NIMG-29. ELEVATION OF GLUTAMINE AND CITRATE BY MR SPECTROSCOPY IS AN IMAGING BIOMARKER OF RAPID CELL PROLIFERATION IN GLIOMAS

Abstract Prior studies suggested glutamine metabolism in cancers may be altered to meet the high demands of nucleotide biosynthesis in cancers. We conducted 1H MR spectroscopy in 18 glioma patients and analyzed the metabolic data together with post-gadolinium MRI and cell proliferation rate (MIB-1 label index). The optimized MRS (TE 97 ms PRESS) provided well discernible signal of glutamine at 2.45 ppm and a negative-polarity signal of citrate at 2.6 ppm, without considerable overlaps with neighboring signals. The 18 patients had biopsy-proven anaplastic gliomas or glioblastomas. Concurrent elevation of glutamine and citrate was identified in 15 gliomas. These gliomas presented with enhancement in post-gadolinium MRI, indicative of broken blood-brain barrier (BBB). The 15 gliomas were grouped as subset-1 while the other 3 gliomas that had elevated citrate without elevation of glutamine were grouped as subset-2. Citrate level was significantly different between the two subsets of gliomas (1.4+/-0.5 vs. 1.6+/-0.4 mM). However, subst-1 had significantly higher choline (4.7+/-1.8 vs. 1.6+/-0.3 mM, p< 0.01) and higher MIB-1 compared with subset-2. Given that choline is a cellularity marker, a finding of high choline and high MIB-1 with elevation of glutamine and citrate suggests that the tumors have high tumor cellularity and cell multiplication competence. Of the 18 gliomas, 13 were IDH mutated with elevated 2HG. The glutamine and citrate levels in IDH-mutant gliomas were not significantly different from those in IDH wildtype gliomas. In conclusion, high-grade gliomas undergo a metabolic rearrangement of concurrent elevation of glutamine and citrate to attain malignant characters such as high cellularity, rapid cell proliferation, and BBB breakdown. IDH mutant and IDH wildtype gliomas may share a common metabolic rearrangement of glutamine-mediated citrate elevation to attain malignancy. Measurements of glutamine and citrate may serve a potential imaging biomarker for aggressive gliomas.

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Glycine by MR spectroscopy is an imaging biomarker of glioma aggressiveness

Neuro-Oncology ◽

10.1093/neuonc/noaa034 ◽

2020 ◽

Vol 22 (7) ◽

pp. 1018-1029 ◽

Cited By ~ 5

Author(s):

Vivek Tiwari ◽

Elena V Daoud ◽

Kimmo J Hatanpaa ◽

Ang Gao ◽

Song Zhang ◽

...

Keyword(s):

Cell Proliferation ◽

Patient Survival ◽

Inverse Correlation ◽

Metabolic Imaging ◽

Imaging Biomarker ◽

Resonance Spectroscopy ◽

Nucleotide Biosynthesis ◽

Glycine Concentration ◽

Non Invasive ◽

Mib 1

Abstract Background High-grade gliomas likely remodel the metabolic machinery to meet the increased demands for amino acids and nucleotides during rapid cell proliferation. Glycine, a non-essential amino acid and intermediate of nucleotide biosynthesis, may increase with proliferation. Non-invasive measurement of glycine by magnetic resonance spectroscopy (MRS) was evaluated as an imaging biomarker for assessment of tumor aggressiveness. Methods We measured glycine, 2-hydroxyglutarate (2HG), and other tumor-related metabolites in 35 glioma patients using an MRS sequence tailored for co-detection of glycine and 2HG in gadolinium-enhancing and non-enhancing tumor regions on 3T MRI. Glycine and 2HG concentrations as measured by MRS were correlated with tumor cell proliferation (MIB-1 labeling index), expression of mitochondrial serine hydroxymethyltransferase (SHMT2), and glycine decarboxylase (GLDC) enzymes, and patient overall survival. Results Elevated glycine was strongly associated with presence of gadolinium enhancement, indicating more rapidly proliferative disease. Glycine concentration was positively correlated with MIB-1, and levels higher than 2.5 mM showed significant association with shorter patient survival, irrespective of isocitrate dehydrogenase status. Concentration of 2HG did not correlate with MIB-1 index. A high glycine/2HG concentration ratio, >2.5, was strongly associated with shorter survival (P < 0.0001). GLDC and SHMT2 expression were detectable in all tumors with glycine concentration, demonstrating an inverse correlation with GLDC. Conclusions The data suggest that aggressive gliomas reprogram glycine-mediated one-carbon metabolism to meet the biosynthetic demands for rapid cell proliferation. MRS evaluation of glycine provides a non-invasive metabolic imaging biomarker that is predictive of tumor progression and clinical outcome. Key Points 1. Glycine and 2-hydroxyglutarate in glioma patients are precisely co-detected using MRS at 3T. 2. Tumors with elevated glycine proliferate and progress rapidly. 3. A high glycine/2HG ratio is predictive of shortened patient survival.

