Gadolinium-based contrast agents aggravate mechanical and thermal hyperalgesia in a nitroglycerine-induced migraine model in male mice.

In the diagnosis of migraine, which is a neurovascular disease, gadolinium-based contrast agents (GBCAs) are used to rule out more serious conditions. On the other hand, it remains unclear as a scientific gap whether GBCAs may trigger migraine-related pain. The aim of this study was to investigate the effect of GBCAs on mechanical and thermal pain behaviour in a nitroglycerin (NTG)-induced migraine model in mice. NTG (10 mg/kg) was administered intraperitoneally to adult (6-8weeks old) BALB/c mice 2 h before behavioral tests 5 times every other day on days 1st, 3rd, 5th and 9th to induce migraine model (N = 50). As GBCAs, gadobenate dimeglumine (linear-ionic), Gadodiamide (linear-nonionic), and gadobutrol (macrocyclic-nonionic) were delivered intravenously through the tail vein of mice for 5 days on test days. Mechanical pain threshold (plantar and facial withdrawal threshold) was evaluated by plantar von Frey and periorbital von Frey tests on days 1st, 5th, and 9th, and thermal pain threshold (latency) was evaluated by hot plate and cold plate tests on days 3rd and 7th. There was a statistically significant increase in mechanical and thermal hyperalgesia in NTG administered groups compared to the control group. Gadodiamide, gadobutrol and gadobenate dimeglumine administration significantly decreased latency, paw and facial withdrawal threshold (0.18 ± 0.05, 0.17 ± 0.07, 0.16 ± 0.09; 9th day values respectively) compared to NTG group (0.27 ± 0.05). The results of this in vivo study show that GBCAs produce effects that may trigger migraine attacks in migraine. It is recommended that these effects be further investigated and supported by further clinical studies.

Investigation of imaging features in contrast-enhanced magnetic resonance imaging of benign and malignant breast lesions.

PURPOSE: This study aimed to enhance the diagnostic accuracy of contrast-enhanced breast magnetic resonance imaging (MRI) using gadobutrol for differentiating benign breast lesions from malignant ones. Moreover, this study sought to address the limitations of current imaging techniques and criteria based on the Breast Imaging Reporting and Data System (BI-RADS). MATERIALS AND METHODS: In a multicenter retrospective study conducted in Japan, 200 women were included, comprising 100 with benign lesions and 100 with malignant lesions, all classified under BI-RADS categories 3 and 4. The MRI protocol included 3D fast gradient echo T1- weighted images with fat suppression, with gadobutrol as the contrast agent. The analysis involved evaluating patient and lesion characteristics, including age, size, location, fibroglandular tissue, background parenchymal enhancement (BPE), signal intensity, and the findings of mass and non-mass enhancement. In this study, univariate and multivariate logistic regression analyses were performed, along with decision tree analysis, to identify significant predictors for the classification of lesions. RESULTS: Differences in lesion characteristics were identified, which may influence malignancy risk. The multivariate logistic regression model revealed age, lesion location, shape, and signal intensity as significant predictors of malignancy. Decision tree analysis identified additional diagnostic factors, including lesion margin and BPE level. The decision tree models demonstrated high diagnostic accuracy, with the logistic regression model showing an area under the curve of 0.925 for masses and 0.829 for non-mass enhancements. CONCLUSION: This study underscores the importance of integrating patient age, lesion location, and BPE level into the BI-RADS criteria to improve the differentiation between benign and malignant breast lesions. This approach could minimize unnecessary biopsies and enhance clinical decision-making in breast cancer diagnostics, highlighting the effectiveness of gadobutrol in breast MRI evaluations.

The effect of delay time after injecting gadobutrol on the diagnosis of endolymphatic hydrops.

OBJECTIVES: The aim of this study was to reduce the time delay between gadolinium injection and 3D-FLAIR (three-dimensional fluid-attenuated inversion recovery) MRI by using a single dose of intravenous gadobutrol in Menière's disease patients. METHODS: 17 patients diagnosed with definite unilateral Meniere's disease underwent 3D-FLAIR MRI scans at 2, 4, and 6 h post-intravenous administration of a single-dose of gadobutrol. The signal intensity ratio of bilateral inner ear, cochlear and vestibular hydrops was measured at 2 h, 4 h and 6 h, while the differences in signal intensity ratio and endolymphatic hydrops were evaluated at three time points. RESULTS: The cochlea, vestibule, and semicircular canal exhibit clear structural features with distinct perilymph-endolymph boundaries at 2 h, 4 h, and 6 h. The signal intensity ratio of the affected ear was significantly higher than that of the unaffected ear at 2 h, 4 h, and 6 h. The signal intensity ratio at 4 h and 6 h in both the affected and unaffected ears was significantly higher than that at 2 h, but there was no significant difference between 4 h and 6 h. Cochlear hydrops and vestibular hydrops show no significant differences at these time points, demonstrating excellent consistency. CONCLUSIONS: We have demonstrated that 3D-FLAIR images acquired 2 h after intravenous administration of a single-dose gadobutrol are of high quality and equally effective as those obtained at the conventional 4-h time point for diagnosing endolymphatic hydrops in Menière's disease. In clinical practice, the delay time can be safely shortened to 2 h.

