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Multimodal Imaging Study of Gadolinium Presence in Rat Cere

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Lin zhehao

on 12 October 2018

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Transcript of Multimodal Imaging Study of Gadolinium Presence in Rat Cere

Why Choose MRI Images?
Professor :
Chia-Hung Hsieh

Investigative Radiology ,September 2018
Contrast agent
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
Marlène Rasschaert, MS, Josef A. Schroeder, PhD, Ting-Di Wu, PhD, Sergio Marco, PhD, Andréa Emerit, MS,Heiko Siegmund, BS, Claudia Fischer, BS,§Nathalie Fretellier, PhD, Jean-Marc Idée, PharmD, MS,Claire Corot, PharmD, PhD,Christoph Brochhausen, MD, PhD,and Jean-Luc Guerquin-Kern, PhD
Student : Zhe-Hao Lin (107210701)
Date : 2018.10.12
Introduction
Material and Methods
Outline
Result
Discussion and Conclusion
-MRI images
-Contrast agent
-Side effect and Disorder
-Purpose
MRI images offer better imaging resolution in soft tissue than CT.
MRI is an non-invasive examination without radiation exposure.
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MRI provides not only the anatomical images but more importantly, the various functional images of the tissue.
How does MRI work ?
0
B
0
B
B
RF
MRI is the abbreviation of
Magnetic Resonance Imaging
and its signal relies on strong magnetic field.
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Once the atomic number or mass is
odd
, it can become MRI active Nuclei. ex : 1-H, 13-C, 19-F, 31-P....
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B
Absence of a strong magnetic field, hydrogen nuclei are randomly aligned.
When the strong magnetic field , is applied, the hydrogen nuclei precess about the direction of the field.
The RF pulse,
Brf
, causes the net magnetic moment of the nuclei, M, to tilt away from Bo.
During realignment, the nuclei lose energy and a measurable RF signal.
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B
When the RF pulse stops, the nuclei return to equilibrium such that is again parallel to Bo .

