Penetration and distribution of gadolinium-based contrast agents into the cerebrospinal fluid in healthy rats: a potential pathway of entry into the brain tissue

Jošt, Gregor; Frenzel, Thomas; Lohrke, Jessica; Lenhard, Diana C.; Naganawa, Shinji; Pietsch, Hubertus

doi:10.1007/s00330-016-4654-2

Cited by 123 publications

(143 citation statements)

References 41 publications

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“…In their study, Naganawa et al attributed entry into the CSF to permeation from the peripheral part of the cranial nerve or nerve sheath. Since no differences have been found in CSF Gd levels up to 24 hours after injection of either linear or macrocyclic GBCAs, the differences we observe both in the cerebellum and cerebrum after macrocyclic GBCA exposure must be due to a more efficient clearance of gadoteridol. As noted above, such clearance may reflect differences in molecular features, such as lower molecular weight and lower viscosity.…”

Section: Discussioncontrasting

confidence: 49%

Differences in gadolinium retention after repeated injections of macrocyclic MR contrast agents to rats

Bussi

Coppo

Botteron

et al. 2017

Magnetic Resonance Imaging

110

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PurposeTo compare the levels of gadolinium in the blood, cerebrum, cerebellum, liver, femur, kidneys, and skin after multiple exposure of rats to the macrocyclic gadolinium‐based contrast agents (GBCAs) gadoterate, gadobutrol, and gadoteridol.Materials and MethodsFifty male Wistar Han rats were randomized to three exposure groups (n = 15 per group) and one control group (n = 5). Animals in the exposure groups received a total of 20 GBCA administrations (four administrations per week for 5 consecutive weeks) at a dose of 0.6 mmol/kg bodyweight. After a 28‐day recovery period animals were sacrificed and the blood and tissues harvested for determination of gadolinium (Gd) levels. Gd determination was performed by inductively coupled plasma mass spectrometry (ICP‐MS).ResultsAfter 28 days' recovery no Gd was found in the blood, liver, or skin of any animal in any group. Significantly lower levels of Gd were noted with gadoteridol compared to gadoterate and gadobutrol in the cerebellum (0.150 ± 0.022 vs. 0.292 ± 0.057 and 0.287 ± 0.056 nmol/g, respectively; P < 0.001), cerebrum (0.116 ± 0.036 vs. 0.250 ± 0.032 and 0.263 ± 0.045 nmol/g, respectively; P < 0.001), and kidneys (25 ± 13 vs. 139 ± 88 [P < 0.01] and 204 ± 109 [P < 0.001], respectively). Higher levels of Gd were noted in the femur (7.48 ± 1.37 vs. 5.69 ± 1.75 and 8.60 ± 2.04 nmol/g, respectively) with significantly less Gd determined for gadoterate than for gadobutrol (P < 0.001) and gadoteridol (P < 0.05).ConclusionDifferences exist between macrocyclic agents in terms of their propensity to accumulate in tissues. The observed differences in Gd concentration point to differences in GBCA washout rates in this setting and in this experimental model, with gadoteridol being the GBCA that is most efficiently removed from both cerebral and renal tissues. Level of Evidence: 2 Technical Efficacy: Stage 5J. Magn. Reson. Imaging 2018;47:746–752.

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Section: Discussioncontrasting

confidence: 49%

Differences in gadolinium retention after repeated injections of macrocyclic MR contrast agents to rats

Bussi

Coppo

Botteron

et al. 2017

Magnetic Resonance Imaging

110

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“…Thirdly, it is possible that gadolinium may reach the brain parenchyma without permeating through the BBB, namely across the choroid plexus into the CSF (Jost et al . ), and subsequent equilibration with the brain interstitial fluid via the glymphatic pathway (Iliff et al . ).…”

Section: Introductionmentioning

confidence: 99%

Blood–brain barrier permeability measured using dynamic contrast‐enhanced magnetic resonance imaging: a validation study