Interval between contrast administration and T1-weighted MRI for cerebral adrenoleukodystrophy: a single-case observation.

In adrenoleukodystrophy (ALD), contrast enhancement (CE) is a disease activity marker, but there is uncertainty about the optimal delay, if any, between contrast injection and magnetic resonance imaging (MRI) acquisition to avoid false-negative results. We acquired axial two-dimensional (2D) and three-dimensional (3D) T1-weighted gradient-echo every 6 min from 0 to 36 min after contrast administration (gadobutrol 0.1 mmol/kg) in an ALD patient with enlarging white matter lesions and progressive neuropsychological symptoms, using a 3-T magnet. The image signal over time was qualitatively assessed and measured in two regions of interest. On 3D sequences, no definite CE was appreciated, whereas on 2D sequences, CE was noticed after 6 min and definitely evident after 12 min, when 73% of the maximum signal intensity was measured. In ALD subjects, contrast-enhanced 2D T1-weighted gradient-echo sequences acquired at least 10 min after contrast injection may be considered to reduce false negative results.Relevance statementOur report is the first attempt to find an optimal delay between contrast administration and T1-weighted acquisition in cALD patients in order to correctly detect disease activity and avoid false negative results.Key points• The optimal time between contrast injection and image acquisition for MRI of adrenoleukodystrophy is unknown.• Contrast enhancement predicts adrenoleukodystrophy progression and could help patient's selection for the therapy.• We acquired two post-contrast T1-GRE-2D/3D sequences several times to find the best injection-time.• T1-weighted 2D GRE resulted more sensitive than T1-weighted 3D GRE even after long intervals from injection.• A delay of about 10 min may minimize false negatives.

Half-Dose versus Single-Dose Gadobutrol for Extracellular Volume Measurements in Cardiac Magnetic Resonance.

BACKGROUND: Cardiac magnetic resonance (CMR) imaging with gadolinium-based contrast agents offers unique non-invasive insights into cardiac tissue composition. Myocardial extracellular volume (ECV) has evolved as an objective and robust parameter with broad diagnostic and prognostic implications. For the gadolinium compound gadobutrol, the recommended dose for cardiac imaging, including ECV measurements, is 0.1 mmol/kg (single dose). This dose was optimized for late enhancement imaging, a measure of focal fibrosis. Whether a lower dose is sufficient for ECV measurements is unknown. We aim to evaluate the accuracy of ECV measurements using a half dose of 0.05 mmol/kg gadobutrol compared to the standard single dose of 0.1 mmol/kg. METHODS AND RESULTS: From a contemporary trial (NCT04747366, registered 10 February 2021), a total of 25 examinations with available T1 mapping before and after 0.05 and 0.1 mmol/kg gadobutrol were analyzed. ECV values were calculated automatically from pre- and post-contrast T1 relaxation times. T1 and ECV Measurements were performed in the midventricular septum. ECV values after 0.05 and 0.1 mmol/kg gadobutrol were correlated (R2 = 0.920, p < 0.001). ECV values after 0.05 mmol/kg had a bias of +0.9% (95%-CI [0.4; 1.4], p = 0.002) compared to 0.1 mmol/kg gadobutrol, with limits of agreement from -1.5 to 3.3%. CONCLUSIONS: CMR with a half dose of 0.05 mmol/kg gadobutrol overestimated ECV by 0.9% compared with a full dose of 0.1 mmol/kg, necessitating adjustment of normal values when using half-dose ECV imaging.

Evaluating blood supply changes in the osteonecrosis of the femoral head using gadobutrol-based steady-state MR angiography.

