基于化学交换饱和转移机制的磁共振pH成像脉冲序列设计
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摘要
人体组织病变多伴随细胞内外酸碱平衡(pH)紊乱,如脑卒中,肾衰竭,肿瘤及一些炎症。快速准确地检测人体病变组织酸碱环境对疾病的早期诊断以及后续治疗意义重大,然而,当前在体测定人体内环境pH值的手段十分有限。近来发现磁共振技术可以无损地测定组织的pH值。早期多用磁共振频谱测定动物组织细胞内外pH值,但其分辨率较低,难以应用于临床。新近发现的化学交换饱和转移(Chemical exchange saturation transfer,CEST)技术有可能获得组织pH的高分辨空间分布信息。本研究的目的是通过修改MT序列激发三池模型,以获得pH依赖的化学交换饱和转移效应(CEST),探讨临床1.5 T场强下磁共振pH成像的可行性。
本研究主要包括三方面内容:第一,探讨化学交换饱和转移理论,分析其与pH值之间的关系。主要探讨三池模型的布洛赫方程唯象理论,分析化学交换速率与pH值的关系,并综述了最新的APT pH成像技术。上述问题的的深入讨论将对序列设计工作具有理论指导意义。第二,脉冲序列设计原理及其实现。研究射频脉冲和梯度场脉冲成像原理,针对CEST pH成像遇到的困难,修改磁化传递脉冲并在EPIC平台上编程实现。第三,扫描模型实验。使用MT-SE序列扫描三池模型,验证三池模型化学交换饱和转移理论,并对比了MT SE序列与常规SE序列在检测pH值方面的差异。结果显示MT SE序列较常规SE序列具有更大的pH敏感性,认为在临床1.5 T场强具有磁共振pH成像的可行性。
本课题属于前沿课题。国内未见“基于CEST的pH成像研究”方面的研究报道,国外仅有少数小组将其应用于pH成像方面,目前该研究仍处于探索阶段。本文在编译平台上成功地模拟了MT脉冲序列。本文对CEST的理论描述及MRI脉冲序列成像原理的研究可为后续工作者理解、开发新的pH特异的脉冲序列提供借鉴意义。
Acid-based balance is altered in a variety of common pathologies, including ischemia, renal failure, cancer and inflammation. It is of importance to rapidly and accurately detect the acid-base environment of human lesions in early disease diagnosis and follow-up treatment.However, It is known that there are few effective tools available to evaluate pH values in vivo.Recently the Magnetic Resonance is found to provide a non-invasive tool of estimating pH value. MRS was first introduced to measure intra- and extracellular pH, but the inherent low resolution of spectroscopy makes it difficult to be applied to clinic. A new technique known as Chemical Exchange Saturation Transfer (CEST) may provide an high-resolution image of the spatial distribution of pH values in humans. In this research, we used the modified MT-SE sequence to scan the tissue-like pH phantom on 1.5T scanner, with the purpose of exploring the feasibility of CEST MR pH imaging on a clinical scanner.
This study includes three aspects. Firstly, investigate chemical exchange saturation transfer theory and its relationship with pH value. It is mainly to investigate the Bloch equations of the three-pool model modified, the relationship between pH value and chemical exchange rate, and review the progress of APT pH imaging. Detailed study of on this issue will be of theoretical significance for the design of pulse sequence. Secondly, the pulse sequence design theory and its programming. It is to study the RF pulse and gradient pulse imaging principle. For CEST pH imaging difficulties, the MR pulse sequence program workstation is used to accomplish the magnetization transfer pulse program on the platform of EPIC. Thirdly, the scanning model experiment. The MT-SE sequence scanning three pool model is performed to verify its CEST effect, and the results were compared with the routine SE in the detection of pH value. Ourresults show that MT SE sequence has a greater pH sensitivity than the routine SE sequence. We concluded that it is feasible to get pH imaging map in 1.5T MRI scanner.
This subject is a global problem. No "based on CEST pH imaging" related work was reported in China, and there are only a few pH imaging groups abroad, whose studies on pH imaging are still at an initial stage. We successfully implemented MT pulse sequence programming andsimulation in EPIC workstation. In addition, the theoretical description of CEST and the principle of MRI pulse sequence in this thesis will help the follow-up workers to understand and design the new pH-specific pulse sequences.
