Abstract
The glycine level in the brain is known to be altered in neuropsychiatric disorders, such as schizophrenia and Alzheimer's disease (AD). Several studies have reported the in vivo measurement of glycine concentrations in the brain using proton magnetic resonance spectroscopy (1H-MRS), but 1H-MRS is not capable of imaging the distribution of glycine concentration with high spatial resolution. Chemical exchange saturation transfer magnetic resonance imaging (CEST-MRI) is a new technology that can detect specific molecules, including amino acids, in tissues. To validate the measurements of glycine concentrations in living tissues using CEST from glycine to water (GlyCEST), we extracted the brain tissues from mice and performed biochemical tests. In wild-type C57BL/6 mice, GlyCEST effects were found to be higher in the thalamus than in the cerebral cortex (P < 0.0001, paired t-test), and this result was in good agreement with the biochemical results. In 5xFAD mice, an animal model of AD, GlyCEST measurements demonstrated that glycine concentrations in the cerebral cortex (P < 0.05, unpaired t-test) and thalamus (P < 0.0001, unpaired t-test), but not in the hippocampus, were decreased compared to those in wild-type mice. These findings suggest that we have successfully applied the CEST-MRI technique to map the distribution of glycine concentrations in the murine brain. The present method also captured the changes in cerebral glycine concentrations in mice with AD. Imaging the distribution of glycine concentrations in the brain can be useful in investigating and elucidating the pathological mechanisms of neuropsychiatric disorders.
Highlights
Glycine, which is the simplest amino acid found in the proteins of living organisms, is known to act as an inhibitory neurotransmitter in the brainstem and spinal cord of the central nervous system [1, 2]
Correlation between glycine using the CEST-MRI technique (GlyCEST) (%) and Glycine Concentrations. e z-spectra, giving the ratios of water signal intensities with (Msat) and without (M0) selective saturation, showed that the Msat/M0 ratio decreased with glycine concentrations increasing from 0 to 10.0 mM (Figure 1(a)). e z-spectra showed an asymmetry between the positive and negative saturation offsets from the water resonance; the CESTasymmetry in each saturation offset was evaluated by the same computation as used for obtaining GlyCEST (%) (Figure 1(b)). e CEST asymmetry increased with increasing glycine concentrations
WT mice (n 9) were imaged for GlyCEST, and Region of interest (ROI) were placed in the cortex and thalamus based on the corresponding regions on T2-weighted spin-echo morphological images (T2WI) images (Figure 3(a))
Summary
Glycine, which is the simplest amino acid found in the proteins of living organisms, is known to act as an inhibitory neurotransmitter in the brainstem and spinal cord of the central nervous system [1, 2]. It acts in the cerebrum as a coagonist for the N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor [3, 4]. In patients with AD, blood and brain glycine concentrations differ from those in healthy subjects [10, 11], other studies have shown that glycine concentrations are unchanged in patients with AD [12]. We hypothesized that these inconsistent data could be caused by variations in glycine concentrations in the different areas of the brain. us, the measurement of regional glycine concentrations and imaging of glycine concentration distributions in the brain may provide knowledge on the pathogenesis of AD and facilitate the staging of this disease
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