Despite recent advances in surgery, radiation, and chemotherapy, malignant gliomas remain universally fatal, with a median survival of 12-15 months for glioblastoma and 2-5 years for anaplastic astrocytoma. Limitations in neuroimaging complicate the clinical management of patients with gliomas, and impede efficient testing of new therapeutics. Amide proton transfer (APT) imaging is a novel molecular MRI technique that generates image contrast based on the endogenous cellular proteins in tissue. This APT imaging project has been extremely successful during the first grant period (7/09-4/13). We developed several relatively fast three- dimensional APT imaging sequences at 3T and 7T and established several effective image acquisition protocols and image processing approaches for imaging of human brain tumors. In addition, we demonstrated that APT imaging is a highly valuable addition to the MRI armamentarium for the more specific characterization of human brain tumors. Notably, our preclinical study in various glioma models and models of radiation- induced necrosis in rats clearly showed that active glioma (hyperintense) and radiation necrosis (hypointense or isointense) exhibited opposite APT-MRI signals, and could thus readily be distinguished. These preclinical results are exciting, and, if validated with appropriately powered studies in patients, the implications for clinical care and experimental therapeutics will be enormous. The ultimate goal for APT imaging is its standard use in a clinical setting on a variety of MRI systems from different vendors. However, clinical APT-MRI experiments are often limited by scanner hardware constraints (particularly amplifier duty cycle and pulse length) and specific absorption rate (SAR) requirements. Therefore, current APT imaging protocols vary substantially among different institutes, far from being optimized, and the results acquired from different research centers are difficult to compare to one another. The overall goals of this renewal application are to refine this important protein-based molecular MRI technology into a sensitive, user-friendly, and clinically reproducible approach and to demonstrate its potential to help resolve several diagnostic dilemmas in brain cancer therapy. Based on the results obtained in the previous grant period and recent progress in the field, we have designed the following three specific aims: (1) implement and optimize the parallel RF transmission (pTX)-based APT-MRI technique at 3T;(2) evaluate the clinical value of APT-MRI in identifying non-Gd-enhancing high-grade gliomas;and (3) quantify the accuracy of APT-MRI in distinguishing pseudoprogression from true tumor progression in GBM treated with chemoradiation therapy. If this step of the APT investigation is successful, this research will provide the optimized approaches and critical sensitivity and specificity data required to translate this important APT-MRI technology into the clinic.

Public Health Relevance

This renewal project aims to refine the novel protein-based amide proton transfer (APT) imaging technology into a sensitive and highly reproducible approach and to evaluate the ultimate potential of this important MRI technique for the noninvasive molecular diagnosis of malignant brain tumors before and after treatment. The evaluation will address some major diagnostic dilemmas in the management of patients with brain cancer. If successful, the research will significantly improve the accuracy of tissue sampling and response assessment for patients with malignant brain tumors, directly and rapidly impacting patient care.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Liu, Guoying
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
Schools of Medicine
United States
Zip Code
Jiang, Shanshan; Yu, Hao; Wang, Xianlong et al. (2016) Molecular MRI differentiation between primary central nervous system lymphomas and high-grade gliomas using endogenous protein-based amide proton transfer MR imaging at 3 Tesla. Eur Radiol 26:64-71
Zhang, Yi; Heo, Hye-Young; Lee, Dong-Hoon et al. (2016) Selecting the reference image for registration of CEST series. J Magn Reson Imaging 43:756-61
Heo, Hye-Young; Lee, Dong-Hoon; Zhang, Yi et al. (2016) Insight into the quantitative metrics of chemical exchange saturation transfer (CEST) imaging. Magn Reson Med :
Ma, Bo; Blakeley, Jaishri O; Hong, Xiaohua et al. (2016) Applying amide proton transfer-weighted MRI to distinguish pseudoprogression from true progression in malignant gliomas. J Magn Reson Imaging 44:456-62
Lee, Dong-Hoon; Heo, Hye-Young; Zhang, Kai et al. (2016) Quantitative assessment of the effects of water proton concentration and water T1 changes on amide proton transfer (APT) and nuclear overhauser enhancement (NOE) MRI: The origin of the APT imaging signal in brain tumor. Magn Reson Med :
Heo, Hye-Young; Zhang, Yi; Jiang, Shanshan et al. (2016) Quantitative assessment of amide proton transfer (APT) and nuclear overhauser enhancement (NOE) imaging with extrapolated semisolid magnetization transfer reference (EMR) signals: II. Comparison of three EMR models and application to human brain glioma at Magn Reson Med 75:1630-9
Yu, Yang; Lee, Dong-Hoon; Peng, Shin-Lei et al. (2016) Assessment of Glioma Response to Radiotherapy Using Multiple MRI Biomarkers with Manual and Semiautomated Segmentation Algorithms. J Neuroimaging 26:626-634
Deng, Min; Chen, Shu-Zhong; Yuan, Jing et al. (2016) Chemical Exchange Saturation Transfer (CEST) MR Technique for Liver Imaging at 3.0 Tesla: an Evaluation of Different Offset Number and an After-Meal and Over-Night-Fast Comparison. Mol Imaging Biol 18:274-82
Heo, Hye-Young; Zhang, Yi; Lee, Dong-Hoon et al. (2016) Accelerating chemical exchange saturation transfer (CEST) MRI by combining compressed sensing and sensitivity encoding techniques. Magn Reson Med :
Zhang, Yi; Heo, Hye-Young; Lee, Dong-Hoon et al. (2016) Chemical exchange saturation transfer (CEST) imaging with fast variably-accelerated sensitivity encoding (vSENSE). Magn Reson Med :

Showing the most recent 10 out of 49 publications