In Vivo MR Techniques in Drug Discovery and Development

by Beckmann; Nicolau

• ISBN13: 9780849330261
• ISBN10: 0849330262
• Edition: 1st
• Format: Hardcover
• Copyright: 2006-06-02
• Publisher: CRC Press

Summary

Imaging technologies are receiving much attention in the pharmaceutical industry because of their potential for accelerating drug discovery and development. Magnetic Resonance (MR) Imaging is one of the principal modalities since it allows anatomical, functional, metabolic, and to a certain extent even target-related information to be gathered in vivo at high resolution, favoring the characterization of a disease state and the corresponding drug intervention. The non-invasiveness of MR strengthens the link between preclinical and clinical pharmaceutical research, contributing to improve the characterization of compound effects in early stages of the discovery process in order to increase the chances of success in later phases of drug development. Edited by a leading researcher in MR technology, with contributions from foremost experts in academia and the pharmaceutical industry, this title illustrates the use of MR techniques throughout the drug discovery and development process, from target identificationand validation to clinical studies. Numerous chapters focus on individual disease areas, including neurological, cardiac, and pulmonary disorders, cancer studies, diabetes, arthritis, solid organ transplantation, and stem cell-based therapies, showing that different imaging solutions are needed for specific organs.

Table of Contents

The Drug Discovery and Development Process: A Brief Overview	1	(6)
Alex Matter
The Drug Discovery and Development Process: Opportunities and Challenges for MR Techniques	7	(22)
Nicolau Beckmann
Markus Rudin
Introduction	7	(2)
Imaging in Drug Research	9	(7)
Computerized Tomography	10	(1)
Positron Emission Tomography	10	(2)
Single Photon Emission Computed Tomography	12	(1)
Ultrasound	13	(1)
Optical Imaging	14	(1)
Bioluminescence	14	(1)
Near-Infrared Fluorescence Imaging	14	(2)
Benefits and Limitations of MRI/S	16	(1)
In vivo MR Techniques in Drug Research	16	(4)
Target Identification and Validation	17	(1)
Lead Finding, Validation, and Optimization	17	(1)
Profiling Compounds in Animal Models of Diseases	17	(2)
Safety Evaluation	19	(1)
Clinical Studies	19	(1)
Measuring at Different Scales	20	(2)
Molecular Imaging	22	(1)
Concluding Remarks	23	(6)
References	24	(5)
Editorial Comments	29	(16)
Imaging as Biomarker for Decision-Making in Drug Development	31	(14)
Richard Hargreaves
John A. Wagner
Introduction	31	(2)
Biomarker Lexicon	33	(3)
Terminology	34	(1)
Progression from Validation to Qualification	34	(1)
Biomarker Nomenclature	35	(1)
Imaging Biomarkers	36	(1)
Application and Qualification of Imaging Biomarkers	36	(1)
Imaging in Cardiovascular Disease	37	(2)
Cardiovascular Imaging Biomarkers	38	(1)
Imaging in Neuroscience	39	(3)
Positron Emission Tomography	39	(1)
Alzheimer's Disease Imaging: A Multimodality Challenge	40	(2)
Summary	42	(3)
References	42	(3)
Editorial Comments	45	(28)
Design of Contrast Agents for Molecular Imaging In Vivo	47	(26)
Silvio Aime
Giovanni B. Giovenzana
Dario Longo
Enzo Terreno
Introduction	47	(1)
Paramagnetic Mn(II) and Gd(III) Complexes	48	(6)
Iron Oxide Particles	54	(1)
