Background Nuclear imaging modalities can quantify cardiac volumes and left ventricular ejection fraction (LVEF), but systematic differences between techniques complicate direct comparison. Phantom-based evaluations comparing myocardial perfusion and blood-pool methods are scarce.Methods We used a dynamic two-compartment cardiac phantom (myocardium and left ventricular [LV] lumen) with adjustable stroke volume and heart rate. Static and gated acquisitions were performed on cadmium-zinc-telluride equilibrium radionuclilde angiocardiography (CZT-ERNA) and gated positron emission tomography myocardial perfusion imaging (PET-MPI) under identical volumes and heart-rate settings. Computed tomography (CT) served as the reference for end-diastolic volume (EDV) and end-systolic volume (ESV). LVEF was derived from these volumes for all modalities. We also assessed the impact of phantom position relative to detectors, as well as the effect of attenuation correction via a thorax phantom.Results CZT-ERNA overestimated static LV volumes relative to CT, whereas PET-MPI underestimated them. Both modalities underestimated LVEF compared with CT-derived values, with a larger bias for PET-MPI. On PET-MPI, attenuation correction produced similar volumes with and without the thorax phantom. CZT-ERNA volumes decreased as detector distance increased.Conclusion Under controlled phantom conditions, CZT-ERNA and PET-MPI show inverse biases for LV volumes and both underestimated LVEF versus CT. These findings point to the influence of reconstruction and contouring algorithms, attenuation correction, and camera positioning. The dynamic phantom enables direct comparison of perfusion- and blood-pool-based measurements and may support modality-specific calibration when translating absolute values across techniques.

We investigated the feasibility of using a dopamine transporter (DaT) tracer ligand ([123I]FP-CIT) along with novel multi-pinhole brain collimators for dynamic brain single photon emission computed tomography (SPECT) in suspected Parkinson's disease patients. Thirteen patients underwent dynamic tracer acquisitions before standard imaging. Uptake values were corrected for partial volume effects. Specific binding ratio (SBRcalc) was calculated, reflecting binding potential relative to non-displaceable binding (BPND) in the cortex. Additional pharmacokinetic parameters (BPND, R1, k2) were estimated using the simplified reference tissue model, revealing differences between Kahraman low-score (LS) and high-score (HS) groups. Results showed increasing striatal tracer uptake until 100 min post-injection, with consistent values afterward. Uptake and SBRcalc ratios matched visual assessment. LS patients had lower putamen than caudate nucleus tracer uptake, decreased BPND values, while R1 and k2 values were comparable to HS patients. In conclusion, dynamic multi-pinhole SPECT using DaT tracer with the extraction of pharmacokinetic parameters is feasible and could help enable early differentiation of reduced and normal DaT values.

Abstract Background Heart failure due to myocardial infarction (MI) involves fibrosis driven by epicardium‐derived cells (EPDCs) and cardiac fibroblasts, but strategies to inhibit and provide cardio‐protection remains poor. The imprinted gene, non‐canonical NOTCH ligand 1 (Dlk1), has previously been shown to mediate fibrosis in the skin, lung and liver, but very little is known on its effect in the heart. Methods Herein, human pericardial fluid/plasma and tissue biopsies were assessed for DLK1, whereas the spatiotemporal expression of Dlk1 was determined in mouse hearts. The Dlk1 heart phenotype in normal and MI hearts was assessed in transgenic mice either lacking or overexpressing Dlk1. Finally, in/ex vivo cell studies provided knowledge on the molecular mechanism. Results Dlk1 was demonstrated in non‐myocytes of the developing human myocardium but exhibited a restricted pericardial expression in adulthood. Soluble DLK1 was twofold higher in pericardial fluid (median 45.7 [34.7 (IQR)) μg/L] from cardiovascular patients (n = 127) than in plasma (median 26.1 μg/L [11.1 (IQR)]. The spatial and temporal expression pattern of Dlk1 was recapitulated in mouse and rat hearts. Similar to humans lacking Dlk1, adult Dlk1−/− mice exhibited a relatively mild developmental, although consistent cardiac phenotype with some abnormalities in heart size, shape, thorax orientation and non‐myocyte number, but were functionally normal. However, after MI, scar size was substantially reduced in Dlk1−/− hearts as compared with Dlk1+/+ littermates. In line, high levels of Dlk1 in transgenic mice Dlk1fl/flxWT1GFPCre and Dlk1fl/flxαMHCCre/+Tam increased scar size following MI. Further mechanistic and cellular insight demonstrated that pericardial Dlk1 mediates cardiac fibrosis through epithelial to mesenchymal transition (EMT) of the EPDC lineage by maintaining Integrin β8 (Itgb8), a major activator of transforming growth factor β and EMT. Conclusions Our results suggest that pericardial Dlk1 embraces a, so far, unnoticed role in the heart augmenting cardiac fibrosis through EMT. Monitoring DLK1 levels as well as targeting pericardial DLK1 may thus offer new venues for cardio‐protection.

