CEST MRI of Biomolecules
Kannie WY Chan1

1Kannie WY Chan, City University of Hong Kong, Hong Kong


Chemical Exchange Saturation Transfer (CEST) MRI allows us to access molecular information with an enhanced sensitivity. Various contributing proton exchange mechanisms provide ample information for imaging biomolecules and their related pathophysiology. This molecular contrast is sensitive to alterations of exchanging environments in vivo, e.g. CEST contrast of proteins in the brain is different from that in brain tumors with acidic pH. Thus, CEST contrast characterized by the z-spectrum provides readouts for comprehensive physiological and molecular assessments. This talk will present CEST imaging of biomolecules in the brain, and its applications, challenges and opportunities in studying brain tumors and neurological disorders.

Target audience

Researchers/clinicians who are interested in imaging biomolecules in vivo using CEST MRI.


CEST MRI measures exchangeable protons on molecules and its exchanging environment, e.g. amide protons on proteins. Z-spectrum is typically used to measure CEST contrast, which indicates the type and amount of exchangeable protons. It also measures the contributions from nuclear Overhauser enhancement (NOE) (1-3) and magnetization transfer (MT) (4,5). By studying these exchange processes, we can reveal pathophysiological changes in greater details, in particular in brain tumor and other neuropathologies. This talk will describe the CEST basics to image biomolecules, CEST imaging approaches and what the Z-spectrum can tell us about biomolecules in vivo.

The unique feature of CEST MRI as compared to other MRI contrast mechanisms is the enhanced sensitivity in detecting biomolecules via the proton exchange with bulk water (6-9). A variety of CEST approaches are available to highlight specific biomolecules, such as imaging proteins using amide proton transfer (APT) (9-12); imaging metabolites using glucoCEST (13-17), gluCEST (18-26), and CrCEST (27-32). For examples, APT has shown promises in differentiating tumor recurrence from radiation necrosis (12,33) and glucoCEST indicates glucose uptake and perfusion-related parameters in brain tumors (13,16,17). Moreover, CEST MRI is pH sensitive since the exchange rate is pH dependent. This feature can be applied to study tissue acidification or stroke. NOE and MT could indicate aliphatic and macromolecular contributions in neurological disorders, such as multiple sclerosis. In the view of the complexity of processes that contributing to the Z-spectrum, the pulse sequence and saturation parameters used for acquisitions have to be carefully selected in order to highlight the relevant processes for pathophysiological characterization. In conjunction, new analysis approaches have been developed in an attempt to specify the actual signal contributions, with reference to the conventional analysis of the Z-spectrum using MTRasym to minimize direct saturation.

CEST MRI provides great opportunities for imaging biomolecules in vivo. It generates unique molecular information for evaluating neuropathology, such as brain tumor and stroke, paving ways for precision medicine.


No acknowledgement found.


