Deleterious phenotypes in wild Arabidopsis arenosa populations are common and linked to runs of homozygosity.

In this study, we aimed to systematically assess the frequency at which potentially deleterious phenotypes appear in natural populations of the outcrossing model plant Arabidopsis arenosa, and to establish their underlying genetics. For this purpose, we collected seeds from wild A. arenosa populations and screened over 2,500 plants for unusual phenotypes in the greenhouse. We repeatedly found plants with obvious phenotypic defects, such as small stature and necrotic or chlorotic leaves, among first-generation progeny of wild A. arenosa plants. Such abnormal plants were present in about 10% of maternal sibships, with multiple plants with similar phenotypes in each of these sibships, pointing to a genetic basis of the observed defects. A combination of transcriptome profiling, linkage mapping and genome-wide runs of homozygosity patterns using a newly assembled reference genome indicated a range of underlying genetic architectures associated with phenotypic abnormalities. This included evidence for homozygosity of certain genomic regions, consistent with alleles that are identical by descent being responsible for these defects. Our observations suggest that deleterious alleles with different genetic architectures are segregating at appreciable frequencies in wild A. arenosa populations.

Pervasive under-dominance in gene expression underlying emergent growth trajectories in Arabidopsis thaliana hybrids.

BACKGROUND: Complex traits, such as growth and fitness, are typically controlled by a very large number of variants, which can interact in both additive and non-additive fashion. In an attempt to gauge the relative importance of both types of genetic interactions, we turn to hybrids, which provide a facile means for creating many novel allele combinations. RESULTS: We focus on the interaction between alleles of the same locus, i.e., dominance, and perform a transcriptomic study involving 141 random crosses between different accessions of the plant model species Arabidopsis thaliana. Additivity is rare, consistently observed for only about 300 genes enriched for roles in stress response and cell death. Regulatory rare-allele burden affects the expression level of these genes but does not correlate with F1 rosette size. Non-additive, dominant gene expression in F1 hybrids is much more common, with the vast majority of genes (over 90%) being expressed below the parental average. Unlike in the additive genes, regulatory rare-allele burden in the dominant gene set is strongly correlated with F1 rosette size, even though it only mildly covaries with the expression level of these genes. CONCLUSIONS: Our study underscores under-dominance as the predominant gene action associated with emergence of rosette growth trajectories in the A. thaliana hybrid model. Our work lays the foundation for understanding molecular mechanisms and evolutionary forces that lead to dominance complementation of rare regulatory alleles.

The genetic and physiological basis of Arabidopsis thaliana tolerance to Pseudomonas viridiflava.

The opportunistic pathogen Pseudomonas viridiflava colonizes > 50 agricultural crop species and is the most common Pseudomonas in the phyllosphere of European Arabidopsis thaliana populations. Belonging to the P. syringae complex, it is genetically and phenotypically distinct from well-characterized P. syringae sensu stricto. Despite its prevalence, we lack knowledge of how A. thaliana responds to its native isolates at the molecular level. Here, we characterize the host response in an A. thaliana - P. viridiflava pathosystem. We measured host and pathogen growth in axenic infections and used immune mutants, transcriptomics, and metabolomics to determine defense pathways influencing susceptibility to P. viridiflava infection. Infection with P. viridiflava increased jasmonic acid (JA) levels and the expression of ethylene defense pathway marker genes. The immune response in a susceptible host accession was delayed compared with a tolerant one. Mechanical injury rescued susceptibility, consistent with an involvement of JA. The JA/ethylene pathway is important for suppression of P. viridiflava, yet suppression capacity varies between accessions. Our results shed light on how A. thaliana can suppress the ever-present P. viridiflava, but further studies are needed to understand how P. viridiflava evades this suppression to spread broadly across A. thaliana populations.

Contrasting patterns of microbial dominance in the Arabidopsis thaliana phyllosphere.