Neuroimaging holds an essential position in global healthcare, as brain-related disorders are a substantial and growing burden. Non-degenerative disorders such as stress, depression and anxiety share common function related traits of diffuse and fluctuating changes, such as change in brain-based functions of mood, behavior and cognitive abilities, where underlying physiological mechanism remain unresolved. In this study we developed a novel application for studying intra-subject task-activated brain function by the quantitative physiological measurement of the change in glucose metabolism in a single scan setup. Data were acquired on a PET/MR-scanner. We implemented a functional [18F]-FDG PET-scan with double boli-tracer administration and finger-tapping activation, as proof-of-concept, in five healthy participants. The [18F]-FDG data were analyzed using a two-tissue compartment double boli kinetic model with an image-derived input function. For stand-alone visual reference, blood oxygenation level dependent (BOLD) functional MRI (fMRI) was acquired in the same session and analyzed separately. We were able to measure the cerebral glucose metabolic rate during baseline as well as activation. Results showed increased glucose metabolic rate during activation by 36.3–87.9% mean 62.0%, locally in the peak seed region of M1 in the brain, on an intra-subject level, as well as very good spatial accuracy on group level, and localization compared to the BOLD fMRI result at subject and group level. Our novel method successfully determined the relative increase in the cerebral metabolic rate of glucose on a voxel level with good visual association to fMRI at the subject-level, holding promise for future individual clinical application. This approach will be easily adapted in future clinical perspectives and pharmacological interventions studies.

Lymphedema is a common complication following breast cancer treatment with axillary lymphadenectomy and radiotherapy. Currently, there is no curative treatment for this disease, hence there is a need for new therapeutic suggestions. The aim of this study was to investigate the effect of hyaluronidase (HYAL) injections after inducing hindlimb lymphedema in 36 female C57BL/6 mice. HYAL injections were administered every second day for 14 days in three groups: (1) HYAL for 1 week followed by saline for 1 week, (2) HYAL for 2 weeks, and (3) saline injections for 2 weeks. Volume of the lymphedema limb was weekly assessed with micro-computed tomography (μ-CT) scans for a total course of 6 weeks. Lymph vessel morphometry was assessed in the end of the study after staining cross-sections of the hindlimb for anti-LYVE-1 blindly. Lymphatic function was assessed by lymphoscintigraphy to assess lymphatic clearance. There was a significant reduction of the volume of lymphedema in mice treated with HYAL-7 compared with mice treated with HYAL-14 (p < 0.05) and saline (p < 0.05). No differences were detected in lymph vessel morphometry and the lymphoscintigraphy between groups. Short-term treatment with HYAL-7 might be a potential therapeutic suggestion for secondary lymphedema induced in mouse hindlimbs. In the future, clinical studies are needed to investigate the potential of HYAL treatment in human beings.