OBJECTIVES: Assess the feasibility of using gadobutrol-based steady-state (SS) MR angiography (MRA) to evaluate the blood supply changes of osteonecrosis of the femoral head (ONFH). MATERIALS AND METHODS: Participants were recruited in this prospective study from December 2021 to May 2022 in a single center. The number of superior retinacular arteries (SRAs), inferior retinacular arteries (IRAs), anterior retinacular arteries (ARAs), and overall retinacular arteries (ORAs), as well as the affected rates of SRA and IRA, were determined and compared between healthy and ONFH hips and between hips across the Association Research Circulation Osseous (ARCO) staging I-IV. RESULTS: Twenty healthy and 64 ONFH hips were evaluated in 54 participants. There were significant differences between ARCO I-IV for the number of ORAs (mean of 3.5, 2.3, 1.7, and 0.8 for ARCO I-IV, respectively; p < .001), SRAs (median of 2.5, 1, 0.5, and 0 for ARCO I-IV, respectively; p < .001), and the affected rate of SRAs (20.00%, 65.22%, 77.78%, 92.31% for ARCO I-IV, respectively, p = 0.002). There were significant differences between ONFH and healthy hips for the number of ORAs (median of 5 vs. 2; p < .001), SRAs (median of 3 vs. 1; p < .001), IRAs (median of 1 vs. 1; p < .001), ARAs (median of 0 vs. 0; p = 0.04), and also the affected rate of SRAs (5.00% vs. 67.20%, p < .001) and IRAs (30% vs. 84.4%, p < .001). CONCLUSION: Gadobutrol-enhanced SS MRA is a feasible method for evaluation of hemodynamics in ONFH. CLINICAL RELEVANCE STATEMENT: Gadobutrol-enhanced magnetic resonance angiography can evaluate blood supply changes of ONFH and therefore helps to aid in the diagnosis and guide treatment of ONFH. KEY POINTS: • Gadobutrol-enhanced magnetic resonance angiography showed changes in the retinacular artery related to the severity of femoral osteonecrosis. • Gadobutrol-enhanced magnetic resonance angiography revealed a reduced blood supply to the ischemic necrotic femoral head compared to the healthy counterparts.

Prospective T1 mapping to assess gadolinium retention in brain after intrathecal gadobutrol.

PURPOSE: A possible pathway behind gadolinium retention in brain is leakage of contrast agents from blood to cerebrospinal fluid and entry into brain along perivascular (glymphatic) pathways. The object of this study was to assess for signs of gadolinium retention in brain 4 weeks after intrathecal contrast enhanced MRI. METHODS: We prospectively applied standardized T1 mapping of the brain before and 4 weeks after intrathecal administration of 0.5 mmol gadobutrol in patients under work-up of cerebrospinal fluid circulation disorders. Due to methodological limitations, a safety margin for percentage change in T1 time was set to 3%. Region-wise differences were assessed by pairwise comparison using t-tests and forest plots, and statistical significance was accepted at .05 level (two-tailed). RESULTS: In a cohort of 76 participants (mean age 47.2 years ± 17.9 [standard deviation], 47 women), T1 relaxation times remained unchanged in cerebral cortex and basal ganglia 4 weeks after intrathecal gadobutrol. T1 was reduced from 1082 ± 46.7 ms to 1070.6 ± 36.5 ms (0.98 ±2.9%) (mean [standard deviation]) (p=0.001) in white matter, thus within the pre-defined 3% safety margin. The brain stem and cerebellum could not be assessed due to poor alignment of posterior fossa structures at scans from different time points. CONCLUSION: Gadolinium retention was not detected in the cerebral hemispheres 4 weeks after an intrathecal dose of 0.5 mmol gadobutrol, implying that presence of contrast agents in cerebrospinal fluid is of minor importance for gadolinium retention in brain.

Gadolinium retention in a rat model of subtotal renal failure: are there differences among macrocyclic GBCAs?

BACKGROUND: Gd levels are higher in tissues of animals with compromised renal function, but studies to compare levels after exposure to different macrocyclic gadolinium-based contrast agents (GBCAs) are lacking. We compared Gd levels in tissues of subtotally nephrectomised (SN) rats after repeated exposure to macrocyclic GBCAs. METHODS: Sprague-Dawley SN male rats (19 per group) received 16 injections of gadoteridol, gadobutrol, or gadoterate meglumine at 0.6 mmol Gd/kg 4 times/weeks over 4 weeks. A control group of healthy male rats (n = 10) received gadoteridol at the same dosage. Plasma urea and creatinine levels were monitored. Blood, cerebrum, cerebellum, liver, femur, kidney(s), skin and peripheral nerves were harvested for Gd determination by inductively coupled plasma-mass spectrometry at 28 and 56 days after the end of treatment. RESULTS: Plasma urea and creatinine levels were roughly twofold higher in SN rats than in healthy rats at all timepoints. At day 28, Gd levels in the peripheral nerves of gadobutrol- or gadoterate-treated SN animals were 5.4 or 7.2 times higher than in gadoteridol-treated animals (p < 0.001). Higher Gd levels after administration of gadobutrol or gadoterate versus gadoteridol were also determined in kidneys (p ≤ 0.002), cerebrum (p ≤ 0.001), cerebellum (p ≤ 0.003), skin (p ≥ 0.244), liver (p ≥ 0.053), and femur (p ≥ 0.271). At day 56, lower Gd levels were determined both in SN and healthy rats for all GBCAs and tissues, except the femur. CONCLUSIONS: Gd tissue levels were lower following gadoteridol exposure than following gadobutrol or gadoterate exposure.

