Magnetic resonance imaging techniques for the quantitative analysis of skeletal muscle: State of the art.

Background: Magnetic resonance imaging (MRI) is the dominant 3D imaging modality to quantify muscle properties in skeletal muscle disorders, in inherited and acquired muscle diseases, and in sarcopenia, in cachexia and frailty. Methods: This review covers T1 weighted and Dixon sequences, introduces T2 mapping, diffusion tensor imaging (DTI) and non-proton MRI. Technical concepts, strengths, limitations and translational aspects of these techniques are discussed in detail. Examples of clinical applications are outlined. For comparison 31P-and 13C-MR Spectroscopy are also addressed. Results: MRI technology provides a rich toolset to assess muscle deterioration. In addition to classical measures such as muscle atrophy using T1 weighted imaging and fat infiltration using Dixon sequences, parameters characterizing inflammation from T2 maps, tissue sodium using non-proton MRI techniques or concentration or fiber architecture using diffusion tensor imaging may be useful for an even earlier diagnosis of the impairment of muscle quality. Conclusion: Quantitative MRI provides new options for muscle research and clinical applications. Current limitations that also impair its more widespread use in clinical trials are lack of standardization, ambiguity of image segmentation and analysis approaches, a multitude of outcome parameters without a clear strategy which ones to use and the lack of normal data.

Multimodal Positron Emission Tomography Imaging to Quantify Uptake of 89Zr-Labeled Liposomes in the Atherosclerotic Vessel Wall.

Nanotherapy has recently emerged as an experimental treatment option for atherosclerosis. To fulfill its promise, robust noninvasive imaging approaches for subject selection and treatment evaluation are warranted. To that end, we present here a positron emission tomography (PET)-based method for quantification of liposomal nanoparticle uptake in the atherosclerotic vessel wall. We evaluated a modular procedure to label liposomal nanoparticles with the radioisotope zirconium-89 (89Zr). Their biodistribution and vessel wall targeting in a rabbit atherosclerosis model was evaluated up to 15 days after intravenous injection by PET/computed tomography (CT) and PET/magnetic resonance imaging (PET/MRI). Vascular permeability was assessed in vivo using three-dimensional dynamic contrast-enhanced MRI (3D DCE-MRI) and ex vivo using near-infrared fluorescence (NIRF) imaging. The 89Zr-radiolabeled liposomes displayed a biodistribution pattern typical of long-circulating nanoparticles. Importantly, they markedly accumulated in atherosclerotic lesions in the abdominal aorta, as evident on PET/MRI and confirmed by autoradiography, and this uptake moderately correlated with vascular permeability. The method presented herein facilitates the development of nanotherapy for atherosclerotic disease as it provides a tool to screen for nanoparticle targeting in individual subjects' plaques.

Multi institutional quantitative phantom study of yttrium-90 PET in PET/MRI: the MR-QUEST study.

BACKGROUND: Yttrium-90 (90Y) radioembolization involves the intra-arterial delivery of radioactive microspheres to treat hepatic malignancies. Though this therapy involves careful pre-treatment planning and imaging, little is known about the precise location of the microspheres once they are administered. Recently, there has been growing interest post-radioembolization imaging using positron-emission tomography (PET) for quantitative dosimetry and identifying lesions that may benefit from additional salvage therapy. In this study, we aim to measure the inter-center variability of 90Y PET measurements as measured on PET/MRI in preparation for a multi-institutional prospective phase I/II clinical trial. Eight institutions participated in this study and followed a standardized phantom filling and imaging protocol. The NEMA NU2-2012 body phantom was filled with 3 GBq of 90Y chloride solution. The phantom was imaged for 30 min in listmode on a Siemens Biograph mMR non-TOF PET/MRI scanner at five time points across 10 days (0.3-3.0 GBq). Raw PET data were sent to a central site for image reconstruction and data analysis. Images were reconstructed with optimal parameters determined from a previous study. Volumes of interest (VOIs) matching the known sphere diameters were drawn on the vendor-provided attenuation map and propagated to the PET images. Recovery coefficients (RCs) and coefficient of variation of the RCs (COV) were calculated from these VOIs for each sphere size and activity level. RESULTS: Mean RCs ranged from 14.5 to 75.4%, with the lowest mean RC coming from the smallest sphere (10 mm) on the last day of imaging (0.16 MBq/ml) and the highest mean RC coming from the largest sphere (37 mm) on the first day of imaging (2.16 MBq/ml). The smaller spheres tended to exhibit higher COVs. In contrast, the larger spheres tended to exhibit lower COVs. COVs from the 37 mm sphere were < 25.3% in all scans. For scans with ≥ 0.60 MBq/ml, COVs were ≤ 25% in spheres ≥ 22 mm. However, for all other spheres sizes and activity levels, COVs were usually > 25%. CONCLUSIONS: Post-radioembolization dosimetry of lesions or other VOIs ≥ 22 mm in diameter can be consistently obtained (< 25% variability) at a multi-institutional level using PET/MRI for any clinically significant activity for 90Y radioembolization.

