Gadolinium Presence in Rat Skin: Assessment of Histopathologic Changes Associated with Small Fiber Neuropathy.

Background The presence of gadolinium traces in the skin after administration of gadolinium-based contrast agents (GBCAs) raised safety concerns regarding a potential association with small fiber neuropathy (SFN). Purpose To investigate signs of SFN in rat foot pads by quantification of the intraepidermal nerve fiber density (IENFD) after multiple GBCA administrations and to evaluate gadolinium concentration, chemical species, and clearance. Materials and Methods Fifty rats received eight intravenous injections of either gadodiamide, gadobutrol, gadoterate, gadoteridol (8 × 0.6 mmol per kilogram of body weight), or saline (1.2 mL per kilogram of body weight), within 2 weeks and were sacrificed 5 days or 5 weeks after the last injection. IENFD was determined with protein gene product (PGP) 9.5 immunofluorescent staining and blinded and automated image analysis. The gadolinium and GBCA concentrations were measured with inductively coupled plasma mass spectrometry (ICP-MS), laser ablation ICP-MS, and matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI). P values were calculated using linear contrasts of model analysis. Results The IENFD (measured as geometric mean [SD] and in number of nerve fibers per millimeter of epidermis) was not significantly altered after 5 days (saline, 8.4 [1.1]; gadobutrol, 9.7 [1.2]; gadoterate, 9.2 [1.2]; gadoteridol, 9.9 [1.3]; gadodiamide, 10.5 [1.2]) or 5 weeks (saline, 19.7 [1.4]; gadobutrol, 16.4 [1.6]; gadoterate, 14.3 [1.6]; gadoteridol, 22.2 [1.8]; gadodiamide, 17.9 [1.4]). Gadolinium skin concentrations were highest for gadodiamide after 5 days (16.0 nmol/g [1.1]) and 5 weeks (10.6 nmol/g [1.2], -33%). Macrocyclic agents were lower at 5 days (gadoteridol, 2.6 nmol/g [1.2]; gadobutrol, 2.7 nmol/g [1.1]; and gadoterate, 2.3 nmol/g [1.2]) and efficiently cleared after 5 weeks (gadoteridol, -95%; gadobutrol and gadoterate, -96%). The distribution of gadolinium and IENF did not visually overlap. For macrocyclic agents, gadolinium was found in sweat glands and confirmed to be intact chelate. Conclusion There were no signs of SFN in rat foot pads using multiple dosing regimens at two time points after administration of GBCAs. Macrocyclic GBCAs exhibited lower levels of gadolinium in the skin and were effectively eliminated within 5 weeks compared with linear gadodiamide, and intact macrocyclic GBCA was detected in sweat glands. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Clement in this issue.

Impact of concentration and dilution of three macrocyclic gadolinium-based contrast agents on MRI signal intensity at 1.5T and 3T and different pulse sequences: results of a phantom study in human plasma.

BACKGROUND: Many factors influence the increase in signal intensity (SI) provided by magnetic resonance imaging (MRI) contrast media. PURPOSE: To assess the impact of different gadolinium concentrations and dilutions of three macrocyclic gadolinium-based contrast agents (GBCA) on SI. MATERIAL AND METHODS: This phantom study investigated gadobutrol, gadoteridol, and gadoterate in human plasma of a healthy donor pool at 37 °C. Different molar concentrations served to mimic conditions typically relevant for steady-state imaging; different dilutions served to mimic influence on first-pass bolus imaging. For SI measurement at 1.5T and 3T, we used two Magnetom Scanners (Siemens), applying the T1-weighted sequences Flash 2D/3D and VIBE. Regions of interest were placed on the central slice of the test vials. RESULTS: In the concentration series, gadobutrol showed the highest SI of all three GBCAs up to 2 mM, followed by gadoteridol and gadoterate. No major differences were seen between 1.5T and 3T. In the dilution series, gadobutrol showed the highest SI of all three GBCAs up to 10 mL/L. The highest effect was recorded with Flash 3D and VIBE at 3T. CONCLUSION: SIs measured in phantoms using three macrocyclic GBCAs strongly depend on their relaxivity and on the local concentration. The latter can be influenced-when comparing dilutions-by their initial concentration in their formulation. Furthermore, the pulse sequences and the chosen parameters have essential influence. At steady-state concentrations (≤2 mM) and first-pass bolus dilutions (up to 10 ml/L), gadobutrol showed highest SIs, followed by gadoterate and gadoteridol.

Long-term Excretion of Gadolinium-based Contrast Agents: Linear versus Macrocyclic Agents in an Experimental Rat Model.

