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The peptide hormone ghrelin is produced in cardiomyocytes and acts through the myocardial growth hormone secretagogue receptor (GHSR) to promote cardiomyocyte survival. Administration of ghrelin may have therapeutic effects on post-myocardial infarction (MI) outcomes. Therefore, there is a need to develop molecular imaging probes that can track the dynamics of GHSR in health and disease to better predict the effectiveness of ghrelin-based therapeutics. We designed a high-affinity GHSR ligand labeled with 18 F for imaging by PET and characterized its in vivo properties in a canine model of MI. Methods: We rationally designed and radiolabeled with 18 F a quinazolinone derivative ([ 18 F]LCE470) with subnanomolar binding affinity to GHSR. We determined the sensitivity and in vivo and ex vivo specificity of [ 18 F]LCE470 in a canine model of surgically induced MI using PET/MRI, which allowed for anatomic localization of tracer uptake and simultaneous determination of global cardiac function. Uptake of [ 18 F]LCE470 was determined by time-activity curve and SUV analysis in 3 regions of the left ventricle-area of infarct, territory served by the left circumflex coronary artery, and remote myocardium-over a period of 1.5 y. Changes in cardiac perfusion were tracked by [ 13 N]NH 3 PET. Results: The receptor binding affinity of LCE470 was measured at 0.33 nM, the highest known receptor binding affinity for a radiolabeled GHSR ligand. In vivo blocking studies in healthy hounds and ex vivo blocking studies in myocardial tissue showed the specificity of [ 18 F]LCE470, and sensitivity was demonstrated by a positive correlation between tracer uptake and GHSR abundance. Post-MI changes in [ 18 F]LCE470 uptake occurred independently of perfusion tracer distributions and changes in global cardiac function. We found that the regional distribution of [ 18 F]LCE470 within the left ventricle diverged significantly within 1 d after MI and remained that way throughout the 1.5-y duration of the study. Conclusion: [ 18 F]LCE470 is a high-affinity PET tracer that can detect changes in the regional distribution of myocardial GHSR after MI. In vivo PET molecular imaging of the global dynamics of GHSR may lead to improved GHSR-based therapeutics in the treatment of post-MI remodeling., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Neurodegenerative disorders, including Multiple Sclerosis (MS), are heterogenous disorders which affect the myelin sheath of the central nervous system (CNS). Magnetic Resonance Imaging (MRI) provides a non-invasive method for studying, diagnosing, and monitoring disease progression. As an emerging research area, many studies have attempted to connect MR metrics to underlying pathophysiological presentations of heterogenous neurodegeneration. Most commonly, small animal models are used, including Experimental Autoimmune Encephalomyelitis (EAE), Theiler's Murine Encephalomyelitis (TMEV), and toxin models including cuprizone (CPZ), lysolecithin, and ethidium bromide (EtBr). A contrast and comparison of these models is presented, with focus on the cuprizone model, followed by a review of literature studying neurodegeneration using MRI and the cuprizone model. Conventional MRI methods including T 1 Weighted (T 1 W) and T 2 Weighted (T 2 W) Imaging are mentioned. Quantitative MRI methods which are sensitive to diffusion, magnetization transfer, susceptibility, relaxation, and chemical composition are discussed in relation to studying the CPZ model. Overall, additional studies are needed to improve both the sensitivity and specificity of MRI metrics for underlying pathophysiology of neurodegeneration and the relationships in attempts to clear the clinico-radiological paradox. We therefore propose a multiparametric approach for the investigation of MR metrics for underlying pathophysiology., (© 2024. The Author(s), under exclusive licence to European Society for Magnetic Resonance in Medicine and Biology (ESMRMB).)

Bacteria constitute a significant part of the biomass of the human microbiota, but their interactions are complex and difficult to replicate outside the host. Exploiting the superior resolution of magnetic resonance imaging (MRI) to examine signal parameters of selected human isolates may allow tracking of their dispersion throughout the body. Here we investigate longitudinal and transverse MRI relaxation rates and found significant differences between several bacterial strains. Common commensal strains of lactobacilli display notably high MRI relaxation rates, partially explained by elevated cellular manganese content, while other species contain more iron than manganese. Lactobacillus crispatus show particularly high values, 4-fold greater than any other species; up to 60-fold greater signal than relevant tissue background; and a linear relationship between relaxation rate and fraction of live cells. Different bacterial strains have detectable, repeatable MRI relaxation rates that in the future may enable monitoring of their persistence in the human body for enhanced molecular imaging., (© 2024. The Author(s).)

Chimeric antigen receptor (CAR) cell therapies utilize CARs to redirect immune cells towards cancer cells expressing specific antigens like human epidermal growth factor receptor 2 (HER2). Despite their potential, CAR T cell therapies exhibit variable response rates and adverse effects in some patients. Non-invasive molecular imaging can aid in predicting patient outcomes by tracking infused cells post-administration. CAR-T cells are typically autologous, increasing manufacturing complexity and costs. An alternative approach involves developing CAR natural killer (CAR-NK) cells as an off-the-shelf allogeneic product. In this study, we engineered HER2-targeted CAR-NK cells co-expressing the positron emission tomography (PET) reporter gene human sodium-iodide symporter (NIS) and assessed their therapeutic efficacy and PET imaging capability in a HER2 ovarian cancer mouse model.NK-92 cells were genetically modified to express a HER2-targeted CAR, the bioluminescence imaging reporter Antares, and NIS. HER2-expressing ovarian cancer cells were engineered to express the bioluminescence reporter Firefly luciferase (Fluc). Co-culture experiments demonstrated significantly enhanced cytotoxicity of CAR-NK cells compared to naive NK cells. In vivo studies involving mice with Fluc-expressing tumors revealed that those treated with CAR-NK cells exhibited reduced tumor burden and prolonged survival compared to controls. Longitudinal bioluminescence imaging demonstrated stable signals from CAR-NK cells over time. PET imaging using the NIS-targeted tracer 18F-tetrafluoroborate ([ 18 F]TFB) showed significantly higher PET signals in mice treated with NIS-expressing CAR-NK cells.Overall, our study showcases the therapeutic potential of HER2-targeted CAR-NK cells in an aggressive ovarian cancer model and underscores the feasibility of using human-derived PET reporter gene imaging to monitor these cells non-invasively in patients., (© 2024. The Author(s).)

Background: Ischemic heart disease (IHD) is linked to brain white matter (WM) breakdown but how age or disease effects WM integrity, and whether it is reversible using cardiac rehabilitation (CR), remains unclear., Purpose: To assess the effects of brain aging, cardiovascular disease, and CR on WM microstructure in brains of IHD patients following a cardiac event., Study Type: Retrospective., Population: Thirty-five IHD patients (9 females; mean age = 59 ± 8 years), 21 age-matched healthy controls (10 females; mean age = 59 ± 8 years), and 25 younger controls (14 females; mean age = 26 ± 4 years)., Field Strength/sequence: 3 T diffusion-weighted imaging with single-shot echo planar imaging acquired at 3 months and 9 months post-cardiac event., Assessment: Tract-based spatial statistics (TBSS) and tractometry were used to compare fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) in cerebral WM between: 1) older and younger controls to distinguish age-related from disease-related WM changes; 2) IHD patients at baseline (pre-CR) and age-matched controls to investigate if cardiovascular disease exacerbates age-related WM changes; and 3) IHD patients pre-CR and post-CR to investigate the neuroplastic effect of CR on WM microstructure., Statistical Tests: Two-sample unpaired t-test (age: older vs. younger controls; IHD: IHD pre-CR vs. age-matched controls). One-sample paired t-test (CR: IHD pre- vs. post-CR). Statistical threshold: P < 0.05 (FWE-corrected)., Results: TBSS and tractometry revealed widespread WM changes in older controls compared to younger controls while WM clusters of decreased FA in the fornix and increased MD in body of corpus callosum were observed in IHD patients pre-CR compared to age-matched controls. Robust WM improvements (increased FA, increased AD) were observed in IHD patients post-CR., Data Conclusion: In IHD, both brain aging and cardiovascular disease may contribute to WM disruptions. IHD-related WM disruptions may be favorably modified by CR., Level of Evidence: 3 TECHNICAL EFFICACY: Stage 2., (© 2023 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare condition caused by severe ADAMTS13 deficiency, leading to platelet aggregation and thrombosis. Despite treatment, patients are prone to cognitive impairment and depression. We investigated brain changes in iTTP patients during remission using advanced magnetic resonance imaging (MRI) techniques, correlating these changes with mood and neurocognitive tests. Twenty iTTP patients in remission (30 days post-haematological remission) were compared with six healthy controls. MRI scans, including standard and specialized sequences, were conducted to assess white matter health. Increased T1 relaxation times were found in the cingulate cortex (p < 0.05), and elevated T2 relaxation times were observed in the cingulate cortex, frontal, parietal and temporal lobes (p < 0.05). Pathological changes in these areas are correlated with impaired cognitive and depressive scores in concentration, short-term memory and verbal memory. This study highlights persistent white matter damage in iTTP patients, potentially contributing to depression and cognitive impairment. Key regions affected include the frontal lobe and cingulate cortex. These findings have significant implications for the acute and long-term management of iTTP, suggesting a need for re-evaluation of treatment approaches during both active phases and remission. Further research is warranted to enhance our understanding of these complexities., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Magnetic Resonance Imaging (MRI) is commonly used to follow the progression of neurodegenerative conditions, including multiple sclerosis (MS). MRI is limited by a lack of correlation between imaging results and clinical presentations, referred to as the clinico-radiological paradox. Animal models are commonly used to mimic the progression of human neurodegeneration and as a tool to help resolve the paradox. Most studies focus on later stages of white matter (WM) damage whereas few focus on early stages when oligodendrocyte apoptosis has just begun. The current project focused on these time points, namely weeks 2 and 3 of cuprizone (CPZ) administration, a toxin which induces pathophysiology similar to MS. In vivo T 2 -weighted (T 2 W) and Magnetization Transfer Ratio (MTR) maps and ex vivo Diffusion Tensor Imaging (DTI), Magnetization Transfer Imaging (MTI), and relaxometry (T 1 and T 2 ) values were obtained at 7 T. Significant changes in T 2 W signal intensity and non-significant changes in MTR were observed to correspond to early WM damage, whereas significant changes in both corresponded with full demyelination. Some DTI metrics decrease with simultaneous increase in others, indicating acute demyelination. MTI metrics T 2 A , T 2 B , f and R were observed to have contradictory changes across CPZ administration. T 1 relaxation times were observed to have stronger correlations to disease states during later stages of CPZ treatment, whereas T 2 had weak correlations to early WM damage. These results all suggest the need for multiple metrics and further studies at early and late time points of demyelination. Further research is required to continue investigating the interplay between various MR metrics during all weeks of CPZ administration.