Combined PET/DCE-MRI in a Rabbit Model of Atherosclerosis: Integrated Quantification of Plaque Inflammation, Permeability, and Burden During Treatment With a Leukotriene A4 Hydrolase Inhibitor.

OBJECTIVES: The authors sought to develop combined positron emission tomography (PET) dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) to quantify plaque inflammation, permeability, and burden to evaluate the efficacy of a leukotriene A4 hydrolase (LTA4H) inhibitor in a rabbit model of atherosclerosis. BACKGROUND: Multimodality PET/MRI allows combining the quantification of atherosclerotic plaque inflammation, neovascularization, permeability, and burden by combined 18F-fluorodeoxyglucose (18F-FDG) PET, DCE-MRI, and morphological MRI. The authors describe a novel, integrated PET-DCE/MRI protocol to noninvasively quantify these parameters in aortic plaques of a rabbit model of atherosclerosis. As proof-of-concept, the authors apply this protocol to assess the efficacy of the novel LTA4H inhibitor BI691751. METHODS: New Zealand White male rabbits (N = 49) were imaged with integrated PET-DCE/MRI after atherosclerosis induction and 1 and 3 months after randomization into 3 groups: 1) placebo; 2) high-dose BI691751; and 3) low-dose BI691751. All animals were euthanized at the end of the study. RESULTS: Among the several metrics that were quantified, only maximum standardized uptake value and target-to-background ratio by 18F-FDG PET showed a modest, but significant, reduction in plaque inflammation in rabbits treated with low-dose BI691751 (p = 0.03), whereas no difference was detected in the high-fat diet and in the high-dose BI691751 groups. No differences in vessel wall area by MRI and area under the curve by DCE-MRI were detected in any of the groups. No differences in neovessel and macrophage density were found at the end of study among groups. CONCLUSIONS: The authors present a comprehensive, integrated 18F-FDG PET and DCE-MRI imaging protocol to noninvasively quantify plaque inflammation, neovasculature, permeability, and burden in a rabbit model of atherosclerosis on a simultaneous PET/MRI scanner. A modest reduction was found in plaque inflammation by 18F-FDG PET in the group treated with a low dose of the LTA4H inhibitor BI691751.

Optimization of yttrium-90 PET for simultaneous PET/MR imaging: A phantom study.

PURPOSE: Positron emission tomography (PET) imaging of yttrium-90 in the liver post radioembolization has been shown useful for personalized dosimetry calculations and evaluation of extrahepatic deposition. The purpose of this study was to quantify the benefits of several MR-based data correction approaches offered by using a combined PET/MR system to improve Y-90 PET imaging. In particular, the feasibility of motion and partial volume corrections were investigated in a controlled phantom study. METHODS: The ACR phantom was filled with an initial concentration of 8 GBq of Y-90 solution resulting in a contrast of 10:1 between the hot cylinders and the background. Y-90 PET motion correction through motion estimates from MR navigators was evaluated by using a custom-built motion stage that simulated realistic amplitudes of respiration-induced liver motion. Finally, the feasibility of an MR-based partial volume correction method was evaluated using a wavelet decomposition approach. RESULTS: Motion resulted in a large (∼40%) loss of contrast recovery for the 8 mm cylinder in the phantom, but was corrected for after MR-based motion correction was applied. Partial volume correction improved contrast recovery by 13% for the 8 mm cylinder. CONCLUSIONS: MR-based data correction improves Y-90 PET imaging on simultaneous PET/MR systems. Assessment of these methods must be studied further in the clinical setting.