本研究主要包括三方面内容:第一,探讨化学交换饱和转移理论,分析其与pH值之间的关系。主要探讨三池模型的布洛赫方程唯象理论,分析化学交换速率与pH值的关系,并综述了最新的APT pH成像技术。上述问题的的深入讨论将对序列设计工作具有理论指导意义。第二,脉冲序列设计原理及其实现。研究射频脉冲和梯度场脉冲成像原理,针对CEST pH成像遇到的困难,修改磁化传递脉冲并在EPIC平台上编程实现。第三,扫描模型实验。使用MT-SE序列扫描三池模型,验证三池模型化学交换饱和转移理论,并对比了MT SE序列与常规SE序列在检测pH值方面的差异。结果显示MT SE序列较常规SE序列具有更大的pH敏感性,认为在临床1.5 T场强具有磁共振pH成像的可行性。
本课题属于前沿课题。国内未见“基于CEST的pH成像研究”方面的研究报道,国外仅有少数小组将其应用于pH成像方面,目前该研究仍处于探索阶段。本文在编译平台上成功地模拟了MT脉冲序列。本文对CEST的理论描述及MRI脉冲序列成像原理的研究可为后续工作者理解、开发新的pH特异的脉冲序列提供借鉴意义。
Acid-based balance is altered in a variety of common pathologies, including ischemia, renal failure, cancer and inflammation. It is of importance to rapidly and accurately detect the acid-base environment of human lesions in early disease diagnosis and follow-up treatment.However, It is known that there are few effective tools available to evaluate pH values in vivo.Recently the Magnetic Resonance is found to provide a non-invasive tool of estimating pH value. MRS was first introduced to measure intra- and extracellular pH, but the inherent low resolution of spectroscopy makes it difficult to be applied to clinic. A new technique known as Chemical Exchange Saturation Transfer (CEST) may provide an high-resolution image of the spatial distribution of pH values in humans. In this research, we used the modified MT-SE sequence to scan the tissue-like pH phantom on 1.5T scanner, with the purpose of exploring the feasibility of CEST MR pH imaging on a clinical scanner.
This study includes three aspects. Firstly, investigate chemical exchange saturation transfer theory and its relationship with pH value. It is mainly to investigate the Bloch equations of the three-pool model modified, the relationship between pH value and chemical exchange rate, and review the progress of APT pH imaging. Detailed study of on this issue will be of theoretical significance for the design of pulse sequence. Secondly, the pulse sequence design theory and its programming. It is to study the RF pulse and gradient pulse imaging principle. For CEST pH imaging difficulties, the MR pulse sequence program workstation is used to accomplish the magnetization transfer pulse program on the platform of EPIC. Thirdly, the scanning model experiment. The MT-SE sequence scanning three pool model is performed to verify its CEST effect, and the results were compared with the routine SE in the detection of pH value. Ourresults show that MT SE sequence has a greater pH sensitivity than the routine SE sequence. We concluded that it is feasible to get pH imaging map in 1.5T MRI scanner.
This subject is a global problem. No "based on CEST pH imaging" related work was reported in China, and there are only a few pH imaging groups abroad, whose studies on pH imaging are still at an initial stage. We successfully implemented MT pulse sequence programming andsimulation in EPIC workstation. In addition, the theoretical description of CEST and the principle of MRI pulse sequence in this thesis will help the follow-up workers to understand and design the new pH-specific pulse sequences.
引文
[1] McLean LA, Roscoe J, Jorgensen NK, Gorin FA, Cala PM. Malignant gliomas display altered pH regulation by NHE1 compared with nontransformed astrocytes. American journal of physiology 2000. 278(4):C676-688.
[2] Gallagher FA, Kettunen MI, Day SE, Hu DE, Ardenkjaer-Larsen JH, Zandt R, Jensen PR, Karlsson M, Golman K, Lerche MH et al. Magnetic resonance imaging of pH in vivo using hyperpolarized 13C-labelled bicarbonate. Nature 2008, 453(7197):940-943.
[3] Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nature reviews 2004, 4(11):891-899.
[4] Shrode LD, Tapper H, Grinstein S. Role of intracellular pH in proliferation, transformation, and apoptosis. Journal of bioenergetics and biomembranes 1997, 29(4):393-399.
[5] Ling W, Regatte RR, Navon G, Jerschow A. Assessment of glycosaminoglycan concentration in vivo by chemical exchange-dependent saturation transfer (gagCEST). Proceedings of the National Academy of Sciences of the United States of America 2008, 105(7):2266-2270.
[6] Schroder L, Lowery TJ, Hilty C, Wemmer DE, Pines A. Molecular imaging using a targeted magnetic resonance hyperpolarized biosensor. Science (New York, NY 2006, 314(5798):446-449.
