Biological effects of MRI contrast agents: gadolinium retention, potential mechanisms and a role for phosphorus.

No discussion of challenges for chemistry in molecular imaging would be complete without addressing the elephant in the room-which is that the purest of chemical compounds needs to interact with a biological system in a manner that does not perturb normal biology while still providing efficacious feedback to assist in diagnosis of disease. In the past decade, magnetic resonance imaging (MRI) agents long considered inert have produced adverse effects in certain patient populations under certain treatment regimens. More recently, inert blood pool agents have been found to deposit in the brain. Release of free metal is often suspected as the culprit but that hypothesis has yet to be validated. In addition, even innocuous agents can cause painful side effects during injection in some patients. In this brief review, we summarize known biological effects for gadolinium- and iron-based MRI contrast agents, and discuss some of the potential mechanisms for the observed biological effects, including the potential role of phosphorus imbalance, related to kidney disease or cancer, in destabilizing gadolinium-based chelates and precipitating free gadolinium.This article is part of the themed issue 'Challenges for chemistry in molecular imaging'.

Feasibility of bone marrow edema detection using dual-energy cone-beam computed tomography.

BACKGROUND: Dual-energy (DE) detection of bone marrow edema (BME) would be a valuable new diagnostic capability for the emerging orthopedic cone-beam computed tomography (CBCT) systems. However, this imaging task is inherently challenging because of the narrow energy separation between water (edematous fluid) and fat (health yellow marrow), requiring precise artifact correction and dedicated material decomposition approaches. PURPOSE: We investigate the feasibility of BME assessment using kV-switching DE CBCT with a comprehensive CBCT artifact correction framework and a two-stage projection- and image-domain three-material decomposition algorithm. METHODS: DE CBCT projections of quantitative BME phantoms (water containers 100-165 mm in size with inserts presenting various degrees of edema) and an animal cadaver model of BME were acquired on a CBCT test bench emulating the standard wrist imaging configuration of a Multitom Rax twin robotic x-ray system. The slow kV-switching scan protocol involved a 60 kV low energy (LE) beam and a 120 kV high energy (HE) beam switched every 0.5° over a 200° angular span. The DE CBCT data preprocessing and artifact correction framework consisted of (i) projection interpolation onto matched LE and HE projections views, (ii) lag and glare deconvolutions, and (iii) efficient Monte Carlo (MC)-based scatter correction. Virtual non-calcium (VNCa) images for BME detection were then generated by projection-domain decomposition into an Aluminium (Al) and polyethylene basis set (to remove beam hardening) followed by three-material image-domain decomposition into water, Ca, and fat. Feasibility of BME detection was quantified in terms of VNCa image contrast and receiver operating characteristic (ROC) curves. Robustness to object size, position in the field of view (FOV) and beam collimation (varied 20-160 mm) was investigated. RESULTS: The MC-based scatter correction delivered > 69% reduction of cupping artifacts for moderate to wide collimations (> 80 mm beam width), which was essential to achieve accurate DE material decomposition. In a forearm-sized object, a 20% increase in water concentration (edema) of a trabecular bone-mimicking mixture presented as ∼15 HU VNCa contrast using 80-160 mm beam collimations. The variability with respect to object position in the FOV was modest (< 15% coefficient of variation). The areas under the ROC curve were > 0.9. A femur-sized object presented a somewhat more challenging task, resulting in increased sensitivity to object positioning at 160 mm collimation. In animal cadaver specimens, areas of VNCa enhancement consistent with BME were observed in DE CBCT images in regions of MRI-confirmed edema. CONCLUSION: Our results indicate that the proposed artifact correction and material decomposition pipeline can overcome the challenges of scatter and limited spectral separation to achieve relatively accurate and sensitive BME detection in DE CBCT. This study provides an important baseline for clinical translation of musculoskeletal DE CBCT to quantitative, point-of-care bone health assessment.

Quantitative Dual-Energy Imaging of Bone Marrow Edema Using Multisource Cone-Beam CT with Model-Based Decomposition.

