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.

How Should We Measure Neurotoxicity of Gadolinium-Based Contrast Agents? No abstract available

Gadolinium Retention in the Brain: What Do We Need to Consider for Clinical Use? No abstract available

Gadolinium Presence in the Brain After Administration of the Liver-Specific Gadolinium-Based Contrast Agent Gadoxetate: A Systematic Comparison to Multipurpose Agents in Rats Objective Clinical studies have reported different results regarding the signal intensity (SI) increase in the dentate nucleus on unenhanced T1-weighted magnetic resonance imaging (MRI) after repeated administrations of gadolinium-based contrast agents (GBCAs). The aim of this study was to evaluate MRI SI changes and gadolinium (Gd) brain concentrations in an animal model after repeated administration of liver-specific linear gadoxetate in comparison to multipurpose linear and macrocyclic GBCAs. Recently, it was demonstrated that small amounts of GBCAs are able to cross the blood–cerebrospinal fluid (CSF) barrier. Therefore, a secondary aim was to test if the administration of these GBCAs directly into the CSF results in a similar MRI pattern and brain Gd concentration than after systemic intravenous injection. Materials and Methods Forty-eight Han-Wistar rats were equally divided into the following 4 groups: gadoxetate (liver-specific linear), gadodiamide (multipurpose linear), gadobutrol (multipurpose macrocyclic), and control (saline, artificial CSF). For systemic application, 6 animals per group received 8 intravenous injections on 4 consecutive days per week over 2 weeks using a dose of 0.15 mmol/kg for gadoxetate and 0.6 mmol/kg for multipurpose GBCAs per injection, which corresponds to the recommended clinical dose in humans. For CSF application, 6 animals per group received one intracisternal administration of 0.31 μmol Gd (gadoxetate) and 1.25 μmol Gd (multipurpose GBCAs) or an equal volume of artificial CSF. Brain MRI was performed after a period of 5 weeks to evaluate the SI in deep cerebellar nuclei (DCN) and brain stem. Subsequently, animals were euthanized and their brains were dissected for Gd quantification by inductively coupled plasma-mass spectrometry. Results Visually evident increased SIs in the DCN were observed in blinded image review only after administration of gadodiamide. The respective SI ratios between DCN and brain stem were significantly higher compared with the control groups (P = 0.009 and P = 0.002 for intravenous and intracisternal application, respectively), whereas no difference was found for gadoxetate and gadobutrol (P ≥ 0.9). Inductively coupled plasma–mass spectrometry revealed the lowest Gd content in the brain tissue after administration for gadoxetate. The mean Gd concentrations in the cerebellum were 0.08 nmol/g (gadoxetate), 2.66 nmol/g (gadodiamide), and 0.26 nmol/g (gadobutrol) after intravenous administration, and 0.28 nmol/g (gadoxetate), 3.23 nmol/g (gadodiamide), and 0.69 nmol/g (gadobutrol) after intracisternal application. Conclusions This rat study demonstrates distinct differences in the presence of gadolinium in the brain between the liver-specific linear gadoxetate and the multipurpose linear GBCA gadodiamide. No MRI signal alterations were observed after 8 dose-adapted intravenous or a single intracisternal administrations of gadoxetate and multipurpose macrocyclic gadobutrol. The Gd concentrations in the brain 5 weeks after intravenous administration of gadoxetate were an order of magnitude lower compared with gadodiamide and slightly lower than for gadobutrol. Likely reasons for these differences are the 4-fold lower dose, the dual excretion pathway, and the higher complex stability of gadoxetate compared with multipurpose linear GBCAs. The similar findings for both routes of GBCA administration underlines the assumption that the very small amount of GBCAs that cross the blood-CSF barrier is further transported into the brain tissue.

