A New Era in Magnetic Resonance Contrast Media.

ABSTRACT: Next-generation gadolinium-based contrast agents (GBCAs), including both high relaxivity agents and targeted agents, and manganese-based agents with a high probably of commercial success are discussed in some depth. It is highly likely that gadopiclenol and gadoquatrane, both next-generation high relaxivity gadolinium-based compounds, will come in time to replace the current macrocyclic gadolinium chelates, despite the wide acceptance, very high safety profile, and high stability of the latter group. Current research has also made possible the development of 2 new targeted gadolinium chelates, which look very promising, with the potential to improve cancer detection (for both MT218 and ProCA32.collagen) as well as diseases of collagen (for the latter agent). Further work with manganese-based compounds, a topic left fallow for more than 20 years, has also now produced 2 agents with high potential for clinical use, one (manganese chloride tetrahydrate, administered orally) developed primarily for imaging of the liver and the other (Mn-PyC3A, administered intravenously) as a gadolinium-free replacement for the GBCAs. New detail has recently emerged regarding specific circumscribed subregions of the brain with specialized cytoarchitecture and functions in which high gadolinium concentrations are seen following injection of the linear agent gadodiamide. These findings pave the way for tailored functional neurological testing, specifically in patients at potential risk due to the continued wide use in many countries across the world of the linear GBCAs. The impact of artificial intelligence is also critically discussed, with its most likely applications being dose reduction and new clinical indications.

Scientific Advances and Technical Innovations in Musculoskeletal Radiology.

ABSTRACT: Decades of technical innovations have propelled musculoskeletal radiology through an astonishing evolution. New artificial intelligence and deep learning methods capitalize on many past innovations in magnetic resonance imaging (MRI) to reach unprecedented speed, image quality, and new contrasts. Similarly exciting developments in computed tomography (CT) include clinically applicable molecular specificity and substantially improved spatial resolution of musculoskeletal structures and diseases. This special issue of Investigative Radiology comprises a collection of expert summaries and reviews on the most impactful innovations and cutting-edge topics in musculoskeletal radiology, including radiomics and deep learning methods for musculoskeletal disease detection, high-resolution MR neurography, deep learning-driven ultra-fast musculoskeletal MRI, MRI-based synthetic CT, quantitative MRI, modern low-field MRI, 7.0 T MRI, dual-energy CT, cone beam CT, kinematic CT, and synthetic contrast generation in musculoskeletal MRI.

The Clinical Utility of Magnetic Resonance Imaging According to Field Strength, Specifically Addressing the Breadth of Current State-of-the-Art Systems, Which Include 0.55 T, 1.5 T, 3 T, and 7 T.

ABSTRACT: This review provides a balanced perspective regarding the clinical utility of magnetic resonance systems across the range of field strengths for which current state-of-the-art units exist (0.55 T, 1.5 T, 3 T, and 7 T). Guidance regarding this issue is critical to appropriate purchasing, usage, and further dissemination of this important imaging modality, both in the industrial world and in developing nations. The review serves to provide an important update, although to a large extent this information has never previously been openly presented. In that sense, it serves also as a position paper, with statements and recommendations as appropriate.

Advocating the Development of Next-Generation, Advanced-Design Low-Field Magnetic Resonance Systems.

New next-generation low-field magnetic resonance imaging systems (operating in the range of 0.5 T) hold great potential for increasing access to clinical diagnosis and needed health care both in developed countries and worldwide. The relevant history concerning the choice of field strength, which resulted in 1.5 T still dominating today the number of installed systems, is considered, together with design advances possible because of interval developments, since low field was considered for clinical use in the 1980s, and current research. The potential impact of low-cost, advanced-generation low-field magnetic resonance imaging systems, properly designed, is high in terms of further dissemination of health care-across the gamut from industrial to developing countries-regardless of disease entity and anatomic region of involvement, with major niche applications likely as well.

Gadolinium-Based MRI Contrast Agents Induce Mitochondrial Toxicity and Cell Death in Human Neurons, and Toxicity Increases With Reduced Kinetic Stability of the Agent.

