Background: Gadolinium-1,4,7,10-Tetraazacyclodecane-1,4,7,10-tetraacetic acid (Gd DOTA) and similar magnetic resonance imaging (MRI) contrast agents are suggested as markers for myocardial blood flow (MBF). Contrary to MRI, the positron emission tomography (PET) signal is directly proportional to radioactivity concentration, and hence a PET-analog of Gd-DOTA could be used to assess the kinetics of DOTA-based agents without the challenges of measuring Gd concentrations with MRI. The aim of the present work was to assess the suitability of Gd-DOTA as a marker of MBF by comparing 68Ga-DOTA as a PET analog of Gd-DOTA to the gold standard for noninvasive measurement of MBF, 15 O-water PET. Methods: A total of 24 patients underwent dynamic 15 O-water-PET during rest and pharmacological stress, followed by 68Ga-DOTA-PET and Gd-DOTA dynamic contrast-enhanced MRI on an integrated PET/MR scanner. 68Ga-DOTA-PET was analyzed using single-tissue and two-tissue irreversible compartment models. The dynamic contrast-enhanced MRI perfusion data were analyzed using a single-tissue reversible compartment model. K 1 of 68Ga-DOTA was compared with 15 O-water. Permeability-surface area product for 68Ga-DOTA was estimated using the Renkin-Crone equation. Results: Kinetics of 68Ga-DOTA were well-described by a single-tissue compartment model. The permeability-surface area product of 68Ga-DOTA was 0.70 + 0.15 & times; MBF (mL/ cm3 /min), corresponding to an extraction of around 30% at typical hyperemic MBF values. Average whole-myocardium 68Ga-DOTA K 1 values ranged between 0.35 and 1.36 mL/cm3 /min compared to 0.68 and 4.55 mL/cm3 /min for 15 O-water. 68Ga-DOTA and Gd-DOTA K 1 values showed no significant differences. The correlation between 68Ga-DOTA MBF and 15 O-water MBF was moderate (r 2 = 0.66). Conclusions: Extraction of DOTA is low and depends on flow, resulting in a high variability and uncertainty of hyperemic MBF values.

Obesity surgery (OS) and diet-induced weight loss rapidly improve insulin resistance. We aim to investigate the impact of either Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) surgery compared with a diet low in energy (low-calorie diet; LCD) on body composition, glucose control and insulin sensitivity, assessed both at the global and tissue-specific level in individuals with obesity but not diabetes. In this parallel group randomised controlled trial, patients on a waiting list for OS were randomised (no blinding, sealed envelopes) to either undergo surgery directly or undergo an LCD before surgery. At baseline and 4 weeks after surgery (n=15, 11 RYGB and 4 SG) or 4 weeks after the start of LCD (n=9), investigations were carried out, including an OGTT and hyperinsulinaemic–euglycaemic clamps during which concomitant simultaneous whole-body [18F]fluorodeoxyglucose-positron emission tomography (PET)/MRI was performed. The primary outcome was HOMA-IR change. One month after bariatric surgery and initiation of LCD, both treatments induced similar reductions in body weight (mean ± SD: −7.7±1.4 kg and −7.4±2.2 kg, respectively), adipose tissue volume (7

PurposeWe aimed to characterize the RYGB-induced changes in the dynamics of brain glucose uptake. We addressed heterogeneity between brain regions during experimental normo- and hypoglycemia and explored associations with anthropometric and metabolic outcomes of RYGB.MethodsAnalyses of regional brain glucose uptake were performed on 9 individuals with obesity and no diabetes, investigated with combined brain 18F-FDG-PET and fMRI during hyperinsulinemic normo- and hypoglycemic clamp, one month before and four months after RYGB. FDG clearance, reflecting glucose uptake rate, was assessed in 38 brain regions, covering all cortical areas and subcortical nuclei, during hyperinsulinemic normo- and hypoglycemia. Correlation analyses were performed to identify associations with other outcomes of RYGB.ResultsFDG uptake rate during hypoglycemia was higher than during normoglycemia in all brain regions, both before and after RYGB. Moreover, in most regions and especially in cortical areas involved in inhibitory behavioral control, FDG uptake rate tended to be reduced after surgery during normoglycemia but elevated during hypoglycemia. However, these post-surgical changes in FDG uptake rate were opposite in the hypothalamus. Thus, the hypo-to-normoglycemia FDG clearance ratio tended to increase in all brain regions following RYGB, but not in the amygdala and the hypothalamus. Changes in regional FDG uptake rate after RYGB during normoglycemia were associated with weight loss and improved systemic insulin sensitivity.ConclusionUsing dynamic FDG-PET, we show region-specific patterns of changes in glucose utilization following RYGB. In the hypothalamus, glucose uptake during normoglycemia tended to rise after RYGB while it was reduced in cortical regions involved in behavioral control. Following RYGB, the hypothalamus and amygdala, in contrast to other regions, displayed trends of reduced glucose uptake during hypoglycemia. These pilot results highlight the brain effects of RYGB and suggest behavioral and neuroendocrine adaptations which contribute to its antidiabetic effects.