Sphingomonas is one of the most abundant bacterial genera in the phyllosphere of wild Arabidopsis thaliana, but relative to Pseudomonas, the ecology of Sphingomonas and its interaction with plants is poorly described. We analyzed the genomic features of over 400 Sphingomonas isolates collected from local A. thaliana populations, which revealed much higher intergenomic diversity than for the considerably more uniform Pseudomonas isolates found in the same host populations. Variation in Sphingomonas plasmid complements and additional genomic features suggest high adaptability of this genus, and the widespread presence of protein secretion systems hints at frequent biotic interactions. While some of the isolates showed plant-protective phenotypes in lab tests, this was a rare trait. To begin to understand the extent of strain sharing across alternate hosts, we employed amplicon sequencing and a bulk-culturing metagenomics approach on both A. thaliana and neighboring plants. Our data reveal that both Sphingomonas and Pseudomonas thrive on other diverse plant hosts, but that Sphingomonas is a poor competitor in dying or dead leaves.

Predictable and stable epimutations induced during clonal plant propagation with embryonic transcription factor.

Clonal propagation is frequently used in commercial plant breeding and biotechnology programs because it minimizes genetic variation, yet it is not uncommon to observe clonal plants with stable phenotypic changes, a phenomenon known as somaclonal variation. Several studies have linked epigenetic modifications induced during regeneration with this newly acquired phenotypic variation. However, the factors that determine the extent of somaclonal variation and the molecular changes underpinning this process remain poorly understood. To address this gap in our knowledge, we compared clonally propagated Arabidopsis thaliana plants derived from somatic embryogenesis using two different embryonic transcription factors- RWP-RK DOMAIN-CONTAINING 4 (RKD4) or LEAFY COTYLEDON2 (LEC2) and from two epigenetically distinct founder tissues. We found that both the epi(genetic) status of the explant and the regeneration protocol employed play critical roles in shaping the molecular and phenotypic landscape of clonal plants. Phenotypic variation in regenerated plants can be largely explained by the inheritance of tissue-specific DNA methylation imprints, which are associated with specific transcriptional and metabolic changes in sexual progeny of clonal plants. For instance, regenerants were particularly affected by the inheritance of root-specific epigenetic imprints, which were associated with an increased accumulation of salicylic acid in leaves and accelerated plant senescence. Collectively, our data reveal specific pathways underpinning the phenotypic and molecular variation that arise and accumulate in clonal plant populations.

ARADEEPOPSIS, an Automated Workflow for Top-View Plant Phenomics using Semantic Segmentation of Leaf States.

Linking plant phenotype to genotype is a common goal to both plant breeders and geneticists. However, collecting phenotypic data for large numbers of plants remain a bottleneck. Plant phenotyping is mostly image based and therefore requires rapid and robust extraction of phenotypic measurements from image data. However, because segmentation tools usually rely on color information, they are sensitive to background or plant color deviations. We have developed a versatile, fully open-source pipeline to extract phenotypic measurements from plant images in an unsupervised manner. ARADEEPOPSIS (https://github.com/Gregor-Mendel-Institute/aradeepopsis) uses semantic segmentation of top-view images to classify leaf tissue into three categories: healthy, anthocyanin rich, and senescent. This makes it particularly powerful at quantitative phenotyping of different developmental stages, mutants with aberrant leaf color and/or phenotype, and plants growing in stressful conditions. On a panel of 210 natural Arabidopsis (Arabidopsis thaliana) accessions, we were able to not only accurately segment images of phenotypically diverse genotypes but also to identify known loci related to anthocyanin production and early necrosis in genome-wide association analyses. Our pipeline accurately processed images of diverse origin, quality, and background composition, and of a distantly related Brassicaceae. ARADEEPOPSIS is deployable on most operating systems and high-performance computing environments and can be used independently of bioinformatics expertise and resources.

RPW8/HR repeats control NLR activation in Arabidopsis thaliana.

