1st Edition
Chemical Exchange Saturation Transfer Imaging Advances and Applications
This is the first textbook dedicated to CEST imaging and covers the fundamental principles of saturation transfer, key features of CEST agents that enable the production of imaging contrast, and practical aspects of preparing image-acquisition and post-processing schemes suited for in vivo applications. CEST is a powerful MRI contrast mechanism with unique features, and the rapid expansion it has seen over the past 15 years since its original discovery in 2000 has created a need for a graduate-level handbook describing all aspects of pre-clinical, translational, and clinical CEST imaging. The book provides an illustrated historical perspective by leaders at the five key sites who developed CEST imaging, from the initial saturation transfer NMR experiments performed in the 1960s in Stockholm, Sweden, described by Sture Forsén, to the work on integrating the basic principles of CEST into imaging by Robert Balaban, Dean Sherry, Silvio Aime, and Peter van Zijl in the United States and Italy.
The editors, Drs. Michael T. McMahon, Assaf A. Gilad, Jeff W. M. Bulte, and Peter C. M. van Zijl, have been pioneers developing this field at the Johns Hopkins University School of Medicine and the Kennedy Krieger Institute including contributions to Nature Medicine, Nature Biotechnology, Nature Materials, and the Proceedings of the National Academy of Sciences. As recognition for their initial development of the field, Drs. van Zijl and Balaban were awarded the Laukien Prize in April 2016, established in 1999 to honor the memory of Professor Gunther Laukien, a co-founder of Bruker Biospin GmbH.
Section I: From the 1960s to the 2010s: How Saturation Transfer Was First Discovered and Then Migrated Into Imaging
Discovery of the "Saturation Transfer" Method
Development of Chemical Exchange Saturation Transfer in Bethesda
History of In Vivo Exchange Transfer Spectroscopy and Imaging in Baltimore
Before There Was CEST
Early CEST Experiments
Amide Proton Transfer–Weighted MRI
Expansion of the CEST Efforts
Translation to Human Scanners
Active Growth in CEST
Early Discovery and Investigations of paraCEST Agents in Dallas
Birth of CEST Agents in Torino
Section II: Pulse Sequence, Imaging, and Post-processing Schemes for Detecting CEST Contrast
General Theory of CEST Image Acquisition and Post-Processing
Introduction
Theory
Post-Processing
Conclusion
Uniform-MT Method to Separate CEST Contrast from Asymmetric MT Effects
Saturation of a Spin-1/2 System
Uniform Saturation of a Dipolar-Coupled Spin-1/2 System
Uniform-MT Methodology
Application to Brain MRI
Application to Knee MRI
Summary
HyperCEST Imaging
HyperCEST in the Historic Context of CEST Development
Hyperpolarized Xenon NMR
Xenon Host Structures
Phospholipid Membrane Studies/Delta Spectroscopy
Live Cell NMR of Exchanging Xenon
Conclusion
Section III: diaCEST/paraCEST/lipoCEST Contrast Probes
Current Landscape of diaCEST Imaging Agents
Introduction
Molecules with Alkyl Amines and Amides
Molecules with Alkyl Hydroxyls
N-H Containing Heterocyclic Compounds
Salicylic Acid and Anthranilic Acid Analogues
Macromolecules with Labile Protons
Fluorine and Chemical Exchange Saturation Transfer
Evolution of Genetically Encoded CEST MRI Reporters: Opportunities and Challenges
Introduction
CEST MRI Contrast Generation Mechanism
Genetically Encoded CEST MRI Reporters
Genetically Encoded Hyperpolarized Xenon (129Xe) CEST MRI Reporters
Considerations in Developing CEST MRI Genetically Encoded Reporters
Current Challenges and Future Directions
Conclusion
ParaCEST Agents: Design, Discovery, and Implementation
Introduction
Lanthanide-Induced Shifts
T1 and T2 Considerations in the Design of paraCEST Agents
Water Molecule Exchange, Proton Exchange, and CEST Contrast
Modulation of Inner-Sphere Water Exchange Rates
Techniques to Measure Exchange Rates