Purpose To investigate the long-term course of MRI signal intensity (SI) changes and the presence of gadolinium in the rat brain during a 1-year period after multiple administrations of gadolinium-based contrast agents (GBCAs). Materials and Methods Rats received a linear GBCA (gadodiamide, gadopentetate dimeglumine, gadobenate dimeglumine), a macrocyclic GBCA (gadobutrol, gadoterate meglumine, gadoteridol), or saline. Animals received eight injections over 2 weeks (1.8 mmol/kg per injection). Brain MRI and gadolinium measurements were performed with inductively coupled plasma mass spectrometry (ICP-MS) and laser ablation ICP-MS 5, 26, and 52 weeks after administration. Results Animals that received linear GBCAs showed higher deep cerebellar nuclei (DCN)-to-brainstem SI ratios compared with the saline group (P < .001 at all time points). After 1 year, mean gadolinium concentrations in the cerebellum were 3.38 nmol/g (gadodiamide), 2.13 nmol/g (gadopentetate dimeglumine), and 1.91 nmol/g (gadobenate dimeglumine). For linear agents, laser ablation ICP-MS revealed gadolinium depositions in the cerebellar nuclei. For macrocyclic GBCAs, the DCN-to-brainstem SI ratios did not significantly differ from those in the saline group (P > .42) and the cerebellar gadolinium concentrations decreased between weeks 5 and 52, reaching 0.08 nmol/g (gadobutrol), 0.04 nmol/g (gadoterate meglumine), and 0.07 nmol/g (gadoteridol). The respective laser ablation ICP-MS analysis showed no gadolinium depositions. Conclusion Increased signal intensity in the deep cerebellar nuclei of rats persists for at least 1 year after administration of linear gadolinium-based contrast agents (GBCAs), in line with persistent brain gadolinium concentrations with no elimination after the initial 5-week period. The animals that received macrocyclic GBCAs showed an ongoing elimination of gadolinium from the brain during the entire observation period. © RSNA, 2018.

Impact of brain tumors and radiotherapy on the presence of gadolinium in the brain after repeated administration of gadolinium-based contrast agents: an experimental study in rats.

PURPOSE: To investigate the impact of blood-brain barrier (BBB) alterations induced by an experimental tumor and radiotherapy on MRI signal intensity (SI) in deep cerebellar nuclei (DCN) and the presence of gadolinium after repeated administration of a linear gadolinium-based contrast agent in rats. METHODS: Eighteen Fischer rats were divided into a tumor (gliosarcoma, GS9L model), a radiotherapy, and a control group. All animals received 5 daily injections (1.8 mmol/kg) of gadopentetate dimeglumine. For tumor-bearing animals, the BBB disruption was confirmed by contrast-enhanced MRI. Animals from the tumor and radiation group underwent radiotherapy in 6 fractions of 5 Gray. The SI ratio between DCN and brain stem was evaluated on T1-weigthed MRI at baseline and 1 week after the last administration. Subsequently, the brain was dissected for gadolinium quantification by inductively coupled plasma-mass spectrometry. Statistical analysis was done with the Kruskal-Wallis test. RESULTS: An increased but similar DCN/brain stem SI ratio was found for all three groups (p = 0.14). The gadolinium tissue concentrations (median, nmol/g) were 6.7 (tumor), 6.3 (radiotherapy), and 6.8 (control) in the cerebellum (p = 0.64) and 17.8/14.6 (tumor), 20.0/18.9 (radiotherapy), and 17.8/15.9 (control) for the primary tumor (p = 0.98) and the contralateral hemisphere (p = 0.41) of the cerebrum, respectively. CONCLUSION: An experimental brain tumor treated by radiotherapy or radiotherapy alone did not alter DCN signal hyperintensity and gadolinium concentration in the rat brain 1 week after repeated administration of gadopentetate. This suggests that a local BBB disruption does not affect the amount of retained gadolinium in the brain.

DCE-MR imaging of orbital lesions: diagnostic performance of the tumor flow residence time τ calculated by a multi-compartmental pharmacokinetic tumor model based on individual factors.