Main Routes for the Conjugation of Imaging Probes to Targeting Vectors	55	(6)
Accumulation of Imaging Probes at the Target Site	61	(5)
Understanding the In Vivo Relaxation Efficacy of MR-Imaging Probes	66	(1)
Nonuniformly Distributed Targets	66	(1)
Intracellular Distribution of the Imaging Probe	67	(1)
Future Perspectives	67	(6)
References	68	(5)
Editorial Comments	73	(20)
Rapid Phenotyping of Mice with MRI	75	(18)
X. Josette Chen
R. Mark Henkelman
Introduction	75	(1)
How MRI Changes for Mouse Phenotyping	76	(1)
Hardware	76	(1)
Pulse Sequences	76	(1)
Increasing Throughput	77	(1)
Animal Preparation for In Vivo Imaging	77	(4)
Anesthesia and Monitoring	78	(1)
Considerations for Multiple Mice	78	(1)
The Mouse Loading System	79	(1)
The Induction Chamber	79	(1)
The Sled	80	(1)
Imaging Specific Organs	81	(3)
Brain	81	(1)
Heart	82	(1)
Other Organs	82	(1)
Whole Body Imaging	83	(1)
Post Mortem Imaging	84	(2)
Excised Organs	84	(1)
Whole Body Perfusion	84	(2)
Image Analysis and Atlases	86	(1)
Conclusions	87	(6)
Acknowledgments	90	(1)
References	90	(3)
Editorial Comments	93	(76)
Magnetic Resonance Imaging and Spectroscopy in Transgenic Mice Modeling Alzheimer's Disease	95	(16)
Thomas Mueggler
Introduction	95	(1)
Transgenic Models of Alzheimer's Disease	96	(3)
Alzheimer's Disease: Pathological Hallmarks	96	(1)
Transgenic Approach to Model AD Pathology	96	(3)
Phenotyping AD Mouse Models Using MRI/MRS	99	(6)
Structural MRI and MRS in Transgenic Models of AD	99	(1)
Detection of β-Amyloid Deposits Using MRI	99	(2)
Assessment of Brain Atrophy	101	(1)
Brain Tissue Relaxation Times, Diffusion Properties, and Cerebrovascular Flow Abnormalities	102	(1)
Assessment of the Neurochemical Profile Using MRS	103	(1)
From Structural to Functional Readouts	103	(1)
Functional MRI in Transgenic Models of AD	103	(1)
Introduction: Functional MRI in Mice	103	(1)
Functional MRI Readouts in Transgenic Mouse Models of AD	104	(1)
Conclusion	105	(6)
References	106	(5)
Imaging Alzheimer's Disease with MRI	111	(12)
Scott A. Small
Introduction	111	(1)
The Anatomy and Pathophysiology of Alzheimer's Disease	112	(2)
Imaging the Cell-Sickness Stage of AD with Functional MRI	114	(3)
Imaging the Histologic Stage of Alzheimer's Disease with Structural and Contrast-Enhanced MRI	117	(2)
Imaging the Cell-Death Stage of Alzheimer's Disease with Volumetric MRI	119	(1)
Conclusion	119	(4)
Acknowledgments	120	(1)
References	120	(3)
MRI and MRS in Animal Models of Focal Cerebral Ischemia	123	(24)
Markus Rudin
Peter R. Allegrini
Martin Rausch
Introduction	123	(1)
Pathophysiology of Stroke	124	(2)
Animal Models of Stroke	126	(3)
Global Cerebral Ischemia Models in Rodents	126	(1)
Focal Cerebral Ischemia Models in Rodents	127	(1)
Mechanism-Specific Neurotoxic/Excitotoxic Lesion Models in Rats	128	(1)
Experimental Stroke: Disease Phenotyping Using MRI/MRS	129	(3)
Therapy Concepts	132	(3)
Recanalization	132	(1)
Maintenance of Low Intracellular Ca2+ Levels	132	(1)
Free Radical Scavengers	133	(1)
Antiapoptotic Therapy Using Inhibitors of Death Proteases	134	(1)
Antiinflammatory Therapy	134	(1)
Regeneration/Stem Cell Therapy	134	(1)
Noninvasive Assessment of Therapy Response Using MR Techniques	135	(4)
Effect of Cytoprotective Drugs on Cerebral Energy Metabolism	135	(1)
Structural Changes Following Focal Cerebral Ischemia	136	(1)
