RPS 311 - Gadolinium retention and neurovascular imaging

RPS 311-K
Keynote lecture
RPS 311-1
Gadolinium retention in the human body: the awareness of radiologists and impacts on daily radiology practice
Purpose: To assess the awareness and impact of awareness of the emerging gadolinium retention data on the preferences of radiologists in daily radiology practice and to demonstrate gadolinium-enhanced MRI exercise diversities across radiologists with respect to background factors like the type of affiliations, experience in radiology, attendance to scientific events, and scope of daily radiology practice.
Methods: A 21 question survey was addressed to radiologists who were at least one year from completing residency and/or fellowship training. A closed survey link was emailed to the members of the Turkish Society of Radiology and was active for four weeks (October-November 2018). The results were presented as descriptive data and grouped findings were statistically analysed.
Results: 1,133 eligible members received the emails and 335 radiologists completed the survey. 89% of respondents were aware of emerging gadolinium retention data. 45% of respondents decreased the amount of gadolinium administration and/or the frequency of gadolinium-enhanced scans since the emergence of gadolinium retention data. 88% of radiologists, who were aware of the molecular classification, used a macrocyclic agent. 39% (n=130) switched to a macrocyclic agent from linear agents within the last three years. Radiologists? attitude toward gadolinium retention was significantly associated with their background factors. The observance of HDN due to gadolinium retention was uncommon in daily practice (64% never observed).
Conclusion: Gadolinium retention data affected radiologists? approach to contrast-enhanced MRI scans, mostly in the form of switching to a macrocyclic gadolinium agent and increasing the indicative threshold for gadolinium administration. The translation of recent gadolinium retention data to clinical practice varied among radiologists with respect to background factors like experience in radiology and subspeciality training.
Limitations: The study was conducted in a single European country and may not necessarily be applicable worldwide.
Ethics: n/a
Funding: No funding was received for this work.
RPS 311-2
MRI evidence of progressive gadolinium deposition in bone during monthly triple-dose gadolinium CE-MRIs and its relationship to hypophosphataemia
To investigate for MRI evidence of calvarial gadolinium (Gd) deposition during monthly high-dose contrast administration over two years and at 10 years, and to interrogate whether osseous Gd deposition correlates with hypophosphataemia.
Methods: The study cohort consisted of a retrospective analysis of 67 patients with MS or CIS who had participated in the BECOME trial and who received monthly off-label triple-dose gadopentetate dimeglumine (0.3mmol/kg) enhanced MRIs for up to 26 months. Pre-MRI blood samples were collected. An ROI mask was created in the diploic space (DS) using manual segmentation and co-registered to track signal intensity (SI) changes on fat-suppressed non-Gd T1-weighted. S/N ratios (SI Bone/SI Air) established an average SI change over time. To evaluate the association between SI changes and hypophosphataemia, we performed linear mixed regression modelling with a random intercept to test the linear trend in the SI change between the groups with and without hypophosphataemia.
Results: The monthly rate of T1-SI change in the diploic space during the first 14 months of triple-dose Gd administration was S/N=0.039 (S.E. 0.008; p<0.0001). ~10 years after the study termination, diploic S/N decreased to pre-study levels (N=28). Patients who developed hypophosphataemia (<2.5 mg/dl) at least once experienced a significantly slower increase of T1-hyperintensity compared to patients without hypophosphataemia (mean monthly S/N difference=0.034; p=0.037). Those who experienced >=1 episode of moderate hypophosphataemia (<2.0 mg/dl) did not experience any significant change in monthly diploic S/N.
Conclusion: Monthly administration of triple-dose Gd is associated with progressive T1 hyperintensity in the cranial diploic space, suggesting Gd deposition in bone. This change was lower in patients who developed hypophosphataemia and washed out after 10 years.
Limitations: The volume averaging, segmentation technique, and updates in MRI technique.
Ethics: n/a
Funding: Guerbet.
RPS 311-3
Gadolinium-based contrast agent in the aqueous chamber of infantile healthy eyes promptly after intravenous injection
Purpose: To investigate whether a gadolinium-based contrast agent (GBCA) can be detected on T1-weighted MRIs in the anterior chamber of infantile eyes promptly post-injection (p.i.).
Methods: Orbital MRIs of 200 healthy eyes of children suffering from retinoblastoma were assessed. The MRIs were performed with orbital coils with the children under general anaesthesia.
Differences of signal intensity ratios (?SIRs) of the AC to the lense were determined between pre- and post-contrast-enhanced T1-weighting (Dotarem®, 0.1 ml/kg, mean p.i. time=12min).
