Tsang-Wei Tu1,2, Jaclyn Witko2, and Joseph Frank2
1Howard University, Washington, DC, United States, 2National Institutes of Health, Bethesda, MD, United States
Synopsis
This study compared the endogenous glucoCEST
contrast to the glucoCEST with exogenous glucose delivered as contrast agent in
experimental TBI. By giving relatively low concentration (0.3g/kg) of 2DG
solution, the post-contrast glucoCEST weighted images could magnify the
contrast changes in the brains before and after TBI. Meanwhile, the endogenous
glucoCEST weighted images also detected the same pattern of decreased contrast in
the TBI brains and that was validated by 2DG autoradiography. Our findings
substantiate that the glucoCEST technique has potential to detect the
hypometabolic syndrome following TBI, even without using exogenous contrast
agent.
Introduction
Recently, the endogenous glucoCEST weighted MRI
has also been shown useful to detect the delayed glucose hypometabolism in
experimental TBI without delivering exogenous glucose as contrast agent.1
Question arises in regards to whether the endogenous glucoCEST contrast is reflecting
the changes of glucose metabolism under complications from other metabolites (e.g.
myo-inositol, creatine, glutamate) in the living tissue. To elucidate the
source of contrast changes in the glucoCEST weighted MRI in TBI, the current
study compared the endogenous glucoCEST contrast to the glucoCEST with exogenous
glucose delivered as contrast agent in experimental TBI. The MRI results were compared
to the gold standard 14C-2-deoxyglucose (2DG) autoradiography for
evaluating the sensitivity and specificity in the detection of hypometabolic
syndrome following TBI by glucoCEST.Materials and Methods
6 female 12-week-old SD rats had mild TBI in 2 consecutive
days using a 2m height/450g weight drop model.2 The animals were
imaged before the induction of TBI as the normal control and 1 week after TBI. GlucoCEST
datasets were acquired in vivo using a Bruker 9.4T scanner by 2D fast spin echo
(TR/TE 2.1s/10.4ms; rare factor 4; in plane resolution: 200µm2, thickness:
0.8mm) with (MT) and without (M0) MT saturation pulses (2μT/2s).
The first glucoCEST experiment was acquired without exogenous contrast agent by
MT offset frequences (Δω) from -1.6kHz to +1.6kHz with 100Hz stepping to sample
33 points in the frequency offset range from -4ppm to +4ppm covering three glucose
chemical shifts (1.2, 2.1, 2.9 ppm).3 Procedure according to the
WAter Saturation Shift Referencing (WASSR) method was applied to correct the B0
and B1 field inhomogeneity of the CEST data.4 Thereafter,
20 dynamic glucoCEST enhancement (DGE) experiments (same imaging parameters
except for rare factor 8; resolution 850µm2; 13 CEST points; scan
time: 2m44s/each repetition, total scan: ~60 mins) were performed by delivering
0.3g/kg 2DG solution through tail vein catheter after 4 baseline acquisitions. The
first CEST experiment was then
repeated again with second delivering of 2DG solution in the same dose. The glucoEST
weighted MRI contrast was derived by MTR asymmetry analysis calculating the
area under the curve (a.u.c.) according to previous glucoCEST literatures: (1) 0.75-1.7
ppm5, (2) 0.75-4 ppm6 and (3) 1.2 (±0.4), 2.1 (±0.2), 2.9
(±0.1) ppm1 for detecting the proton metabolites of glucose. After
each scan, 3 rats were randomly selected and processed for 14C-2DG
autoradiography. Data were examined by one-way ANOVA using Prism v6.0 and
Matlab scripts.Results
Figure 1 compared the in vivo glucoCEST images, with or
without the delivering of 2DG, of the normal and TBI rat brains. The glucoCEST
images derived from 0.75-1.7 ppm displayed few contrast enhancements after
giving 2DG, while both of pre- and post-contrast images show decreased contrast
in the TBI brains than the normal brains. The glucoCEST images derived from 0.75-4
ppm exhibited significant increase of contrast in post-contrast images. In the
TBI brain, the glucoCEST images contrast was clearly decreased no matter in pre-
or post-2DG injection. After delivery of 2DG, the glucoCEST contrast derived by
integrating the a.u.c. in glucose chemical shifts at 1.2 (±0.4), 2.1 (±0.2),
2.9 (±0.1) ppm increased ~20% in the brains (Fig. 2A); similarly, the TBI brains
exhibited decreasing glucoCEST contrast significantly in both pre- and post-2DG
injection. 2DG autoradiography also showed comparable pattern of the contrast changes
that the TBI brains exhibited decreased glucose uptake and metabolism (Fig. 2B).
The corresponding quantification indicated that the post-contrast glucoCEST has
stronger significant changes (p<0.01) comparing to the pre-contrast
glucoCEST (p<0.05, Fig. 3). The DGE experiments showed lesser contrast
enhancement in the TBI brains than that in the normal brains (Fig. 4). Discussion
Mild TBI has been termed “a silent epidemic”, in part
because the hypometabolic syndrome may last for years that current imaging
technologies are insensitive to recognize it.4 The current study
demonstrated that the uptake of 2DG was decreased significantly in the rat
model of TBI showing hypometabolic syndrome. By giving relatively low concentration
(0.3g/kg) of 2DG solution, the post-contrast glucoCEST weighted images could magnify
the contrast changes in the brains before and after TBI. At the same time, the
endogenous glucoCEST weighted images also detected the same pattern of contrast
change, which was further validated by 2DG autoradiography. The hypometabolic
state of the brain following TBI might be caused by the alternated cerebral
blood flow, damaged glucose transporter, inflammation, activated astrocyte–neuron
lactate shuttle and increasing cell death. Our findings substantiate that the glucoCEST
technique has strong potential to be the non-invasive imaging modality for detecting
the hypometabolic syndrome following TBI, even without using exogenous contrast
agent.Acknowledgements
No acknowledgement found.References
1. Tu
et al., ISMRM abstract 2017, #4522.
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Tu et al., Annals of Neurology 2016 79: 907-920.
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Kim et al., MRM 2009 61:1441-1450.
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Nasrallah et al., JCBFM 2013 33: 1270-1278
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Walker-Samuel et al., Nat.Med. 2013 19: 1067-1072
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Rusnak et al., Nat.Rev.Neu. 2013 9:186-187