Background: After myocardial infarction, fibrosis and an ongoing dysregulated inflammatory response have been shown to lead to adverse cardiac remodeling. FDG PET is an imaging modality sensitive to inflammation as long as suppression protocols are observed while gadolinium enhanced MRI can be used to determine extracellular volume (ECV), a measure of fibrosis. In patients, glucose suppression is achieved variously through a high fat diet, fasting and injection of heparin. To emulate this process in canines, a heparin injection and lipid infusion are used, leading to similar fatty acids in the blood. The aim of this study was to examine the effect of glucose suppression on the uptake of FDG in the infarcted myocardial tissue and also on the determination of ECV in both the infarcted tissue and in the myocardium remote to the zone of infarction during a long constant infusion of FDG and Gd-DTPA., Results: Extracellular volume was affected neither by suppression nor the length of the constant infusion in remote and infarcted tissue. Metabolic rate of glucose in infarcted tissue decreased during and after suppression of glucose uptake by lipid infusion and heparin injection. An increase in fibrosis and inflammatory cells was found in the center of the infarct as compared to remote tissue., Conclusion: The decrease in the metabolic rate of glucose in the infarcted tissue suggests that inflammatory cells may be affected by glucose suppression through heparin injection and lipid infusion., (© 2023. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Isolated local failure (ILF) can occur in patients who initially receive definitive radiation therapy for prostate cancer. Salvage therapy for ILF includes high dose rate (HDR) brachytherapy. Prostate Specific Membrane Antigen (PSMA) Positron Emission Tomography (PET) can accurately detect ILF and can exclude extraprostatic disease. Lutetium-177 PSMA Radioligand Therapy (RLT) is a novel treatment for prostate cancer that can target prostate cancer accurately, while sparing radiation dose to normal tissues., Methods: ROADSTER is a phase I/II randomized, single-institution study. Patients with an ILF of prostate cancer after definitive initial radiation therapy are eligible. The ILF will be confirmed with biopsy, magnetic resonance imaging (MRI) and PSMA PET. Patients will be randomized between HDR brachytherapy in two fractions (a standard of care salvage treatment at our institution) (cohort 1) or one treatment of intravenous Lutetium-177 PSMA RLT, followed by one fraction of HDR brachytherapy (cohort 2). The primary endpoints for the phase I portion of the study (n = 12) will be feasibility, defined as 10 or more patients completing the study protocol within 24 months of study activation; and safety, defined as zero or one patients in cohort 2 experiencing grade 3 or higher toxicity in the first 6 months post-treatment. If feasibility and safety are achieved, the study will expand to a phase II study (n = 30 total) where preliminary efficacy data will be evaluated. Secondary endpoints include changes in prostate specific antigen levels, acute toxicity, changes in quality of life, and changes in translational biomarkers. Translational endpoints will include interrogation of blood, urine, and tissue for markers of DNA damage and immune activation with each treatment., Discussion: ROADSTER explores a novel salvage therapy for ILF after primary radiotherapy with combined Lutetium-177 PSMA RLT and HDR brachytherapy. The randomized phase I/II design will provide a contemporaneous patient population treated with HDR alone to facilitate assessment of feasibility, tolerability, and biologic effects of this novel therapy., Trial Registration: NCT05230251 (ClinicalTrials.gov)., (© 2023. The Author(s).)

Introduction: The reliance on glycolytic metabolism is a hallmark of tumor metabolism. Excess acid and protons are produced, leading to an acidic tumor environment. Therefore, we explored the relationship between the tumor glycolytic metabolism and tissue pH by comparing 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) and hyperpolarized [1- 13 C]pyruvate MR spectroscopy imaging (MRSI) to chemical exchange saturation transfer (CEST) MRI measurements of tumor pH., Methods: 10 6 C6 glioma cells were implanted in the brains of male Wistar rats (N = 11) using stereotactic surgery. A 60-min PET acquisition after a bolus of FDG was performed at 11-13 days post implantation, and standardized uptake value (SUV) was calculated. CEST measurements were acquired the following day before and during constant infusion of glucose solution. Tumor intracellular pH (pHi) was evaluated using amine and amide concentration-independent detection (AACID) CEST MRI. The change of pH i (∆pH i ) was calculated as the difference between pH i pre- and during glucose infusion. Rats were imaged immediately with hyperpolarized [1- 13 C]pyruvate MRSI. Regional maps of the ratio of Lac:Pyr were acquired. The correlations between SUV, Lac:Pyr ratio, and ∆pH i were evaluated using Pearson's correlation., Results: A decrease of 0.14 in pH i was found after glucose infusion in tumor region. Significant correlations between tumor glycolysis measurements of Lac:Pyr and ∆pH i within the tumor (ρ = 0.83, P = 0.01) and peritumoral region (ρ = 0.76, P = 0.028) were observed. No significant correlations were found between tumor SUV and ∆pH i within the tumor (ρ =  - 0.45, P = 0.17) and peritumor regions (ρ =  - 0.6, P = 0.051)., Conclusion: AACID detected the changes in pH i induced by glucose infusion. Significant correlations between tumor glycolytic measurement of Lac:Pyr and tumoral and peritumoral pH i and ∆pH i suggest the intrinsic relationship between tumor glycolytic metabolism and the tumor pH environment as well as the peritumor pH environment., (© 2022. The Author(s), under exclusive licence to World Molecular Imaging Society.)

Stem cell-based therapies have demonstrated significant potential in clinical applications for many debilitating diseases. The ability to non-invasively and dynamically track the location and viability of stem cells post administration could provide important information on individual patient response and/or side effects. Multi-modal cell tracking provides complementary information that can offset the limitations of a single imaging modality to yield a more comprehensive picture of cell fate. In this study, mesenchymal stem cells (MSCs) were engineered to express human sodium iodide symporter (NIS), a clinically relevant positron emission tomography (PET) reporter gene, as well as labeled with superparamagnetic iron oxide nanoparticles (SPIOs) to allow for detection with magnetic particle imaging (MPI). MSCs were additionally engineered with a preclinical bioluminescence imaging (BLI) reporter gene for comparison of BLI cell viability data to both MPI and PET data over time. MSCs were implanted into the hind limbs of immunocompromised mice and imaging with MPI, BLI and PET was performed over a 30-day period. MPI showed sensitive detection that steadily declined over the 30-day period, while BLI showed initial decreases followed by later rapid increases in signal. The PET signal of MSCs was significantly higher than the background at later timepoints. Early-phase imaging (day 0-9 post MSC injections) showed correlation between MPI and BLI data ( R 2 = 0.671), while PET and BLI showed strong correlation for late-phase (day 10-30 post MSC injections) imaging timepoints ( R 2 = 0.9817). We report the first use of combined MPI and PET for cell tracking and show the complementary benefits of MPI for sensitive detection of MSCs early after implantation and PET for longer-term measurements of cell viability.