OBJECTIVES: This preclinical study was devised to investigate potential cellular toxicity in human neurons induced by gadolinium-based contrast agents (GBCAs) used for contrast-enhanced magnetic resonance imaging (MRI). Neurons modeling a subset of those in the basal ganglia were tested, because the basal ganglia region is 1 of 2 brain regions that displays the greatest T1-dependent signal hyperintensity changes. METHODS: Eight GBCAs were tested. Dopaminergic neurons modeling a subset of those in the basal ganglia were differentiated from an established human neuroblastoma cell line and exposed to increasing concentrations of each agent for 7 days. The tested dosages ranged from clinically relevant concentrations measured in some autopsy patients who had received repeated injections of contrast for MRI, to higher concentrations to reveal dose-dependent toxicity trends. Cell death, mitochondrial membrane potential, mitochondrial oxidative capacity, and mitochondrial function measured by oxygen consumption were quantified in cells treated with each GBCA or the osmolality control mannitol and compared to untreated cells which served as a negative control. RESULTS: Mannitol caused no change from negative controls in any of the tests, at any concentration tested. For all GBCAs, cell death increased with exposure dose, with toxicity at clinically relevant doses for agents with lower kinetic stability. Reduction of mitochondrial membrane potential and oxidative respiratory function also generally mirrored the agents' structural kinetic stabilities, with greater impairment at lower concentration for the less stable agents. CONCLUSIONS: In human neurons modeling a subset of those in the basal ganglia, these results demonstrate a toxic effect of gadolinium-containing MRI contrast agents on mitochondrial respiratory function and cell viability. Toxicity increases as agent concentration increases and as the kinetic stability of the agent decreases.

Motion in Magnetic Resonance: New Paradigms for Improved Clinical Diagnosis.

Recent innovations in magnetic resonance, involving both hardware and software, that effectively deal with motion-whether inadvertent on the part of the patient or due to respiration and cardiac contraction-are reviewed, emphasizing major current advances. New technology involving motion sensing (kinetic, respiratory, and beat) is enabling simpler, faster, and more robust monitoring of the sources of motion. This information is being integrated, with new innovative imaging approaches, to effectively manage motion and its impact on image quality. Additional impact has been made by the use of compressed sensing and simultaneous multislice imaging, with these techniques maturing and being adopted to decrease scan time and thus the effect of motion. Guidance in terms of clinical use for techniques that effectively combat motion is provided, focusing on enabling faster and improved clinical scans. Magnetic resonance imaging is on the cusp of a major new leap forward in terms of image quality and clinical utility enabled by these technological advances.

In vitro T2 relaxivities of the Gd-based contrast agents (GBCAs) in human blood at 1.5 and 3 T.

BACKGROUND: The availability of data in the medical literature for the T2 relaxivities of the Gd-based contrast agents (GBCAs) is limited. A comprehensive comparison between the agents available commercially (other than in Europe) is lacking, with no data available that most closely reflect the clinic, which is in human whole blood at body temperature. PURPOSE: To complement the existing literature by determining T2 relaxivity data for eight GBCAs in vitro. MATERIAL AND METHODS: The relaxivities of eight GBCAs diluted in human whole blood at 1.5 and 3 T were determined at 37 ± 0.5 °C. Gd was in the range of 0-4 mM. Multi-echo sequences with variable echo times were acquired using a phantom containing a dilution series with each agent, and SigmaPlot 12.0 was used to calculate the R2 relaxation rate and finally r2. Statistical comparisons between agents and field strengths were conducted. RESULTS: The relationship between R2 vs. Gd was observed to be linear at 1.5 and 3 T, with a mild increase in r2 from 1.5 to 3 T for all GBCAs. T2 relaxivity data were compared with prior results. The GBCAs are closely clustered into two groups, with higher r2 noted for the two lipophilic (those with partial hepatobiliary excretion) compounds. CONCLUSION: The r2 values at 1.5 and 3 T, determined for the eight GBCAs still clinically available (other than in Europe), provide a definitive baseline for future evaluations, including theoretical calculations of signal intensity and their clinical impact on T2-weighted scans.

Dechelation (Transmetalation): Consequences and Safety Concerns With the Linear Gadolinium-Based Contrast Agents, In View of Recent Health Care Rulings by the EMA (Europe), FDA (United States), and PMDA (Japan).

