Silver, Nicholas Charles; (2001) Magnetization transfer imaging to investigate tissue structure and optimise detection of blood brain barrier leakage in multiple sclerosis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Magnetic resonance imaging (MRI) has become a powerful research tool for in vivo evaluation and monitoring of multiple sclerosis (MS). Conventional MRI techniques detect changes in the density or relaxation characteristics of "free" water protons. They are sensitive but lack pathological specificity. Magnetization transfer (MT) imaging provides a method for evaluating those protons "bound" to macromolecular structures. 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 MT imaging techniques is provided. Issues related to quality assurance and standardization for MT imaging are explored. In part two, MT ratio (MTR) is explored as a putative quantitative marker of demyelination and associated tissue destruction. In part three, MT contrast (MTC) is explored as a novel mechanism for improving the detection of focal contrast-enhancing lesions. A normative database for MTR in healthy white matter is presented in chapter four. Highest values are found where myelin density is greatest. Minor age-related MTR reduction is observed. In chapter five, MTR is evaluated in central pontine myelinolysis, a rare neurological condition characterised pathologically by severe demyelination. The results support myelin as the predominant contributor to MTR values in white matter. In chapter six, MTR 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 MTR prior to visible lesion formation. No evidence was found to suggest significant demyelination prior to opening of the blood-brain barrier. Chapter seven details the novel application of MTR measurement in the cervical spinal cord and preliminary data are presented showing reduction in MS. Further studies in this clinically eloquent region will be of interest. The potential for MTC to improve gadolinium enhancing lesion detection in MS is explored in the chapters eight and nine. First, a cross-sectional study explores how the detection of enhancing lesions may be improved by MTC; in conjunction with a triple-dose gadolinium and subsequent delay prior to imaging, sensitivity was more than doubled. Triple-dose improved sensitivity more than MTC. 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.

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