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A small-animal positron emission tomography (PET) scanner using PS-APD (position-sensitive avalanche photodiode) detectors has been developed for simultaneous PET/MRI imaging. In this scanner, up to 16 detector modules (one PS-APD per module) are used, and each detector module produces 4 signals to be digitized with their peak values. This leads to as many as 64 analog outputs to the data acquisition (DAQ) system, requiring 64 DAQ channels. In the future, the system will be extended to 32 modules, resulting in 128 channels. It is possible to sample all channels simultaneously, but most of them do not contain useful data, since only one coincidence event (producing data on 8 channels) is identified each time. The purpose of this work was to develop a general-purpose method for reducing the number of analog inputs to the data acquisition for the sparse fast analog signals produced in a PET scanner. To achieve this, a multiplexer board was designed to sample coincidence events from the PET scanner. The effect of the multiplexer on signal quality was evaluated and the average peak-to-valley ratios in detector flood histograms with and without multiplexer were 2.97 and 3.02 respectively. On-board coincidence, pile-up rejection and multiple coincidence rejection functions were implemented and worked as expected. The dead time performance was also characterized. Index Terms--Avalanche photodiodes, data acquisition, multiplexing, positron emission tomography (PET).

The probability of nodal and distant metastasis in patients (pts) with very-low, low, and favorable intermediate risk (FIR) prostate cancer (PCa) is considered low. Current NCCN and AUA/ASTRO guidelines do not recommend PSMA PET staging for these men. However, it has been reported that pts assigned to the FIR category are more likely than low-risk pts to have adverse pathological findings (upstaging and upgrading) at radical prostatectomy (RP) with a trend toward shorter recurrence-free survival. Early detection of clinically significant disease, extraprostatic extension, seminal vesicle invasion, N1 or M1 disease may change medical management in FIR pts and improve treatment outcomes. The purpose of this study is to explore whether piflufolastat F 18 PET/CT or PET/MR can detect higher risk disease in men previously assessed as FIR by standard of care methods. We hypothesize that piflufolastat F 18 PET will detect non-organ confined disease or upgrade pts to International Society of Urologic Pathologists (ISUP) grade ≥3 PCa in at least 5% of FIR subjects. This trial will also assess the ability for PET to better assess the volume and extent of the intraprostatic cancers. MIRROR is a phase 4, open label single arm multicenter study designed to evaluate the diagnostic performance and safety of piflufolastat F 18 in men with newly diagnosed FIR PCa. Eligible male pts must be ≥18 years of age, no prior PCa treatment, have a life expectancy of at least 13 months as determined by investigator, and confirmed FIR PCa per 2023 NCCN guidelines. The date of the prostate biopsy should be no sooner that 2 weeks and no later than 3 months prior to piflufolastat F 18 PSMA PET imaging. Participants will receive a single dose of piflufolastat F 18 injection followed by a single PET/CT or PET/MRI from mid-thigh through skull vertex acquired at 1 to 2 hours post-injection. Pts with a positive study scan results suspicious for PCa ISUP grade ≥3 or non-organ confined disease may be asked to undergo additional diagnostic test(s) for PCa and/or RP with pelvic lymph node dissection within 2 to 90 days after study scan to determine a truth standard. Pts will be monitored for up to 12 months to collect information about PCa treatment decisions and PSA results. The primary objective is to determine the detection rate defined as the proportion of participants with PCa in whom piflufolastat F 18 PET detected intraprostatic ISUP grade ≥3 lesions as confirmed by pathology, or in whom piflufolastat F 18 PET detected the presence of either/or extraprostatic extension, seminal vesicle invasion, regional lymph node involvement, distant metastases. Additional objectives include: change in intended patient clinical management, correct localization rate, true detection rate, sensitivity, specificity, PPV & NPV against reference standard. The study is currently open in the US. NCT06074510 TBD. TBD. [ABSTRACT FROM AUTHOR]

Purpose: We propose a novel approach for PET respiratory motion correction using tagged-MRI and simultaneous PET-MRI acquisitions.Methods: We use a tagged-MRI acquisition followed by motion tracking in the phase domain to estimate the nonrigid deformation of biological tissues during breathing. In order to accurately estimate motion even in the presence of noise and susceptibility artifacts, we regularize the traditional HARP tracking strategy using a quadratic roughness penalty on neighboring displacement vectors (R-HARP). We then incorporate the motion fields estimated with R-HARP in the system matrix of an MLEM PET reconstruction algorithm formulated both for sinogram and list-mode data representations. This approach allows reconstruction of all detected coincidences in a single image while modeling the effect of motion both in the emission and the attenuation maps. At present, tagged-MRI does not allow estimation of motion in the lungs and our approach is therefore limited to motion correction in soft tissues. Since it is difficult to assess the accuracy of motion correction approaches in vivo, we evaluated the proposed approach in numerical simulations of simultaneous PET-MRI acquisitions using the NCAT phantom. We also assessed its practical feasibility in PET-MRI acquisitions of a small deformable phantom that mimics the complex deformation pattern of a lung that we imaged on a combined PET-MRI brain scanner.Results: Simulations showed that the R-HARP tracking strategy accurately estimated realistic respiratory motion fields for different levels of noise in the tagged-MRI simulation. In simulations of tumors exhibiting increased uptake, contrast estimation was 20% more accurate with motion correction than without. Signal-to-noise ratio (SNR) was more than 100% greater when performing motion-corrected reconstruction which included all counts, compared to when reconstructing only coincidences detected in the first of eight gated frames. These results were confirmed in our proof-of-principle PET-MRI acquisitions, indicating that our motion correction strategy is accurate, practically feasible, and is therefore ready to be tested in vivo.Conclusions: This work shows that PET motion correction using motion fields measured with tagged-MRI in simultaneous PET-MRI acquisitions can be made practical for clinical application and that doing so has the potential to remove motion blur in whole-body PET studies of the torso. [ABSTRACT FROM AUTHOR]

Patients with advanced gastric cancer (GCa) have limited treatment options, and alternative treatment approaches are necessary to improve their clinical outcomes. Because fibrin is abundant in gastric tumors but not in healthy tissues, we hypothesized that fibrin could be used as a high-concentration depot for a high-energy beta-emitting cytotoxic radiopharmaceutical delivered to tumor cells. We showed that fibrin is present in 64 to 75% of primary gastric tumors and 50 to 100% of metastatic gastric adenocarcinoma cores. First-in-human 64 Cu-FBP8 fibrin-targeted positron emission tomography (PET) imaging in seven patients with gastric or gastroesophageal junction cancer showed high probe uptake in all target lesions with tumor-to-background (muscle) uptake ratios of 9.9 ± 6.6 in primary ( n = 7) and 11.2 ± 6.6 in metastatic ( n = 45) tumors. Using two mouse models of human GCa, one fibrin-high (SNU-16) and one fibrin-low (NCI-N87), we showed that PET imaging with a related fibrin-specific peptide, CM500, labeled with copper-64 ( 64 Cu-CM500) specifically bound to and precisely quantified tumor fibrin in both models. We then labeled the fibrin-specific peptide CM600 with yttrium-90 and showed that 90 Y-CM600 effectively decreased tumor growth in these mouse models. Mice carrying fibrin-high SNU-16 tumors experienced tumor growth inhibition and prolonged survival in response to either a single high dosage or fractionated lower dosage of 90 Y-CM600, whereas mice carrying fibrin-low NCI-N87 tumors experienced prolonged survival in response to a fractionated lower dosage of 90 Y-CM600. These results lay the foundation for a fibrin-targeted theranostic that may expand options for patients with advanced GCa.