The issue of dechelation (transmetallation) in vivo after administration of the linear gadolinium-based contrast agents, and potential safety concerns, is considered on the basis of an extensive, focused literature review. Early indications of potential problems included the high level of excess ligand used in the formulation of 2 agents (indeed the 2 least stable thermodynamically) and interference with laboratory tests when blood was drawn from patients relatively soon after administration of these same agents. The advent of nephrogenic systemic fibrosis in the late 2000s raised additional major concerns.The correlation in 2014 of dentate nucleus hyperintensity on precontrast T1-weighted scans with multiple prior injections of linear gadolinium chelates, in patients with normal renal function, has driven subsequent research concerning dechelation of these agents in vivo. Unexpectedly high levels of gadolinium in the bone, skin, and liver have been found long term after administration, in animal models and in humans, although the latter data are limited. Bone may serve as a long-term reservoir, with a residual excretion phase for gadolinium after intravenous injection of the linear agents due to a subsequent slow release from bone. Many different patient populations could be vulnerable and potentially later develop clinical symptoms, although at this stage there are only limited data and small retrospective uncontrolled studies. Possible vulnerable populations include children, menopausal women, patients with osteoporosis (who are predisposed to fractures and often slow to heal or heal poorly), those receiving multiple doses, those with proinflammatory conditions, moderate renal dysfunction, or an undefined genetic predisposition. Of particular concern would be nephrogenic systemic fibrosis-like symptoms-including particularly pain and skin/joint symptoms, or disease related to the incorporation of gadolinium in hydroxyapatite in bone, in small subgroups of patients with a not yet defined propensity and/or cofactor. These concerns have led to withdrawal of the linear agents from the largest clinical market, Europe, with the exception of the hepatobiliary agents for delayed liver imaging, an indication that cannot be fulfilled by the current macrocyclic gadolinium chelates (for which these concerns do not apply).

Advocating the Development of Next-Generation High-Relaxivity Gadolinium Chelates for Clinical Magnetic Resonance.

The question of improved relaxivity, and potential efficacy therein, for a next-generation of magnetic resonance gadolinium chelates with extracellular distribution and renal excretion, which could also be viewed from the perspective of dose, is addressed on the basis of historical development, animal experimentation, and human trials. There was no systematic evaluation that preceded the choice of 0.1 mmol/kg as the standard dose for human imaging with the gadolinium chelates. In part, this dose was chosen owing to bloodwork abnormalities seen in phase I and phase II studies. Animal investigations and early clinical trials demonstrated improved lesion detectability at higher doses in the brain, liver, and heart. By designing an agent with substantially improved relaxivity, higher enhancement equivalent to that provided with the conventional gadolinium agents at high dose could be achieved, translating to improved diagnosis and, thus, clinical care. Implicit in the development of such high-relaxivity agents would be stability equivalent to or exceeding that of the currently approved macrocyclic agents, given current concern regarding dechelation and gadolinium deposition in the brain, skin, and bone with the linear agents that were initially approved. Development of such next-generation agents with a substantial improvement in relaxivity, in comparison with the current group of approved agents, with a 2-fold increase likely achievable, could lead to improved lesion enhancement, characterization, diagnosis, and, thus, clinical efficacy.

Critical Questions Regarding Gadolinium Deposition in the Brain and Body After Injections of the Gadolinium-Based Contrast Agents, Safety, and Clinical Recommendations in Consideration of the EMA's Pharmacovigilance and Risk Assessment Committee Recommendation for Suspension of the Marketing Authorizations for 4 Linear Agents.