Abstract Background Gadolinium-DOTA (Gd-DOTA) and similar MRI contrast agents are increasingly being used as markers for myocardial blood flow (MBF). Accurate quantification of MBF with MR contrast agents is challenging as it requires (1) correct conversion of the MR signal to Gd concentration, (2) an appropriate kinetic model to estimate the uptake rate constant from plasma to tissue, and (3) correction for the limited extraction of the contrast agent. An earlier comparison showed moderate agreement between MBF using single-sequence Gd-DOTA MRI and simultaneous 15O-water PET (1) but new dual-sequence methods are suggested to overcome some of the challenges of quantitative Gd-DOTA MRI. Contrary to MRI, the PET signal is directly proportional to radioactivity concentration and hence a PET analogue of Gd-DOTA, 68Ga-DOTA, could be used to assess the kinetics of DOTA without the challenges of measuring Gd concentrations with MRI. Purpose The aim of the present work was to assess the suitability of DOTA as a marker of MBF by comparing 68Ga-DOTA and Gd-DOTA to the gold standard for non-invasive measurement of MBF, 15O-water PET. Methods 25 patients underwent dynamic 15O-water-PET during rest and pharmacological stress followed by simultaneous dynamic rest and stress 68Ga-DOTA-PET and single-sequence (N=14) or dual-sequence (N=11) Gd-DOTA dynamic contrast enhanced MRI on an integrated PET-MR scanner. 15O-water PET was analysed automatically, and volumes of interest were transferred to the co-registered 68Ga-DOTA-PET images. 68Ga-DOTA-PET and Gd-DOTA MRI were analysed using the single tissue compartment model and the uptake rate constant K1 of 68Ga-DOTA and Gd-DOTA was compared to that of 15O-water. Permeability-surface area product of DOTA was estimated using the Renkin-Crone equation. Results Kinetics of 68Ga-DOTA were well-described by a single-tissue compartment model. Extraction was low for DOTA, with average whole myocardium 68Ga-DOTA K1 values ranging between 0.28 and 1.13 mL/cm3/min compared to 0.62 and 4.20 mL/cm3/min for 15O-water. The permeability surface area product of 68Ga-DOTA was 0.48 mL/cm3/min, corresponding to an extraction of around 20% at typical hyperemic MBF values. Correlations between 68Ga-DOTA and 15O-water K1 stress values were poor (r2 0.29 at the global and 0.26 at the regional level). Single-sequence Gd-DOTA significantly overestimated K1 compared to 68Ga-DOTA (regression slope 1.4; Wilcoxon p 0.002) whereas there was no significant difference and a moderate correlation (slope 1.1; r2 0.54) between dual-sequence Gd-DOTA K1 and 68Ga-DOTA K1. Conclusion Extraction of DOTA is low resulting in a high uncertainty in hyperemic MBF values. Although new dual-sequence techniques seem to overcome some of the challenges of quantitative Gd-DOTA MRI, the low DOTA extraction along with the complexity of quantifying Gd-DOTA concentrations with MRI suggest that DOTA cannot be considered a suitable agent for accurate measurement of MBF.