In Vivo PET Imaging of HDL in Multiple Atherosclerosis Models.

OBJECTIVES: The goal of this study was to develop and validate a noninvasive imaging tool to visualize the in vivo behavior of high-density lipoprotein (HDL) by using positron emission tomography (PET), with an emphasis on its plaque-targeting abilities. BACKGROUND: HDL is a natural nanoparticle that interacts with atherosclerotic plaque macrophages to facilitate reverse cholesterol transport. HDL-cholesterol concentration in blood is inversely associated with risk of coronary heart disease and remains one of the strongest independent predictors of incident cardiovascular events. METHODS: Discoidal HDL nanoparticles were prepared by reconstitution of its components apolipoprotein A-I (apo A-I) and the phospholipid 1,2-dimyristoyl-sn-glycero-3-phosphocholine. For radiolabeling with zirconium-89 ((89)Zr), the chelator deferoxamine B was introduced by conjugation to apo A-I or as a phospholipid-chelator (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-deferoxamine B). Biodistribution and plaque targeting of radiolabeled HDL were studied in established murine, rabbit, and porcine atherosclerosis models by using PET combined with computed tomography (PET/CT) imaging or PET combined with magnetic resonance imaging. Ex vivo validation was conducted by radioactivity counting, autoradiography, and near-infrared fluorescence imaging. Flow cytometric assessment of cellular specificity in different tissues was performed in the murine model. RESULTS: We observed distinct pharmacokinetic profiles for the two (89)Zr-HDL nanoparticles. Both apo A-I- and phospholipid-labeled HDL mainly accumulated in the kidneys, liver, and spleen, with some marked quantitative differences in radioactivity uptake values. Radioactivity concentrations in rabbit atherosclerotic aortas were 3- to 4-fold higher than in control animals at 5 days' post-injection for both (89)Zr-HDL nanoparticles. In the porcine model, increased accumulation of radioactivity was observed in lesions by using in vivo PET imaging. Irrespective of the radiolabel's location, HDL nanoparticles were able to preferentially target plaque macrophages and monocytes. CONCLUSIONS: (89)Zr labeling of HDL allows study of its in vivo behavior by using noninvasive PET imaging, including visualization of its accumulation in advanced atherosclerotic lesions. The different labeling strategies provide insight on the pharmacokinetics and biodistribution of HDL's main components (i.e., phospholipids, apo A-I).

Attenuation Correction for Magnetic Resonance Coils in Combined PET/MR Imaging: A Review.

With the introduction of clinical PET/magnetic resonance (MR) systems, novel attenuation correction methods are needed, as there are no direct MR methods to measure the attenuation of the objects in the field of view (FOV). A unique challenge for PET/MR attenuation correction is that coils for MR data acquisition are located in the FOV of the PET camera and could induce significant quantitative errors. In this review, current methods and techniques to correct for the attenuation of a variety of coils are summarized and evaluated.

Simultaneous carotid PET/MR: feasibility and improvement of magnetic resonance-based attenuation correction.

