Amide Proton Transfer Imaging in the Central Nervous System: Recent Advances and Clinical Applications

Weiwei Wang; Hongjun Jiang; Ning Wang; Chao Yang; Yanwei Miao

doi:10.71321/xzrpzs21

Authors

Weiwei Wang The First Affiliated Hospital of Dalian Medical University
Hongjun Jiang The First Affiliated Hospital of Dalian Medical University
Ning Wang The First Affiliated Hospital of Dalian Medical University
Chao Yang The First Affiliated Hospital of Dalian Medical University
Yanwei Miao The First Affiliated Hospital of Dalian Medical University

DOI:

https://doi.org/10.71321/xzrpzs21

Keywords:

Amide proton transfer (APT), chemical exchange saturation transfer (CEST), magnetic resonance molecular imaging, central nervous system (CNS), brain tumor, cerebral infarction, neurodegenerative disease

Abstract

Amide proton transfer (APT) imaging, as a novel magnetic resonance molecular imaging technique based on the chemical exchange saturation transfer (CEST) effect, indirectly reflects molecular-level information such as tissue protein concentration, pH, and microenvironment by detecting the exchange between intracellular free water and amide protons in proteins/peptides. Since it was first proposed by Professor Jinyuan Zhou in 2003, the technique has achieved significant progress in theoretical modeling, sequence optimization, and clinical translation, particularly in its expanding application to central nervous system diseases. In recent years, APT has been widely used for tumor grading, stroke staging, early identification of hypoxic-ischemic encephalopathy (HIE), and pathological tracking of neurodegenerative diseases. This review systematically summarizes the principles and advantages of APT imaging, with a focus on its recent applications in brain tumors, cerebral infarction, and neurodegenerative diseases. It also discusses signal variation characteristics and underlying mechanisms in different disease states, as well as current clinical applications and technical challenges.
Keywords: Amide proton transfer (APT); chemical exchange saturation transfer (CEST); magnetic resonance molecular imaging; central nervous system (CNS); brain tumor; cerebral infarction; neurodegenerative disease

References

[1] Zhou J, Payen JF, Wilson DA, Traystman RJ, van Zijl PC. Using the amide proton signals of intracellular proteins and peptides to detect pH effects in MRI. Nat Med. 2003;9(8):1085-90. https://doi.org/10.1038/nm907.

[2] 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. https://doi.org/ 10.1002/mrm.10651.

[3] Kulanthaivelu K, Jabeen S, Saini J, Raju S, Nalini A, Sadashiva N, et al. Amide proton transfer imaging for differentiation of tuberculomas from high-grade gliomas: Preliminary experience. Neuroradiol J. 2021;34(5):440-448. https://doi.org/10.1177/19714009211002766.

[4] Mu R, Qin X, Zheng W, Yang P, Huang B, Li X, et al. Amide proton transfer could be a surrogate imaging marker for predicting vascular cognitive impairment. Brain Res Bull. 2023;204:110793. https://doi.org/10.1016/j.brainresbull.2023.110793.

[5] Essed RA, Prysiazhniuk Y, Wamelink IJ, Azizova A, Keil VC. Performance of amide proton transfer imaging to differentiate true progression from therapy-related changes in gliomas and metastases. Eur Radiol. 2025;35(2):580-591. https://doi.org/10.1007/s00330-024-11004-y.

[6] Zhou J, Zaiss M, Knutsson L, Sun PZ, Ahn SS, Aime S, et al. Review and consensus recommendations on clinical APT-weighted imaging approaches at 3T: Application to brain tumors. Magn Reson Med. 2022;88(2):546-574. https://doi.org/10.1002/mrm.29241.

[7] Zhou J, Zhu H, Lim M, Blair L, Quinones-Hinojosa A, Messina SA, et al. Three-dimensional amide proton transfer MR imaging of gliomas: Initial experience and comparison with gadolinium enhancement. J Magn Reson Imaging. 2013;38(5):1119-28.https://doi.org/10.1002/jmri.24067.

[8] Togao O, Hiwatashi A, Yamashita K, Kikuchi K, Keupp J, Yoshimoto K, et al. Grading diffuse gliomas without intense contrast enhancement by amide proton transfer MR imaging: comparisons with diffusion- and perfusion-weighted imaging. Eur Radiol. 2017;27(2):578-588. https://doi.org/10.1007/s00330-016-4328-0.