1. Zhang S, Keupp J, Wang X, Dimitrov I, Madhuranthakam AJ, Lenkinski RE, Vinogradov E. Z-spectrum appearance and interpretation in the presence of fat: Influence of acquisition parameters. Magn Reson Med 2018;79(5):2731-2737. 2. Jones CK, Huang A, Xu J, Edden RA, Schar M, Hua J, Oskolkov N, Zaca D, Zhou J, McMahon MT, Pillai JJ, van Zijl PC. Nuclear Overhauser enhancement (NOE) imaging in the human brain at 7T. Neuroimage 2013;77:114-124. 3. Lu J, Zhou J, Cai C, Cai S, Chen Z. Observation of true and pseudo NOE signals using CEST-MRI and CEST-MRS sequences with and without lipid suppression. Magn Reson Med 2015;73(4):1615-1622. 4. van Zijl PC, Yadav NN. Chemical exchange saturation transfer (CEST): what is in a name and what isn't? Magn Reson Med 2011;65(4):927-948. 5. van Zijl PCM, Lam WW, Xu J, Knutsson L, Stanisz GJ. Magnetization Transfer Contrast and Chemical Exchange Saturation Transfer MRI. Features and analysis of the field-dependent saturation spectrum. Neuroimage 2018;168:222-241. 6. Aime S, Castelli DD, Crich SG, Gianolio E, Terreno E. Pushing the sensitivity envelope of lanthanide-based magnetic resonance imaging (MRI) contrast agents for molecular imaging applications. Acc Chem Res 2009;42(7):822-831. 7. Sherry AD, Woods M. Chemical exchange saturation transfer contrast agents for magnetic resonance imaging. Annu Rev Biomed Eng 2008;10:391-411. 8. 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. 9. Zhou J, Wilson DA, Sun PZ, Klaus JA, Van Zijl PC. Quantitative description of proton exchange processes between water and endogenous and exogenous agents for WEX, CEST, and APT experiments. Magn Reson Med 2004;51(5):945-952. 10. Heo HY, Jones CK, Hua J, Yadav N, Agarwal S, Zhou J, van Zijl PC, Pillai JJ. Whole-brain amide proton transfer (APT) and nuclear overhauser enhancement (NOE) imaging in glioma patients using low-power steady-state pulsed chemical exchange saturation transfer (CEST) imaging at 7T. J Magn Reson Imaging 2016;44(1):41-50. 11. 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):1085-1090. 12. Zhou J, Tryggestad E, Wen Z, Lal B, Zhou T, Grossman R, Wang S, Yan K, Fu DX, Ford E, Tyler B, Blakeley J, Laterra J, van Zijl PC. Differentiation between glioma and radiation necrosis using molecular magnetic resonance imaging of endogenous proteins and peptides. Nat Med 2011;17(1):130-134. 13. Chan KW, McMahon MT, Kato Y, Liu G, Bulte JW, Bhujwalla ZM, Artemov D, van Zijl PC. Natural D-glucose as a biodegradable MRI contrast agent for detecting cancer. Magn Reson Med 2012;68(6):1764-1773. 14. Nasrallah FA, Pages G, Kuchel PW, Golay X, Chuang KH. Imaging brain deoxyglucose uptake and metabolism by glucoCEST MRI. J Cereb Blood Flow Metab 2013. 15. Walker-Samuel S, Ramasawmy R, Torrealdea F, Rega M, Rajkumar V, Johnson SP, Richardson S, Goncalves M, Parkes HG, Arstad E, Thomas DL, Pedley RB, Lythgoe MF, Golay X. In vivo imaging of glucose uptake and metabolism in tumors. Nat Med 2013;19(8):1067-1072. 16. Xu X, Chan KW, Knutsson L, Artemov D, Xu J, Liu G, Kato Y, Lal B, Laterra J, McMahon MT, van Zijl PC. Dynamic glucose enhanced (DGE) MRI for combined imaging of blood-brain barrier break down and increased blood volume in brain cancer. Magnetic resonance in medicine 2015;74(6):1556-1563. 17. Xu X, Yadav NN, Knutsson L, Hua J, Kalyani R, Hall E, Laterra J, Blakeley J, Strowd R, Pomper M, Barker P, Chan K, Liu G, McMahon MT, Stevens RD, van Zijl PC. Dynamic Glucose-Enhanced (DGE) MRI: Translation to Human Scanning and First Results in Glioma Patients. Tomography 2015;1(2):105-114. 