Background Imaging of idiopathic inflammatory myopathies (IIMs) is challenging, and no pathognomonic signs exist. Different tracers have been tested for this purpose, mainly inflammation markers including technetium-99m-pyrophosphate (PYP). We aimed to examine the utility of fluorine-18-fluorodeoxyglucose (FDG) relative to PYP in idiopathic inflammatory myopathy (IIM). Methods Using visual grading and CT-guided muscular segmentation and standardized uptake values (SUVs), we assessed muscular tracer uptake qualitatively and quantitatively, comparing FDG uptake in eight patients with recent-onset IIM and 24 healthy control persons and FDG and PYP uptake in seven patients. Results Muscular FDG and PYP uptake was increased in all patients. However, uptake distribution and signal intensity differed considerably. FDG scans revealed clear involvement of certain muscle groups including core and swallowing muscles and, in addition, abnormality in diseased extra-muscular organs. PYP was mainly visible in bones, whereas muscular PYP uptake was generally discrete and primarily located in the extremities. Quantitatively, FDG uptake was significantly higher in patients than in controls; the volume-weighted SUVmean for all right-side muscles was 0.84 versus 0.60 g/ml (95% confidence interval (CI) for mean difference 0.14–0.34, p = 0.0001). FDG SUVmean values were up to four times higher than PYP mean values in upper limb muscles (95% CI for the mean ratio 2.37–3.77, p = 0.0004) and two–three times higher in lower limb muscles (95% CI for the mean ratio 2.28–2.71, p < 0.0001). Conclusions Muscular FDG uptake was higher in treatment-naïve IIM patients than in healthy controls and more distinct than PYP uptake in patients with a potential to reveal extra-muscular IIM involvement and malignancy. Thus, FDG appears to be superior to PYP in the diagnostic evaluation of IIM.

1124 Objectives: To evaluate the performance of a novel clinical multi-pinhole (MPH) brain SPECT system based on a hypothesis of superior image quality compared to traditional parallel hole low energy high resolution (LEHR) collimators. Methods: We conducted the study using a triple-head SPECT scanner from Mediso Medical Imaging Systems equipped with novel MPH collimators designed for high resolution and high sensitivity brain imaging. Each collimator plate made of 18 mm tungsten had 30 pinhole apertures creating overlapping and non-overlapping projections. We first measured spatial sensitivity using a Tc-99m point source. By moving the point source within the entire scanner field of view one position at a time, we established a complete sensitivity curve in both axial- and transaxial- direction. Second, using a mini Derenzo phantom with rod diameters of 2 to 7 mm, we assessed the spatial resolution visually. Third, we evaluated the quality of scatter correction with an I-123 line source placed in a 15 cm diameter water cylinder. From the reconstructed images, we calculated the scatter fraction as the fraction of counts within the water volume divided by counts within the central part containing the line source. All measurements were repeated on a dual-head Siemens Symbia SPECT scanner mounted with parallel hole LEHR collimators for comparison. Finally, a patient suspected of having Parkinson’s disease underwent a DaTSCAN. A 15 min SPECT-CT MPH acquisition was performed 2.5 h after injection of 150 MBq I-123-FP-CIT, followed immediately by a 32 min LEHR dual-headed SPECT-CT acquisition 3 h p.i. All MPH acquisitions used a 20% energy window on the Tc-99m or I-123 primary energy peak, respectively. Reconstruction of the MPH scans was performed with both attenuation and scatter correction using a Monte Carlo-based algorithm simulating both aperture and scatter medium. Dual-headed LEHR acquisitions collected data from a 15% energy window; reconstructions applied attenuation correction, scatter correction and resolution recovery. Scatter correction of the LEHR acquisitions was based on window subtraction of adjacent windows; for Tc-99m we applied a dual energy window procedure and for I-123 a triple window procedure. Results: Peak spatial sensitivity of the MPH system was 700 cps/MBq compared to 180 cps/MBq for the dual-headed LEHR. The MPH spatial resolution images revealed visible rods with 5 mm diameter whereas the on LEHR images rods of 7 mm were only partially visible. The scatter fraction from the MPH acquisition was 0.3% compared to 33.2% from the LEHR acquisition. The MPH patient scan visually revealed a higher image quality in terms of better delineation of the striatum and higher image contrast between cerebral cortical regions and the brain ventricles compared to LEHR scan. Conclusions: The image quality in terms of sensitivity, resolution and scatter fraction was evaluated. In the central field of view, the MPH sensitivity was 3.9 times higher than conventional LEHR imaging. Spatial resolution was significantly improved. Elimination of scatter from the higher energy peaks of I-123 yields images of high quantitative value. Patient scan suggested that the dedicated MPH system visually improves image quality with reduced imaging duration. The novel MPH system has great potential to improve image quality of brain SPECT examinations.