Results: A highly significant signal intensity increase was found in the AC of healthy eyes 12min p.i. (median ?SIR=+0.08, p<0.0001).
In addition, gadolinium-enhancement showed a strong negative correlation with children?s age in multivariate analysis with adjustment for p.i. time (p<0.0001).
Conclusion: GBCA leakage into the AC of healthy infantile eyes was found promptly after injection. The negative correlation between the patient's age and GBCA-enhancement might be explained by a maturation process of the blood-aqueous barrier or Schlemm's canal. Future studies should assess the duration and potential diagnostic applications as well as possible safety concerns of gadolinium presence in the AC.
Limitations: T1-weighting is semi-quantitative in nature, that's why the calculated ?SIRs do not allow conclusions to be drawn regarding true GBCA concentrations.
Furthermore, serial p.i. scans would have been desirable as the concentration peak of the GBCA in the AC might have exceeded the p.i. time. However, ?SIRs of the longest p.i. times did not clearly surpass the other ?SIRs, which suggests that AC enhancement might have already reached saturation.
Ethics: This retrospective study was approved by the ethics committee of the University of Essen.
Funding: No funding was received for this work.
RPS 311-4
High signal intensity in the globus pallidus (GP) and dentate nucleus (DN) on unenhanced T1-weighted magnetic resonance images: an assessment of two macrocyclic gadolinium-based agents
Purpose: To compare changes in the signal intensity (SI) measured at the dentate nucleus (DN) and globus pallidus (GP) on unenhanced T1-weighted magnetic resonance (MR) images in patients who received gadobutrol (gadavist) to those who received gadoterate meglumine (dotarem).
Methods: 47 patients with CNS tumours who had undergone at least 4 MRI exams were divided into two groups. Group 1=25 patients who underwent gadoterate meglumine-enhanced MR imaging. Group 2=22 patients who underwent gadobutrol-enhanced MR imaging. Region of interest measurements were applied to unenhanced T1-weighted images by two radiologists. GP to the thalamus (TH), DN to middle cerebellar peduncle (MCP) SI ratio, and relative change (Rchange) between the initial and final examinations were calculated for each patient. The differences in the mean Rchange were analysed using a non-parametric regression test. The relationship between Rchange and the number of enhanced MR imaging examinations was evaluated using a Pearson correlation coefficient.
Results: Gadobutrol-enhanced MR imaging showed a significant increase in Rchange for DN-MCP (P<0.004). Contrarily, gadoterate meglumine-enhanced MR imaging showed no significant increase in Rchange for DN-MCP. There was a significant linear association between the number of MRI examinations and an increase in Rchange for DN-MCP (r=0.56, P=0.001) and for GP-TH (r=0.53, P=0.007) in patients who received gadobutrol.
Conclusion: A statistically significant dose-dependent T1-weighted signal increment observed in DN and GP is associated with multiple gadobutrol administrations but not with gadoterate meglumine administrations.
Limitations: A retrospective design consisting of patients with CNS tumours and damaged blood brain barrier, lacking a control group of patients who never received GBCAs.
Ethics: The institutional review board approved this study.
Funding: No funding was received for this work.
RPS 311-5
The absence of T1 hyperintensity in the brain of high-risk iron-loaded thalassemia patients after multiple administrations of high-dose gadobutrol
Purpose: We evaluated signal changes in the dentate nucleus, globus pallidus, pons, and thalamus (normalised to the deep cerebellum white matter) in T1-weighted magnetic resonance (MR) images after serial injections of gadobutrol in patients with thalassemia without neurological lesions.
Methods: Three study groups were scanned at both 1.5T and 3T: 15 thalassemia patients who were transfused and chelated with ?4 gadobutrol administrations at a high dose (0.2 mmol/Kg per scan) for cardiovascular MR, 8 thalassemia patients, and 13 healthy subjects who never received gadolinium-based contrast agents (GBCA). The iron overload was assessed by the T2* technique.
Results: Demographics were comparable among the groups.
Signal intensity (SI) ratios and T2* values at 1.5T in all regions were comparable among the three groups. No correlation was detected between SI ratios and T2* values.
In patients with more than 4 GBCA administrations, the SI ratios were not associated with the total cumulative gadolinium dose and the total number of contrast-enhanced examinations.
The SI ratios at 1.5T were significantly higher than those obtained at 3T. Moreover, no correlation was found between SI ratios at 1.5T and 3T.