[7] Terreno E, Castelli DD, Milone L, Rollet S, Stancanello J, Violante E, Aime S. First ex-vivo MRI co-localization of two LIPOCEST agents. Contrast media & molecular imaging 2008, 3(1):38-43.
[8] Dagher AP, Aletras A, Choyke P, Balaban RS. Imaging of urea using chemical exchange-dependent saturation transfer at 1.5T. J Magn Reson Imaging 2000, 12(5):745-748.
[9] Wolff SD, Balaban RS. Magnetization transfer contrast (MTC) and tissue water proton relaxation in vivo. Magn Reson Med 1989, 10(1):135-144.
[10] Guivel-Scharen V, Sinnwell T, Wolff SD, Balaban RS. Detection of proton chemical exchange between metabolites and water in biological tissues. J Magn Reson 1998, 133:36-45.
[11] Sherry AD, Woods M. Chemical exchange saturation transfer contrast agents for magneticresonance imaging. Annual review of biomedical engineering 2008, 10:391-411.
[12] Wike-Hooley JL, Haveman J, Reinhold HS. The relevance of tumour pH to the treatment of malignant disease. Radiother Oncol 1984, 2(4):343-366.
[13] Gillies RJ, Raghunand N, Garcia-Martin ML, Gatenby RA. pH imaging. A review of pH measurement methods and applications in cancers. IEEE Eng Med Biol Mag 2004, 23(5):57-64.
[14] Stubbs M, Bhujwalla ZM, Tozer GM, Rodrigues LM, Maxwell RJ, Morgan R, Howe FA, Griffiths JR. An assessment of 31P MRS as a method of measuring pH in rat tumours. NMR in biomedicine 1992, 5(6):351-359.
[15] Gillies RJ, Liu Z, Bhujwalla Z. 31P-MRS measurements of extracellular pH of tumors using 3-aminopropylphosphonate. The American journal of physiology 1994, 267(1 Pt 1):C195-203.
[16] Ojugo AS, McSheehy PM, McIntyre DJ, McCoy C, Stubbs M, Leach MO, Judson IR, Griffiths JR. Measurement of the extracellular pH of solid tumours in mice by magnetic resonance spectroscopy: a comparison of exogenous (19)F and (31)P probes. NMR in biomedicine 1999, 12(8):495-504.
[17]吴仁华,刘伟文,陈耀文,王慧,沈智威, terBrugge K, Mikulis DJ.无损伤地构建脑ATP和脑pH值空间分布图是否可行[J].中外健康文摘2008, 5(8):90-92.
[18] Gil MS, Cruz F, Ballesteros P. Imidazol-1-ylalkanoateesters and their corresponding acids. A novel series of extrinsic 1H NMR probes for intracellular pH. Bioorganic and Med Chem Lett 1992, 2(12):1717-1722.
[19] Gil S, Zaderenzo P, Ballesteros P. Imidazol-1-ylalkanoic acids as extrinsic 1H NMR probes for the determination of intracellular pH, extracellular pH and cell volume. Bioorganic and Med Chem Lett 1994, 2(5):305-314.
[20] van Sluis R, Bhujwalla ZM, Raghunand N, Ballesteros P, Alvarez J, Cerdan S, Galons JP, Gillies RJ. In vivo imaging of extracellular pH using 1H MRSI. Magn Reson Med 1999, 41(4):743-750.
[21] Bhujwalla ZM, Artemov D, Ballesteros P, Cerdan S, Gillies RJ, Solaiyappan M. Combined vascular and extracellular pH imaging of solid tumors. NMR in biomedicine 2002, 15(2):114-119.
[22]邱庆春,韦茂彬,沈智威,吴仁华.基于不同pH值的磁共振T2加权成像[J].中国医学物理学杂志2009, 26(5):1405-1408.
[23] KM W, RS B. Determination of pH using water protons and chemical exchange dependent saturation transfer (CEST). Magn Reson Med 2000, 44:799-802.
[24] Garcia-Martin ML, Martinez GV, Raghunand N, Sherry AD, Zhang S, Gillies RJ. High resolution pH(e) imaging of rat glioma using pH-dependent relaxivity. Magn Reson Med 2006, 55(2):309-315.
[25] Aime S, Barge A, Delli Castelli D, Fedeli F, Mortillaro A, Nielsen FU, Terreno E.Paramagnetic lanthanide(III) complexes as pH-sensitive chemical exchange saturation transfer (CEST) contrast agents for MRI applications. Magn Reson Med 2002, 47(4):639-648.
