Abstract Until recognition of the association of nephrogenic systemic fibrosis (NSF) and gadolinium based contrast agents (GBCA) in 2006, these agents were considered extremely safe and without major ...adverse effects. Even after the recognition of NSF, most physicians considered all GBCAs to be safe when used in patients with normal renal function. This belief has been called into question with the discovery by Kanda in 2014 that Gd is deposited in brain tissue in patients with normal kidney function. Since that initial report, there have been a number of important studies analyzing the effects of various GBCAs in brain using MR T1 signal intensity measurements and postmortem tissue analyses with inductively coupled plasma mass spectrometry. From these our knowledge and understanding of some key issues surrounding these observations has rapidly evolved. This report reviews and summarizes many recent human and animal studies in combination with past studies to better understand Gd tissue deposition not only in brain but also in bone and skin. Brain tissue deposition was initially demonstrated to occur with less stable Group 1 linear agents but recent postmortem studies now confirm that Gd deposition also occurs with more stable linear agents as well as with macrocyclic agents although at much lower levels. Although no adverse health effects have been documented to date, even for the Group 1 agents that deposit Gd in higher amounts, the implications for possible unrecognized toxicity is discussed. Future studies are being pursued that may provide better understanding of the various chemical forms of Gd that are deposited in tissues. This may help elucidate relative risks of different types of agents, mechanisms involved and even recognition of potential downstream toxic effects.
OBJECTIVEThe purpose of this study was to determine whether gadolinium (Gd) is deposited in brain and bone tissues in patients receiving only non–Group 1 agents, either macrocyclic or linear protein ...interacting Gd-based contrast agents, with normal renal function. Group 1 agents are linear agents most associated with nephrogenic systemic fibrosis that the US Federal Drug Administration has defined as contraindicated in patients at risk for this disease.
MATERIALS AND METHODSThis study was institutional review board approved and Health Insurance Portability and Accountability Act compliant for retrospective review of records and also had signed autopsy consent authorizing use of decedentʼs tissue in research studies. Tissue samples were collected from 9 decedents undergoing autopsy who had contrast-enhanced magnetic resonance imaging (MRI) with only single agent exposure to a non–Group 1 Gd-based contrast agent. Decedents with only noncontrast MRI or no MRI served as controls. Multiple brain areas, including globus pallidus and dentate nucleus, as well as bone and skin, were sampled and analyzed for Gd using inductively coupled plasma mass spectrometry. Gadolinium levels were compared between groups of decedents using the Mann-Whitney test and between brain and bone tissues of the same cases using the Wilcoxon signed-rank test.
RESULTSOf the 9 decedents, 5 received gadoteridol (ProHance; Bracco Diagnostics, Princeton, NJ), 2 received gadobutrol (Gadovist; Bayer Healthcare, Whippany, NJ), and 1 each had gadobenate (MultiHance; Bracco Diagnostics) and gadoxetate (Eovist; Bayer Healthcare). Gadolinium was found with all agents in all brain areas sampled with highest levels in globus pallidus and dentate. Bone levels measured 23 times higher (median) than brain levels (P = 0.008 for bone vs globus pallidus) and showed a significant correlation (r = 0.81, P = 0.022). In controls, Gd levels in the brain were at or below limits of measurement and were significantly lower compared with study cases (P = 0.005 for globus pallidus).
CONCLUSIONGadolinium deposition in normal brain and bone tissue occurs with macrocyclic and linear protein interacting agents in patients with normal renal function. Deposition of Gd in cortical bone occurs at much higher levels compared with brain tissue and shows a notable correlation between the two. Thus, the bone may serve as a surrogate to estimate brain deposition if brain Gd were to become a useful clinical or research marker.
Background
Retained gadolinium from gadolinium-based contrast agents (GBCAs) used in MR exams has been inferred based on signal changes on serial brain MRI and subsequently demonstrated ...pathologically in adults. Retention has been similarly inferred in children but pathological demonstration in pediatric patients is limited. The long-term effects of retained gadolinium are unknown but are potentially of greater concern in children given their increased vulnerability from continuing development and their expected longer period of exposure. Several factors can influence gadolinium retention. In adults as well as in children, greater accumulation has been demonstrated based on MR signal changes with linear compared with macrocyclic gadolinium chelates, attributed to lower chelate affinity with linear agents. Effects of age at exposure on retention are unknown, while differences in GBCA washout rates are still under investigation and might affect gadolinium retention relative to time of GBCA administration.
Objective
The purpose of this study was to confirm whether gadolinium brain deposits are present in pediatric patients who received GBCAs and to quantify the amounts present.