Background: Positron emission tomography (PET) in combination with magnetic resonance imaging (MRI) could allow inflammatory complications near total knee arthroplasty (TKA) to be studied early in their development. However, attenuation of the PET signal by the metal TKA implants imparts substantial error into measurements of tracer activity, and conventional MR-based attenuation correction (AC) methods have large signal voids in the vicinity of metal implants., Purpose: To evaluate a segmentation-based AC approach to measure tracer uptake from PET/MRI scans near TKA implants., Methods: A TKA implant (Triathlon, Stryker, Mahwah, USA) was implanted into a cadaver. Four vials were filled with [ 18 F]fluorodeoxyglucose with known activity concentration (4.68 MBq total, 0.76 MBq/mL) and inserted into the knee. Images of the knee were acquired using a 3T PET/MRI system (Biograph mMR, Siemens Healthcare, Erlangen, Germany). Models of the implant components were registered to the MR data using rigid-body transformations and the other tissue classes were manually segmented. These segments were used to create the segmentation-based map and complete the AC. Percentage error of the resulting measured activities was calculated by comparing the measured and known amounts of activity in each vial., Results: The original AC resulted in a percentage error of 64.1% from the known total activity. Errors in the individual vial activities ranged from 40.2 to 82.7%. Using the new segmentation-based AC, the percentage error of the total activity decreased to 3.55%. Errors in the individual vials were less than 15%., Conclusions: The segmentation-based AC technique dramatically reduced the error in activity measurements that result from PET signal attenuation by the metal TKA implant. This approach may be useful to enhance the reliability of PET/MRI measurements for numerous applications., (© 2022. The Author(s).)

Background: Following myocardial infarction, tissue undergoes pathophysiological changes involving inflammation and scar tissue formation. However, little is known about the pathophysiology and prognostic significance of any corresponding changes in remote myocardium. The aim of this study was to investigate the potential application of a combined constant infusion of 18 F-FDG and Gd-DTPA to quantitate inflammation and extracellular volume (ECV) from 3 to 40 days after myocardial infarction., Methods: Eight canine subjects were imaged at multiple time points following induction of an MI with a 60-minute concurrent constant infusion of Gd-DTPA and 18 F-FDG using a hybrid PET/MRI scanner., Results: There was a significant increase in ECV in remote myocardium on day 14 post-MI (P = .034) and day 21 (P = .021) compared to the baseline. ECV was significantly elevated in the infarcted myocardium compared to remote myocardium at all time points post-MI (days 3, 7, 14, 21, and 40) (P < .001) while glucose uptake was also increased within the infarct on days 3, 7, 14, and 21 but not 40., Conclusions: The significant increase in ECV in remote tissue may be due to an ongoing inflammatory process in the early weeks post-infarct., (© 2021. American Society of Nuclear Cardiology.)

Background: The aims of this study were to investigate the application of a constant infusion (CI) to mitigate the issue of constantly changing Gd-DTPA contrast levels in a bolus injection for extracellular volume (ECV) measurements by (a) comparing a CI alone to a bolus alone and a bolus followed by CI in healthy myocardium, (b) evaluating the impact of glucose suppression using heparin on ECV., Methods: Five healthy canine subjects were imaged to compare three different protocols for injecting Gd-DTPA and FDG: bolus alone, CI alone, bolus followed by CI. Suppression of myocardial glucose uptake was induced using a continuous infusion of 20% lipid at a rate of 0.25 mL·min -1 ·kg -1 as well as 2000 units of intravenous heparin injected 20 minutes prior to FDG/Gd-DTPA injection., Results: There was no significant effect on ECV measurement when heparin was used for glucose suppression at equilibrium irrespective of infusion protocol). Measurements of ECV in myocardium, regardless of infusion protocol showed no significant difference at all time points (P = 0.21) prior to washout., Conclusions: The suppression of myocardial uptake of [ 18 F]FDG with heparin did not alter the determination of myocardial ECV though a larger sample size may show differences. Further, the infusion protocol (bolus or constant infusion) had no effect on the calculated ECV., (© 2021. American Society of Nuclear Cardiology.)

Brain metastases affect more breast cancer patients than ever before due to increased overall patient survival with improved molecularly targeted treatments. Approximately 25-34% of breast cancer patients develop brain metastases in their lifetime. Due to the blood-brain barrier (BBB), the standard treatment for breast cancer brain metastases (BCBM) is surgery, stereotactic radiosurgery (SRS) and/or whole brain radiation therapy (WBRT). At the cost of cognitive side effects, WBRT has proven efficacy in treating brain metastases when used with local therapies such as SRS and surgery. This review investigated the potential use of glial activation positron emission tomography (PET) imaging for radiation treatment of BCBM. In order to put these studies into context, we provided background on current radiation treatment approaches for BCBM, our current understanding of the brain microenvironment, its interaction with the peripheral immune system, and alterations in the brain microenvironment by BCBM and radiation. We summarized preclinical literature on the interactions between glial activation and cognition and clinical studies using translocator protein (TSPO) PET to image glial activation in the context of neurological diseases. TSPO-PET is not employed clinically in assessing and guiding cancer therapies. However, it has gained traction in preclinical studies where glial activation was investigated from primary brain cancer, metastases and radiation treatments. Novel glial activation PET imaging and its applications in preclinical studies using breast cancer models and glial immunohistochemistry are highlighted. Lastly, we discuss the potential clinical application of glial activation imaging to improve the therapeutic ratio of radiation treatments for BCBM., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2022 Published by Elsevier B.V. on behalf of European Society of Radiotherapy & Oncology.)

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening disorder of systemic microthrombosis and organ ischemia. The etiology of chronic cerebrovascular outcomes in iTTP survivors is largely unknown. In this pilot study, we measured blood-brain barrier (BBB) permeability in patients with iTTP at the start of remission and 6 months later. This prospective pilot study included 7 adult patients with incident iTTP. Eligibility criteria included ADAMTS13 activity < 10% and detectable inhibitor at diagnosis. Patients were recruited from London Health Sciences Centre in Canada (2017-2019) within 3 days of hospital admission and followed for 6 months after remission (defined as normalization of platelet count and lactate dehydrogenase with no clinical signs or symptoms of microvascular injury for more than 30 days after the last plasma exchange). All patients had cerebral computed tomography perfusion scans with BBB permeability surface product measurements. Patients (5 women, 2 men) had a mean age of 48 years (range, 21-77 years). At diagnosis, patients had a mean platelet count of 22 (standard deviation [SD], 25) × 109/L. At the start of remission, mean BBB permeability surface product was 0.91 (0.30) mL/min/100 g. Six months later, the mean permeability surface product was 0.56 (0.22) mL/min/100 g, with a mean difference of -0.312 mL/min/100 g (95% confidence interval: -0.4729 to -0.1510; P = .0032). In this pilot study of patients with iTTP, pathologically increased BBB permeability was evident, and although there was some improvement, this persisted 6 months after remission. Future work will explore the chronicity of these findings and their clinical implications., (© 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Purpose: Localized prostate cancer (PCa) in patients is characterized by a dominant focus in the gland (dominant intraprostatic lesion, DIL). Accurate DIL identification may enable more accurate diagnosis and therapy through more precise targeting of biopsy, radiotherapy and focal ablative therapies. The goal of this study is to validate the performance of [ 18 F]DCFPyL PET and CT perfusion (CTP) for detecting and localizing DIL against digital histopathological images., Methods: Multi-modality image sets: in vivo T2-weighted (T2w)-MRI, 22-min dynamic [ 18 F]DCFPyL PET/CT, CTP, and 2-h post-injection PET/MR were acquired in patients prior to radical prostatectomy. The explanted gland with implanted fiducial markers was imaged with T2w-MRI. All images were co-registered to the pathologist-annotated digital images of whole-mount mid-gland histology sections using fiducial markers and anatomical landmarks. Regions of interest encompassing DIL and non-DIL tissue were drawn on the digital histopathological images and superimposed on PET and CTP parametric maps. Logistic regression with backward elimination of parameters was used to select the most sensitive parameter set to distinguish DIL from non-DIL voxels. Leave-one-patient-out cross-validation was performed to determine diagnostic performance., Results: [ 18 F]DCFPyL PET and CTP parametric maps of 15 patients were analyzed. SUV Late and a model combining K i and k 4 of [ 18 F]DCFPyL achieved the most accurate performance distinguishing DIL from non-DIL voxels. Both detection models achieved an AUC of 0.90 and an error rate of < 10%. Compared to digital histopathology, the detected DILs had a mean dice similarity coefficient of 0.8 for the K i and k 4 model and 0.7 for SUV Late ., Conclusions: We have validated using co-registered digital histopathological images that parameters from kinetic analysis of 22-min dynamic [ 18 F]DCFPyL PET can accurately localize DILs in PCa for targeting of biopsy, radiotherapy, and focal ablative therapies. Short-duration dynamic [ 18 F]DCFPyL PET was not inferior to SUV Late in this diagnostic task., Clinical Trial Registration Number: NCT04009174 (ClinicalTrials.gov)., (© 2021. The Author(s).)