Errors in quantification of carotid positron emission tomography (PET) in simultaneous PET/magnetic resonance (PET/MR) imaging when not incorporating bone in MR-based attenuation correction (MRAC) maps, and possible solutions, remain to be fully explored. In this study, we demonstrated techniques to improve carotid vascular PET/MR quantification by adding a bone tissue compartment to MRAC maps and deriving continuous Dixon-based MRAC (MRACCD) maps. We demonstrated the feasibility of applying ultrashort echo time-based bone segmentation and generation of continuous Dixon MRAC to improve PET quantification on five subjects. We examined four different MRAC maps: system standard PET/MR MRAC map (air, lung, fat, soft tissue) (MRACPET/MR), standard PET/MR MRAC map with bone (air, lung, fat, soft tissue, bone) (MRACPET/MRUTE), MRACCD map (no bone) and continuous Dixon-based MRAC map with bone (MRACCDUTE). The same PET emission data was then reconstructed with each respective MRAC map and a CTAC map (PETPET/MR, PETPET/MRUTE, PETCD, PECDUTE) to assess effects of the different attenuation maps on PET quantification in the carotid arteries and neighboring tissues. Quantitative comparison of MRAC attenuation values for each method compared to CTAC showed small differences in the carotid arteries with UTE-based segmentation of bone included and/or continuous Dixon MRAC; however, there was very good correlation for all methods in the voxel-by-voxel comparison. ROI-based analysis showed a similar trend in the carotid arteries with the lowest correlation to PETCTAC being PETPETMR and the highest correlation to PETCTAC being PETCDUTE. We have demonstrated the feasibility of applying UTE-based segmentation and continuous Dixon MRAC maps to improve carotid PET/MR vascular quantification.

Feasibility of (18)F-Fluorodeoxyglucose radiotracer dose reduction in simultaneous carotid PET/MR imaging.

The purpose of this study was to develop and validate low dose (18)F-FDG-PET acquisition protocols for detection of inflamed carotid plaques specifically for simultaneous PET/MR imaging. The hypothesis was that increasing the duration of the PET acquisition to match that of the MR acquisition might allow for the use of lower levels of the radiotracer, while preserving quantification and image quality. Seven subjects were scanned twice at least one week apart on a simultaneous PET/MR scanner using either the standard clinical dose of (18)F-FDG (373 ± 63 MBq) for 8 minutes or a low dose (93 ± 17 MBq) for 75 minutes. A maximum absolute percent difference of only 4.17% and 7.49% in the left and right carotid TBR was found between the standard dose and four time points of the low dose acquisitions (8, 24, 45, 75 minutes). Only the 8-minute low dose PET data was significantly different in terms of SNR (P = 0.009; % difference = -51%) and qualitative image quality evaluation (P = 0.0005; % difference = -45%). Our preliminary findings indicate that up to 75% reduction of the clinical standard (18)F-FDG dose could be achieved using the proposed acquisition scheme while maintaining accurate quantification and SNR.

Quantitative carotid PET/MR imaging: clinical evaluation of MR-Attenuation correction versus CT-Attenuation correction in (18)F-FDG PET/MR emission data and comparison to PET/CT.

Current PET/MR systems employ segmentation of MR images and subsequent assignment of empirical attenuation coefficients for quantitative PET reconstruction. In this study we examine the differences in the quantification of (18)F-FDG uptake in the carotid arteries between PET/MR and PET/CT scanners. Five comparisons were performed to asses differences in PET quantification: i) PET/MR MR-based AC (MRAC) versus PET/MR CTAC, ii) PET/MR MRAC versus PET/CT, iii) PET/MR MRAC with carotid coil versus PET/MR MRAC without coil, iv) PET/MR MRAC scan 2 versus PET/MR MRAC scan 1, and v) PET/MR CTAC versus PET/CT. Standardized uptakes values (SUV) mean and SUV maximum were calculated for six regions-of-interests: left and right carotid arteries, left and right lungs, spine and muscle. Pearson's Correlation and Bland-Altman plots were used to compare SUV mean and maximum within each ROI of each patient. PET/MR emission data reconstructed with MRAC versus PET/MR emission data reconstructed with CTAC had percent differences of SUV mean ranging from -2.0% (Absolute Difference, -0.02) to 7.4% (absolute difference, 0.06). Percent differences within the carotid arteries proved to correlate well with differences of SUV mean of 5.4% (Absolute Difference, 0.07) in the left carotid and 2.7% (Absolute Difference, 0.03) in the right carotid. Pearson's correlation and Bland-Altman of PET/MR with MRAC versus PET/MR with CTAC showed high correlation between SUV mean (R(2)=0.80, mean difference 0.03 ± 0.18 SUV, p=0.3382), demonstrating excellent correlation within ROIs analyzed. The results of this study support the use of (18)F-FDG PET/MR for quantitative measure of inflammation in the carotid arteries.