Assessment of Drug Efficacy Using Functional Readouts	137	(1)
Cell Tracking to Assess the Efficacy of Cell-Based Therapies	138	(1)
Conclusion	139	(8)
References	140	(7)
MRI in Clinical Studies of Stroke	147	(22)
Eric Juettler
Jochen B. Fiebach
Peter D. Schellinger
Introduction	147	(1)
Current Status of the Use of MRI in the Diagnosis and Therapy of Stroke	148	(13)
Diagnosis and Treatment of Acute Stroke and Underlying Etiology Based on MRI	149	(4)
Comparison of MRI with Other Imaging Techniques	153	(1)
Time Needed for Imaging and Availability of Imaging Techniques	153	(1)
Exclusion of Other Causes of Acute Stroke Symptoms	153	(4)
Detection of Ischemic Tissue	157	(1)
Distinction between Irreversibly Damaged Tissue and Tissue at Risk	157	(1)
Identification of Patients Who May Profit from Thrombolytic Treatment	158	(1)
Identification of Patients to Whom Thrombolytic Treatment Is Harmful	159	(1)
Stroke Treatment Based on a Multiparametric Stroke-MRI Protocol	160	(1)
The Use of MRI in Current and Upcoming Stroke Trials	161	(1)
Conclusions	162	(7)
References	163	(6)
Editorial Comments	169	(84)
Pharmacologic Magnetic Resonance Imaging (phMRI)	171	(50)
Bruce G. Jenkins
Ji-Kyung Choi
Joseph B. Mandeville
Yin-Ching Iris Chen
Introduction	172	(9)
Imaging Techniques for Studying Neuronal Activity	172	(1)
Pharmacologic MRI Compared with PET and Autoradiography. How Well Do Hemodynamic Changes Reflect Receptor Distributions?	173	(3)
Neurovascular Coupling: Many Neurotransmitters Are Vasoactive	176	(5)
Methodologies	181	(13)
Magnetic Resonance Techniques Used for Collecting Hemodynamic Data	181	(1)
The Original Technique: First Pass Bolus Mapping of Changes in rCBV	182	(1)
CBF-Based Techniques	182	(2)
BOLD Techniques	184	(1)
IRON CBV Mapping	185	(3)
Advantages and Disadvantages of MR Techniques: Brain -- Vein Controversies Revisited	188	(2)
Theoretical Framework for Contrast-to-Noise Ratio	190	(2)
Field Strength Dependencies of Bold and Iron	192	(1)
Nonhemodynamic MR Techniques of Potential Use for phMRI	192	(1)
Magnetic Resonance Spectroscopy	192	(1)
Manganese Enhanced MRI	193	(1)
The Confounds of Respiratory Gases and Anesthesia	194	(3)
Basic Drug Challenge Designs	197	(5)
Acute Model	197	(1)
Antagonism and Agonism of Acute Drug Challenges	198	(1)
The Acute Model for Examining the Effects of Chronic Drug Administration	199	(1)
Pharmacodynamics	199	(2)
Modeling CBV Changes Induced in the Brain Using a Pharmacologic Model	201	(1)
Current Applications of phMRI Techniques	202	(19)
Criteria for Demonstration That the Hemodynamic Effects Are Due to the Neurotransmitter System in Question	202	(2)
Application of the above Criteria to Study the Dopaminc System	204	(2)
phMRI Studies of Drug Abuse	206	(1)
Dopaminergic Drugs	206	(2)
Nicotine	208	(1)
Heroin	208	(1)
phMRI Studies of Neurodegeneration	209	(1)
Rat and Monkey Models of Parkinson's Disease	210	(2)
Acknowledgments	212	(1)
References	212	(9)
Brain fMRI in Clinical Pharmacological Studies	221	(16)
Irene Tracey
Petra Schweinhardt
Chas Bountra
Introduction	221	(1)
Metabolic Functional Imaging Methods: PET and fMRI	221	(3)
Pharmacological fMRI, Paradigm Design, and Data Analysis	224	(2)
Applications of Pharmacological fMRI in Clinical Research and Drug Development	226	(6)
Alzheimer's Disease and Mild Cognitive Impairment	227	(1)
Depression	227	(1)
Schizophrenia	227	(1)