Purpose: This study presents for the first time in humans the biodistribution, clearance and dosimetry estimates of [ 64 Cu]Fibrin Binding Probe #8 ([ 64 Cu]FBP8) in healthy subjects. [ 64 Cu]FBP8-PET previously demonstrated its potential in two recent applications: thrombus imaging and pulmonary fibrosis., Procedures: This prospective study included 8 healthy subjects to evaluate biodistribution, safety and dosimetry estimates of [ 64 Cu]FBP8, a fibrin-binding positron emission tomography (PET) probe. All subjects underwent up to 3 sessions of PET/Magnetic Resonance Imaging (PET/MRI) 0-2 h, 4 h and 24 h post injection. Dosimetry estimates were obtained using OLINDA 2.2 software., Results: Subjects were injected with 400 MBq of [ 64 Cu]FBP8. Subjects did not experience adverse effects due to the injection of the probe. [ 64 Cu]FBP8 PET images demonstrated fast blood clearance (half-life = 67 min) and renal excretion of the probe, showing low background signal across the body. The organs with the higher doses were: the urinary bladder (0.075 vs. 0.091 mGy/MBq for males and females, respectively); the kidneys (0.050 vs. 0.056 mGy/MBq respectively); and the liver (0.027 vs. 0.035 mGy/MBq respectively). The combined mean effective dose for males and females was 0.016 ± 0.0029 mSv/MBq, lower than the widely used [ 18 F]fluorodeoxyglucose ([ 18 F]FDG, 0.020mSv/MBq)., Conclusions: This study demonstrates the following properties of the [ 64 Cu]FBP8 probe: low dosimetry estimates; fast blood clearance and renal excretion; low background signal; and whole-body acquisition within 20 min in a single session. These properties provide the basis for [ 64 Cu]FBP8 to be an excellent candidate for whole-body non-invasive imaging of fibrin, an important driver/feature in many cardiovascular, oncological and neurological conditions., Competing Interests: Declarations. Ethical Approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Financial Support and Conflict of Interest: This work was supported by grants from the National Heart Lung and Blood Institute (R01HL109448) and the National Institutes of Health (NIH) Office of the Director (S10OD028499). Peter Caravan holds equity in and receives consulting income from Collagen Medical LLC and Reveal Pharmaceuticals, and has research funding from Transcode Therapeutics, Pliant Therapeutics, and Canon Medical. David Izquierdo-Garcia receives funding from the PolyBio Research Foundation and the Spanish Ministry of Universities., (© 2024. The Author(s), under exclusive licence to World Molecular Imaging Society.)

Pancreatic ductal adenocarcinoma (PDAC) is an invasive and rapidly progressive malignancy. A major challenge in patient management is the lack of a reliable imaging tool to monitor tumor response to treatment. Tumor-associated fibrosis characterized by high type I collagen is a hallmark of PDAC, and fibrosis further increases in response to neoadjuvant chemoradiotherapy (CRT). We hypothesized that molecular positron emission tomography (PET) using a type I collagen-specific imaging probe, 68 Ga-CBP8 can detect and measure changes in tumor fibrosis in response to standard treatment in mouse models and patients with PDAC. Methods: We evaluated the specificity of 68 Ga-CBP8 PET to tumor collagen and its ability to differentiate responders from non-responders based on the dynamic changes of fibrosis in nude mouse models of human PDAC including FOLFIRNOX-sensitive (PANC-1 and PDAC6) and FOLFIRINOX-resistant (SU.86.86). Next, we demonstrated the specificity and sensitivity of 68 Ga-CBP8 to the deposited collagen in resected human PDAC and pancreas tissues. Eight male participant (49-65 y) with newly diagnosed PDAC underwent dynamic 68 Ga-CBP8 PET/MRI, and five underwent follow up 68 Ga-CBP8 PET/MRI after completing standard CRT. PET parameters were correlated with tumor collagen content and markers of response on histology. Results: 68 Ga-CBP8 showed specific binding to PDAC compared to non-binding 68 Ga-CNBP probe in two mouse models of PDAC using PET imaging and to resected human PDAC using autoradiography (P < 0.05 for all comparisons). 68 Ga-CBP8 PET showed 2-fold higher tumor signal in mouse models following FOLFIRINOX treatment in PANC-1 and PDAC6 models (P < 0.01), but no significant increase after treatment in FOLFIRINOX resistant SU.86.86 model. 68 Ga-CBP8 binding to resected human PDAC was significantly higher (P < 0.0001) in treated versus untreated tissue. PET/MRI of PDAC patients prior to CRT showed significantly higher 68 Ga-CBP8 uptake in tumor compared to pancreas (SUV mean : 2.35 ± 0.36 vs. 1.99 ± 0.25, P = 0.036, n = 8). PET tumor values significantly increased following CRT compared to untreated tumors (SUV mean : 2.83 ± 0.30 vs. 2.25 ± 0.41, P = 0.01, n = 5). Collagen deposition significantly increased in response to CRT (59 ± 9% vs. 30 ± 9%, P=0.0005 in treated vs. untreated tumors). Tumor and pancreas collagen content showed a positive direct correlation with SUV mean (R 2 = 0.54, P = 0.0007). Conclusions: This study demonstrates the specificity of 68 Ga-CBP8 PET to tumor type I collagen and its ability to differentiate responders from non-responders based on the dynamic changes of fibrosis in PDAC. The results highlight the potential use of collagen PET as a non-invasive tool for monitoring response to treatment in patients with PDAC., Competing Interests: Competing Interests: PC has equity in and is a consultant to Collagen Medical LLC, has equity in Reveal Pharmaceuticals Inc., and has research support from Transcode Therapeutics and Pliant Therapeutics. PC is a co-inventor of US Patent 10,471,162 which covers 68Ga-CBP8 and is assigned to the General Hospital Corporation. SE has research support from Sofie Biosciences, Telix, and Novartis Pharmaceuticals. ARP has held Equity in C2i Genomics, XGenomes, Cadex, Vionix and Parithera. In the last 36 months, she has served as an advisor/consultant for Eli Lilly, Mirati, Pfizer, Inivata, Biofidelity, Checkmate Pharmaceuticals, FMI, Guardant, Abbvie, Bayer, Delcath, Taiho, CVS, Value Analytics Lab, Seagen, Saga, AZ, Scare Inc, Illumina, Taiho, Hookipa, Kahar Medical, Xilio Therapeutics, Sirtex, Takeda, and Science For America. She receives fees from Up to Date. She has received travel fees from Karkinos Healthcare. She has been on the DSMC for a Roche study and on the Steering Committee for Exilixis. She has received research funding to the Institution from PureTech, PMV Pharmaceuticals, Plexxicon, Takeda, BMS, Mirati, Novartis, Erasca, Genentech, Daiichi Sankyo, Syndax, Revolution Medicine and Parthenon. UM is a co-founder, shareholder, and consultant (Scientific Advisory Board) of CytoSite BioPharma. TSH is a consultant for Synthetic Biologics, Novocure, Boston Scientific, Neogenomics, Merck, GSK, NextCure, serves on the advisory board of PanTher Therapeutics (Equity), and Lustgarten Foundation, and has received research funding from Taiho, Astra-Zeneca, BMS, GSK, ItraOp and Ipsen. GMB has sponsored research agreements through her institution with: Olink Proteomics, Teiko Bio, InterVenn Biosciences, Palleon Pharmaceuticals. She served on advisory boards for Iovance, Merck, Nektar Therapeutics, Novartis, and Ankyra Therapeutics. She consults for Merck, InterVenn Biosciences, Iovance, and Ankyra Therapeutics. She holds equity in Ankyra Therapeutics. Other authors declare that they have no competing interests., (© The author(s).)