Objective: Abdominal aortic aneurysm (AAA) is a common age-related vascular disease characterized by progressive weakening and dilatation of the aortic wall. Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix (ECM) protein involved in the induction of vascular remodeling. This study aimed to investigate if MFAP4 facilitates the development of AAA and characterize the underlying MFAP4-mediated mechanisms.Approach and Results: Double apolipoprotein E- and Mfap4-deficient (ApoE−/−Mfap4−/−) and control apolipoprotein E-deficient (ApoE−/−) mice were infused subcutaneously with angiotensin II (Ang II) for 28 days. Mfap4 expression was localized within the adventitial and medial layers and was upregulated after Ang II treatment. While Ang II-induced blood pressure increase was independent of Mfap4 genotype, ApoE−/−Mfap4−/− mice exhibited significantly lower AAA incidence and reduced maximal aortic diameter compared to ApoE−/− littermates. The ApoE−/−Mfap4−/− AAAs were further characterized by reduced macrophage infiltration, matrix metalloproteinase (MMP)-2 and MMP-9 activity, proliferative activity, collagen content, and elastic membrane disruption. MFAP4 deficiency also attenuated activation of integrin- and TGF-β-related signaling within the adventitial layer of AAA tissues. Finally, MFAP4 stimulation promoted human monocyte migration and significantly upregulated MMP-9 activity in macrophage-like THP-1 cells.Conclusion: This study demonstrates that MFAP4 induces macrophage-rich inflammation, MMP activity, and maladaptive remodeling of the ECM within the vessel wall, leading to an acceleration of AAA development and progression. Collectively, our findings suggest that MFAP4 is an essential aggravator of AAA pathology that acts through regulation of monocyte influx and MMP production.

Background: Lymphedema is one of the most common complications following breast cancer. Axillary lymph node dissection and radiotherapy are two well-known risk factors resulting in either removal or damage to the lymph nodes. As stem cells are known for their regenerative capabilities, they could theoretically repair/restore the damaged lymph vessels leading to a decrease in lymphedema. Methods: We evaluated the treatment of SVF and ASC on a mouse lymphedema model. Forty-five mice were allocated into three groups containing 15 mice each. The SVF group was injected with 100 mu l containing 1 x 10(6) SVF, the ASC group with 100 mu l ml containing 1 x 10(6) ASC and the NS with 100 mu l ml of NS. Volumes of the mice were assessed weekly by mu CT hindlimb volumetry for a total of 8 weeks. Lymph vessel morphometry was assessed by cross-sections of both hindlimbs stained for anti-LYVE1. Lymphatic function was assessed by lymphatic clearance. Results: The volume change between the groups was non-significant throughout all 8 weeks. The immunohistochemistry showed a statistically significant difference between the hindlimbs in ASC vs. NS group p= 0.032, 95% CI [-2121, -103]. Conclusion: The volume of the hindlimbs showed that treatment with SVF or ASC yielded very similar results compared to the control group when assessed after 8 weeks. In week two the biggest difference between ASC and NS was seen but the difference diminished during the 8 weeks. The secondary outcomes showed that the lymph vessel lumen decreased when treated with ASC compared to the control group. Lymphoscintigraphy yielded non-significant results.