Markerless attenuation correction for carotid MRI surface receiver coils in combined PET/MR imaging.

The purpose of the study was to evaluate the effect of attenuation of MR coils on quantitative carotid PET/MR exams. Additionally, an automated attenuation correction method for flexible carotid MR coils was developed and evaluated. The attenuation of the carotid coil was measured by imaging a uniform water phantom injected with 37 MBq of 18F-FDG in a combined PET/MR scanner for 24 min with and without the coil. In the same session, an ultra-short echo time (UTE) image of the coil on top of the phantom was acquired. Using a combination of rigid and non-rigid registration, a CT-based attenuation map was registered to the UTE image of the coil for attenuation and scatter correction. After phantom validation, the effect of the carotid coil attenuation and the attenuation correction method were evaluated in five subjects. Phantom studies indicated that the overall loss of PET counts due to the coil was 6.3% with local region-of-interest (ROI) errors reaching up to 18.8%. Our registration method to correct for attenuation from the coil decreased the global error and local error (ROI) to 0.8% and 3.8%, respectively. The proposed registration method accurately captured the location and shape of the coil with a maximum spatial error of 2.6 mm. Quantitative analysis in human studies correlated with the phantom findings, but was dependent on the size of the ROI used in the analysis. MR coils result in significant error in PET quantification and thus attenuation correction is needed. The proposed strategy provides an operator-free method for attenuation and scatter correction for a flexible MRI carotid surface coil for routine clinical use.

Attenuation correction for flexible magnetic resonance coils in combined magnetic resonance/positron emission tomography imaging.

INTRODUCTION: Attenuation correction for magnetic resonance (MR) coils is a new challenge that came about with the development of combined MR and positron emission tomography (PET) imaging. This task is difficult because such coils are not directly visible on either PET or MR acquisitions with current combined scanners and are therefore not easily localized in the field of view. This issue becomes more evident when trying to localize flexible MR coils (eg, cardiac or body matrix coil) that change position and shape from patient to patient and from one imaging session to another. In this study, we proposed a novel method to localize and correct for the attenuation and scatter of a flexible MR cardiac coil, using MR fiducial markers placed on the surface of the coil to allow for accurate registration of a template computed tomography (CT)-based attenuation map. MATERIALS AND METHODS: To quantify the attenuation properties of the cardiac coil, a uniform cylindrical water phantom injected with 18F-fluorodeoxyglucose (18F-FDG) was imaged on a sequential MR/PET system with and without the flexible cardiac coil. After establishing the need to correct for the attenuation of the coil, we tested the feasibility of several methods to register a precomputed attenuation map to correct for the attenuation. To accomplish this, MR and CT visible markers were placed on the surface of the cardiac flexible coil. Using only the markers as a driver for registration, the CT image was registered to the reference image through a combination of rigid and deformable registration. The accuracy of several methods was compared for the deformable registration, including B-spline, thin-plate spline, elastic body spline, and volume spline. Finally, we validated our novel approach both in phantom and patient studies. RESULTS: The findings from the phantom experiments indicated that the presence of the coil resulted in a 10% reduction in measured 18F-FDG activity when compared with the phantom-only scan. Local underestimation reached 22% in regions of interest close to the coil. Various registration methods were tested, and the volume spline was deemed to be the most accurate, as measured by the Dice similarity metric. The results of our phantom experiments showed that the bias in the 18F-FDG quantification introduced by the presence of the coil could be reduced by using our registration method. An overestimation of only 1.9% of the overall activity for the phantom scan with the coil attenuation map was measured when compared with the baseline phantom scan without coil. A local overestimation of less than 3% was observed in the ROI analysis when using the proposed method to correct for the attenuation of the flexible cardiac coil. Quantitative results from the patient study agreed well with the phantom findings. CONCLUSIONS: We presented and validated an accurate method to localize and register a CT-based attenuation map to correct for the attenuation and scatter of flexible MR coils. This method may be translated to clinical use to produce quantitatively accurate measurements with the use of flexible MR coils during MR/PET imaging.

