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Glutamate Metabolism Mapping after Oral Administration of 1-13C-Glc using 1H MRSI in the human brain at 9.4 T
Theresia Ziegs1, Loreen Ruhm1, Andrew Wright1, and Anke Henning1,2
1High-Field MR Center, Max Planck Institute for Biological Cybernetics, Tuebingen, Germany, 2Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, United States

Synopsis

Glutamate is the major excitatory neurotransmitter in the brain and malfunction of glutamatergic metabolism is associated with various neurological disorders. Respective metabolic rates can be determined via direct 13C or indirect 1H-[13C] MRS after intake of 13C labelled tracers. In this work, labeling effects after oral intake of [13C-1]glucose are observed in human brain using a 1H-FID-MRSI sequence at 9.4T. Spectral time series of GM and WM voxels as well as metabolite maps show regionally distinct and tissue type specific labelling induced changes of Glu and Gln spectral pattern that allow for the determination of 13C label uptake rates.

Introduction

Glutamate is the major excitatory transmitter in the brain and malfunction of glutamatergic metabolism is associated with various neurological and psychiatric disorders1-7. For better insights into the function of the glutamatergic system, metabolic rates can be determined via direct 13C or indirect 1H-[13C] magnetic resonance spectroscopy after the administration of a 13C labelled tracer such as [13C-1]glucose. Subsequent changes in the spectra due to the incorporation of the 13C nuclei from Glc into different metabolites further downstream from glycolysis to the TCA cycle and into the glutamatergic metabolism can be observed by either direct 13C or indirect 1H-[13C] MRS. Boumezbeur et al. showed the feasibility to observe 13C label incorporation by observing additional peak splitting due to J-coupling between protons and 13C nuclei using conventional 1H MRS8 in monkeys, which abandons the need of specialized 13C hardware and scan software. This single voxel 1H MRS approach has been recently reproduced in the human brain and observation of respective change in Glu and Gln have been shown9-12.
In the present work, the feasibility of measuring metabolic uptake curves in a highly spatially and temporally resolved manner by 1H MRSI for more metabolites and in more voxels than ever before in human brain is shown. The [1-13C]Glc was administered orally instead of intravenous and the spectra were measured with a 2D 1H MRSI sequence in the human brain at 9.4T.

Methods

The study was performed after IRB approval and signed consent of all five volunteers, who fastened for 9 hours before the measurement started. For each volunteer a solution containing 0.75g of [13C-1]glucose (Aldrich Chemical Company, Miamisburg, Ohio, USA; API for clinical studies) per kilogram body weight were prepared. All measurements were performed using a 9.4T Magnetom whole-body MR scanner (Siemens Healthineers, Erlangen, Germany) with an in-house built radiofrequency (RF) array coil with 18 transmit and 32 receive channels13. The transversal MRSI slice (FOV 220 mm x 220 mm x 7 mm) were positioned just above the Corpus Callosum (Figure 1). The slice was B0 shimmed using the vendor implemented image-based second-order B0 shimming routine. A customized 1H FID MRSI sequence14 (resolution 32x32, TR = 300 ms, TE*=1.5 ms, flip angle = 48°, spectral width= 8000 Hz, acquisition time = 128 ms) with water suppression was acquired15 before a non-water suppressed reference scan with the same resolutions was acquired with the same parameters as the MRSI scan. The scan time for one MRSI acquisition was 3.6 minutes. After the mentioned measurements were executed, the scanner table was pulled out and the volunteers drunk the [13C-1]glucose solution as fast as possible (if possible while lying down and keeping the head as still as possible while drinking). After this short break, the scanner table was pushed back into the scanner. After verification whether repositioning of the MRSI slice was needed due to motion, 1H MRSI data acquisition was resumed immediately and as many as possible MRSI data sets we recorded to fill a total scan time of 2 hours. In a different session, an MP2RAGE image from each volunteer was acquired.
The MRSI data was reconstructed with in-house-written Matlab code15 and fitted using LCModel16 with a basis set simulated with VeSPA17 that included basis spectra for 12C and 13C Glu and Gln as well as a simulated relaxation corrected MM spectrum18-20.

