Integrated Approach of Amide Proton Transfer Imaging in the Assessment of Brain Tumors: Basic Concepts and Current Use
Molecular imaging using endogenous molecules has always generated interest because the methodology does not have the adverse effects of gadolinium (Gd) contrast agents and has clinical benefits for pediatric patients or patients with a contraindication to an exogenous contrast agent. Amide proton transfer (APT) imaging is gaining attention as a relatively new in vivo molecular imaging technique that has higher sensitivity and spatial resolution than magnetic resonance spectroscopy imaging. APT imaging is a subset of the chemical exchange saturation transfer (CEST) mechanism, which can offer unique image contrast by selectively saturating protons in target molecules exchanged with protons in bulk water.
APT imaging has been applied to brain tumor imaging in both experimental and clinical studies. It has been used in diverse applications to evaluate brain tumors: characterizing a tumor and its differential diagnosis, tumor grading as an index for tumor proliferation, and treatment monitoring.
1. Differential Diagnosis from Mimics
A differential diagnosis between necrotic, contrast-enhancing, low-grade tumors and high-grade tumors is often difficult when using contrast-enhanced or advanced imaging with perfusion or diffusion-weighted imaging. Because a high-grade tumor has higher APT asymmetry from its accelerated cell proliferation-derived high protein content, APT imaging can be used to differentiate a low-grade tumor mimicking a high-grade tumor. In a previous study including 19 low-grade tumors (i.e., three astrocytomas, seven oligodendrogliomas, three pleomorphic xanthoastrocytomas, four pilocytic astrocytomas, and two hemangioblastomas), APT asymmetry was found to be significantly higher in high-grade tumors than in low-grade ones (1).
2. Proliferative Index and Tumor Grading
Since high-grade tumors show accelerated cell proliferation and increased protein expression compared to low-grade tumors, APT imaging that indirectly reflects protein content may be suitable for tumor grading (2). Other advanced MR imaging techniques used for patients with brain gliomas (i.e., contrast enhancement, diffusion-weighted, and perfusion-weighted imaging) are insufficient for tumor grading. A recent study (3) showed that APT imaging had a linear positive correlation with the pathologic tissue proliferative index (Ki-67) (R = 0.43, P = 0.01) and cell density (R = 0.38, P < 0.05).
3. Therapeutic Monitoring
Identifying an imaging biomarker that reflects a therapeutic response is clinically important to determine whether to discontinue current treatment and/or to initiate other treatment options. The first experimental study of APT for therapeutic monitoring of glioblastoma (4) was demonstrated for quantitative assessment of treatment response during chemotherapy. One course of temozolomide (TMZ 80 mg/kg i.p. for three days) was applied to a tumor mouse model, and APT asymmetry was measured before and after treatment with a one-week interval. APT asymmetry was decreased in the treated groups but increased in the control group. Interestingly, although there were no detectable differences in tumor volume, cell density, and apoptosis rate between the two groups, the cellular proliferative index (Ki-67) levels were substantially reduced in the treated tumors. The correlation between Ki-67 and APT asymmetry indicates that APT imaging may serve as a sensitive biomarker of an early treatment response. This is particularly important in neuro-oncologic imaging where a treatment-related reaction known as “pseudoprogression” often results in an increase in the contrast-enhancing lesion.
4. Future Use for Oncolytic Virotherapy
Oncolytic virotherapy for brain tumors is currently in phase I clinical trials. Oncolytic viruses have the potential to improve the treatment of incurable cancers (5) such as glioblastoma. The delivery of replicating oncolytic viruses has been difficult to image, but a recent experimental study showed the potential use of APT imaging on a 9.4-T magnet as a tool to visualize replicating oncolytic viruses (5). The MTR asymmetry was calculated for a frequency offset of 3.6 ppm for lysine-rich protein (LRP, which contains an exchangeable amide proton). Before and after oncolytic virotherapy (within 8-10 hours after injection), a significant increase in tumor APT asymmetry was observed for LRP containing virus-infected tumors but not for LRP empty virus-infected tumors (P = 0.02; Fig 7). The ability to noninvasively image on oncolytic viruses at the acute stage of infection could be useful in the development of a future targeted therapy (5, 6).
In this lecture, I will introduce integrated approach of APT imaging for brain tumors, particularly with regard to the benefit in clinics. Clinical applications for APT imaging are described from two perspectives: in the diagnosis and monitoring of the treatment response in brain glioma by reflecting endogenous mobile proteins and peptides, and its adjunctive role to current MR or PET imaging sequences.
Ho Sung Kim, M.D., Ph.D.
Ha-Kyu Jeong, Ph.D.
Jochen Keupp, Ph.D.
1. Park JE, Kim HS, Park KJ, Choi CG, Kim SJ. Histogram Analysis of Amide Proton Transfer Imaging to Identify Contrast-enhancing Low-Grade Brain Tumor That Mimics High-Grade Tumor: Increased Accuracy of MR Perfusion. Radiology 2015;277:151-161
2. 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;16:441-448 3. Park JE, Kim HS, Park KJ, Kim SJ, Kim JH, Smith SA. Pre- and Posttreatment Glioma: Comparison of Amide Proton Transfer Imaging with MR Spectroscopy for Biomarkers of Tumor Proliferation. Radiology 2015:142979
4. Sagiyama K, Mashimo T, Togao O, Vemireddy V, Hatanpaa KJ, Maher EA, et al. In vivo Chemical exchange saturation transfer imaging allows early detection of a therapeutic response in glioblastoma. Proc Natl Acad Sci U S A 2014;111:4542-4547
5. Farrar CT, Buhrman JS, Liu G, Kleijn A, Lamfers ML, McMahon MT, et al. Establishing the Lysine-rich Protein CEST Reporter Gene as a CEST MR Imaging Detector for Oncolytic Virotherapy. Radiology 2015;275:746-754
6. Choyke PL. Science to Practice: Monitoring Oncolytic Virus Therapy with Chemical Exchange Saturation Transfer MR Imaging--Wishful Thinking? Radiology 2015;275:625-626