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Multimodal Imaging Study of Gadolinium Presence in Rat Cerebellum: Differences Between Gd Chelates, Presence in the Virchow-Robin Space, Association With Lipofuscin, and Hypotheses About Distribution Pathway.
Rasschaert M
,
Schroeder JA
,
Wu TD
,
Marco S
,
Emerit A
,
Siegmund H
,
Fischer C
,
Fretellier N
,
Idée JM
,
Corot C
,
Brochhausen C
,
Guerquin-Kern JL
.
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PURPOSE: The aim of this study was to investigate, based on in-depth multimodal imaging, the presence of Gd deposits, their ultrastructure, location, and co-location with endogenous elements, in the cerebellum, after repeated administrations of gadolinium-based contrast agents (GBCAs).
METHODS: Rats sensitized by subtotal nephrectomy received 20 daily intravenous injections of 0.6 mmol Gd/kg for 5 weeks of commercial forms of either gadoterate, gadobenate or gadodiamide, or saline (n = 2/group). The study was randomized and blinded. Magnetic resonance imaging examination was performed weekly. One month after the last injection, electron microscopy analysis of the deep cerebellar nuclei, the granular layer of cerebellar cortex, and the choroid plexus was performed. Elemental analysis of deposits was carried out by electron energy loss spectroscopy. Secondary ion mass spectroscopy was used for complementary chemical mapping.
RESULTS: A T1 hypersignal was evidenced in the deep cerebellar nuclei of rats treated with linear GBCAs, and Gd deposits were identified in all the studied cerebellar structures with gadobenate and gadodiamide (except in the granular layer in gadobenate-treated rats). No such effect was found with the macrocyclic GBCA gadoterate. Most of the Gd deposits revealed a characteristic spheroid "sea urchin-like" morphology, rich in phosphorus, and were localized in the basal lamina of microvessels, in the perivascular Virchow-Robin space, and in the interstitium. Gd was also identified in the glial cells, associated with lipofuscin pigments, for these same groups.
CONCLUSIONS: Transmission electron microscopy analysis of cerebellums of renally impaired rats repeatedly injected with gadobenate and gadodiamide revealed the presence of Gd. Spheroid Gd depositions consisting of a filamentous meshwork were observed in the wall of microvessels, in perivascular Virchow-Robin space, and in the interstitium. Gd was also found in choroid plexus and was associated with pigments (likely lipofuscin) in glial cells. This is consistent with the involvement of the glymphatic distribution pathway for GBCAs. No insoluble Gd deposits were detected in rats injected with the macrocyclic GBCA gadoterate and controls.
FIGURE 1. T1-weighted MRI (4.7 T) examination of the animals analyzed by TEM, after an injection-free, washout period of one month, in the plane containing DCN, and associated atlas (copyright Elsevier Inc, with permission).23 A T1 hypersignal was visible in the DCN of rats from the gadobenate (E–F) and gadodiamide groups (G–H) (arrows), but not in the saline (A–B) and gadoterate (C–D) groups.
FIGURE 2. Gd-containing deposits in sea urchin–shaped spheroidal inclusions (asterisks) observed intramembraneously in the basal lamina of vessels in the DCN of rats that received gadobenate (panels C and G) and gadodiamide (panels D and H). In the gadoterate (panels B and F) and saline (panels A and E) groups, the electron-dense structures sporadically observed in the vessel wall never displayed the characteristic sea urchin shape, were not located in the basal lamina, and were always negative for Gd when analyzed by EELS. BL indicates basal lamina; EC, endothelial cell; L, Lumen of the microvessel; P, pericyte.
FIGURE 3. Sea urchin–like, spheroid-shaped Gd deposits (red circles) localized in the basal lamina (1) and in the perivascular (also known as Virchow-Robin) space (2) (DCN of a gadodiamide-treated rat). A indicates Astrocyte end-feet; BL, basal lamina (yellow arrows = BL of glia limitans; orange arrows = unified basal lamina of endothelial cell and pericyte adluminal side; red arrow = basal lamina of one pericyte abluminal side; red stars= BL coalescence of glia limitans and pericyte or of endothelial cell); EC, endothelial cell; L, lumen of vessel; P, pericyte; PVS, perivascular (also known as Virchow-Robin) space.
FIGURE 4. Typical sea urchin–like, spheroid-shaped deposits observed in the interstitium of the DCN of rats treated with gadobenate (A) and gadodiamide (B). In the gadoterate and saline groups, no deposits were found in the interstitium (data not shown).