The Bacillus Calmette-Guérin (BCG) vaccine, which has been used for > 100 years to prevent tuberculosis, is well-established for bladder cancer treatment, and under study for neurological and autoimmune diseases. In patients with type 1 diabetes (T1D), BCG vaccinations have been shown in randomized clinical trials to gradually lower blood sugar to near normal levels. This effect appears to be driven by a BCG-induced shift in lymphoid cells' glucose metabolism from oxidative phosphorylation to aerobic glycolysis. The latter is a state of high glucose utilization that draws more glucose from the blood. Apart from blood, it is unknown whether BCG establishes residence in any organs and alters their glucose metabolism. In this two-year-long clinical trial in type 1 diabetics, we use positron emission tomography (PET) and x-ray computed tomography (CT) to map organs that increase their uptake of the glucose analogue 18 F-fluorodeoxyglucose ( 18 F-FDG) before versus after BCG vaccinations. We also injected BALB/c mice with BCG to test for the presence of BCG in various organs. Results from both studies point to the spleen as the dominant site for glucose uptake and BCG residence. The human spleen is significant because its 47% increase in 18 F-FDG uptake by a large population of lymphocytes and monocytes might help to explain BCG's systemic lowering of blood glucose to near normal levels. Findings suggest that the spleen, triggered by BCG, assumes a critical role in systemic glucose regulation in the absence of a functional pancreas., (© 2024. The Author(s).)

Compartmentalized meningeal inflammation is thought to represent one of the key players in the pathogenesis of cortical demyelination in multiple sclerosis. PET targeting the 18 kDa mitochondrial translocator protein (TSPO) is a molecular-specific approach to quantifying immune cell-mediated density in the cortico-meningeal tissue compartment in vivo. This study aimed to characterize cortical and meningeal TSPO expression in a heterogeneous cohort of multiple sclerosis cases using in vivo simultaneous MR-PET with 11C-PBR28, a second-generation TSPO radioligand, and ex vivo immunohistochemistry. Forty-nine multiple sclerosis patients (21 with secondary progressive and 28 with relapsing-remitting multiple sclerosis) with mixed or high affinity binding for 11C-PBR28 underwent 90-min 11C-PBR28 simultaneous MR-PET. Tracer binding was measured using 60-90 min normalized standardized uptake value ratios sampled at mid-cortical depth and ∼3 mm above the pial surface. Data in multiple sclerosis patients were compared to 21 age-matched healthy controls. To characterize the nature of 11C-PBR28 PET uptake, the meningeal and cortical lesion cellular expression of TSPO was further described in post-mortem brain tissue from 20 cases with secondary progressive multiple sclerosis and five age-matched healthy donors. Relative to healthy controls, patients with multiple sclerosis exhibited abnormally increased TSPO signal in the cortex and meningeal tissue, diffusively in progressive disease and more localized in relapsing-remitting multiple sclerosis. In multiple sclerosis, increased meningeal TSPO levels were associated with increased Expanded Disability Status Scale scores (P = 0.007, by linear regression). Immunohistochemistry, validated using in situ sequencing analysis, revealed increased TSPO expression in the meninges and adjacent subpial cortical lesions of post-mortem secondary progressive multiple sclerosis cases relative to control tissue. In these cases, increased TSPO expression was related to meningeal inflammation. Translocator protein immunostaining was detected on meningeal MHC-class II+ macrophages and cortical-activated MHC-class II+ TMEM119+ microglia. In vivo arterial blood data and neuropathology showed that endothelial binding did not significantly account for increased TSPO cortico-meningeal expression in multiple sclerosis. Our findings support the use of TSPO-PET in multiple sclerosis for imaging in vivo inflammation in the cortico-meningeal brain tissue compartment and provide in vivo evidence implicating meningeal inflammation in the pathogenesis of the disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Abstract: Neuroendocrine neoplasms are a heterogeneous group of gastrointestinal and lung tumors. Their diverse clinical manifestations, variable locations, and heterogeneity present notable diagnostic challenges. This article delves into the imaging modalities vital for their detection and characterization. Computed tomography is essential for initial assessment and staging. At the same time, magnetic resonance imaging (MRI) is particularly adept for liver, pancreatic, osseous, and rectal imaging, offering superior soft tissue contrast. The article also highlights the limitations of these imaging techniques, such as MRI's inability to effectively evaluate the cortical bone and the questioned cost-effectiveness of computed tomography and MRI for detecting specific gastric lesions. By emphasizing the strengths and weaknesses of these imaging techniques, the review offers insights into optimizing their utilization for improved diagnosis, staging, and therapeutic management of neuroendocrine neoplasms., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: This study presents the biodistribution, clearance and dosimetry estimates of [ 64 Cu]Fibrin Binding Probe #8 ([ 64 Cu]FBP8) in healthy subjects., Procedures: This prospective study included 8 healthy subjects to evaluate biodistribution, safety and dosimetry estimates of [ 64 Cu]FBP8, a fibrin-binding positron emission tomography (PET) probe. All subjects underwent up to 3 sessions of PET/Magnetic Resonance Imaging (PET/MRI) 0-2 hours, 4h and 24h post injection. Dosimetry estimates were obtained using OLINDA 2.2 software., Results: Subjects were injected with ~400 MBq of [ 64 Cu]FBP8. Subjects did not experience adverse effects due to the injection of the probe. [ 64 Cu]FBP8 PET images demonstrated fast blood clearance (half-life = 67 min) and renal excretion of the probe, showing low background signal across the body. The organs with the higher doses were: the urinary bladder (0.075 vs. 0.091 mGy/MBq for males and females, respectively); the kidneys (0.050 vs. 0.056 mGy/MBq respectively); and the liver (0.027 vs. 0.035 mGy/MBq respectively). The combined mean effective dose for males and females was 0.016 ± 0.0029 mSv/MBq, lower than the widely used [ 18 F]fluorodeoxyglucose ([ 18 F]FDG, 0.020mSv/MBq)., Conclusions: This study demonstrates the following properties of the [ 64 Cu]FBP8 probe: low dosimetry estimates; fast blood clearance and renal excretion; low background signal; and whole-body acquisition within 20 minutes in a single session. These properties provide the basis for [ 64 Cu]FBP8 to be an excellent candidate for whole-body non-invasive imaging of fibrin, an important driver/feature in many cardiovascular, oncological and neurological conditions.

Sex-based differences in the prevalence of autism spectrum disorder (ASD) are well-documented, with a male-to-female ratio of approximately 4:1. The clinical presentation of the core symptoms of ASD can also vary between sexes. Previously, positron emission tomography (PET) studies have identified alterations in the in vivo levels of translocator protein (TSPO)-a mitochondrial protein-in primarily or only male adults with ASD, with our group reporting lower TSPO relative to whole brain mean in males with ASD. However, whether in vivo TSPO levels are altered in females with ASD, specifically, is unknown. This is the first pilot study to measure in vivo TSPO in the brain in adult females with ASD using [ 11 C]PBR28 PET-magnetic resonance imaging (MRI). Twelve adult females with ASD and 10 age- and TSPO genotype-matched controls (CON) completed one or two [ 11 C]PBR28 PET-MRI scans. Females with ASD exhibited elevated [ 11 C]PBR28 standardized uptake value ratio (SUVR) in the midcingulate cortex and splenium of the corpus callosum compared to CON. No brain area showed lower [ 11 C]PBR28 SUVR in females with ASD compared to CON. Test-retest over several months showed stable [ 11 C]PBR28 SUVR across time in both groups. Elevated regional [ 11 C]PBR28 SUVR in females with ASD stand in stark contrast to our previous findings of lower regional [ 11 C]PBR28 SUVR in males with ASD. Preliminary evidence of regionally elevated mitochondrial protein TSPO relative to whole brain mean in ASD females may reflect neuroimmuno-metabolic alterations specific to females with ASD., (© 2024. The Author(s).)