Patton (1994)
Gadolinium Based Contrast agent
Paramagnetic materials include oxygen and ions of various metals like Fe (iron), Mg (magnesium), and Gd (gadolinium). These ions have
unpaired electrons
, resulting in a positive magnetic susceptibility.
The effect on MRI is an increase in the T1 and T2 relaxation rates (decrease in the T1 and T2 times).
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At the proper concentration, gadolinium contrast agents facilitate T1 relaxation enhancement, increasing T1-weighted images signal .
MultiHance
- gadobenate
- linear ionic
Structure
Stability
Clinical Dose
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log Keq= 22.6
-
0.1 mmol/kg
Omniscan
- gadodiamide
- linear nonionic
Structure
Stability
Clinical Dose
-
log Keq= 16.9
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0.1 mmol/kg
ProHance
- gadoteridol
- cyclic nonionic
Structure
Stability
Clinical Dose
-
log Keq= 23.8
-
0.1 mmol/kg
Dotarem
- gadoterate
- cyclic ionic
Structure
Stability
Clinical Dose
-
log Keq= 25.4
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0.1 mmol/kg
J. Ramalho et.al (2015)
J. Ramalho et.al (2015)
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Gadobenate Linear ionic
Gadodiamide Linear nonionic
Gadoterate
Macrocyclic ionic
Side effect and disorder
If a Gd(III) chelate has
high thermodynamic stability
and
low kinetic stability
,
transmetallation
with endogenous metal ions such as zinc (
Zn2+
), copper (
Cu2+
) and calcium
(Ca2+
) in the plasma can result in the release of free gadolinium ions (Gd3+), which can deposit in the body . Long-term tissue accumulation of toxic Gd3+ can cause
toxic side effects
, including
nephrogenic systemicfibrosis
.
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Wu et al. (2010)
Mechanism of Gd washing out in metabolic organ is still unclear. The most of Gd elimination by kidney but some specific type may through liver.
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Nephrongenic systemic fibrosis, NSF
Nonionic linear chelate binds Gd3+ less tightly than other chelates, allowing endogenous cations such as Cu2+, Fe3+, Zn2+,and Ca2+ to compete with Gd3+for chelate binding. This allows free Gd3+ to be released into the circulation when it may ultimately deposit in tissues.
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Nephrogenic systemic fibrosis in kidney disease Perazella. (2009)
Underlying kidney disease is exposed to a linear GdBCAs. Due to an
increased half-life
, retained GdBCAs under goes
transmetallation
with endogenous cations (Fe3+,Ca2+,etc.) allowing free Gd3+ bound to phosphate to enter tissues.
Nephrogenic systemic fibrosis in kidney disease Perazella. (2009)
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Gd retention was observed in almost all brain areas after injections of the L-GBCAs, gadobenate dimeglumine and gadodiamide. Brain structures with higher Gd uptake corresponded to those structures containing more Fe.
Rasschaert et al. (2018)
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Gadolinium Retention, Brain T1 Hyperintensity and Endogenous Metals
Purpose
1. By multimodal imaging to investigate possible
presence
,
ultrastructural morphology
.
2. Finding out
precise localization
, shape, and
co-
location
with endogenous elements of Gd deposits in cerebellum.
-Protocol
-TEM/EELS
-NanoSIMS
Methods
Subtotally nephrectomized female Sprague Dawley rats aged 10 weeks
Study Design
EELS and NanoSIMS
Energy-Filtered Transmission Electron Microscopy /Energy-loss spectrum
High-Spatial Resolution Secondary Ion Mass Spectroscopy
Magnetic Resonance Imaging
After repeated injections GdBCAs, T1 hypersignal was observed in the DCN in all rats treat with linear GdBCAs.
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Energy Filtered Transmission Electron MicroScopy
Gd deposits were observed(
sea urchin like
) in the vessel wall in a space between 2 basal laminas consistent with perivascular Virchow Robin Space. (Left)
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Similar Gd deposits were observed in the interstitium of DCN in all rats with linear GdBCAs injection. (Right)
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Detailed EELS analysis of Gd sea urchins spheroids revealed heterogeneous presence of Gd. Copresence of Ca, N and O was also occasionally detected.(data not shown)
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Gadolinium was also identified in membrane-bound electron dense pigment aggregates, located in the glial cells of the DCN.
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NanoSIMS analysis revealed its environment filling with
Gd
and rich
Sulfur
,which is a characteristic of
lipofuscin
.
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Phosphorous
was also sometimes identified in some of the aforementioned aggregates, with quite a good correlation with location of
Gd
.
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In the choroid plexus, Gd deposits were identified in
fibrocyte like cells
. In these fibrocyte-like cells, Gd was found to be associated with membrane -bound pigment(likely lipofuscin).
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In
Gadodiamide group
, Gd-positive structure was found in the basal lamina of a blood vessel.
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1. Gd deposits were identified in the
basal lamina
of cerebellar microvessels, in the perivascular
Virchow-Robin space
and also in the interstitium but never observed into endothelial cells, unlike a
postmortem clinical study
in gadodiamide-treated suject, no Gd existed in the nucleus of neuronal cells.
2. Through NanoSIMS technique that spheroidal sea urchin Gd deposits were rich in
phosphorous
, consistent with the hypothesis of a Gd storage in the form of insoluble
GdPO4
. It is likely that these insoluble Gd species are not responsible for
T1 signal enhancement
. But these mesh-like structure may exist water accessibility, the possibility of some T1 relaxivity effect can not be totally ruled out.
3. Intracellular Gd was found in linear GdBCAs in
glial cell
, associated with membrane-bound pigment which were characterized as
lipofuscin
because of their typical ultrastructural features and high local amount of
sulfur
inclusions.
4. In healthy rats, approximately 50% of the linear GdBCAs gadobenate is taken by
hepatocytes
, unlike
gadodiamide
and
gadoterate
that are exexclusively excreted by the
kidneys
. Therefore, in renally impaired rats, the tissue of Gd concentration may be
underestimated
.
Discussion
I have a question...?
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MRI presents multi-plane reconstruction slice images.
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Substances in MRI can be divided into
ferromanetism
,
paramagnetism
,
superparamagnetism
and
diamagetism
.
Full transcript