[26] 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, 9:1085-1090.
[27] Forsen S, Hoffman RA. Study of moderately rapid chemical exchange reactions by means of nuclear magnetic double resonance. J Chem Phys 1963, 39:2892-2901.
[28] 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.
[29] Mori S, Eleff SM, Pilatus U, Mori N, van Zijl PC. Proton NMR spectroscopy of solvent-saturable resonances: a new approach to study pH effects in situ. Magn Reson Med 1998, 40(1):36-42.
[30] Sun PZ, Zhou J, Sun W, Huang J, van Zijl PC. Detection of the ischemic penumbra using pH-weighted MRI. J Cereb Blood Flow Metab 2007, 27(6):1129-1136.
[31] Woods M, Woessner DE, Sherry AD. Paramagnetic lanthanide complexes as PARACEST agents for medical imaging. Chemical Society reviews 2006, 35(6):500-511.
[32] McMahon MT, Gilad AA, Zhou J, Sun PZ, Bulte JW, van Zijl PC. Quantifying exchange rates in chemical exchange saturation transfer agents using the saturation time and saturation power dependencies of the magnetization transfer effect on the magnetic resonance imaging signal (QUEST and QUESP): Ph calibration for poly-L-lysine and a starburst dendrimer. Magn Reson Med 2006, 55(4):836-847.
[33] Sun PZ, Farrar CT, Sorensen AG.. Correction for artifacts induced by B(0) and B(1) field inhomogeneities in pH-sensitive chemical exchange saturation transfer (CEST) imaging. Magn Reson Med 2007, 58(6):1207-1215.
[34] Jordi SP, Elena PM, Laura D, Pilar LL. Novel Generation of pH Indicators for Proton Magnetic Resonance Spectroscopic Imaging. J Med Chem 2007(50):4539-4542.
[35]尹建忠. MRI基础[M].天津科技翻译出版公司2004,天津.
[36] Brown MA. MRI Basic Principles and Applications. Wiley-Liss 2003.
[37]裘祖文,裴奉奎.核磁共振波谱[M].科学出版社1989,北京.
[38]苗英,林伟,钱春娥,朱碧波,任宏,韩国灿.对比增强磁化传递MRI在肺癌脑内小转移灶成像中的价值[J].中华放射学杂志2004, 38(12):1252-1255.
[39] Sun PZ, Zhou J, Huang J, van Zijl P. Simplified quantitative description of amide proton transfer (APT) imaging during acute ischemia. Magn Reson Med 2007, 57(2):405-410.
[40] Zhou J, van Zijl PCM. Chemical exchange saturation transfer imaging and spectroscopy. Prog NMR Spectrom 2006, 48:109-136.
[41] 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.
[42] Woessner DE, Zhang S, Merritt ME, Sherry AD. Numerical solution of the Bloch equations provides insights into the optimum design of PARACEST agents for MRI. Magn Reson Med 2005, 53(4):790-799.
[43] Englander SW, Downer NW, Teitelbaum H. Hydrogen exchange. Annu Rev Biochem 1972, 41:903-924.
[44] Howe FA, Barton SJ, Cudlip SA, Stubbs M, Saunders DE, Murphy M, Wilkins P, Opstad KS, Doyle VL, McLean MA et al. Metabolic profiles of human brain tumors using quantitative in vivo 1H magnetic resonance spectroscopy. Magn Reson Med 2003, 49(2):223-232.
[45]曾晓庄,包尚联.核磁共振成像物理原理和脉冲序列设计[M].中国医药科技出版社2007,北京.
[46] GE Medieal Systems Technical Publications, Direction 2189431. EPIC Software Reference Manual Complete reference manual for use of the EPIC language.
[47] Liney G. MRI in Clinical Practice. Springer 2006, Singapore.
[48]胡家灯. MRI对人体健康的影响[J].医疗装备2000, 13(1):15-16.
[2] Gallagher FA, Kettunen MI, Day SE, Hu DE, Ardenkjaer-Larsen JH, Zandt R, Jensen PR, Karlsson M, Golman K, Lerche MH et al. Magnetic resonance imaging of pH in vivo using hyperpolarized 13C-labelled bicarbonate. Nature 2008, 453(7197):940-943.
[3] Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nature reviews 2004, 4(11):891-899.
[4] Shrode LD, Tapper H, Grinstein S. Role of intracellular pH in proliferation, transformation, and apoptosis. Journal of bioenergetics and biomembranes 1997, 29(4):393-399.