Results

A high spectral quality and a high reproducibility of the 1H MRSI data was obtained across the entire transversal brain slice parallel to the Corpus Callosum using ultra-short TE and TR 1H FID-MRSI in five volunteers (Figure 1). Spectral pattern changes over time related to 13C label incorporation into glutamate could be observed in individual voxels (Figure 1). Summed spectra from grey matter (GM) rich and white matter (WM) rich brain tissue revealed 13C labelling induced spectral pattern changes for a number of additional metabolites (Figure 2). High quality spatially and temporally resolved 12C concentration maps and relative change maps could be derived for [4-12C]Glu, [3-12C]Glx and [2-12C]Glx peaks with a high temporal (3.6 min) and spatial resolution (32x32 grid with nominal voxel size of 0.33 μL) (Figure3). These glutamate metabolism images allow for a distinction of GM and WM in the human brain. In addition whole brain summed spectra allowed to derive signal intensity curves for [4-12C]Glu, [3-12C]Glx, [2-12C]Glx, [4-12C]Gln, total Asp and [6-12C]NAA (Figure 4). From the observed decrease in 12C labelled metabolite concentration the respective increase in 13C label uptake can be derived (Figure 5). Summed spectra of GM rich and WM rich spectra finally allowed the investigation of tissue type specific 13C label incorporation via the decreasing [4-12C]Glu, [3-12C]Glx, [2-12C]Glx and [4-12C]Gln signal amplitudes (Figure 5).

Discussion & Conclusion

This work demonstrates for the first time that glutamatergic metabolism can be investigated with high spatial and temporal resolution by 1H MRSI at 9.4T in the human brain. No specialized 13C hardware or scan software was needed and the scan protocol as well as the oral intake of [13C-1]glucose was well tolerated by all subjects. Since the distinction of Glu and Gln was possible the data allow for modelling of neurotransmitter turnover rates in the human brain in GM versus WM in future.

Acknowledgements

Funding by the ERC Starting Grant (SYNAPLAST MR, Grant Number: 679927) of the European Union and the Cancer Prevention and Research Institute of Texas (CPRIT, Grant Number: RR180056) is gratefully acknowledged.

References

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12. Ziegs T, Dorst J, Henning A. 13C-Glucose Labeling Effects measured in the Occipital Lobe and the Frontal Cortex using short TE 1H MC-semiLASER SVS at 9.4T. Proceedings of the 29th annual scientific meeting of ISMRM, May 15th – 20th 2021

13. Avdievich NI, Giapitzakis I-A, Bause J, Shajan G, Scheffler K, Henning A. Double-row 18-loop transceive-32-loop receive tight-fit array provides for whole-brain coverage, high transmit performance, and SNR improvement near the brain center at 9.4T. Magn Reson Med. 2019;81(5):3392-3405. doi:10.1002/mrm.27602

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Figures

Figure 1: 1H MRSI data quality: (left) MRSI slice (220 mm x 220 mm x 7 mm; resolution 32x32) parallel to the corpus callosum with pre-Glc spectra for all voxels within the brain and (right) spectra and difference spectra for different time points after the 13C labelled Glc intake from two voxel positions in gray versus white matter. Data are from volunteer 1.

Figure 2: Spectral pattern changes upon 13C label incorporation: Temporal series of summed spectra for voxels with high (>60 %) gray matter a) and white matter content b) with the corresponding difference spectra. Colors indicate the measured time points. c) Last difference spectrum for high gray matter voxels with corresponding decreased peaks indicated in red, and increased peaks indicated in green as far as determination of the corresponding metabolites were possible.

Figure 3: Mapping of 13C label incorporation effects: (top) White matter, gray matter and CSF segmentation of the MRSI slice. (left) Concentration maps (/tCr) for different time points after 1-13C labelled Glc intake of [4-12C]Glu, [3-12C]Glu, [2-12C]Glu peaks and (right) the corresponding relative changes to the first MRSI data set in %. Data are from volunteer 1.

Figure 4: Time courses of metabolite signal intensities after 13C glucose intake: mean amplitude of [4-12C]Glu, [3-12C]Glx, [2-12C]Glx, [4-12C]Gln, Asp, NAA and Cr for all voxels within the brain for all volunteers separately. Colors indicate different volunteers.

Figure 5: Tissue type specific 13C label uptake: (left) Temporal changes of the Glu and Gln peak amplitudes for all volunteers (dots) including exponential fits (solid lines) for all voxels with a high GM (> 60 %, black), WM (> 60 %, blue) or higher CSF (> 20 %, red) content. (right) 13C label uptake rates calculated from the exponential fit for all volunteers (thin lines) and the mean increase (thick lines) for voxels with high GM (black) and WM (blue) content.

Proc. Intl. Soc. Mag. Reson. Med. 30 (2022)
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DOI: https://doi.org/10.58530/2022/3540