Purpose: Chemical exchange saturation transfer MRI using an infusion of glucose (glucoCEST) is sensitive to the distribution of glucose in vivo; however, whether glucoCEST is more related to perfusion or glycolysis is still debatable. We compared glucoCEST to computed tomography perfusion (CTP), [ 18 F] fluorodeoxyglucose positron emission tomography (FDG-PET), and hyperpolarized [1- 13 C] pyruvate magnetic resonance spectroscopy imaging (MRSI) in a C6 rat model of glioma to determine if glucoCEST is more strongly correlated with measurements of perfusion or glycolysis., Methods: 10 6 C6 glioma cells were implanted in Wistar rat brains (n = 11). CTP (including blood volume, BV; blood flow, BF; and permeability surface area product, PS) and FDG-PET standardized uptake value (SUV) were acquired at 11 to 13 days post-surgery. GlucoCEST measurements (∆CEST) were acquired the following day on a 9.4 T MRI before and after an infusion of glucose solution. This was followed by MRSI on a 3.0 T MRI after the injection of hyperpolarized [1- 13 C] pyruvate to generate regional maps of the lactate:pyruvate ratio (Lac:Pyr). Pearson's correlations between glucoCEST, CTP, FDG-PET, and Lac:Pyr ratio were evaluated., Results: Tumors had significantly higher SUV, BV, and PS than the contralateral brain. Tumor ∆CEST was most strongly correlated with CTP measurements of BV (ρ = 0.74, P = 0.01) and PS (ρ = 0.55, P = 0.04). No significant correlation was found between glycolysis measurements of SUV or Lac:Pyr with tumor ∆CEST. PS significantly correlated with SUV (ρ = 0.58, P = 0.005) and Lac:Pyr (ρ = 0.75, P = 0.005). BV significantly correlated with Lac:Pyr (ρ = 0.57, P = 0.02), and BF significantly correlated with SUV (ρ = 0.49, P = 0.02)., Conclusion: This study determined that glucoCEST is more strongly correlated to measurements of perfusion than glycolysis. GlucoCEST measurements have additional confounds, such as sensitivity to changing pH, that merit additional investigation., (© 2021. World Molecular Imaging Society.)

Objective: Hybrid PET/MRI may improve detection of seizure-onset zone (SOZ) in drug-resistant epilepsy (DRE), however, concerns over PET bias from MRI-based attenuation correction (MRAC) have limited clinical adoption of PET/MRI. This study evaluated the diagnostic equivalency and potential clinical value of PET/MRI against PET/CT in DRE., Materials and Methods: MRI, FDG-PET and CT images (n = 18) were acquired using a hybrid PET/MRI and a CT scanner. To assess diagnostic equivalency, PET was reconstructed using MRAC (RESOLUTE) and CT-based attenuation correction (CTAC) to generate PET/MRI and PET/CT images, respectively. PET/MRI and PET/CT images were compared qualitatively through visual assessment and quantitatively through regional standardized uptake value (SUV) and z-score assessment. Diagnostic accuracy and sensitivity of PET/MRI and PET/CT for SOZ detection were calculated through comparison to reference standards (clinical hypothesis and histopathology, respectively)., Results: Inter-reader agreement in visual assessment of PET/MRI and PET/CT images was 78 % and 81 %, respectively. PET/MRI and PET/CT were strongly correlated in mean SUV (r = 0.99, p < 0.001) and z-scores (r = 0.92, p < 0.001) across all brain regions. MRAC SUV bias was <5% in most brain regions except the inferior temporal gyrus, temporal pole, and cerebellum. Diagnostic accuracy and sensitivity were similar between PET/MRI and PET/CT (87 % vs. 85 % and 83 % vs. 83 %, respectively)., Conclusion: We demonstrate here that PET/MRI with optimal MRAC can yield similar diagnostic performance as PET/CT. Nevertheless, further exploration of the potential added value of PET/MRI is necessary before clinical adoption of PET/MRI for epilepsy imaging., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Accurate quantification of radioactivity, measured by an integrated positron emission tomography (PET) and magnetic resonance imaging (MRI) system, is still a challenge. One aspect of such a challenge is to correct for the hardware attenuation, such as the patient table and radio frequency (RF) resonators. For PET/MRI systems, computed tomography (CT) is commonly used to produce hardware attenuation correction (AC) maps, by converting Hounsfield units (HU) to a linear attenuation coefficients (LAC) map at the PET energy level 511 keV, using a bilinear model. The model does not address beam hardening, nor higher density materials, which can lead to inaccurate corrections., Purpose: In this study, we introduce a transmission-based (TX-based) AC technique with a static Germanium-68 (Ge-68) transmission source to generate hardware AC maps using the PET/MRI system itself, without the need for PET or medical CT scanners. The AC TX-based maps were generated for a homogeneous cylinder, made of acrylic as a validator. The technique thereafter was applied to the patient table and posterior part of an RF-phased array used in cardiovascular PET/MRI imaging. The proposed TX-based, and the CT-based, hardware maps were used in reconstructing PET images of one cardiac patient, and the results were analysed and compared., Results: The LAC derived by the TX-based method for the acrylic cylinder is estimated to be 0.10851 ± 0.00380 cm -1 compared to the 0.10698 ± 0.00321 cm -1 theoretical value reported in the literature. The PET photon counts were reduced by 8.7 ± 1.1% with the patient table, at the region used in cardiac scans, while the CT-based map, used for correction, over-estimated counts by 4.3 ± 1.3%. Reconstructed in vivo images using TX-based AC hardware maps have shown 4.1 ± 0.9% mean difference compared to those reconstructed images using CT-based AC., Conclusions: The LAC of the acrylic cylinder measurements using the TX-based technique was in agreement with those in the literature confirming the validity of the technique. The over-estimation of photon counts caused by the CT-based model used for the patient table was improved by the TX-based technique. Therefore, TX-based AC of hardware using the PET/MRI system itself is possible and can produce more accurate images when compared to the CT-based hardware AC in cardiac PET images.

Hybrid PET/MR imaging is an emerging imaging modality combining positron emission tomography (PET) and magnetic resonance imaging (MRI) in the same system. Since the introduction of clinical PET/MRI in 2011, it has had some impact (e.g., imaging the components of inflammation in myocardial infarction), but its role could be much greater. Many opportunities remain unexplored and will be highlighted in this review. The inflammatory process post-myocardial infarction has many facets at a cellular level which may affect the outcome of the patient, specifically the effects on adverse left ventricular remodeling, and ultimately prognosis. The goal of inflammation imaging is to track the process non-invasively and quantitatively to determine the best therapeutic options for intervention and to monitor those therapies. While PET and MRI, acquired separately, can image aspects of inflammation, hybrid PET/MRI has the potential to advance imaging of myocardial inflammation. This review contains a description of hybrid PET/MRI, its application to inflammation imaging in myocardial infarction and the challenges, constraints, and opportunities in designing data collection protocols. Finally, this review explores opportunities in PET/MRI: improved registration, partial volume correction, machine learning, new approaches in the development of PET and MRI pulse sequences, and the use of novel injection strategies.

Background: Inflammatory cardiac disorders, in particular, sarcoidosis, play an important role in left ventricular dysfunction, conduction abnormalities, and arrhythmias. In this study, we compared the imaging characteristics and diagnostic information obtained when patients were imaged sequentially with PET/CT and then with hybrid PET/MRI on the same day following a single 18 F-FDG injection., Methods: Ten patients with known or suspected sarcoidosis underwent imaging in sequence of (a) 99m Tc-MIBI, (b) 18 F-FDG with PET/CT, and (c) 18 F-FDG with 3T PET/MRI. Images were compared quantitatively by determination of SUV max and SUV on a voxel by voxel basis, and qualitatively by two experienced observers., Results: When both platforms were compared quantitatively, similar data for the evaluation of enhanced 18 F-FDG uptake were obtained. Qualitatively, there were (1) several instances of normal perfusion with delayed enhancement and/or focal 18 F-FDG uptake, (2) comparable enhanced 18 F-FDG uptake on PET/CT vs. PET/MRI, and (3) diversity in disease patterns with delayed enhancement only, increased 18 F-FDG uptake only, or both., Conclusion: In this limited patient study, PET/CT and PET/MR provided similar diagnostic data for 18 F-FDG uptake, and the concurrent acquisition of MR images provided further insight into the disease process.