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NIMG-24. GLYCINE AND GLUTAMINE BY MR SPECTROSCOPY ARE IMAGING BIOMARKERS OF GLIOMA AGGRESSIVENESS

Neuro-Oncology ◽

10.1093/neuonc/noaa215.637 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii152-ii152

Author(s):

Changho Choi ◽

Pegah Askari ◽

Elena Daoud ◽

Kimmo Hatanpaa ◽

Jack Raisanen ◽

...

Keyword(s):

Cell Proliferation ◽

Overall Survival ◽

Imaging Biomarker ◽

Imaging Biomarkers ◽

P Value ◽

Resonance Spectroscopy ◽

Poor Survival ◽

Female Age ◽

Kaplan Meier ◽

Mib 1

Abstract Cancers reprogram their metabolism and the resulting alterations in metabolite concentrations may be closely related to the clinical behavior of the tumors. We evaluated glycine, glutamine and 2-hydroxyglutarate (2HG) in 16 adult subjects with glioblastomas (9 male and 7 female; age 43-64 years, median 58) noninvasively using proton magnetic resonance spectroscopy and examined their association with the cell proliferation rate (MIB-1 labeling index) and overall survival. MRS was acquired using point-resolved spectroscopy (PRESS TE 97ms) at 3T. Metabolite levels were quantified with reference to water. The concentrations of glycine and glutamine were both positively correlated with MIB-1 (p=.002 and .0008 respectively). The sum of glycine and glutamine levels showed stronger association with MIB-1 (p< .0001). In the Kaplan-Meier overall survival analysis, the median survival was significantly shorter in patients with glycine levels higher than 2.3 mM than those with concentrations less than 2.3 mM. For glutamine, the patients with higher than 5.7 mM showed association with poor survival. The log-rank p value was substantially smaller in glutamine compared to glycine (p=.008 vs .04). The sum of glycine and glutamine levels showed stronger association with overall survival. 2HG level greater than 1 mM was associated with long survival, which was as expected since elevation of 2HG represents IDH mutant tumors and IDH mutation carries favorable prognosis. Given the association of low 2HG with poor survival, we tested metabolic ratios to 2HG, in which 2HG estimates < 1 mM were put as 1 mM. The glycine/2HG, glutamine/2HG, and (glycine+glutamine)/2HG showed stronger association with overall survival, compared to glycine, glutamine, and glycine+glutamine. Our data suggested that increased metabolism of glycine and glutamine is closely associated with rapid cell proliferation and poor clinical outcome, suggesting the metabolites as an MRS imaging biomarker of glioma aggressiveness.

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1H-MR spectroscopy at 7.0 T and intra-individual comparison to 3.0 T and 1.5 T

RöFo - Fortschritte auf dem Gebiet der Röntgenstrahlen und der bildgebenden Verfahren ◽

10.1055/s-2007-972152 ◽

2007 ◽

Vol 179 (03) ◽

Cited By ~ 1

Author(s):

F Traeber ◽

JR Duraj ◽

J Gieseke ◽

FG Hoogenraad ◽

CK Kuhl ◽

...

Keyword(s):

Mr Spectroscopy ◽

1H Mr Spectroscopy ◽

Individual Comparison ◽

3.0 T

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1H MR Spectroscopy in Parkinson's Disease and Progressive Supranuclear Palsy: Preliminary Study

Journal of the Korean Radiological Society ◽

10.3348/jkrs.1996.34.6.711 ◽

1996 ◽

Vol 34 (6) ◽

pp. 711

Author(s):

Kee Hyun Chang ◽

Beom Seok Jeon ◽

In Chan Song ◽

Dong Sung Kim ◽

Kwan Hong Min ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Progressive Supranuclear Palsy ◽

Mr Spectroscopy ◽

1H Mr Spectroscopy ◽

Preliminary Study

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In Vivo Single Voxel 1H MR Spectroscopy in Cerebral Glioma

Journal of the Korean Radiological Society ◽

10.3348/jkrs.1996.35.3.307 ◽

1996 ◽

Vol 35 (3) ◽

pp. 307 ◽

Cited By ~ 2

Author(s):

In Chan Song ◽

Kee Hyun Chang ◽

Moon Hee Han ◽

Hee Won Jung ◽

Dong Sung Kim ◽

...