Tet-Regulated Expression and Optical Clearing for In Vivo Visualization of Genetically Encoded Chimeric dCas9/Fluorescent Protein Probes.

The catalytically inactive mutant of Cas9 (dCas9) endonuclease has multiple biomedical applications, with the most useful being the activation/repression of transcription. dCas9 family members are also emerging as potential experimental tools for gene mapping at the level of individual live cells and intact tissue. We performed initial testing on a set of tools for Cas9-mediated visualization of nuclear compartments. We investigated doxycycline (Dox)-inducible (Tet-On) intracellular distribution of constructs encoding dCas9 orthologs from St. thermophilus (St) and N. meningitides (Nm) fused with EGFP and mCherry fluorescent proteins (FP) in human A549 cells. We also studied time-dependent expression of these chimeric fluorescent constructs (dCas9-FP) after Tet-On induction in live cells and compared it with the time course of dCas9-FP expression in experimental dCas9-FP-expressing tumor xenografts using a combination of fluorescence imaging and in vivo contrast-assisted magnetic resonance imaging for assessing the extent of tumor perfusion. In vivo Dox-induction of mCherry-chimera expression occurred in tumor xenografts as early as 24 h post-induction and was visualized by using optical clearing (OC) of the skin. OC via topical application of gadobutrol enabled high-contrast imaging of FP expression in tumor xenografts due to a 1.1-1.2-fold increase in FI in both the red and green channels.

Characterization of optical clearing mechanisms in muscle during treatment with glycerol and gadobutrol solutions.

The recent increasing interest in the application of radiology contrasting agents to create transparency in biological tissues implies that the diffusion properties of those agents need evaluation. The comparison of those properties with the ones obtained for other optical clearing agents allows to perform an optimized agent selection to create optimized transparency in clinical applications. In this study, the evaluation and comparison of the diffusion properties of gadobutrol and glycerol in skeletal muscle was made, showing that although gadobutrol has a higher molar mass than glycerol, its low viscosity allows for a faster diffusion in the muscle. The characterization of the tissue dehydration and refractive index matching mechanisms of optical clearing was made in skeletal muscle, namely by the estimation of the diffusion coefficients for water, glycerol and gadobutrol. The estimated tortuosity values of glycerol (2.2) and of gadobutrol (1.7) showed a longer path-length for glycerol in the muscle.

Gadolinium Accumulation and Toxicity on In Vitro Grown Stevia rebaudiana: A Case-Study on Gadobutrol.

Gadolinium-based contrast agents are molecular complexes which are extensively used for diagnostic purposes. Apart from their tremendous contribution to disease diagnostics, there are several issues related to their use. They are extremely stable complexes and potential contaminants of surface and ground waters, an issue which is documented worldwide. The irrigation of fields with contaminated surface waters or their fertilization with sludge from wastewater treatment plants can lead to the introduction of Gd into the human food supply chain. Thus, this study focused on the potential toxicity of Gd on plants. For this purpose, we have studied the molecular effects of gadobutrol (a well-known MRI contrast agent) exposure on in vitro-grown Stevia rebaudiana. The effects of gadobutrol on plant morphology, on relevant plant metabolites such as chlorophylls, carotenoids, ascorbic acids (HPLC), minerals (ICP-OES), and on the generation of free radical species (MDA assay and EPR) were assessed. Exposures of 0.01, 0.05, 0.1, 1, and 3 mM gadobutrol were used. We found a correlation between the gadobutrol dose and the plant growth and concentration of metabolites. Above the 0.1. mM dose of gadobutrol, the toxic effects of Gd+3 ions became significant.

Time optimization of gadobutrol-enhanced brain MRI for metastases and primary tumors using a dynamic contrast-enhanced imaging.