Inflammation, Atherosclerosis, and Coronary Artery Disease: PET/CT for the Evaluation of Atherosclerosis and Inflammation.

Atherosclerosis is a prevalent cardiovascular disease marked by inflammation and the formation of plaque within arterial walls. As the disease progresses, there is an increased risk of major cardiovascular events. Owing to the nature of atherosclerosis, it is imperative to develop methods to further understand the physiological implications and progression of the disease. The combination of positron emission tomography (PET)/computed tomography (CT) has proven to be promising for the evaluation of atherosclerotic plaques and inflammation within the vessel walls. The utilization of the radiopharmaceutical tracer, 18F-fluorodeoxyglucose ((18)F-FDG), with PET/CT is invaluable in understanding the pathophysiological state involved in atherosclerosis. In this review, we will discuss the use of (18)F-FDG-PET/CT imaging for the evaluation of atherosclerosis and inflammation both in preclinical and clinical studies. The potential of more specific novel tracers will be discussed. Finally, we will touch on the potential benefits of using the newly introduced combined PET/magnetic resonance imaging (MRI) for non-invasive imaging of atherosclerosis.

Cyclic stretch of alveolar epithelial cells alters cytoskeletal micromechanics.

Cytoplasmic transport of large molecules such as plasmid DNA (pDNA) has been shown to increase when cells are subjected to mild levels of cyclic stretch for brief periods. In the case of pDNA, this is in part due to the increased active transport of pDNA along stabilized, acetylated microtubules in the cytoplasm, whose levels are increased in response to stretch. It also has been shown that disruption of the dense actin network leads to increased pDNA and macromolecule diffusion as well. We hypothesize that stretch not only increases active transport of pDNA but also, similar to actin disrupting drugs, decreases cytoplasmic stiffness leading to a less restive pathway for macromolecules to diffuse. To test this we used particle tracking microrheology to measure cytoplasmic mechanics. We conclude that while cyclic stretch transiently decreases cytoplasmic stiffness and increases diffusivity, stretch-independent modulation of the levels of acetylated, stable microtubules has no effect on cytoplasmic stiffness. Furthermore, stretching cells that have maximally acetylated microtubules increases cytoplasmic trafficking of pDNA, without increasing levels of acetylated microtubules. These findings suggest that stretch-enhanced gene transfer may occur by two independent mechanisms: increased levels of acetylated microtubules for directed active transport, and reduced cytoplasmic stiffness for increased diffusion.

Kinetics and thermodynamics of salt-dependent T7 gene 2.5 protein binding to single- and double-stranded DNA.

Bacteriophage T7 gene 2.5 protein (gp2.5) is a single-stranded DNA (ssDNA)-binding protein that has essential roles in DNA replication, recombination and repair. However, it differs from other ssDNA-binding proteins by its weaker binding to ssDNA and lack of cooperative ssDNA binding. By studying the rate-dependent DNA melting force in the presence of gp2.5 and its deletion mutant lacking 26 C-terminal residues, we probe the kinetics and thermodynamics of gp2.5 binding to ssDNA and double-stranded DNA (dsDNA). These force measurements allow us to determine the binding rate of both proteins to ssDNA, as well as their equilibrium association constants to dsDNA. The salt dependence of dsDNA binding parallels that of ssDNA binding. We attribute the four orders of magnitude salt-independent differences between ssDNA and dsDNA binding to nonelectrostatic interactions involved only in ssDNA binding, in contrast to T4 gene 32 protein, which achieves preferential ssDNA binding primarily through cooperative interactions. The results support a model in which dimerization interactions must be broken for DNA binding, and gp2.5 monomers search dsDNA by 1D diffusion to bind ssDNA. We also quantitatively compare the salt-dependent ssDNA- and dsDNA-binding properties of the T4 and T7 ssDNA-binding proteins for the first time.