Purpose: We investigated the feasibility of dual-energy (DE) detection of bone marrow edema (BME) using a dedicated extremity cone-beam CT (CBCT) with a unique three-source x-ray unit. The sources can be operated at different energies to enable single-scan DE acquisitions. However, they are arranged parallel to the axis of rotation, resulting in incomplete sampling and precluding the application of DE projection-domain decompositions (PDD) for beam-hardening reduction. Therefore, we propose a novel combination of a model-based "one-step" DE two-material decomposition followed by a constrained image-domain change-of-basis to obtain virtual non-calcium (VNCa) images for BME detection. Methods: DE projections were obtained using an "alternating-kV" protocol by operating the peripheral two sources of the CBCT system at low-energy (60 kV, 0.105 mAs/frame) and the central source at high-energy (100 kV, 0.028 mAs/frame), for a total of 600 frames over 216° of gantry rotation. Projections were processed with detector lag, glare and fast Monte Carlo (MC)-based iterative scatter corrections. Model-based material decomposition (MBMD) was then implemented to obtain aluminum (Al) and polyethylene (PE) volume fraction images with minimal beam-hardening. Statistical ray weights in MBMD were modified to account for regions with highly oblique sampling by the peripheral sources. To generate the VNCa maps, image-domain decomposition (IDD) constrained by the volume conservation principle (VCP) was performed to convert the Al and PE MBMD images into volume fractions of water, fat and cortical bone. Accuracy of BME detection was evaluated using physical phantom data acquired on the multi-source extremity CBCT scanner. Results: The proposed framework estimated the volume of BME with ~10% error. The MC-based scatter corrections and the modified MBMD ray weights were essential to achieve such performance - the error without MC scatter corrections was >30%, whereas the uniformity of estimated VNCa images was 3x improved using the modified weights compared to the conventional weights. Conclusions: The proposed DE decomposition framework was able to overcome challenges of high scatter and incomplete sampling to achieve BME detection on a CBCT system with axially-distributed x-ray sources.

Computed Tomography: State-of-the-Art Advancements in Musculoskeletal Imaging.

ABSTRACT: Although musculoskeletal magnetic resonance imaging (MRI) plays a dominant role in characterizing abnormalities, novel computed tomography (CT) techniques have found an emerging niche in several scenarios such as trauma, gout, and the characterization of pathologic biomechanical states during motion and weight-bearing. Recent developments and advancements in the field of musculoskeletal CT include 4-dimensional, cone-beam (CB), and dual-energy (DE) CT. Four-dimensional CT has the potential to quantify biomechanical derangements of peripheral joints in different joint positions to diagnose and characterize patellofemoral instability, scapholunate ligamentous injuries, and syndesmotic injuries. Cone-beam CT provides an opportunity to image peripheral joints during weight-bearing, augmenting the diagnosis and characterization of disease processes. Emerging CBCT technologies improved spatial resolution for osseous microstructures in the quantitative analysis of osteoarthritis-related subchondral bone changes, trauma, and fracture healing. Dual-energy CT-based material decomposition visualizes and quantifies monosodium urate crystals in gout, bone marrow edema in traumatic and nontraumatic fractures, and neoplastic disease. Recently, DE techniques have been applied to CBCT, contributing to increased image quality in contrast-enhanced arthrography, bone densitometry, and bone marrow imaging. This review describes 4-dimensional CT, CBCT, and DECT advances, current logistical limitations, and prospects for each technique.

Model-based three-material decomposition in dual-energy CT using the volume conservation constraint.