Ischemic Stroke	228	(1)
Pain	228	(4)
Conclusions	232	(5)
References	233	(4)
Imaging Inflammatory Processes of the Brain: Multiple Sclerosis as an Example	237	(16)
Martin Rausch
Iris-Katharina Penner
Cedric Berger
Markus Rudin
Physiological Aspects of Neuroinflammatory Processes	237	(2)
Multiple Sclerosis: Pathophysiology and Clinical Presentation	239	(1)
Animal Models for Multiple Sclerosis	239	(1)
In Vivo MRI in Multiple Sclerosis	240	(9)
Concepts	240	(1)
Imaging of Structural Changes	240	(1)
Assessment of BBB Leakage: Gd-Enhancing Lesions	240	(1)
T2 Hyperintense Lesions and Multicomponent T2 Mapping	241	(1)
Magnetization Transfer Contrast	242	(1)
T1-Hypointense Lesions	243	(1)
Neurodegeneration and Atrophy	243	(1)
Functional MRI	244	(1)
Receptor-Specific Contrast Agents	245	(1)
Cell Labeling	246	(2)
Imaging of Drug Effects	248	(1)
Conclusions	249	(4)
References	249	(4)
Editorial Comments	253	(60)
Functional and Molecular Magnetic Resonance Imaging of Preclinical Cancer Models in Drug Discovery and Development	255	(26)
Zaver M. Bhujwalla
Kristine Glunde
Ellen Ackerstaff
Arvind P. Pathak
Barjor Gimi
Noriko Mori
Venu Raman
Dmitri Artemov
Introduction	255	(2)
Intact Cell Perfusion Studies	257	(3)
Studying Cancer Cell Invasion	257	(3)
Studying Therapeutic Response	260	(1)
In Vivo Human Tumor Xenograft Studies	260	(10)
Multiparametric MR Studies of Human Tumor Xenografts	260	(1)
Multiparametric/Multimodality Transgenic Tumor Model Studies	261	(3)
Imaging Interstitial Fluid Transport with MRI	264	(1)
Detecting Antiangiogenic Effects	264	(1)
MR Methods to Detect Drug Delivery	265	(5)
Identifying Targets with MR	270	(3)
MRI of Receptor and Gene Expression	273	(2)
Conclusion	275	(6)
Acknowledgments	275	(1)
References	275	(6)
MR for Clinical Pharmacological Studies in Cancer	281	(20)
Geoffrey S. Payne
David J. Collins
Elizabeth M. Charles-Edwards
Mounia Beloueche-Bahari
Martin O. Leach
Introduction	281	(1)
Functional Magnetic Resonance Imaging	282	(7)
Intrinsic Contrast Mechanisms	282	(1)
Diffusion-Weighted MRI	283	(1)
IntraVoxel Incoherent Motion	283	(1)
Arterial Spin Labeling	283	(1)
Blood Oxygen-Level Dependent Contrast	284	(1)
Dynamic Contrast Enhanced MRI in Clinical Drug Trials	284	(1)
Low Molecular Weight Agents	284	(1)
Measurement Methodology	285	(1)
Pharmacokinetic Analysis	286	(1)
Software Requirements for DCE-MRI	287	(1)
Higher Molecular Weight Contrast Agents	288	(1)
Clinical Therapeutic Trials	289	(1)
Applications Using Magnetic Resonance Spectroscopy	289	(3)
General Issues	289	(2)
Drug Uptake and Metabolism	291	(1)
Assessment of Treatment Response	292	(1)
Novel Therapeutics Targeting Molecular Processes	292	(3)
MRS Monitoring of Ras--Raf--MEK--ERK Signaling Inhibition	293	(1)
MRS Monitoring of Hsp90 Inhibition	294	(1)
Novel Diagnostic Agents for Evaluating the Tissue Microenvironment	295	(1)
Conclusions	295	(6)
References	296	(5)
Molecular Imaging in Cancer Therapies of the Future	301	(12)
Chrit Moonen
Introduction	301	(1)
Definition of Molecular Imaging	302	(1)
Improved Diagnostics by Molecular Imaging for Individualized Therapy	303	(3)
Seeing Genes in Action	303	(1)
Expression of Exogenous Genes	303	(1)
Expression of Endogenous Genes	303	(3)
Seeing Drugs in Action	306	(1)
Therapy Guided by Molecular Imaging	306	(2)
Combined Diagnostic and Therapeutic (Contrast) Agents	306	(1)
