance sophisticated interaction position estimation algorithms are required. There are a number of algorithms in the literature applied to different crystal dimensions and different photodetectors. However, the different crystal properties and photodetector array geometries have an impact on the algorithm performance. In this work we analysed, through Monte Carlo simulations, different combinations of realistic crystals and photodetector parameters to better understand their influence on the interaction position estimation accuracy, with special emphasis on the DoI. We used an interaction position estimation based on an analytical model for the present work. Different photodetector granulation schemes were investigated. The impact of the number of crystal faces readout by photodetectors was studied by simulating scenarios with one and two photodetectors. In addition, crystals with different levels of reflection and aspect ratios (AR) were analysed. Results showed that the impact of photodetector granularity is mainly shown near the edges and specially in the corners of the crystal. The resulting intrinsic spatial resolution near the centre with a 12 × 12 × 10 mm(3) LYSO crystal was 0.7-0.9 mm, while the average spatial resolution calculated on the entire crystal was 0.77 ± 0.18 mm for all the simulated geometries with one and two photodetectors. Having front and back photodetectors reduced the DoI bias (Euclidean distance between estimated DoI and real DoI) and improved the transversal resolution near the corners. In scenarios with one photodetector, small AR resulted in DoI inaccuracies for absorbed events at the entrance of the crystal. These inaccuracies were slightly reduced either by increasing the AR or reducing the amount of reflected light, and highly mitigated using two photodetectors. Using one photodetector, we obtained a piecewise DoI error model with a DoI resolution of 0.4-0.9 mm for a 1.2 AR crystal, and we observed that including a second photodetector or reducing the amount of reflections reduced the DoI bias but did not significantly improve the DoI resolution. Translating the piecewise DoI error model obtained in this study to image reconstruction we obtained a spatial resolution variability of 0.39 mm using 85% of the FoV, compared to 2.59 mm and 1.87 mm without DoI correction or with a dual layer system, respectively.