Sandeep K. Ganji

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

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.

Prospective Longitudinal Analysis of 2-Hydroxyglutarate Magnetic Resonance Spectroscopy Identifies Broad Clinical Utility for the Management of Patients With IDH-Mutant Glioma

Purpose Proton magnetic resonance spectroscopy (MRS) of the brain can detect 2-hydroxyglutarate (2HG), the oncometabolite produced in neoplasms harboring a mutation in the gene coding for isocitrate dehydrogenase ( IDH). We conducted a prospective longitudinal imaging study to determine whether quantitative assessment of 2HG by MRS could serve as a noninvasive clinical imaging biomarker for IDH-mutated gliomas. Patients and Methods 2HG MRS was performed in 136 patients using point-resolved spectroscopy at 3 T in parallel with standard clinical magnetic resonance imaging and assessment. Data were analyzed in patient cohorts representing the major phases of the glioma clinical course and were further subgrouped by histology and treatment type to evaluate 2HG. Histologic correlations were performed. Results Quantitative 2HG MRS was technically and biologically reproducible. 2HG concentration > 1 mM could be reliably detected with high confidence. During the period of indolent disease, 2HG concentration varied by less than ± 1 mM, and it increased sharply with tumor progression. 2HG concentration was positively correlated with tumor cellularity and significantly differed between high- and lower-grade gliomas. In response to cytotoxic therapy, 2HG concentration decreased rapidly in 1p/19q codeleted oligodendrogliomas and with a slower time course in astrocytomas and mixed gliomas. The magnitude and time course of the decrease in 2HG concentration and magnitude of the decrease in tumor volume did not differ between oligodendrogliomas treated with temozolomide or carmustine. Criteria for 2HG MRS were established to make a presumptive molecular diagnosis of an IDH mutation in gliomas technically unable to undergo a surgical procedure. Conclusion 2HG concentration as measured by MRS was reproducible and reliably reflected the disease state. These data provide a basis for incorporating 2HG MRS into clinical management of IDH-mutated gliomas.

T2 measurement of J‐coupled metabolites in the human brain at 3T

Proton T2 relaxation times of metabolites in the human brain were measured using point resolved spectroscopy at 3T in vivo. Four echo times (54, 112, 246 and 374 ms) were selected from numerical and phantom analyses for effective detection of the glutamate multiplet at ~ 2.35 ppm. In vivo data were obtained from medial and left occipital cortices of five healthy volunteers. The cortices contained predominantly gray and white matter, respectively. Spectra were analyzed with LCModel software using volume‐localized calculated spectra of brain metabolites. The estimate of the signal strength vs. TE was fitted to a monoexponential function for estimation of apparent T2 (T2†). T2† was estimated to be similar between the brain regions for creatine, choline, glutamate and myo‐inositol, but significantly different for N‐acetylaspartate singlet and multiplet. T2†s of glutamate and myo‐inositol were measured as 181 ± 16 and 197 ± 14 ms (mean ± SD, N = 5) for medial occipital cortices, and 180 ± 12 and 196 ± 17 ms for left occipital cortices, respectively. Copyright

A comparative study of short‐ and long‐TE 1H MRS at 3 T for in vivo detection of 2‐hydroxyglutarate in brain tumors

2‐Hydroxyglutarate (2HG) is produced in gliomas with mutations of isocitrate dehydrogenase (IDH) 1 and 2. The 1H resonances of the J‐coupled spins of 2HG are extensively overlapped with signals from other metabolites. Here, we report a comparative study at 3 T of the utility of the point‐resolved spectroscopy sequence with a standard short TE (35 ms) and a long TE (97 ms), which had been theoretically designed for the detection of the 2HG 2.25‐ppm resonance. The performance of the methods is evaluated using data from phantoms, seven healthy volunteers and 22 subjects with IDH‐mutated gliomas. The results indicate that TE = 97 ms provides higher detectability of 2HG than TE = 35 ms, and that this improved capability is gained when data are analyzed with basis spectra that include the effects of the volume localizing radiofrequency and gradient pulses. Copyright

Compressive Sensing Could Accelerate 1H MR Metabolic Imaging in the Clinic

PURPOSE To retrospectively evaluate the fidelity of magnetic resonance (MR) spectroscopic imaging data preservation at a range of accelerations by using compressed sensing. MATERIALS AND METHODS The protocols were approved by the institutional review board of the university, and written informed consent to acquire and analyze MR spectroscopic imaging data was obtained from the subjects prior to the acquisitions. This study was HIPAA compliant. Retrospective application of compressed sensing was performed on 10 clinical MR spectroscopic imaging data sets, yielding 600 voxels from six normal brain data sets, 163 voxels from two brain tumor data sets, and 36 voxels from two prostate cancer data sets for analysis. The reconstructions were performed at acceleration factors of two, three, four, five, and 10 and were evaluated by using the root mean square error (RMSE) metric, metabolite maps (choline, creatine, N-acetylaspartate [NAA], and/or citrate), and statistical analysis involving a voxelwise paired t test and one-way analysis of variance for metabolite maps and ratios for comparison of the accelerated reconstruction with the original case. RESULTS The reconstructions showed high fidelity for accelerations up to 10 as determined by the low RMSE (< 0.05). Similar means of the metabolite intensities and hot-spot localization on metabolite maps were observed up to a factor of five, with lack of statistically significant differences compared with the original data. The metabolite ratios of choline to NAA and choline plus creatine to citrate did not show significant differences from the original data for up to an acceleration factor of five in all cases and up to that of 10 for some cases. CONCLUSION A reduction of acquisition time by up to 80%, with negligible loss of information as evaluated with clinically relevant metrics, has been successfully demonstrated for hydrogen 1 MR spectroscopic imaging.

