Amide Proton Transfer (APT) weighted imaging is an emerging MRI method that generates image contrast different from conventional MRI. APT weighted imaging is a chemical exchange saturation transfer (CEST) MRI method and its signal is based on the concentration of endogenous proteins and peptides typically present in high-grade brain tumor tissue. Therefore, APT weighted imaging does not require any contrast agent administration.
Physicians at Phoenix Children’s Hospital (PCH) have been studying the value of APT in clinical practice to investigate to what extent APT weighted imaging could be used in the diagnostic and post-therapy imaging of children with brain tumors. Their results suggest APT weighted imaging has the potential to provide higher confidence in determining both the grade of tumor and the extent of residual tumor post-surgery. Many treatment pathways rely on accurate determination of the aggressiveness or “grade” of tumors for the optimal selection amongst treatment options to offer the best possible care choice for patients.
MRI is widely used for visualizing primary brain tumors and secondary lesions in oncology patients. Its excellent soft tissue contrast and functional imaging provide radiologists information on the location, size, morphology, composition and physiology of lesions to help them in diagnosing and staging. Still, there are cases where radiologists would like to have additional capabilities for their diagnosis, for instance in distinguishing high-grade and low-grade tumors with more confidence and ultimately for performing the numerous follow-up MRI exams without contrast administration in children after brain tumor resection.
In the United States alone, nearly 80,000 new cases of primary brain tumor are expected to be diagnosed in 2017, including more than 26,000 primary malignant brain tumors.[1] Gliomas represent 75% of all malignant tumors, and 55% of these are glioblastoma with 12,930 cases predicted for 2017.[1,2]
Given that incidence, and the impact of the correct diagnosis and appropriate treatment paths, oncologists and radiologists weclome
In APT weighted imaging and other CEST methods, the MRI signal is generated by a mechanism different from that of basic MRI. These CEST techniques are based on the chemical exchange of hydrogen atoms. The signal of amide protons of peptide bonds in proteins is too low to be measured in normal MRI. The hydrogen (proton) exchange between protein amide groups and surrounding water allows a different way to measure these amide protons.
In APT a narrow RF prepulse (saturation pulse) at the amide hydrogen’s frequency is given to attenuate its MR signal. Because the amide group and water continually exchange hydrogen atoms, the number of saturated protons will build up in water, so that the measured water signal will become lower. The change of the MRI signal of water provides an indirect way to measure the presence of amide. APT images are usually presented as color maps, created by using an asymmetry calculation so that presence of APT is shown as a positive colored signal.
Tumor grading can affect critical decision making
The choice of treatment paths often strongly depends on the tumor grade. Common treatment options for high-grade tumors include surgical tumor resection followed by additional therapy such as radiation and or chemotherapy. Quick and decisive action is desirable in these cases as median survival for glioblastoma, for instance, is between 12.6 and 14.6 months, although longer rates have been reported.[8,9]
Given the lower tumor growth rate of low-grade tumors, a range of potential treatment options exist for these cases. The selection of the most appropriate treatment is based on the balance of therapeutic benefits and side effects. At times, surveillance imaging may play a role while the choices of definitive therapy are being considered.[10]
MR imaging is often used by radiologists and physicians in estimating the grade of brain tumors, but there is sometimes still uncertainty.[9,11] Differentiating between low-grade and high-grade tumors is not straightforward, even for the highly experienced radiologist. Gadolinium enhancement is not always specific for tumor grade, as some high-grade tumors demonstrate no gadolinium enhancement and certain low-grade tumors occasionally enhance (e.g. DNET). Gadolinium enhancement also occurs in any area of a blood-brain barrier disruption, such as treatment-related injury.[12]
The power of APT for grading brain tumors with MRI
While the gold standard for grading of gliomas is histopathology after biopsy, MRI is often used in monitoring glioma patients, and APT can be a valuable addition to the MRI exam in these patients.
Tumor grade and APT signal have been observed to be commonly positively correlated: high-grade tumors tend to exhibit a high APT contrast.[12-15] APT images can be seen to visualize tumor with more emphasis than post-contrast images, resulting in a scan that may be easier to interpret. Scientific studies comparing tumor grades with APT signal in adult glioma suggest that APT can support tumor grading, separating high-grade from low-grade, even when traditional MRI is inconclusive.[5,13,14]
Dr. Jeffrey Miller, pediatric radiologist at PCH also noticed the relation between APT contrast and tumor grades in the studies done at his hospital. “In several cases we have seen a high APT signal in high-grade tumors and moderately increased APT signal in cases with intermediate and low-grade tumors that have the characteristic of high signal change on T2 and FLAIR, and no contrast enhancement.”
He points out the potential clinical implications of this observation. “When we’re faced with patients where the diagnosis is a little bit ambiguous, we often have to make choices and value judgements, which could mean either just following up the tumor or lesion, with the risk that it could change when we were wrong and there could be time lost. Or we have to go into invasive situations where we have to biopsy.”