Materials and methods
Brain autopsy specimens from 10 pediatric patients between 1 year and 13 years of age who underwent at least one contrast-enhanced MR exam were analyzed for elemental gadolinium using inductively coupled plasma mass spectrometry. Brain samples included white matter, basal ganglia (putamen, globus pallidus), thalamus, dentate nucleus and tumor tissue as available. Type and dose of contrast agent, number and timing of contrast-enhanced MR exams and renal function (estimated glomerular filtration rate eGFR) were documented for each child.
Results
Patient exposures ranged from 1 dose to 20 doses of GBCAs including both macrocyclic and linear ionic agents. Gadolinium was found to be present in brain tissue in all children and was generally highest in the globus pallidus. Those who received only macrocyclic agents showed lower levels of gadolinium retention.
Conclusion
This study demonstrates pathological confirmation of gadolinium retention in brain tissue of a series of pediatric patients exposed to GBCAs including not only linear ionic agents but also macrocyclic agents with both nonionic and ionic compounds. The distribution and deposition levels in this small pediatric population are comparable with the findings in adults. While the clinical significance of these deposits remains unknown, at this point it would be prudent to exert caution and avoid unnecessary use of GBCAs in pediatric patients.
Rodent models of obesity induced by consuming high-fat diet (HFD) are characterized by inflammation both in peripheral tissues and in hypothalamic areas critical for energy homeostasis. Here we ...report that unlike inflammation in peripheral tissues, which develops as a consequence of obesity, hypothalamic inflammatory signaling was evident in both rats and mice within 1 to 3 days of HFD onset, prior to substantial weight gain. Furthermore, both reactive gliosis and markers suggestive of neuron injury were evident in the hypothalamic arcuate nucleus of rats and mice within the first week of HFD feeding. Although these responses temporarily subsided, suggesting that neuroprotective mechanisms may initially limit the damage, with continued HFD feeding, inflammation and gliosis returned permanently to the mediobasal hypothalamus. Consistent with these data in rodents, we found evidence of increased gliosis in the mediobasal hypothalamus of obese humans, as assessed by MRI. These findings collectively suggest that, in both humans and rodent models, obesity is associated with neuronal injury in a brain area crucial for body weight control.
Measurement of vessel stenosis by using ultrasonography or angiography remains the principal method for determining the severity of carotid atherosclerosis and the need for endarterectomy. The ...ipsilateral stroke rate, however--even in patients with severely stenotic vessels--is relatively low, which suggests that the amount of luminal narrowing may not represent the optimal means of assessing clinical risk. As a result, some patients may undergo unnecessary surgery. Improved imaging techniques are, therefore, needed to enable reliable identification of high-risk plaques that lead to cerebrovascular events. High-spatial-resolution magnetic resonance (MR) imaging has been described as one promising modality for this purpose, because the technique allows direct visualization of diseased vessel wall and can be used to characterize the morphology of individual atherosclerotic carotid plaques. The purpose of this report is to review the current state of carotid plaque MR imaging and the use of carotid MR to evaluate plaque morphology and composition.
Introduction
Magnetic resonance (MR) diffusion-weighted imaging (DWI), dynamic susceptibility contrast-enhanced perfusion imaging (DSC), and MR spectroscopy (MRS) techniques provide specific ...physiologic information that may distinguish malignant glioma progression from post-radiation change, yet no single technique is completely reliable. We propose a simple, multiparametric scoring system to improve diagnostic accuracy beyond that of each technique alone.
Methods
Fifteen subjects with lesions suspicious for glioma progression following radiation therapy who had also undergone 3-tesla DWI, DSC, and MRS studies of the lesion were retrospectively reviewed. Minimum apparent diffusion coefficient (ADC) ratio, maximum regional cerebral blood volume (rCBV) ratio, and maximum MRS choline/creatine (Cho/Cr) and choline/
N
-acetyl-aspartate (Cho/NAA) metabolic peak-height ratios were quantified within each lesion. Each parameter (ADC ratio, rCBV ratio, and combined Cho/Cr and Cho/NAA ratios) was scored as either glioma progression (one point) or radiation change (zero point) based upon thresholds derived from our own data. For each lesion, the combined parameters yielded a multiparametric score (0 to 3) for prediction of tumor progression or post-radiation change.
Results
Optimum thresholds for ADC ratio (1.30), rCBV ratio (2.10), and either combined Cho/Cr (1.29) and Cho/NAA (1.06) yielded diagnostic accuracies of 86.7%, 86.7%, and 84.6%, respectively (
p
< 0.05). A combined multiparametric score threshold of 2 improved diagnostic accuracy to 93.3% (
p
< 0.05).
