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Background: Prior studies suggested that canonical Activin Receptor II (ActRII) and BMP receptor (BMPR) ligands can have opposing, distinct effects on skeletal muscle depending in part on differential downstream SMAD activation. It was therefore of interest to test ActRII ligands versus BMP ligands in settings of muscle differentiation and in vivo. Methods and results: In human skeletal muscle cells, both ActRII ligands and BMP ligands inhibited myogenic differentiation: ActRII ligands in a SMAD2/3-dependent manner, and BMP ligands via SMAD1/5. Surprisingly, a neutralizing ActRIIA/B antibody mitigated the negative effects of both classes of ligands, indicating that some BMPs act at least partially through the ActRII receptors in skeletal muscle. Gene expression analysis showed that both ActRII and BMP ligands repress muscle differentiation genes in human myoblasts and myotubes. In mice, hepatic BMP9 over-expression induced liver toxicity, caused multi-organ wasting, and promoted a pro-atrophy gene signature despite elevated SMAD1/5 signaling in skeletal muscle. Local overexpression of BMP7 or BMP9, achieved by intramuscular AAV delivery, induced heterotopic ossification. Elevated SMAD1/5 signaling with increased expression of BMP target genes was also observed in sarcopenic muscles of old rats. Conclusions: The canonical ActRII ligand-SMAD2/3 and BMP ligand-SMAD1/5 axes can both block human myoblast differentiation. Our observations further demonstrate the osteoinductive function of BMP ligands while pointing to a potential relevancy of blocking the BMP-SMAD1/5 axis in the setting of therapeutic anti-ActRIIA/B inhibition. [ABSTRACT FROM AUTHOR]

Purpose: Cardiac perfusion PET data can be reconstructed as a dynamic sequence and kinetic modeling performed to quantify myocardial blood flow, or reconstructed as static gated images to quantify function. Parametric images from dynamic PET are conventionally not gated, to allow use of all events with lower noise. An alternative method for dynamic PET is to incorporate the kinetic model into the reconstruction algorithm itself, bypassing the generation of a time series of emission images and directly producing parametric images. So‐called “direct reconstruction” can produce parametric images with lower noise than the conventional method because the noise distribution is more easily modeled in projection space than in image space. In this work, we develop direct reconstruction of cardiac‐gated parametric images for 82Rb PET with an extension of the Parametric Motion compensation OSEM List mode Algorithm for Resolution‐recovery reconstruction for the one tissue model (PMOLAR‐1T). Methods: PMOLAR‐1T was extended to accommodate model terms to account for spillover from the left and right ventricles into the myocardium. The algorithm was evaluated on a 4D simulated 82Rb dataset, including a perfusion defect, as well as a human 82Rb list mode acquisition. The simulated list mode was subsampled into replicates, each with counts comparable to one gate of a gated acquisition. Parametric images were produced by the indirect (separate reconstructions and modeling) and direct methods for each of eight low‐count and eight normal‐count replicates of the simulated data, and each of eight cardiac gates for the human data. For the direct method, two initialization schemes were tested: uniform initialization, and initialization with the filtered iteration 1 result of the indirect method. For the human dataset, event‐by‐event respiratory motion compensation was included. The indirect and direct methods were compared for the simulated dataset in terms of bias and coefficient of variation as a function of iteration. Results: Convergence of direct reconstruction was slow with uniform initialization; lower bias was achieved in fewer iterations by initializing with the filtered indirect iteration 1 images. For most parameters and regions evaluated, the direct method achieved the same or lower absolute bias at matched iteration as the indirect method, with 23%–65% lower noise. Additionally, the direct method gave better contrast between the perfusion defect and surrounding normal tissue than the indirect method. Gated parametric images from the human dataset had comparable relative performance of indirect and direct, in terms of mean parameter values per iteration. Changes in myocardial wall thickness and blood pool size across gates were readily visible in the gated parametric images, with higher contrast between myocardium and left ventricle blood pool in parametric images than gated SUV images. Conclusions: Direct reconstruction can produce parametric images with less noise than the indirect method, opening the potential utility of gated parametric imaging for perfusion PET. [ABSTRACT FROM AUTHOR]

Background: We quantified myocardial blood flow with Rb PET using parameters of the generalized Renkin-Crone model estimated from Rb and O-water images reconstructed with time-of-flight and point spread function modeling. Previous estimates of rubidium extraction have used older-generation scanners without time-of-flight or point spread function modeling. We validated image-derived input functions with continuously collected arterial samples. Methods: Nine healthy subjects were scanned at rest and under pharmacological stress on the Siemens Biograph mCT with Rb and O-water PET, undergoing arterial blood sampling with each scan. Image-derived input functions were estimated from the left ventricle cavity and corrected with tracer-specific population-based scale factors determined from arterial data. Kinetic parametric images were generated from the dynamic PET images by fitting the one-tissue compartment model to each voxel's time activity curve. Mean myocardial blood flow was determined from each subject's O-water k images. The parameters of the generalized Renkin-Crone model were estimated from these water-based flows and mean myocardial Rb K estimates. Results: Image-derived input functions showed improved agreement with arterial measurements after a scale correction. The Renkin-Crone model fit ( a = 0.77, b = 0.39) was similar to those previously published, though b was lower. Conclusions: We have presented parameter estimates for the generalized Renkin-Crone model of extraction for Rb PET using human Rb and O-water PET from high-resolution images using a state-of-the-art time-of-flight-capable scanner. These results provide a state-of-the-art methodology for myocardial blood flow measurement with Rb PET. [ABSTRACT FROM AUTHOR]

Positron emission tomography (PET) imaging with the glucose analog 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F] FDG) has demonstrated clinical utility for the monitoring of brain glucose metabolism alteration in progressive neurodegenerative diseases. We examined dynamic [(18)F]FDG PET imaging and kinetic modeling of atlas-based regions to evaluate regional changes in the cerebral metabolic rate of glucose in the widely-used 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease. Following a bolus injection of 18.5 ± 1 MBq [(18)F]FDG and a 60-minute PET scan, image-derived input functions from the vena cava and left ventricle were used with three models, including Patlak graphical analysis, to estimate the influx constant and the metabolic rate in ten brain regions. We observed statistically significant changes in [(18)F]FDG uptake ipsilateral to the 6-OHDA injection in the basal ganglia, olfactory bulb, and amygdala regions; and these changes are of biological relevance to the disease. These experiments provide further validation for the use of [(18)F]FDG PET imaging in this model for drug discovery and development.