“It would be very impactful and valuable to have a sequence like APT weighted imaging, which could assist us in making those decisions with more confidence. That would be meaningful for the individual patients and take out some ambiguity in what we are doing.”
“However, in order to reach that lofty goal, we will need more investigation, use the sequence in a larger population, and gain more understanding of situations and conditions where APT has its maximal value.”
MRI may be performed after tumor resection, to look for residual tumor or tumor regrowth. Also here, the different contrast mechanism of APT may help in diagnosis. Dr. Miller remembers a particular case.
“After a very good resection, we saw small changes on the postcontrast T1-weighted and the T2-weighted images that looked like a post-surgical little bit of fluid. Interestingly, however, we saw a focal area of APT signal, right in the center of that abnormality. As we usually do when a bit unsure, we followed it up and, unfortunately, found tumor regrowth in that region,” Dr. Miller says. “Cases like this motivate me, and others who care about this population, to investigate how this APT method could be used on large scale in this population and help us in providing high value diagnostic information.”
The hospital’s physicians also saw a case where APT had a negative predictive value. Following the resection of a highgrade tumor, they saw a similar small change in the images of this patient. However in this case, the APT signal was rather low. In a recent rescanning of this patient, no recurrence was seen.
1. American Brain Tumor Association, Brain Tumor Statistics.
2. Central Brain Tumor Registry of the United States, 2016 CBTRUS Fact Sheet.
3. Togao O, Hiwatashi A, Keupp J, Yamashita K, Kikuchi K, Yoshiura T, Yoneyama M, Kruiskamp MJ, Sagiyama K, Takahashi M, Honda H. Amide Proton Transfer Imaging of Diffuse Gliomas: Effect of Saturation Pulse Length in Parallel Transmission-Based Technique. PLOS ONE 2016; doi: 10.1371/journal.pone.0155925.
4. Togao O, Keupp J, Hiwatashi A, Yamashita K, Kikuchi K, Yoneyama M, Honda H. Amide Proton Transfer Imaging of Brain Tumors Using a Self-Corrected 3D Fast Spin-Echo Dixon Method: Comparison with Separate B0 correction Magn Res Med 2016 early view; doi: 10.1002/mrm.26322.
5. Togao O, Yoshiura T, Keupp J, Hiwatashi A, Yamashita K, Kikuchi K, Suzuki, YS, Iwak, T, Hata N, Mizoguchi M, Yoshimoto K, Sagiyama K, Takahashi M, Honda H Amide proton transfer imaging of adult diffuse gliomas: correlation with histopathological grades. Neuro-Oncology 2014; 16(3), 441–448.
6. Jiang S, Eberhart CG, Zhang Y, Heo HY, Wen Z, Blair L, Qin H, Lim M, Quinones- Hinojosa A6, Weingart JD, Barker PB, Pomper MG, Laterra J, van Zijl PCM, Blakeley JO, Zhou J. Amide proton transfer-weighted magnetic resonance image-guided stereotactic biopsy in patients with newly diagnosed gliomas. Eur J Cancer 201783:9-18; doi: 10.1016/j.ejca.2017.06.009.
7. Zhou, J. (2011). Amide Proton Transfer Imaging of the Human Brain. Magnetic Resonance Neuroimaging. Methods in Molecular Biology (Clifton, N.J.), 711, 227–237.
8. American Brain Tumor Association, Brain Tumor Information, Types of Tumors, Glioblastoma (GBM)
9. Lobera, A, Coobs, B, Naul, LG, Zee, CS. Imaging in Glioblastoma Multiforme. Medscape.
10. Paleologos, N. Low Grade Glioma: Update in Treatment and Care. ABTA Patient and Family Conference, 2014.
11. Upadhyay, N, Waldman, A D, Conventional MRI evaluation of gliomas. The British Journal of Radiology 2011; 84: S107–S111.
12. Wen, Z, Hu, S, Huang, F, Wang, X, Guo, L, Quan, X, Wang, S, Zhou, J, MR Imaging of High-Grade Brain Tumors Using Endogenous Protein and Peptide- Based Contrast. NeuroImage 20110; 51(2), 616–622.
13. Park KJ, Kim HS, Park JE et al. 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; doi: 10.1007/s00330- 016-4261-2.
14. 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 2016, 278 :514; doi: 10.1148/ radiol.2015142979.
15. Wang X, Yu H, Jiang S, Wang Y, Wang Y, Zhang G, Jiang C, Song G, Zhang Y, Heo H-Y, Zhou J, Wen Z. Qualitative and quantitative analysis of amide proton transferweighted MR images at 3 Tesla of adult gliomas. Abstract #1105, ISMRM 2017.
16. Miller JH, Hu HH, Pokorney A, Cornejo P, Towbin R. MRI Brain Signal Intensity Changes of a Child During the Course of 35 Gadolinium Contrast Examinations. Pediatrics 2015;136;e1637.
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