Local Drug Delivery Guided by Molecular Imaging	306	(1)
Image Guided Spatio-Temporal Control of Gene Expression	307	(1)
Tracking of Labeled (Stem) Cells	308	(1)
Conclusion	308	(5)
Acknowledgments	309	(1)
References	309	(4)
Editorial Comments	313	(36)
Cardiac MR Techniques Applied to Small Rodents	315	(14)
Matthias Nahrendorf
Wolfgang R. Bauer
Introduction	315	(1)
Cine MRI for Assessment of Morphology and Function of the Left Ventricle	316	(1)
Myocardial Motion Analysis by Tagging Techniques	317	(1)
Myocardial Motion Analysis by Phase Contrast Techniques	318	(1)
Cine MRI for Assessment of Right Ventricular Function and Morphology	318	(1)
Measurement of Blood Supply to the Myocardium	319	(2)
Pathophysiology of the Cardiovascular System, Myocardial Infarction, and Ischemia	321	(2)
Remodeling of Microcirculation after Myocardial Infarction	323	(1)
Phenotypisation of Transgenic Animals	324	(1)
Conclusions	325	(4)
References	325	(4)
Cardiac MRI Techniques for Clinical Drug Trials	329	(20)
Sebastian Kelle
Eike Nagel
Introduction	329	(1)
Pathophysiology of Cardiac Disease	330	(2)
Volume Overload	330	(1)
Pressure Overload	330	(1)
Coronary Artery Disease	330	(1)
Myocardial Infarction/Viability	331	(1)
Systemic Disease/Cardiomyopathies	331	(1)
Diagnostic Options	332	(1)
Clinical Applications	333	(9)
Cardiac MR for the Assessment of Left Ventricular Mass/Volumes/Function	333	(1)
Cardiac MR for the Detection of Coronary Artery Disease	334	(1)
Dobutamine Stress MR	335	(1)
Perfusion	336	(3)
Coronary Artery Imaging	339	(1)
Vessel Wall Imaging	340	(1)
Cardiac MR for the Assessment of Myocardial Infarction and Viability	340	(1)
Contrast Enhancement	340	(1)
Inotropic Stress	341	(1)
Cardiac MR in Systemic Disease/Cardiomyopathies	342	(1)
Plaque Imaging	342	(1)
Discussion	342	(7)
References	344	(5)
Editorial Comments	349	(42)
Lung MRI in Small Rodents as a Tool for the Evaluation of Drugs in Models of Airways Diseases	351	(22)
Nicolau Beckmann
Yannick Cremillieux
Bruno Tigani
Harry Karmouty Quintana
Francois-Xavier Ble
John R. Fozard
Introduction	351	(1)
MRI of the Lung	352	(4)
Proton Imaging	352	(2)
Hyperpolarized Gas Imaging	354	(1)
Lung Perfusion	355	(1)
Rat Models of Airways Diseases	356	(1)
Application of MRI to Models of Airways Diseases	357	(7)
Lung Inflammation	357	(1)
Lung Ventilation	358	(1)
Elastase-Induced Emphysema Model	359	(1)
Airway Smooth Muscle Contraction	360	(3)
Pulmonary Embolism	363	(1)
Airway Remodeling and Hyporesponsiveness Induced by Inflammation	363	(1)
Drug Treatment Analysis	364	(2)
Discussion	366	(7)
Acknowledgments	368	(1)
References	368	(5)
Clinical Applications of MRI in Respiratory Diseases	373	(18)
Christian Fink
Hans-Ulrich Kauczor
Introduction	373	(1)
Lung MRI	373	(4)
Morphological MRI	373	(1)
Pulmonary MRA	374	(1)
Functional MRI	375	(1)
Ventilation Imaging	375	(1)
Perfusion Imaging	376	(1)
Imaging of Respiratory Mechanics	377	(1)
MRI for the Assessment of Airways Diseases	377	(2)
Diseases Affecting Large Airways	377	(1)
Diseases Affecting Small Airways	378	(1)
MRI for the Assessment of Parenchymal Disease	379	(2)
MRI for the Assessment of Pulmonary Vascular Disease	381	(4)
MRI in Clinical Trials	385	(6)
References	386	(5)
Editorial Comments	391	(44)
MR in Preclinical Diabetes and Obesity Drug Discovery	393	(22)
Beat M. Jucker