BACKGROUND: Differentiating benign from malignant orbital lesions by imaging and clinical presentation can be challenging. PURPOSE: To differentiate benign from malignant orbital masses using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) based on tumor flow residence time τ calculated with the aid of a pharmacokinetic tumor model. MATERIAL AND METHODS: Sixty patients with orbital masses were investigated by 3-T MRI including dynamic sequences. The signal intensity-time curve after i.v. contrast medium administration within lesions was approximated by Gd-concentration profiles on the basis of model calculations where the tumor is embedded in a whole-body kinetic model. One output of the model was tumor flow residence time τ, defined as the ratio of the tumor volume and the tumor blood flow rate. Receiver operating characteristic (ROC) curves were used to analyze the diagnostic performance of τ. The results were compared with those of Ktrans, kep, ve, iAUC, and ADC. RESULTS: Thirty-one benign and 29 malignant orbital masses were identified (reference standard: histopathology, clinical characteristics). Mean τ was significantly longer for benign masses (94 ± 48 s) than for malignant masses (21 ± 19 s, P < 0.001). ROC analysis revealed the highest area under the curve (AUC = 0.94) for τ in orbital masses compared to standard methods. CONCLUSION: Tumor flow residence times τ of benign and malignant orbital masses are valuable in the diagnostic work-up of orbital tumors. Measures of diagnostic accuracy were superior for τ compared to ADC, Ktrans, ve, and iAUC.

The impact of injector-based contrast agent administration in time-resolved MRA.

OBJECTIVES: Time-resolved contrast-enhanced MR angiography (4D-MRA), which allows the simultaneous visualization of the vasculature and blood-flow dynamics, is widely used in clinical routine. In this study, the impact of two different contrast agent injection methods on 4D-MRA was examined in a controlled, standardized setting in an animal model. METHODS: Six anesthetized Goettingen minipigs underwent two identical 4D-MRA examinations at 1.5 T in a single session. The contrast agent (0.1 mmol/kg body weight gadobutrol, followed by 20 ml saline) was injected using either manual injection or an automated injection system. A quantitative comparison of vascular signal enhancement and quantitative renal perfusion analyses were performed. RESULTS: Analysis of signal enhancement revealed higher peak enhancements and shorter time to peak intervals for the automated injection. Significantly different bolus shapes were found: automated injection resulted in a compact first-pass bolus shape clearly separated from the recirculation while manual injection resulted in a disrupted first-pass bolus with two peaks. In the quantitative perfusion analyses, statistically significant differences in plasma flow values were found between the injection methods. CONCLUSIONS: The results of both qualitative and quantitative 4D-MRA depend on the contrast agent injection method, with automated injection providing more defined bolus shapes and more standardized examination protocols. KEY POINTS: • Automated and manual contrast agent injection result in different bolus shapes in 4D-MRA. • Manual injection results in an undefined and interrupted bolus with two peaks. • Automated injection provides more defined bolus shapes. • Automated injection can lead to more standardized examination protocols.

Experimental studies on artifacts and tumor enhancement on gadoxetic acid-enhanced arterial phase liver MRI in a rabbit VX2 tumor model.

Background Rapid injection of gadoxetic acid is reported to produce more frequent artifacts and lower vascular enhancement on arterial phase liver magnetic resonance imaging (MRI). However, its effect on tumor enhancement and the mechanism of the artifacts remain unclear. Purpose To evaluate the effect of rapid injection of gadoxetic acid on artifacts and tumor enhancement during arterial phase liver MRI, and on arterial blood gases (ABGs) which may explain the cause of the artifacts. Material and Methods ABG analysis was performed in 13 free-breathing rabbits after rapid injection (1 mL/s; injection time = 0.6-0.8 s) of gadoxetic acid (0.025 mmol/kg). Dynamic liver MRI was performed in six anesthetized rabbits with VX2 tumors under a ventilation stoppage after rapid and slow injection (0.25 mL/s; injection time = 2.4-3.2 s) of gadoxetic acid. Artifacts and signal enhancement on arterial phase imaging were compared with those obtained after rapid injection of gadopentetic acid (Gd-DTPA, 0.1 mmol/kg) using a Friedman test or Kruskal-Wallis test. Results ABG analysis did not find any significant changes. Artifacts were not related to injection protocols ( P = 0.95). Aortic enhancement with slow injection of gadoxetic acid was significantly higher than that with rapid injection ( P < 0.05), and was comparable to that with Gd-DTPA injection. Tumor enhancement obtained with gadoxetic acid was not significantly different between rapid and slow injection, and was significantly lower than that with Gd-DTPA injection ( P < 0.05). Conclusion Rapid injection of gadoxetic acid did not affect ABGs and may not be the cause of the artifacts. It lowered vascular enhancement but not arterial tumor enhancement.

Penetration and distribution of gadolinium-based contrast agents into the cerebrospinal fluid in healthy rats: a potential pathway of entry into the brain tissue.

