Role of Amide Proton Transfer (APT)-MRI of Endogenous Proteins and Peptides in Brain Tumor Imaging



Amide proton transfer (APT) imaging is a novel molecular MRI technique that can provide endogenous contrast related to mobile protein content in tissue. The preclinical studies and pilot clinical data have shown initial potential for APT imaging to assess brain tumors, such as differentiating between tumor and peritumoral edema, separating high- from low-grade gliomas, and distinguishing between active tumor and radiation necrosis. In this chapter, we briefly introduce the basic principle of APT imaging and overview its current applications for brain tumor assessment in animal models and in patients.


Apparent Diffusion Coefficient Radiation Necrosis Magnetization Transfer Ratio Chemical Exchange Saturation Transfer Peritumoral Edema 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This study was supported in part by grants from NIH (EB009112, EB009731, EB015032, and RR015241).


  1. 1.
    Kelly PJ, Daumas-Duport C, Kispert DB, Kall BA, Scheithauer BW, Illig JJ. Imaging-based stereotaxic serial biopsies in untreated intracranial glial neoplasms. J Neurosurg. 1987;66(6):865–74.PubMedCrossRefGoogle Scholar
  2. 2.
    Scott JN, Brasher PM, Sevick RJ, Rewcastle NB, Forsyth PA. How often are nonenhancing supratentorial gliomas malignant? A population study. Neurology. 2002;59:947–9.PubMedCrossRefGoogle Scholar
  3. 3.
    Segall HD, Destian S, Nelson MD. CT and MR imaging in malignant gliomas. In: Apuzzo MLJ, editor. Malignant cerebral glioma. Park Ridge, IL: American Association of Neurological Surgeons; 1990. p. 63–78.Google Scholar
  4. 4.
    Knopp EA, Cha S, Johnson G, et al. Glial neoplasms: dynamic contrast-enhanced T2*-weighted MR imaging. Radiology. 1999;211(3):791–8.PubMedGoogle Scholar
  5. 5.
    Hasebroock KM, Serkova NJ. Toxicity of MRI and CT contrast agents. Expert Opin Drug Metab Toxicol. 2009;5(4):403–16.PubMedCrossRefGoogle Scholar
  6. 6.
    Ersoy H, Rybicki FJ. Biochemical safety profiles of gadolinium-based extracellular contrast agents and nephrogenic systemic fibrosis. J Magn Reson Imaging. 2007;26(5):1190–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Zhou J, Payen J, Wilson DA, Traystman RJ, van Zijl PCM. Using the amide proton signals of intracellular proteins and peptides to detect pH effects in MRI. Nat Med. 2003;9:1085–90.PubMedCrossRefGoogle Scholar
  8. 8.
    Zhou J, Lal B, Wilson DA, Laterra J, van Zijl PC. Amide proton transfer (APT) contrast for imaging of brain tumors. Magn Reson Med. 2003;50(6):1120–6.PubMedCrossRefGoogle Scholar
  9. 9.
    Jia G, Abaza R, Williams JD, et al. Amide proton transfer MR imaging of prostate cancer: a preliminary study. J Magn Reson Imaging. 2011;33(3):647–54.PubMedCrossRefGoogle Scholar
  10. 10.
    Jones CK, Schlosser MJ, van Zijl PC, Pomper MG, Golay X, Zhou J. Amide proton transfer imaging of human brain tumors at 3T. Magn Reson Med. 2006;56(3):585–92.PubMedCrossRefGoogle Scholar
  11. 11.
    Wen Z, Hu S, Huang F, et al. MR imaging of high-grade brain tumors using endogenous protein and peptide-based contrast. Neuroimage. 2010;51(2):616–22.PubMedCrossRefGoogle Scholar
  12. 12.
    Zhou J, Blakeley JO, Hua J, et al. Practical data acquisition method for human brain tumor amide proton transfer (APT) imaging. Magn Reson Med. 2008;60(4):842–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Sun PZ, Zhou J, Sun W, Huang J, van Zijl PCM. Detection of the ischemic penumbra using pH-weighted MRI. J Cereb Blood Flow Metab. 2007;27:1129–36.PubMedCrossRefGoogle Scholar
  14. 14.
    Zhao X, Wen Z, Huang F, et al. Saturation power dependence of amide proton transfer image contrasts in human brain tumors and strokes at 3 T. Magn Reson Med. 2011;66:1033–41.PubMedCrossRefGoogle Scholar
  15. 15.
