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The effect of [6,6'-2H2]glucose dose on human brain deuterium metabolic imaging at 7T
Narjes Ahmadian1, Maaike Konig2, Mark Gosselink2, Ayhan Gursan2, Sigrid Otto3, Kiki Tesselaar3, Pieter van Eijsden4, Dennis Klomp2, Jeanine Prompers2, and Evita Wiegers2
1Radiology and Neurosurgery, UMC Utrecht, Utrecht, Netherlands, 2Radiology, University Medical Center Utrecht, Utrecht, Netherlands, 3CTI Lab support, University Medical Center Utrecht, Utrecht, Netherlands, 4Neurosurgery, University Medical Center Utrecht, Utrecht, Netherlands

Synopsis

Keywords: Deuterium, Spectroscopy

Motivation: Deuterium metabolic imaging (DMI) is used to study metabolic processes, but the effect of varying substrate doses on DMI data in the brain is not yet known

Goal(s): Comparing different doses aims to reduce cost, while still achieving sufficient sensitivity for DMI

Approach: Three healthy participants received different doses of [6,6'-2H2]glucose on two occasions and underwent dynamic 7T DMI scans

Results: In 120-minutes after ingesting [6,6'-2H2]glucose , there is no clear difference in the signal of 2H-glucose/2H-Glx in the brain between the 0. 50-0.75g/kg doses. However, there was an earlier decrease in the signal when using the 0.25g/kg dose in one subject.

Impact: We compared three different doses [6,6'-2H2]glucose for Deuterium Metabolic Imaging of the brain, at 7T. Metabolite signals were comparable for the 0.50g/kg and 0.75g/kg doses, making 0.50g/kg a potential cost-saving alternative for clinical translation.

Introduction

Deuterium metabolic imaging (DMI) is a novel, non-invasive metabolic imaging technique typically undertaken with oral intake of 2H-labeled substrates, such as [6,6'-2H2]glucose, to acquire three-dimensional metabolic maps1. DMI can be used to dynamically monitor glycolytic and oxidative glucose metabolism in the brain3,4 , or can be used to generate metabolic maps at a single time point for imaging regional metabolic alterations, such as those found in tumors2-4.

In most human studies, [6,6'-2H2]glucose is administered at 0.75-0.80 g/kg body weight5-8. It is however unknown how the [6,6'-2H2]glucose dose affects the various metabolite signals in dynamic DMI data of the brain. The objective of this study was therefore to compare three different doses of [6,6'-2H2]glucose necessary for signal detection in the human brain during dynamic DMI at 7T.

Methods

Experimental protocol
Three healthy subjects underwent two scanning sessions with at least a 2-week interval, receiving different doses of [6,6'-2H2]glucose dissolved in water (0.2g/ml) (Table-1). Subjects fasted overnight and were scanned in the morning. Subjects received an intravenous catheter for blood sampling at 10-minute intervals. They were placed in a 7T MR scanner (Philips, Best, NL), using a custom-built 2H transmit bore coil and a head coil equipped with 8 2H-receive loops and 8 1H-transmit/receive dipole antennas (Figure-3)9.

Prior to [6,6'-2H2]glucose administration, B0-shimming was performed and T1-weighted images were acquired. A baseline DMI scan was conducted, followed by oral administration of [6,6'-2H2]glucose through a 1.5 m tube, while subjects remained in the MR system. DMI data acquisition lasted ~120 minutes.
The DMI data was acquired using a 3D FID-MRSI sequence: voxel size:12x12x12 mm3, field of view: 240x180x216 mm3, repetition time (TR): 100 ms, echo time (TE): 1.82 ms, spectral bandwidth: 2800 Hz, 256 data points, 4 sample averages at the center of k-space, and an acquisition time of 11:44 minutes/scan.

Post-processing
The data were processed with an in-house MATLAB script (Matlab R2021a, MathWorks, USA) and included spatial Fourier transformation, phase correction. Signal from the 8 2H receive channels was combined using whitened singular-value decomposition (WSVD). Deuterated water (HDO), glucose (2H-Glc), and glutamate/glutamine (2H-Glx) signals were fitted with AMARES, using Lorentzian line shapes10. To quantify, the signals were normalized to the baseline HDO signal amplitude in the same voxel and adjusted for label loss11. The T1-weighted image was processed with a SPM12 algorithm for gray matter, white matter, and cerebrospinal fluid segmentation, to account for a voxel-wise fractional water content12. For visualization, PCA-denoising, spectral zero-filling, and apodization with a 5-Hz exponential function were applied13.