Background: PSMA-PET 1 has shown good concordance with histology, but there is a need to investigate the ability of PSMA-PET to delineate DIL 2 boundaries for guided biopsy and focal therapy planning., Objective: To determine threshold and margin combinations that satisfy the following criteria: ≥95% sensitivity with max specificity and ≥95% specificity with max sensitivity., Design, Setting and Participants: We registered pathologist-annotated whole-mount mid-gland prostatectomy histology sections cut in 4.4 mm intervals from 12 patients to pre-surgical PSMA-PET/MRI by mapping histology to ex-vivo imaging to in-vivo imaging. We generated PET-derived tumor volumes using boundaries defined by thresholded PET volumes from 1-100% of SUV 3 max in 1% intervals. At each interval, we applied margins of 0-30 voxels in one voxel increments, giving 3000 volumes/patient., Outcome Measurements: Mean and standard deviation of sensitivity and specificity for cancer detection within the 2D oblique histologic planes that intersected with the 3D PET volume for each patient., Results and Limitations: A threshold of 67% SUV max with an 8.4 mm margin achieved a (mean ± std.) sensitivity of 95.0 ± 7.8% and specificity of 76.4 ± 14.7%. A threshold of 81% SUV max with a 5.1 mm margin achieved sensitivity of 65.1 ± 28.4% and specificity of 95.1 ± 5.2%., Conclusions: Preliminary evidence of thresholding and margin expansion of PSMA-PET images targeted at DILs validated with histopathology demonstrated excellent mean sensitivity and specificity in the setting of focal therapy/boosting and guided biopsy. These parameters can be used in a larger validation study supporting clinical translation., Competing Interests: Conflicts of interest The author(s) declare(s) that there is no conflict of interest. Funding sources were not involved in the conduct of the research and preparation of the article., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Accurate and sensitive imaging biomarkers are required to study the progression of white matter (WM) inflammation in neurodegenerative diseases. Radioligands targeting the translocator protein (TSPO) are considered sensitive indicators of neuroinflammation, but it is not clear how well the expression of TSPO coincides with major histocompatibility complex class II (MHCII) molecules in WM. This study aimed to test the ability of TSPO to detect activated WM microglia that are immunohistochemically positive for MHCII in rat models of prodromal Alzheimer's disease and acute subcortical stroke., Methods: Fischer 344 wild-type (n = 12) and TgAPP21 (n = 11) rats were imaged with [ 18 F]FEPPA PET and MRI to investigate TSPO tracer uptake in the corpus callosum, a WM region known to have high levels of MHCII activated microglia in TgAPP21 rats. Wild-type rats subsequently received an endothelin-1 (ET1) subcortical stroke and were imaged at days 7 and 28 post-stroke before immunohistochemistry of TSPO, GFAP, iNOS, and the MHCII rat antigen, OX6., Results: [ 18 F]FEPPA PET was not significantly affected by genotype in WM and only detected increases near the ET1 infarct (P = 0.033, infarct/cerebellum uptake ratio: baseline = 0.94 ± 0.16; day 7 = 2.10 ± 0.78; day 28 = 1.77 ± 0.35). Immunohistochemistry confirmed that only the infarct (TSPO cells/mm 2 : day 7 = 555 ± 181; day 28 = 307 ± 153) and WM that is proximal to the infarct had TSPO expression (TSPO cells/mm 2 : day 7 = 113 ± 93; day 28 = 5 ± 7). TSPO and iNOS were not able to detect the chronic WM microglial activation that was detected with MHCII in the contralateral corpus callosum (day 28 OX6% area: saline = 0.62 ± 0.38; stroke = 4.30 ± 2.83; P = .029)., Conclusion: TSPO was only expressed in the stroke-induced insult and proximal tissue and therefore was unable to detect remote and non-insult-related chronically activated microglia overexpressing MHCII in WM. This suggests that research in neuroinflammation, particularly in the WM, would benefit from MHCII-sensitive radiotracers.

Background: Hybrid PET/MRI can non-invasively improve localization and delineation of the epileptic focus (EF) prior to surgical resection in medically refractory epilepsy (MRE), especially when MRI is negative or equivocal. In this study, we developed a PET-guided diffusion tractography (PET/DTI) approach combining 18 F-fluorodeoxyglucose PET (FDG-PET) and diffusion MRI to investigate white matter (WM) integrity in MRI-negative MRE patients and its potential impact on epilepsy surgical planning., Methods: FDG-PET and diffusion MRI of 14 MRI-negative or equivocal MRE patients were used to retrospectively pilot the PET/DTI approach. We used asymmetry index (AI) mapping of FDG-PET to detect the EF as brain areas showing the largest decrease in FDG uptake between hemispheres. Seed-based WM fiber tracking was performed on DTI images with a seed location in WM 3 mm from the EF. Fiber tractography was repeated in the contralateral brain region (opposite to EF), which served as a control for this study. WM fibers were quantified by calculating the fiber count, mean fractional anisotropy (FA), mean fiber length, and mean cross-section of each fiber bundle. WM integrity was assessed through fiber visualization and by normalizing ipsilateral fiber measurements to contralateral fiber measurements. The added value of PET/DTI in clinical decision-making was evaluated by a senior neurologist., Results: In over 60% of the patient cohort, AI mapping findings were concordant with clinical reports on seizure-onset localization and lateralization. Mean FA, fiber count, and mean fiber length were decreased in 14/14 (100%), 13/14 (93%), and 12/14 (86%) patients, respectively. PET/DTI improved diagnostic confidence in 10/14 (71%) patients and indicated that surgical candidacy be reassessed in 3/6 (50%) patients who had not undergone surgery., Conclusions: We demonstrate here the utility of AI mapping in detecting the EF based on brain regions showing decreased FDG-PET activity and, when coupled with DTI, could be a powerful tool for detecting EF and assessing WM integrity in MRI-negative epilepsy. PET/DTI could be used to further enhance clinical decision-making in epilepsy surgery.

Background: Simultaneous cardiovascular imaging with positron emission tomography (PET) and magnetic resonance imaging (MRI) requires tools such as radio frequency (RF) phased arrays to achieve high temporal and spatial resolution in the MRI, as well as accurate quantification of PET. Today, high-density phased arrays (> 16 channels) used for cardiovascular PET/MRI are not designed to achieve low PET attenuation, and correcting the PET attenuation they cause requires off-line reconstruction, extra time and resources., Purpose: Motivated by previous work assessing the MRI performance of a novel prospectively designed 32-channel phased array, this study assessed the PET image quality with this array in place. Guided by NEMA standards, PET performance was measured using global PET counts, regional background variation (BV), contrast recovery (CR) and contrast-to-noise ratio (CNR) for both the novel array and standard arrays (mMR 12-channel and MRI 32-channel). Nonattenuation-corrected (NAC) data from all arrays (and each part of the array) were processed and compared to no-array, and relative percentage difference (RPD) of the global means was estimated and reported for each part of the arrays. Attenuation correction (AC) of PET images (water in the phantom) using two approaches, MR-based AC map (MRAC) and dual-energy CT-based map (DCTAC), was performed, and RPD compared for each part of the arrays. Percent mean attenuation within regions of interests of the phantom images from each array were compared using a two-way analysis of variance (ANOVA)., Results: The NAC data of the anterior part of the novel array recorded the least PET attenuation (≤ 2%); while the full novel array (anterior and posterior together) AC data, produced by MRAC and DCTAC approaches, recorded attenuation of 1.5 ± 2.9% and 0.0 ± 2.5%, respectively. The novel array PET count loss was significantly lower ( p = 0.001) than those caused by the standard arrays., Conclusions: Results of this novel 32-channel cardiac array PET performance evaluation, together with its previously reported MRI performance assessment, suggest the novel array to be a strong alternative to the standard arrays currently used for cardiovascular hybrid PET/MRI imaging. It enables accurate PET quantification and high-temporal and spatial resolution for MR imaging., Competing Interests: Competing interestsThe first author declares that he owns limited number of shares in Ceresesna Inc., (© The Author(s) 2020.)

Background: Magnetic resonance imaging (MRI) T2 and T1ρ relaxation are increasingly being proposed as imaging biomarkers potentially capable of detecting biochemical changes in articular cartilage before structural changes are evident. We aimed to: 1) summarize MRI methods of published studies investigating T2 and T1ρ relaxation time in participants at risk for but without radiographic knee OA; and 2) compare T2 and T1ρ relaxation between participants at-risk for knee OA and healthy controls., Methods: We conducted a systematic review of studies reporting T2 and T1ρ relaxation data that included both participants at risk for knee OA and healthy controls. Participant characteristics, MRI methodology, and T1ρ and T2 relaxation data were extracted. Standardized mean differences (SMDs) were calculated within each study. Pooled effect sizes were then calculated for six commonly segmented knee compartments., Results: 55 articles met eligibility criteria. There was considerable variability between scanners, coils, software, scanning protocols, pulse sequences, and post-processing. Moderate risk of bias due to lack of blinding was common. Pooled effect sizes indicated participants at risk for knee OA had lengthened T2 relaxation time in all compartments (SMDs from 0.33 to 0.74; p < 0.01) and lengthened T1ρ relaxation time in the femoral compartments (SMD from 0.35 to 0.40; p < 0.001)., Conclusions: T2 and T1ρ relaxation distinguish participants at risk for knee OA from healthy controls. Greater standardization of MRI methods is both warranted and required for progress towards biomarker validation.