OBJECTIVE: Signal hyperintensity on unenhanced MRI in certain brain regions has been reported after multiple administrations of some, but not all, gadolinium-based contrast agents (GBCAs). One potential initial pathway of GBCA entry into the brain, infiltration from blood into the cerebrospinal fluid (CSF), was systematically evaluated in this preclinical study. METHODS: GBCA infiltration and distribution in the CSF were investigated in healthy rats using repeated fluid-attenuated MRI up to 4 h after high-dose (1.8 mmol/kg) administration of six marketed and one experimental GBCA. Additionally, gadolinium measurements in CSF, blood and brain tissue samples (after 24 h) were performed using inductively coupled plasma mass spectrometry. RESULTS: Enhanced MRI signals in the CSF spaces with similar distribution kinetics were observed for all GBCAs. No substantial differences in the gadolinium concentrations among the marketed GBCAs were found in the CSF, blood or brain tissue. After 4.5 h, the concentration in the CSF was clearly higher than in blood but was almost completely cleared and lower than the brain tissue concentration after 24 h. CONCLUSIONS: In contrast to the brain signal hyperintensities, no differences in penetration and distribution into the CSF of healthy rats exist among the marketed GBCAs. KEY POINTS: • Gadolinium-based contrast agents can cross the blood-CSF barrier. • Fluid-attenuated MRI shows GBCA distribution with CSF flow. • GBCA structure and physicochemical properties do not impact CSF penetration and distribution. • GBCA clearance from CSF was almost complete within 24 h in rats. • CSF is a potential pathway of GBCA entry into the brain.

Hafnium-Based Contrast Agents for X-ray Computed Tomography.

Heavy-metal-based contrast agents (CAs) offer enhanced X-ray absorption for X-ray computed tomography (CT) compared to the currently used iodinated CAs. We report the discovery of new lanthanide and hafnium azainositol complexes and their optimization with respect to high water solubility and stability. Our efforts culminated in the synthesis of BAY-576, an uncharged hafnium complex with 3:2 stoichiometry and broken complex symmetry. The superior properties of this asymmetrically substituted hafnium CA were demonstrated by a CT angiography study in rabbits that revealed excellent signal contrast enhancement.

What Evidence Is There That Gadobutrol Causes Increasing Signal Intensity within the Dentate Nucleus and Globus Pallidus on Unenhanced T1W MRI in Patients with RRMS?

KEY POINTS : The study by Stojanov et al does not convincingly support the conclusion that gadobutrol causes higher T1 enhancement in brain on unenhanced MRI. The study by Stojanov et al does not rule out confounding factors . The study by Stojanov et al has limitations in study design.

Revival of monophasic contrast injection protocols: superiority of a monophasic injection protocol compared to a biphasic injection protocol in high-pitch CT angiography.

BACKGROUND: Biphasic injection protocols are frequently used because they yield homogenous contrast enhancement. We hypothesize that with faster scanners and shorter scan times, biphasic injection protocols are no longer necessary. PURPOSE: To evaluate whether a monophasic injection protocol is equivalent to a biphasic protocol in terms of contrast enhancement and homogeneity. MATERIAL AND METHODS: Repeated high-pitch CTA (pitch 3) and conventional standard-pitch computed tomography angiography (CTA) (pitch 1.2) from the cervical region to the symphysis was performed in seven beagles (11.2 ± 2.5 kg) in a cross-over study design. Arterial contrast enhancement was measured along the z-axis in the ascending, descending, and abdominal aorta and the iliac arteries. The z-axis is the longitudinal axis of the human body and at the same time the direction in which the CT table is moving. The data were analyzed using repeated measures ANOVA with a post-hoc t-test and visual assessment of the scans. RESULTS: In high-pitch CTA, monophasic injection protocols were superior to biphasic injection protocols in enhancement levels (P < 0.05) and enhancement homogeneity along the z-axis (P < 0.05). In conventional CTA, enhancement levels did not differ. Contrast homogeneity was better for biphasic protocols. CONCLUSION: High-pitch CTA monophasic injection protocols are superior to biphasic injection protocols, due to a higher and more homogeneous contrast enhancement with the same amount of contrast medium used.

Automated Tube Voltage Selection for Radiation Dose Reduction in CT Angiography Using Different Contrast Media Concentrations and a Constant Iodine Delivery Rate.

