In 1988, the first contrast agent specifically designed for magnetic resonance imaging (MRI), gadopentetate dimeglumine (Magnevist
®
), became available for clinical use. Since then, a plethora of ...studies have investigated the potential of MRI contrast agents for diagnostic imaging across the body, including the central nervous system, heart and circulation, breast, lungs, the gastrointestinal, genitourinary, musculoskeletal and lymphatic systems, and even the skin. Today, after 25 years of contrast-enhanced (CE-) MRI in clinical practice, the utility of this diagnostic imaging modality has expanded beyond initial expectations to become an essential tool for disease diagnosis and management worldwide. CE-MRI continues to evolve, with new techniques, advanced technologies, and novel contrast agents bringing exciting opportunities for more sensitive, targeted imaging and improved patient management, along with associated clinical challenges. This review aims to provide an overview on the history of MRI and contrast media development, to highlight certain key advances in the clinical development of CE-MRI, to outline current technical trends and clinical challenges, and to suggest some important future perspectives.
Funding
Bayer HealthCare.
Retrospective studies in patients with primary brain tumors or other central nervous system pathologies as well as postmortem studies have suggested that gadolinium (Gd) deposition occurs in the ...dentate nucleus (DN) and globus pallidus (GP) after multiple administrations of primarily linear Gd-based contrast agents (GBCAs). However, this deposition has not been associated with any adverse effects or histopathological alterations. The aim of this preclinical study was to systematically examine differences between linear and macrocyclic GBCAs in their potential to induce changes in brain and skin histology including Gd distribution in high spatial resolution.
Fifty male Wistar-Han rats were randomly allocated into control (saline, n = 10 rats) and 4 GBCA groups (linear GBCAs: gadodiamide and gadopentetate dimeglumine, macrocyclic GBCAs: gadobutrol and gadoteridol; n = 10 rats per group). The animals received 20 daily intravenous injections at a dose of 2.5 mmol Gd/kg body weight. Eight weeks after the last GBCA administration, the animals were killed, and the brain and skin samples were histopathologically assessed (hematoxylin and eosin; cresyl violet Nissl) and by immunohistochemistry. The Gd concentration in the skin, bone, brain, and skeletal muscle samples were analyzed using inductively coupled plasma mass spectroscopy (ICP-MS, n = 4). The spatial Gd distribution in the brain and skin samples was analyzed in cryosections using laser ablation coupled with ICP-MS (LA-ICP-MS, n = 3). For the ultra-high resolution of Gd distribution, brain sections of rats injected with gadodiamide or saline (n = 1) were assessed by scanning electron microscopy coupled to energy dispersive x-ray spectroscopy and transmission electron microscopy, respectively.
No histological changes were observed in the brain. In contrast, 4 of 10 animals in the gadodiamide group but none of the animals in other groups showed macroscopic and histological nephrogenic systemic fibrosis-like skin lesions. The Gd concentrations observed in the skin/brain samples (in nanomole Gd per gram of tissue) for each agent were as follows: gadodiamide: 1472 ± 115/11.1 ± 5.1, gadopentetate dimeglumine: 80.8 ± 6.2/13.1 ± 7.3, gadobutrol: 1.1 ± 0.5/0.7 ± 0.4, and gadoteridol: 1.7 ± 0.8/0.5 ± 0.2. The average detected residual Gd concentration in the brain was approximately 15-fold higher for linear than for macrocyclic GBCAs. The highest amounts of Gd found in brain corresponded to less than 0.0002% of the injected dose per gram of tissue. Using LA-ICP-MS, high Gd concentrations in the deep cerebellar nuclei and in the granular layer of the cerebellar cortex were detected only for linear gadodiamide and gadopentetate dimeglumine but not for gadoteridol or gadobutrol. The energy dispersive x-ray spectroscopy analysis revealed Gd-containing spots in the skin of animals administered gadodiamide and gadopentetate dimeglumine. Transmission electron microscopy revealed several Gd-containing spots in the region of the dentate nuclei in the brain of 1 animal injected with gadodiamide.
After repeated high dosing, nephrogenic systemic fibrosis-like macroscopic and histopathological lesions of the skin were observed only in some of the gadodiamide-treated animals. No histopathological findings were detected in the rodent brain. The administration of linear GBCAs was associated with significantly higher Gd concentrations in the brain and skin compared with macrocyclic GBCA administration. The results of LA-ICP-MS demonstrated local accumulation of Gd within the deep cerebellar nuclei and the granular layer only after the administration of linear agents. In summary, the detected low Gd concentrations in the skin and brain were well correlated with the higher kinetic stability of macrocyclic GBCA.
Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver an opinion on dried yellow mealworm (Tenebrio molitor larva) ...as a novel food (NF) pursuant to Regulation (EU) 2015/2283. The term yellow mealworm refers to the larval form of the insect species Tenebrio molitor. The NF is the thermally dried yellow mealworm, either as whole dried insect or in the form of powder. The main components of the NF are protein, fat and fibre (chitin). The Panel notes that the levels of contaminants in the NF depend on the occurrence levels of these substances in the insect feed. The Panel notes that there are no safety concerns regarding the stability of the NF if the NF complies with the proposed specification limits during its entire shelf life. The NF has a high protein content, although the true protein levels in the NF are overestimated when using the nitrogen‐to‐protein conversion factor of 6.25, due to the presence of non‐protein nitrogen from chitin. The applicant proposed to use the NF as whole, dried insect in the form of snacks, and as a food ingredient in a number of food products. The target population proposed by the applicant is the general population. The Panel notes that considering the composition of the NF and the proposed conditions of use, the consumption of the NF is not nutritionally disadvantageous. The submitted toxicity studies from the literature did not raise safety concerns. The Panel considers that the consumption of the NF may induce primary sensitisation and allergic reactions to yellow mealworm proteins and may cause allergic reactions in subjects with allergy to crustaceans and dust mites. Additionally, allergens from the feed may end up in the NF. The Panel concludes that the NF is safe under the proposed uses and use levels.
To examine potential gadolinium (Gd) accumulation in the brain of healthy mice after long-term oral administration of Gd-containing food pellets and to investigate whether Gd leads to adverse central ...nervous system (CNS) effects, specifically focussing on locomotor impairment in Gd exposed compared to control animals.
The local Animal Experimental Ethics Committee approved all procedures and applications. Fifteen female C57Bl/6 mice were orally exposed to a daily intake of 0.57 mmol Gd chloride/ kg body weight over a period of 90 weeks from the age of 4 weeks on. Gd-free, but otherwise equivalent experimental diets were given to the control group (N = 13). The animals were monitored daily by animal caretakers regarding any visible signs of distress and evaluated clinically every four weeks for the first 60 weeks and afterwards every two weeks for a better temporal resolution of potential long-term effects regarding impairment of motor performance and loss of body weight. The individual Gd content was measured using mass spectrometry in a sub-cohort of N = 6 mice.
The absolute brain Gd levels of the Gd-exposed mice were significantly increased compared to control mice (0.033± 0.009 vs. 0.006± 0.002 nmol Gd/ g brain tissue). Long-term oral Gd exposure over almost the entire life-span did not lead to adverse CNS effects including locomotor changes (rotarod performance, p = 0.1467) in healthy mice throughout the study period. Gd-exposed mice showed less increased body weight compared to control mice during the study period (p = 0.0423). Histopathological alterations, such as hepatocellular vacuolization due to fatty change in the liver and a loss of nucleated cells in the red pulp of the spleen, were found in peripheral organs of both groups.
Low levels of intracerebral Gd caused by chronic oral exposure over almost the entire life span of mice did not lead to alterations in locomotor abilities in healthy mice throughout the normal aging process.
Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Food and Food Allergens (NDA) was asked to deliver an opinion on the safety of frozen and dried formulations from ...house crickets (Acheta domesticus) as a novel food pursuant to Regulation (EU) 2015/2283. The NF is proposed in three formulations: (i) frozen, (ii) dried, (iii) ground. The main components of the NF are protein, fat and fibre (chitin) in the dried form of the NF, and water, protein, fat and fibre (chitin) in the frozen form of the NF. The Panel notes that the concentrations of contaminants in the NF depend on the occurrence levels of these substances in the insect feed. The Panel further notes that there are no safety concerns regarding the stability of the NF if the NF complies with the proposed specification limits during its entire shelf‐life. The NF has a high‐protein content, although the true protein levels in the NF are overestimated when using the nitrogen‐to‐protein conversion factor of 6.25, due to the presence of non‐protein nitrogen from chitin. The applicant proposed to use the NF in the form of a snack, and as a food ingredient in a number of food products. The target population proposed by the applicant is the general population. The Panel notes that, considering the composition of the NF and the proposed conditions of use, the consumption of the NF is not nutritionally disadvantageous. The Panel notes that no genotoxicity and no subchronic toxicity studies with the NF were provided by the applicant. Considering that no safety concerns arise from the history of use of A. domesticus or from the compositional data of the NF, the Panel identified no other safety concerns than allergenicity. The Panel considers that the consumption of the NF might trigger primary sensitisation to A. domesticus proteins and may cause allergic reactions in subjects allergic to crustaceans, mites and molluscs. Additionally, allergens from the feed may end up in the NF. The Panel concludes that the NF is safe under the proposed uses and use levels.
Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver an opinion on frozen and dried formulations from whole yellow ...mealworm (Tenebrio molitor larva) as a novel food (NF) pursuant to Regulation (EU) 2015/2283. The term yellow mealworm refers to the larval form of the insect species Tenebrio molitor. The NF comprises the frozen and freeze‐dried formulations of the yellow mealworm, whole or in the form of powder. The frozen formulation consists mainly of water, crude protein and fat whereas the freeze‐dried formulations of crude protein, fat, digestible carbohydrates and fibre (chitin). The Panel notes that the levels of contaminants in the NF depend on the occurrence levels of these substances in the insect feed. The Panel notes furthermore that there are no safety concerns regarding the stability of the NF if the NF complies with the proposed specification limits during its entire shelf‐life. The dried formulations of the NF have a high protein content, although the true protein levels in the NF are overestimated when using the nitrogen‐to‐protein conversion factor of 6.25, due to the presence of non‐protein nitrogen from chitin. The applicant proposed to use the NF as whole frozen or whole dried insect, or in the form of powder, added as an ingredient to various food products such as cereal bars, pasta, meat imitates and bakery products. The target population is the general population. The Panel notes that, considering that the NF will not be the sole source of dietary protein, and the composition of the NF and the proposed conditions of use, the consumption of the NF is not nutritionally disadvantageous. The submitted toxicity studies from the literature did not raise safety concerns. The Panel considers that the consumption of the NF may induce primary sensitisation and allergic reactions to yellow mealworm proteins and may cause allergic reactions in subjects with allergy to crustaceans and dust mites. Additionally, allergens from the feed may end up in the NF. The Panel concludes that the NF is safe under the proposed uses and use levels.
Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Food and Food Allergens (NDA) was asked to deliver an opinion on the safety of frozen and dried formulations from ...migratory locust (Locusta migratoria) as a novel food pursuant to Regulation (EU) 2015/2283. The term migratory locust refers to the adult of the insect species Locusta migratoria. The NF is proposed in three formulations i) frozen without legs and wings; ii) dried without legs and wings; iii) ground with legs and wings. The main components of the NF are protein, fat and fibre (chitin) in the dried form of the NF, and water, protein, fat and fibre (chitin) in the frozen form of the NF. The Panel notes that the concentration of contaminants in the NF depends on the occurrence levels of these substances in the insect feed. The Panel notes that there are no safety concerns regarding the stability of the NF if the NF complies with the proposed specification limits during its entire shelf‐life. The NF has a high protein content, although the true protein levels in the NF are overestimated when using the nitrogen‐to‐protein conversion factor of 6.25, due to the presence of non‐protein nitrogen from chitin. The applicant proposed to use the NF as frozen, dried and ground in the form of snack, and as a food ingredient in a number of food products. The target population proposed by the applicant is the general population. The Panel notes that considering the composition of the NF and the proposed conditions of use, the consumption of the NF is not nutritionally disadvantageous. The submitted history of use and toxicity studies from literature did not raise safety concerns. The Panel considers that the consumption of the NF might trigger primary sensitisation to L. migratoria proteins and may cause allergic reactions in subjects with allergy to crustaceans, mites and molluscs. Additionally, allergens from the feed may end up in the NF. The Panel concludes that the NF is safe under the proposed uses and use levels.
Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver an opinion on pasteurised Akkermansia muciniphila as a novel ...food (NF) pursuant to Regulation (EU) 2015/2283. A. muciniphila is a well‐characterised non‐toxin producing, avirulent microorganism that has been reported as part of normal gut microbiota. The NF, pasteurised A. muciniphila, is proposed by the applicant to be used as a food supplement at max. 5 × 1010 cells/day by adults excluding pregnant and lactating women, and in foods for special medical purposes. The Panel considers that the production process of the NF is sufficiently described and that the information provided on the composition of the NF is sufficient for its characterisation. Taking into account the composition of the NF and the proposed conditions of use, the consumption of the NF is not nutritionally disadvantageous. Based on literature data, and by applying an uncertainty factor of 200 to the no observed adverse effect level (NOAEL) of a 90‐day repeated dose oral toxicity study in rats, the Panel concludes that the consumption of 3.4 × 1010 cells/day is safe for the target population under the provision that the number of viable cells in the NF is < 10 colony forming units (CFU)/g (i.e. limit of detection).
Gadolinium based contrast agents (GBCAs) are widely used in clinical MRI since the mid-1980s. Recently, concerns have been raised that trace amounts of Gadolinium (Gd), detected in brains even long ...time after GBCA application, may cause yet unrecognized clinical consequences. We therefore assessed the behavioral phenotype, neuro-histopathology, and Gd localization after repeated administration of linear (gadodiamide) or macrocyclic (gadobutrol) GBCA in rats. While most behavioral tests revealed no difference between treatment groups, we observed a transient and reversible decrease of the startle reflex after gadodiamide application. Residual Gd in the lateral cerebellar nucleus was neither associated with a general gene expression pathway deregulation nor with neuronal cell loss, but in gadodiamide-treated rats Gd was associated with the perineuronal net protein aggrecan and segregated to high molecular weight fractions. Our behavioral finding together with Gd distribution and speciation support a substance class difference for Gd presence in the brain after GBCA application.
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