18. Cai K, Haris M, Singh A, Kogan F, Greenberg JH, Hariharan H, Detre JA, Reddy R. Magnetic resonance imaging of glutamate. Nat Med 2012;18(2):302-306. 19. Cai K, Singh A, Roalf DR, Nanga RP, Haris M, Hariharan H, Gur R, Reddy R. Mapping glutamate in subcortical brain structures using high-resolution GluCEST MRI. NMR Biomed 2013;26(10):1278-1284. 20. Haris M, Nath K, Cai K, Singh A, Crescenzi R, Kogan F, Verma G, Reddy S, Hariharan H, Melhem ER, Reddy R. Imaging of glutamate neurotransmitter alterations in Alzheimer's disease. NMR Biomed 2013;26(4):386-391. 21. Kogan F, Singh A, Debrosse C, Haris M, Cai K, Nanga RP, Elliott M, Hariharan H, Reddy R. Imaging of glutamate in the spinal cord using GluCEST. Neuroimage 2013;77:262-267. 22. Crescenzi R, DeBrosse C, Nanga RP, Reddy S, Haris M, Hariharan H, Iba M, Lee VM, Detre JA, Borthakur A, Reddy R. In vivo measurement of glutamate loss is associated with synapse loss in a mouse model of tauopathy. Neuroimage 2014;101:185-192. 23. Bagga P, Crescenzi R, Krishnamoorthy G, Verma G, Nanga RP, Reddy D, Greenberg J, Detre JA, Hariharan H, Reddy R. Mapping the alterations in glutamate with GluCEST MRI in a mouse model of dopamine deficiency. J Neurochem 2016;139(3):432-439. 24. Roalf DR, Nanga RPR, Rupert PE, Hariharan H, Quarmley M, Calkins ME, Dress E, Prabhakaran K, Elliott MA, Moberg PJ, Gur RC, Gur RE, Reddy R, Turetsky BI. Glutamate imaging (GluCEST) reveals lower brain GluCEST contrast in patients on the psychosis spectrum. Mol Psychiatry 2017;22(9):1298-1305. 25. Wang R, Reddy PH. Role of Glutamate and NMDA Receptors in Alzheimer's Disease. J Alzheimers Dis 2017;57(4):1041-1048. 26. Bagga P, Pickup S, Crescenzi R, Martinez D, Borthakur A, D'Aquilla K, Singh A, Verma G, Detre JA, Greenberg J, Hariharan H, Reddy R. In vivo GluCEST MRI: Reproducibility, background contribution and source of glutamate changes in the MPTP model of Parkinson's disease. Sci Rep 2018;8(1):2883. 27. Kogan F, Stafford RB, Englund EK, Gold GE, Hariharan H, Detre JA, Reddy R. Perfusion has no effect on the in vivo CEST effect from Cr (CrCEST) in skeletal muscle. NMR Biomed 2017;30(1). 28. Cai K, Singh A, Poptani H, Li W, Yang S, Lu Y, Hariharan H, Zhou XJ, Reddy R. CEST signal at 2ppm (CEST@2ppm) from Z-spectral fitting correlates with creatine distribution in brain tumor. NMR Biomed 2015;28(1):1-8. 29. Cai K, Tain RW, Zhou XJ, Damen FC, Scotti AM, Hariharan H, Poptani H, Reddy R. Creatine CEST MRI for Differentiating Gliomas with Different Degrees of Aggressiveness. Mol Imaging Biol 2017;19(2):225-232. 30. Haris M, Nanga RP, Singh A, Cai K, Kogan F, Hariharan H, Reddy R. Exchange rates of creatine kinase metabolites: feasibility of imaging creatine by chemical exchange saturation transfer MRI. NMR Biomed 2012;25(11):1305-1309. 31. Kogan F, Haris M, Singh A, Cai K, Debrosse C, Nanga RP, Hariharan H, Reddy R. Method for high-resolution imaging of creatine in vivo using chemical exchange saturation transfer. Magn Reson Med 2014;71(1):164-172. 32. Chen L, Zeng H, Xu X, Yadav NN, Cai S, Puts NA, Barker PB, Li T, Weiss RG, van Zijl PCM, Xu J. Investigation of the contribution of total creatine to the CEST Z-spectrum of brain using a knockout mouse model. NMR Biomed 2017;30(12). 33. Mehrabian H, Desmond KL, Soliman H, Sahgal A, Stanisz GJ. Differentiation between Radiation Necrosis and Tumor Progression Using Chemical Exchange Saturation Transfer. Clin Cancer Res 2017;23(14):3667-3675.
Proc. Intl. Soc. Mag. Reson. Med. 26 (2018)