Skip to main content
Top
Published in: European Journal of Nuclear Medicine and Molecular Imaging 6/2020

Open Access 01-06-2020 | Glioblastoma | Original Article

Imaging glioma biology: spatial comparison of amino acid PET, amide proton transfer, and perfusion-weighted MRI in newly diagnosed gliomas

Authors: S. Schön, J. Cabello, F. Liesche-Starnecker, M. Molina-Romero, P. Eichinger, M. Metz, I. Karimov, C. Preibisch, J. Keupp, A. Hock, B. Meyer, W. Weber, C. Zimmer, T. Pyka, I. Yakushev, J. Gempt, B. Wiestler

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 6/2020

Login to get access

Abstract

Purpose

Imaging glioma biology holds great promise to unravel the complex nature of these tumors. Besides well-established imaging techniques such O-(2-[18F]fluoroethyl)-l-tyrosine (FET)-PET and dynamic susceptibility contrast (DSC) perfusion imaging, amide proton transfer–weighted (APTw) imaging has emerged as a promising novel MR technique. In this study, we aimed to better understand the relation between these imaging biomarkers and how well they capture cellularity and vascularity in newly diagnosed gliomas.

Methods

Preoperative MRI and FET-PET data of 46 patients (31 glioblastoma and 15 lower-grade glioma) were segmented into contrast-enhancing and FLAIR-hyperintense areas. Using established cutoffs, we calculated hot-spot volumes (HSV) and their spatial overlap. We further investigated APTw and CBV values in FET-HSV. In a subset of 10 glioblastoma patients, we compared cellularity and vascularization in 34 stereotactically targeted biopsies with imaging.

Results

In glioblastomas, the largest HSV was found for APTw, followed by PET and CBV (p < 0.05). In lower-grade gliomas, APTw–HSV was clearly lower than in glioblastomas. The spatial overlap of HSV was highest between APTw and FET in both tumor entities and regions. APTw correlated significantly with cellularity, similar to FET, while the association with vascularity was more pronounced in CBV and FET.

