Preliminary Phantom Experiments to Map Amino Acids and Neurotransmitters Using MRI

Jang-Hoon Oh; Hyug-Gi Kim; Dong-Cheol Woo; Sun Jung Rhee; Soo Yeol Lee; Geon-Ho Jahng

doi:10.14316/pmp.2018.29.1.29

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Oh, Kim, Woo, Rhee, Lee, and Jahng: Preliminary Phantom Experiments to Map Amino Acids and Neurotransmitters Using MRI

Original Article

Progress in Medical Physics 2018;29(1):29-41.

Published online: 20 March 2018

DOI: https://doi.org/10.14316/pmp.2018.29.1.29

Preliminary Phantom Experiments to Map Amino Acids and Neurotransmitters Using MRI

Jang-Hoon Oh^∗, Hyug-Gi Kim^∗, Dong-Cheol Woo^†, Sun Jung Rhee^‡, Soo Yeol Lee^§, Geon-Ho Jahng^‡

^∗Department of Biomedical Engineering, Graduate School, Kyung Hee University, Yongin, Korea

^†Biomedical Research Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

^‡Department of Radiology, Kyung Hee University Hospital at Gangdong, College of Medicine, Kyung Hee University, Seoul, Korea

^§Department of Biomedical Engineering, College of Electronics and Information, Kyung Hee University, Yongin, Korea

Corresponding author Geon-Ho Jahng (ghjahng@gmail.com) Tel: 82-2-440-6187 Fax: 82-2-440-6932

Received 23 March 2018 Revised 30 March 2018 Accepted 30 March 2018

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The objective of this study was to evaluate the chemical exchange saturation transfer (CEST) effect of amino acids and neurotransmitters, which exist in the human brain, depending on the concentration, pH, and amplitude of the saturation radiofrequency field. Phantoms were developed with asparagine (Asn), γ-aminobutyric acid (GABA), glutamate (Glu), glycine (Gly), and myoinositol (MI). Each chemical had three different concentrations of 10, 30, and 50 mM and three different pH values of 5.6, 6.2, and 7.4. Full Z-spectrum CEST images for each phantom were acquired with a continuous-wave radiofrequency (RF) saturation pulse with two different B₁ amplitudes of 2 μT and 4 μT using an animal 9.4T MRI system. A voxel-based CEST asymmetry was mapped to evaluate exchangeable protons based on amide (−NH), amine (−NH₂), and hydroxyl (−OH) groups for the five target molecules. For all target molecules, the CEST effect was increased with increasing concentration and B1 amplitude; however, the CEST effect with varying pH displayed a different trend depending on the characteristics of the molecule. On CEST asymmetric maps, Glu and MI were well visualized around 3.0 and 0.9 ppm, respectively, and were well separated macroscopically at a pH of 7.4. The exchange rates of Asn, Glu, BABA, and Gly usually decreased with increasing pH. The CEST effect was dependent on the concentration, acidity of the target molecules, and B1 amplitude of the saturation RF pulse. The CEST effect for Asn can be observed in a 9.4T MRI system. The results of this study are based on applying the CEST technique in patients with neurodegenerative diseases when proteins in the brain are increased with disease progression.

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Keywords: 9.4T MRI, Chemical exchange saturation transfer, Amino acid, Neurotransmitter, Exchange rate

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Fig. 1.

Original phantom images at a concentration of 50 mM and pH 5.6 obtained by using an animal 9.4T MRI system. The target molecules were located in five small tubes for glycine (Gly), glutamate (Glu), myoinositol (MI), asparagine (Asn), and gamma-aminobutyric acid (GABA), respectively. These tubes were placed in a large container and fixed by filling with 2% agarose solution that had been boiled.

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Fig. 2.

Normalized Z-spectra and CEST asymmetric curves with 10 (red), 30 (green), and 50 mM (blue) concentrations with a B₁ amplitude of 2μT at pH 5.6 for (a) asparagine, (b) glutamate, (c) GABA, (d) glycine, and (e) myoinositol. The left vertical axis is percentage of the CEST asymmetry, and the right one is the normalized signal ratio for the Z-spectrum.

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Fig. 3.

CEST asymmetric maps with 10, 30, and 50 mM concentrations for the five targeted molecules with the B₁ amplitude of 2 μT and at pH 5.6. The layout of the phantom was shown in Fig. 1. The asymmetric maps were calculated at the specific frequencies which have the highest CEST asymmetries for the five target molecules (Asn=2.91 ppm, Glu=3.06 ppm, GABA and Gly=2.76 ppm, and MI=0.92 ppm). The image scale of the asymmetric maps is 0∼40%.

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Fig. 4.

Normalized Z-spectra and CEST asymmetric curves with 5.6 (blue), 6.2 (green), and 7.4 (red) pH values with a B₁ amplitude of 2 μT and a concentration of 50 mM for (a) asparagine, (b) glutamate, (c) GABA, (d) glycine, and (e) myoinositol. The left vertical axis is percentage of the CEST asymmetry, and the right one is the normalized signal ratio for the Z-spectrum.

