Magnetization Transfer Imaging to Investigate Tissue Structure and Optimise Detection of Blood Brain Barrier Leakage in Multiple Sclerosis Dr Nicholas Charles Silver, MBBS; MRCP A thesis submitted to the University of London for the degree of Doctor of Philosophy March 2001 NMR Research Unit Institute of Neurology University College London Queen Square London WCIN 3BG United Kingdom ProQuest Number: U643048 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest. ProQuest U643048 Published by ProQuest LLC(2016). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 Abstract Magnetic resonance imaging (MRI) has become a powerful researeh tool for in vivo evaluation and monitoring of multiple sclerosis (MS). Conventional MRI techniques detect changes in the density or relaxation characteristies of “free” water protons. They are sensitive but lack pathological specificity. Magnetization transfer (MX) imaging provides a method for evaluating those protons “bound” to maeromolecular struetures. Part one of this thesis outlines the clinical and pathological features of MS and discusses the importance of demyelination and blood-brain barrier breakdown. An introduction to MRI and MX imaging techniques is provided. Issues related to quality assuranee and standardization for MX imaging are explored. In part two, MX ratio (MXR) is explored as a putative quantitative marker of demyelination and associated tissue destruetion. In part three, MX contrast (MXC) is explored as a novel mechanism for improving the detection of focal contrast-enhancing lesions. A normative database for MXR in healthy white matter is presented in ehapter four. Highest values are found where myelin density is greatest. Minor age-related MXR reduction is observed. In ehapter five, MXR is evaluated in central pontine myelinolysis, a rare neurological condition characterised pathologieally by severe demyelination. The results support myelin as the predominant contributor to MXR values in white matter. In ehapter six, MXR is employed as a putative marker of demyelination to explore the relationships between demyelination and blood-brain barrier damage in acute MS lesions. New techniques for registering two-dimensional images were implemented to allow reliable measurement of MXR prior to visible lesion formation. No evidence was found to suggest signifieant demyelination prior to opening of the blood-brain barrier. Chapter seven details the novel application of MXR measurement in the cervieal spinal eord and preliminary data are presented showing reduction in MS. Further studies in this clinically eloquent region will be of interest. The potential for MXC to improve gadolinium enhancing lesion deteetion in MS is explored in the ehapters eight and nine. First, a cross-seetional study explores how the detection of enhancing lesions may be improved by MXC; in conjunction with a triple-dose gadolinium and subsequent delay prior to imaging, sensitivity was more than doubled. Xriple-dose improved sensitivity more than MXC. Finally, a serial study is presented that confirms a significant increase in longitudinal sensitivity for such techniques. The potential benefits for monitoring phase II exploratory treatment trials in MS are evaluated. Acknowledgements Thanks to my supervisor David Miller for his guidance and unfailing support throughout my time in research. I have benefited from both his global vision and attention to detail. I would especially like to thank Ian McDonald for his clarity, wisdom and kindness, all of which have provided a continued source of inspiration. Thanks also to Alan Thompson for his input. Many thanks to Paul Tofts and Gareth Barker for their theoretical and practical input. I am indebted to Tina Good for her radiological expertise, enthusiasm, and friendship. Thanks also to Ivan Moseley and Mary Gawne-Caine. I have enjoyed the international collaboration afforded by MAGNIMS and would particularly like to thank Achim Gass and Wolfgang Schreiber for their helpful suggestions and Massimo Fillipi and Maria Pia Sormani for their collaboration. I am grateful to Mark Symms for his genuine enthusiasm and novel ideas. This thesis would not have been possible without the dedication and hard work of all of the radiographers in the unit. Special thanks to Dave MacManus and also to Alison Fletcher, Beth Gunn, and Andrew Howe. Thanks to my fellow “Moorfields Clinic” colleagues who provided invaluable “out of hours”advice. In particular, thanks to Gavin Giovannoni for his collaboration and inspiration, John