Objective. We develop a model-based optimization algorithm for 'one-step' dual-energy (DE) CT decomposition of three materials directly from projection measurements.Approach.Since the three-material problem is inherently undetermined, we incorporate the volume conservation principle (VCP) as a pair of equality and nonnegativity constraints into the objective function of the recently reported model-based material decomposition (MBMD). An optimization algorithm (constrained MBMD, CMBMD) is derived that utilizes voxel-wise separability to partition the volume into a VCP-constrained region solved using interior-point iterations, and an unconstrained region (air surrounding the object, where VCP is violated) solved with conventional two-material MBMD. Constrained MBMD (CMBMD) is validated in simulations and experiments in application to bone composition measurements in the presence of metal hardware using DE cone-beam CT (CBCT). A kV-switching protocol with non-coinciding low- and high-energy (LE and HE) projections was assumed. CMBMD with decomposed base materials of cortical bone, fat, and metal (titanium, Ti) is compared to MBMD with (i) fat-bone and (ii) fat-Ti bases.Main results.Three-material CMBMD exhibits a substantial reduction in metal artifacts relative to the two-material MBMD implementations. The accuracies of cortical bone volume fraction estimates are markedly improved using CMBMD, with ∼5-10× lower normalized root mean squared error in simulations with anthropomorphic knee phantoms (depending on the complexity of the metal component) and ∼2-2.5× lower in an experimental test-bench study.Significance.In conclusion, we demonstrated one-step three-material decomposition of DE CT using volume conservation as an optimization constraint. The proposed method might be applicable to DE applications such as bone marrow edema imaging (fat-bone-water decomposition) or multi-contrast imaging, especially on CT/CBCT systems that do not provide coinciding LE and HE ray paths required for conventional projection-domain DE decomposition.

Dual-Energy Cone-Beam CT with Three-Material Decomposition for Bone Marrow Edema Imaging.

We investigate the feasibility of bone marrow edema (BME) detection using a kV-switching Dual-Energy (DE) Cone-Beam CT (CBCT) protocol. This task is challenging due to unmatched x-ray paths in the low-energy (LE) and high-energy (HE) spectral channels, CBCT non-idealities such as x-ray scatter, and narrow spectral separation between fat (bone marrow) and water (BME). We propose a comprehensive DE decomposition framework consisting of projection interpolation onto matching LE and HE view angles, fast Monte Carlo scatter correction with low number of tracked photons and Gaussian denoising, and two-stage three-material decompositions involving two-material (fat-Aluminium) Projection-Domain Decomposition (PDD) followed by image-domain three-material (fat-water-bone) base-change. Performance in BME detection was evaluated in simulations and experiments emulating a kV-switching CBCT wrist imaging protocol on a robotic x-ray system with 60 kV LE beam, 120 kV HE beam, and 0.5° angular shift between the LE and HE views. Cubic B-spline interpolation was found to be adequate to resample HE and LE projections of a wrist onto common view angles required by PDD. The DE decomposition maintained acceptable BME detection specificity (<0.2 mL erroneously detected BME volume compared to 0.85 mL true BME volume) over +/-10% range of scatter magnitude errors, as long as the scatter shape was estimated without major distortions. Physical test bench experiments demonstrated successful discrimination of ~20% change in fat concentrations in trabecular bone-mimicking solutions of varying water and fat content.

Feasibility of Dual-Energy Cone-Beam CT of Bone Marrow Edema Using Dual-Layer Flat Panel Detectors.