Physicochemical and Pharmacokinetic Profiles of Gadopiclenol: A New Macrocyclic Gadolinium Chelate With High T1 Relaxivity Objectives We aimed to evaluate gadopiclenol, a newly developed extracellular nonspecific macrocyclic gadolinium-based contrast agent (GBCA) having high relaxivity properties, which was designed to increase lesion detection and characterization by magnetic resonance imaging. Methods We described the molecular structure of gadopiclenol and measured the r1 and r2 relaxivity properties at fields of 0.47 and 1.41 T in water and human serum. Nuclear magnetic relaxation dispersion profile measurements were performed from 0.24 mT to 7 T. Protonation and complexation constants were determined using pH-metric measurements, and we investigated the acid-assisted dissociation of gadopiclenol, gadodiamide, gadobutrol, and gadoterate at 37°C and pH 1.2. Applying the relaxometry technique (37°C, 0.47 T), we investigated the risk of dechelation of gadopiclenol, gadoterate, and gadodiamide in the presence of ZnCl2 (2.5 mM) and a phosphate buffer (335 mM). Pharmacokinetics studies of radiolabeled 153Gd-gadopiclenol were performed in Beagle dogs, and protein binding was measured in rats, dogs, and humans plasma and red blood cells. Results Gadopiclenol [gadolinium chelate of 2,2′,2″-(3,6,9-triaza-1(2,6)-pyridinacyclodecaphane-3,6,9-triyl)tris(5-((2,3-dihydroxypropyl)amino)-5-oxopentanoic acid); registry number 933983-75-6] is based on a pyclen macrocyclic structure. Gadopiclenol exhibited a very high relaxivity in water (r1 = 12.2 mM−1·s−1 at 1.41 T), and the r1 value in human serum at 37°C did not markedly change with increasing field (r1 = 12.8 mM−1·s−1 at 1.41 T and 11.6 mM−1·s−1 at 3 T). The relaxivity data in human serum did not indicate protein binding. The nuclear magnetic relaxation dispersion profile of gadopiclenol exhibited a high and stable relaxivity in a strong magnetic field. Gadopiclenol showed high kinetic inertness under acidic conditions, with a dissociation half-life of 20 ± 3 days compared with 4 ± 0.5 days for gadoterate, 18 hours for gadobutrol, and less than 5 seconds for gadodiamide and gadopentetate. The pharmacokinetic profile in dogs was typical of extracellular nonspecific GBCAs, showing distribution in the extracellular compartment and no metabolism. No protein binding was found in rats, dogs, and humans. Conclusions Gadopiclenol is a new extracellular and macrocyclic Gd chelate that exhibited high relaxivity, no protein binding, and high kinetic inertness. Its pharmacokinetic profile in dogs was similar to that of other extracellular nonspecific GBCAs.

Targeted Biopsy Validation of Peripheral Zone Prostate Cancer Characterization With Magnetic Resonance Fingerprinting and Diffusion Mapping Objective This study aims for targeted biopsy validation of magnetic resonance fingerprinting (MRF) and diffusion mapping for characterizing peripheral zone (PZ) prostate cancer and noncancers. Materials and Methods One hundred four PZ lesions in 85 patients who underwent magnetic resonance imaging were retrospectively analyzed with apparent diffusion coefficient (ADC) mapping, MRF, and targeted biopsy (cognitive or in-gantry). A radiologist blinded to pathology drew regions of interest on targeted lesions and visually normal peripheral zone on MRF and ADC maps. Mean T1, T2, and ADC were analyzed using linear mixed models. Generalized estimating equations logistic regression analyses were used to evaluate T1 and T2 relaxometry combined with ADC in differentiating pathologic groups. Results Targeted biopsy revealed 63 cancers (low-grade cancer/Gleason score 6 = 10, clinically significant cancer/Gleason score ≥7 = 53), 15 prostatitis, and 26 negative biopsies. Prostate cancer T1, T2, and ADC (mean ± SD, 1660 ± 270 milliseconds, 56 ± 20 milliseconds, 0.70 × 10−3 ± 0.24 × 10−3 mm2/s) were significantly lower than prostatitis (mean ± SD, 1730 ± 350 milliseconds, 77 ± 36 milliseconds, 1.00 × 10−3 ± 0.30 × 10−3 mm2/s) and negative biopsies (mean ± SD, 1810 ± 250 milliseconds, 71 ± 37 milliseconds, 1.00 × 10−3 ± 0.33 × 10−3 mm2/s). For cancer versus prostatitis, ADC was sensitive and T2 specific with comparable area under curve (AUC; (AUCT2 = 0.71, AUCADC = 0.79, difference between AUCs not significant P = 0.37). T1 + ADC (AUCT1 + ADC = 0.83) provided the best separation between cancer and negative biopsies. Low-grade cancer T2 and ADC (mean ± SD, 75 ± 29 milliseconds, 0.96 × 10−3 ± 0.34 × 10−3 mm2/s) were significantly higher than clinically significant cancers (mean ± SD, 52 ± 16 milliseconds, 0.65 ± 0.18 × 10−3 mm2/s), and T2 + ADC (AUCT2 + ADC = 0.91) provided the best separation. Conclusions T1 and T2 relaxometry combined with ADC mapping may be useful for quantitative characterization of prostate cancer grades and differentiating cancer from noncancers for PZ lesions seen on T2-weighted images.