Alcohol use disorder (AUD) is a disorder of clinical and public health significance requiring novel and improved therapeutic solutions. Both environmental and genetic factors play a significant role in its pathophysiology. However, the underlying epigenetic molecular mechanisms that link the gene-environment interaction in AUD remain largely unknown. In this proof-of-concept study, we showed, for the first time, the neuroepigenetic biomarker capability of non-invasive imaging of class I histone deacetylase (HDAC) epigenetic enzymes in the in vivo brain for classifying AUD patients from healthy controls using a machine learning approach in the context of precision diagnosis. Eleven AUD patients and 16 age- and sex-matched healthy controls completed a simultaneous positron emission tomography-magnetic resonance (PET/MR) scan with the HDAC-binding radiotracer [ 11 C]Martinostat. Our results showed lower HDAC expression in the anterior cingulate region in AUD. Furthermore, by applying a genetic algorithm feature selection, we identified five particular brain regions whose combined [ 11 C]Martinostat relative standard uptake value (SUVR) features could reliably classify AUD vs. controls. We validate their promising classification reliability using a support vector machine classifier. These findings inform the potential of in vivo HDAC imaging biomarkers coupled with machine learning tools in the objective diagnosis and molecular translation of AUD that could complement the current diagnostic and statistical manual of mental disorders (DSM)-based intervention to propel precision medicine forward., Competing Interests: C.W. and J.M.H. are inventors of the [11C]Martinostat epigenetic PET radiotracer imaging probe used in this project., (© 2024 The Author(s).)

Purpose: Radiation-induced lung injury (RILI) is a progressive inflammatory process seen after irradiation for lung cancer. The disease can be insidious, often characterized by acute pneumonitis followed by chronic fibrosis with significant associated morbidity. No therapies are approved for RILI, and accurate disease quantification is a major barrier to improved management. Here, we sought to noninvasively quantify RILI using a molecular imaging probe that specifically targets type 1 collagen in mouse models and patients with confirmed RILI., Methods and Materials: Using a murine model of lung radiation, mice were imaged with EP-3533, a type 1 collagen probe, to characterize the development of RILI and to assess disease mitigation after losartan treatment. The human analog probe 68 Ga-CBP8, targeting type 1 collagen, was tested on excised human lung tissue containing RILI and was quantified via autoradiography. 68 Ga-CBP8 positron emission tomography was used to assess RILI in vivo in 6 human subjects., Results: Murine models demonstrated that probe signal correlated with progressive RILI severity over 6 months. The probe was sensitive to mitigation of RILI by losartan. Excised human lung tissue with RILI had increased binding versus unirradiated control tissue, and 68 Ga-CBP8 uptake correlated with collagen proportional area. Human imaging revealed significant 68 Ga-CBP8 uptake in areas of RILI and minimal background uptake., Conclusions: These findings support the ability of a molecular imaging probe targeted at type 1 collagen to detect RILI in preclinical models and human disease, suggesting a role for targeted molecular imaging of collagen in the assessment of RILI., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Simultaneous positron emission tomography (PET)/magnetic resonance imaging (MRI) scanners and inserts are valuable tools for accurate diagnosis, treatment planning, and monitoring due to their complementary information. However, the integration of a PET system into an MRI scanner presents technical challenges for a distortion-free operation., Purpose: We aim to develop a PET insert dedicated to breast imaging in combination with the 3T PET/MRI scanner Biograph mMR (Siemens Healthineers) as well as a brain PET insert for the 7T MRI scanner MAGNETOM Terra (Siemens Healthineers). For this development, we selected as a basis the C13500 series PET modules (Hamamatsu Photonics K.K.) as they offer an all-in-one solution with a scalable, modular design for compact integration with state-of-the-art performance. The original PET modules were not designed to be operated with an MRI scanner, therefore we implemented several modifications such as signal transmission via plastic optical fiber, radio frequency (RF) shielding of the front-end electronics, and filter for the power supply lines. In this work, we evaluated the mutual MRI compatibility between the modified PET modules and the 3T and 7T MRI scanner., Methods: We used a proof-of-concept setup with two detectors to comprehensively evaluate a potential distortion of the performance of the modified PET modules whilst exposing them to a variety of MR sequences up to the peak operation conditions of the Biograph mMR. A method using the periodicity of the sequences to identify distortions of the PET events in the phase of RF pulse transmission was introduced. Vice versa, the potential distortion of the Biograph mMR was evaluated by vendor proprietary MRI compatibility test sequences. Afterwards, these studies were extended to the MAGNETOM Terra., Results: No distortions were introduced by gradient field switching (field strength up to 20 mT/m at a slew rate of 66.0 T/ms -1 ). However, RF pulse transmission induced a reduction of the single event rate from 33.0 kcounts/s to 32.0 kcounts/s and a degradation of the coincidence resolution time from 251 to 299 ps. Further, the proposed method revealed artifacts in the energy and timing histograms. Finally, by using the front-end filters it was possible to prevent any RF pulse induced distortion of event rate, energy, or time stamps even for a 700° flip angle (45.5 μT) sequence. The evaluations to assess potential distortions of the MRI scanner showed that carefully designed RF shielding boxes for the PET modules were required to prevent distortion of the RF spectra. The increase in B 0 field inhomogeneity of 0.254 ppm and local changes of the B 1 field of 12.5% introduced by the PET modules did not qualitatively affect the MR imaging with a spin echo and MPRAGE sequence for the Biograph mMR and the MAGNETOM Terra, respectively., Conclusion: Our study demonstrates the feasibility of using a modified version of the PET modules in combination with 3T and 7T MRI scanners. Building upon the encouraging MRI compatibility results from our proof-of-concept detectors, we will proceed to develop PET inserts for breast and brain imaging using these modules., (© 2023 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

The expansion of acute myeloid leukemia (AML) blasts not only suppresses normal hematopoiesis, but also alters the microenvironment. The interplay of different components of the bone marrow gives rise to altered metabolic states and activates signaling pathways which lead to resistance and impede effective therapy. Therefore, the underlying processes and mechanisms represent attractive therapeutic leverage points for overcoming therapy resistance in AML. Here, we briefly discuss resistance mechanisms based on cell interactions and secreted soluble factors in the hematopoietic niche and provide an overview of niche-related therapeutic targets currently undergoing preclinical and clinical investigation which may help improve the outcome in AML therapy., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Dedicated brain PET scanners are optimized to provide high sensitivity and high spatial resolution compared with existing whole-body PET systems, and they can be much cheaper to produce and install in various clinical and research settings. Advancements in detector technology over the past few years have placed several standalone PET, PET/computed tomography, and PET/MR systems on or near the commercial market; the features and capabilities of these systems will be reviewed here., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: The purpose of this study was to examine the efficacy of the Nutrition and Exercise for Wellness and Recovery (NEW-R) intervention for improving competency and behaviors related to diet, physical activity, and weight management., Methods: Participants with psychiatric disabilities were recruited from four community mental health agencies and a hospital-based psychiatric outpatient clinic and randomly assigned to the NEW-R intervention (N=55) or control condition (N=58). Outcome measures included the Perceived Competence Scale, Health-Promoting Lifestyle Profile (HPLP), and weight change; random-effects regression models were used. A follow-up analysis examined the interactions of group, time, and site., Results: Fifty of the 55 intervention participants and 57 of the 58 control participants completed the study. The two groups did not differ significantly on any measured baseline characteristic. The intervention group had statistically significant improvements, compared with the control group, in perceived competence for exercise and healthy eating, total HPLP score, and scores on two HPLP subscales (nutrition and spiritual growth). No significant difference between groups was found for weight loss. A study condition × time × site effect was observed: at the three sites where mean weight loss occurred, NEW-R participants lost significantly more weight than did control participants., Conclusions: NEW-R offers promise as an intervention that can initiate the change to healthy lifestyle behaviors and boost perceived competence in a healthy lifestyle. It may also be effective for weight loss when administered in supportive settings.