Integrated positron emission tomography and magnetic resonance imaging (PET/MRI) is an imaging technology that provides complementary anatomical and functional information for medical diagnostics. Both PET and MRI are highly susceptible to motion artifacts due, in part, to long acquisition times. The simultaneous acquisition of the two modalities presents the opportunity to use MRI navigator techniques for motion correction of both PET and MRI data. For this task, we propose spherical navigator echoes (SNAVs)-3D k-space navigators that can accurately and rapidly measure rigid body motion in all six degrees of freedom. SNAVs were incorporated into turbo FLASH (tfl)-a product fast gradient echo sequence-to create the tfl-SNAV pulse sequence. Acquiring in vivo brain images from a healthy volunteer with both sequences first compared the tfl-SNAV and product tfl sequences. It was observed that incorporation of the SNAVs into the image sequence did not have any detrimental impact on the image quality. The SNAV motion correction technique was evaluated using an anthropomorphic brain phantom. Following a stationary reference image where the tfl-SNAV sequence was acquired along with simultaneous list-mode PET, three identical PET/MRI scans were performed where the phantom was moved several times throughout each acquisition. This motion-up to 11° and 14 mm-resulted in motion artifacts in both PET and MR images. Following SNAV motion correction of the MRI and PET list-mode data, artifact reduction was achieved for both the PET and MR images in all three motion trials. The corrected images have improved image quality and are quantitatively more similar to the ground truth reference images.

Significant advances in positron emission tomography (PET) and magnetic resonance imaging (MRI) brain imaging in the early detection of dementia indicate that hybrid PET/MRI would be an effective tool to screen for dementia in the population living with lifestyle risk factors. Here we investigate the associated costs and benefits along with the needed imaging infrastructure. A demographic analysis determined the prevalence of dementia and its incidence. The expected value of the screening program was calculated assuming a sensitivity and specificity of 0.9, a prevalence of 0.1, a QALY factor of 0.348, a willingness to pay $114,000 CAD and the cost per PET/MRI scan of $2,000 CAD. It was assumed that each head PET/MRI could screen 3,000 individuals per year. The prevalence of dementia is increasing by almost two-fold every 20 years due to the increased population at ages where dementia is more prevalent. It has been shown that a five-year delay in the incidence of dementia would decrease the prevalence by some 45%. In Canada, a five-year delay corresponds to a health care savings of $27,000 CAD per subject per year. The expected value for screening was estimated at $23,745 CAD. The number of subjects to be screened per year in Canada, USA, and China between 60 and 79 was 11,405,000. The corresponding number of head-only hybrid PET/MRI systems needed is 3,800. A brain PET/MRI screening program is financially justifiable with respect to health care costs and justifies the continuing development of MRI compatible brain PET technology., Competing Interests: The authors have no conflict of interest to report.

Background: Cardiovascular imaging using hybrid positron emission tomography (PET) and magnetic resonance imaging (MRI) requires a radio frequency phased array resonator capable of high acceleration factors in order to achieve the shortest breath-holds while maintaining optimal MRI signal-to-noise ratio (SNR) and minimum PET photon attenuation. To our knowledge, the only two arrays used today for hybrid PET/MRI cardiovascular imaging are either incapable of achieving high acceleration or affect the PET photon count greatly., Purpose: This study is focused on the evaluation of the MRI performance of a novel third-party prototype 32-channel phased array designed for simultaneous PET/MRI cardiovascular imaging. The study compares the quality parameters of MRI parallel imaging, such as g-factor, noise correlation coefficients, and SNR, to the conventional arrays (mMR 12-channel and MRI-only 32-channel) currently used with hybrid PET/MRI systems. The quality parameters of parallel imaging were estimated for multiple acceleration factors on a phantom and three healthy volunteers. Using a Germanium-68 (Ge-68) phantom, preliminary measurements of PET photon attenuation caused by the novel array were briefly compared to the photon counts produced from no-array measurements., Results: The global mean of the g-factor and SNR g produced by the novel 32-channel PET/MRI array were better than those produced by the MRI-only 32-channel array by 5% or more. The novel array has resulted in MRI SNR improvements of > 30% at all acceleration factors, in comparison to the mMR12-channel array. Preliminary evaluation of PET transparency showed less than 5% photon attenuation caused by both anterior and posterior parts of the novel array., Conclusions: The MRI performance of the novel PET/MRI 32-channel array qualifies it to be a viable alternative to the conventional arrays for cardiovascular hybrid PET/MRI. A detailed evaluation of the novel array's PET performance remains to be conducted, but cursory assessment promises significantly reduced attenuation., Competing Interests: Competing interestsThe first author declares that he owns limited number of shares in Ceresesna Inc., (© The Author(s) 2019.)

Although PET with 15 O-water is the gold standard for imaging cerebral blood flow (CBF), quantification requires measuring the arterial input function (AIF), which is an invasive and noisy procedure. To circumvent this problem, we propose a noninvasive PET/MRI approach that eliminates the need to measure AIF by using global CBF determined by phase-contrast (PC) MRI as a reference region. This approach not only is noninvasive but also involves no additional imaging time, because PC MRI and 15 O-water PET are acquired simultaneously. The purpose of this study was to test the accuracy of this hybrid method in an animal model in which AIF was measured directly and CBF was varied by changing the arterial CO 2 tension. Methods: PET and MRI data were simultaneously acquired in juvenile pigs at hypocapnia ( n = 5), normocapnia ( n = 5), and hypercapnia ( n = 4). CBF was measured by the MRI reference method and by PET alone using an MRI-compatible blood sampling system to measure AIF. Results: Global CBF estimates from PC MRI and 15 O-water PET agreed well, with a correlation coefficient of 0.9 and a slope of 0.88. Strong positive correlations ( R 2 > 0.96) were also found between regional CBF generated by the PET-only and the MRI-reference methods. Conclusion: These findings demonstrate the accuracy of this hybrid PET/MRI approach, which might prove useful in patients for whom obtaining accurate CBF measurements is challenging., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Alzheimer's disease (AD) pathology causes microstructural changes in the brain. These changes, if quantified with magnetic resonance imaging (MRI), could be studied for use as an early biomarker for AD. The aim of our study was to determine if T 1 relaxation, diffusion tensor imaging (DTI), and quantitative magnetization transfer imaging (qMTI) metrics could reveal changes within the hippocampus and surrounding white matter structures in ex vivo transgenic mouse brains overexpressing human amyloid precursor protein with the Swedish mutation. Delineation of hippocampal cell layers using DTI color maps allows more detailed analysis of T 1 -weighted imaging, DTI, and qMTI metrics, compared with segmentation of gross anatomy based on relaxation images, and with analysis of DTI or qMTI metrics alone. These alterations are observed in the absence of robust intracellular Aβ accumulation or plaque deposition as revealed by histology. This work demonstrates that multiparametric quantitative MRI methods are useful for characterizing changes within the hippocampal substructures and surrounding white matter tracts of mouse models of AD., (Copyright © 2018. Published by Elsevier Inc.)

We characterize a compact MR-compatible PET insert for simultaneous preclinical PET/MRI. Although specifically designed with the strict size constraint to fit inside the 114-mm inner diameter of the BGA-12S gradient coil used in the BioSpec 70/20 and 94/20 series of small-animal MRI systems, the insert can easily be installed in any appropriate MRI scanner or used as a stand-alone PET system. Methods: The insert consists of a ring of 16 detector-blocks each made from depth-of-interaction-capable dual-layer-offset arrays of cerium-doped lutetium-yttrium oxyorthosilicate crystals read out by silicon photomultiplier arrays. Scintillator crystal arrays are made from 22 × 10 and 21 × 9 crystals in the bottom and top layers, respectively, with respective layer thicknesses of 6 and 4 mm, arranged with a 1.27-mm pitch, resulting in a useable field of view 28 mm long and about 55 mm wide. Results: Spatial resolution ranged from 1.17 to 1.86 mm full width at half maximum in the radial direction from a radial offset of 0-15 mm. With a 300- to 800-keV energy window, peak sensitivity was 2.2% and noise-equivalent count rate from a mouse-sized phantom at 3.7 MBq was 11.1 kcps and peaked at 20.8 kcps at 14.5 MBq. Phantom imaging showed that features as small as 0.7 mm could be resolved. 18 F-FDG PET/MR images of mouse and rat brains showed no signs of intermodality interference and could excellently resolve substructures within the brain. Conclusion: Because of excellent spatial resolvability and lack of intermodality interference, this PET insert will serve as a useful tool for preclinical PET/MR., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

One-third of patients with heart disease develop heart failure, which is diagnosed through imaging and detection of circulating biomarkers. Imaging strategies reveal morphologic and functional changes but fall short of detecting molecular abnormalities that can lead to heart failure, and circulating biomarkers are not cardiac specific. Thus, there is critical need for biomarkers that are endogenous to myocardial tissues. The cardiac growth hormone secretagogue receptor 1a (GHSR1a), which binds the hormone ghrelin, is a potential biomarker for heart failure. We have synthesized and characterized a novel ghrelin peptidomimetic tracer, an 18 F-labeled analogue of G-7039, for positron emission tomography (PET) imaging of cardiac GHSR1a. In vitro analysis showed enhanced serum stability compared to natural ghrelin and significantly increased cellular uptake in GHSR1a-expressing OVCAR cells. Biodistribution studies in mice showed that tissue uptake of the tracer was independent of circulating ghrelin levels, and there was negligible cardiac uptake and high uptake in the liver, intestines, and kidneys. Specificity of tracer uptake was assessed using ghsr -/- mice; both static and dynamic PET imaging revealed no difference in cardiac uptake, and there was no significant correlation between cardiac standardized uptake values and GHSR1a expression. Our study lays the groundwork for further refinement of peptidomimetic PET tracers targeting cardiac GHSR1a.

