Non-invasive detection of glycine as a biomarker of malignancy in childhood brain tumours using in-vivo ¹ H MRS at 1.5 Tesla confirmed by ex-vivo high-resolution magic-angle spinning NMR

Abstract

Management of brain tumours in children would benefit from improved non-invasive diagnosis, characterisation and prognostic biomarkers. Metabolite profiles derived from in-vivo MRS have been shown to provide such information. Studies indicate that using optimum a priori information on metabolite contents in the construction of linear combination (LC) models of MR spectra leads to improved metabolite profile estimation. Glycine (Gly) is usually neglected in such models due to strong overlap with myo-inositol (mI) and a low concentration in normal brain. However, biological studies indicate that Gly is abundant in high-grade brain tumours. This study aimed to investigate the quantitation of Gly in paediatric brain tumours using MRS analysed by LCModel, and its potential as a non-invasive biomarker of malignancy. Single-voxel MRS was performed using PRESS (TR 1500 ms, TE 30 ms/135 ms) on a 1.5 T scanner. Forty-seven cases (18 high grade (HG), 17 low grade (LG), 12 ungraded) were retrospectively selected if both short-TE and long-TE MRS (n = 33) or short-TE MRS and high-resolution magic-angle spinning (HRMAS) of matched surgical samples (n = 15) were available. The inclusion of Gly in LCModel analyses led to significantly reduced fit residues for both short-TE and long-TE MRS (p < 0.05). The Gly concentrations estimated from short-TE MRS were significantly correlated with the long-TE values (R = 0.91, p < 0.001). The Gly concentration estimated by LCModel was significantly higher in HG versus LG tumours for both short-TE (p < 1e-6) and long-TE (p = 0.003) MRS. This was consistent with the HRMAS results, which showed a significantly higher normalised Gly concentration in HG tumours (p < 0.05) and a significant correlation with the normalised Gly concentration measured from short-TE in-vivo MRS (p < 0.05). This study suggests that glycine can be reliably detected in paediatric brain tumours using in-vivo MRS on standard clinical scanners and that it is a promising biomarker of tumour aggressiveness.

Metabolite Levels in Paediatric Brain Tumours Correlate with Histological Features

“…It is likely that lactate detected in vivo in brain tumours is a measure of abnormal metabolic activity and not exclusively linked to tumour necrosis. The significant association between tumour grade and individual metabolites such as total choline, PCh, lipids and macromolecules, Gly, and Tau is also consistent with prior work, with elevated levels of these metabolites previously reported in high-grade brain tumours [14,37,45,47,70]. An association between increased NAA in low-grade glial tumours has also been previously identified [71].…”

“…Tumour cells in astrocytic neoplasms stain intensely with antibodies to GFAP [36]; however, mIns in tumours has not yet been linked convincingly to this. Gly was detected in paediatric brain tumours in vivo by Davies et al [37] and it has been shown to be significantly higher in high-grade versus low-grade tumours. NAA is commonly regarded as a neuronal marker as it has been found to be preferentially highly expressed in neurons rather than glial cells [38].…”

Non-invasive grading of astrocytic tumours from the relative contents of myo-inositol and glycine measured by in vivo mrs

“…ADP bound to F-actin in muscle microfilaments). In this respect, binding of gly to multimeric channel proteins in the plasma membrane of PC-12 cells (50) or to a glycine-sensitive anion death channel in sinusoidal endothelial cells (51) have been proposed. Increased gly content protects various types of cells from necrotic or apoptotic death induced by ATP depletion (PC-12 cells, (51)), hypoxia (hepatic sinusoidal cells, (52)) or ischaemia-reperfusion derived reoxygenation injury (cardiomyocytes, (53)).…”

MR Spectroscopic Imaging

“…Higher myoinositol levels in brain tumors may support the diagnosis of a low-grade astrocytoma , whereas higher glycine concentrations were found in high-grade gliomas as demonstrated in Fig. 6 Davies et al 2010).…”