Measurement of glycine in the human brain in vivo by 1H-MRS at 3 T: Application in brain tumors

Glycine is a key metabolic intermediate required for the synthesis of proteins, nucleic acids, and other molecules, and its detection in cancer could, therefore, provide biologically relevant information about the growth of the tumor. Here, we report measurement of glycine in human brain and gliomas by an optimized point‐resolved spectroscopy sequence at 3 T. Echo time dependence of the major obstacle, myo‐inositol (mI) multiplet, was investigated with numerical simulations, incorporating the 3D volume localization. The simulations indicated that a subecho pair (TE1, TE2) = (60, 100) ms permits detection of both glycine and mI with optimum selectivity. In vivo validation of the optimized point‐resolved spectroscopy was conducted on the right parietal cortex of five healthy volunteers. Metabolite signals estimated from LCModel were normalized with respect to the brain water signal, and the concentrations were evaluated assuming the total creatine concentration at 8 mM. The glycine concentration was estimated as 0.6 ± 0.1 mM (mean ± SD, n = 5), with a mean Cramér‐Rao lower bound of 9 ± 1%. The point‐resolved spectroscopy sequence was applied to measure the glycine levels in patients with glioblastoma multiforme. Metabolite concentrations were obtained using the water signal from the tumor mass. The study revealed that a subset of human gliomas contains glycine levels elevated 1.5–8 fold relative to normal. Magn Reson Med, 2011.

Proton T2 measurement and quantification of lactate in brain tumors by MRS at 3 Tesla in vivo

To evaluate the T2 relaxation time of lactate (Lac) in brain tumors and the correlation of the T2 and concentration with tumor grades.

Measurement of regional variation of GABA in the human brain by optimized point-resolved spectroscopy at 7 T in vivo.

The 1H resonances of γ‐aminobutyric acid (GABA) in the human brain in vivo are extensively overlapped with the neighboring abundant resonances of other metabolites and remain indiscernible in short‐TE MRS at 7 T. Here we report that the GABA resonance at 2.28 ppm can be fully resolved by means of echo time optimization of a point‐resolved spectroscopy (PRESS) scheme. Following numerical simulations and phantom validation, the subecho times of PRESS were optimized at (TE, TE2) = (31, 61) ms for detection of GABA, glutamate (Glu), glutamine (Gln), and glutathione (GSH). The in vivo feasibility of the method was tested in several brain regions in nine healthy subjects. Spectra were acquired from the medial prefrontal, left frontal, medial occipital, and left occipital brain and analyzed with LCModel. Following the gray and white matter (GM and WM) segmentation of T1‐weighted images, linear regression of metabolite estimates was performed against the fractional GM contents. The GABA concentration was estimated to be about seven times higher in GM than in WM. GABA was overall higher in frontal than in occipital brain. Glu was about twice as high in GM as in WM in both frontal and occipital brain. Gln was significantly different between frontal GM and WM while being similar between occipital GM and WM. GSH did not show significant dependence on tissue content. The signals from N‐acetylaspartylglutamate were clearly resolved, giving the concentration more than 10 times higher in WM than in GM. Our data indicate that the PRESS TE = 92 ms method provides an effective means for measuring GABA and several challenging J‐coupled spin metabolites in human brain at 7 T. Copyright

Measurement of glycine in gray and white matter in the human brain in vivo by 1H-MRS at 7.0 T

The concentration of glycine (Gly) was measured in gray matter (GM) and white matter (WM) in the human brain using single‐voxel localized 1H MRS at 7 T. A point‐resolved spectroscopy sequence with echo time = 150 ms was used for measuring Gly levels in various regions of the frontal and occipital lobes in 11 healthy volunteers and one subject with a glioblastoma. The point‐resolved spectroscopy spectra were analyzed with LCModel using basis functions generated from density matrix simulations that included the effects of volume localized radio‐frequency and gradient pulses. The fraction of GM and white matter within the voxels was obtained from T1‐weighted image segmentation. The metabolite concentrations within the voxels, estimated with respect to the GM + WM water concentrations, were fitted to a linear function of fractional GM content. The Gly concentrations in pure GM and white matter were estimated to be 1.1 and 0.1 mM, with 95% confidence intervals 1.0–1.2 and 0.0–0.2, respectively. Magn Reson Med, 2012.

Detection of 2‐hydroxyglutarate in brain tumors by triple‐refocusing MR spectroscopy at 3T in vivo

To test the efficacy of triple‐refocusing MR spectroscopy (MRS) for improved detection of 2‐hydroxyglutarate (2HG) in brain tumors at 3T in vivo.