FIGURE 5. A, Typical sea urchin–like, spheroid-shaped deposits (arrow) in the DCN of a gadodiamide-treated rat. B, Higher magnification of this deposit showed its precise location in the basal lamina confluence of a microvessel, and EELS suggested heterogeneous Gd distribution (as shown in the adjacent spectra). C, 12C14N− (carbon-nitrogen group) image of the analyzed area (delimited by dashes, NanoSIMS chemical mapping), showing high 12C14N− content in the Gd deposit (arrow); D, overlay of P (red, NanoSIMS) and TEM (gray) images, showing that this characteristic Gd deposit was rich in phosphorus (arrow); E, overlay of sulfur (blue, NanoSIMS) and TEM (gray) images showing that this Gd deposit was also rich in sulfur. Ax indicates axon; BL, basal lamina; EC, endothelial cell; L, lumen of the vessel; MS, axon myelin sheaths.
FIGURE 6. Ultrastructure and EELS analysis results of Gd associated with intracellular membrane-bound pigment inclusions, in the DCN of rats that received gadobenate (A and B) and gadodiamide (C and D). Gd was never detected by EELS in pigment inclusions in rats from the gadoterate and saline groups (data not shown). Ax indicates axon; cP, cell protrusion; N, nucleus.
FIGURE 7. Correlative imaging by TEM and NanoSIMS of Gd-positive pigments (areas 1 and 2) examinated by EELS (C1 and C2: higher magnification of areas 1 and 2, respectively), in the DCN of a rat from the gadodiamide group. These pigments were found, by NanoSIMS, to be rich in sulfur (A), consistent with the hypothesis that they are lipofuscin pigments. Presence of P was observed in some parts of the pigments (B1, B2), coinciding with Gd-positive areas observed by EELS (C1, C2, respectively).
FIGURE 8. Examples of Gd-positive inclusions detected in the choroid plexus area. A, Topology of a perivascular fragment of a circulating fibrocyte-like cell bearing a lipofuscin-like pigment inclusion; note its localization in the interstitial space between the blood vessel and the epithelial choroidal cells (gadobenate group). C, Overview displaying pleomorphic non–membrane-bound electron-dense inclusions found in a basal lamina fold of the choroidal epithelium (gadodiamide group). E, Location of a partial spheroid, sea urchin–like structure found in the basal lamina of a pericyte (gadodiamide group). B, D, and F, Higher magnification of the inclusion (in panels A, C, and E, respectively) displaying the areas selected for EELS analysis. Insert in B, electron-dense lipofuscin inclusion with electron spectroscopic imaging–mapped Gd distribution (red). Insert in B, Gd mapping by electron spectroscopic imaging on the membrane-bound lysosomal lipofuscin inclusion (higher magnification). BL indicates basal lamina; CP, choroid plexus epithelial cell; F, circulating fibrocyte-like cell; L, lumen of the venule; 4 V, fourth ventricle.
Bacyinski,
The Paravascular Pathway for Brain Waste Clearance: Current Understanding, Significance and Controversy.
2017, Pubmed
Bacyinski,
The Paravascular Pathway for Brain Waste Clearance: Current Understanding, Significance and Controversy.
2017,
Pubmed
Cao,
Effect of Renal Function on Gadolinium-Related Signal Increases on Unenhanced T1-Weighted Brain Magnetic Resonance Imaging.
2016,
Pubmed
Egerton,
New techniques in electron energy-loss spectroscopy and energy-filtered imaging.
2003,
Pubmed
Eide,
MRI with intrathecal MRI gadolinium contrast medium administration: a possible method to assess glymphatic function in human brain.
2015,
Pubmed
Fedorow,
Neuromelanin in human dopamine neurons: comparison with peripheral melanins and relevance to Parkinson's disease.
2005,
Pubmed
Frenzel,
Quantification and Assessment of the Chemical Form of Residual Gadolinium in the Brain After Repeated Administration of Gadolinium-Based Contrast Agents: Comparative Study in Rats.
2017,
Pubmed
Gianolio,
Gadolinium Retention in the Rat Brain: Assessment of the Amounts of Insoluble Gadolinium-containing Species and Intact Gadolinium Complexes after Repeated Administration of Gadolinium-based Contrast Agents.
2017,
Pubmed
Gilissen,
A neuronal aging pattern unique to humans and common chimpanzees.
2016,
Pubmed
Gilissen,
Distinct types of lipofuscin pigment in the hippocampus and cerebellum of aged cheirogaleid primates.
2013,
Pubmed
Guerquin-Kern,
Progress in analytical imaging of the cell by dynamic secondary ion mass spectrometry (SIMS microscopy).
2005,
Pubmed
Haylor,
Skin gadolinium following use of MR contrast agents in a rat model of nephrogenic systemic fibrosis.
2012,
Pubmed
Heinsen,
Lipofuscin in the cerebellar cortex of albino rats: an electron microscopic study.
1979,
Pubmed
Höhn,
Lipofuscin: formation, effects and role of macroautophagy.
2013,
Pubmed
Idée,
Role of thermodynamic and kinetic parameters in gadolinium chelate stability.
2009,
Pubmed
Iliff,
Brain-wide pathway for waste clearance captured by contrast-enhanced MRI.