Conclusions

We found a relevant spatial overlap in glioblastomas between hotspots of APTw and FET both in contrast-enhancing and FLAIR-hyperintense tumor. As suggested by earlier studies, APTw was lower in lower-grade gliomas compared with glioblastomas. APTw meaningfully contributes to biological imaging of gliomas.
Literature
1.
go back to reference Heiss P, Mayer S, Herz M, Wester HJ, Schwaiger M, Senekowitsch-Schmidtke R. Investigation of transport mechanism and uptake kinetics of O-(2-[18F]fluoroethyl)-L-tyrosine in vitro and in vivo. J Nucl Med. 1999;40:1367–73.PubMed Heiss P, Mayer S, Herz M, Wester HJ, Schwaiger M, Senekowitsch-Schmidtke R. Investigation of transport mechanism and uptake kinetics of O-(2-[18F]fluoroethyl)-L-tyrosine in vitro and in vivo. J Nucl Med. 1999;40:1367–73.PubMed
2.
go back to reference Jansen NL, Schwartz C, Graute V, Eigenbrod S, Lutz J, Egensperger R, et al. Prediction of oligodendroglial histology and LOH 1p/19q using dynamic [(18)F]FET-PET imaging in intracranial WHO grade II and III gliomas. Neuro-Oncol. 2012;14:1473–80.CrossRef Jansen NL, Schwartz C, Graute V, Eigenbrod S, Lutz J, Egensperger R, et al. Prediction of oligodendroglial histology and LOH 1p/19q using dynamic [(18)F]FET-PET imaging in intracranial WHO grade II and III gliomas. Neuro-Oncol. 2012;14:1473–80.CrossRef
3.
go back to reference Kunz M, Thon N, Eigenbrod S, Hartmann C, Egensperger R, Herms J, et al. Hot spots in dynamic (18)FET-PET delineate malignant tumor parts within suspected WHO grade II gliomas. Neuro-Oncol. 2011;13:307–16.CrossRef Kunz M, Thon N, Eigenbrod S, Hartmann C, Egensperger R, Herms J, et al. Hot spots in dynamic (18)FET-PET delineate malignant tumor parts within suspected WHO grade II gliomas. Neuro-Oncol. 2011;13:307–16.CrossRef
4.
go back to reference Galldiks N, Dunkl V, Stoffels G, Hutterer M, Rapp M, Sabel M, et al. Diagnosis of pseudoprogression in patients with glioblastoma using O-(2-[18F]fluoroethyl)-L-tyrosine PET. Eur J Nucl Med Mol Imaging. 2015;42:685–95.CrossRef Galldiks N, Dunkl V, Stoffels G, Hutterer M, Rapp M, Sabel M, et al. Diagnosis of pseudoprogression in patients with glioblastoma using O-(2-[18F]fluoroethyl)-L-tyrosine PET. Eur J Nucl Med Mol Imaging. 2015;42:685–95.CrossRef
5.
go back to reference Jain R, Gutierrez J, Narang J, Scarpace L, Schultz LR, Lemke N, et al. In vivo correlation of tumor blood volume and permeability with histologic and molecular angiogenic markers in gliomas. Am J Neuroradiol. 2011;32:388–94.CrossRef Jain R, Gutierrez J, Narang J, Scarpace L, Schultz LR, Lemke N, et al. In vivo correlation of tumor blood volume and permeability with histologic and molecular angiogenic markers in gliomas. Am J Neuroradiol. 2011;32:388–94.CrossRef
6.
go back to reference Law M, Yang S, Wang H, Babb JS, Johnson G, Cha S, et al. Glioma grading: sensitivity, specificity, and predictive values of perfusion MR imaging and proton MR spectroscopic imaging compared with conventional MR imaging. Am J Neuroradiol. 2003;24:1989–98.PubMed Law M, Yang S, Wang H, Babb JS, Johnson G, Cha S, et al. Glioma grading: sensitivity, specificity, and predictive values of perfusion MR imaging and proton MR spectroscopic imaging compared with conventional MR imaging. Am J Neuroradiol. 2003;24:1989–98.PubMed
7.
go back to reference Kickingereder P, Sahm F, Radbruch A, Wick W, Heiland S, von Deimling A, et al. IDH mutation status is associated with a distinct hypoxia/angiogenesis transcriptome signature which is non-invasively predictable with rCBV imaging in human glioma. Sci Rep. 2015;5:16238.CrossRef Kickingereder P, Sahm F, Radbruch A, Wick W, Heiland S, von Deimling A, et al. IDH mutation status is associated with a distinct hypoxia/angiogenesis transcriptome signature which is non-invasively predictable with rCBV imaging in human glioma. Sci Rep. 2015;5:16238.CrossRef
8.
