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Quantification of Human Brain Metabolites using Two-Dimensional J-Resolved Metabolite-Cycled semiLASER at 9.4 T

Saipavitra Murali-Manohar^1,2, Tamas Borbath^1,2, Andrew Martin Wright^1,3, and Anke Henning^1,4
¹High Field Magentic Resonance, Max Planck Institute for Biological Cybernetics, Tuebingen, Germany, ²Faculty of Science, University of Tuebingen, Tuebingen, Germany, ³IMPRS for Cognitive Neuroscience, Tuebingen, Germany, ⁴Advanced Imaging Research Center, UT Southwestern Medical Center, Dallas, TX, United States

Synopsis

Crowded proton spectra with severely overlapped J-coupled resonances pose a challenge in the reliable quantification of metabolites in the human brain. Several advanced techniques such as editing methods, multi-dimensional spectroscopy methods, sophisticated processing or quantification pipelines were proposed in the past. In this work, we present a two-dimensional metabolite-cycled semiLASER technique at 9.4 T with maximum echo sampling scheme. This method helps well resolve the J-coupled peaks and clearly distinguish them. 2D spectral fitting is performed using ProFit2.0 and the metabolites are quantified using internal water referencing after correcting the fitted concentration for tissue content and relaxation effects.

Purpose

Reliable quantification of metabolites in the human brain has always been one of the prime aims of the magnetic resonance spectroscopy (MRS) community to understand metabolic processes and changes in them during various pathologies¹. Consequently, there is constant development in better localization and quantification techniques. Bringing together the advantages of ultra-high field and two-dimensional J-resolved spectroscopy, here we performed quantitative 2D J-resolved semiLASER localization at 9.4 T in a voxel in the occipital lobe of the human brain. Furthermore, we quantified 16 metabolites in mmol/kg using the internal water referencing method².

Methods

All experiments were performed on a 9.4T Siemens Magnetom whole-body MRI scanner (Erlangen, Germany). A home-built 8Tx16Rx coil³ was used in surface coil transmit mode for spectroscopy experiments driving power only to the bottom three channels, while receiving signal with all channels. A 2D J-resolved metabolite-cycled⁴ semiLASER sequence (Figure 1a) was implemented and optimized using phantom experiments. Ten healthy volunteers participated in this study after providing written informed consent. A GM-rich 2×2×2 cm³ voxel was chosen in the occipital lobe (Figure 1b). FASTESTMAP⁵ was used to shim and power calibration^6,7 was performed on the voxel of interest. Spectra were then acquired using 2D J-resolved MC semiLASER (TR:6000 ms, TE_start:24 ms, TE steps $$$∆t$$$:2ms, number of TE steps $$$n$$$:85, TE_last:194 ms, Averages per TE:8, Transmitter reference frequency:2.4 ppm).

Water reference scans with the same acquisition parameters as metabolite spectra (except Averages per TE:1 and Transmitter reference frequency:4.7 ppm) were acquired.

2D J-resolved macromolecule (MM) spectra were acquired from 5 healthy volunteers using a double inversion recovery⁸ 2D J-resolved MC semiLASER sequence (TR:8000 ms, TE_start:24 ms, $$$∆t$$$: 2ms, $$$n$$$:60, TE_last:144 ms, Averages per TE:8, Transmitter reference frequency: 2.4 ppm, Bandwidth:8000 Hz) with TI₁/TI₂=2360/625 ms respectively.

Both metabolite and MM data were preprocessed in a similar fashion as described in Murali-Manohar et al⁹., taking into account $$$n$$$ of 85 and 60 respectively. Additionally zeroth and first order phase correction were performed in the preprocessing part of the ProFit^10,11 tool.
MP2RAGE¹² images were acquired by driving power to all eight channels. Tissue segmentation was performed using SPM12¹³.

Metabolite basis sets for N-acetyl-aspartate (NAA), N-acetyl-aspartyl-glutamate (NAAG), γ‐aminobutyric acid (GABA), aspartate (Asp), creatine (Cr), glutamate (Glu), glutamine (Gln), glutathione (GSH), glycerophosphocholine (GPC), glucose (Glc), glycine (Glyc), myo‐inositol (mI), scyllo‐inositol (Scy), lactate (Lac), phosphocreatine (PCr), phosphocholine (PCho), phosphoethanolamine (PE), and taurine (Tau) were simulated using VesPA¹⁴ for semiLASER sequence (85 TEs) including real pulse shapes. GPC, PCho and PE combined together is denoted by tCho. The sum of experimentally acquired MM spectra was included in the basis set to account for the MM contribution in the fitting of metabolite spectra.

The 2D metabolite spectra were then fitted using ProFit 2.0¹⁵ after Fourier transformation in both direct (f₂) and indirect (f₁) dimensions. Quantification of metabolites was performed using internal water referencing². The fitted metabolite concentrations were corrected for tissue content, and T₁ and T₂ relaxation times of both water and metabolites. Final quantification results are reported in mmol/kg.