Varatharaj

Liljeroth

Darekar

et al. 2018

The Journal of Physiology

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Key points The blood–brain barrier (BBB) is an important and dynamic structure which contributes to homeostasis in the central nervous system.BBB permeability changes occur in health and disease but measurement of BBB permeability in humans is not straightforward.Dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) can be used to model the movement of gadolinium contrast into the brain, expressed as the influx constant K i.Here evidence is provided that K i as measured by DCE‐MRI behaves as expected for a marker of overall BBB leakage.These results support the use of DCE‐MRI for in vivo studies of human BBB permeability in health and disease. AbstractBlood–brain barrier (BBB) leakage can be measured using dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) as the influx constant K i. To validate this method we compared measured K i with biological expectations, namely (1) higher K i in healthy individual grey matter (GM) versus white matter (WM), (2) GM/WM cerebral blood volume (CBV) ratio close to the histologically established GM/WM vascular density ratio, (3) higher K i in visibly enhancing multiple sclerosis (MS) lesions versus MS normal appearing white matter (NAWM), and (4) higher K i in MS NAWM versus healthy individual NAWM. We recruited 13 healthy individuals and 12 patients with MS and performed whole‐brain 3D DCE‐MRI at 3 T. K i and CBV were calculated using Patlak modelling for manual regions of interest (ROI) and segmented tissue masks. K i was higher in control GM versus WM (P = 0.001). CBV was higher in GM versus WM (P = 0.005, mean ratio 1.9). K i was higher in visibly enhancing MS lesions versus MS NAWM (P = 0.002), and in MS NAWM versus controls (P = 0.014). Bland–Altman analysis showed no significant difference between ROI and segmentation methods (P = 0.638) and an intra‐class correlation coefficient showed moderate single measure consistency (0.610). K i behaves as expected for a compound marker of permeability and surface area. The GM/WM CBV ratio measured by this technique is in agreement with the literature. This adds evidence to the validity of K i measured by DCE‐MRI as a marker of overall BBB leakage.

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“…However, recent data, not yet replicated in animals, show that intrathecal injection of a GBCA leads to T1 signal hyperintensity of the dentate nucleus and globus pallidus, suggesting entry via the glymphatic system, which is a brain-wide cerebrospinal fluid (CSF)-interstitial fluid mechanism by which interstitial solutes are cleared. 41 That CSF is a potential pathway of GBCA entry into the brain was confirmed in a recent animal study by Jost et al 42 No differences in penetration and distribution into the CSF was noted between the 6 evaluated, marketed GBCAs.…”

Section: Recent Animal Investigationsmentioning

confidence: 80%

Critical Questions Regarding Gadolinium Deposition in the Brain and Body After Injections of the Gadolinium-Based Contrast Agents, Safety, and Clinical Recommendations in Consideration of the EMA's Pharmacovigilance and Risk Assessment Committee Recommendation for Suspension of the Marketing Authorizations for 4 Linear Agents

2017

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For magnetic resonance, the established class of intravenous contrast media is the gadolinium-based contrast agents. In the 3 decades since initial approval, these have proven in general to be very safe for human administration. However, in 2006, a devastating late adverse reaction to administration of the less stable gadolinium-based contrast agents was identified, nephrogenic systemic fibrosis. The result of actions taken by the European Medicines Agency and the US Food and Drug Administration, stratifying the agents by risk and contraindicating specific agents in severe renal dysfunction, has led to no new cases being identified in North America or Europe. Subsequently, in 2014, long-term deposition in the brain of gadolinium was first shown, after administration of 2 nonionic linear chelates, gadodiamide, and gadopentetate dimeglumine. This has led to an intense focus on the question of in vivo distribution, possible dechelation, and subsequent deposition of gadolinium, together with substantial clarification of the phenomenon as well as stratification of the agents on this basis. This review focuses on 8 critical questions regarding gadolinium deposition in the brain and body, with the answers and discussion therein important for future regulatory decisions and clinical practice. It is now clear that dechelation of gadolinium occurs in vivo with the linear agents and is responsible for this phenomenon, with key experts in the field recommending, except where there is no suitable alternative, a shift in clinical practice from the linear to macrocyclic agents. In addition, on March 10, 2017, the Pharmacovigilance and Risk Assessment Committee of the European Medicines Agency recommended suspension of the marketing authorization for 4 linear gadolinium contrast agents-specifically Omniscan, Optimark, Magnevist, and MultiHance (gadodiamide, gadoversetamide, gadopentetate dimeglumine, and gadobenate dimeglumine)-for intravenous injection. Cited in the report was convincing evidence of gadolinium deposition in the brain months after injection of these linear agents. Primovist/Eovist (gadoxetic acid disodium) will remain available, being used at a lower dose for liver imaging, because it meets an important diagnostic need. In addition, a formulation of Magnevist for intra-articular injection will remain available because of its very low gadolinium concentration.

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Penetration and distribution of gadolinium-based contrast agents into the cerebrospinal fluid in healthy rats: a potential pathway of entry into the brain tissue

Cited by 123 publications

References 41 publications

Differences in gadolinium retention after repeated injections of macrocyclic MR contrast agents to rats

Differences in gadolinium retention after repeated injections of macrocyclic MR contrast agents to rats

Blood–brain barrier permeability measured using dynamic contrast‐enhanced magnetic resonance imaging: a validation study

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