OBJECTIVE: The purpose of this study was to systematically investigate radiation dose reduction using automated tube voltage selection during CT angiography (CTA) and to evaluate the impact of contrast medium (CM) injection protocols on dose reduction. MATERIALS AND METHODS: A circulation phantom containing the thoracic and abdominal vasculature was used. Four different concentrations of CM (iopromide 300 and 370 mg I/mL and iomeprol 350 and 400 mg I/mL) were administered while maintaining an identical iodine delivery rate (1.8 g I/s) and total iodine load (20.0 g). Three different scanning protocols for CTA of the thoracoabdominal aorta were used: protocol A, no dose modulation; protocol B, automated tube current modulation (CARE Dose4D); and protocol C, automated tube voltage selection (CARE kV). The dose-length product was recorded to calculate the effective dose. Attenuation values (in Hounsfield units), image noise levels, and signal-to-noise ratios (SNRs) in six predefined intravascular sites (three thoracic and three abdominal) were measured by two readers. All values were analyzed using the Kruskal-Wallis test and two-way ANOVA. RESULTS: There was a significant reduction in the effective dose (in millisieverts) for protocols B (mean ± SD, 2.03 ± 0.1 mSv) and C (1.00 ± 0.0 mSv) compared with protocol A (4.34 ± 0.0 mSv). The dose was reduced by 53% for protocol B and by 77% for protocol C. No significant differences were found in the effective dose among the different CM injection protocols within the scanning protocols; all p values were > 0.05. The attenuation values and SNRs were comparable among all the different CM injection protocols; all p values were > 0.05. CONCLUSION: A large radiation dose reduction (77%) can be achieved using automated tube voltage selection independent of the CM injection protocol.

Dual-energy computed tomography for the assessment of early treatment effects of regorafenib in a preclinical tumor model: comparison with dynamic contrast-enhanced CT and conventional contrast-enhanced single-energy CT.

OBJECTIVES: The potential diagnostic value of dual-energy computed tomography (DE-CT) compared to dynamic contrast-enhanced CT (DCE-CT) and conventional contrast-enhanced CT (CE-CT) in the assessment of early regorafenib treatment effects was evaluated in a preclinical setting. METHODS: A rat GS9L glioma model was examined with contrast-enhanced dynamic DE-CT measurements (80 kV/140 kV) for 4 min before and on days 1 and 4 after the start of daily regorafenib or placebo treatment. Tumour time-density curves (0-240 s, 80 kV), DE-CT (60 s) derived iodine maps and the DCE-CT (0-30 s, 80 kV) based parameters blood flow (BF), blood volume (BV) and permeability (PMB) were calculated and compared to conventional CE-CT (60 s, 80 kV). RESULTS: The regorafenib group showed a marked decrease in the tumour time-density curve, a significantly lower iodine concentration and a significantly lower PMB on day 1 and 4 compared to baseline, which was not observed for the placebo group. CE-CT showed a significant decrease in tumour density on day 4 but not on day 1. The DE-CT-derived iodine concentrations correlated with PMB and BV but not with BF. CONCLUSIONS: DE-CT allows early treatment monitoring, which correlates with DCE-CT. Superior performance was observed compared to single-energy CE-CT. KEY POINTS: • Regorafenib treatment response was evaluated by CT in a rat tumour model. • Dual-energy contrast-enhanced CT allows early treatment monitoring of targeted anti-tumour therapies. • Dual-energy CT showed higher diagnostic potential than conventional contrast enhanced single-energy CT. • Dual-energy CT showed diagnostic potential comparable to dynamic contrast-enhanced CT. • Dual-energy CT is a promising method for efficient clinical treatment response evaluation.

Comprehensive Analysis of the Spatial Distribution of Gadolinium, Iron, Manganese, and Phosphorus in the Brain of Healthy Rats After High-Dose Administrations of Gadodiamide and Gadobutrol.