Didier Laurent
Introduction	394	(2)
Diabetes	394	(1)
Obesity	394	(1)
MRI/S vs. Conventional Methodologies to Assess Metabolism	394	(2)
Applications to Drug Discovery	396	(1)
Metabolic Disease Targets	396	(2)
Diabetes: Current Therapies and Targets	396	(1)
MR Applications to Diabetes Drug Discovery	396	(1)
Obesity: Current Therapies and Targets	397	(1)
MR Applications to Obesity Drug Studies	397	(1)
Preclinical Animal Models of Diabetes and Obesity	398	(2)
Rodents	398	(1)
Nonhuman Primates	399	(1)
MRI/S Techniques	400	(6)
1H MRS	400	(1)
Intramyocellular Lipid Spectroscopy	400	(1)
Hepatic Lipid Spectroscopy	400	(1)
1H MRI	400	(1)
Whole Body Lipid Distribution Imaging	400	(3)
13C MRS	403	(1)
Carbohydrate Metabolism: Glycogen Synthesis and Glycolysis	403	(1)
Tri-Carboxylic Acid Cycle Turnover	403	(1)
Relative Fat vs. Glucose Oxidation: Isotope Analysis	403	(1)
31P MRS	403	(1)
Glucose-6-Phosphate	403	(1)
ATP Synthesis Flux	404	(2)
Mitochondrial Energetic Coupling	406	(1)
Experimental Limitations	406	(2)
Sensitivity	406	(1)
Animal Handling and Preparation	407	(1)
Administration of 13C-Labeled Compounds	408	(1)
Safety	408	(1)
Translation to Clinical Studies	408	(7)
References	409	(6)
MR in Clinical Diabetes Research and Drug Trials	415	(20)
Michael Roden
Background	416	(1)
Non-MRS Methods for Metabolic Research in Humans	416	(1)
MRS for Metabolic Research in Humans	416	(2)
1H MRS	417	(1)
31P MRS	417	(1)
13C MRS	417	(1)
Clinical Studies on Skeletal Muscle Metabolism	418	(4)
Defects in Type 2 Diabetic Patients	418	(1)
Defects in Type 1 Diabetic Patients	419	(1)
Defects in Offspring of Type 2 Diabetic Patients	419	(1)
Nutrient-Induced Insulin Resistance and Obesity	420	(1)
The Role of Intramyocellular Fat	421	(1)
Liver	422	(3)
Defects in Type 1 Diabetic Patients	423	(1)
Defects in Patients with other Pancreas Disorders	424	(1)
Defects in Type 2 Diabetic Patients	424	(1)
The Role of Intrahepatic Fat	425	(1)
Clinical Drug Trials in Metabolic Diseases	425	(5)
Insulin Treatment in Diabetes Mellitus	425	(1)
Type 1 Diabetes	425	(1)
Type 2 Diabetes	426	(1)
Gestational Diabetes	427	(1)
Oral Antidiabetic Drugs	427	(1)
Metformin	427	(1)
Insulin Sensitizer	428	(1)
Insulin Secretagogues	429	(1)
Treatment of Lipodystrophy	429	(1)
Leptin	429	(1)
Insulin Sensitizers	430	(1)
Conclusions	430	(5)
Acknowledgments	430	(1)
References	431	(4)
Editorial Comments	435	(52)
Rheumatoid and Osteoarthritis: Preclinical Applications of In Vivo MR	437	(28)
Didier Laurent
Nicolau Beckmann
Introduction	437	(1)
Animal Models of Arthritis	438	(1)
Monitoring Disease Progression in Animal Models	439	(1)
Non-MRI Imaging Readouts in Animal Models of Arthritis	440	(1)
MRI Readouts in Animal Models of RA	441	(6)
Qualitative Analysis of Soft Tissue and Bony Changes	441	(2)
Quantitative Analyses	443	(1)
Joint Inflammation	443	(1)
Angiogenesis	443	(2)
Macrophage Infiltration	445	(1)
Bony Changes	446	(1)
MRI Readouts in OA: Applications to Animals Studies	447	(6)
Biomechanical Properties of Cartilage in Relation to Its Composition	447	(1)
Cartilage Thickness and Volume	448	(1)
Functional Properties of Cartilage	448	(1)
Water Content	448	(1)
Proteoglycan Content	449	(3)
Collagen Integrity	452	(1)
MRI Contrast Agents in Arthritis	453	(1)
Discussion	454	(11)
Appendix 22.1. Delayed Gadolinium-Enhanced MRI	456	(2)