In many plant species, conflicts between divergent elements of the immune system, especially nucleotide-binding oligomerization domain-like receptors (NLR), can lead to hybrid necrosis. Here, we report deleterious allele-specific interactions between an NLR and a non-NLR gene cluster, resulting in not one, but multiple hybrid necrosis cases in Arabidopsis thaliana. The NLR cluster is RESISTANCE TO PERONOSPORA PARASITICA 7 (RPP7), which can confer strain-specific resistance to oomycetes. The non-NLR cluster is RESISTANCE TO POWDERY MILDEW 8 (RPW8) / HOMOLOG OF RPW8 (HR), which can confer broad-spectrum resistance to both fungi and oomycetes. RPW8/HR proteins contain at the N-terminus a potential transmembrane domain, followed by a specific coiled-coil (CC) domain that is similar to a domain found in pore-forming toxins MLKL and HET-S from mammals and fungi. C-terminal to the CC domain is a variable number of 21- or 14-amino acid repeats, reminiscent of regulatory 21-amino acid repeats in fungal HET-S. The number of repeats in different RPW8/HR proteins along with the sequence of a short C-terminal tail predicts their ability to activate immunity in combination with specific RPP7 partners. Whether a larger or smaller number of repeats is more dangerous depends on the specific RPW8/HR autoimmune risk variant.

PORCUPINE regulates development in response to temperature through alternative splicing.

Recent findings suggest that alternative splicing has a critical role in controlling the responses of plants to temperature variations. However, alternative splicing factors in plants are largely uncharacterized. Here we establish the putative splice regulator, PORCUPINE (PCP), as temperature-specific regulator of development in Arabidopsis thaliana. Our findings point to the misregulation of WUSCHEL and CLAVATA3 as the possible cause for the meristem defects affecting the pcp-1 loss-of-function mutants at low temperatures.

Linking imaging to omics utilizing image-guided tissue extraction.

Phenotypic heterogeneity is commonly observed in diseased tissue, specifically in tumors. Multimodal imaging technologies can reveal tissue heterogeneity noninvasively in vivo, enabling imaging-based profiling of receptors, metabolism, morphology, or function on a macroscopic scale. In contrast, in vitro multiomics, immunohistochemistry, or histology techniques accurately characterize these heterogeneities in the cellular and subcellular scales in a more comprehensive but ex vivo manner. The complementary in vivo and ex vivo information would provide an enormous potential to better characterize a disease. However, this requires spatially accurate coregistration of these data by image-driven sampling as well as fast sample-preparation methods. Here, a unique image-guided milling machine and workflow for precise extraction of tissue samples from small laboratory animals or excised organs has been developed and evaluated. The samples can be delineated on tomographic images as volumes of interest and can be extracted with a spatial accuracy better than 0.25 mm. The samples remain cooled throughout the procedure to ensure metabolic stability, a precondition for accurate in vitro analysis.

SUV-quantification of physiological lung tissue in an integrated PET/MR-system: Impact of lung density and bone tissue.

PURPOSE: The aim of the study was to investigate the influence of lung density changes as well as bone proximity on the attenuation correction of lung standardized uptake values (SUVs). METHODS AND MATERIALS: 15 patients with mostly oncologic diseases were examined in 18F-FDG-PET/CT and subsequently in a fully integrated PET/MR scanner. From each PET dataset acquired in PET/MR, four different PET reconstructions were computed using different attenuation maps (µ-maps): i) CT-based µ-map (gold standard); ii) CT-based µ-map in which the linear attenuation coefficients (LAC) of the lung tissue was replaced by the lung LAC from the MR-based segmentation method; iii) based on reconstruction ii), the LAC of bone structures was additionally replaced with the LAC from the MR-based segmentation method; iv) the vendor-provided MR-based µ-map (segmentation-based method). Those steps were performed using MATLAB. CT Hounsfield units (HU) and SUVmean was acquired in different levels and regions of the lung. Relative differences between the differently corrected PETs were computed. RESULTS: Compared to the gold standard, reconstruction ii), iii) and iv) led to a relative underestimation of SUV in the posterior regions of -9.0%, -13.4% and -14.0%, respectively. Anterior and middle regions were less affected with an overestimation of about 6-8% in reconstructions ii)-iv). CONCLUSION: It could be shown that both, differences in lung density and the vicinity of bone tissue in the µ-map may have an influence on SUV, mostly affecting the posterior lung regions.