Background: Myocardial feature tracking (FT) provides a comprehensive analysis of myocardial deformation from cine balanced steady-state free-precession images (bSSFP). However, FT remains time-consuming, precluding its clinical adoption., Purpose: To compare left-ventricular global radial strain (GRS) and global circumferential strain (GCS) values measured using automated DeepStrain analysis of short-axis cine images to those calculated using manual commercially available FT analysis., Study Type: Retrospective, single-center., Population: A total of 30 healthy subjects and 120 patients with cardiac disease for DeepStrain development. For evaluation, 47 healthy subjects (36 male, 53 ± 5 years) and 533 patients who had undergone a clinical cardiac MRI (373 male, 59 ± 14 years). FIELD STRENGTH/SEQUENCE: bSSFP sequence at 1.5 T (Phillips) and 3 T (Siemens)., Assessment: Automated DeepStrain measurements of GRS and GCS were compared to commercially available FT (Circle, cvi42) measures obtained by readers with 1 year and 3 years of experience. Comparisons were performed overall and stratified by scanner manufacturer., Statistical Tests: Paired t-test, linear regression slope, Pearson correlation coefficient (r)., Results: Overall, FT and DeepStrain measurements of GCS were not significantly different (P = 0.207), but measures of GRS were significantly different. Measurements of GRS from Philips (slope = 1.06 [1.03 1.08], r = 0.85) and Siemens (slope = 1.04 [0.99 1.09], r = 0.83) data showed a very strong correlation and agreement between techniques. Measurements of GCS from Philips (slope = 0.98 [0.98 1.01], r = 0.91) and Siemens (slope = 1.0 [0.96 1.03], r = 0.88) data similarly showed a very strong correlation. The average analysis time per subject was 4.1 ± 1.2 minutes for FT and 34.7 ± 3.3 seconds for DeepStrain, representing a 7-fold reduction in analysis time., Data Conclusion: This study demonstrated high correlation of myocardial GCS and GRS measurements between freely available fully automated DeepStrain and commercially available manual FT software, with substantial time-saving in the analysis., Evidence Level: 3 TECHNICAL EFFICACY: Stage 3., (© 2022 International Society for Magnetic Resonance in Medicine.)

The 68 Ga-Collagen Binding Probe #8, 68 Ga-CBP8, is a peptide-based, type I collagen-targeted probe developed for imaging of tissue fibrosis. The aim of this study was to determine the biodistribution, dosimetry, and pharmacokinetics of 68 Ga-CBP8 in healthy human subjects. Methods: Nine healthy volunteers (5 male and 4 female) underwent whole-body 68 Ga-CBP8 PET/MRI using a Biograph mMR scanner. The subjects were imaged continuously for up to 2 h after injection of 68 Ga-CBP8. A subset of subjects underwent an additional imaging session 2-3 h after probe injection. OLINDA/EXM software was used to calculate absorbed organ and effective dose estimates based on up to 17 regions of interest (16 for men) defined on T2-weighted MR images and copied to the PET images, assuming a uniform distribution of probe concentration in each region. Serial blood sampling up to 90 min after probe injection was performed to assess blood clearance and metabolic stability. Results: The mean injected activity (±SD) of 68 Ga-CBP8 was 220 ± 100 MBq (range, 113-434 MBq). No adverse effects related to probe administration were detected. 68 Ga-CBP8 demonstrated an extracellular distribution with predominantly rapid renal clearance. Doses on the urinary bladder were 0.15 versus 0.19 mGy/MBq for men versus women. The highest absorbed doses for the rest of the organs were measured in the kidneys (0.078 vs. 0.088 mGy/MBq) and the liver (0.032 vs. 0.041 mGy/MBq). The mean effective dose was 0.018 ± 0.0026 mSv/MBq using a 1-h voiding model. The 68 Ga-CBP8 signal in the blood demonstrated biexponential pharmacokinetics with an initial distribution half-life of 4.9 min (95% CI, 2.4-9.4 min) and a 72-min elimination half-life (95% CI, 47-130 min). The only metabolite observed had a long blood plasma half-life, suggesting protein-bound 68 Ga. Conclusion: 68 Ga-CBP8 displays favorable in-human characteristics and dosimetry similar to that of other gallium-based probes. 68 Ga-CBP8 could therefore be used for noninvasive collagen imaging across a range of human fibrotic diseases., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Objective: To compare standard (STD-DWI) single-shot echo-planar imaging DWI and simultaneous multislice (SMS) DWI during whole-body positron emission tomography (PET)/MRI regarding acquisition time, image quality, and lesion detection., Methods: Eighty-three adults (47 females, 57%), median age of 64 years (IQR 52-71), were prospectively enrolled from August 2018 to March 2020. Inclusion criteria were (a) abdominal or pelvic tumors and (b) PET/MRI referral from a clinician. Patients were excluded if whole-body acquisition of STD-DWI and SMS-DWI sequences was not completed. The evaluated sequences were axial STD-DWI at b-values 50-400-800 s/mm 2 and the apparent diffusion coefficient (ADC), and axial SMS-DWI at b-values 50-300-800 s/mm 2 and ADC, acquired with a 3-T PET/MRI scanner. Three radiologists rated each sequence's quality on a five-point scale. Lesion detection was quantified using the anatomic MRI sequences and PET as the reference standard. Regression models were constructed to quantify the association between all imaging outcomes/scores and sequence type., Results: The median whole-body STD-DWI acquisition time was 14.8 min (IQR 14.1-16.0) versus 7.0 min (IQR 6.7-7.2) for whole-body SMS-DWI, p < 0.001. SMS-DWI image quality scores were higher than STD-DWI in the abdomen (OR 5.31, 95% CI 2.76-10.22, p < 0.001), but lower in the cervicothoracic junction (OR 0.21, 95% CI 0.10-0.43, p < 0.001). There was no significant difference in the chest, mediastinum, pelvis, and rectum. STD-DWI detected 276/352 (78%) lesions while SMS-DWI located 296/352 (84%, OR 1.46, 95% CI 1.02-2.07, p = 0.038)., Conclusions: In cancer staging and restaging, SMS-DWI abbreviates acquisition while maintaining or improving the diagnostic yield in most anatomic regions., Key Points: • Simultaneous multislice diffusion-weighted imaging enables faster whole-body image acquisition. • Simultaneous multislice diffusion-weighted imaging maintains or improves image quality when compared to single-shot echo-planar diffusion-weighted imaging in most anatomical regions. • Simultaneous multislice diffusion-weighted imaging leads to superior lesion detection., (© 2022. The Author(s), under exclusive licence to European Society of Radiology.)