15O-water PET is the gold standard for noninvasive quantification of myocardial blood flow. In addition to evaluation of ischemia, the assessment of cardiac function and remodeling is important in all cardiac diseases. However, since 15O-water is freely diffusible and standard uptake images show little contrast between the myocardium and blood pool, the assessment of left-ventricular (LV) volumes and ejection fraction (EF) is challenging. Therefore, the aim of the present study was to investigate the feasibility of calculating LV volumes and EF from first-pass analysis of 15O-water PET, by comparison with cardiac magnetic resonance imaging (CMR) using a hybrid PET/MR scanner. Twenty-four patients with known or suspected CAD underwent a simultaneous ECG-gated cardiac PET/MR scan. The 15O-water first-pass images (0-50 seconds) were analyzed using the CarPET software and the CMR images were analyzed using the software Segment, for LV volumes and EF calculations. The LV volumes and EF were compared using correlation and Bland–Altman analysis. In addition, inter- and intra-observer variability of LV volumes and EF were assessed for both modalities. The correlation between PET and CMR was strong for volumes (r > 0.84) and moderate for EF (r = 0.52), where the moderate correlation for EF was partly due to the small range of EF values. Agreement was high for all parameters, with a slight overestimation of PET values for end-diastolic volume but with no significant mean bias for other parameters. Inter- and intra-observer agreement of volumes was high and comparable between PET and CMR. For EF, inter-observer agreement was higher for PET and intra-observer agreement was higher for CMR. LV volumes and EF can be calculated by first-pass analysis of a 15O-water PET scan with high accuracy and comparable precision as with CMR.