Comprehensive Oncologic Imaging in Infants and Preschool Children With Substantially Reduced Radiation Exposure Using Combined Simultaneous ¹8F-Fluorodeoxyglucose Positron Emission Tomography/Magnetic Resonance Imaging: A Direct Comparison to ¹8F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography.

OBJECTIVE: The aim of this study was to evaluate the clinical applicability and technical feasibility of fluorodeoxyglucose (FDG) positron emission tomography (PET)/magnetic resonance imaging (MRI) compared with FDG PET/computed tomography (CT) in young children focusing on lesion detection, PET quantification, and potential savings in radiation exposure. METHODS: Twenty examinations (10 PET/CT and 10 PET/MRI examinations) were performed prospectively in 9 patients with solid tumors (3 female, 6 male; mean age, 4.8 [1-6] years). Fluorodeoxyglucose PET/CT and FDG PET/MRI were performed sequentially after a single tracer injection. Lesion detection and analysis were performed independently in PET/CT and PET/MRI. Potential changes in diagnostic or therapeutic patient management were recorded. Positron emission tomography quantification in PET/MRI was evaluated by comparing standardized uptake values resulting from MRI-based and CT-based attenuation correction. Effective radiation doses of PET and CT were estimated. RESULTS: Twenty-one PET-positive lesions were found congruently in PET/CT and PET/MRI. Magnetic resonance imaging enabled significantly better detection of morphologic PET correlates compared with CT. Eight suspicious PET-negative lesions were identified by MRI, of which one was missed in CT. Sensitivity, specificity, and accuracy for correct lesion classification were not significantly different (90%, 47%, and 62% in PET/CT; 100%, 68%, and 79% in PET/MRI, respectively). In 4 patients, the use of PET/MRI resulted in a potential change in diagnostic management compared with PET/CT, as local and whole-body staging could be performed within 1 single examination. In 1 patient, PET/MRI initiated a change in therapeutic management. Positron emission tomography quantification using MRI-based attenuation correction was accurate compared with CT-based attenuation correction. Higher standardized uptake value deviations of about 18% were observed in the lungs due to misclassification in MRI-based attenuation maps. Potential reduction in radiation dose was 48% in PET/MRI compared with PET/CT (P < 0.05). CONCLUSIONS: FDG PET/MRI is at least equivalent to FDG PET/CT for oncologic imaging in young children. Specifically, superior soft tissue contrast of MRI results in higher confidence in lesion interpretation. Substantial savings in radiation exposure can be achieved, and the number of necessary imaging examinations can be reduced using PET/MRI compared with PET/CT.

Comparison of Positron Emission Tomography Quantification Using Magnetic Resonance- and Computed Tomography-Based Attenuation Correction in Physiological Tissues and Lesions: A Whole-Body Positron Emission Tomography/Magnetic Resonance Study in 66 Patients.