Conclusion: Our study describes the lack of increased SI in T1-weighted MR images after repeated administrations of gadobutrol for cardiovascular MR studies in a high-risk population (high dose per scan, iron overload that can facilitate the transmetallation of gadolinium). A potential role of chelation therapy cannot be excluded. Moreover, SI ratios in the sampled anatomical areas differ between 1.5T and 3T machine, which is to be taken into account in trials or group analysis studies.
Limitations: The limited sample size.
Ethics: Ethics committee approval obtained.
Funding: E-MIOT project: ?no-profit support? from industrial sponsorships (Chiesi Farmaceutici, ApoPharma, Bayer).

RPS 311-6
No changes in T1 relaxometry after a mean of eleven administrations of gadobutrol
Purpose: Quantitative T1 relaxometry is the benchmark in imaging potential gadolinium deposition and is known to be superior to semi-quantitative signal-intensity-ratio analyses. However, T1 relaxometry studies are rare, commonly limited to a few target structures, and reported results are inconsistent.
We systematically investigated quantitative T1 relaxation times (qT1) of a variety of brain nuclei after serial application of gadobutrol.
Methods: Retrospectively, qT1 measurements were performed in a patient cohort with a mean number of 11 gadobutrol applications (n=46) compared to a control group with no prior GBCA administration (n=48). 13 target structures were evaluated including the dentate nucleus, globus pallidus (GP), thalamus, hippocampus, putamen, caudate, amygdala, and frontal white matter. Subsequently, a multivariate regression analysis was performed.
Results: No assessed site revealed a significant correlation between qT1 and the number of gadobutrol administrations in multivariate regression analyses. A significant negative correlation between qT1 and age was found for the GP and thalamus (p<0.05 each).
Conclusion: No T1 relaxation time shortening was found in any assessed brain structure after the serial injection of 11 doses gadobutrol.
Limitations: Unknown injections of GBCAs cannot definitely be excluded. However, a potentially higher GBCA exposition would have increased the probability of qT1 changes even more.
Moreover, cerebral involvement was more frequent in the GBCA group. Therefore, this potential confounder was included in the multivariate analysis even though this would have theoretically just meant an even higher vulnerability for cerebral GBCA leakage and deposition.
Ethics: Written informed consent was waived due to the retrospective character of this institutional review board approved study.
Funding: This study was financially supported by Bayer AG (Berlin, Germany). The authors had sole control of the data and the information submitted for publication.
RPS 311-7
A comparison of the effects of gadolinium-based contrast agents on neuronal cells
Purpose: Gadolinium-based contrast agents (GBCAs) are widely used in magnetic resonance imaging (MRI). Recently, an increased signal intensity has been reported in specific brain areas such as the dentate nucleus, globus pallidus, and cerebellum after repeated administrations of GBCAs. The aim of the study was to investigate the toxic effects of GBCAs on neuronal cells by using SH-SY5Y neuroblastoma cells.
Methods: For toxicity assays, SH-SY5Y cells were seeded in 96-well dishes (5,000 cells/well) and incubated with different doses (0-1,000 µM) of several macrocyclic (gadoteric acid and gadobutrol) and linear GBCAs (gadoversetamide, gadopentetic acid, gadodiamide, and gadoxetic acid) for 72 hours. Cell viability and mitochondrial activity were evaluated by using MTS assay, colony-forming assay, and Hoechst staining. Alpoptotic markers, Bax and Bcl-2, were assessed by Western blotting. The results were expressed as mean ± SEM. A p<0.05 was accepted as statistically significant.
Results: Both macrocyclic and linear GBCAs significantly and dose-dependently reduced cell viability in neuronal cells compared to untreated cells. Cell viability was measured between 89.49±4.09 % and 60.99±0.77% in GBCAs-treated groups. In addition, neurotoxicity was more prominent in linear GBCAs-treated cultures (p<0.0005). Bax protein levels were increased in GBCA-treated cells, especially those treated with linear agents, whereas Bcl-2 expression was decreased concomitantly.
Conclusion: The results of the study indicate that exposure to specific GBCAs, even at low micro-molar concentrations, may have detrimental effects on neuronal survival. Further investigations are required to clarify the molecular mechanism underlying GBCAs-induced cell death.
Limitations: The in vitro study should be supported an in vivo study.
Ethics: n/a
Funding: No funding was received for this work.