go back to reference Law M, Young RJ, Babb JS, Peccerelli N, Chheang S, Gruber ML, et al. Gliomas: predicting time to progression or survival with cerebral blood volume measurements at dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging. Radiology. 2008;247:490–8.CrossRef Law M, Young RJ, Babb JS, Peccerelli N, Chheang S, Gruber ML, et al. Gliomas: predicting time to progression or survival with cerebral blood volume measurements at dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging. Radiology. 2008;247:490–8.CrossRef
9.
go back to reference Kickingereder P, Wiestler B, Burth S, Wick A, Nowosielski M, Heiland S, et al. Relative cerebral blood volume is a potential predictive imaging biomarker of bevacizumab efficacy in recurrent glioblastoma. Neuro-Oncol. 2015;17:1139–47.CrossRef Kickingereder P, Wiestler B, Burth S, Wick A, Nowosielski M, Heiland S, et al. Relative cerebral blood volume is a potential predictive imaging biomarker of bevacizumab efficacy in recurrent glioblastoma. Neuro-Oncol. 2015;17:1139–47.CrossRef
10.
go back to reference Yan K, Fu Z, Yang C, Zhang K, Jiang S, Lee D-H, et al. Assessing amide proton transfer (APT) MRI contrast origins in 9 L gliosarcoma in the rat brain using proteomic analysis. Mol Imaging Biol. 2015;17:479–87.CrossRef Yan K, Fu Z, Yang C, Zhang K, Jiang S, Lee D-H, et al. Assessing amide proton transfer (APT) MRI contrast origins in 9 L gliosarcoma in the rat brain using proteomic analysis. Mol Imaging Biol. 2015;17:479–87.CrossRef
11.
go back to reference Togao O, Yoshiura T, Keupp J, Hiwatashi A, Yamashita K, Kikuchi K, et al. Amide proton transfer imaging of adult diffuse gliomas: correlation with histopathological grades. Neuro-Oncol. 2014;16:441–8.CrossRef Togao O, Yoshiura T, Keupp J, Hiwatashi A, Yamashita K, Kikuchi K, et al. Amide proton transfer imaging of adult diffuse gliomas: correlation with histopathological grades. Neuro-Oncol. 2014;16:441–8.CrossRef
12.
go back to reference Choi YS, Ahn SS, Lee S-K, Chang JH, Kang S-G, Kim SH, et al. Amide proton transfer imaging to discriminate between low- and high-grade gliomas: added value to apparent diffusion coefficient and relative cerebral blood volume. Eur Radiol. 2017;27:3181–9.CrossRef Choi YS, Ahn SS, Lee S-K, Chang JH, Kang S-G, Kim SH, et al. Amide proton transfer imaging to discriminate between low- and high-grade gliomas: added value to apparent diffusion coefficient and relative cerebral blood volume. Eur Radiol. 2017;27:3181–9.CrossRef
13.
go back to reference Zhou J, Tryggestad E, Wen Z, Lal B, Zhou T, Grossman R, et al. Differentiation between glioma and radiation necrosis using molecular magnetic resonance imaging of endogenous proteins and peptides. Nat Med. 2011;17:130–4.CrossRef Zhou J, Tryggestad E, Wen Z, Lal B, Zhou T, Grossman R, et al. Differentiation between glioma and radiation necrosis using molecular magnetic resonance imaging of endogenous proteins and peptides. Nat Med. 2011;17:130–4.CrossRef
15.
go back to reference Wiestler B, Kluge A, Lukas M, Gempt J, Ringel F, Schlegel J, et al. Multiparametric MRI-based differentiation of WHO grade II/III glioma and WHO grade IV glioblastoma. Sci Rep. 2016;6:35142.CrossRef Wiestler B, Kluge A, Lukas M, Gempt J, Ringel F, Schlegel J, et al. Multiparametric MRI-based differentiation of WHO grade II/III glioma and WHO grade IV glioblastoma. Sci Rep. 2016;6:35142.CrossRef
16.
go back to reference Togao O, Hiwatashi A, Yamashita K, Kikuchi K, Keupp J, Yoshimoto K, et al. Grading diffuse gliomas without intense contrast enhancement by amide proton transfer MR imaging: comparisons with diffusion- and perfusion-weighted imaging. Eur Radiol. 2017;27:578–88.CrossRef Togao O, Hiwatashi A, Yamashita K, Kikuchi K, Keupp J, Yoshimoto K, et al. Grading diffuse gliomas without intense contrast enhancement by amide proton transfer MR imaging: comparisons with diffusion- and perfusion-weighted imaging. Eur Radiol. 2017;27:578–88.CrossRef
17.