Purpose: The clinical utility of FDG-PET in diagnosing frontotemporal dementia (FTD) has been well demonstrated over the past decades. On the contrary, the diagnostic value of arterial spin labelling (ASL) MRI - a relatively new technique - in clinical diagnosis of FTD has yet to be confirmed. Using simultaneous PET/MRI, we evaluated the diagnostic performance of ASL in identifying pathological abnormalities in FTD (FTD) to determine whether ASL can provide similar diagnostic value as FDG-PET., Methods: ASL and FDG-PET images were compared in 10 patients with FTD and 10 healthy older adults. Qualitative and quantitative measures of diagnostic equivalency were used to determine the diagnostic utility of ASL compared to FDG-PET. Sensitivity, specificity, and inter-rater reliability were calculated for each modality from scores of subjective visual ratings and from analysis of regional mean values in thirteen a priori regions of interest (ROI). To determine the extent of concordance between modalities in each patient, individual statistical maps generated from comparison of each patient to controls were compared between modalities using the Jaccard similarity index (JI)., Results: Visual assessments revealed lower sensitivity, specificity and inter-rater reliability for ASL (66.67%/62.12%/0.2) compared to FDG-PET (88.43%/90.91%/0.61). Across all regions, ASL performed lower than FDG-PET in discriminating patients from controls (areas under the receiver operating curve: ASL = 0.75 and FDG-PET = 0.87). In all patients, ASL identified patterns of reduced perfusion consistent with FTD, but areas of hypometabolism exceeded hypoperfused areas (group-mean JI = 0.30 ± 0.22)., Conclusion: This pilot study demonstrated that ASL can detect similar spatial patterns of abnormalities in individual FTD patients compared to FDG-PET, but its sensitivity and specificity for discriminant diagnosis of a patient from healthy individuals remained unmatched to FDG-PET. Further studies at the individual level are required to confirm the clinical role of ASL in FTD management.

A full-ring PET insert consisting of 16 PET detector modules was designed and constructed to fit within the 114 mm diameter gradient bore of a Bruker 7 T MRI. The individual detector modules contain two silicon photomultiplier (SiPM) arrays, dual-layer offset LYSO crystal arrays, and high-definition multimedia interface (HDMI) cables for both signal and power transmission. Several different RF shielding configurations were assessed prior to construction of a fully assembled PET insert using a combination of carbon fibre and copper foil for RF shielding. MR-compatibility measurements included field mapping of the static magnetic field (B 0 ) and the time-varying excitation field (B 1 ) as well as acquisitions with multiple pulse sequences: spin echo (SE), rapid imaging with refocused echoes (RARE), fast low angle shot (FLASH) gradient echo, and echo planar imaging (EPI). B 0 field maps revealed a small degradation in the mean homogeneity (+0.1 ppm) when the PET insert was installed and operating. No significant change was observed in the B 1 field maps or the image homogeneity of various MR images, with a 9% decrease in the signal-to-noise ratio (SNR) observed only in EPI images acquired with the PET insert installed and operating. PET detector flood histograms, photopeak amplitudes, and energy resolutions were unchanged in individual PET detector modules when acquired during MRI operation. There was a small baseline shift on the PET detector signals due to the switching amplifiers used to power MRI gradient pulses. This baseline shift was observable when measured with an oscilloscope and varied as a function of the gradient duty cycle, but had no noticeable effect on the performance of the PET detector modules. Compact front-end electronics and effective RF shielding led to minimal cross-interference between the PET and MRI systems. Both PET detector and MRI performance was excellent, whether operating as a standalone system or a hybrid PET/MRI.

Unlabelled: Inflammation that occurs after acute myocardial infarction plays a pivotal role in healing by facilitating the creation of a supportive scar. (18)F-FDG, which is taken up avidly by macrophages, has been proposed as a marker of cell-based inflammation. However, its reliability as an accurate indicator of inflammation has not been established, particularly in the early postinfarction period when regional myocardial perfusion is often severely compromised., Methods: Nine adult dogs underwent left anterior descending coronary occlusion with or without reperfusion. Animals were imaged between 7 and 21 d after infarction with PET/MR imaging after bolus injection of gadolinium-diethylenetriaminepentaacetic acid (DTPA), bolus injection of (18)F-FDG, bolus injection of (99)Tc-DTPA to simulate the distribution of gadolinium-DTPA (which represents its partition coefficient in well-perfused tissue), and injection of (111)In-labeled white blood cells 24 h earlier. After sacrifice, myocardial tissue concentrations of (18)F, (111)In, and (99)Tc were determined in a well counter. Linear regression analysis evaluated the relationships between the concentrations of (111)In and (18)F and the dependence of the ratio of (111)In/(18)F to the apparent distribution volume of (99m)Tc-DTPA., Results: In 7 of 9 animals, (111)In increased as (18)F increased with the other 2 animals, showing weak negative slopes. With respect to the dependence of (111)In/(18)F with partition coefficient, 4 animals showed no dependence and 4 showed a weak positive slope, with 1 animal showing a negative slope. Further, in regions of extensive microvascular obstruction, (18)F significantly underestimated the extent of the presence of (111)In., Conclusion: In the early post-myocardial infarction period, (18)F-FDG PET imaging after a single bolus administration may underestimate the extent and degree of inflammation within regions of microvascular obstruction., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Purpose: To evaluate a potential approach for improved attenuation correction (AC) of PET in simultaneous PET and MRI brain imaging, a straightforward approach that adds bone information missing on Dixon AC was explored., Methods: Bone information derived from individual T1-weighted MRI data using segmentation tools in SPM8, were added to the standard Dixon AC map. Percent relative difference between PET reconstructed with Dixon+bone and with Dixon AC maps were compared across brain regions of 13 oncology patients. The clinical potential of the improved Dixon AC was investigated by comparing relative perfusion (rCBF) measured with arterial spin labeling to relative glucose uptake (rPETdxbone) measured simultaneously with (18)F-flurodexoyglucose in several regions across the brain., Results: A gradual increase in PET signal from center to the edge of the brain was observed in PET reconstructed with Dixon+bone. A 5-20% reduction in regional PET signals were observed in data corrected with standard Dixon AC maps. These regional underestimations of PET were either reduced or removed when Dixon+bone AC was applied. The mean relative correlation coefficient between rCBF and rPETdxbone was r = 0.53 (p < 0.001). Marked regional variations in rCBF-to-rPET correlation were observed, with the highest associations in the caudate and cingulate and the lowest in limbic structures. All findings were well matched to observations from previous studies conducted with PET data reconstructed with computed tomography derived AC maps., Conclusion: Adding bone information derived from T1-weighted MRI to Dixon AC maps can improve underestimation of PET activity in hybrid PET-MRI neuroimaging.

Optic chiasm lesions in myelin oligodendrocyte glycoprotein (MOG)-experimental autoimmune encephalomyelitis (EAE) mice were characterized using magnetic resonance imaging (MRI) and validated using electron microscopy (EM). MR images were collected from 3 days after induction to remission, approximately 20 days after induction. Hematoxylin and eosin, solochrome cyanin-stained sections, and EM images were obtained from the optic chiasms of some mice approximately 4 days after disease onset when their scores were thought to be the highest. T2-weighted imaging and apparent diffusion coefficient map hyperintensities corresponded to abnormalities in the optic chiasms of EAE mice. Mixed inflammation was concentrated at the lateral surface. Degeneration of oligodendrocytes, myelin, and early axonal damage were also apparent. A marked increase in chiasm thickness was observed. T2-weighted and diffusion-weighted MRI can detect abnormalities in the optic chiasms of MOG-EAE mice. MRI is an important method in the study of this model toward understanding optic neuritis.

Recently, positron emission tomography (PET) is playing an increasingly important role in the diagnosis and staging of cancer. Combined PET and X-ray computed tomography (PET-CT) scanners are now the modality of choice in cancer treatment planning. More recently, the combination of PET and magnetic resonance imaging (MRI) is being explored in many sites. Combining PET and MRI has presented many challenges since the photo-multiplier tubes (PMT) in PET do not function in high magnetic fields, and conventional PET detectors distort MRI images. Solid state light sensors like avalanche photo-diodes (APDs) and more recently silicon photo-multipliers (SiPMs) are much less sensitive to magnetic fields thus easing the compatibility issues. This paper presents the results of a group of Canadian scientists who are developing a PET detector ring which fits inside a high field small animal MRI scanner with the goal of providing simultaneous PET and MRI images of small rodents used in pre-clinical medical research. We discuss the evolution of both the crystal blocks (which detect annihilation photons from positron decay) and the SiPM array performance in the last four years which together combine to deliver significant system performance in terms of speed, energy and timing resolution.