[5] Ling W, Regatte RR, Navon G, Jerschow A. Assessment of glycosaminoglycan concentration in vivo by chemical exchange-dependent saturation transfer (gagCEST). Proceedings of the National Academy of Sciences of the United States of America 2008, 105(7):2266-2270.
[6] Schroder L, Lowery TJ, Hilty C, Wemmer DE, Pines A. Molecular imaging using a targeted magnetic resonance hyperpolarized biosensor. Science (New York, NY 2006, 314(5798):446-449.
[7] Terreno E, Castelli DD, Milone L, Rollet S, Stancanello J, Violante E, Aime S. First ex-vivo MRI co-localization of two LIPOCEST agents. Contrast media & molecular imaging 2008, 3(1):38-43.
[8] Dagher AP, Aletras A, Choyke P, Balaban RS. Imaging of urea using chemical exchange-dependent saturation transfer at 1.5T. J Magn Reson Imaging 2000, 12(5):745-748.
[9] Wolff SD, Balaban RS. Magnetization transfer contrast (MTC) and tissue water proton relaxation in vivo. Magn Reson Med 1989, 10(1):135-144.
[10] Guivel-Scharen V, Sinnwell T, Wolff SD, Balaban RS. Detection of proton chemical exchange between metabolites and water in biological tissues. J Magn Reson 1998, 133:36-45.
[11] Sherry AD, Woods M. Chemical exchange saturation transfer contrast agents for magneticresonance imaging. Annual review of biomedical engineering 2008, 10:391-411.
[12] Wike-Hooley JL, Haveman J, Reinhold HS. The relevance of tumour pH to the treatment of malignant disease. Radiother Oncol 1984, 2(4):343-366.
[13] Gillies RJ, Raghunand N, Garcia-Martin ML, Gatenby RA. pH imaging. A review of pH measurement methods and applications in cancers. IEEE Eng Med Biol Mag 2004, 23(5):57-64.
[14] Stubbs M, Bhujwalla ZM, Tozer GM, Rodrigues LM, Maxwell RJ, Morgan R, Howe FA, Griffiths JR. An assessment of 31P MRS as a method of measuring pH in rat tumours. NMR in biomedicine 1992, 5(6):351-359.
[15] Gillies RJ, Liu Z, Bhujwalla Z. 31P-MRS measurements of extracellular pH of tumors using 3-aminopropylphosphonate. The American journal of physiology 1994, 267(1 Pt 1):C195-203.
[16] Ojugo AS, McSheehy PM, McIntyre DJ, McCoy C, Stubbs M, Leach MO, Judson IR, Griffiths JR. Measurement of the extracellular pH of solid tumours in mice by magnetic resonance spectroscopy: a comparison of exogenous (19)F and (31)P probes. NMR in biomedicine 1999, 12(8):495-504.
[17]吴仁华,刘伟文,陈耀文,王慧,沈智威, terBrugge K, Mikulis DJ.无损伤地构建脑ATP和脑pH值空间分布图是否可行[J].中外健康文摘2008, 5(8):90-92.
[18] Gil MS, Cruz F, Ballesteros P. Imidazol-1-ylalkanoateesters and their corresponding acids. A novel series of extrinsic 1H NMR probes for intracellular pH. Bioorganic and Med Chem Lett 1992, 2(12):1717-1722.
[19] Gil S, Zaderenzo P, Ballesteros P. Imidazol-1-ylalkanoic acids as extrinsic 1H NMR probes for the determination of intracellular pH, extracellular pH and cell volume. Bioorganic and Med Chem Lett 1994, 2(5):305-314.
[20] van Sluis R, Bhujwalla ZM, Raghunand N, Ballesteros P, Alvarez J, Cerdan S, Galons JP, Gillies RJ. In vivo imaging of extracellular pH using 1H MRSI. Magn Reson Med 1999, 41(4):743-750.
[21] Bhujwalla ZM, Artemov D, Ballesteros P, Cerdan S, Gillies RJ, Solaiyappan M. Combined vascular and extracellular pH imaging of solid tumors. NMR in biomedicine 2002, 15(2):114-119.
[22]邱庆春,韦茂彬,沈智威,吴仁华.基于不同pH值的磁共振T2加权成像[J].中国医学物理学杂志2009, 26(5):1405-1408.
[23] KM W, RS B. Determination of pH using water protons and chemical exchange dependent saturation transfer (CEST). Magn Reson Med 2000, 44:799-802.