Purpose: We investigated the feasibility of detection and quantification of bone marrow edema (BME) using dual-energy (DE) Cone-Beam CT (CBCT) with a dual-layer flat panel detector (FPD) and three-material decomposition. Methods: A realistic CBCT system simulator was applied to study the impact of detector quantization, scatter, and spectral calibration errors on the accuracy of fat-water-bone decompositions of dual-layer projections. The CBCT system featured 975 mm source-axis distance, 1,362 mm source-detector distance and a 430 × 430 mm2 dual-layer FPD (top layer: 0.20 mm CsI:Tl, bottom layer: 0.55 mm CsI:Tl; a 1 mm Cu filter between the layers to improve spectral separation). Tube settings were 120 kV (+2 mm Al, +0.2 mm Cu) and 10 mAs per exposure. The digital phantom consisted of a 160 mm water cylinder with inserts containing mixtures of water (volume fraction ranging 0.18 to 0.46) - fat (0.5 to 0.7) - Ca (0.04 to 0.12); decreasing fractions of fat indicated increasing degrees of BME. A two-stage three-material DE decomposition was applied to DE CBCT projections: first, projection-domain decomposition (PDD) into fat-aluminum basis, followed by CBCT reconstruction of intermediate base images, followed by image-domain change of basis into fat, water and bone. Sensitivity to scatter was evaluated by i) adjusting source collimation (12 to 400 mm width) and ii) subtracting various fractions of the true scatter from the projections at 400 mm collimation. The impact of spectral calibration was studied by shifting the effective beam energy (± 2 keV) when creating the PDD lookup table. We further simulated a realistic BME imaging framework, where the scatter was estimated using a fast Monte Carlo (MC) simulation from a preliminary decomposition of the object; the object was a realistic wrist phantom with an 0.85 mL BME stimulus in the radius. Results: The decomposition is sensitive to scatter: approx. <20 mm collimation width or <10% error of scatter correction in a full field-of-view setting is needed to resolve BME. A mismatch in PDD decomposition calibration of ± 1 keV results in ~25% error in fat fraction estimates. In the wrist phantom study with MC scatter corrections, we were able to achieve ~0.79 mL true positive and ~0.06 mL false positive BME detection (compared to 0.85 mL true BME volume). Conclusions: Detection of BME using DE CBCT with dual-layer FPD is feasible, but requires scatter mitigation, accurate scatter estimation, and robust spectral calibration.

Bmi1 Regulates Wnt Signaling in Hematopoietic Stem and Progenitor Cells.

Polycomb group protein Bmi1 is essential for hematopoietic stem cell (HSC) self-renewal and terminal differentiation. However, its target genes in hematopoietic stem and progenitor cells are largely unknown. We performed gene expression profiling assays and found that genes of the Wnt signaling pathway are significantly elevated in Bmi1 null hematopoietic stem and progenitor cells (HSPCs). Bmi1 is associated with several genes of the Wnt signaling pathway in hematopoietic cells. Further, we found that Bmi1 represses Wnt gene expression in HSPCs. Importantly, loss of ß-catenin, which reduces Wnt activation, partially rescues the HSC self-renewal and differentiation defects seen in the Bmi1 null mice. Thus, we have identified Bmi1 as a novel regulator of Wnt signaling pathway in HSPCs. Given that Wnt signaling pathway plays an important role in hematopoiesis, our studies suggest that modulating Wnt signaling may hold potential for enhancing HSC self-renewal, thereby improving the outcomes of HSC transplantation.

Model-based dual-energy tomographic image reconstruction of objects containing known metal components.

Dual-energy (DE) decomposition has been adopted in orthopedic imaging to measure bone composition and visualize intraarticular contrast enhancement. One of the potential applications involves monitoring of callus mineralization for longitudinal assessment of fracture healing. However, fracture repair usually involves internal fixation hardware that can generate significant artifacts in reconstructed images. To address this challenge, we develop a novel algorithm that combines simultaneous reconstruction-decomposition using a previously reported method for model-based material decomposition (MBMD) augmented by the known-component (KC) reconstruction framework to mitigate metal artifacts. We apply the proposed algorithm to simulated DE data representative of a dedicated extremity cone-beam CT (CBCT) employing an x-ray unit with three vertically arranged sources. The scanner generates DE data with non-coinciding high- and low-energy projection rays when the central source is operated at high tube potential and the peripheral sources at low potential. The proposed algorithm was validated using a digital extremity phantom containing varying concentrations of Ca-water mixtures and Ti implants. Decomposition accuracy was compared to MBMD without the KC model. The proposed method suppressed metal artifacts and yielded estimated Ca concentrations that approached the reconstructions of an implant-free phantom for most mixture regions. In the vicinity of simple components, the errors of Ca density estimates obtained by incorporating KC in MBMD were ∼1.5-5× lower than the errors of conventional MBMD; for cases with complex implants, the errors were ∼3-5× lower. In conclusion, the proposed method can achieve accurate bone mineral density measurements in the presence of metal implants using non-coinciding DE projections acquired on a multisource CBCT system.

Author Correction: Mutant p53 drives clonal hematopoiesis through modulating epigenetic pathway.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Antioxidant Sensing by Spiropyrans: Substituent Effects and NMR Spectroscopic Studies.

