Mutations in isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) have been shown to be present in most World Health Organization grade 2 and grade 3 gliomas in adults. These mutations are associated with the accumulation of 2-hydroxyglutarate (2HG) in the tumor. Here we report the noninvasive detection of 2HG by proton magnetic resonance spectroscopy (MRS). We developed and optimized the pulse sequence with numerical and phantom analyses for 2HG detection, and we estimated the concentrations of 2HG using spectral fitting in the tumors of 30 subjects. Detection of 2HG correlated with mutations in IDH1 or IDH2 and with increased levels of D-2HG by mass spectrometry of the resected tumors. Noninvasive detection of 2HG may prove to be a valuable diagnostic and prognostic biomarker.

/pdf/2-hydroxyglutarate-detection-by-magnetic-resonance-23t9ud57m0.pdf

2-hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas.

Following the impetus of early clinical and experimental investigations, in vivo and in vitro MRS studies of tumours pointed in the eighties to the possible significance of signals arising from phospholipid (PL) precursors and catabolites as novel biochemical indicators of in vivo tumour progression and response to therapy. In the present decade, MRS analyses of individual components contributing to the 31P PME (phosphomonoester) and PDE (phosphodiester) resonances, as well as to the 1H 'choline peak', have reinforced some of these expectations. Moreover, the absolute quantification of these signals provided the basis for addressing more specific (although still open) questions on the biochemical mechanisms responsible for the formation of intracellular pools of PL derivatives in tumours, under different conditions of cell proliferative status and/or malignancy level. This article is aimed at providing an overview on: (a) quantitative MRS measurements on the contents of phosphocholine (PCho), phosphoethanolamine (PEtn) and their glycerol derivatives ģlycerol 3-phosphocholine (GPC) and glycerol 3-phosphoethanolamine (GPE)[ in human tumours and cells (with particular attention to breast and brain cancer and lymphomas), as well as in normal mammalian tissues (including developing organs and rapidly proliferating tissues); (b) possible correlations of MRS parameters like PEtn/PCho and PCho/GPC ratios with in vitro cell growth status and/or cell tumorigenicity; and (c) current and new hypotheses on the role and interplay of biosynthetic and catabolic pathways of the choline and ethanolamine cycles in modulating the intracellular sizes of PCho and PEtn pools, either in response to mitogenic stimuli or in relation to malignant transformation.

Tumour phospholipid metabolism.

A strategy for using tissue water as a concentration standard in (1)H magnetic resonance spectroscopic imaging studies on the brain is presented, and the potential errors that may arise when the method is used are examined. The sensitivity of the method to errors in estimates of the different water compartment relaxation times is shown to be small at short echo times (TEs). Using data from healthy human subjects, it is shown that different image segmentation approaches that are commonly used to account for partial volume effects (SPM2, FSL's FAST, and K-means) lead to different estimates of metabolite levels, particularly in gray matter (GM), owing primarily to variability in the estimates of the cerebrospinal fluid (CSF) fraction. While consistency does not necessarily validate a method, a multispectral segmentation approach using FAST yielded the lowest intersubject variability in the estimates of GM metabolites. The mean GM and white matter (WM) levels of N-acetyl groups (NAc, primarily N-acetylaspartate), choline (Ch), and creatine (Cr) obtained in these subjects using the described method with FAST multispectral segmentation are reported: GM [NAc] = 17.16 +/- 1.19 mM; WM [NAc] = 14.26 +/- 1.38 mM; GM [Ch] = 3.27 +/- 0.47 mM; WM [Ch] = 2.65 +/- 0.25 mM; GM [Cr] = 13.98 +/- 1.20 mM; and WM [Cr] = 7.10 +/- 0.67 mM.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/mrm.20901

Use of tissue water as a concentration reference for proton spectroscopic imaging.

The development of magnetic resonance imaging (MRI) for use in medical investigation has provided a huge forward leap in the field of diagnosis, particularly with avoidance of exposure to potentially dangerous ionizing radiation. With decreasing costs and better availability, the use of MRI is becoming ever more pervasive throughout clinical practice. Understanding the principles underlying this imaging modality and its multiple applications can be used to appreciate the benefits and limitations of its use, further informing clinical decision-making. In this article, the principles of MRI are reviewed, with further discussion of specific clinical applications such as parallel, diffusion-weighted, and magnetization transfer imaging. MR spectroscopy is also considered, with an overview of key metabolites and how they may be interpreted. Finally, a brief view on how the use of MRI will change over the coming years is presented.

Magnetic Resonance Imaging: Principles and Techniques: Lessons for Clinicians.

This clinical protocol describes virus-based gene transfer for Canavan disease, a childhood leukodystrophy. Canavan disease, also known as Van Bogaert-Bertrand disease, is a monogeneic, autosomal recessive disease in which the gene coding for the enzyme aspartoacylase (ASPA) is defective. The lack of functional enzyme leads to an increase in the central nervous system of the substrate molecule, N-acetyl-aspartate (NAA), which impairs normal myelination and results in spongiform degeneration of the brain. No effective treatment currently exists; however, virus-based gene transfer has the potential to arrest or reverse the course of this otherwise fatal condition. This procedure involves neurosurgical administration of ~900 billion genomic particles (~10 billion infectious particles) of recombinant adeno-associated virus (AAV) containing the aspartoacylase gene (ASPA) directly to affected regions of the brain in each of 21 patients with Canavan disease. Pre- and post-delivery assessments include a battery o...

Gene Therapy of Canavan Disease: AAV-2 Vector for Neurosurgical Delivery of Aspartoacylase Gene (ASPA) to the Human Brain

Absolute metabolite quantification by in vivo NMR spectroscopy: II. A multicentre trial of protocols for in vivo localised proton studies of human brain

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Absolute metabolite quantification by in vivo NMR spectroscopy: II. A multicentre trial of protocols for in vivo localised proton studies of human brain