OBJECTIVE: Attenuation correction (AC) in fully integrated positron emission tomography (PET)/magnetic resonance (MR) systems plays a key role for the quantification of tracer uptake. The aim of this prospective study was to assess the accuracy of standardized uptake value (SUV) quantification using MR-based AC in direct comparison with computed tomography (CT)-based AC of the same PET data set on a large patient population. MATERIALS AND METHODS: Sixty-six patients (22 female; mean [SD], 61 [11] years) were examined by means of combined PET/CT and PET/MR (11C-choline, 18F-FDG, or 68Ga-DOTATATE) subsequently. Positron emission tomography images from PET/MR examinations were corrected with MR-derived AC based on tissue segmentation (PET(MR)). The same PET data were corrected using CT-based attenuation maps (µ-maps) derived from PET/CT after nonrigid registration of the CT to the MR-based µ-map (PET(MRCT)). Positron emission tomography SUVs were quantified placing regions of interest or volumes of interest in 6 different body regions as well as PET-avid lesions, respectively. RESULTS: The relative differences of quantitative PET values when using MR-based AC versus CT-based AC were varying depending on the organs and body regions assessed. In detail, the mean (SD) relative differences of PET SUVs were as follows: -7.8% (11.5%), blood pool; -3.6% (5.8%), spleen; -4.4% (5.6%)/-4.1% (6.2%), liver; -0.6% (5.0%), muscle; -1.3% (6.3%), fat; -40.0% (18.7%), bone; 1.6% (4.4%), liver lesions; -6.2% (6.8%), bone lesions; and -1.9% (6.2%), soft tissue lesions. In 10 liver lesions, distinct overestimations greater than 5% were found (up to 10%). In addition, overestimations were found in 2 bone lesions and 1 soft tissue lesion adjacent to the lung (up to 28.0%). CONCLUSIONS: Results obtained using different PET tracers show that MR-based AC is accurate in most tissue types, with SUV deviations generally of less than 10%. In bone, however, underestimations can be pronounced, potentially leading to inaccurate SUV quantifications. In addition, SUV overestimations were found for some lesions close to lung borders. This has to be taken into account when comparing PET/CT- and PET/MR-derived SUVs.

Combined unsupervised-supervised classification of multiparametric PET/MRI data: application to prostate cancer.

Multiparametric medical imaging data can be large and are often complex. Machine learning algorithms can assist in image interpretation when reliable training data exist. In most cases, however, knowledge about ground truth (e.g. histology) and thus training data is limited, which makes application of machine learning algorithms difficult. The purpose of this study was to design and implement a learning algorithm for classification of multidimensional medical imaging data that is robust and accurate even with limited prior knowledge and that allows for generalization and application to unseen data. Local prostate cancer was chosen as a model for application and validation. 16 patients underwent combined simultaneous [(11) C]-choline positron emission tomography (PET)/MRI. The following imaging parameters were acquired: T2 signal intensities, apparent diffusion coefficients, parameters Ktrans and Kep from dynamic contrast-enhanced MRI, and PET standardized uptake values (SUVs). A spatially constrained fuzzy c-means algorithm (sFCM) was applied to the single datasets and the resulting labeled data were used for training of a support vector machine (SVM) classifier. Accuracy and false positive and false negative rates of the proposed algorithm were determined in comparison with manual tumor delineation. For five of the 16 patients rates were also determined in comparison with the histopathological standard of reference. The combined sFCM/SVM algorithm proposed in this study revealed reliable classification results consistent with the histopathological reference standard and comparable to those of manual tumor delineation. sFCM/SVM generally performed better than unsupervised sFCM alone. We observed an improvement in accuracy with increasing number of imaging parameters used for clustering and SVM training. In particular, including PET SUVs as an additional parameter markedly improved classification results. A variety of applications are conceivable, especially for imaging of tissues without easily available histopathological correlation.

Quantitative Evaluation of Segmentation- and Atlas-Based Attenuation Correction for PET/MR on Pediatric Patients.