The development of stimuli-responsive small molecules for probing biologically active antioxidants such as glutathione (GSH) has important ramifications in the detection of oxidative stress. An ideal sensor for biological applications should exhibit sufficient sensitivity and selectivity for detection at physiological concentrations and be reversible to allow continuous and dynamic monitoring of antioxidant levels. Designing a suitable sensor thus requires a detailed understanding of activation properties and mechanism of action. In this work, we report a new set of GSH-responsive spiropyrans and demonstrate how changes in the electronic structure of spiropyrans influence GSH sensing with high specificity versus other structurally similar and biologically relevant redox-active molecules. The sensitivity, selectivity, kinetics, binding constant, and reversibility of GSH-responsive-substituted spiropyrans were investigated using UV-vis spectroscopy and laser irradiation experiments. Detailed studies of the mechanism of interaction between spiropyrans with GSH were investigated using NMR spectroscopy. Understanding how electronic effects impact the sensing ability of spiropyrans toward antioxidants and elucidating the mechanism of the spiropyran-GSH interaction will facilitate the design of more effective sensors for detection of antioxidants in vivo.

Mutant p53 drives clonal hematopoiesis through modulating epigenetic pathway.

Clonal hematopoiesis of indeterminate potential (CHIP) increases with age and is associated with increased risks of hematological malignancies. While TP53 mutations have been identified in CHIP, the molecular mechanisms by which mutant p53 promotes hematopoietic stem and progenitor cell (HSPC) expansion are largely unknown. Here we discover that mutant p53 confers a competitive advantage to HSPCs following transplantation and promotes HSPC expansion after radiation-induced stress. Mechanistically, mutant p53 interacts with EZH2 and enhances its association with the chromatin, thereby increasing the levels of H3K27me3 in genes regulating HSPC self-renewal and differentiation. Furthermore, genetic and pharmacological inhibition of EZH2 decreases the repopulating potential of p53 mutant HSPCs. Thus, we uncover an epigenetic mechanism by which mutant p53 drives clonal hematopoiesis. Our work will likely establish epigenetic regulator EZH2 as a novel therapeutic target for preventing CHIP progression and treating hematological malignancies with TP53 mutations.

Necdin modulates leukemia-initiating cell quiescence and chemotherapy response.

Acute myeloid leukemia (AML) is a devastating illness which carries a very poor prognosis, with most patients living less than 18 months. Leukemia relapse may occur because current therapies eliminate proliferating leukemia cells but fail to eradicate quiescent leukemia-initiating cells (LICs) that can reinitiate the disease after a period of latency. While we demonstrated that p53 target gene Necdin maintains hematopoietic stem cell (HSC) quiescence, its roles in LIC quiescence and response to chemotherapy are unclear. In this study, we utilized two well-established murine models of human AML induced by MLL-AF9 or AML1-ETO9a to determine the role of Necdin in leukemogenesis. We found that loss of Necdin decreased the number of functional LICs and enhanced myeloid differentiation in vivo, leading to delayed development of leukemia induced by MLL-AF9. Importantly, Necdin null LICs expressing MLL-AF9 were less quiescent than wild-type LICs. Further, loss of Necdin enhanced the response of MLL-AF9+ leukemia cells to chemotherapy treatment, manifested by decreased viability and enhanced apoptosis. We observed decreased expression of Bcl2 and increased expression of p53 and its target gene Bax in Necdin null leukemia cells following chemotherapy treatment, indicating that p53-dependent apoptotic pathways may be activated in the absence of Necdin. In addition, we found that loss of Necdin decreased the engraftment of AML1-ETO9a+ hematopoietic stem and progenitor cells in transplantation assays. However, Necdin-deficiency did not affect the response of AML1-ETO9a+ hematopoietic cells to chemotherapy treatment. Thus, Necdin regulates leukemia-initiating cell quiescence and chemotherapy response in a context-dependent manner. Our findings suggest that pharmacological inhibition of Necdin may hold potential as a novel therapy for leukemia patients with MLL translocations.