Results

Figure 2a shows the 2D J-resolved spectrum acquired at 9.4T from the Braino phantom. The peaks are well-resolved and due to the small chemical shift displacement (1.5% for NAA peak (2.008 ppm), 5% for Lac (1.31 ppm) and 9% for mI (4.05 ppm) with respect to Transmitter reference frequency:2.4 ppm) resulting from semi-LASER there are barely any J-refocused peaks^16,17 present. A 2D J-resolved MC semiLASER spectrum from a representative subject is shown in Figure 2b. Spectra from all the healthy volunteers had a similar quality without any artifacts. The SNR of the NAA peak at 2.008 ppm is 906 ± 147 with respect to the noise window from -4.0 to -1.0 ppm. A representative metabolite spectral fit is shown in Figure 3. The minimum residual shows the good quality of fit. The fit quality was similar for all the datasets. Finally, Figure 4 shows a bar plot of concentrations of metabolites calculated in mmol/kg and Table 1 compares the quantification results in mmol/kg with previous literatures^9,18,19.

Discussion

As seen from Figure 2a, the use of an adiabatic (bandwidth: 8000 Hz) localization technique resulted in minimization of J-refocused peaks^16,17 due to minimized chemical shift displacement. Consequently, the J-resolved peaks have maximum possible intensity, which leads to more accurate detection of J-coupled metabolites. This study quantifies and reports concentration values of 16 metabolites in mmol/kg using a 2D J-resolved localization technique at 9.4T in the human brain for the first time. The calculated millimolal concentration values lie within the range of values that are reported in previous literature^18,20–22 for all metabolites except for Tau and mI due to a possible oppositely phased residual mI peak in the experimental MM spectra²³. Therefore, removal of the residual mI peaks in the 2D MM spectra is necessary in the future for accurate estimation of mI and Tau concentrations. For metabolites such as Asp, GABA, and Gln, the values from this study are closer to previous literature values^18–22 when compared to results of the previous 1D MRS study⁹. Moreover, the 2D MRS technique could decently quantify Glc and Lac that are otherwise challenging to quantify in 1D MRS studies even at 9.4 T.

Acknowledgements

This project was co-sponsored by Horizon 2020/ CDS-QUAMRI (634541), SYNAPLAST (679927) and CPRIT (RR180056) grants.

References

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15. Fuchs A, Boesiger P, Schulte RF, Henning A. ProFit revisited. Magn Reson Med. 2014;71(2):458-468.

16. Edden RAE, Barker PB. If J doesn’t evolve, it won’t J-resolve: J-PRESS with bandwidth-limited refocusing pulses. Magn Reson Med. 2011;65(6):1509-1514.

17. Lin M, Kumar A, Yang S. Two-dimensional J-resolved LASER and semi-LASER spectroscopy of human brain. Magn Reson Med. 2014;71(3):911-920.

18. Mekle R, Mlynárik V, Gambarota G, Hergt M, Krueger G, Gruetter R. MR spectroscopy of the human brain with enhanced signal intensity at ultrashort echo times on a clinical platform at 3T and 7T. Magn Reson Med. 2009;61(6):1279-1285.

19. Deelchand DK, Moortele P-F Van de, Adriany G, et al. In vivo 1H NMR spectroscopy of the human brain at 9.4 T: Initial results. J Magn Reson. 2010;206(1):74-80.

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Figures

Figure 1: a) 2D J-resolved MC semiLASER sequence implemented at 9.4 T. The excitation and adiabatic pulse bandwidths are 8000Hz. This leads to a chemical shift displacement of 10% between NAA (2.008 ppm) and mI (4.05 ppm). This means that even after accounting for the displacement in all three directions still there is a 73% voxel overlap occurring in the voxels for the two mentioned resonances. b) High-resolution MP2RAGE images showing the voxel positioning for the acquisition of in vivo data. Tissue segmentation resulted in GM/WM/CSF content: 67.3 ± 8.6/ 28.5 ± 8.6/ 3.7 ± 1.5%.

Figure 2: a) Two-dimensional J-resolved MC semiLASER spectrum (TE_start: 24 ms, TR: 6000 ms, $$$n$$$=85, $$$∆t$$$=2 ms) acquired at 9.4T from a Braino phantom. Lactate peaks at 1.31 and 4.09 ppm (maximum separated in the upfield proton spectrum) were considered to calculate reduction in the intensity of the J-refocused peaks according to the equation given in Lin et al¹⁷. This resulted in 86% reduction in the intensity and hence, there are barely any J-refocused peaks in the spectrum. b) Two-dimensional J-resolved MC semiLASER spectrum from a representative subject acquired at 9.4T.

Figure 3: A representative fit of the in vivo 2D J-resolved semiLASER spectrum using ProFit2.0¹⁵. The fit residue is minimum indicating that the tailored 2D basis set fits the acquired data well. The data, fit and residue are all scaled similarly.

Figure 4: A comparison between the metabolite concentrations measured in the occipital lobe in this study and previous literature^9,18,19 is shown. The concentration values obtained using 2D spectral fitting for Asp, Gln and GABA are in line with previous literature^18,19; however, the previous 1D MRS study⁹ using MC semiLASER reported elevated values of these metabolites in comparison. In conclusion, 2D MRS may perform better for the quantification of overlapped and J-coupled resonances such as Asp, Gln and GABA, and additionally also allows for the quantification of Glc and Lac.

Table 1: Quantification results from this study are reported for 16 metabolites after correcting for tissue content and water and metabolite relaxation times. ProFit2.0¹⁵ accounts for the T₂ relaxation effects of the metabolites. T₁ relaxation times at 9.4 T from Wright et al²⁴ were used to account for the T₁-weighting of metabolites. Additionally, results from the previous 1D MRS study⁹ (relaxation corrections performed) and previous quantification results^18,19 (T₂ relaxation correction not performed) reported at ultra-high field are also provided.

Proc. Intl. Soc. Mag. Reson. Med. 29 (2021)

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