Interoception is awareness of one's own internal bodily states. Currently, no participation-based measure of interoception exists. The purpose of this study was to identify items with adequate psychometric properties for a participation-based interoceptive measure grounded in Dunn's Sensory Processing Framework named the Sensory Profile: Interoception (SPI). Using a cross-sectional psychometric design, internal consistency was examined by calculating Cronbach's alpha for each of the four subscales of the SPI. Concurrent validity was studied using Pearson Product Moment Correlations to identify relationships between the SPI and the Adolescent Adult Sensory Profile (A/ASP) subscales. Interoception items correlating most strongly with their intended subscale were identified, maintaining 70 of the original 101 items ( N = 55). The resulting subscales (sensitivity, avoiding, registration, and seeking) had good internal consistency (α = .63-.88) and correlated moderately with the corresponding A/ASP subscale. The findings provide preliminary support for the SPI's internal consistency and concurrent validity.

FLT3 tyrosine kinase inhibitor (TKI) therapy evolved into a standard therapy in FLT3-mutated AML. TKI resistance, however, develops frequently with poor outcomes. We analyzed acquired TKI resistance in AML cell lines by multilayered proteome analyses. Leupaxin (LPXN), a regulator of cell migration and adhesion, was induced during early resistance development, alongside the tyrosine kinase PTK2B which phosphorylated LPXN. Resistant cells differed in cell adhesion and migration, indicating altered niche interactions. PTK2B and LPXN were highly expressed in leukemic stem cells in FLT3-ITD patients. PTK2B/FAK inhibition abrogated resistance-associated phenotypes, such as enhanced cell migration. Altered pathways in resistant cells, assessed by nascent proteomics, were largely reverted upon PTK2B/FAK inhibition. PTK2B/FAK inhibitors PF-431396 and defactinib synergized with different TKIs or daunorubicin in FLT3-mutated AML. Midostaurin-resistant and AML cells co-cultured with mesenchymal stroma cells responded particularly well to PTK2B/FAK inhibitor addition. Xenograft mouse models showed significant longer time to leukemia symptom-related endpoint upon gilteritinib/defactinib combination treatment in comparison to treatment with either drug alone. Our data suggest that the leupaxin-PTK2B axis plays an important role in acquired TKI resistance in AML. PTK2B/FAK inhibitors act synergistically with currently used therapeutics and may overcome emerging TKI resistance in FLT3-mutated AML at an early timepoint., (© 2022. The Author(s).)

Growing number of methods for attenuation-coefficient map estimation from magnetic resonance (MR) images have recently been proposed because of the increasing interest in MR-guided radiotherapy and the introduction of positron emission tomography (PET) MR hybrid systems. We propose a deep-network ensemble incorporating stochastic-binary-anatomical encoders and imaging-modality variational autoencoders, to disentangle image-latent spaces into a space of modality-invariant anatomical features and spaces of modality attributes. The ensemble integrates modality-modulated decoders to normalize features and image intensities based on imaging modality. Besides promoting disentanglement, the architecture fosters uncooperative learning, offering ability to maintain anatomical structure in a cross-modality reconstruction. Introduction of a modality-invariant structural consistency constraint further enforces faithful embedding of anatomy. To improve training stability and fidelity of synthesized modalities, the ensemble is trained in a relativistic generative adversarial framework incorporating multiscale discriminators. Analyses of priors and network architectures as well as performance validation were performed on computed tomography (CT) and MR pelvis datasets. The proposed method demonstrated robustness against intensity inhomogeneity, improved tissue-class differentiation, and offered synthetic CT in Hounsfield units with intensities consistent and smooth across slices compared to the state-of-the-art approaches, offering median normalized mutual information of 1.28, normalized cross correlation of 0.97, and gradient cross correlation of 0.59 over 324 images., Competing Interests: Declaration of Competing Interest There is no known competing financial interests or personal relationships that could affect or influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Compartmental modeling analysis of 11 C-raclopride (RAC) PET data can be used to measure the dopaminergic response to intra-scan behavioral tasks. Bias in estimates of binding potential (BP ND ) and its dynamic changes (ΔBP ND ) can arise both when head motion is present and when the compartmental model used for parameter estimation deviates from the underlying biology. The purpose of this study was to characterize the effects of motion and model bias within the context of a behavioral task challenge, examining the impacts of different mitigation strategies. Seventy healthy adults were administered bolus plus constant infusion RAC during a simultaneous PET/magnetic resonance (MR) scan with a reward task experiment. BP ND and ΔBP ND were estimated using an extension of the Multilinear Reference Tissue Model (E-MRTM2) and a new method (DE-MRTM2) was proposed to selectively discount the contribution of the initial uptake period. Motion was effectively corrected with a standard frame-based approach, which performed equivalently to a more complex reconstruction-based approach. DE-MRTM2 produced estimates of ΔBP ND in putamen and nucleus accumbens that were significantly different from those estimated from E-MRTM2, while also decoupling ΔBP ND values from first-pass k 2 ' estimation and removing skew in the spatial bias distribution of parametric ΔBP ND estimates within the striatum.

Scholars and providers are coming to realize that one's ability to notice and respond to internal body sensations (i.e., interoception) contributes to an overall sense of wellbeing. Research has demonstrated a relationship between interoceptive awareness and anxiety, for example. Currently, however, tools for evaluating one's interoception lack the conceptual foundation and clarity necessary to identify everyday behaviors that specifically reflect interoceptive awareness. Unlike existing interoceptive measures, the Sensory Profile Interoception (SPI) scale is participation-based and grounded in Dunn's Sensory Processing framework. In this study we investigated concurrent validity by correlating the SPI with the Adolescent/Adult Sensory Profile (A/ASP); we investigated construct validity by correlating the SPI with the Perth Alexithymia Scale (PAS), the Body Awareness Scale (BAS), and the State-Trait Anxiety Inventory (STAI). Using the REDCAP online platform, 74 college-aged participants completed the measures. Using Spearman rank order correlations there were statistically significant relationships between the corresponding sensory pattern subscales on SPI and A/ASP ( r = 0.277 to r = 0.582). The PAS was only weakly related to the registration subscale of the SPI ( r = 0.260). The BAS had significant relationships with seeking and avoiding on the SPI ( r = 0.496 and r = 0.385). The STAI had significant relationships with sensitivity and registrations of the SPI ( r = 0.266 and r = 0.361 for state; r = 0.403 and r = 0.321 for trait). Taken together, these findings provide evidence of construct validity of the SPI to identify participation patterns associated with both high and low interoception. With the more precise information the SPI provides, professionals can design tailored interventions to support everyday life goals and researchers can study interoception within authentic activities., Competing Interests: WD and CB were authors of the Adolescent/Adult Sensory Profile, a measure that was used in this study. We receive royalties for the assessment. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Dunn, Brown, Breitmeyer and Salwei.)

Mothers are highly responsive to their offspring. In non-human mammals, mothers secrete dopamine in the nucleus accumbens (NAcc) in response to their pups. Yet, it is still unknown which aspect of the offspring behavior elicits dopaminergic responses in mothers. Here, we tested whether infants' affective signals elicit dopaminergic responses in the NAcc of human mothers. First, we conducted a behavioral analysis on videos of infants' free play and quantified the affective signals infants spontaneously communicated. Then, we presented the same videos to mothers during a magnetic resonance-positron emission tomography scan. We traced the binding of [11C]raclopride to free D2/3-type receptors to assess maternal dopaminergic responses during the infant videos. When mothers observed videos with many infant signals during the scan, they had less [11C]raclopride binding in the right NAcc. Less [11C]raclopride binding indicates that less D2/3 receptors were free, possibly due to increased endogenous dopamine responses to infants' affective signals. We conclude that NAcc D2/3 receptors are involved in maternal responsiveness to affective signals of human infants. D2/3 receptors have been associated with maternal responsiveness in nonhuman animals. This evidence supports a similar mechanism in humans and specifies infant-behaviors that activate the maternal dopaminergic system, with implications for social neuroscience, development and psychopathology., (© The Author(s) 2021. Published by Oxford University Press.)