    Forsen S, Hoffman RA. Study of moderately rapid chemical exchange reactions by means of nuclear magnetic double resonance. J Chem Phys. 1963;39:2892–901.CrossRefGoogle Scholar
  16. 16.
    Ward KM, Aletras AH, Balaban RS. A new class of contrast agents for MRI based on proton chemical exchange dependent saturation transfer (CEST). J Magn Reson. 2000;143(1):79–87.PubMedCrossRefGoogle Scholar
  17. 17.
    Sherry AD, Woods M. Chemical exchange saturation transfer contrast agents for magnetic resonance imaging. Annu Rev Biomed Eng. 2008;10:391–411.PubMedCrossRefGoogle Scholar
  18. 18.
    Terreno E, Castelli DD, Aime S. Encoding the frequency dependence in MRI contrast media: the emerging class of CEST agents. Contrast Media Mol Imaging. 2010;5(2):78–98.PubMedGoogle Scholar
  19. 19.
    van Zijl PCM, Yadav NN. Chemical exchange saturation transfer (CEST): what is in a name and what isn’t? Magn Reson Med. 2011;65:927–48.PubMedCrossRefGoogle Scholar
  20. 20.
    Zhou J, van Zijl PC. Chemical exchange saturation transfer imaging and spectroscopy. Prog NMR Spectsc. 2006;48:109–36.CrossRefGoogle Scholar
  21. 21.
    Hua J, Jones CK, Blakeley J, Smith SA, van Zijl PC, Zhou J. Quantitative description of the asymmetry in magnetization transfer effects around the water resonance in the human brain. Magn Reson Med. 2007;58(4):786–93.PubMedCrossRefGoogle Scholar
  22. 22.
    Goplen D, Wang J, Enger PO, et al. Protein disulfide isomerase expression is related to the invasive properties of malignant glioma. Cancer Res. 2006;66(20): 9895–902.PubMedCrossRefGoogle Scholar
  23. 23.
    Niclou SP, Fack F, Rajcevic U. Glioma proteomics: status and perspectives. J Proteomics. 2010;73(10):1823–38.PubMedCrossRefGoogle Scholar
  24. 24.
    Salhotra A, Lal B, Laterra J, Sun PZ, van Zijl PCM, Zhou J. Amide proton transfer imaging of 9L gliosarcoma and human glioblastoma xenografts. NMR Biomed. 2008;21:489–97.PubMedCrossRefGoogle Scholar
  25. 25.
    Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987–96.PubMedCrossRefGoogle Scholar
  26. 26.
    Maier SE, Sun Y, Mulkern RV. Diffusion imaging of brain tumors. NMR Biomed. 2010;23(7):849–64.PubMedCrossRefGoogle Scholar
  27. 27.
    Wippold 2nd FJ, Lammle M, Anatelli F, Lennerz J, Perry A. Neuropathology for the neuroradiologist: palisades and pseudopalisades. AJNR Am J Neuroradiol. 2006;27(10):2037–41.PubMedGoogle Scholar
  28. 28.
    Xu Z, Marko NF, Angelov L, et al. Impact of preexisting tumor necrosis on the efficacy of stereotactic radiosurgery in the treatment of brain metastases in women with breast cancer. Cancer. 2011;118(5): 1323–33.PubMedCrossRefGoogle Scholar
  29. 29.
    Kumar AJ, Leeds NE, Fuller GN, et al. Malignant gliomas: MR imaging spectrum of radiation therapy- and chemotherapy-induced necrosis of the brain after treatment. Radiology. 2000;217(2):377–84.PubMedGoogle Scholar
  30. 30.
    Brandsma D, Stalpers L, Taal W, Sminia P, van den Bent MJ. Clinical features, mechanisms, and management of pseudoprogression in malignant gliomas. Lancet Oncol. 2008;9(5):453–61.PubMedCrossRefGoogle Scholar
  31. 31.
    Yaman E, Buyukberber S, Benekli M, et al. Radiation induced early necrosis in patients with malignant gliomas receiving temozolomide. Clin Neurol Neurosurg. 2010;112(8):662–7.PubMedCrossRefGoogle Scholar
  32. 32.