Background: Magnetic resonance imaging (MRI) of transgenic mouse models of Alzheimer's disease is valuable to understand better the structural changes that occur in the brain and could provide a means to test drug treatments. A hallmark pathological feature of Alzheimer's disease is atrophy of the hippocampus, which is an early biomarker of the disease. MRI can be used to detect and monitor this biomarker., Method: Repeated measurements using in vivo 3D T2-weighted imaging of mice were used to assess the methods. Each mouse was imaged twice in one week and twice the following week and no changes in volume were expected. The hippocampus was segmented both manually and semi-automatically. Registration was done to gain information on shape changes. The volumes from each mouse were compared intra-mouse, between mice and to hippocampus volume values in the literature., Results: A reliable method was developed which was able to detect difference in volumes of hippocampus between mice when performed by a single individual. The semi-automated segmentation was unable to detect the same level of differences. The semi-automated segmentation method gave larger hippocampus volumes, with 78-87% reliability between the manual and semi-automated segmentation. Although more accurate, the manual segmentation is laborious and suffers from inter- and intra-variability., Conclusion: These results suggest that manual segmentation is still considered the most reliable segmentation method for small structures. However, if performing longitudinal studies, where there is at least one year between imaging sessions, the segmentation should be done all at once at the end of all the imaging sessions. If segmentation is done after each imaging session, with at least a year passing between segmentations, very small variations in volumes can be missed. This method provides a means to quantify the volume of the hippocampus in a live mouse using manual segmentation, which is the first step toward studying hippocampus atrophy in a mouse model of Alzheimer's disease., (Copyright © 2013 Elsevier B.V. All rights reserved.)

In this study we present a method of 3D system response calculation for analytical computer simulation and statistical image reconstruction for a magnetic resonance imaging (MRI) compatible positron emission tomography (PET) insert system that uses a dual-layer offset (DLO) crystal design. The general analytical system response functions (SRFs) for detector geometric and inter-crystal penetration of coincident crystal pairs are derived first. We implemented a 3D ray-tracing algorithm with 4π sampling for calculating the SRFs of coincident pairs of individual DLO crystals. The determination of which detector blocks are intersected by a gamma ray is made by calculating the intersection of the ray with virtual cylinders with radii just inside the inner surface and just outside the outer-edge of each crystal layer of the detector ring. For efficient ray-tracing computation, the detector block and ray to be traced are then rotated so that the crystals are aligned along the X-axis, facilitating calculation of ray/crystal boundary intersection points. This algorithm can be applied to any system geometry using either single-layer (SL) or multi-layer array design with or without offset crystals. For effective data organization, a direct lines of response (LOR)-based indexed histogram-mode method is also presented in this work. SRF calculation is performed on-the-fly in both forward and back projection procedures during each iteration of image reconstruction, with acceleration through use of eight-fold geometric symmetry and multi-threaded parallel computation. To validate the proposed methods, we performed a series of analytical and Monte Carlo computer simulations for different system geometry and detector designs. The full-width-at-half-maximum of the numerical SRFs in both radial and tangential directions are calculated and compared for various system designs. By inspecting the sinograms obtained for different detector geometries, it can be seen that the DLO crystal design can provide better sampling density than SL or dual-layer no-offset system designs with the same total crystal length. The results of the image reconstruction with SRFs modeling for phantom studies exhibit promising image recovery capability for crystal widths of 1.27-1.43 mm and top/bottom layer lengths of 4/6 mm. In conclusion, we have developed efficient algorithms for system response modeling of our proposed PET insert with DLO crystal arrays. This provides an effective method for both 3D computer simulation and quantitative image reconstruction, and will aid in the optimization of our PET insert system with various crystal designs.

The cuprizone mouse model of demyelination was used to investigate the influence that white matter changes have on different magnetic resonance imaging results. In vivo T2 -weighted and magnetization transfer images (MTIs) were acquired weekly in control (n = 5) and cuprizone-fed (n = 5) mice, with significant increases in signal intensity in T2 -weighted images (p < 0.001) and lower magnetization transfer ratio (p < 0.001) in the corpus callosum of the cuprizone-fed mice starting at 3 weeks and peaking at 4 and 5 weeks, respectively. Diffusion tensor imaging (DTI), quantitative MTI (qMTI), and T1/T2 measurements were used to analyze freshly excised tissue after 6 weeks of cuprizone administration. In multicomponent T2 analysis with 10 ms echo spacing, there was no visible myelin water component associated with the short T2 value. Quantitative MTI metrics showed significant differences in the corpus callosum and external capsule of the cuprizone-fed mice, similar to previous studies of multiple sclerosis in humans and animal models of demyelination. Fractional anisotropy was significantly lower and mean, axial, and radial diffusivity were significantly higher in the cuprizone-fed mice. Cellular distributions measured in electron micrographs of the corpus callosum correlated strongly to several different quantitative MRI metrics. The largest Spearman correlation coefficient varied depending on cellular type: T1 versus the myelinated axon fraction (ρ = -0.90), the bound pool fraction (ƒ) versus the myelin sheath fraction (ρ = 0.93), and axial diffusivity versus the non-myelinated cell fraction (ρ = 0.92). Using Pearson's correlation coefficient, ƒ was strongly correlated to the myelin sheath fraction (r = 0.98) with a linear equation predicting myelin content (5.37ƒ - 0.25). Of the calculated MRI metrics, ƒ was the strongest indicator of myelin content, while longitudinal relaxation rates and diffusivity measurements were the strongest indicators of changes in tissue structure., (Copyright © 2013 John Wiley & Sons, Ltd.)

Pathological hallmarks of Alzheimer's disease include memory deficits, accumulation of amyloid beta (Abeta) plaques, the appearance of neurofibrillary tangles, and dysregulation of calcium homeostasis, which has been linked to mutations in the presenilin gene that code for presenilin (PS) proteins. PSs are a family of multi-pass transmembrane proteins where normal presenilins (PS1 and PS2) are highly localized in the endoplasmic reticulum (ER). Several past studies have explored alterations in long-term potentiation (LTP), a proposed molecular correlate of memory, and in behavioral tests of spatial memory in a variety of PS1 models. These reports suggest that calcium plays a role in these alterations, but mechanistic explanations for changes in LTP and in behavioral tests of memory are still lacking. To test the hypothesis that calcium-related mechanisms, such as changes in calcium buffering, are associated with alterations in LTP and memory, we utilized in vitro experimental paradigms of LTP in hippocampal slices obtained from the PS1-M146V transgenic mouse model of Alzheimer's disease (AD). We also used the in vivo Morris water maze (MWM), a test for hippocampal dependent spatial memory. In addition, we used cellular assays to explore molecular mechanisms. We confirm that PS1 mutations (M146V) enhance LTP. We also find increases in some parameters of the MWM, and alterations in other parameters, such as path length indicating impairment in cognitive functioning in PS1-M146V mice. In addition, these findings are observed in association with increased calbindin D28K expression in the CA1 hippocampus of PS1-M146V mice., (Copyright (c) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.)

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that has been characterized by gross cortical atrophy, cellular neurodegeneration, reactive gliosis, and the presence of microscopic extracellular amyloid plaques and intracellular neurofibrillary tangles. Earlier diagnoses of AD would be in the best interest of managing the patient and would allow for earlier therapeutic intervention. By measuring the apparent diffusion coefficient (ADC) using diffusion-weighted imaging (DWI), a type of magnetic resonance imaging (MRI), one can quantify alterations in water diffusivity resulting from microscopic structural changes in the cell at early stages that are associated with pathophysiological processes of brain injury and/or disease progression. Whether or not this methodology is useful for AD is a question under examination. For example, DWI in suspected AD patients has shown increases in mean ADC values in the hippocampus and diminished diffusion anisotropy in the posterior white matter. However, in some cases, hippocampal ADC values appear not to change in AD patients. Moreover, to our knowledge, all DWI studies in suspected AD patients to date are technically incomplete in experimental design, because corresponding histological sections demonstrating actual plaque deposition are lacking and so it is not clear that ADC changes actually correspond to plaque deposition. In our study, we used DWI in the TgCRND8 transgenic model of Alzheimer's disease in conjunction with histological techniques and found robust plaque deposition in the transgenic strain in older animals (12-16 months old). However, we did not find statistically significant changes (p > 0.05) in ADC values (although ADC values in TgCRND8 mice did decrease in all regions examined) in mice 12-16 months old. Collectively, recent results from human studies and in rodent AD transgenic models support our findings and suggest that amyloid beta plaque load is not likely the major or primary component contributing to diffusional changes, if they occur.