RPS 311-8
Dynamic susceptibility MR perfusion imaging of the brain: not just a question of contrast molarity
Purpose: Dynamic-susceptibility-contrast (DSC) perfusion (PWI) MR is based on the quantification of the signal loss on T2*-weighted images during the first pass of a contrast bolus through the brain immediately after injection of a gadolinium (Gd)-based contrast agent. Gd-based contrast agents with higher molarity are generally considered more suitable for DSC imaging, although a greater loss of signal intensity can be achieved using a faster bolus of a less viscous contrast agent that might compensate for lower molarity. The aim of this cross-sectional study was to retrospectively analyse and compare DSC PWI studies performed with gadobutrol (1M) and gadoteridol (0.5M) on the healthy hemisphere of patients with brain tumours.
Methods: DSC-PWI MRs of 36 patients (9 pts gadobutrol flow 4 ml/s, 15 pts gadoteridol 4 ml/s, and 12 pts gadoteridol 6 ml/s) with brain tumours involving only one hemisphere were retrospectively evaluated. A quantitative assessment was performed. A neuroradiologist manually positioned 4 ROIs (2 in proximity to MCA and 2 in proximity of the occipital cortex) in the healthy hemispheres. A simplified formulation of the gamma-variate (GV) model function was applied to estimate the mean of maximum (peak), AUC, and FHWM of the perfusion parameter derived from DR2* signal. Each derived CBV parametric map was qualitatively reviewed by two neuroradiologists by assigning a 4-point imaging quality score.
Results: No quantitative nor qualitative differences between the two contrast agents were observed in terms of peak, AUC, FHWM, and quality score. The agreement between readers was excellent (k=0.81).
Conclusion: In this DSC MRI study, no significant differences were found between gadobutrol and gadoteridol in terms of quantitative and qualitative perfusional parameters.
Limitations: A single-center cross-sectional study with a small group of patients.
Ethics: n/a
Funding: No funding was received for this work.
RPS 311-9
Impact of the novel contrast agent gadopiclenol on decision making in patients with brain metastases
Purpose: Brain metastases (BM) are either treated with stereotactic radiosurgery (SRS) or whole-brain radiotherapy (WBRT), whereas the number of lesions detected is crucial for choosing adequate modality. Here we evaluate the impact on decision making and treatment planning of BM using the novel contrast agent, gadopiclenol.
Methods: This is a post-hoc analysis of data from a phase IIb study, where patients underwent two separate MRI scans with gadopiclenol and gadobenate dimeglumine, both at 0.1 mmol/kg. Patients with ?1BM detected in any scan were subjected to an investigator-blinded analysis. Radiation treatment plans (SRS or WBRT) were calculated for both MRIs, with the gross tumour volume (GTV) indicating the contrast-enhancing aspects of the tumour and the V12Gy indicating the volume receiving ?12Gy.
Results: A total of 13 patients (31% females) were eligible for this analysis. In 2 patients, gadopiclenol-based MRI scanning detected additional BMs that were undetected with gadobenate-based scans. In one patient, a single metastasis was seen only with gadopiclenol, changing the decision from no treatment to SRS. In the second patient, gadopiclenol detected 5 additional metastases, changing the decision from SRS to WBRT. In addition, the mean GTV was higher in therapy plans calculated on gadopiclenol-based scans than on gadobenate-based scans (4.74 vs 4.32 cm3), indicating a different appearance of BM sizes. Logically, the mean V12Gy was also higher with gadopiclenol than with gadobenate-based scans (14 vs 11 cm3).
Conclusion: Gadopiclenol improved the detection of BM in 2 of 13 patients, which led to a change in treatment decisions (from no therapy to SRS and from SRS to WBRT) and to treatment plans with larger GTVs.
Limitations: The small patient numbers.
Ethics: Ethics committee approval obtained.
Funding: The study was sponsored by Guerbet.
RPS 311-10
The value of 4D-MR angiography at 3T compared to DSA for the follow-up of treated dural arteriovenous fistulas
Purpose: The value of 4D-MRA for the follow-up of treated dural arteriovenous fistulas (DAVF) has rarely been evaluated.
We hypothesized that this technique could be valuable for the follow-up and post-therapeutic assessment of DAVF. The purpose of this study was to evaluate the performance of 4D-MRA at 3T for the follow-up of patients with treated DAVF.
Methods: Patients treated for a DAVF in two centres from 2008-2019 were included if they met the following criteria: DAVF treated by embolisation or surgery and imaging during the follow-up with both 4D-MRA at 3T and DSA performed within 6 months. One reader analysed DSA and two readers analysed 4D-MRA.
For both modalities, 4D-MRA and DSA, readers first evaluated in a binary fashion whether a residual/recurrent DAVF was present or not. Then, when present, each residual/recurrent DAVF was classified according to the criteria of Cognard et al. The intertechnic agreement was assessed for detection of residual/recurrent DAVF and bleeding risk grading using Cohen?s kappa.