    Graves EE, Nelson SJ, Vigneron DB, et al. Serial proton MR spectroscopic imaging of recurrent malignant gliomas after gamma knife radiosurgery. AJNR Am J Neuroradiol. 2001;22:613–24.PubMedGoogle Scholar
  33. 33.
    Sugahara T, Korogi Y, Tomiguchi S, et al. Posttherapeutic intraaxial brain tumor: The value of perfusion-sensitive contrast-enhanced MR imaging for differentiating tumor recurrence from nonneoplastic contrast-enhancing tissue. AJNR Am J Neuroradiol. 2000;21:901–9.PubMedGoogle Scholar
  34. 34.
    Galban CJ, Chenevert TL, Meyer CR, et al. The parametric response map is an imaging biomarker for early cancer treatment outcome. Nat Med. 2009;15: 572–6.PubMedCrossRefGoogle Scholar
  35. 35.
    Wang S, Chen Y, Lal B, et al. Evaluation of radiation necrosis and malignant glioma in rat models using diffusion tensor MR imaging. J Neurooncol. 2011;107(1):51–60. doi: 10.1007/s11060-011-0719-x.PubMedCrossRefGoogle Scholar
  36. 36.
    Yang I, Aghi MK. New advances that enable identification of glioblastoma recurrence. Nat Rev Clin Oncol. 2009;6:648–57.PubMedCrossRefGoogle Scholar
  37. 37.
    Wang SL, Wu EX, Qiu DQ, Leung LHT, Lau HF, Khong PL. Longitudinal diffusion tensor magnetic resonance imaging study of radiation-induced white matter damage in a rat model. Cancer Res. 2009;69:1190–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Burger PC, Dubois PJ, Schold Jr SC, et al. Computerized tomographic and pathologic studies of the untreated, quiescent, and recurrent glioblastoma multiforme. J Neurosurg. 1983;58(2):159–69.PubMedCrossRefGoogle Scholar
  39. 39.
    Howe FA, Barton SJ, Cudlip SA, et al. Metabolic profiles of human brain tumors using quantitative in vivo 1H magnetic resonance spectroscopy. Magn Reson Med. 2003;49(2):223–32.PubMedCrossRefGoogle Scholar
  40. 40.
    Hobbs SK, Shi G, Homer R, Harsh G, Atlas SW, Bednarski MD. Magnetic resonance image-guided proteomics of human glioblastoma multiforme. J Magn Reson Imaging. 2003;18(5):530–6.PubMedCrossRefGoogle Scholar
  41. 41.
    Zhou J, Tryggestad E, Wen Z, et al. Differentiation between glioma and radiation necrosis using molecular magnetic resonance imaging of endogenous proteins and peptides. Nat Med. 2011;17(1):130–4.PubMedCrossRefGoogle Scholar
  42. 42.
    Wong J, Armour E, Kazanzides P, et al. High-resolution, small animal radiation research platform with X-ray tomographic guidance capabilities. Int J Radiant Oncol Biol Phys. 2008;71:1591–9.CrossRefGoogle Scholar
  43. 43.
    Macdonald DR, Cascino TL, Schold Jr SC, Cairncross JG. Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol. 1990;8(7):1277–80.PubMedGoogle Scholar
  44. 44.
    Jones CK, Polders D, Hua J, et al. In vivo 3D whole-brain pulsed steady state chemical exchange saturation transfer at 7T. Magn Reson Med. 2012;67(6):1579–89.PubMedCrossRefGoogle Scholar
  45. 45.
    Zhu H, Jones CK, van Zijl PC, Barker PB, Zhou J. Fast 3D chemical exchange saturation transfer (CEST) imaging of the human brain. Magn Reson Med. 2010;64(3):638–44.PubMedCrossRefGoogle Scholar
  46. 46.
    Keupp J, Baltes C, Harvey PR, van den Brink J. Parallel RF transmission based MRI technique for highly sensitive detection of amide proton transfer in the human brain. Paper presented at: Proceedings of the 19th annual meeting ISMRM 2011; Montreal.Google Scholar
  47. 47.
    Mougin OE, Coxon RC, Pitiot A, Gowland PA. Magnetization transfer phenomenon in the human brain at 7 T. Neuroimage. 2010;49(1):272–81.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of RadiologyJohns Hopkins University School of MedicineBaltimoreUSA
  2. 2.F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger InstituteBaltimoreUSA

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