BACKGROUND:Breast cancer-related lymphedema (BCRL) is a feared late complication. Treatment options are lacking at present. Recent studies have suggested that mesenchymal stromal cells can alleviate lymphedema. Herein, we report the results from the first human pilot study with adipose-derived regenerative cells (ADRCs) for treating BCRL with 1 year of follow-up.MATERIAL AND METHODS:We included 10 patients with BCRL. ADRCs were injected directly into the axillary region together with a scar-releasing fat grafting procedure. Primary endpoint was change in arm volume. Secondary endpoints were change in patient-reported outcomes, changes in lymph flow, and safety.RESULTS:During follow-up, no significant change in volume was noted. Patient-reported outcomes improved significantly with time. Five patients reduced their use of conservative management. Quantitative lymphoscintigraphy did not improve on the lymphedema-affected arms. ADRCs were well tolerated, and only minor transient adverse events related to liposuction were noted.CONCLUSIONS:In this pilot study, a single injection of ADRCs improved lymphedema based on patient-reported outcome measures, and there were no serious adverse events during the follow-up period. Lymphoscintigraphic evaluation showed no improvement after ADRC treatment. There was no change in excess arm volume. Results of this trial need to be confirmed in randomized clinical trials.

Background: The imprinted gene Delta like non-canonical Notch ligand 1 (Dlk1) is considered an inhibitor of adipogenesis, but its in vivo impact on fat mass indeed remains elusive and controversial. Methods: Fat deposits were assessed by MRI and DXA scanning in two cohorts of non-diabetic men, whereas glucose disposal rate (GDR) was determined during euglycemic hyperinsulinemic clamp. Blood analyte measurements were used for correlation and mediation analysis to investigate how age, BMI, and fat percentage affect the relation between DLK1 and GDR. Confirmatory animal studies performed in normal (NC) and high fat diet (HFD) fed Dlk1(+/+) and Dlk1(-/-) mice included DXA scanning, glucose tolerance tests (GTTs), blood measurements, and skeletal muscle glucose uptake studies by positron emission tomography (PET), histology, qRT-PCR. and in vitro cell studies. Findings: Overall, DLK1 is positively correlated with fat amounts, which is consistent with a negative linear relationship between DLK1 and GDR. This relationship is not mediated by age, BMI, or fat percentage. In support, DLK1 also correlates positively with HOMA-IR and ADIPO-IR in these humans, but has no linear relationship with the early diabetic inflammation marker MCP-1. In Dlk1(-/-) mice, the increase in fat percentage and adipocyte size induced by HFD is attenuated, and these animals are protected against insulin resistance. These Dlk1 effects seem independent of gluconeogenesis, but at least partly relies on increased in vivo glucose uptake in skeletal muscles by Dlk1 regulating the major glucose transporter Glut4 in vivo as well as in two independent cell lines. Interpretation: Thus, instead of an adipogenic inhibitor. Dlk1 should be regarded as a factor causally linked to obesity and insulin resistance, and may be used to predict development of type 2 diabetes. (C) 2019 The Authors. Published by Elsevier B.V.

BACKGROUND:Lymphoscintigraphy is commonly used to assess breast cancer-related lymphedema. However, a reliable quantitative method that clearly distinguishes normal lymphatic function from lymphedema is desired. We propose a quantitative method based upon the physiological mean transit time (MTT) measure of lymph fluid passing through the arm.METHODS AND RESULTS:Eleven patients, aged 34-68 years, with unilateral arm lymphedema following breast cancer treatment underwent simultaneous bilateral lymphoscintigraphy using intradermal injection of 99mTc-labeled human serum albumin (HSA). Imaging was performed at 30-45 minute intervals for 5 hours. Time activity curves from each injection site and each arm region were recorded. The input into the arm region was obtained as the (minus) time derivative of the injection site activity curve. In the proposed model the arm activity curve was considered to arise from the convolution of the retention function and the input function. The retention function was obtained by fitting the calculated arm activity curve to the measured arm activity curve. The MTT of activity passing through the arm was calculated as the time integral of the resulting retention function. All measured time activity curves were well described by the model. The MTT of the lymphedema arm (mean 60.1 minutes, range 22-105 minutes) was markedly different from that of the contralateral normal arm (mean 5.4 minutes, range 1.2-8.7 minutes), p < 0.0001.CONCLUSION:The proposed model showed great similarity with measured time activity curves and was capable of quantitatively distinguishing lymphatic function of the lymphedema arm from that of the normal arm in terms of calculated MTT.