To the Editor: Adverse cardiovascular outcomes have been associated with radiation therapy (RT) and adjuvant chemotherapy in patients with breast cancer. Long-term effects may be increased among patients with left-sided tumors who receive unwanted irradiation to cardiac segments that lie within the treatment field.1 Ionizing radiation damages healthy heart tissue via microvascular changes, inflammation, and edema, followed by reduced perfusion, fibrosis, and depressed ventricular systolic and diastolic function.2, 3 Myocardial edema, fibrosis, and myocyte atrophy have been demonstrated using T1 and T2 relaxation times (T1 and T2) acquired with cardiovascular magnetic resonance imaging (MRI) in a spectrum of cardiac disorders, including breast cancer patients late after anthracycline or trastuzumab treatment.4-8 The aim of this study is to investigate whether T1 and T2, measured in a single breath hold with three-dimensional (3D)-QALAS techniques (3D-quantification using an interleaved Look-Locker acquisition sequence with T2 preparation pulse),9 can detect myocardial changes early in RT treatment in breast cancer patients, and assess the impact of cardiac radiation dose and concomitant chemotherapy on the evolution of those changes during and early following RT. Ten female breast cancer patients aged 55 ± 9 years with stage I–III disease undergoing 3D conformal RT were studied. Radiation burden to the left anterior descending artery and heart were measured as mean and near maximum dose, D2%.10 Seven patients had left-sided and three had right-sided breast cancer. Five patients received RT alone; five patients received RT plus chemotherapy. Four of five chemotherapy patients also received trastuzumab before, during, and after RT (Table 1). Patients were recruited at Linköping University, Sweden, between January 2015 and October 2016 and gave written informed consent to participate in the study. Approval was granted from the Regional Ethical Review Board in Linköping. Patients were examined within 1 week prior to start of RT (examination 1), 2–3 weeks after RT initiation (examination 2), and 1 and 6 months following RT completion (examinations 3 and 4). Myocardial T1 and T2, left ventricular mass (LVM), and ejection fraction (LVEF) were measured with MRI. Global LV longitudinal strain (GLS) and mitral valve E/é ratio were measured with speckle-tracking and Doppler echocardiography. Cardiac MRI examinations were performed using a Philips Ingenia 3 T system and included a short-axis cine steady-state free precession (SSFP) acquisition and a native 3D-QALAS9 acquisition at end diastole. The 3D-QALAS acquisition had a resolution of 2.0 mm × 2.0 mm in-plane, a slice thickness of 12.0 mm (reconstructed to 2.0 mm × 2.0 mm × 6.0 mm), flip angle of 5°, and SENSE factor of 2 and 1.2 in phase and slice directions. Echo time was 1.2 msec and repetition time was 2.6 msec. The 3D-QALAS acquisition provided 13 short-axis LV slices. An experienced observer used commercially available software (Segment version 2.1 R6274) to analyze cine data. LVM and LVEF were calculated from manually drawn LV contours. Quantitative T1 and T2 maps from the 3D-QALAS acquisitions were generated using SyMRI (SyntheticMR, Sweden). For each 3D-QALAS acquisition, epi- and endocardial borders were manually contoured on T1 and T2 maps from 13 LV slices using Segment version 1.9 R3644. T1 and T2 were measured in each segment, and values from all segments averaged to represent the overall T1 and T2 for each examination. T1 and T2 were compared between examinations using IBM SPSS Statistics version 25 (Armonk, NY). Linear mixed models with repeated measures analysis were used to investigate differences in each myocardial segment over time. The model included time and myocardial segment as fixed classification factors and patient as a random classification factor. Changes in LVM, LVEF, GLS, and E/é ratio between examinations 1 and 4 were assessed using Student's t-test. Statistical significance was set as P < 0.05. Eight patients completed four examinations; two patients completed three and two examinations each. T1 increased and T2 decreased significantly between examination 4 and earlier examinations (Fig. 1). T1 increases were most apparent between examinations 3 and 4 and occurred in left-sided but not in right-sided breast cancer patients (average increase 7.6% vs. 0.1%, respectively). T2 decreases were more evident between examinations 1 and 2, and among right- compared to left-sided patients (average decrease 13.4% vs. 0.6%). Between examinations 1 and 4, LVM increased by 2.1 g, GLS fell by 3.0%, and E/é increased by 0.8 (P < 0.05 for all three). LVEF did not change. Patients receiving chemotherapy had larger changes in T1, T2, and LVM between examinations 1 and 4 than those undergoing RT alone (T1: +6.0 vs. +3.4%; T2: −9.2 vs. +0.1%; LVM: +6.0% vs. −2.2%). T1 and T2 relaxation times detected myocardial changes during and up to 6 months after RT which were associated with deterioration of LV systolic and diastolic function. A significant increase in T1 occurred after RT completion among patients with left-sided cancers and higher cardiac radiation doses, but not in patients with right-sided cancers, suggesting a causal role for RT. T2 decreased significantly from examination 1 to 4, with a notable early decrease among the right-sided patients who had the lowest cardiac radiation exposure, suggesting that early T2 decline may not be an RT effect. The early T2 fall was seen in patients who had received chemotherapy, raising the possibility that preceding myocardial edema or inflammation due to chemotherapy may have also impacted the early T2 fall.8 T1 and T2 relaxation times detect RT effects on the myocardium early in the treatment of breast cancer patients that are associated with decreased systolic and diastolic LV function. Changes in T1, T2, and LVM suggest myocardial edema or fibrosis developed in patients receiving RT, and that the temporal evolution of those changes might be influenced by both the cardiac radiation dose and exposure to concomitant chemotherapy and trastuzumab. T1 and T2 relaxation times may assist early detection of tissue changes that presage longer-term cardiovascular risk in patients undergoing RT for breast cancer treatment. Confirmation merits larger and longer-term studies. The authors thank statistician Mats G. Fredriksson, PhD, for valuable advice on the statistical methods used in this study. This study was partially financed through ALF Grants, Region Ostergotland LIO-284291, LIO-284411, and LIO-448281, and LIU Cancer Projects Grants 2012. 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. SK contributed to the study design, analyzed the results, performed the statistical analysis, and drafted the manuscript. AMF recruited the patients and contributed to the study design. JEE contributed to analyze the results and to the study design. AD and TE contributed to the study design. AFB edited the manuscript. All authors have critically read and revised the manuscript and approved the final version.