go back to reference Park JE, Lee JY, Kim HS, Oh J-Y, Jung SC, Kim SJ, et al. Amide proton transfer imaging seems to provide higher diagnostic performance in post-treatment high-grade gliomas than methionine positron emission tomography. Eur Radiol. 2018;28:3285–95.CrossRef Park JE, Lee JY, Kim HS, Oh J-Y, Jung SC, Kim SJ, et al. Amide proton transfer imaging seems to provide higher diagnostic performance in post-treatment high-grade gliomas than methionine positron emission tomography. Eur Radiol. 2018;28:3285–95.CrossRef
19.
go back to reference Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol (Berl). 2016;131:803–20.CrossRef Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol (Berl). 2016;131:803–20.CrossRef
20.
go back to reference Togao O, Keupp J, Hiwatashi A, Yamashita K, Kikuchi K, Yoneyama M, et al. Amide proton transfer imaging of brain tumors using a self-corrected 3D fast spin-echo dixon method: comparison with separate B0 correction. Magn Reson Med. 2017;77:2272–9.CrossRef Togao O, Keupp J, Hiwatashi A, Yamashita K, Kikuchi K, Yoneyama M, et al. Amide proton transfer imaging of brain tumors using a self-corrected 3D fast spin-echo dixon method: comparison with separate B0 correction. Magn Reson Med. 2017;77:2272–9.CrossRef
21.
go back to reference Koesters T, Friedman KP, Fenchel M, Zhan Y, Hermosillo G, Babb J, et al. Dixon sequence with superimposed model-based bone compartment provides highly accurate PET/MR attenuation correction of the brain. J Nucl Med. 2016;57:918–24.CrossRef Koesters T, Friedman KP, Fenchel M, Zhan Y, Hermosillo G, Babb J, et al. Dixon sequence with superimposed model-based bone compartment provides highly accurate PET/MR attenuation correction of the brain. J Nucl Med. 2016;57:918–24.CrossRef
22.
go back to reference Unterrainer M, Vettermann F, Brendel M, Holzgreve A, Lifschitz M, Zähringer M, et al. Towards standardization of 18F-FET PET imaging: do we need a consistent method of background activity assessment? EJNMMI Res. 2017;7:48.CrossRef Unterrainer M, Vettermann F, Brendel M, Holzgreve A, Lifschitz M, Zähringer M, et al. Towards standardization of 18F-FET PET imaging: do we need a consistent method of background activity assessment? EJNMMI Res. 2017;7:48.CrossRef
23.
go back to reference Kluge A, Lukas M, Toth V, Pyka T, Zimmer C, Preibisch C. Analysis of three leakage-correction methods for DSC-based measurement of relative cerebral blood volume with respect to heterogeneity in human gliomas. Magn Reson Imaging. 2016;34:410–21.CrossRef Kluge A, Lukas M, Toth V, Pyka T, Zimmer C, Preibisch C. Analysis of three leakage-correction methods for DSC-based measurement of relative cerebral blood volume with respect to heterogeneity in human gliomas. Magn Reson Imaging. 2016;34:410–21.CrossRef
25.
go back to reference Boxerman JL, Schmainda KM, Weisskoff RM. Relative cerebral blood volume maps corrected for contrast agent extravasation significantly correlate with glioma tumor grade, whereas uncorrected maps do not. Am J Neuroradiol. 2006;27:859–67.PubMed Boxerman JL, Schmainda KM, Weisskoff RM. Relative cerebral blood volume maps corrected for contrast agent extravasation significantly correlate with glioma tumor grade, whereas uncorrected maps do not. Am J Neuroradiol. 2006;27:859–67.PubMed
26.
go back to reference Leenders KL. PET: blood flow and oxygen consumption in brain tumors. J Neuro-Oncol. 1994;22:269–73.CrossRef Leenders KL. PET: blood flow and oxygen consumption in brain tumors. J Neuro-Oncol. 1994;22:269–73.CrossRef
27.
go back to reference Yushkevich PA, Piven J, Hazlett HC, Smith RG, Ho S, Gee JC, et al. User-guided 3D active contour segmentation of anatomical structures: significantly improved efficiency and reliability. NeuroImage. 2006;31:1116–28.CrossRef Yushkevich PA, Piven J, Hazlett HC, Smith RG, Ho S, Gee JC, et al. User-guided 3D active contour segmentation of anatomical structures: significantly improved efficiency and reliability. NeuroImage. 2006;31:1116–28.CrossRef