[9] Borges de Almeida G, Pascuzzo R, Mambrin F, Aquino D, Verri M, Moscatelli M, et al. The Role of Amide Proton Transfer (APT)-Weighted Imaging in Glioma: Assessment of Tumor Grading, Molecular Profile and Survival in Different Tumor Components. Cancers (Basel). 2024;16(17):3014. https://doi.org/10.3390/cancers16173014.

[10] Joo B, Han K, Ahn SS, Choi YS, Chang JH, Kang SG, et al. Amide proton transfer imaging might predict survival and IDH mutation status in high-grade glioma. Eur Radiol. 2019;29(12):6643-6652. https://doi.org/10.1007/s00330-019-06203-x.

[11] Paech D, Dreher C, Regnery S, Meissner JE, Goerke S, Windschuh J, et al. Relaxation-compensated amide proton transfer (APT) MRI signal intensity is associated with survival and progression in high-grade glioma patients. Eur Radiol. 2019;29(9):4957-4967. https://doi.org/10.1007/s00330-019-06066-2.

[12] Wu M, Jiang T, Guo M, Duan Y, Zhuo Z, Weng J, et al. Amide proton transfer-weighted imaging and derived radiomics in the classification of adult-type diffuse gliomas. Eur Radiol. 2023;34(5):2986-2996. https://doi.org/10.1007/s00330-023-10343-6.

[13] Liang HX, Wang ZY, Li Y, Ren AN, Chen ZF, Wang XZ, et al. The application value of support vector machine model based on multimodal MRI in predicting IDH-1mutation and Ki-67 expression in glioma. BMC Med Imaging. 2024;24(1):244.https://doi.org/10.1186/s12880-024-01414-1.

[14] Koike H, Morikawa M, Ishimaru H, Ideguchi R, Uetani M, Hiu T, et al. Amide proton transfer MRI differentiates between progressive multifocal leukoencephalopathy and malignant brain tumors: a pilot study. BMC Med Imaging. 2022;22(1):227. https://doi.org/10.1186/s12880-022-00959-3.

[15] Huang Q, Wu J, Le N, Shen Y, Guo P, Schreck KC, et al. CEST2022: Amide proton transfer-weighted MRI improves the diagnostic performance of multiparametric non-contrast-enhanced MRI techniques in patients with post-treatment high-grade gliomas. Magn Reson Imaging. 2023;102:222-228. https://doi.org/10.1016/j.mri.2023.06.003.

[16] Jiang S, Guo P, Heo HY, Zhang Y, Wu J, Jin Y, et al. Radiomics analysis of amide proton transfer-weighted and structural MR images for treatment response assessment in malignant gliomas. NMR Biomed. 2023;36(1):e4824. https://doi.org/10.1002/nbm.4824.

[17] Hou H, Diao Y, Yu J, Xu M, Wang L, Li Z, et al. Differentiation of true progression from treatment response in high-grade glioma treated with chemoradiation: a comparison study of 3D-APTW and 3D-PcASL imaging and DWI. NMR Biomed. 2023;36(1):e4821. https://doi.org/10.1002/nbm.4821.

[18] Guo P, Unberath M, Heo HY, Eberhart CG, Lim M, Blakeley JO, et al. Learning-based analysis of amide proton transfer-weighted MRI to identify true progression in glioma patients. Neuroimage Clin. 2022;35:103121. https://doi.org/10.1016/j.nicl.2022.103121.

[19] Chen K, Jiang XW, Deng LJ, She HL. Differentiation between glioma recurrence and treatment effects using amide proton transfer imaging: A mini-Bayesian bivariate meta-analysis. Front Oncol. 2022;12:852076. https://doi.org/10.3389/fonc.2022.852076.

[20] Jiang S, Eberhart CG, Zhang Y, Heo HY, Wen Z, Blair L, et al. Amide proton transfer-weighted magnetic resonance image-guided stereotactic biopsy in patients with newly diagnosed gliomas. Eur J Cancer. 2017;83:9-18. https://doi.org/10.1016/j.ejca.2017.06.009.

[21] Jin T, Wang J, Chung J, Hitchens TK, Sun D, Mettenburg J, et al. Amide proton transfer MRI at 9.4 T for differentiating tissue acidosis in a rodent model of ischemic stroke. Magn Reson Med. 2024;92(5):2140-2148. https://doi.org/10.1002/mrm.30194.