UNLABELLED: Pediatric imaging is regarded as a key application for combined PET/MR imaging systems. Because existing MR-based attenuation-correction methods were not designed specifically for pediatric patients, we assessed the impact of 2 potentially influential factors: inter- and intrapatient variability of attenuation coefficients and anatomic variability. Furthermore, we evaluated the quantification accuracy of 3 methods for MR-based attenuation correction without (SEGbase) and with bone prediction using an adult and a pediatric atlas (SEGwBONEad and SEGwBONEpe, respectively) on PET data of pediatric patients. METHODS: The variability of attenuation coefficients between and within pediatric (5-17 y, n = 17) and adult (27-66 y, n = 16) patient collectives was assessed on volumes of interest (VOIs) in CT datasets for different tissue types. Anatomic variability was assessed on SEGwBONEad/pe attenuation maps by computing mean differences to CT-based attenuation maps for regions of bone tissue, lungs, and soft tissue. PET quantification was evaluated on VOIs with physiologic uptake and on 80% isocontour VOIs with elevated uptake in the thorax and abdomen/pelvis. Inter- and intrapatient variability of the bias was assessed for each VOI group and method. RESULTS: Statistically significant differences in mean VOI Hounsfield unit values and linear attenuation coefficients between adult and pediatric collectives were found in the lungs and femur. The prediction of attenuation maps using the pediatric atlas showed a reduced error in bone tissue and better delineation of bone structure. Evaluation of PET quantification accuracy showed statistically significant mean errors in mean standardized uptake values of -14% ± 5% and -23% ± 6% in bone marrow and femur-adjacent VOIs with physiologic uptake for SEGbase, which could be reduced to 0% ± 4% and -1% ± 5% using SEGwBONEpe attenuation maps. Bias in soft-tissue VOIs was less than 5% for all methods. Lung VOIs showed high SDs in the range of 15% for all methods. For VOIs with elevated uptake, mean and SD were less than 5% except in the thorax. CONCLUSION: The use of a dedicated atlas for the pediatric patient collective resulted in improved attenuation map prediction in osseous regions and reduced interpatient bias variation in femur-adjacent VOIs. For the lungs, in which intrapatient variation was higher for the pediatric collective, a patient- or group-specific attenuation coefficient might improve attenuation map accuracy. Mean errors of -14% and -23% in bone marrow and femur-adjacent VOIs can affect PET quantification in these regions when bone tissue is ignored.

Segmentation-based attenuation correction in positron emission tomography/magnetic resonance: erroneous tissue identification and its impact on positron emission tomography interpretation.

OBJECTIVES: The objective of this study was to evaluate the frequency and characteristics of artifacts in segmentation-based attenuation correction maps (µ-maps) of positron emission tomography/magnetic resonance (PET/MR) and their impact on PET interpretation and the standardized uptake value (SUV) quantification in normal tissue and lesions. MATERIALS AND METHODS: The study was approved by the local institutional review board. Attenuation maps of 100 patients with PET/MR and preceding PET/computed tomography examination were retrospectively inspected for artifacts (tracers: 2-deoxy-2-[¹8F]fluoro-D-glucose (¹8F-FDG), ¹¹C-Choline, 68Ga-DOTATOC, 68Ga-DOTATATE, ¹¹C-Methionine). The artifacts were subdivided into 9 different groups on the basis of their localization and appearance. The impact of µ-map artifacts in normal tissue and lesions on PET interpretation was evaluated qualitatively via visual analysis in synopsis with the non-attenuation-corrected (NAC) PET as well as quantitatively by comparing the SUV in artifact regions to reference regions. RESULTS: Attenuation map artifacts were found in 72% of the head/neck data sets, 61% of the thoracic data sets, 25% of the upper abdominal data sets, and 26% of the pelvic data sets. The most frequent localizations of the overall 276 artifacts were around metal implants (16%), in the lungs (19%), and outer body contours (31%). Twenty-one percent of all PET-avid lesions (38 of 184 lesions) were affected by artifacts in the majority without further consequences for visual PET interpretation. However, 9 PET-avid lung lesions were masked owing to µ-map artifacts and, thus, were only detectable on the NAC PET or additional MR imaging sequences. Quantitatively, µ-map artifacts led to significant SUV changes in areas with erroneous assignment of air instead of soft tissue (ie, metal artifacts) and of soft tissue instead of lung. Nevertheless, no change in diagnosis would have been caused by µ-map artifacts. CONCLUSIONS: Attenuation map artifacts that occur in a considerable percentage of PET/MR data sets have the potential to falsify PET quantification and visual PET interpretation. Nevertheless, on the basis of the present data, in the clinical interpretation setup, no changes in diagnosis due to µ-map artifacts may occur, especially when the µ-maps are checked for artifacts and PET/MR is read in synopsis with the NAC PET, if artifacts are present.