While Roux-en-Y Gastric Bypass (RYGB)surgery in obese individuals typically improves glycemic control and preventsdiabetes, it also frequently causes hypoglycemia. Previous work showed attenuatedcounter-regulatory responses following RYGB. The underlying mechanisms as wellas the clinical consequences are unclear. In this study, 11 non-diabeticsubjects with severe obesity were investigated pre- and post-RYGB duringhyperinsulinemic hypoglycemic clamps. Assessments were made of hormones,cognitive function, cerebral blood flow by arterial spin labeling, brain glucosemetabolism by FDG PET and activation of brain networks by functional MRI. Post-vs pre-surgery, we found a general increase of cerebral blood flow but adecrease of total brain FDG uptake during normoglycemia. During hypoglycemia, therewas a marked increase in total brain FDG uptake and this was similar for post-and pre-surgery, whereas hypothalamic FDG uptake was reduced. Duringhypoglycemia, attenuated responses of counterregulatory hormones andimprovements in cognitive function were seen post-surgery. In earlyhypoglycemia, there was increased activation post- vs pre-surgery of neural networksin CNS regions implicated in glucose regulation such as the thalamus and hypothalamus.The results suggest adaptiveresponses of the brain that contribute to lowering of glycemia following RYGB, andthe underlying mechanisms should be further elucidated.

3110 Introduction: In PET imaging, respiratory motion can severely impair image quality, especially in tissues near the diaphragm, and consequently may lead to poorer lesion detection, delineation and quantitation. Respiratory gating has been available for many years. Previously available gating techniques involve separate devices and are hard to implement in routine clinical practice, respiratory gating has therefore often not been utilized to its full extent. Data-driven gating (DDG), based on detection of respiratory signal using principal component analysis of dynamic sinogram data, would allow for routine implementation of respiratory gating. To date, DDG has only been validated for FDG-PET. The aim of the present work was to assess the effectivity of respiratory signal detection in DDG and its effect on standardized uptake values (SUV) for 68Ga-DOTATOC. Methods: Fifteen patients underwent a whole-body PET-CT scan 1 h after injection of 1.5 MBq/kg body weight of 68Ga-DOTATOC on a General Electric Discovery MI 4-ring PET-Scanner, with 2 min acquisition per bed position. MotionFree (GE-Healthcare), a principal component analysis based respiratory DDG software, was applied prospectively and the scan time per bed position was doubled for beds where a respiratory motion signal was detected in the raw data. Quiescent period gated images, containing 50 % of the doubled scan time data, were reconstructed with Q. Static software (GE Healthcare). All images were reconstructed using TOF-OSEM (3 iterations, 16 subsets) with resolution recovery. SUVmax measurements on 68Ga-DOTATOC positive lesions (n=22) without and with DDG were compared. Also, the effectiveness of the detection of respiratory signal was evaluated retrospectively. Results: Using the same threshold value for respiratory motion detection as recommended by the manufacturer for FDG (r = 15), motion was detected on mean 2.2 bed positions per scan. DDG resulted in a mean 16% (range -2 - 47) increase in SUVmax (p = 0.0001). Conclusions: Using the same threshold as for FDG, respiration signals were detected in considerably more bed positions than previously reported for FDG (mean 2.2 versus 1.2), likely due to the higher image contrast for 68Ga-DOTATOC than for FDG. DDG yielded significantly higher SUVmax values as compared to non-gated images.

BackgroundDiffuse myocardial fibrosis is associated with adverse outcomes, although detection and quantification is challenging. Cardiac MR relaxation times mapping represents a promising imaging biomarker for diffuse myocardial fibrosis.PurposeTo investigate whether relaxation times can detect longitudinal changes in myocardial tissue composition associated with diffuse fibrosis in patients with severe aortic stenosis (AS) before and after aortic valve replacement (AVR).Study typeProspective longitudinal study.Population/Subjects/Phantom/Specimen/Animal ModelFifteen patients with severe AS.Field Strength/Sequence3T / 3(3)3(3)5‐MOLLI, T2‐GraSE, and 3D‐QALAS.AssessmentPatients underwent MR examinations at three timepoints: before AVR, as well as 3 and 12 months after AVR. Data from each patient was analyzed in 16 myocardial segments.Statistical TestsThe segment‐wise T1 and T2 data were analyzed over time after surgery using linear mixed models for repeated measures analysis.ResultsThe results showed that T1 relaxation times were significantly (P < 0.05) shorter 3 and 12 months postoperative than preoperative and that the T2 relaxation times were significantly (P < 0.05) longer 3 and 12 months postoperative than preoperative for both 3D and 2D mapping methods. No significant changes were seen between 3 and 12 months postoperative for any of the methods (P = 0.06/0.19 for T1 with 3D‐QALAS/MOLLI and P = 0.09/0.25 for T2 with 3D‐QALAS/GraSE).Data ConclusionWe demonstrated that changes in myocardial relaxation times and thus tissue characteristics can be observed within 3 months after AVR surgery. The significant changes in relaxation times from preoperative examinations to the follow‐up may be interpreted as a reduction of interstitial fibrosis in the left ventricular wall.Level of Evidence: 1Technical Efficacy: Stage 3J. Magn. Reson. Imaging 2018;48:799–807.