For magnetic resonance, the established class of intravenous contrast media is the gadolinium-based contrast agents. In the 3 decades since initial approval, these have proven in general to be very safe for human administration. However, in 2006, a devastating late adverse reaction to administration of the less stable gadolinium-based contrast agents was identified, nephrogenic systemic fibrosis. The result of actions taken by the European Medicines Agency and the US Food and Drug Administration, stratifying the agents by risk and contraindicating specific agents in severe renal dysfunction, has led to no new cases being identified in North America or Europe. Subsequently, in 2014, long-term deposition in the brain of gadolinium was first shown, after administration of 2 nonionic linear chelates, gadodiamide, and gadopentetate dimeglumine. This has led to an intense focus on the question of in vivo distribution, possible dechelation, and subsequent deposition of gadolinium, together with substantial clarification of the phenomenon as well as stratification of the agents on this basis. This review focuses on 8 critical questions regarding gadolinium deposition in the brain and body, with the answers and discussion therein important for future regulatory decisions and clinical practice. It is now clear that dechelation of gadolinium occurs in vivo with the linear agents and is responsible for this phenomenon, with key experts in the field recommending, except where there is no suitable alternative, a shift in clinical practice from the linear to macrocyclic agents. In addition, on March 10, 2017, the Pharmacovigilance and Risk Assessment Committee of the European Medicines Agency recommended suspension of the marketing authorization for 4 linear gadolinium contrast agents-specifically Omniscan, Optimark, Magnevist, and MultiHance (gadodiamide, gadoversetamide, gadopentetate dimeglumine, and gadobenate dimeglumine)-for intravenous injection. Cited in the report was convincing evidence of gadolinium deposition in the brain months after injection of these linear agents. Primovist/Eovist (gadoxetic acid disodium) will remain available, being used at a lower dose for liver imaging, because it meets an important diagnostic need. In addition, a formulation of Magnevist for intra-articular injection will remain available because of its very low gadolinium concentration.

Material-Dependent Implant Artifact Reduction Using SEMAC-VAT and MAVRIC: A Prospective MRI Phantom Study.

OBJECTIVE: The aim of this study was to compare the degree of artifact reduction in magnetic resonance imaging achieved with slice encoding for metal artifact correction (SEMAC) in combination with view angle tilting (VAT) and multiacquisition variable resonance image combination (MAVRIC) for standard contrast weightings and different metallic materials. METHODS: Four identically shaped rods made of the most commonly used prosthetic materials (stainless steel, SS; titanium, Ti; cobalt-chromium-molybdenum, CoCr; and oxidized zirconium, oxZi) were scanned at 3 T. In addition to conventional fast spin-echo sequences, metal artifact reduction sequences (SEMAC-VAT and MAVRIC) with varying degrees of artifact suppression were applied at different contrast weightings (T1w, T2w, PDw). Two independent readers measured in-plane and through-plane artifacts in a standardized manner. In addition, theoretical frequency-offset and frequency-offset-gradient maps were calculated. Interobserver agreement was assessed using intraclass correlation coefficient. RESULTS: Interobserver agreement was almost perfect (intraclass correlation coefficient, 0.86-0.99). Stainless steel caused the greatest artifacts, followed by CoCr, Ti, and oxZi regardless of the imaging sequence. While for Ti and oxZi rods scanning with weak SEMAC-VAT showed some advantage, for SS and CoCr, higher modes of SEMAC-VAT or MAVRIC were necessary to achieve artifact reduction. MAVRIC achieved better artifact reduction than SEMAC-VAT at the cost of longer acquisition times. Simulations matched well with the apparent geometry of the frequency-offset maps. CONCLUSIONS: For Ti and oxZi implants, weak SEMAC-VAT may be preferred as it is faster and produces less artifact than conventional fast spin-echo. Medium or strong SEMAC-VAT or MAVRIC modes are necessary for significant artifact reduction for SS and CoCr implants.

Speed in Clinical Magnetic Resonance.

The relevant clinical accelerated magnetic resonance techniques that are available currently for routine patient examinations are reviewed, presenting and discussing the benefits therein when compared with more conventional scans. The focus is on clinical use and practicality, with the review divided into 3 sections. Improvements in 3-dimensional acquisition are first discussed, specifically controlled aliasing in parallel imaging results in higher acceleration, related radial techniques, and CAIPI-Dixon-TWIST-VIBE. Simultaneous multislice imaging is then reviewed, focusing on current implementation for 2-dimensional imaging, including both echo-planar and fast spin echo techniques. The final topic is that of sparse reconstruction (data sparsity), discussing the principles therein, challenges, and current applications. Guidance in terms of clinical use for accelerated techniques is provided, focusing on enabling faster and improved clinical scan results.

Safety of the Gadolinium-Based Contrast Agents for Magnetic Resonance Imaging, Focusing in Part on Their Accumulation in the Brain and Especially the Dentate Nucleus.