[22] Heo HY, Zhang Y, Burton TM, Jiang S, Zhao Y, van Zijl PCM, et al. Improving the detection sensitivity of pH-weighted amide proton transfer MRI in acute stroke patients using extrapolated semisolid magnetization transfer reference signals. Magn Reson Med. 2017;78(3):871-880. https://doi.org/10.1002/mrm.26799.

[23] Heo HY, Tee YK, Harston G, Leigh R, Chappell MA. Amide proton transfer imaging in stroke. NMR Biomed. 2023;36(6):e4734. https://doi.org/10.1002/nbm.4734.

[24] Song G, Li C, Luo X, Zhao X, Zhang S, Zhang Y, et al. Evolution of Cerebral Ischemia Assessed by Amide Proton Transfer-Weighted MRI. Front Neurol. 2017;8:67. https://doi.org/10.3389/fneur.2017.00067.

[25] Momosaka D, Togao O, Kikuchi K, Kikuchi Y, Wakisaka Y, Hiwatashi A. Correlations of amide proton transfer-weighted MRI of cerebral infarction with clinico-radiological findings. PLoS One. 2020;15(8):e0237358. https://doi.org/10.1371/journal.pone.0237358.

[26] Zhou L, Pan W, Huang R, Wang T, Wei Z, Wang H, et al. Amide Proton Transfer-Weighted MRI, Associations with Clinical Severity and Prognosis in Ischemic Strokes. J Magn Reson Imaging. 2024;60(6):2509-2517. https://doi.org/10.1002/jmri.29333.

[27] Zhang C, Yong X, Cao Y, Hsu YC, Shi H, Wu F, et al. Amide proton transfer MRI may reflect effective reperfusion and predict functional outcomes in patients with ischemic stroke. J Cereb Blood Flow Metab. 2025;45(3):421-430. https://doi.org/10.1177/0271678X241297110.

[28] Yu L, Chen Y, Chen M, Luo X, Jiang S, Zhang Y, et al. Amide Proton Transfer MRI Signal as a Surrogate Biomarker of Ischemic Stroke Recovery in Patients With Supportive Treatment. Front Neurol. 2019;10:104. https://doi.org/10.3389/fneur.2019.00104.

[29] Zheng Y, Wang XM. Measurement of Lactate Content and Amide Proton Transfer Values in the Basal Ganglia of a Neonatal Piglet Hypoxic-Ischemic Brain Injury Model Using MRI. AJNR Am J Neuroradiol. 2017;38(4):827-834. https://doi.org/10.3174/ajnr.A5066.

[30] Chen S, Liu X, Mei Y, Li C, Ren D, Zhong M, et al. Early identification of neonatal mild hypoxic-ischemic encephalopathy by amide proton transfer magnetic resonance imaging: A pilot study. Eur J Radiol. 2019;119:108620. https://doi.org/10.1016/j.ejrad.2019.07.021.

[31] Chen S, Liu X, Lin J, Mei Y, Deng K, Xue Q, et al. Application of amide proton transfer imaging for the diagnosis of neonatal hypoxic-ischemic encephalopathy. Front Pediatr. 2022;10:996949. https://doi.org/10.3389/fped.2022.996949.

[32] Guo Y, Zhu X, Li J, Zhu B, Ye Y, Peng X. Amide proton transfer and apparent diffusion coefficient analysis reveal susceptibility of brain regions to neonatal hypoxic-ischemic encephalopathy. Heliyon. 2024;10(18):e38062. https://doi.org/10.1016/j.heliyon.2024.e38062.

[33] Tang X, Zhang H, Zhou J, Kang H, Yang S, Cui H, et al. Brain development in children with developmental delay using amide proton transfer-weighted imaging and magnetization transfer imaging. Pediatr Investig. 2020;4(4):250-256. https://doi.org/10.1002/ped4.12237.

[34] Zheng Y, Wang X, Zhao X. Magnetization Transfer and Amide Proton Transfer MRI of Neonatal Brain Development. Biomed Res Int. 2016;2016:3052723. https://doi.org/10.1155/2016/3052723.

[35] Zhang H, Kang H, Zhao X, Jiang S, Zhang Y, Zhou J, et al. Amide Proton Transfer (APT) MR imaging and Magnetization Transfer (MT) MR imaging of pediatric brain development. Eur Radiol. 2016;26(10):3368-76. https://doi.org/10.1007/s00330-015-4188-z.