OBJECTIVES: After the administration of gadolinium-based contrast agents (GBCAs), residual gadolinium (Gd) has been detected in a few distinct morphological structures of the central nervous system (CNS). However, a systematic, comprehensive, and quantitative analysis of the spatial Gd distribution in the entire brain is not yet available. The first aim of this study is to provide this analysis in healthy rats after administration of high GBCA doses. The second aim is to assess the spatial distributions and possible Gd colocalizations of endogenous iron (Fe), manganese (Mn), and phosphorus (P). In addition, the presence of Gd in proximity to blood vessels was assessed by immunohistochemistry. MATERIALS AND METHODS: Male rats were randomly assigned to 3 groups (n = 3/group): saline (control), gadodiamide (linear GBCA), and gadobutrol (macrocyclic GBCA) with cumulative Gd doses of 14.4 mmol/kg of body mass. Five weeks after the last administration, the brains were collected and cryosectioned. The spatial distributions of Gd, Fe, Mn, and P were analyzed in a total of 130 sections, each covering the brain in 1 of the 3 perpendicular anatomical orientations, using laser ablation coupled with inductively coupled plasma mass spectrometry. Quantitative spatial element maps were generated, and the concentrations of Gd, Fe, and Mn were measured in 31 regions of interest covering various distinct CNS structures. Correlation analyses were performed to test for possible colocalization of Gd, Fe, and Mn. The spatial proximity of Gd and blood vessels was studied using metal-tagged antibodies against von Willebrand factor with laser ablation coupled with inductively coupled plasma mass spectrometry. RESULTS: After administration of linear gadodiamide, high Gd concentrations were measured in many distinct structures of the gray matter. This involved structures previously reported to retain Gd after linear GBCA, such as the deep cerebellar nuclei or the globus pallidus, but also structures that had not been reported so far including the dorsal subiculum, the retrosplenial cortex, the superior olivary complex, and the inferior colliculus. The analysis in all 3 orientations allowed the localization of Gd in specific subregions and layers of certain structures, such as the hippocampus and the primary somatosensory cortex. After macrocyclic gadobutrol, the Gd tissue concentration was significantly lower than after gadodiamide. Correlation analyses of region of interest concentrations of Gd, Fe, and Mn revealed no significant colocalization of Gd with endogenous Fe or Mn in rats exposed to either GBCA. Immunohistochemistry revealed a colocalization of Gd traces with vascular endothelium in the deep cerebellar nuclei after gadobutrol, whereas the majority of Gd was found outside the vasculature after gadodiamide. CONCLUSIONS: In rats exposed to gadodiamide but not in rats exposed to gadobutrol, high Gd concentrations were measured in various distinct CNS structures, and structures not previously reported were identified to contain Gd, including specific subregions and layers with different cytoarchitecture and function. Knowledge of these distinct spatial patterns may pave the way for tailored functional neurological testing. Signs for the localization of the remaining Gd in the vascular endothelium were prominent for gadobutrol but not gadodiamide. The results also indicate that local transmetalation with endogenous Fe or Mn is unlikely to explain the spatial patterns of Gd deposition in the brain, which argues against a general role of these metals in local transmetalation and release of Gd ions in the CNS.

AI as a New Frontier in Contrast Media Research: Bridging the Gap Between Contrast Media Reduction, the Contrast-Free Question and New Application Discoveries.

ABSTRACT: Artificial intelligence (AI) techniques are currently harnessed to revolutionize the domain of medical imaging. This review investigates 3 major AI-driven approaches for contrast agent management: new frontiers in contrast agent dose reduction, the contrast-free question, and new applications. By examining recent studies that use AI as a new frontier in contrast media research, we synthesize the current state of the field and provide a comprehensive understanding of the potential and limitations of AI in this context. In doing so, we show the dose limits of reducing the amount of contrast agents and demonstrate why it might not be possible to completely eliminate contrast agents in the future. In addition, we highlight potential new applications to further increase the radiologist's sensitivity at normal doses. At the same time, this review shows which network architectures provide promising approaches and reveals possible artifacts of a paired image-to-image conversion. Furthermore, current US Food and Drug Administration regulatory guidelines regarding AI/machine learning-enabled medical devices are highlighted.

Countering Calcium Blooming With Personalized Contrast Media Injection Protocols: The 1-2-3 Rule for Photon-Counting Detector CCTA.

OBJECTIVE: Photon-counting detector computed tomography (PCD-CT) enables spectral data acquisition of CT angiographies allowing for reconstruction of virtual monoenergetic images (VMIs) in routine practice. Specifically, it has potential to reduce the blooming artifacts associated with densely calcified plaques. However, calcium blooming and iodine attenuation are inversely affected by energy level (keV) of the VMIs, creating a challenge for contrast media (CM) injection protocol optimization. A pragmatic and simple rule for calcium-dependent CM injection protocols is investigated and proposed for VMI-based coronary CT angiography with PCD-CT. MATERIALS AND METHODS: A physiological circulation phantom with coronary vessels including calcified lesions (maximum CT value >700 HU) with a 50% diameter stenosis was injected into at iodine delivery rates (IDRs) of 0.3, 0.5, 0.7, 1.0, 1.5, 2.0, 2.5, and 3.0 g I/s. Images were acquired using a first-generation dual-source PCD-CT and reconstructed at various VMI levels (between 45 and 190 keV). Iodine attenuation in the coronaries was measured at each IDR for each keV, and blooming artifacts from the calcified lesions were assessed including stenosis grading error (as % overestimation vs true lumen). The IDR to achieve 300 HU at each VMI level was then calculated and compared with stenosis grading accuracy to establish a general rule for CM injection protocols. RESULTS: Plaque blooming artifacts and intraluminal iodine attenuation decreased with increasing keV. Fixed windowing (representing absolute worst case) resulted in stenosis overestimation from 77% ± 4% at 45 keV to 5% ± 2% at 190 keV, whereas optimized windowing resulted in overestimation from 29% ± 3% at 45 keV to 4% ± 1% at 190 keV. The required IDR to achieve 300 HU showed a strong linear correlation to VMI energy ( R2 = 0.98). Comparison of this linear plot versus stenosis grading error and blooming artifact demonstrated that multipliers of 1, 2, and 3 times the reference IDR for theoretical clinical regimes of no, moderate, and severe calcification density, respectively, can be proposed as a general rule. CONCLUSIONS: This study provides a proof-of-concept in an anthropomorphic phantom for a simple pragmatic adaptation of CM injection protocols in coronary CT angiography with PCD-CT. The 1-2-3 rule demonstrates the potential for reducing the effects of calcium blooming artifacts on overall image quality.

