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Improved localisation for 2-hydroxyglutarate detection at 3T using long-TE semi-LASER.

ABSTRACT: 2-hydroxyglutarate (2-HG) has emerged as a biomarker of tumour cell IDH mutations that may enable the differential diagnosis of glioma patients. At 3 Tesla, detection of 2-HG with magnetic resonance spectroscopy is challenging because of metabolite signal overlap and a spectral pattern modulated by slice selection and chemical shift displacement. Using density matrix simulations and phantom experiments, an optimised semi-LASER scheme (TE = 110 ms) improves localisation of the 2-HG spin system considerably compared to an existing PRESS sequence. This results in a visible 2-HG peak in the in vivo spectra at 1.9 ppm in the majority of IDH mutated tumours. Detected concentrations of 2-HG were similar using both sequences, although the use of semi-LASER generated narrower confidence intervals. Signal overlap with glutamate and glutamine, as measured by pairwise fitting correlation was reduced. Lactate was readily detectable across glioma patients using the method presented here (mean CLRB: (10±2)%). Together with more robust 2-HG detection, long TE semi-LASER offers the potential to investigate tumour metabolism and stratify patients in vivo at 3T.

SUBMITTER: Berrington A

PROVIDER: S-EPMC4990123 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) are frequently found in brain tumors, and the resulting onco-metabolite, 2-hydroxyglutarate (2HG), has been suggested to be a potential diagnostic and prognostic biomarker of the diseases. Indeed, recent studies have demonstrated the feasibility of non-invasively detecting 2HG by using proton magnetic resonance spectroscopy (1H-MRS). Due to severe spectral overlaps of 2HG with its background metabolites and spectral baselines, however, the majority of those previous studies employed spectral editing methods with long echo times (TEs) instead of the most commonly used short TE approach with spectral fitting. Consequently, the results obtained with spectral editing methods may potentially be prone to errors resulting from substantial signal loss due to relaxation. Given that the spectral region where the main signal of 2HG resides is particularly sensitive to spectral baseline in metabolite quantification, we have investigated the impact of incorporating voxel-specifically measured baselines into the spectral basis set on the performance of the conventional short TE approach in 2HG detection in rodent models (Fisher 344 rats; n = 19) of IDH1/2 mutant-overexpressing F98 glioma at 9.4T. Metabolite spectra were acquired (SPECIAL sequence) for a tumor region and the contralateral normal region of the brain for each animal. For the estimation of spectral baselines metabolite-nulled spectra were obtained (double-inversion-recovery SPECIAL sequence) for each individual voxels. Data were post-processed with and without the measured baselines using MRUI and LCModel-the two most widely used data post-processing packages. Our results demonstrate that in-vivo detection of 2HG using the conventional short TE approach is challenging even at 9.4T. However, incorporation of voxel-specifically measured spectral baselines may potentially improve its performance. Upon more thorough validation in a larger number of animals and more importantly in human patients, the potential utility of the proposed short TE acquisition with voxel-specific baseline measurement approach in 2HG detection may need to be considered in the study design.

Project description:BackgroundIn the backdrop of challenge to obtain a protein structure under the known limitations of both experimental and theoretical techniques, the need of a fast as well as accurate protein structure evaluation method still exists to substantially reduce a huge gap between number of known sequences and structures. Among currently practiced theoretical techniques, homology modelling backed by molecular dynamics based optimization appears to be the most popular one. However it suffers from contradictory indications of different validation parameters generated from a set of protein models which are predicted against a particular target protein. For example, in one model Ramachandran Score may be quite high making it acceptable, whereas, its potential energy may not be very low making it unacceptable and vice versa. Towards resolving this problem, the main objective of this study was fixed as to utilize a simple experimentally derived output, Surface Roughness Index of concerned protein of unknown structure as an intervening agent that could be obtained using ordinary microscopic images of heat denatured aggregates of the same protein.ResultIt was intriguing to observe that direct experimental knowledge of the concerned protein, however simple it may be, might give insight on acceptability of its particular structural model out of a confusion set of models generated from database driven comparative technique for structure prediction. The result obtained from a widely varying structural class of proteins indicated that speed of protein structure evaluation can be further enhanced without compromising with accuracy by recruiting simple experimental output.ConclusionIn this work, a semi-empirical methodological approach was provided for improving protein structure evaluation. It showed that, once structure models of a protein were obtained through homology technique, the problem of selection of a best model out of a confusion set of Pareto-optimal structures could be resolved by employing a structure agent directly obtainable through experiment with the same protein as experimental ingredient. Overall, in the backdrop of getting a reasonably accurate protein structure of pathogens causing epidemics or biological warfare, such approach could be of use as a plausible solution for fast drug design.

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Improved localisation for 2-hydroxyglutarate detection at 3T using long-TE semi-LASER.

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