28.
go back to reference Pauleit D, Floeth F, Hamacher K, Riemenschneider MJ, Reifenberger G, Müller H-W, et al. O-(2-[18F]fluoroethyl)-L-tyrosine PET combined with MRI improves the diagnostic assessment of cerebral gliomas. Brain. 2005;128:678–87.CrossRef Pauleit D, Floeth F, Hamacher K, Riemenschneider MJ, Reifenberger G, Müller H-W, et al. O-(2-[18F]fluoroethyl)-L-tyrosine PET combined with MRI improves the diagnostic assessment of cerebral gliomas. Brain. 2005;128:678–87.CrossRef
29.
go back to reference Göttler J, Lukas M, Kluge A, Kaczmarz S, Gempt J, Ringel F, et al. Intra-lesional spatial correlation of static and dynamic FET-PET parameters with MRI-based cerebral blood volume in patients with untreated glioma. Eur J Nucl Med Mol Imaging. 2017;44:392–7.CrossRef Göttler J, Lukas M, Kluge A, Kaczmarz S, Gempt J, Ringel F, et al. Intra-lesional spatial correlation of static and dynamic FET-PET parameters with MRI-based cerebral blood volume in patients with untreated glioma. Eur J Nucl Med Mol Imaging. 2017;44:392–7.CrossRef
30.
go back to reference Brat DJ, Verhaak RGW, Aldape KD, Yung WKA, Salama SR, Cooper LAD, et al. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med. 2015;372:2481–98.CrossRef Brat DJ, Verhaak RGW, Aldape KD, Yung WKA, Salama SR, Cooper LAD, et al. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med. 2015;372:2481–98.CrossRef
31.
go back to reference Brennan CW, Verhaak RGW, McKenna A, Campos B, Noushmehr H, Salama SR, et al. The somatic genomic landscape of glioblastoma. Cell. 2013;155:462–77.CrossRef Brennan CW, Verhaak RGW, McKenna A, Campos B, Noushmehr H, Salama SR, et al. The somatic genomic landscape of glioblastoma. Cell. 2013;155:462–77.CrossRef
32.
go back to reference Capper D, Jones DTW, Sill M, Hovestadt V, Schrimpf D, Sturm D, et al. DNA methylation-based classification of central nervous system tumours. Nature. 2018;555:469–74.CrossRef Capper D, Jones DTW, Sill M, Hovestadt V, Schrimpf D, Sturm D, et al. DNA methylation-based classification of central nervous system tumours. Nature. 2018;555:469–74.CrossRef
33.
go back to reference Park KJ, Kim HS, Park JE, Shim WH, Kim SJ, Smith SA. Added value of amide proton transfer imaging to conventional and perfusion MR imaging for evaluating the treatment response of newly diagnosed glioblastoma. Eur Radiol. 2016;26:4390–403.CrossRef Park KJ, Kim HS, Park JE, Shim WH, Kim SJ, Smith SA. Added value of amide proton transfer imaging to conventional and perfusion MR imaging for evaluating the treatment response of newly diagnosed glioblastoma. Eur Radiol. 2016;26:4390–403.CrossRef
34.
go back to reference Liesche F, Lukas M, Preibisch C, Shi K, Schlegel J, Meyer B, et al. 18F-Fluoroethyl-tyrosine uptake is correlated with amino acid transport and neovascularization in treatment-naive glioblastomas. Eur J Nucl Med Mol Imaging. 2019;46:2163–8.CrossRef Liesche F, Lukas M, Preibisch C, Shi K, Schlegel J, Meyer B, et al. 18F-Fluoroethyl-tyrosine uptake is correlated with amino acid transport and neovascularization in treatment-naive glioblastomas. Eur J Nucl Med Mol Imaging. 2019;46:2163–8.CrossRef
Metadata
Title
Imaging glioma biology: spatial comparison of amino acid PET, amide proton transfer, and perfusion-weighted MRI in newly diagnosed gliomas
Authors
S. Schön
J. Cabello
F. Liesche-Starnecker
M. Molina-Romero
P. Eichinger
M. Metz
I. Karimov
C. Preibisch
J. Keupp
A. Hock
B. Meyer
W. Weber
C. Zimmer
T. Pyka
I. Yakushev
J. Gempt
B. Wiestler
Publication date
01-06-2020
Publisher
Springer Berlin Heidelberg
Published in
European Journal of Nuclear Medicine and Molecular Imaging / Issue 6/2020
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI
https://doi.org/10.1007/s00259-019-04677-x

Other articles of this Issue 6/2020

European Journal of Nuclear Medicine and Molecular Imaging 6/2020 Go to the issue