Payam Nahavandi1, Ian F Harrison1, May Z Thin1, John J Connell1, Ozama Ismail1, Yolanda Ohene1, Jack A Wells1, and Mark F Lythgoe1
1Centre for Advanced Biomedical Imaging, Division of Medicine, University College London, London, United Kingdom
Synopsis
Recently, evidence for gadolinium retention in the brain
was provided, raising concerns regarding the safety of these agents. This
accumulation raised important questions, most crucially, by which pathway does
gadolinium enter the brain. We provide insight into this by dynamic monitoring of
the infiltration and clearance of gadolinium into the brain parenchyma following
an IV injection. Following gadolinium injection, inflow of contrast into the
cerebrospinal fluid spaces was prominent. 25mins post injection, contrast
enhancement is detected in the periventricular regions and hypothalamus. This
finding provides insight into the entry routes by which gadolinium infiltrates
the brain following a systemic administration.
Introduction
Recent evidence for the retention of gadolinium (Gd) based
contrast agents in the brain following repeated IV delivery, has led to safety concerns.1 As yet, it is
unclear as to the route of ingress and clearance from the brain. We aim to
address this question by visualizing the infiltration of Gd into the brain parenchyma following systemic
(IV) injection. This method may also enable the assessment of rates of
interstitial solute clearance, and thus represents a novel and minimally
invasive measure of glymphatic function, which has been proposed as a key
pathway for waste removal, and may be important in the aetiology of many
prominent neuro-degenerative diseases.2Methods
Data reported here were acquired from 6 healthy C57/B6 mice
(2-3 months of age) using a 9.4T Agilent MRI scanner (anesthesia: isoflurane
in air/O2). A 3D T1-weighted gradient echo sequence was employed
with parameters: TR = 15ms, TE = 3.4ms, flip angle = 15°, NA = 3, FOV = 1.5 ×
1.5 × 2.0cm, acquisition time = 12.5 min, matrix size: 128 × 128 × 128, image
resolution: 0.12 × 0.12 × 0.15mm. The baseline image was followed by an
intravenous injection of a high dose bolus
(10mmol/Kg) of Gadodiamide (Omniscan, GE Healthcare). Results
Following IV delivery of Gd, inflow of contrast agent into
the cerebrospinal fluid (CSF) spaces, notably the ventricular system, was
prominent (fig1-red arrows). This demonstrates the ability of this agent to cross the
blood-CSF barrier and suggests that entry to the brain parenchyma may be via
the CSF.
In order to quantify the inflow and clearance of the gadolinium
from the CSF, time-intensity curves from manually drawn regions of interest
(ROIs) were obtained (fig2).
Infiltration of Gd was observed into parenchymal regions
immediately surrounding the ventricles, with contrast enhancement in the
periventricular regions and hypothalamus 25 minutes post injection (fig3). This
finding provides insight into the entry routes by which gadolinium infiltrates
the brain following a systemic administration.
Discussion
A previous report noted hyper intensity on
T1-weighted images (unenhanced) in
the dentate nucleus and globus pallidus regions in patients who received
repeated doses of linear gadolinium based contrast agents which raised
safety concerns. The mechanism of contrast accumulation in these brain regions
could not be established, mainly due to the fact that the experiments were
performed at a single time-point where the contrast agent had already been
deposited in the brain. In this study, the infiltration and clearance of gadolinium
into the mouse brain was dynamically monitored following a systemic injection. We provide evidence
that the primary route of infiltration of contrast agent into the brain is via
the blood-CSF barrier. We further demonstrate, for the first time, that
gadolinium appears to infiltrate the brain parenchyma immediately proximal to
the ventricles. By monitoring the washout of Gd from the tissue, this methodology may
also represent a useful tool to image glymphatic clearance and its role in
neuro-degenerative conditions such as Alzheimer's disease, non-invasively.Conclusion
We have captured the dynamic inflow of contrast agent from the blood to
brain for the first time, using a minimally invasive approach. Initial analysis
suggests that Omniscan appears to accumulate in the CSF spaces before moving
into periventricular regions. Work is ongoing to fully characterize this
pathway across all brain regions. Acknowledgements
This work is supported by the
EPSRC-funded UCL Centre for Doctoral Training in Medical Imaging (EP/L016478/1)
and the Department of Health’s NIHR-funded Biomedical Research Centre at
University College London Hospitals.References
1- Kanda T, et al. High Signal
Intensity in the Dentate Nucleus and Globus Pallidus on Unenhanced T1-weighted
MR Images: Relationship with Increasing Cumulative Dose of a Gadolinium-based
Contrast Material. Radiology 2014 270:3, 834-841
2- Iliff J. J, et al. A
paravascular pathway facilitates CSF flow through the brain parenchyma and the
clearance of interstitial solutes, including amyloid beta. Science
translational medicine 4, 147ra111, doi:10.1126/scitranslmed.3003748 (2012).