BACKGROUND: Recent advances in rapid imaging techniques necessitate the reconsideration of the optimal imaging delay time for contrast-enhanced T1-weighted imaging. The aim of our study was to determine the optimal contrast-enhanced T1-weighted imaging delay time from the obtained time-signal intensity curve (TIC) using gadobutrol in patients with brain metastases, primary brain tumors, and meningiomas. METHODS: This prospective study enrolled 78 patients with brain metastases (n = 39), primary brain tumors (n = 22), or meningiomas (n = 17) who underwent 7-min dynamic contrast-enhanced imaging with single-dose gadobutrol. Based on the time-to-peak (TTP) derived from the TIC, we selected four different time points for analysis. Lesion conspicuity, enhanced rate (ER) and contrast rate (CR) of 116 index lesions were evaluated. Statistical comparisons were made for the four different time points using the Friedman test. RESULTS: Maximum TTP (305.20 ± 63.47 s) was similar across all three groups (p = 0.342). Lesion conspicuity, CR and ER increased over time in all index lesions; however, no significant difference between the 5- and 7-min images was observed. The longest diameter in all groups differed significantly among time points (p < 0.001); the perpendicular diameter did not differ between the 5- and 7-min images. CONCLUSIONS: Maximum contrast enhancement and lesion conspicuity was achieved 5-7 min after a single gadobutrol injection for brain metastases detection and for primary brain tumor/meningioma evaluation. Acquiring images 5 min after gadobutrol injection is the optimal timing for brain tumor detection during MRI work-up.

Population pharmacokinetic modeling of CSF to blood clearance: prospective tracer study of 161 patients under work-up for CSF disorders.

BACKGROUND: Quantitative measurements of cerebrospinal fluid to blood clearance has previously not been established for neurological diseases. Possibly, variability in cerebrospinal fluid clearance may affect the underlying disease process and may possibly be a source of under- or over-dosage of intrathecally administered drugs. The aim of this study was to characterize the cerebrospinal fluid to blood clearance of the intrathecally administered magnetic resonance imaging contrast agent gadobutrol (Gadovist, Bayer Pharma AG, GE). For this, we established a population pharmacokinetic model, hypothesizing that cerebrospinal fluid to blood clearance differs between cerebrospinal fluid diseases. METHODS: Gadobutrol served as a surrogate tracer for extra-vascular pathways taken by several brain metabolites and drugs in cerebrospinal fluid. We estimated cerebrospinal fluid to blood clearance in patients with different cerebrospinal fluid disorders, i.e. symptomatic pineal and arachnoid cysts, as well as tentative spontaneous intracranial hypotension due to cerebrospinal fluid leakage, idiopathic intracranial hypertension, or different types of hydrocephalus (idiopathic normal pressure hydrocephalus, communicating- and non-communicating hydrocephalus). Individuals with no verified cerebrospinal fluid disturbance at clinical work-up were denoted references. RESULTS: Population pharmacokinetic modelling based on 1,140 blood samples from 161 individuals revealed marked inter-individual variability in pharmacokinetic profiles, including differences in absorption half-life (time to 50% of tracer absorbed from cerebrospinal fluid to blood), time to maximum concentration in blood and the maximum concentration in blood as well as the area under the plasma concentration time curve from zero to infinity. In addition, the different disease categories of cerebrospinal fluid diseases demonstrated different profiles. CONCLUSIONS: The present observations of considerable variation in cerebrospinal fluid to blood clearance between individuals in general and across neurological diseases, may suggest that defining cerebrospinal fluid to blood clearance can become a useful diagnostic adjunct for work-up of cerebrospinal fluid disorders. We also suggest that it may become useful for assessing clearance capacity of endogenous brain metabolites from cerebrospinal fluid, as well as measuring individual cerebrospinal fluid to blood clearance of intrathecal drugs.

Optimized 3D-FLAIR sequences to shorten the delay between intravenous administration of gadolinium and MRI acquisition in patients with Menière's disease.