[24] Garcia-Martin ML, Martinez GV, Raghunand N, Sherry AD, Zhang S, Gillies RJ. High resolution pH(e) imaging of rat glioma using pH-dependent relaxivity. Magn Reson Med 2006, 55(2):309-315.
[25] Aime S, Barge A, Delli Castelli D, Fedeli F, Mortillaro A, Nielsen FU, Terreno E.Paramagnetic lanthanide(III) complexes as pH-sensitive chemical exchange saturation transfer (CEST) contrast agents for MRI applications. Magn Reson Med 2002, 47(4):639-648.
[26] 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, 9:1085-1090.
[27] Forsen S, Hoffman RA. Study of moderately rapid chemical exchange reactions by means of nuclear magnetic double resonance. J Chem Phys 1963, 39:2892-2901.
[28] 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.
[29] Mori S, Eleff SM, Pilatus U, Mori N, van Zijl PC. Proton NMR spectroscopy of solvent-saturable resonances: a new approach to study pH effects in situ. Magn Reson Med 1998, 40(1):36-42.
[30] Sun PZ, Zhou J, Sun W, Huang J, van Zijl PC. Detection of the ischemic penumbra using pH-weighted MRI. J Cereb Blood Flow Metab 2007, 27(6):1129-1136.
[31] Woods M, Woessner DE, Sherry AD. Paramagnetic lanthanide complexes as PARACEST agents for medical imaging. Chemical Society reviews 2006, 35(6):500-511.
[32] McMahon MT, Gilad AA, Zhou J, Sun PZ, Bulte JW, van Zijl PC. Quantifying exchange rates in chemical exchange saturation transfer agents using the saturation time and saturation power dependencies of the magnetization transfer effect on the magnetic resonance imaging signal (QUEST and QUESP): Ph calibration for poly-L-lysine and a starburst dendrimer. Magn Reson Med 2006, 55(4):836-847.
[33] Sun PZ, Farrar CT, Sorensen AG.. Correction for artifacts induced by B(0) and B(1) field inhomogeneities in pH-sensitive chemical exchange saturation transfer (CEST) imaging. Magn Reson Med 2007, 58(6):1207-1215.
[34] Jordi SP, Elena PM, Laura D, Pilar LL. Novel Generation of pH Indicators for Proton Magnetic Resonance Spectroscopic Imaging. J Med Chem 2007(50):4539-4542.
[35]尹建忠. MRI基础[M].天津科技翻译出版公司2004,天津.
[36] Brown MA. MRI Basic Principles and Applications. Wiley-Liss 2003.
[37]裘祖文,裴奉奎.核磁共振波谱[M].科学出版社1989,北京.
[38]苗英,林伟,钱春娥,朱碧波,任宏,韩国灿.对比增强磁化传递MRI在肺癌脑内小转移灶成像中的价值[J].中华放射学杂志2004, 38(12):1252-1255.
[39] Sun PZ, Zhou J, Huang J, van Zijl P. Simplified quantitative description of amide proton transfer (APT) imaging during acute ischemia. Magn Reson Med 2007, 57(2):405-410.
[40] Zhou J, van Zijl PCM. Chemical exchange saturation transfer imaging and spectroscopy. Prog NMR Spectrom 2006, 48:109-136.
[41] 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.
[42] Woessner DE, Zhang S, Merritt ME, Sherry AD. Numerical solution of the Bloch equations provides insights into the optimum design of PARACEST agents for MRI. Magn Reson Med 2005, 53(4):790-799.
[43] Englander SW, Downer NW, Teitelbaum H. Hydrogen exchange. Annu Rev Biochem 1972, 41:903-924.
[44] Howe FA, Barton SJ, Cudlip SA, Stubbs M, Saunders DE, Murphy M, Wilkins P, Opstad KS, Doyle VL, McLean MA et al. Metabolic profiles of human brain tumors using quantitative in vivo 1H magnetic resonance spectroscopy. Magn Reson Med 2003, 49(2):223-232.
[45]曾晓庄,包尚联.核磁共振成像物理原理和脉冲序列设计[M].中国医药科技出版社2007,北京.
[46] GE Medieal Systems Technical Publications, Direction 2189431. EPIC Software Reference Manual Complete reference manual for use of the EPIC language.
[47] Liney G. MRI in Clinical Practice. Springer 2006, Singapore.
[48]胡家灯. MRI对人体健康的影响[J].医疗装备2000, 13(1):15-16.