Conclusion
In this small series combining 3-T DWI, DSC, and MRS diagnostic results using a simple, multiparametric scoring system has potential to improve overall diagnostic accuracy in distinguishing glioma progression from post-radiation change beyond that of each technique alone.
OBJECTIVEThe aim of this study was to assess gadolinium deposition in the skin of a patient with normal renal function, based on estimated glomerular filtration rate values greater than 59 ...mL/min/1.73 m after exposure to large cumulative doses of gadolinium-based contrast agents (GBCAs).
MATERIALS AND METHODSThe patient underwent 61 contrasted brain MRI scans over the course of 11 years. Skin biopsies from the forearm and lower extremity were analyzed with inductively coupled plasma mass spectrometry (ICP-MS), laser ablation ICP-MS, and hydrophilic interaction liquid chromatography ICP-MS.
RESULTSThe ICP-MS demonstrated high levels of gadolinium deposition (14.5 ± 0.4 μg/g), similar to previously reported gadolinium levels within the skin of patients with nephrogenic systemic fibrosis. The laser ablation ICP-MS demonstrated deposition of gadolinium within the deep layers of skin. Speciation analysis using hydrophilic interaction liquid chromatography ICP-MS demonstrated the presence of intact gadolinium-chelate species, although most of the gadolinium present could not be further characterized. Light microscopy demonstrated increased CD34 immunoreactivity in the connective tissue septations of the subcutaneous adipose tissue. The patient had no history of skin disorders and did not have a history of nephrogenic systemic fibrosis but did have severe joint contractures of unknown etiology.
CONCLUSIONSOur results, in contradiction to published literature, suggest that in patients with normal renal function, exposure to GBCAs in extremely high cumulative doses can lead to significant gadolinium deposition in the skin. This finding is in line with more recent reports of gadolinium deposition in the brain of patients with normal renal function. Future studies are required to address possible clinical consequences of gadolinium deposition in the skin, brain, and potentially other organs in patients with normal renal function. We recommend, in addition to following current US Food and Drug Administration and American College of Radiology guidelines based on estimated glomerular filtration rate values, that caution be used when administering large cumulative doses of GBCAs and that total cumulative dose of each agent administered is recorded in the patientʼs medical record.
To evaluate the clinical utility of fast whole-brain macromolecular proton fraction ( MPF macromolecular proton fraction ) mapping in multiple sclerosis ( MS multiple sclerosis ) and compare MPF ...macromolecular proton fraction with established quantitative magnetic resonance (MR) imaging measures of tissue damage including magnetization transfer ( MT magnetization transfer ) ratio and relaxation rate (R1).
In this institutional review board-approved and HIPAA-compliant study, 14 healthy control participants, 18 relapsing-remitting MS multiple sclerosis ( RRMS relaxing-remitting MS ) patients, and 12 secondary progressive MS multiple sclerosis ( SPMS secondary progressive MS ) patients provided written informed consent and underwent 3-T MR imaging. Three-dimensional MPF macromolecular proton fraction maps were reconstructed from MT magnetization transfer -weighted images and R1 maps by the single-point method. Mean MPF macromolecular proton fraction , R1, and MT magnetization transfer ratio in normal-appearing white matter ( WM white matter ), gray matter ( GM gray matter ), and lesions were compared between subject groups by using analysis of variance. Correlations (Pearson r) between imaging data and clinical scores (Expanded Disability Status Scale EDSS and MS multiple sclerosis Functional Composite MSFC MS functional composite ) were compared by using Hotelling-Williams test.
RRMS relaxing-remitting MS patients had lower WM white matter and GM gray matter MPF macromolecular proton fraction than controls, with percentage decreases of 6.5% (P < .005) and 5.4% (P < .05). MPF macromolecular proton fraction in SPMS secondary progressive MS was reduced relative to RRMS relaxing-remitting MS in WM white matter , GM gray matter , and lesions by 6.4% (P < .005), 13.4% (P < .005), and 11.7% (P < .05), respectively. EDSS Expanded Disability Status Scale and MSFC MS functional composite demonstrated strongest correlations with MPF macromolecular proton fraction in GM gray matter (r = -0.74 and 0.81; P < .001) followed by WM white matter (r = -0.57 and 0.72; P < .01) and lesions (r = -0.42 and 0.50; P < .05). R1 and MT magnetization transfer ratio in all tissues were significantly less correlated with clinical scores than GM gray matter MPF macromolecular proton fraction (P < .05).
MPF macromolecular proton fraction mapping enables quantitative assessment of demyelination in normal-appearing brain tissues and shows primary clinical relevance of GM gray matter damage in MS multiple sclerosis . MPF macromolecular proton fraction outperforms MT magnetization transfer ratio and R1 in detection of MS multiple sclerosis -related tissue changes.
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