Assessment of murine brain tissue shrinkage caused by different histological fixatives using magnetic resonance and computed tomography imaging.

Especially for neuroscience and the development of new biomarkers, a direct correlation between in vivo imaging and histology is essential. However, this comparison is hampered by deformation and shrinkage of tissue samples caused by fixation, dehydration and paraffin embedding. We used magnetic resonance (MR) imaging and computed tomography (CT) imaging to analyze the degree of shrinkage on murine brains for various fixatives. After in vivo imaging using 7 T MRI, animals were sacrificed and the brains were dissected and immediately placed in different fixatives, respectively: zinc-based fixative, neutral buffered formalin (NBF), paraformaldehyde (PFA), Bouin-Holland fixative and paraformaldehyde-lysine-periodate (PLP). The degree of shrinkage based on mouse brain volumes, radiodensity in Hounsfield units (HU), as well as non-linear deformations were obtained. The highest degree of shrinkage was observed for PLP (68.1%, P < 0.001), followed by PFA (60.2%, P<0.001) and NBF (58.6%, P<0.001). The zinc-based fixative revealed a low shrinkage with only 33.5% (P<0.001). Compared to NBF, the zinc-based fixative shows a slightly higher degree of deformations, but is still more homogenous than PFA. Tissue shrinkage can be monitored non-invasively with CT and MR. Zinc-based fixative causes the smallest degree of brain shrinkage and only small deformations and is therefore recommended for in vivo ex vivo comparison studies.

Simultaneous whole-body PET/MR imaging in comparison to PET/CT in pediatric oncology: initial results.

PURPOSE: To compare positron emission tomography (PET)/magnetic resonance (MR) imaging and PET/computed tomography (CT) for lesion detection and interpretation, quantification of fluorine 18 ((18)F) fluorodeoxyglucose (FDG) uptake, and accuracy of MR-based PET attenuation correction in pediatric patients with solid tumors. Materials and Methods This prospective study had local ethics committee and German Federal Institute for Drugs and Medical Devices approval. Written informed consent was obtained from all patients and legal guardians. Twenty whole-body (18)F-FDG PET/CT and (18)F-FDG PET/MR examinations were performed in 18 pediatric patients (median age, 14 years; range, 11-17 years). (18)F-FDG PET/CT and (18)F-FDG PET/MR data were acquired sequentially on the same day for all patients. PET standardized uptake values (SUVs) were quantified with volume of interest measurements in lesions and healthy tissues. MR-based PET attenuation correction was compared with CT-derived attenuation maps (µ-maps). Lesion detection was assessed with separate reading of PET/CT and PET/MR data. Estimates of radiation dose were derived from the applied doses of (18)F-FDG and CT protocol parameters. Descriptive statistical analyses were performed to report correlation coefficients and relative deviations for comparison of SUVs, rates of lesion detection, and percentage reductions in radiation dose. RESULTS: PET SUVs showed strong correlations between PET of PET/CT (PETCT) and PET of PET/MR (PETMR) (r > 0.85 for most tissues). Apart from drawbacks of MR-based PET attenuation correction in osseous structures and lungs, similar SUVs were found on PET images corrected with CT-based µ-maps (13.1% deviation of SUVs for bone marrow and <5% deviation for other tissues). Lesion detection rate with PET/MR imaging was equivalent to that with PET/CT (61 areas of focal uptake on PETMR images vs 62 areas on PETCT images). Advantages of PET/MR were observed especially in soft-tissue regions. Furthermore, PET/MR offered significant dose reduction (73%) compared with PET/CT. CONCLUSION: Pediatric oncologic PET/MR is technically feasible, showing satisfactory performance for PET quantification with SUVs similar to those of PET/CT. Compared with PET/CT, PET/MR demonstrates equivalent lesion detection rates while offering markedly reduced radiation exposure. Thus, PET/MR is a promising modality for the clinical work-up of pediatric malignancies. Online supplemental material is available for this article.