Summary
Transition Metal paraCEST Probes as Alternatives to Lanthanides
Introduction
Coordination Chemistry of Iron(II), Cobalt(II), and Nickel(II)
NMR Spectra, CEST Spectra, and Imaging
Responsive Agents
Toward In Vivo Studies
Summary
Responsive paraCEST MRI Contrast Agents and Their Biomedical Applications
Introduction
ParaCEST Agents That Detect Enzyme Activities
ParaCEST Agents That Detect Nucleic Acids
ParaCEST Agents That Detect Metabolites
ParaCEST Agents That Detect Ions
ParaCEST Agents That Detect Redox State
ParaCEST Agents That Measure pH
ParaCEST Agents That Measure Temperature
Future Directions for Clinical Translation of paraCEST Agents
Saturating Compartmentalized Water Protons: Liposome- and Cell-Based CEST Agents
Introduction
Basic Features of lipoCEST/cellCEST Agents
Applications
Section IV: Emerging Clinical Applications of CEST imaging
Principles and Applications of Amide Proton Transfer Imaging
Introduction
APT Imaging Principle and Theory
APT Imaging of Stroke
Differentiation between Ischemia and Hemorrhage
APT Imaging of Brain Tumors
Differentiation between Active Glioma and Radiation Necrosis
Conclusions and Future Directions
Cartilage and Intervertebral Disc Imaging and Glycosaminoglycan Chemical Exchange Saturation Transfer (gagCEST) Experiment
Introduction
Composition and Organization of Cartilage
Composition and Organization of Intervertebral Disc
MRI Techniques for Measuring GAG (Other than CEST)
GagCEST
Conclusion
GlucoCEST: Imaging Glucose in Tumors
Introduction
Cancer Metabolism and the Warburg Effect
Imaging Methods Targeting Metabolism
GlucoCEST: The Concept
GlucoCEST: State of the Art
GlucoCEST: Good Practices
Conclusion: Remaining Open Questions
Creatine Chemical Exchange Saturation Transfer Imaging
Introduction
Study of Energy Metabolism: 31P MRS
Development of Creatine CEST
Summary
Iodinated Contrast Media as pH-Responsive CEST Agents
Iopamidol as a diaCEST Agent in Preclinical Studies
Iopamidol as diaCEST Agent on a Clinical MRI Scanner (3 T)
Iopromide as a diaCEST Agent in Preclinical Studies
Iobitridol as a diaCEST Agent in Preclinical Studies
Conclusion
Biography
Michael T. McMahon, Ph.D, is an Associate Professor of Radiology at the Johns Hopkins University School of Medicine and a Research Scientist in the F.M. Kirby Research Center for Functional Brain Imaging at the Kennedy Krieger Institute. Dr. McMahon earned his Ph.D. in physical chemistry from the University of Illinois at Urbana-Champaign in 1999 and was awarded a fellowship to continue his training at the Massachusetts Institute of Technology before taking a Research Associate position with Peter van Zijl in 2003. His research at Johns Hopkins University and Kennedy Krieger Institute is focused on the development of diaCEST contrast agents for medical applications and imaging schemes to maximize their potential. Dr. McMahon has been elected to the position of Program Director for the Cellular and Molecular Imaging Study Group at the International Society for Magnetic Resonance in Medicine (ISMRM) and together with Drs. Gilad, Bulte and van Zijl organized the third CEST imaging workshop (OctoberCEST) in Annapolis, MD.
Dr. Jeff W.M. Bulte, Ph.D, is a Professor of Radiology in the Division of MR Research, with joint appointments in Oncology, Biomedical Engineering, and Chemical & Biomolecular Engineering. He serves as the Director of the Cellular Imaging Section in the Institute for Cell Engineering at the Johns Hopkins University School of Medicine. In 1991, Dr. Bulte obtained his Ph.D. summa cum laude from the University of Groningen, The Netherlands. He then spent 10 years in the Laboratory of Diagnostic Radiology Research at the National Institutes of Health before moving to Johns Hopkins University in 2001. He has won several awards, including an ISMRM Gold Medal and the Torsten Almén Award for Pioneering Research in Contrast Media.