Keyword(s):

Mr Spectroscopy ◽

Cerebral Glioma ◽

1H Mr Spectroscopy ◽

Single Voxel

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MR imaging and 1H-MR spectroscopy in a case of juvenile Alexander disease

Brain and Development ◽

10.1016/s0387-7604(02)00080-3 ◽

2002 ◽

Vol 24 (7) ◽

pp. 723-726 ◽

Cited By ~ 22

Author(s):

Atsushi Imamura ◽

Kenji E. Orii ◽

Shinji Mizuno ◽

Hiroaki Hoshi ◽

Tomio Kondo

Keyword(s):

Mr Imaging ◽

Mr Spectroscopy ◽

Alexander Disease ◽

1H Mr Spectroscopy

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Combined 1H MR spectroscopy and diffusion-weighted MRI improves the prediction of stroke outcome

Neurology ◽

10.1212/wnl.55.4.498 ◽

2000 ◽

Vol 55 (4) ◽

pp. 498-506 ◽

Cited By ~ 79

Author(s):

M. W. Parsons ◽

T. Li ◽

P. A. Barber ◽

Q. Yang ◽

D. G. Darby ◽

...

Keyword(s):

Mr Spectroscopy ◽

Stroke Outcome ◽

Diffusion Weighted Mri ◽

1H Mr Spectroscopy ◽

Diffusion Weighted ◽

And Diffusion

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Proton magnetic resonance spectroscopy in pituitary macroadenomas: preliminary results

Journal of Neurosurgery ◽

10.3171/jns/2008/109/8/0306 ◽

2008 ◽

Vol 109 (2) ◽

pp. 306-312 ◽

Cited By ~ 14

Author(s):

Andreas Stadlbauer ◽

Michael Buchfelder ◽

Christopher Nimsky ◽

Wolfgang Saeger ◽

Erich Salomonowitz ◽

...

Keyword(s):

Magnetic Field ◽

Mr Spectroscopy ◽

Spectroscopy Data ◽

Cell Index ◽

Volume Of Interest ◽

Metabolite Concentrations ◽

The Magnetic Field ◽

Proliferative Cell ◽

Mib 1 ◽

Pituitary Macroadenomas

Object The aim of this study was to correlate proton MR (1H-MR) spectroscopy data with histopathological and surgical findings of proliferation and hemorrhage in pituitary macroadenomas. Methods Quantitative 1H-MR spectroscopy was performed on a 1.5-T unit in 37 patients with pituitary macroadenomas. A point-resolved spectroscopy sequence (TR 2000 msec, TE 135 msec) with 128 averages and chemical shift selective pulses for water suppression was used. Voxel dimensions were adapted to ensure that the volume of interest was fully located within the lesion and to obtain optimal homogeneity of the magnetic field. In addition, water-unsuppressed spectra (16 averages) were acquired from the same volume of interest for eddy current correction, absolute quantification of metabolite signals, and determination of full width at half maximum of the unsuppressed water peak (FWHMwater). Metabolite concentrations of choline-containing compounds (Cho) were computed using the LCModel program and correlated with MIB-1 as a proliferative cell index from a tissue specimen. Results In 16 patients harboring macroadenomas without hemorrhage, there was a strong positive linear correlation between metabolite concentrations of Cho and the MIB-1 proliferative cell index (R = 0.819, p < 0.001). The metabolite concentrations of Cho ranged from 1.8 to 5.2 mM, and the FWHMwater was 4.4–11.7 Hz. Eleven patients had a hemorrhagic adenoma and showed no assignable metabolite concentration of Cho, and the FWHMwater was 13.4–24.4 Hz. In 10 patients the size of the lesion was too small (< 20 mm in 2 directions) for the acquisition of MR spectroscopy data. Conclusions Quantitative 1H-MR spectroscopy provided important information on the proliferative potential and hemorrhaging of pituitary macroadenomas. These data may be useful for noninvasive structural monitoring of pituitary macroadenomas. Differences in the FWHMwater could be explained by iron ions of hemosiderin, which lead to worsened homogeneity of the magnetic field.

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