While COVID-19 research has seen an explosion in the literature, the impact of pandemic-related societal and lifestyle disruptions on brain health among the uninfected remains underexplored. However, a global increase in the prevalence of fatigue, brain fog, depression and other "sickness behavior"-like symptoms implicates a possible dysregulation in neuroimmune mechanisms even among those never infected by the virus. We compared fifty-seven 'Pre-Pandemic' and fifteen 'Pandemic' datasets from individuals originally enrolled as control subjects for various completed, or ongoing, research studies available in our records, with a confirmed negative test for SARS-CoV-2 antibodies. We used a combination of multimodal molecular brain imaging (simultaneous positron emission tomography / magnetic resonance spectroscopy), behavioral measurements, imaging transcriptomics and serum testing to uncover links between pandemic-related stressors and neuroinflammation. Healthy individuals examined after the enforcement of 2020 lockdown/stay-at-home measures demonstrated elevated brain levels of two independent neuroinflammatory markers (the 18 kDa translocator protein, TSPO, and myoinositol) compared to pre-lockdown subjects. The serum levels of two inflammatory markers (interleukin-16 and monocyte chemoattractant protein-1) were also elevated, although these effects did not reach statistical significance after correcting for multiple comparisons. Subjects endorsing higher symptom burden showed higher TSPO signal in the hippocampus (mood alteration, mental fatigue), intraparietal sulcus and precuneus (physical fatigue), compared to those reporting little/no symptoms. Post-lockdown TSPO signal changes were spatially aligned with the constitutive expression of several genes involved in immune/neuroimmune functions. This work implicates neuroimmune activation as a possible mechanism underlying the non-virally-mediated symptoms experienced by many during the COVID-19 pandemic. Future studies will be needed to corroborate and further interpret these preliminary findings., (Copyright © 2022 Elsevier Inc. All rights reserved.)

We recently showed that patients with different chronic pain conditions (such as chronic low back pain, fibromyalgia, migraine and Gulf War illness) demonstrated elevated brain and/or spinal cord levels of the glial marker 18-kDa translocator protein (TSPO), which suggests that neuroinflammation might be a pervasive phenomenon observable across multiple aetiologically heterogeneous pain disorders. Interestingly, the spatial distribution of this neuroinflammatory signal appears to exhibit a degree of disease specificity (e.g. with respect to the involvement of the primary somatosensory cortex), suggesting that different pain conditions may exhibit distinct 'neuroinflammatory signatures'. To explore this hypothesis further, we tested whether neuroinflammatory signal can characterize putative aetiological subtypes of chronic low back pain patients based on clinical presentation. Specifically, we explored neuroinflammation in patients whose chronic low back pain either did or did not radiate to the leg (i.e. 'radicular' versus 'axial' back pain). Fifty-four patients with chronic low back pain, 26 with axial back pain [43.7 ± 16.6 years old (mean ± SD)] and 28 with radicular back pain (48.3 ± 13.2 years old), underwent PET/MRI with 11C-PBR28, a second-generation radioligand for TSPO. 11C-PBR28 signal was quantified using standardized uptake values ratio (validated against volume of distribution ratio; n = 23). Functional MRI data were collected simultaneously to the 11C-PBR28 data (i) to functionally localize the primary somatosensory cortex back and leg subregions; and (ii) to perform functional connectivity analyses (in order to investigate possible neurophysiological correlations of the neuroinflammatory signal). PET and functional MRI measures were compared across groups, cross-correlated with one another and with the severity of 'fibromyalgianess' (i.e. the degree of pain centralization, or 'nociplastic pain'). Furthermore, statistical mediation models were used to explore possible causal relationships between these three variables. For the primary somatosensory cortex representation of back/leg, 11C-PBR28 PET signal and functional connectivity to the thalamus were: (i) higher in radicular compared to axial back pain patients; (ii) positively correlated with each other; (iii) positively correlated with fibromyalgianess scores, across groups; and finally (iv) fibromyalgianess mediated the association between 11C-PBR28 PET signal and primary somatosensory cortex-thalamus connectivity across groups. Our findings support the existence of 'neuroinflammatory signatures' that are accompanied by neurophysiological changes and correlate with clinical presentation (in particular, with the degree of nociplastic pain) in chronic pain patients. These signatures may contribute to the subtyping of distinct pain syndromes and also provide information about interindividual variability in neuroimmune brain signals, within diagnostic groups, that could eventually serve as targets for mechanism-based precision medicine approaches., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: To evaluate if a fully-automatic deep learning method for myocardial strain analysis based on magnetic resonance imaging (MRI) cine images can detect asymptomatic dysfunction in young adults with cardiac risk factors., Methods: An automated workflow termed DeepStrain was implemented using two U-Net models for segmentation and motion tracking. DeepStrain was trained and tested using short-axis cine-MRI images from healthy subjects and patients with cardiac disease. Subsequently, subjects aged 18-45 years were prospectively recruited and classified among age- and gender-matched groups: risk factor group (RFG) 1 including overweight without hypertension or type 2 diabetes; RFG2 including hypertension without type 2 diabetes, regardless of overweight; RFG3 including type 2 diabetes, regardless of overweight or hypertension. Subjects underwent cardiac short-axis cine-MRI image acquisition. Differences in DeepStrain-based left ventricular global circumferential and radial strain and strain rate among groups were evaluated., Results: The cohort consisted of 119 participants: 30 controls, 39 in RFG1, 30 in RFG2, and 20 in RFG3. Despite comparable (>0.05) left-ventricular mass, volumes, and ejection fraction, all groups (RFG1, RFG2, RFG3) showed signs of asymptomatic left ventricular diastolic and systolic dysfunction, evidenced by lower circumferential early-diastolic strain rate (<0.05, <0.001, <0.01), and lower septal circumferential end-systolic strain (<0.001, <0.05, <0.001) compared with controls. Multivariate linear regression showed that body surface area correlated negatively with all strain measures (<0.01), and mean arterial pressure correlated negatively with early-diastolic strain rate (<0.01)., Conclusion: DeepStrain fully-automatically provided evidence of asymptomatic left ventricular diastolic and systolic dysfunction in asymptomatic young adults with overweight, hypertension, and type 2 diabetes risk factors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Morales, Snel, van den Boomen, Borra, van Deursen, Slart, Izquierdo-Garcia, Prakken and Catana.)