Mottershead for his companionship and laboratory “cookery” skills (not forgetting the help from Alison Green and Geoff Keir), Bob Brenner, Nick Losseff (for imparting his statistical and software knowledge and for showing how the best ideas are the simple ones), Ming Lai (for letting me use his data), Charlie Davie, Jonathon O’Riordan and Katia Cikurel. I particularly wish to thank my friends and fellow members of the NMR Unit, including Michael Sailer, Tina Holmes, Val Stevenson, Niall Tubridy, David Werring, Siobhan Leary, Paul Molyneux, Peter Brex, Chris Clark, Jackie Foong, Collette Griffin, Arun Reginald and Geoff Parker. My thanks to you all for your kinship and support through the good times and the bad. Special thanks to my successor, Tony Traboulsee, for proof reading this tome. Thanks also to my non-medical friends, Lany, Moss, Lou, and Jonny for their much appreciated diversions. Thanks to Di for her unfailing support, enthusiasm, and understanding (thank you also for providing me with the most wonderful distractions ever imagined, Amy and Ben). Thank you also to my parents, Trevor and Jill, for their constant encouragement and faith in me. A special thanks to the Multiple Sclerosis Society of Great Britain and Northern Ireland for their generous support throughout my research studentship. Finally, thank you everyone who volunteered to be studied - my heartfelt gratitude to you all for your unerring dedication. Statement of Authorship All projects outlined in this thesis represent my original and personal work. This thesis would not however have been possible without specific individual contributions from collaborators within the NMR Unit and other research centres. With the following exceptions and those listed in the text of this thesis, I was responsible for the initiation and design of all project protocols, recruitment of subjects for study, acquisition of all clinical and radiological data (with help from the individual radiographers who performed all scanning), analysis of all image data, statistical testing, and interpretation of the subsequent results: In Chapter 3, Drs. John Mottershead, Geoff Keir, and Alison Green helped design and manufacture the MTR phantoms. In Chapter 5, Dr Charlie Davie acquired the proton MRS control data from four healthy volunteers. In Chapter 6, Dr Ming Lai recruited and acquired data from three of the subjects. In Chapter 9, Dr Maria Pia Sormani performed the sample size calculations in conjunction with Dr Massimo Filippi. To Diane Table of Contents Page Abstract 2 Acknowledgements 3 Statement of Authorship 4 Dedication 5 Table of Contents 6 List of Figures 11 List of Tables 15 List of Abbreviations 17 List of Publications 18 PART ONE BACKGROUND 1. Introduction 1.1 Personal and social cost implications of multiple sclerosis 21 1.2 Background 22 1.3 Aims 24 1.4 Multiple sclerosis 1.4.1 Clinical background and definitions 25 1.4.2 Diagnosis 25 1.4.3 Clinical manifestations 33 1.4.4 Aetiology 36 1.4.5 Neuropathology 38 1.4.6 Treatment - disease modification 49 1.4.7 Treatment - symptomatic strategies 52 and rehabilitation 1.5 MRI to monitor putative therapies in multiple sclerosis 54 2. Common Methodology 2.1 Introduction 56 2.2 Basic principles of magnetic resonance imaging 2.2.1 Introduction 56 2.2.2 Quantum mechanical description 57 o f magnetic resonance 2.2.3 Classical description of magnetic resonance 59 2.2.4 Factors affecting the NMR signal: 63 Spin-lattice and spin-spin relaxation 2.2.5 Free induction decay and signal detection 66 2.2.6 Spin echoes 67 2.2.7 Relaxation mechanisms 70 2.2.8 Tissue NMR relaxation properties 74 2.2.9 Obtaining spatial information with 76 magnetic resonance imaging 2.2.10 MRIinstrumentation 80 2.2.11 Alternative pulse sequences for imaging 81 2.3 Magnetization Transfer: principles and techniques 2.3.1 Introduction 83 2.3.2 Basic principles of magnetization transfer 84 2.3.3 Saturation transfer 85 2.3.4 Magnetization transfer in biological tissue 87 2.3.5 Preliminary in vivo demonstration of MT 90 effects in biological tissue 2.3.6 In vivo applications of magnetization 91 transfer imaging 2.4 MRI to assess blood-brain barrier integrity 2.4.1 The blood-brain barrier 96 2.4.2 Contrast agents for MRI 97 2.4.3 Pharmacokinetics of gadopentate dimeglumine 101 2.4.4 Safety and tolerance of gadopentate dimeglumine 101 2.4.5 Sensitivity of contrast-enhanced MRI 103 2.5 MRI postprocessing to quantify pathological change 2.5.1 Qualitative MRI 104 2.5.2 Quantitative M RI 105 2.6 Clinical measurement