[36] Zhang H, Zhou J, Peng Y. Amide Proton Transfer-Weighted MR Imaging of Pediatric Central Nervous System Diseases. Magn Reson Imaging Clin N Am. 2021;29(4):631-641. https://doi.org/10.1016/j.mric.2021.06.012.

[37] Lane CA, Hardy J, Schott JM. Alzheimer's disease. Eur J Neurol. 2018;25(1):59-70. https://doi.org/10.1111/ene.13439.

[38] Wang R, Li SY, Chen M, Zhou JY, Peng DT, Zhang C, et al. Amide proton transfer magnetic resonance imaging of Alzheimer's disease at 3.0 Tesla: a preliminary study. Chin Med J (Engl). 2015;128(5):615-9. https://doi.org/10.4103/0366-6999.151658.

[39] Wang R, Chen P, Shen Z, Lin G, Xiao G, Dai Z, et al. Brain Amide Proton Transfer Imaging of Rat With Alzheimer's Disease Using Saturation With Frequency Alternating RF Irradiation Method. Front Aging Neurosci. 2019;11:217. https://doi.org/10.3389/fnagi.2019.00217.

[40] Oh JH, Choi BG, Rhee HY, Lee JS, Lee KM, Park S, et al. Added Value of Chemical Exchange-Dependent Saturation Transfer MRI for the Diagnosis of Dementia. Korean J Radiol. 2021;22(5):770-781. https://doi.org/10.3348/kjr.2020.0700.

[41] Zhang Z, Zhang C, Yao J, Chen X, Gao F, Jiang S, et al. Protein-based amide proton transfer-weighted MR imaging of amnestic mild cognitive impairment. Neuroimage Clin. 2020;25:102153. https://doi.org/10.1016/j.nicl.2019.102153.

[42] Guo Z, Jiang Y, Qin X, Mu R, Meng Z, Zhuang Z, et al. Amide Proton Transfer-Weighted MRI Might Help Distinguish Amnestic Mild Cognitive Impairment From a Normal Elderly Population. Front Neurol. 2021;12:707030. https://doi.org/10.3389/fneur.2021.707030.

[43] Chen X, Gong T, Chen T, Xu C, Li Y, Song Q, et al. Altered glutamate-glutamine and amide proton transfer-weighted values in the hippocampus of patients with amnestic mild cognitive impairment: A novel combined imaging diagnostic marker. Front Neurosci. 2023;17:1089300. https://doi.org/10.3389/fnins.2023.1089300.

[44] Zhuang C, Chen B, Chen Y, Zhang X, Wu R. Pathophysiology of Alzheimer’s disease revealed by chemical exchange saturation transfer MRI. Radiology Science. 2023;2(1):56-70. https://doi.org/10.15212/RADSCI-2023-0004.

[45] Li C, Chen M, Zhao X, Wang R, Chen H, Su W, et al. Chemical Exchange Saturation Transfer MRI Signal Loss of the Substantia Nigra as an Imaging Biomarker to Evaluate the Diagnosis and Severity of Parkinson's Disease. Front Neurosci. 2017;11:489.https://doi.org/10.3389/fnins.2017.00489.

[46] Tian Y, Li X, Chen H, Su W, Li S, Zheng D, et al. Altered Nigral Amide Proton Transfer Imaging Signal Concordant With Motor Asymmetry in Parkinson's Disease: A Multipool CEST MRI Study. NMR Biomed. 2025;38(2):e5310. https://doi.org/10.1002/nbm.5310.

[47] Tian Y, Li X, Wang X, Su W, Li S, Wang W, et al. CEST 2022-three-dimensional amide proton transfer (APT) imaging can identify the changes of cerebral cortex in Parkinson's disease. Magn Reson Imaging. 2023;102:235-241. https://doi.org/10.1016/j.mri.2023.06.006.

[48] Wamelink IJHG, Kuijer JPA, Padrela BE, Zhang Y, Barkhof F, Mutsaerts HJMM, et al. Reproducibility of 3 T APT-CEST in Healthy Volunteers and Patients With Brain Glioma. J Magn Reson Imaging. 2023;57(1):206-215. https://doi.org/10.1002/jmri.28239.

[49] Zhou J, Heo HY, Knutsson L, van Zijl PCM, Jiang S. APT-weighted MRI: Techniques, current neuro applications, and challenging issues. J Magn Reson Imaging. 2019;50(2):347-364. https://doi.org/10.1002/jmri.26645.