Principles of PET/MR Imaging.

Hybrid PET/MR systems have rapidly progressed from the prototype stage to systems that are increasingly being used in the clinics. This review provides an overview of developments in hybrid PET/MR systems and summarizes the current state of the art in PET/MR instrumentation, correction techniques, and data analysis. The strong magnetic field requires considerable changes in the manner by which PET images are acquired and has led, among others, to the development of new PET detectors, such as silicon photomultipliers. During more than a decade of active PET/MR development, several system designs have been described. The technical background of combined PET/MR systems is explained and related challenges are discussed. The necessity for PET attenuation correction required new methods based on MR data. Therefore, an overview of recent developments in this field is provided. Furthermore, MR-based motion correction techniques for PET are discussed, as integrated PET/MR systems provide a platform for measuring motion with high temporal resolution without additional instrumentation. The MR component in PET/MR systems can provide functional information about disease processes or brain function alongside anatomic images. Against this background, we point out new opportunities for data analysis in this new field of multimodal molecular imaging.

On the quantification accuracy, homogeneity, and stability of simultaneous positron emission tomography/magnetic resonance imaging systems.

OBJECTIVE: A potential major application of simultaneous avalanche photodiode-based positron emission tomography (PET)/magnetic resonance imaging (MRI) systems are quantitative brain studies for cerebral blood flow measurements in combination with blood-oxygen-level-dependent or perfusion MRI, requiring a high performance for both modalities. Thus, we evaluated PET quantification accuracy and homogeneity for 2 different simultaneous PET/MRI systems (whole-body and brain scanner) compared with those of a state-of-the-art PET detector (PET/computed tomography) using phantom studies. In addition, we investigated the long-term stability of PET and quality of functional MRI measurements of a clinical whole-body PET/MRI scanner. MATERIALS AND METHODS: Phantom measurements were conducted using spheres filled with [F]-fluoride distributed in a homogeneous cylinder phantom at different positions inside the PET field of view. Recovery values and standard deviations were extracted from resulting PET images. The influence of magnetic resonance-based attenuation correction and that of activity outside the PET field of view on the recovery values of these spheres was evaluated. Furthermore, long-term PET stability of the whole-body PET/MRI system was assessed by evaluating position profiles, energy spectra, count rates, and recovery values from [Ge]-phantom scans. Functional MRI applicability was tested in accordance with the functional Biomedical Information Research Network procedure. RESULTS: The BrainPET system showed high recovery values (up to 99%) but also increased variability (up to 7.4%). Significant underestimations in PET quantification near activity outside the PET field of view were found (up to 80%). Using magnetic resonance-based attenuation correction led to an underestimation in PET activity of approximately 7%. In distinction, the whole-body PET/MRI system revealed performance similar to the PET/computed tomographic scanner (recovery values up to approximately 60% with a variability of approximately 4%). Long-term stability and fMRI performance of the whole-body PET/MRI scanner showed no degradation compared with stand-alone systems. CONCLUSIONS: Homogeneity and accuracy of avalanche photodiode-based PET detectors is comparable with those of the state-of-the-art detectors based on photomultiplier tubes. However, attenuation correction on PET/MRI systems has to be adapted carefully for quantitative PET measurements. The BrainPET system needs improved scatter correction to perform quantitative brain studies. The whole-body PET/MRI scanner, however, is applicable for quantitative brain studies.