Tungsten-Based Contrast Agent for Photon-Counting Detector CT Angiography in Calcified Coronaries: Comparison to Iodine in a Cardiovascular Phantom.

OBJECTIVES: Calcified plaques induce blooming artifacts in coronary computed tomography angiography (CCTA) potentially leading to inaccurate stenosis evaluation. Tungsten represents a high atomic number, experimental contrast agent with different physical properties than iodine. We explored the potential of a tungsten-based contrast agent for photon-counting detector (PCD) CCTA in heavily calcified coronary vessels. MATERIALS AND METHODS: A cardiovascular phantom exhibiting coronaries with calcified plaques was imaged on a first-generation dual-source PCD-CT. The coronaries with 3 different calcified plaques were filled with iodine and tungsten contrast media solutions equating to iodine and tungsten delivery rates (IDR and TDR) of 0.3, 0.5, 0.7, 1.0, 1.5, 2.0, 2.5, and 3.0 g/s, respectively. Electrocardiogram-triggered sequential acquisitions were performed in the spectral mode (QuantumPlus). Virtual monoenergetic images (VMIs) were reconstructed from 40 to 190 keV in 1 keV increments. Blooming artifacts and percentage error stenoses from calcified plaques were quantified, and attenuation characteristics of both contrast media were recorded. RESULTS: Blooming artifacts from calcified plaques were most pronounced at 40 keV (78%) and least pronounced at 190 keV (58%). Similarly, percentage error stenoses were highest at 40 keV (48%) and lowest at 190 keV (2%), respectively. Attenuation of iodine decreased monotonically in VMIs from low to high keV, with the strongest decrease from 40 keV to 100 keV (IDR of 2.5 g/s: 1279 HU at 40 keV, 187 HU at 100 kV, and 35 HU at 190 keV). The attenuation of tungsten, on the other hand, increased monotonically as a function of VMI energy, with the strongest increase between 40 and 100 keV (TDR of 2.5 g/s: 202 HU at 40 keV, 661 HU at 100 kV, and 717 HU at 190 keV). For each keV level, the relationship between attenuation and IDR/TDR could be described by linear regressions ( R2 ≥ 0.88, P < 0.001). Specifically, attenuation increased linearly when increasing the delivery rate irrespective of keV level or contrast medium. Iodine exhibited the highest relative increase in attenuation values at lower keV levels when increasing the IDR. Conversely, for tungsten, the greatest relative increase in attenuation values occurred at higher keV levels when increasing the TDR. When high keV imaging is desirable to reduce blooming artifacts from calcified plaques, IDR has to be increased at higher keV levels to maintain diagnostic vessel attenuation (ie, 300 HU), whereas for tungsten, TDR can be kept constant or can be even reduced at high keV energy levels. CONCLUSIONS: Tungsten's attenuation characteristics in relation to VMI energy levels are reversed to those of iodine, with tungsten exhibiting high attenuation values at high keV levels and vice versa. Thus, tungsten shows promise for high keV imaging CCTA with PCD-CT as-in distinction to iodine-both high vessel attenuation and low blooming artifacts from calcified plaques can be achieved.

Contrast medium injection protocol adjusted for body surface area in combined PET/CT.

