Differentiation between glioma and radiation necrosis using molecular magnetic resonance imaging of endogenous proteins and peptides

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Abstract

Distinguishing tumor recurrence from radiation necrosis following brain tumor therapy remains a major clinical challenge. Here we demonstrate the ability to distinguish these lesions using the amide proton transfer (APT) MRI signals of endogenous cellular proteins and peptides as an imaging biomarker. When comparing two orthotopic glioma models (SF188/V+ glioma and 9L gliosarcoma) with a radiation necrosis model in rats, viable glioma (hyperintense) and radiation necrosis (hypointense to isointense) could be clearly differentiated using APT MRI. When irradiating rats with U87MG gliomas, the APT signals in the irradiated tumors decreased significantly at 3 days and 6 days post-radiation. The amide protons detected by APT provide a unique and non-invasive MRI biomarker for assessing viable malignancy versus radiation necrosis and predicting tumor response to therapy.

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Most cited references 30

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Diffusion-weighted magnetic resonance imaging as a cancer biomarker: consensus and recommendations.

Anwar Padhani, Guoying Liu, Dow Koh … (2009)

On May 3, 2008, a National Cancer Institute (NCI)-sponsored open consensus conference was held in Toronto, Ontario, Canada, during the 2008 International Society for Magnetic Resonance in Medicine Meeting. Approximately 100 experts and stakeholders summarized the current understanding of diffusion-weighted magnetic resonance imaging (DW-MRI) and reached consensus on the use of DW-MRI as a cancer imaging biomarker. DW-MRI should be tested as an imaging biomarker in the context of well-defined clinical trials, by adding DW-MRI to existing NCI-sponsored trials, particularly those with tissue sampling or survival indicators. Where possible, DW-MRI measurements should be compared with histologic indices including cellularity and tissue response. There is a need for tissue equivalent diffusivity phantoms; meanwhile, simple fluid-filled phantoms should be used. Monoexponential assessments of apparent diffusion coefficient values should use two b values (>100 and between 500 and 1000 mm2/sec depending on the application). Free breathing with multiple acquisitions is superior to complex gating techniques. Baseline patient reproducibility studies should be part of study designs. Both region of interest and histogram analysis of apparent diffusion coefficient measurements should be obtained. Standards for measurement, analysis, and display are needed. Annotated data from validation studies (along with outcome measures) should be made publicly available. Magnetic resonance imaging vendors should be engaged in this process. The NCI should establish a task force of experts (physicists, radiologists, and oncologists) to plan, organize technical aspects, and conduct pilot trials. The American College of Radiology Imaging Network infrastructure may be suitable for these purposes. There is an extraordinary opportunity for DW-MRI to evolve into a clinically valuable imaging tool, potentially important for drug development.

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Using the amide proton signals of intracellular proteins and peptides to detect pH effects in MRI.

Jinyuan Zhou, Jean-Francois Payen, David A H Wilson … (2003)

In the past decade, it has become possible to use the nuclear (proton, 1H) signal of the hydrogen atoms in water for noninvasive assessment of functional and physiological parameters with magnetic resonance imaging (MRI). Here we show that it is possible to produce pH-sensitive MRI contrast by exploiting the exchange between the hydrogen atoms of water and the amide hydrogen atoms of endogenous mobile cellular proteins and peptides. Although amide proton concentrations are in the millimolar range, we achieved a detection sensitivity of several percent on the water signal (molar concentration). The pH dependence of the signal was calibrated in situ, using phosphorus spectroscopy to determine pH, and proton exchange spectroscopy to measure the amide proton transfer rate. To show the potential of amide proton transfer (APT) contrast for detecting acute stroke, pH effects were noninvasively imaged in ischemic rat brain. This observation opens the possibility of using intrinsic pH contrast, as well as protein- and/or peptide-content contrast, as diagnostic tools in clinical imaging.

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A new class of contrast agents for MRI based on proton chemical exchange dependent saturation transfer (CEST).

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It has been previously shown that intrinsic metabolites can be imaged based on their water proton exchange rates using saturation transfer techniques. The goal of this study was to identify an appropriate chemical exchange site that could be developed for use as an exogenous chemical exchange dependent saturation transfer (CEST) contrast agent under physiological conditions. These agents would function by reducing the water proton signal through a chemical exchange site on the agent via saturation transfer. The ideal chemical exchange site would have a large chemical shift from water. This permits a high exchange rate without approaching the fast exchange limit at physiological pH (6.5-7.6) and temperature (37 degrees C), as well as minimizing problems associated with magnetic field susceptibility. Numerous candidate chemicals (amino acids, sugars, nucleotides, heterocyclic ring chemicals) were evaluated in this preliminary study. Of these, barbituric acid and 5, 6-dihydrouracil were more fully characterized with regard to pH, temperature, and concentration CEST effects. The best chemical exchange site found was the 5.33-ppm indole ring -NH site of 5-hydroxytryptophan. These data demonstrate that a CEST-based exogenous contrast agent for MRI is feasible.

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Author and article information

Journal

Journal ID (nlm-journal-id): 9502015

Journal ID (pubmed-jr-id): 8791

Journal ID (nlm-ta): Nat Med

Title: Nature medicine

ISSN (Print): 1078-8956

ISSN (Electronic): 1546-170X

Publication date Nihms-submitted: 3 September 2010

Publication date (Electronic): 19 December 2010

Publication date (Print): January 2011

Publication date PMC-release: 1 July 2011

Volume: 17

Issue: 1

Pages: 130-134

Affiliations

[1 ]Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

[2 ]F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, Maryland, USA.

[3 ]Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

[4 ]Department of Radiology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.

[5 ]Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

[6 ]Department of Neurology, Kennedy Krieger Institute, Baltimore, Maryland, USA.

[7 ]Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

[8 ]Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Author notes

[* ]Corresponding author: Jinyuan Zhou, Ph.D. Division of MR Research, Department of Radiology Johns Hopkins University School of Medicine 600 N. Wolfe Street, 336 Park Building Baltimore, MD 21287, U.S.A. Phone: (410) 955-7491 Fax: (410) 614-1977 jzhou@ 123456mri.jhu.edu

AUTHOR CONTRIBUTIONS

J.Z. developed the APT methodology, designed and performed most of the MRI experiments, carried out data analysis, prepared figures, wrote the manuscript, and supervised the project. E.T. & E.F. designed and performed the radiation experiments and contributed to manuscript preparation. Z.W. contributed to MRI experimental work and histological analysis, contributed to manuscript preparation, and provided helpful discussions on related clinical issues. B.L. performed experimental work in the tumor models and performed pathology experiments. T.Z. contributed to MRI experimental work, statistical analysis, and manuscript preparation. R.G. & B.T. contributed to experimental work, especially in the tumor models, and manuscript preparation. S.W. contributed to MRI experimental work, performed histological analysis and statistical analysis, prepared some figures, and contributed to manuscript preparation. K.Y. & D.F. contributed to experimental work and data analysis. J.B. & J.L. contributed to experimental design and manuscript preparation and provided helpful discussions on related clinical issues. P.C.M.Z. developed the APT methodology, contributed to experimental design, and edited the manuscript.

Article

Manuscript ID: nihpa233577

DOI: 10.1038/nm.2268

PMC ID: 3058561

PubMed ID: 21170048

SO-VID: c3473b5d-ff69-4c18-89b5-f9deb4192975

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