2013,
Pubmed
Jessen,
The Glymphatic System: A Beginner's Guide.
2015,
Pubmed
Jost,
Penetration and distribution of gadolinium-based contrast agents into the cerebrospinal fluid in healthy rats: a potential pathway of entry into the brain tissue.
2017,
Pubmed
Joutel,
Perturbations of the cerebrovascular matrisome: A convergent mechanism in small vessel disease of the brain?
2016,
Pubmed
Jung,
Lipofuscin: formation, distribution, and metabolic consequences.
2007,
Pubmed
Kanda,
Gadolinium deposition in the brain.
2016,
Pubmed
Kanda,
Distribution and chemical forms of gadolinium in the brain: a review.
2017,
Pubmed
Lee,
Quantitative Gd-DOTA uptake from cerebrospinal fluid into rat brain using 3D VFA-SPGR at 9.4T.
2018,
Pubmed
Li,
Surface interactions with compartmentalized cellular phosphates explain rare earth oxide nanoparticle hazard and provide opportunities for safer design.
2014,
Pubmed
Lohrke,
Histology and Gadolinium Distribution in the Rodent Brain After the Administration of Cumulative High Doses of Linear and Macrocyclic Gadolinium-Based Contrast Agents.
2017,
Pubmed
Lorusso,
Pharmacokinetics and tissue distribution in animals of gadobenate ion, the magnetic resonance imaging contrast enhancing component of gadobenate dimeglumine 0.5 M solution for injection (MultiHance).
1999,
Pubmed
McDonald,
Comparison of Gadolinium Concentrations within Multiple Rat Organs after Intravenous Administration of Linear versus Macrocyclic Gadolinium Chelates.
2017,
Pubmed
McDonald,
Gadolinium Deposition in Human Brain Tissues after Contrast-enhanced MR Imaging in Adult Patients without Intracranial Abnormalities.
2017,
Pubmed
McDonald,
Intracranial Gadolinium Deposition after Contrast-enhanced MR Imaging.
2015,
Pubmed
Messaoudii,
TomoJ: tomography software for three-dimensional reconstruction in transmission electron microscopy.
2007,
Pubmed
Porta,
Pigments in aging: an overview.
2002,
Pubmed
Quintana,
Morphological and chemical studies of pathological human and mice brain at the subcellular level: correlation between light, electron, and nanosims microscopies.
2007,
Pubmed
Rasschaert,
Moderate Renal Failure Accentuates T1 Signal Enhancement in the Deep Cerebellar Nuclei of Gadodiamide-Treated Rats.
2017,
Pubmed
Rasschaert,
Gadolinium Retention, Brain T1 Hyperintensity, and Endogenous Metals: A Comparative Study of Macrocyclic Versus Linear Gadolinium Chelates in Renally Sensitized Rats.
2018,
Pubmed
Robert,
Methodological Aspects for Preclinical Evaluation of Gadolinium Presence in Brain Tissue: Critical Appraisal and Suggestions for Harmonization-A Joint Initiative.
2018,
Pubmed
Robert,
One-year Retention of Gadolinium in the Brain: Comparison of Gadodiamide and Gadoterate Meglumine in a Rodent Model.
2018,
Pubmed
Runge,
Safety of the Gadolinium-Based Contrast Agents for Magnetic Resonance Imaging, Focusing in Part on Their Accumulation in the Brain and Especially the Dentate Nucleus.
2016,
Pubmed
Schneider,
NIH Image to ImageJ: 25 years of image analysis.
2012,
Pubmed
Schroeder,
Ultrastructural evidence of dermal gadolinium deposits in a patient with nephrogenic systemic fibrosis and end-stage renal disease.
2008,
Pubmed
Smith,
Clearance of Gadolinium from the Brain with No Pathologic Effect after Repeated Administration of Gadodiamide in Healthy Rats: An Analytical and Histologic Study.
2017,
Pubmed
Stevens,
Chronic kidney disease and end-stage renal disease in the elderly population: current prevalence, future projections, and clinical significance.
2010,
Pubmed
Taoka,
Impact of the Glymphatic System on the Kinetic and Distribution of Gadodiamide in the Rat Brain: Observations by Dynamic MRI and Effect of Circadian Rhythm on Tissue Gadolinium Concentrations.
2018,
Pubmed
Thakral,
Gadolinium-induced nephrogenic systemic fibrosis is associated with insoluble Gd deposits in tissues: in vivo transmetallation confirmed by microanalysis.
2009,
Pubmed
Thévenaz,
A pyramid approach to subpixel registration based on intensity.
1998,
Pubmed
Zhang,
Extent of Signal Hyperintensity on Unenhanced T1-weighted Brain MR Images after More than 35 Administrations of Linear Gadolinium-based Contrast Agents.
2017,
Pubmed
da Cunha,
Overview of chemical imaging methods to address biological questions.
2016,
Pubmed