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Fig. 5.

The CEST asymmetric maps with 5.6, 6.2, and 7.4 pH values for the five target molecules with the B₁ amplitude of 2 μT and the concentration of 50 mM. The layout of the phantom was shown in Fig. 1. The asymmetric maps were calculated at the specific frequencies which have the highest CEST asymmetries for the five target molecules (Asn=2.91 ppm, Glu=3.06 ppm, GABA and Gly=2.76 ppm, and MI=0.92 ppm). The image scale of the asymmetric maps is 0∼40%.

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Fig. 6.

Normalized Z-spectra and CEST asymmetric curves with 2 μT (blue) and 4 μT (green) B₁ amplitudes of the saturation RF pulse at a concentration of 50 mM and pH 5.6 for (a) asparagine, (b) glutamate, (c) GABA, (d) glycine, and (e) myoinositol. The left vertical axis is percentage of the CEST asymmetry, and the right one is the normalized signal ratio for the Z-spectrum.

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Fig. 7.

The CEST asymmetric maps with B₁ amplitudes of 2 and 4 μT of the saturation RF pulse at pH 5.6 and the concentration of 50 mM. The layout of the phantom was shown in Fig. 1. The asymmetric maps were calculated at the specific frequencies which have the highest CEST asymmetries for the five target molecules (Asn=2.91 ppm, Glu=3.06 ppm, GABA and Gly=2.76 ppm, and MI=0.92 ppm). The image scale of the asymmetric maps is 0∼40%.

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Fig. 8.

The pseudo-first exchange rate experiments with different pH values at 9.4T at the B₁ amplitude of 2.35 μT and the concentration of 50 mM for (a) asparagine, (b) glutamate, (c) GABA, (d) glycine, and (e) myoinositol. Data points with different saturation durations are shown with a circle (pH 5.6), a cross (pH 6.2), and a triangle (pH 7.4). Results were plotted with a solid line at pH 5.6, a dashed line at pH 6.2, and a dotted line at pH 7.4.

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Table 1.

Summary of the chemical exchange saturation transfer (CEST) asymmetry (%) for five target molecules.

Target molecule	Concentration (mM)	2 μT			4 μT
Target molecule	Concentration (mM)	pH 5.6	pH 6.2	pH 7.4	pH 5.6	pH 6.2	pH 7.4
Asn	10	8.94	8.07	1.92	10.78	14.33	4.74
	30	22.26	14.91	4.38	33.98	31.19	8.70
	50	23.29	21.32	5.86	44.77	42.13	8.67
Glu	10	10.04	10.58	6.50	13.34	14.31	12.25
	30	22.99	18.82	11.69	31.62	30.19	24.61
	50	32.14	32.86	16.81	45.93	48.38	34.69
GABA	10	8.35	9.84	3.15	7.61	16.30	6.82
	30	24.24	17.80	4.03	30.93	33.92	9.30
	50	31.65	26.33	5.02	44.85	47.15	11.51
Gly	10	4.12	8.96	4.58	3.28	11.04	9.93
	30	19.93	20.52	6.14	23.60	33.70	14.64
	50	24.00	27.07	3.94	30.28	46.89	9.62
MI	10	17.98	12.63	15.84	12.12	14.54	20.90
	30	36.69	29.26	30.92	35.50	31.30	30.12
	50	40.40	43.77	48.63	40.43	38.31	44.09

The CEST asymmetry was measured at 2.91 ppm for asparagine (Asn), 3.06 ppm for glutamate (Glu), 2.76 ppm for both γ-aminobutyric acid (GABA) and glycine (Gly), and 0.92 ppm for myoinositol (MI).

Table 2.

Summary of the pseudo-first exchange rate of k₁=k_sw×X_ca [s⁻¹] for the five target molecules at 9.4T.

Target molecule	pH	9.4T
Target molecule	pH	k₁ [s⁻¹]	Resnorm
Asn	pH 5.6	0.1277	0.0017
	pH 6.2	0.0550	0.0006
	pH 7.4	0.0262	0.0004
Glu	pH 5.6	0.1497	0.0045
	pH 6.2	0.1155	0.0021
	pH 7.4	0.0094	0.0001
GABA	pH 5.6	0.1364	0.0028
	pH 6.2	0.1615	0.0029
	pH 7.4	0.0156	0.0005
Gly	pH 5.6	0.1468	0.0029
	pH 6.2	0.0613	0.0008
	pH 7.4	0.0000	0.0010
MI	pH 5.6	0.2332	0.0135
	pH 6.2	0.2302	0.0103
	pH 7.4	0.2637	0.0087

Resnorm: the value of the squared 2-norm of the residual. The k₁ value was measured at 2.91 ppm for asparagine (Asn), 3.06 ppm for glutamate (Glu), 2.76 ppm for both gamma-aminobutyric acid (GABA) and glycine (Gly), and 0.92 ppm for myoinositol (MI).

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