Imaging Features of Hepatocellular Carcinoma: Quantitative and Qualitative Comparison Between MRI-Enhanced With Gd-EOB-DTPA and Gd-DTPA Objectives The aim of this study was to compare the major imaging features of hepatocellular carcinoma (HCC) on magnetic resonance imaging (MRI) scans with Gd-EOB-DTPA (EOB) and extracellular agent (ECA; Gd-DTPA) contrast media. Materials and Methods Among 184 surgically proven HCCs in 169 patients who underwent a liver MRI with either EOB (n = 120) or ECA (n = 49), 55 HCCs were matched according to tumor size, Edmonson grade (major and worst), and gross type for each of the 2 contrast media. For the qualitative analysis, 2 board-certified radiologists independently reviewed arterial phase hyperenhancement, hypointensity on portal venous phase, hypointensity on delayed or transitional phase (DP/TP, 120–150 seconds), and capsule appearance. For the quantitative analysis, a third radiologist measured the signal intensity at each phase by placing the region of interest for tumor and normal liver parenchyma. The lesion-to-liver contrast (LLC) and lesion-to-liver contrast enhancement ratio (LLCER) were calculated. Results On qualitative analysis, hypointensity on DP/TP was seen more frequently with EOB (91% in reader 1, 89% in reader 2) than with ECA (73% in reader 1, 75% in reader 2; P = 0.026). Capsule appearance was seen less frequently with EOB (31% in reader 1, 44% in reader 2) than with ECA (73% in reader 1, 78% in reader 2; P < 0.001). On quantitative analysis, the LLC on arterial phase (AP) was better with ECA (P = 0.003), whereas LLC on DP was better with EOB (P < 0.001). The LLCER from precontrast to AP was higher with ECA (P = 0.022), whereas the LLCER from portal venous phase to DP was higher with EOB (P < 0.001). Conclusions ECA-MRI revealed better LLC on AP and detection rate of capsule appearance than EOB-MRI. EOB-MRI showed superior LLC on TP.

Super-Resolution Contrast-Enhanced Ultrasound Methodology for the Identification of In Vivo Vascular Dynamics in 2D Objectives The aim of this study was to provide an ultrasound-based super-resolution methodology that can be implemented using clinical 2-dimensional ultrasound equipment and standard contrast-enhanced ultrasound modes. In addition, the aim is to achieve this for true-to-life patient imaging conditions, including realistic examination times of a few minutes and adequate image penetration depths that can be used to scan entire organs without sacrificing current super-resolution ultrasound imaging performance. Methods Standard contrast-enhanced ultrasound was used along with bolus or infusion injections of SonoVue (Bracco, Geneva, Switzerland) microbubble (MB) suspensions. An image analysis methodology, translated from light microscopy algorithms, was developed for use with ultrasound contrast imaging video data. New features that are tailored for ultrasound contrast image data were developed for MB detection and segmentation, so that the algorithm can deal with single and overlapping MBs. The method was tested initially on synthetic data, then with a simple microvessel phantom, and then with in vivo ultrasound contrast video loops from sheep ovaries. Tracks detailing the vascular structure and corresponding velocity map of the sheep ovary were reconstructed. Images acquired from light microscopy, optical projection tomography, and optical coherence tomography were compared with the vasculature network that was revealed in the ultrasound contrast data. The final method was applied to clinical prostate data as a proof of principle. Results Features of the ovary identified in optical modalities mentioned previously were also identified in the ultrasound super-resolution density maps. Follicular areas, follicle wall, vessel diameter, and tissue dimensions were very similar. An approximately 8.5-fold resolution gain was demonstrated in vessel width, as vessels of width down to 60 μm were detected and verified (λ = 514 μm). Best agreement was found between ultrasound measurements and optical coherence tomography with 10% difference in the measured vessel widths, whereas ex vivo microscopy measurements were significantly lower by 43% on average. The results were mostly achieved using video loops of under 2-minute duration that included respiratory motion. A feasibility study on a human prostate showed good agreement between density and velocity ultrasound maps with the histological evaluation of the location of a tumor. Conclusions The feasibility of a 2-dimensional contrast-enhanced ultrasound-based super-resolution method was demonstrated using in vitro, synthetic and in vivo animal data. The method reduces the examination times to a few minutes using state-of-the-art ultrasound equipment and can provide super-resolution maps for an entire prostate with similar resolution to that achieved in other studies.