PET/MRI scanners cannot be qualified in the manner adopted for hybrid PET/CT devices. The main hurdle with qualification in PET/MRI is that attenuation correction (AC) cannot be adequately measured in conventional PET phantoms because of the difficulty in converting the MR images of the physical structures (e.g., plastic) into electron density maps. Over the last decade, a plethora of novel MRI-based algorithms has been developed to more accurately derive the attenuation properties of the human head, including the skull. Although promising, none of these techniques has yet emerged as an optimal and universally adopted strategy for AC in PET/MRI. In this work, we propose a path for PET/MRI qualification for multicenter brain imaging studies. Specifically, our solution is to separate the head AC from the other factors that affect PET data quantification and use a patient as a phantom to assess the former. The emission data collected on the integrated PET/MRI scanner to be qualified should be reconstructed using both MRI- and CT-based AC methods, and whole-brain qualitative and quantitative (both voxelwise and regional) analyses should be performed. The MRI-based approach will be considered satisfactory if the PET quantification bias is within the acceptance criteria specified here. We have implemented this approach successfully across 2 PET/MRI scanner manufacturers at 2 sites., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Attenuation correction remains a challenge in pelvic PET/MRI. In addition to the segmentation/model-based approaches, deep learning methods have shown promise in synthesizing accurate pelvic attenuation maps (μ-maps). However, these methods often misclassify air pockets in the digestive tract, potentially introducing bias in the reconstructed PET images. The aims of this work were to develop deep learning-based methods to automatically segment air pockets and generate pseudo-CT images from CAIPIRINHA-accelerated MR Dixon images. Methods: A convolutional neural network (CNN) was trained to segment air pockets using 3-dimensional CAIPIRINHA-accelerated MR Dixon datasets from 35 subjects and was evaluated against semiautomated segmentations. A separate CNN was trained to synthesize pseudo-CT μ-maps from the Dixon images. Its accuracy was evaluated by comparing the deep learning-, model-, and CT-based μ-maps using data from 30 of the subjects. Finally, the impact of different μ-maps and air pocket segmentation methods on the PET quantification was investigated. Results: Air pockets segmented using the CNN agreed well with semiautomated segmentations, with a mean Dice similarity coefficient of 0.75. The volumetric similarity score between 2 segmentations was 0.85 ± 0.14. The mean absolute relative changes with respect to the CT-based μ-maps were 2.6% and 5.1% in the whole pelvis for the deep learning-based and model-based μ-maps, respectively. The average relative change between PET images reconstructed with deep learning-based and CT-based μ-maps was 2.6%. Conclusion: We developed a deep learning-based method to automatically segment air pockets from CAIPIRINHA-accelerated Dixon images, with accuracy comparable to that of semiautomatic segmentations. The μ-maps synthesized using a deep learning-based method from CAIPIRINHA-accelerated Dixon images were more accurate than those generated with the model-based approach available on integrated PET/MRI scanners., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Direct reconstruction methods have been developed to estimate parametric images directly from the measured PET sinograms by combining the PET imaging model and tracer kinetics in an integrated framework. Due to limited counts received, signal-to-noise-ratio (SNR) and resolution of parametric images produced by direct reconstruction frameworks are still limited. Recently supervised deep learning methods have been successfully applied to medical imaging denoising/reconstruction when large number of high-quality training labels are available. For static PET imaging, high-quality training labels can be acquired by extending the scanning time. However, this is not feasible for dynamic PET imaging, where the scanning time is already long enough. In this work, we proposed an unsupervised deep learning framework for direct parametric reconstruction from dynamic PET, which was tested on the Patlak model and the relative equilibrium Logan model. The training objective function was based on the PET statistical model. The patient's anatomical prior image, which is readily available from PET/CT or PET/MR scans, was supplied as the network input to provide a manifold constraint, and also utilized to construct a kernel layer to perform non-local feature denoising. The linear kinetic model was embedded in the network structure as a 1 ×1 ×1 convolution layer. Evaluations based on dynamic datasets of 18 F-FDG and 11 C-PiB tracers show that the proposed framework can outperform the traditional and the kernel method-based direct reconstruction methods.

Objectives: The authors present a novel technique to detect and characterize LAA thrombus in humans using combined positron emission tomography (PET)/cardiac magnetic resonance (CMR) of a fibrin-binding radiotracer, [ 64 Cu]FBP8., Background: The detection of thrombus in the left atrial appendage (LAA) is vital in the prevention of stroke and is currently performed using transesophageal echocardiography (TEE)., Methods: The metabolism and pharmacokinetics of [ 64 Cu]FBP8 were studied in 8 healthy volunteers. Patients with atrial fibrillation and recent TEEs of the LAA (positive n = 12, negative n = 12) were injected with [ 64 Cu]FBP8 and imaged with PET/CMR, including mapping the longitudinal magnetic relaxation time (T 1 ) in the LAA., Results: [ 64 Cu]FBP8 was stable to metabolism and was rapidly eliminated. The maximum standardized uptake value (SUV Max ) in the LAA was significantly higher in the TEE-positive than TEE-negative subjects (median of 4.0 [interquartile range (IQR): 3.0-6.0] vs 2.3 [IQR: 2.1-2.5]; P < 0.001), with an area under the receiver-operating characteristic curve of 0.97. An SUV Max threshold of 2.6 provided a sensitivity of 100% and specificity of 84%. The minimum T 1 (T 1Min ) in the LAA was 970 ms (IQR: 780-1,080 ms) vs 1,380 ms (IQR: 1,120-1,620 ms) (TEE positive vs TEE negative; P < 0.05), with some overlap between the groups. Logistic regression using SUV Max and T 1Min allowed all TEE-positive and TEE-negative subjects to be classified with 100% accuracy., Conclusions: PET/CMR of [ 64 Cu]FBP8 is able to detect acute as well as older platelet-poor thrombi with excellent accuracy. Furthermore, the integrated PET/CMR approach provides useful information on the biological properties of thrombus such as fibrin and methemoglobin content. (Imaging of LAA Thrombosis; NCT03830320)., Competing Interests: Funding Support and Author Disclosures Support for this study was provided in part by the following grants from the National Institutes of Health: R01HL109448 (to Drs Caravan and Sosnovik), R01HL141563 (to Dr Sosnovik), R01HL131907 (to Dr Caravan), R01HL131635 (to Dr Mekkaoui), and R01CA218187 (to Dr Catana); and the following grants to the A. A. Martinos Center for Biomedical Imaging: S10RR022976, S10RR019933, P41EB015896. Dr Caravan is an inventor of [64Cu]FBP8, which is patented by Massachusetts General Hospital. Dr Caravan is a founder of and has financial interests in Collagen Medical, LLC, and Factor 1A, LLC, which are developing fibrin-targeted imaging probes. Factor 1A, LLC has a license to the patent covering the probe [64Cu]FBP8 that used in this study. Dr Caravan’s interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: High-risk atherosclerosis is an underlying cause of cardiovascular events, yet identifying the specific patient population at immediate risk is still challenging. Here, we used a rabbit model of atherosclerotic plaque rupture and human carotid endarterectomy specimens to describe the potential of molecular fibrin imaging as a tool to identify thrombotic plaques., Methods: Atherosclerotic plaques in rabbits were induced using a high-cholesterol diet and aortic balloon injury (N=13). Pharmacological triggering was used in a group of rabbits (n=9) to induce plaque disruption. Animals were grouped into thrombotic and nonthrombotic plaque groups based on gross pathology (gold standard). All animals were injected with a novel fibrin-specific probe 68 Ga-CM246 followed by positron emission tomography (PET)/magnetic resonance imaging 90 minutes later. 68 Ga-CM246 was quantified on the PET images using tissue-to-background (back muscle) ratios and standardized uptake value., Results: Both tissue-to-background (back muscle) ratios and standardized uptake value were significantly higher in the thrombotic versus nonthrombotic group ( P <0.05). Ex vivo PET and autoradiography of the abdominal aorta correlated positively with in vivo PET measurements. Plaque disruption identified by 68 Ga-CM246 PET agreed with gross pathology assessment (85%). In ex vivo surgical specimens obtained from patients undergoing elective carotid endarterectomy (N=12), 68 Ga-CM246 showed significantly higher binding to carotid plaques compared to a D-cysteine nonbinding control probe., Conclusions: We demonstrated that molecular fibrin PET imaging using 68 Ga-CM246 could be a useful tool to diagnose experimental and clinical atherothrombosis. Based on our initial results using human carotid plaque specimens, in vivo molecular imaging studies are warranted to test 68 Ga-CM246 PET as a tool to stratify risk in atherosclerotic patients.