Results: We recorded 59 couples of examinations for 52 patients with a median age of 64 years (range 24-86 years). Sensibility, specificity, predictive positive value, and predictive negative values of 4D-MRA for the detection of a residual/recurrent DAVF were 58.3% (95% CI: 41.8% to 74.8%) and 91.4% (95% CI: 83.9% to 98.8%), respectively. Predictive positive value and predictive negative values of 4D-MRA for the detection of a residual/recurrent DAVF were 82% (95% CI: 71.6% to 93%) and 76% (95% CI: 63.7% to 88.6%). The intertechnic agreement was moderate with k=0.5 (95% CI: 0.3 to 0.7).
Conclusion: 4D-MRA at 3T could be interesting for the follow-up of treated DAVF.
Limitations: A retrospective study.
Ethics: n/a
Funding: No funding was received for this work.
RPS 311-11
The application of neurovascular 4Dflow MRI in the assessment of haemodynamics on patients with Moyamoya disease
Purpose: To analyse and compare the change of haemodynamics between pre and postoperation on patients of Moyamoya disease (MMD) using neurovascular 4Dflow MRI (phase-contrast MRA).
Methods: In this study, 28 MMD patients who underwent an operation of encephaloduroarteriosynangiosis (EDAS) were enrolled. We analysed the haemodynamics of these patients by 4Dflow MRI scanning and compared the parameters between pre and postoperation including wall shear stress (WSS), flow rate, and relative pressure.
Results: The WSS and relative pressure of postoperation measured at the distal part of the internal carotid artery (ICA), the initial part of the anterior cerebral artery (ACA), and the middle cerebral artery (MCA) were significantly lower than those of preoperation (all P?0.05). The flow rate significantly increased (all P?0.05) after the operation.
Conclusion: The operation of EDAS can effectively improve the blood flow of MMD patients and decrease the pressure on the cerebral vascular wall. As a non-invasive, multi-parameter, and quantitative imaging technique, 4Dflow MRI has the potential to improve the diagnosis and assessment of cerebrovascular diseases.
Limitations: The sample size was small.
Ethics: This study was approved by the Ethics Committee of West China Hospital and written informed consent was obtained.
Funding: 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (Program Number: ZYGD18019).
RPS 311-12
Deep learning-based automated detection of cerebral aneurysms: a comparison of reading performance between radiologists and neurosurgeons
Purpose: To demonstrate the effects of deep learning-based computer-aided detection (CAD) on the reader?s performance for the detection of cerebral aneurysms in MR angiography (MRA).
Methods: 200 brain MRA datasets (93 men and 107 women; mean age, 64.7 years±15.3 [standard deviation]; mean aneurysm size, 3.3 mm±1.74), 50 with unruptured cerebral aneurysms and 150 without, were acquired on scanners from 3 different vendors at 1.5 or 3T and were retrospectively evaluated. 20 physicians (10 radiologists including 5 certificated radiologists and 5 non-certificated radiologists, and 10 neurosurgeons including 4 certificated neurosurgeons and 6 non-certificated neurosurgeons) were asked to detect cerebral aneurysms on MRA scans and associated projection images without and with CAD using ResNet?18, a convolutional neural network. The observers' performance was evaluated using a jackknife free-response receiver operating characteristics (JAFROC) analysis.
Results: The figure-of-merit (FOM) values computed using the JAFROC program significantly improved from 0.717 without CAD to 0.751 with CAD for all readers (P<0.001). The average sensitivity increased from 68.2% to 77.2% for all readers, whereas the average specificity decreased from 79.4% to 72.1%. On subgroup analyses, the FOM values increased from 0.647 to 0.697 for non-certificated radiologists, from 0.799 to 0.822 for certificated radiologists, from 0.645 to 0.681 for non-certificated neurosurgeons, and from 0.810 to 0.836 for certificated neurosurgeons. There was no statistical significance in the reading performances between radiologists and neurosurgeons both without CAD (P=0.826) and with CAD (P=0.753). However, the performances between non-certificated neurosurgeons and certificated neurosurgeons with CAD showed a significant difference (P=0.0479).
Conclusion: The diagnostic accuracy of cerebral aneurysms improved for radiologists and neurosurgeons with CAD.
Limitations: n/a
Ethics: This study was approved by the institutional review board.
Funding: This work was funded by LPixel Inc.


Krešimir Dolić (Croatia)

Zsigmond Tamas Kincses (Hungary)

European Society of Radiology

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