Plasma glucose levels were measured using a YSI glucose analyzer (2500 series, YSI, USA). The atom percent excess (APE) of deuterium in plasma glucose was determined through gas chromatography-mass spectrometry14-16.

The linear correlation between plasma and brain 2H glucose was determined through curve-fitting in MATLAB using paired data points collected at the closest time intervals.

Results

For all three doses, plasma glucose APE rapidly increased in the initial 30 minutes following [6,6'-2H2]glucose ingestion (Figure-2). After 60 minutes, no APE difference was observed between the 0.50g/kg and 0.75g/kg doses, but a lower APE was seen at 0.25g/kg. Blood glucose levels, per subject, seem dose independent in the first ~40 minutes.

In Figure-3, 2H MR spectra show temporal changes for three scans with varying [6,6'-2H2]glucose doses in different subjects. Figure-4A displays quantified 2H-Glc and 2H-Glx concentrations, while Figure-4B shows concentration time curves averaged across the entire brain. Average brain 2H-Glc concentrations reached a plateau for all doses, with the lowest plateau in subject 3 (0.25g/kg) and the highest in subject 1 (0.75g/kg), This plateau was not always maintained until the end of the study. Subject 2 showed no apparent difference in brain 2H-Glc concentrations between the 0.25g/kg and 0.75g/kg doses (Figure-4A,B). Average brain 2H-Glx concentrations increased linearly over 120 minutes following glucose administration, except for subject 3 (0.25g/kg), where it plateaued after 95 minutes (Figure-4A,B).

Figure-5 shows a positive linear correlation between plasma 2H glucose and brain 2H glucose (R2=0.75).

Discussion and conclusion

We compared three [6,6'-2H2]glucose doses on plasma glucose 2H APE and brain DMI data. As expected, our data showed a linear relationship between plasma and brain glucose17. APE and brain 2H-Glc and 2H-Glx concentrations were similar for 0.50-0.75g/kg doses. At 0.25g/kg, there was more variability, with one subject showing lower plasma glucose 2H APE and brain 2H-Glc and 2H-Glx concentrations toward the end of the experiment. Our findings suggest a potential reduction in dose from 0.75g/kg to 0.50g/kg for cost savings in future studies, at least at 7T. However, the variability at 0.25g/kg calls for further investigation with a larger subject group.

Acknowledgements

We gratefully acknowledge funding of NWO-VENI 18144-Wiegers

References

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Figures

Table 1. Subject characteristics

Figure 2. Plasma glucose concentration (top row) and plasma glucose 2H APE (bottom row) after oral administration (at T=0 min) of [6,6'-2H2]glucose, using different doses of [6,6'-2H2]glucose in different subjects and during different visits. Plasma glucose 2H APE for subject 2 with a dose of 0.75 g/kg still needs to be analyzed.

Figure 3. 2H MR spectra from a single voxel as a function of time, for three scans performed on different subjects with three different [6,6'-2H2]glucose doses. The 2H glucose signal frequency is indicated by the blue dashed line, and the Glx signal by the red dashed line. On the right side of the figure is the head coil, with 8 2H-receive loops and 8 1H-transmit/receive dipole antennas.

Figure 4.A. Dynamic DMI maps of 2H-Glc and 2H-Glx after oral administration of [6,6'-2H2]glucose for three subjects (central slice) using different doses of [6,6'-2H2]glucose. Metabolite levels were normalized to the baseline HDO signal. B. Time curves of average whole brain brain 2H-Glc (top row) and 2H-Glx (bottom row) concentrations (mM).

Figure 5.Correlation between concentration of plasma 2H glucose and brain 2H glucose among all subjects.

Proc. Intl. Soc. Mag. Reson. Med. 32 (2024)
5077
DOI: https://doi.org/10.58530/2024/5077