In cardiovascular disease, which is the most common cause of death in the world, early diagnosis is crucial for disease outcome.Diagnosis of cardiovascular disease can be challenging, though.Quantification of myocardial T1 and T2 relaxation times with MRI has demonstrated to be a promising method for characterizing myocardial tissue, but long measurement times have hampered clinical use.The overall aim of this doctoral thesis was to develop, validate and, in patient studies, evaluate a very fast three-dimensional method for simultaneous quantification of myocardial T1 and T2 relaxation times with whole coverage of the left ventricle.

PurposeTo investigate the in-vivo precision and clinical feasibility of 3D-QALAS - a novel method for simultaneous three-dimensional myocardial T1- and T2-mapping.MethodsTen healthy subjects and 23 patients with different cardiac pathologies underwent cardiovascular 3T MRI examinations including 3D-QALAS, MOLLI and T2-GraSE acquisitions. Precision was investigated in the healthy subjects between independent scans, between dependent scans and as standard deviation of consecutive scans. Clinical feasibility of 3D-QALAS was investigated for native and contrast enhanced myocardium in patients. Data were analyzed using mean value and 95% confidence interval, Pearson correlation, Paired t-tests, intraclass correlation and Bland-Altman analysis.ResultsAverage myocardial relaxation time values and SD from eight repeated acquisitions within the group of healthy subjects were 1178±18.5ms (1.6%) for T1 with 3D-QALAS, 52.7±1.2ms (2.3%) for T2 with 3D-QALAS, 1145±10.0ms (0.9%) for T1 with MOLLI and 49.2±0.8ms (1.6%) for T2 with GraSE.Myocardial T1 and T2 relaxation times obtained with 3D-QALAS correlated very well with reference methods; MOLLI for T1 (r=0.994) and T2-GraSE for T2 (r=0.818) in the 23 patients. Average native/post-contrast myocardial T1 values from the patients were 1166.2ms/411.8ms for 3D-QALAS and 1174.4ms/438.9ms for MOLLI. Average native myocardial T2 values from the patients were 53.2ms for 3D-QALAS and 54.4ms for T2-GraSE.ConclusionsRepeated independent and dependent scans together with the intra-scan repeatability, demonstrated all a very good precision for the 3D-QALAS method in healthy volunteers. This study shows that 3D T1 and T2 mapping in the left ventricle is feasible in one breath hold for patients with different cardiac pathologies using 3D-QALAS.

Background A novel method for 3D interleaved T1 and T2 mapping of the whole left ventricular myocardium within one breath hold, 3D-QALAS, has recently been developed [1]. The method has been evaluated both in phantoms and in healthy volunteers showing a good correlation to reference relaxation time mapping methods. The aim of this work was to investigate the feasibility of the method in patients with different cardiac pathologies and to extend the tested range of myocardial relaxation times by including measurements post injection of gadolinium (Gd) based contrast agents.

Conclusions3D QALAS allows quantification of both T1 and T2 in the whole left ventricular myocardium within one breath hold, making T1 and T2 quantification clinically applicable to a broader spectrum of diseases.

Quantification of the longitudinal- and transverse relaxation time in the myocardium has shown to provide important information in cardiac diagnostics. Methods for cardiac relaxation time mapping generally demand a long breath hold to measure either T1 or T2 in a single 2D slice. In this paper we present and evaluate a novel method for 3D interleaved T1 and T2 mapping of the whole left ventricular myocardium within a single breath hold of 15 heartbeats.