title: Non-invasive detection of 2-hydroxyglutarate in IDH-mutated gliomas using two-dimensional localized correlation spectroscopy (2D L-COSY) at 7 Tesla.
abstract: BACKGROUND
  Mutations in the isocitrate dehydrogenase enzyme are present in a majority of lower-grade gliomas and secondary glioblastomas. This mis-sense mutation results in the neomorphic reduction of isocitrate dehydrogenase resulting in an accumulation of the "oncometabolite" 2-hydroxyglutarate (2HG). Detection of 2HG can thus serve as a surrogate biomarker for these mutations, with significant translational implications including improved prognostication. Two dimensional localized correlated spectroscopy (2D L-COSY) at 7T is a highly-sensitive non-invasive technique for assessing brain metabolism. This study aims to assess tumor metabolism using 2D L-COSY at 7T for the detection of 2HG in IDH-mutant gliomas.
  
  
  METHODS
  Nine treatment-naïve patients with suspected intracranial neoplasms were scanned at 7T MRI/MRS scanner using the 2D L-COSY technique. 2D-spectral processing and analyses were performed using a MATLAB-based reconstruction algorithm. Cross and diagonal peak volumes were quantified in the 2D L-COSY spectra and normalized with respect to the creatine peak at 3.0 ppm and quantified data were compared with previously-published data from six normal subjects. Detection of 2HG was validated using findings from immunohistochemical (IHC) staining in patients who subsequently underwent surgical resection.
  
  
  RESULTS
  2HG was detected in both of the IDH-mutated gliomas (grade III Anaplastic Astrocytoma and grade II Diffuse Astrocytoma) and was absent in IDH wild-type gliomas and in a patient with breast cancer metastases. 2D L-COSY was also able to resolve complex and overlapping resonances including phosphocholine (PC) from glycerophosphocholine (GPC), lactate (Lac) from lipids and glutamate (Glu) from glutamine (Gln).
  
  
  CONCLUSIONS
  This study demonstrates the ability of 2D L-COSY to unambiguously detect 2HG in addition to other neuro metabolites. These findings may aid in establishing 2HG as a biomarker of malignant progression as well as for disease monitoring in IDH-mutated gliomas.
authors.affiliation: Division of Neuroradiology, Department of Radiology, Perelman School of Medicine at University of Pennsylvania, 3400, Spruce St., Philadelphia, PA, 19014, USA.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Verma
authors.affiliation: Division of Neuroradiology, Department of Radiology, Perelman School of Medicine at University of Pennsylvania, 3400, Spruce St., Philadelphia, PA, 19014, USA. suyash.mohan@uphs.upenn.edu.
authors.forename: Suyash
authors.initials: S
authors.lastname: Mohan
authors.affiliation: Department of Pathology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: MacLean P
authors.initials: MP
authors.lastname: Nasrallah
authors.affiliation: Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Brem
authors.affiliation: Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: John Y K
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Division of Neuroradiology, Department of Radiology, Perelman School of Medicine at University of Pennsylvania, 3400, Spruce St., Philadelphia, PA, 19014, USA.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Chawla
authors.affiliation: Division of Neuroradiology, Department of Radiology, Perelman School of Medicine at University of Pennsylvania, 3400, Spruce St., Philadelphia, PA, 19014, USA.
authors.forename: Sumei
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Radiological Sciences, UCLA, Los Angeles, CA, USA.
authors.forename: Rajakumar
authors.initials: R
authors.lastname: Nagarajan
authors.affiliation: Department of Radiological Sciences, UCLA, Los Angeles, CA, USA.
authors.forename: M Albert
authors.initials: MA
authors.lastname: Thomas
authors.affiliation: Department of Cellular and Molecular Biology, University of Liverpool, Liverpool, UK.
authors.forename: Harish
authors.initials: H
authors.lastname: Poptani
keywords: 2-Hydroxyglutarate; Brain tumor; Correlation spectroscopy; Isocitrate dehydrogenase; Phosphocholine