OBJECTIVES: The aim of this study was to shorten the 4-h delay between the intravenous administration of gadolinium and MRI acquisition for hydrops evaluation using an optimized 3D-FLAIR sequence in patients with Menière's disease. METHODS: This was a single-center prospective study including 29 patients (58 ears), recruited between November 2020 and February 2021. All patients underwent a 3-T MRI with an optimized 3D-FLAIR sequence without contrast then at 1 h, 2 h, and 4 h after intravenous administration of gadobutrol. The signal intensity ratio was quantitatively assessed with the region of interest method. We also evaluated the volume of endolymphatic structures (saccule, utricle) then the presence of endolymphatic hydrops and blood-labyrinthine barrier impairment at each acquisition time. RESULTS: For all ears, the signal intensity ratio was significantly non-inferior at 2 h compared to 4 h, with a mean geometric signal intensity ratio at 0.83 (95% CI: 0.76 to 0.90, one-sided p < .001 for non-inferiority at -30% margin). Mean volume equivalence of saccule and utricle between 2 and 4 h was proven at a ± 0.20 standardized deviation equivalence margin. Intra-rater agreements (Cohen's kappa) were all greater than 0.90 for all endolymphatic hydrops location and blood-labyrinthine-barrier impairment between the 2- and 4-h assessments. CONCLUSIONS: We demonstrated that using an optimized 3D-FLAIR sequence we could shorten the acquisition from 4 to 2 h with a high reliability for the diagnosis of endolymphatic hydrops and blood-labyrinthine-barrier impairment. CLINICAL TRIAL REGISTRATION: Clinical trial no: 38RC15.173 KEY POINTS: • Magnetic resonance imaging with delayed 3D-FLAIR sequences allows the diagnosis of endolymphatic hydrops in patients with definite Menière's disease. • An optimized 3D-FLAIR sequence with a long TR of 16000 ms and a constant flip angle allows for reducing the delay between intravenous injection of gadobutrol and MRI acquisition from 4 to 2 h to diagnose endolymphatic hydrops. • Reducing this delay between intravenous injection and MRI acquisition could have implications for clinical practice for both patients and imaging departments.

Intrathecal Contrast-Enhanced Magnetic Resonance Imaging of Cerebrospinal Fluid Dynamics and Glymphatic Enhancement in Idiopathic Normal Pressure Hydrocephalus.

Idiopathic normal pressure hydrocephalus (iNPH) is a neurodegenerative disease, characterized by cerebrospinal fluid (CSF) flow disturbance. Today, the only available treatment is CSF diversion surgery (shunt surgery). While traditional imaging biomarkers typically assess CSF space anatomy, recently introduced imaging biomarkers of CSF dynamics and glymphatic enhancement, provide imaging of CSF dynamics and thereby more specifically reveal elements of the underlying pathophysiology. The biomarkers address CSF ventricular reflux grade as well as glymphatic enhancement and derive from intrathecal contrast-enhanced MRI. However, the contrast agent serving as CSF tracer is administered off-label. In medicine, the introduction of new diagnostic or therapeutic methods must consider the balance between risk and benefit. To this end, we performed a prospective observational study of 95 patients with iNPH, comparing different intrathecal doses of the MRI contrast agent gadobutrol (0.10, 0.25, and 0.50 mmol, respectively), aiming at the lowest reasonable dose needed to retrieve diagnostic information about the novel MRI biomarkers. The present observations disclosed a dose-dependent enrichment of subarachnoid CSF spaces (cisterna magna, vertex, and velum interpositum) with dose-dependent ventricular reflux of tracer in iNPH, as well as dose-dependent glymphatic tracer enrichment. The association between tracer enrichment in CSF and parenchymal compartments were as well dose-related. Intrathecal gadobutrol in a dose of 0.25 mmol, but not 0.10 mmol, was at 1.5T MRI considered sufficient for imaging altered CSF dynamics and glymphatic enhancement in iNPH, even though 3T MRI provided better sensitivity. Tracer enrichment in CSF at the vertex and within the cerebral cortex and subcortical white matter was deemed too low for maintaining diagnostic information from a dose of 0.10 mmol. We conclude that reducing the intrathecal dose of gadobutrol from 0.50 to 0.25 mmol gadobutrol improves the safety margin while maintaining the necessary diagnostic information about disturbed CSF homeostasis and glymphatic failure in iNPH.

MR and fluorescence imaging of gadobutrol-induced optical clearing of red fluorescent protein signal in an in vivo cancer model.

Multimodality registration of optical and MR images in the same tissue volume in vivo may be enabled by MR contrast agents with an optical clearing (OC) effect. The goals of this study were to (a) investigate the effects of clinical MR contrast agent gadobutrol (GB) and its combinations as a potential OC agent assisting in fluorescence intensity (FI) imaging in vivo and (b) evaluate MRI as a tool for imaging of topical or systemic application of GB for the purpose of OC. Subcutaneous tumor xenografts expressing red fluorescent marker protein were used as disease models. MRI was performed at 1 T 1 H MRI using T1 -weighted 3D gradient-echo (T1w-3D GRE) sequences to measure time-dependent MR signal intensity changes by region of interest analysis after image segmentation. Topical application of 1.0 M or 0.7 M GB-containing OC mixture with water and dimethyl sulfoxide showed similar 30-40% increases of tumor FI during the initial 15 min. Afterwards, the OC effect of GB on FI and tumor/background FI ratio showed a decrease over time in the case of 1.0 M GB, unlike the 0.7 M GB mixture, which resulted in a steady increase of FI and tumor/background ratio for 15-60 min. The use of T1w-3D GRE MR pulse sequences showed that concentrated 1.0 M GB resulted in MR signal loss of the skin due to high magnetic susceptibility and that signal loss coincided with the OC effect. Intravenous injection of 0.3 mmol GB/kg resulted in a rapid but transient 40% increase of FI of the tumors. Overall, 1 T MRI enabled tracking of GB-containing OC compositions on the skin surface and tumor tissue, supporting the observation of a time-dependent FI increase in vivo.