Assaf A. Gilad, Ph.D, is an Associate Professor of Radiology at the Johns Hopkins University School of Medicine and the Institute for Cell Engineering. After obtaining his Ph.D. from the Weizmann Institute of Science, Rehovot, Israel in 2003, he received his postdoctoral training under the supervision of Drs. Jeff Bulte and Peter van Zijl at Johns Hopkins University. In 2007 he joined the Radiology department as junior faculty and has continued to develop new genetically encoded technologies for cellular and sub-cellular molecular CEST imaging.
Peter C.M. van Zijl, Ph.D., is a Professor of Radiology in the Division of MR Research of the Department of Radiology at Johns Hopkins University School of Medicine, and the founding Director of the F.M. Kirby Research Center for Functional Brain Imaging at Kennedy Krieger Research Insitute. Dr. van Zijl received his Ph.D. in mathematics and physics (Physical Chemistry) from the Free University, Amsterdam in 1985. He did fellowships in Chemistry, Carnegie Mellon University (1985-87) and in vivo spectroscopy (National Cancer Institute, NIH from 1987–1990) and was Assistant Professor at Georgetown University from 1990–1992. He moved to Johns Hopkins University in 1992. Dr. van Zijl is a Fellow of both the ISMRM and the ISMAR. He received the Gold medal of the ISMRM in 2007 for contributions in MR spectroscopy, diffusion imaging, and functional MRI. He is a distinguished Investigator of the Academy of Radiology Research (2012) and in 2016, together with Robert Balaban, received the Laukien Prize for his contributions to developing the CEST field.
"This textbook is very helpful for those who are eager to fully understand the principles and development of chemical exchange saturation transfer (CEST) techniques. One strength of this book is in the discussion of probes, and another strength is having Sture Forsén and Robert Balaban describe their early studies. This book will have a great impact promoting the clinical translation of CEST imaging."
—Prof. Renhua Wu, Shantou University, China
"This book presents an in-depth and comprehensive description of CEST physics, techniques, and applications. It is in time for the dawn of label-free molecular imaging that explores chemical exchange phenomena the nature offers. It is also a collection of very updated perspectives of the future of CEST magnetic resonance imaging (MRI), quite informative, and fun to read for imaging physicists, radiologists, and clinician scientists."
—Prof. Ed X. Wu, The University of Hong Kong, Hong Kong
"This is an excellent book on CEST MRI with state-of-the-art chapters from thought leaders in the field. It touches on all aspects of CEST: image acquisition methods and data processing, development of exogenous CEST probes, and applications of CEST in clinical and biomedical imaging. A very valuable addition to biomedical imaging canon, and a text that will be beneficial to students and experts alike."
—Prof. Peter Caravan, Harvard Medical School, USA
"This book has been edited by faculty from one of the leading centers with extensive experience of chemical exchange saturation transfer (CEST) MRI and is the first to focus exclusively on this specific imaging technique. The authors include many of the leaders in the field, and it belongs on the shelf of anyone seriously involved in CEST work. It has broad breadth of coverage which makes it a go-to reference for overviews of many sub-specialty applications. It is clearly valuable as a standard in the field and I expect it will serve as the essential starting point for in-coming graduate students beginning CEST research and for established researchers delving into a new area."
—Dr. Daniel F. Gochberg, Vanderbilt University Institute of Imaging Science, USA
"Chemical exchange saturation transfer (CEST) can be used to detect proteins, peptides, metabolites, and probe molecules in 1H MR images of tissue water, with observation via the water resonance massively increasing the sensitivity of their detection. This timely book describes the history of the technique’s development and the underlying theory and then goes on to review its latest applications. It is a comprehensive and insightful book written by the leaders in the field. It is a must read book for anyone already in the CEST field, or thinking of entering the field and, given the growing popularity of the methods described here, should be read by anybody working in the field of in vivo MR."
—Prof. Kevin Brindle, University of Cambridge, UK, Molecular Imaging and Biology, 2017