OBJECTIVES: To evaluate the effect of contrast medium dose adjustment for body surface area (BSA) compared with a fixed-dose protocol in combined positron emission tomography (PET) and computed tomography (CT) (PET/CT). METHODS: One hundred and twenty patients were prospectively included for (18)F-2-deoxy-fluor-glucose ((18)F-FDG)-PET/CT consisting of a non-enhanced and a venous contrast-enhanced CT, both used for PET attenuation correction. The first 60 consecutive patients received a fixed 148-ml contrast medium dose. The second 60 patients received a dose that was based on their calculated BSA. Mean and maximum standardised FDG uptake (SUVmean and SUVmax) and contrast enhancement (HU) were measured at multiple anatomical sites and PET reconstructions were evaluated visually for image quality. RESULTS: A decrease in the variance of contrast enhancement in the BSA group compared with the fixed-dose group was seen at all anatomical sites. Comparison of tracer uptake SUVmean and SUVmax between the fixed and the BSA group revealed no significant differences at all anatomical sites (all P > 0.05). Comparison of the overall image quality scores between the fixed and the BSA group showed no significant difference (P = 0.753). CONCLUSIONS: BSA adjustment results in increased interpatient homogeneity of contrast enhancement without affecting PET values. In combined PET/CT, a BSA adjusted contrast medium protocol should be used preferably. KEY POINTS: • Intravenous contrast medium is essential for many applications of PET/CT • Body surface area adjustment of contrast medium helps standardise contrast enhancement • Underdosing or overdosing of contrast medium will be reduced • PET image quality is not influenced • BSA adjusted contrast medium protocol should be used preferably in combined PET/CT.

Identification of the iodine concentration that yields the highest intravascular enhancement in MDCT angiography.

OBJECTIVE: The objective of our study was to identify the iodine concentration that yields the highest intravascular contrast enhancement in MDCT angiography by intraindividual comparison in an animal model. MATERIALS AND METHODS: Six pigs underwent repeated chest MDCT examinations under standardized conditions using the same contrast medium (iopromide) with different iodine concentrations (150, 240, 300, and 370 mg I/mL). The contrast injection protocol was adapted to ensure an identical iodine delivery rate of 1.5 g I/s and the same total iodine dose of 300 mg/kg of body weight for all studies. Dynamic CT scans were acquired at the levels of the pulmonary artery and the ascending and descending aorta. Pulmonary and aortic peak enhancement values as well as time to peak (TTP) were calculated from time-enhancement curves. RESULTS: Pulmonary and aortic peak contrast enhancement values were significantly higher with the 240 and 300 mg I/mL contrast media than the 150 and 370 mg I/mL contrast media (e.g., ascending aorta: 240 vs 150, p = 0.0070; 300 vs 150, p = 0.0096; 240 vs 370, p = 0.0262; 300 vs 370, p = 0.0079). TTP values tended to be lower for the 150 mg I/mL contrast medium than for the contrast media with higher iodine concentrations. CONCLUSION: Comparison of contrast media with iodine concentrations ranging from 150 to 370 mg I/mL showed that contrast enhancement was significantly improved with the use of 240 and 300 mg I/mL contrast media given a fixed identical iodine delivery and normalized total iodine load in a porcine model. Contrast media with a moderate iodine concentration are most suitable for obtaining the highest intravascular contrast enhancement in CT angiography.

New Contrast Media for K-Edge Imaging With Photon-Counting Detector CT.

ABSTRACT: The recent technological developments in photon-counting detector computed tomography (PCD-CT) and the introduction of the first commercially available clinical PCD-CT unit open up new exciting opportunities for contrast media research. With PCD-CT, the efficacy of available iodine-based contrast media improves, allowing for a reduction of iodine dosage or, on the other hand, an improvement of image quality in low contrast indications. Virtual monoenergetic image reconstructions are routinely available and enable the virtual monoenergetic image energy to be adapted to the diagnostic task.A key property of PCD-CT is the ability of spectral separation in combination with improved material decomposition. Thus, the discrimination of contrast media from intrinsic or pathological tissues and the discrimination of 2 or more contrasting elements that characterize different tissues are attractive fields for contrast media research. For these approaches, K-edge imaging in combination with high atomic number elements such as the lanthanides, tungsten, tantalum, or bismuth plays a central role.The purpose of this article is to present an overview of innovative contrast media concepts that use high atomic number elements. The emphasis is on improving contrast enhancement for cardiovascular plaque imaging, stent visualization, and exploring new approaches using 2 contrasting elements. Along with the published research, new experimental findings with a contrast medium that incorporates tungsten are included.Both the literature review and the new experimental data demonstrate the great potential and feasibility for new contrast media to significantly increase diagnostic performance and to enable new clinical fields and indications in combination with PCD-CT.