Simultaneous [18F]fluoride and gadobutrol enhanced coronary positron emission tomography/magnetic resonance imaging for in vivo plaque characterization.

AIMS: 18F-sodium fluoride ([18F]fluoride) and gadobutrol are promising probes for positron emission tomography (PET) and magnetic resonance imaging (MRI) characterizing coronary artery disease (CAD) activity. Unlike [18F]fluoride-PET/computed tomography (CT), the potential of PET/MR using [18F]fluoride and gadobutrol simultaneously, has so far not been evaluated. This study assessed feasibility and diagnostic potential of [18F]fluoride and gadobutrol enhanced dual-probe PET/MR in patients with CAD. METHODS AND RESULTS: Twenty-one patients (age, 66.7 ± 6.7 years) with CAD scheduled for invasive coronary angiography (XCA) underwent simultaneous [18F]fluoride (mean activity/effective dose: 157.2 ± 29.7 MBq/3.77 ± 0.72 mSv) and gadobutrol enhanced PET/MR on an integrated PET/MRI (3 T) scanner. Optical coherence tomography (OCT) was used as reference. Target-to-background ratio (TBR, [18F]fluoride-PET) and contrast-to-noise ratio (CNR) values (MRI, gadobutrol) were calculated for each coronary segment. Previously suggested PET/CT-TBR thresholds for adverse coronary events were evaluated. High-risk plaques, i.e. calcified and non-calcified thin-cap fibroatheromas (TCFAs) were predominantly located in segments with a TBR >1.28 (P = 0.012). Plaques containing a lipid core on OCT, were more frequently detected in segments with a TBR >1.25 (P < 0.001). TBR values significantly correlated with maximum calcification thickness (P = 0.009), while fibrous cap thickness was significantly less in segments with a TBR >1.28 (P = 0.044). Above a TBR threshold of >1.28, CNR values significantly correlated with the presence of calcified TCFAs (P = 0.032). CONCLUSION: Simultaneous [18F]fluoride and gadobutrol dual-probe PET/MRI is feasible in clinical practice and may facilitate the identification of high-risk patients. The combination of coronary MR-derived CNR values post gadobutrol and [18F]fluoride based TBR values may improve identification of high-risk plaque features.

Dynamic susceptibility MR perfusion imaging of the brain: not a question of contrast agent molarity.

PURPOSE: Dynamic susceptibility contrast (DSC) perfusion-weighted MR imaging (PWI) is increasingly used in clinical neuroimaging for a range of conditions. More highly concentrated GBCAs (e.g., gadobutrol) are often preferred for DSC imaging because it is thought that more Gd is present in the volume of interest during first pass for a given equivalent injection rate. However, faster injection of a less viscous GBCA (e.g., gadoteridol) might generate a more compact and narrower contrast bolus thus obviating any perceived benefit of higher Gd concentration. This preliminary study aimed to analyze and compare DSC examinations in the healthy brain hemisphere of patients with brain tumors using gadobutrol and gadoteridol administered at injection rates of 4 and 6 mL/s. METHODS: Thirty-nine brain tumor patients studied with DSC-PWI were evaluated. A simplified gamma-variate model function was applied to calculate the mean peak, area under the curve (AUC), and full-width at half-maximum (FHWM) of concentration-time curves derived from ΔR2* signals at four different regions-of-interest (ROIs). Qualitative assessment of the derived CBV maps was also performed independently by 2 neuroradiologists. RESULTS: No qualitative or quantitative differences between the two GBCAs were observed when administered at a flow rate of 4 mL/s. At a flow rate of 6 mL/s, gadoteridol showed lower FWHM values. CONCLUSION: Gadobutrol and gadoteridol are equivalent for clinical assessment of qualitative CBV maps and quantitative perfusion parameters (FHWM) at a flow rate of 4 mL/s. At 6 mL/s, gadoteridol produces a narrower bolus shape and potentially improves quantitative assessment of perfusion parameters.

Investigation of Effects of Gadolinium-Based Contrast Agents on Uterine Contractility Using Isolated Rat Myometrium.

