Lin Chen1,2, Jing Liu1,3, Chengyan Chu1,4, Nirhbay Yadav1,2, Jiadi Xu1,2, Monica Pearl1, Piotr Walczak1,4, Peter van Zijl1,2, Miroslaw Janowski4, and Guanshu Liu1,2
1Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, United States, 2F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Research Institute, Baltimore, MD, United States, 3The First Affiliated Hospital of Jinan University, Guangzhou, China, 4Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland, Baltimore, MD, United States
Synopsis
The use of contrast media, such as Gadolinium-based
contrast agents (GBCA), superparamagnetic iron oxide particles
(SPIO) and carbon dioxide, can improve the conspicuity of MRI, thereby helping
to improve the accuracy of transcathether infusions during endovascular
neurointerventions. In this study, we exploited deuterium oxide (D2O) as a new MRI contrast medium for guiding intra-arterial hyperosmotic
blood brain barrier (BBB) opening in experimental animal models. Compared to
the SPIO-based approach, D2O MRI guidance was found to provide comparable results that can predict the territory of BBB
opening (assessed by Gd-MRI).
Introduction
MRI-guided
endovascular intervention plays an important role in the treatment of various
diseases (1-5).
The use of contrast media, including Gadolinium-based contrast agents (GBCA) (6),
superparamagnetic iron oxide
particles (SPIO) (7) and carbon dioxide (8), can improve the conspicuity
and thereby the accuracy of transcathether intra-arterial injections. However,
the safety and clinical applicability of these agents are still under debate
for the use in patients. Deuterium
oxide (D2O) is a
stable, non-radioactive isotopic form of water with similar physical and
chemical properties as regular water. While traditionally D2O be
only detected using MRI scanners equipped with special 2H-tuned
hardware, a recent new study by Wang et al. successfully utilized the proton replacement effect of D2O to develop it as a negative contrast medium
in 1H-MRI (9). In the present study, we sought to develop
D2O as a novel contrast agent for image guidance
during endovascular neurointervention by accurately determining the perfusion
territory of intra-arterially injected solutions. Methods
All chemicals were purchased from Sigma
Aldrich (Saint Louis, MO, USA) unless otherwise stated. Animal studies were approved by institutional ACUC. Rat experiments were
performed on a horizontal bore 11.7 T Bruker Biospec system (Bruker, Ettlingen,
Germany), with the experimental timeline illustrated in Figure 1. The dynamic
SPIO MRI were performed using an EPI sequence with TR/TE = 2s/9.7ms, segment
factor = 2, slice thickness = 1 mm, FOV =3×3 cm2. The Gd-enhanced MRI
were performed using a FLASH sequence with TR/TE = 100ms/1.7 ms, flip angle =
45°, average number = 8, slice thickness = 0.6 mm, and FOV =3×3 cm2.
The D2O MRI was acquired either using the same EPI or FLASH sequences
to compare with SPIO- or Gd- MRI, respectively. The canine experiment was performed
on a clinical 3T Siemens Trio with a quadrature head coil, and the dynamic T2w*
images were acquired with a GE-EPI (TE = 36 ms, TR = 3000 ms, matrix =
128, and acquisition time = 3 s and 50–100 repetitions) after the injection of SPIO
or D2O. Standard Gd-enhanced images were also acquired after the
injection of mannitol.Results and Discussion
As shown in Figure 2, IA injection of 0.6 mL
D2O caused a rapid (within 50 seconds) signal decrease in the ipsilateral
brain hemisphere (red ROI), attributed to the proton replacement effect of locally
high concentration of D2O. This decrease in MRI signal completely
recovered in approximately 3 minutes due to the washout of D2O. It
should be noted that in certain regions,
D2O clearance took up to several minutes, indicating that D2O entered interstitial and
intracellular spaces. As
expected, there was almost no signal change
in the contralateral hemisphere (blue ROI).
Figure 3 shows the comparison between the SPIO- and D2O MRI
results of a representative rat (Figures 3B and D), revealing similar contrast
enhanced regions. This is further confirmed by comparing the maximal
contrast-enhancement maps (Figures 3C and E) acquired by the two methods, with
a good pixel-wise correlation (Pearson coefficient= 0.8491, Figure 3F) and good
match in the contrast-enhanced regions, which is displayed as yellow color in the
pseudocolor image (Figure 3G) composed of the maximal SPIO-enhancement (red) and maximal
D2O-enhancement (green).
To further prove that D2O-MRI
can be used to predict the transcatheter perfusion territory and BBB opening,
we injected mannitol at the same flow rate as used in D2O infusion and
measured the brain regions with BBB opening as assessed by Gd-enhanced MRI. The
comparison of Gd-MRI and D2O-MRI is shown in Figures 4 B-E, revealing
similar contrast-enhanced areas. There was a good correlation with the Gd-contrast maps, i.e., Pearson coefficient=
0.8468 (Figure 4F). The composite color image (Figure 4G) shows an outstanding match of regions from the two methods.
Quantitatively, the overlapped areas account for 72.45% of the D2O-enhanced
area and 73.37% of the Gd-enhanced areas, indicating that D2O-MRI
can reliably predict the area of BBB opening.
Finally, we performed a 3T D2O-MRI
before the interventional BBB opening for the purpose of drug delivery in a
canine model. The observed infusion area of D2O (Figure 5 B) in the
dog brain correlated well with that of Gd-CE (Figure 5D), and even better than
that of SPIO (Figure 5C). This pilot 3T study demonstrates the feasibility of D2O-MRI
on low field clinical MRI scanners. Conclusion
Our study showed that
D2O is a negative MRI contrast medium suitable for guiding
endovascular neurointerventions. Using
regular 1H MRI scanners, we demonstrated the ability of D2O
MRI to accurately visualize intra-arterial perfusion territory and predict the
regions of BBB opening by mannitol (injected using the same route) in rats and
dogs. As D2O is an inexpersnive agent with well-documented safety
profile, our approach is safe and cost-effective with a good quantitative
ability, and may be useful for a variety of endovascular procedures. Acknowledgements
This work was supported by NIH grant R01CA211087, R01NS091110, and R21NS106436References
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