Agreement and Reproducibility of Proton Density Fat Fraction Measurements Using Commercial MR Sequences Across Different Platforms: A Multivendor, Multi-Institutional Phantom Experiment Objectives The aim of this study was to evaluate the agreement and reproducibility of proton density fat fraction (PDFF) measurements using commercial magnetic resonance (MR) sequences across different imagers, vendors, and field strengths via a phantom experiment. Materials and Methods Eleven fat-water emulsion phantoms of varying fat proportions (ie, 0–50 weight%) were constructed. Phantom PDFFs were estimated using commercial chemical shift–based MR imaging sequences with Siemens 1.5 T and 3.0 T, Philips 3.0 T, and GE 1.5 T and 3.0 T imagers, and MR spectroscopic sequences (HISTO) with Siemens 1.5 T and 3.0 T imagers. Agreement among the estimated PDFF values between commercial sequences was evaluated using Bland-Altman analysis. Reproducibility of the PDFF measurements across commercial sequences was evaluated using the reproducibility coefficient. The test-retest repeatability of the PDFF measurements was evaluated using the repeatability coefficient. Results The repeatability coefficient of the PDFF measurements was 0.31% to 1.58% for the absolute PDFF value for commercial sequences. Statistically significant biases in the estimated PDFF were noted in 19 of 21 pairwise comparisons of commercial sequences (range of mean biases, −4.48% to 8.15% for the absolute PDFF value). The reproducibility coefficient of PDFF measurements was 9.0% for the absolute PDFF value over all commercial sequences and 10.6% for the absolute PDFF value over all chemical shift–based MR imaging sequences. Conclusions The measurement of the PDFF is highly repeatable with commercial MR sequences but is not reproducible across different sequences, imager vendors, and field strengths. The use of the same sequence and imager is therefore recommended for the longitudinal follow-up of hepatic steatosis using commercial MR sequences for PDFF measurements.

Simultaneous Multislice Echo Planar Imaging for Accelerated Diffusion-Weighted Imaging of Malignant and Benign Breast Lesions Objectives Comparison of the diagnostic value of simultaneous multislice (SMS) accelerated diffusion-weighted echo planar imaging (EPI) of malignant and benign lesions of the breast compared with a reference EPI sequence. Materials and Methods The study was approved by the institutional ethics committee. Sixty-eight patients were examined with a diffusion-weighted EPI (reference EPI; TE = 54 milliseconds; TR = 9000 milliseconds; TA, 3:27 minutes) and a diffusion-weighted SMS accelerated EPI (SMS EPI; acceleration factor 2; TE = 58 milliseconds; TR = 4300 milliseconds; TA, 1:53 minutes) in addition to the standard magnetic resonance imaging (MRI) protocol. Further acquisition parameters were as follows: 3 T MAGNETOM Skyra (Siemens Healthcare, Erlangen, Germany), 2.5-mm isotropic resolution, field of view = 185 to 190 × 350 mm2, 62 slices, b = 50 and 800 s/mm2 with 1 and 4 averages, respectively. A dedicated 16-channel bilateral breast coil was used for imaging. Image quality was evaluated with respect to the presence of artifacts, signal voids, and quality of fat suppression. These parameters were rated using a 5-point Likert scale (1 = very strong to 5 = negligible). The apparent diffusion coefficient (ADC) was measured in 72 focal lesions (46 breast carcinomas and 26 benign lesions), and the diagnostic value of the 2 datasets was statistically evaluated and compared. The evaluation was performed a second time excluding cysts. Results Artifacts and signal voids were negligible in both sequences (mean on Likert scale for reference EPI 4.68 vs SMS EPI 4.65, P = 0.52, and mean on Likert scale for reference EPI 4.85 vs SMS EPI 4.77, P = 0.14). Fat suppression was significantly better in SMS EPI (mean on Likert scale 3.28 vs 2.97, P < 0.001, Pearson r = 0.49). For benign lesions, the mean ADC in both EPI sequences was 1.86 · 10−3 mm2/s. For malignant lesions, a mean ADC of 0.90 · 10−3 mm2/s for the reference EPI and 0.89 · 10−3 mm2/s for the SMS EPI was found. No significant difference between the EPI sequences was observed for ADC values (P = 0.75) and for the area under the curve (SMS, 0.985; no SMS, 0.975). The cutoff for differentiation of benign and malignant lesions was at ADC = 1.42 · 10−3 mm2/s for SMS EPI (sensitivity, 1; specificity, 0.88) and at 1.23 · 10−3 mm2/s for the reference EPI (sensitivity, 1; specificity, 0.92). Excluding the cysts, the cutoff for differentiation of benign and malignant lesions was at ADC = 1.11 · 10−3 mm2/s for SMS EPI (sensitivity, 0.89; specificity, 0.93) and at 1.23 · 10−3 mm2/s for the reference EPI (sensitivity, 1; specificity, 0.87). Conclusions Our data indicate that SMS acceleration can be used for diffusion imaging in breast MRI in clinical practice. Simultaneous multislice EPI achieved the same diagnostic accuracy in breast MRI, but in a substantially reduced scan time.