BACKGROUND: Despite concerns about safety, gadolinium-based contrast agents (GBCAs) are still used for abdominal and pelvic imaging during pregnancy. Researchers have mainly focused on teratogenicity, while very little is known about their possible direct effects on uterine contractility, yet free gadolinium potentially impacts contractility through interaction with calcium channels. PURPOSE: To investigate possible effects of selected GBCAs (namely gadoteridol, gadoversetamide, gadobutrol, gadoterate meglumine, and gadoxetic acid) on the contractility of rat myometrium. STUDY TYPE: In vitro organ bath study. ANIMAL MODEL: Myometria were isolated from adult (10-12 weeks old) Sprague Dawley rats, both pregnant (N = 8) and nonpregnant (N = 36). FIELD STRENGTH/SEQUENCE: NA. ASSESSMENT: Myometrial strips were suspended in tissue bath containing physiological saline and isometric contractions were recorded. GBCAs were added to the tissue bath cumulatively, and their effects on contractility parameters (quantified by amplitude, frequency, and area under contractility curve [AUC]) were evaluated by 10-minute intervals. STATISTICAL TESTS: Normality data, checked by Shapiro-Wilk test, were transformed by arcsine when needed. One- or two-way analysis of variance was performed, where appropriate, followed by Student-Newman-Keuls test. A P value of <0.05 was considered statistically significant. RESULTS: All of the assayed GBCAs elicited some alterations in the myometrial contractility in a concentration-dependent manner. Gadoterate meglumine, gadoxetic acid, and gadoversetamide caused a concentration-dependent significant attenuation in AUC (oxytocin-induced, from 100% during control period to 45.1 ± 9.0% (nonpregnant) and 59.9 ± 8.5% (pregnant), for 90 µM gadoterate meglumine; respectively), and frequency of the spontaneous and oxytocin-induced contractions. Gadobutrol and gadoteridol at highest dose significantly attenuated mean AUC and frequency of oxytocin-induced contractions of nonpregnant myometrium. DATA CONCLUSION: Results from this in vitro study indicate that GBCAs elicit modulation of myometrial contractions at clinically relevant concentrations. These effects may account, at least partially, for the known potential side effects (rare cases of miscarriages and elective abortion) of these agents. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 5.

MRA of the Supraaortic Vasculature: Comparison of Gadobutrol and Gadoterate Meglumine at 1.5 T.

BACKGROUND: Gadobutrol (GB) and gadoterate meglumine (GM) are contrast agents used for contrast-enhanced magnetic resonance angiography (CEMRA). Supraaortic vasculature (SAV) CEMRAs are used to evaluate stroke risk and neurologic symptoms. There is a need to compare the SAV CEMRA image quality obtained with GB and GM. PURPOSE: To intra-individually compare MRA images obtained with equimolar GB and GM at 1.5 T in the SAV. STUDY TYPE: Prospective, crossover. POPULATION: Twenty-eight subjects (54 ± 13 years; 17 female). FIELD STRENGTH/SEQUENCE: 1.5 T; three-dimensional (3D) gradient recalled echo. ASSESSMENT: Quantitative image quality was measured by normalized signal intensity (SIn ) [SIn  = SI blood/SD blood] and contrast ratio (CR) [CR = SI blood/SI muscle], determined by an observer (JWC) with 1 year of vascular imaging experience. Three radiologists (AS, PA, and MU) with (5, 5, and 6 years of) vascular imaging experience evaluated image quality by Likert-scale ratings (of image impression, wall conspicuity, and artifact absence). STATISTICAL TESTS: SIn and CR were compared with paired t-tests or Wilcoxon signed-rank tests and Bland-Altman plots. Qualitative ratings were compared with Wilcoxon signed-rank test. RESULTS: No significant difference in SIn was found between GB and GM. CRs with GB were significantly higher than GM at the right common carotid (6.9 ± 2.5 vs. 4.8 ± 1), left internal carotid (7.3 ± 2 vs. 4.4 ± 1.2), right internal carotid (7.7 ± 2.2 vs. 5 ± 1.1), and left vertebral (6.6 ± 2.2 vs. 4.5 ± 1.1) arteries. Bland-Altman plots showed relatively greater differences between GB and GM at higher CRs and SIn s. GM showed significantly higher artifact than GB (3.56 ± 0.52 vs. 3.36 ± 0.46) and significantly lower overall image quality (10.73 ± 1.45 vs. 11.26 ± 1.58) at the left vertebral artery. DATA CONCLUSION: At 1.5 T and equimolar demonstration, GB (0.1 mL/kg, i.e., 0.1 mmol/kg) showed higher CRs in the SAV compared to GM (0.2 mL/kg, i.e., 0.1 mmol/kg) at most vessels. Subjective image quality was not significantly different between the two agents for most vessels. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.