The established class of intravenous contrast media for magnetic resonance imaging is the gadolinium chelates, more generally referred to as the gadolinium-based contrast agents (GBCAs). These can be differentiated on the basis of stability in vivo, with safety and tolerability of the GBCAs dependent upon chemical and biologic inertness. This review discusses first the background in terms of development of these agents and safety discussions therein, and second their relative stability based both on in vitro studies and clinical observations before and including the advent of nephrogenic systemic fibrosis. This sets the stage for the subsequent focus of the review, the current knowledge regarding accumulation of gadolinium in the brain and specifically the dentate nucleus after intravenous administration of the GBCAs and differentiation among agents on this basis. The information available to date, from the initial conception of these agents in 1981 to the latest reports concerning safety, demonstrates a significant difference between the macrocyclic and linear chelates. The review concludes with a discussion of the predictable future, which includes, importantly, a reassessment of the use of the linear GBCAs or a subset thereof.

Simultaneous multi-slice readout-segmented echo planar imaging for accelerated diffusion-weighted imaging of the breast.

OBJECTIVES: Readout-segmented echo planar imaging (rs-EPI) significantly reduces susceptibility artifacts in diffusion-weighted imaging (DWI) of the breast compared to single-shot EPI but is limited by longer scan times. To compensate for this, we tested a new simultaneous multi-slice (SMS) acquisition for accelerated rs-EPI. MATERIALS AND METHODS: After approval by the local ethics committee, eight healthy female volunteers (age, 38.9 ± 13.1 years) underwent breast MRI at 3T. Conventional as well as two-fold (2× SMS) and three-fold (3× SMS) slice-accelerated rs-EPI sequences were acquired at b-values of 50 and 800 s/mm(2). Two independent readers analyzed the apparent diffusion coefficient (ADC) in fibroglandular breast parenchyma. The signal-to-noise ratio (SNR) was estimated based on the subtraction method. ADC and SNR were compared between sequences by using the Friedman test. RESULTS: The acquisition time was 4:21 min for conventional rs-EPI, 2:35 min for 2× SMS rs-EPI and 1:44 min for 3× SMS rs-EPI. ADC values were similar in all sequences (mean values 1.62 × 10(-3)mm(2)/s, p=0.99). Mean SNR was 27.7-29.6, and no significant differences were found among the sequences (p=0.83). CONCLUSION: SMS rs-EPI yields similar ADC values and SNR compared to conventional rs-EPI at markedly reduced scan time. Thus, SMS excitation increases the clinical applicability of rs-EPI for DWI of the breast.

Accelerated magnetic resonance diffusion tensor imaging of the median nerve using simultaneous multi-slice echo planar imaging with blipped CAIPIRINHA.

PURPOSE: To investigate the feasibility of MR diffusion tensor imaging (DTI) of the median nerve using simultaneous multi-slice echo planar imaging (EPI) with blipped CAIPIRINHA. MATERIALS AND METHODS: After federal ethics board approval, MR imaging of the median nerves of eight healthy volunteers (mean age, 29.4 years; range, 25-32) was performed at 3 T using a 16-channel hand/wrist coil. An EPI sequence (b-value, 1,000 s/mm(2); 20 gradient directions) was acquired without acceleration as well as with twofold and threefold slice acceleration. Fractional anisotropy (FA), mean diffusivity (MD) and quality of nerve tractography (number of tracks, average track length, track homogeneity, anatomical accuracy) were compared between the acquisitions using multivariate ANOVA and the Kruskal-Wallis test. RESULTS: Acquisition time was 6:08 min for standard DTI, 3:38 min for twofold and 2:31 min for threefold acceleration. No differences were found regarding FA (standard DTI: 0.620 ± 0.058; twofold acceleration: 0.642 ± 0.058; threefold acceleration: 0.644 ± 0.061; p ≥ 0.217) and MD (standard DTI: 1.076 ± 0.080 mm(2)/s; twofold acceleration: 1.016 ± 0.123 mm(2)/s; threefold acceleration: 0.979 ± 0.153 mm(2)/s; p ≥ 0.074). Twofold acceleration yielded similar tractography quality compared to standard DTI (p > 0.05). With threefold acceleration, however, average track length and track homogeneity decreased (p = 0.004-0.021). CONCLUSION: Accelerated DTI of the median nerve is feasible. Twofold acceleration yields similar results to standard DTI. KEY POINTS: • Standard DTI of the median nerve is limited by its long acquisition time. • Simultaneous multi-slice acquisition is a new technique for accelerated DTI. • Accelerated DTI of the median nerve yields similar results to standard DTI.