Appendix 22.2. MT Sequence Optimization	458	(1)
References	459	(6)
Rheumatoid and Osteoarthritis: Clinical Applications	465	(22)
Manish Kothari
Charles Peterfy
Introduction	465	(1)
Imaging in Rheumatoid Arthritis	466	(6)
MRI of Erosion and Osteitis	467	(2)
Synovitis	469	(1)
Cartilage, Ligaments, and Tendons	470	(1)
Low-Field Imaging in Rheumatoid Arthritis	470	(2)
Osteoarthritis	472	(8)
Conclusions	480	(7)
References	481	(6)
Editorial Comments	487	(48)
In Vivo Magnetic Resonance Techniques in Transplantation Research	489	(22)
Nicolau Beckmann
Detlef Niese
Introduction	489	(1)
Current Criteria for Characterizing Rejection of Grafts	490	(2)
Kidney Transplantation	491	(1)
Heart Transplantation	491	(1)
Liver Transplantation	491	(1)
Lung Transplantation	492	(1)
MR in Animal Studies of Transplantation	492	(5)
Kidney Transplantation	492	(1)
Macrophage Infiltration into Kidney Grafts	493	(1)
Kidney Perfusion	494	(1)
Renography	495	(1)
Heart Transplantation	496	(1)
Macrophage Infiltration into Cardiac Grafts	496	(1)
Permeability of Microvasculature in Cardiac Grafts	496	(1)
Cardiac Contractile Function	497	(1)
Lung Transplantation	497	(1)
MR in Clinical Studies	497	(5)
Kidney Transplantation	497	(1)
Pretransplant Assessment of Donors and Graft Viability	498	(1)
Posttransplant Assessment of Complications	499	(1)
Heart Transplantation	500	(1)
Liver Transplantation	500	(1)
Pretransplant Assessments	501	(1)
Posttransplant Assessments	501	(1)
Lung Transplantation	501	(1)
Toxic Effects of Compounds	502	(1)
MR Techniques for Pharmaceutical Research in Transplantation	503	(8)
Acknowledgments	505	(1)
References	505	(6)
MR Imaging and the Development of Stem Cell-Based Therapies	511	(24)
Piotr Walczak
Jeff W. M. Bulte
Introduction	511	(2)
Stem Cell-Based Therapy for the CNS	513	(8)
Parkinson's Disease	513	(1)
Experiments in Animal Models	514	(1)
Clinical Studies	515	(1)
Spinal Cord Injury	516	(1)
Prevention of Secondary Damage	516	(1)
Regeneration of Spinal Cord	516	(2)
De- and Dysmyelination	518	(2)
Other CNS Disorders	520	(1)
Stem Cell-Based Therapy for the Infarcted Myocardium	521	(1)
Need for Noninvasive Monitoring of Stem Cell-Based Therapies	522	(1)
Preparation of Magnetically Labeled Stem Cells	523	(2)
Peptides and Antibody Coating	523	(1)
Use of Transfection Agents	524	(1)
Other Magnetic Labeling Methods	525	(1)
Monitoring of Stem Cell-Based Therapy by MR	525	(3)
CNS Disorders	525	(3)
Infarcted Myocardium	528	(1)
Conclusions	528	(7)
Acknowledgments	528	(1)
References	529	(6)
Editorial Comments	535	(26)
MRI in Pharmaceutical Safety Assessment	537	(18)
David Reid
Introduction	537	(2)
Advantages of MRI	537	(1)
Pathologies Observable by MRI	538	(1)
Organ Specific Toxicity	539	(11)
Liver	539	(1)
Heart and Cardiovascular System	540	(1)
Kidneys and Urinary System	541	(2)
Lung	543	(1)
Brain and Nervous System	544	(2)
Endocrine Organs	546	(1)
Reproductive System	546	(1)
Other Organs and Tissues	547	(1)
Carcinogenesis	547	(1)
Ex Vivo and Whole Body MRI	548	(2)
MRI in Regulated Studies	550	(1)
Future Developments	551	(4)
Acknowledgments	552	(1)
References	552	(3)
In Vivo MR in Pharmaceutical Research: Essential or Nice to Have?	555	(6)
Nicolau Beckmann
Jeffrey Evelhoch
In Favor of Imaging	555	(1)
Room for Improvements on MR Techniques	556	(1)
Imaging Biomarkers	557	(4)
References	559	(2)
Index	561