A novel diagnostic method (spectral computed tomography of sacroiliac joints) for axial spondyloarthritis.

BACKGROUND/PURPOSE: To evaluate the diagnostic value of spectral computed tomography (CT) of sacroiliac joints for axial spondyloarthritis (SpA). METHODS: We retrospectively analyzed the records of 125 patients with low back pain (LBP) suspected of having SpA. Each patient underwent sacroiliac joint spectral CT examination. Water- and calcium-based material decomposition images were reconstructed. After 3-6 months of follow-up, 76 were diagnosed with SpA, and the remaining 49 patients were diagnosed with nonspecific LBP (nLBP). The slope of sacroiliac bone marrow HU (Hounsfield unit) curve (λHU), CT value, and bone marrow to normal muscle ratios of water and calcium concentrations in the ilium and sacrum were calculated and compared between nLBP and SpA patients. RESULTS: The iliac λHU was 8.26 ± 3.91 for nLBP and 9.81 ± 4.92 for SpA. The mean iliac ratios of water and calcium concentrations were 1.04 ± 0.03 and 21.67 ± 4.40, respectively, for nLBP, and 1.07 ± 0.04 and 111.5 ± 358.98, respectively, for SpA. The mean iliac CT values were 311.12 ± 86.52 HU for nLBP and 423.97 ± 127.51 HU for SpA. There were statistically significant differences in iliac ratios of water and calcium concentrations, CT value, and λHU between nLBP and SpA patients (p < 0.05). The sensitivity of iliac λHU was the highest. The diagnostic odds ratio of ratio of iliac calcium concentration was the highest, and its negative likelihood ratio was the lowest. CONCLUSION: Spectral CT not only shows bone erosion and sclerosis, but also shows and quantitatively measures bone marrow edema in the sacroiliac joints of SpA patients.

Metal Artifact Reduction in Pelvic Computed Tomography With Hip Prostheses: Comparison of Virtual Monoenergetic Extrapolations From Dual-Energy Computed Tomography and an Iterative Metal Artifact Reduction Algorithm in a Phantom Study.

OBJECTIVE: The aim of this study was to directly compare metal artifact reduction (MAR) of virtual monoenergetic extrapolations (VMEs) from dual-energy computed tomography (CT) with iterative MAR (iMAR) from single energy in pelvic CT with hip prostheses. MATERIALS AND METHODS: A human pelvis phantom with unilateral or bilateral metal inserts of different material (steel and titanium) was scanned with third-generation dual-source CT using single (120 kVp) and dual-energy (100/150 kVp) at similar radiation dose (CT dose index, 7.15 mGy). Three image series for each phantom configuration were reconstructed: uncorrected, VME, and iMAR. Two independent, blinded radiologists assessed image quality quantitatively (noise and attenuation) and subjectively (5-point Likert scale). Intraclass correlation coefficients (ICCs) and Cohen κ were calculated to evaluate interreader agreements. Repeated measures analysis of variance and Friedman test were used to compare quantitative and qualitative image quality. Post hoc testing was performed using a corrected (Bonferroni) P < 0.017. RESULTS: Agreements between readers were high for noise (all, ICC ≥ 0.975) and attenuation (all, ICC ≥ 0.986); agreements for qualitative assessment were good to perfect (all, κ ≥ 0.678). Compared with uncorrected images, VME showed significant noise reduction in the phantom with titanium only (P < 0.017), and iMAR showed significantly lower noise in all regions and phantom configurations (all, P < 0.017). In all phantom configurations, deviations of attenuation were smallest in images reconstructed with iMAR. For VME, there was a tendency toward higher subjective image quality in phantoms with titanium compared with uncorrected images, however, without reaching statistical significance (P > 0.017). Subjective image quality was rated significantly higher for images reconstructed with iMAR than for uncorrected images in all phantom configurations (all, P < 0.017). CONCLUSIONS: Iterative MAR showed better MAR capabilities than VME in settings with bilateral hip prosthesis or unilateral steel prosthesis. In settings with unilateral hip prosthesis made of titanium, VME and iMAR performed similarly well.