Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 2002? / Includes bibliographical references (leaves 194-225).

The sites of biosynthesis and incorporation of the abundant CNS myelin proteins 2' , 3' -cyclic nucleotide-3'-phosphodiesterase (CNPase) and P2 protein into the growing myelin membrane were investigated. Cell-free translation systems programmed with mRNA from rat brain, rabbit spinal cord, free and bound polysomes and purified myelin demonstrated conclusively that both CNPase and P2 are synthesized on free polysomes like the myelin basic proteins (MBPs) but unlike the proteolipid protein (PLP), the major intrinsic membrane protein of CNS myelin, which is known to be synthesized at the oligodendrocyte endoplasmic reticulum on bound polysomes (Colman et al., 1982) . These observations were supported by labelling studies on rats in vivo during the period of maximal myelin deposition. Newly synthesized CNPase associated with the myelin membrane very rapidly after labelling (~2 minutes) and this is consistent with the view that there is only a brief delay between synthesis and incorporation into their target membrane for extrinsic-type plasma membrane proteins. An RNA fraction isolated from purified CNS myelin was not enriched in mRNAs coding for CNPase and P2 but a considerable enrichment of mRNAs coding for MBPs was observed. This phenomenon has important implications for the cell biology of myelination since it suggests that although MBPs, CNPase and P2 are all basic extrinsic membrane proteins, and synthesized on free polysomes, different mechanisms for their transport to the myelin membrane exist. The addition of dog pancreatic microsomes (DPM) during translation showed no membrane association for CNPase however, at least 50% of MBPs were observed to non-specifically associate with these membranes. When newly synthesized MBP and P2 were incubated post-translationally with DPM or rabbit spinal cord myelin P2 only associated with myelin whereas MBP showed an equal affinity for both types of membranes. The segregation of MBP free polysomes at the myelin membrane during synthesis ensures that the nascent MBP polypeptides associate with the correct membrane. Recent evidence has shown that the free polysome-mRNA complex is bound to the cytoskeleton during protein synthesis. After extensive characterization of the purified rat brain oligodendrocyte and myelin-associated cytoskeletons it was shown that the synthesis of MBPs and CNPase only occurs from mRNA that is associated with the cytoskeleton and not when it is part of the cytoplasmic mRNA pool. Lipid analysis of the purified rat brain myelin-associated cytoskeleton revealed the presence of tightly bound lipid with a considerable enrichment of cerebroside and sphingomyelin (the latter at the expense of phosphatidylethanolamine). These studies on the cytoskeletal involvement in myelinogenesis suggest that extrinsic CNS myelin proteins are synthesized on the cytoskeleton and that post-translational cytoskeletal transport of these proteins to the growing myelin membrane may take place.

Includes bibliographical references (leaves 194-225) A new method is described that enables longitudinal and cross sections of an individual nerve fibre to be cut at multiple specified sites along the fibre by use of an unique marker system. The method is particularly useful for the correlative study of myelin-axon relationships

Includes bibliographical references (leaves 194-225) / ix, 225, vii leaves : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / A new method is described that enables longitudinal and cross sections of an individual nerve fibre to be cut at multiple specified sites along the fibre by use of an unique marker system. The method is particularly useful for the correlative study of myelin-axon relationships / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 2002?

Thesis (M.Sc.). / Written for the Dept. of Neurology and Neurosurgery. Title from title page of PDF (viewed 2008/05/14). Includes bibliographical references.

Thesis (Ph. D.)--Case Western Reserve University, 2006. / [School of Medicine] Department of Neurosciences. Includes bibliographical references. Available online via OhioLINK's ETD Center.

Thesis (M.S.)--University of Tennessee Health Science Center, 2008. / Title from title page screen (viewed on February 27, 2009). Research advisor: Terrence L. Geiger, MD, PhD. Document formatted into pages (xi, 74 p. : ill.). Vita. Abstract. Includes bibliographical references (p. 64-74).

Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease of the central nervous system (CNS) whereby abnormal autoimmune responses cause damage to myelin, the lipid-rich layer that surrounds and insulates axons. This results in interruptions in communication within the CNS and between the CNS and peripheral nervous system (PNS). This dysfunction contributes to a variety of symptoms that negatively impact the lives of individuals with MS. Sleep disturbances and memory difficulties are two common challenges faced by MS patients, but are not comprehensively understood within the MS literature. Additionally, despite general consensus with regard to the important role that sleep plays in memory function, studies investigating the links between sleep disturbance and memory in MS are sparse. As such, the purpose of this dissertation was to determine whether sleep disturbance helps to explain differential memory functioning in individuals with MS, both cross-sectionally and over time. A sample of 165 early MS patients participated in cognitive measures, gait assessments, sensorimotor assessments, and self-report questionnaires once at baseline, and again 3 years after their initial assessment. Magnetic Resonance Imaging (MRI) data were collected at baseline. The primary predictor variable for the present study was sleep disturbance, as measured by two validated self-report measures of sleep functioning, the Insomnia Severity Index (ISI) and Pittsburgh Sleep Quality Index (PSQI). This study’s primary outcome was memory function, which was assessed by the CANTAB Paired Associate Learning (CANTAB PAL), Brief Visuospatial Memory Test, Revised (BVMT-R), Selective Reminding Test (SRT), and Verbal Paired Associate Learning (VPAL). Additional predictors included mood, disease burden, estimated premorbid intelligence, and demographic variables (age, sex, BMI). As hypothesized, results revealed that changes in sleep significantly predicted changes in memory over time. Patients with stable sleep and worsened sleep demonstrated an average decline in memory z-score from baseline to follow up, whereas patients whose sleep improved demonstrated an average improvement in memory z-score. Cross-sectionally, the presence of sleep disturbance significantly predicted worse memory performance when the ISI was used a measure of sleep disturbance, but not when the PSQI was used as a measure of sleep disturbance. Taken together, results highlight the importance of acknowledging sleep disturbance as an important predictor of memory function in individuals with early MS, paving the way for highly needed efforts toward prevention and intervention. However, findings should be extended to both objective and subjective sleep measures beyond the ISI.

This thesis presents methods for quantitative MRI analysis of brain injury, repair and degeneration in multiple sclerosis (MS) that provide new insights into disease pathogenesis and evolution. / Demyelinated and inflammatory white-matter lesions are hallmark features of MS. A methodology is described to detect regions of acute white-matter lesions that undergo myelin destruction and repair based on analysis of magnetization transfer ratio (MTR) images. Validation is performed based on histopathology and error is assessed based on same-day scans. To quantify the spatial extent and temporal evolution of myelin destruction and repair, data from a 3-year clinical trial is analyzed using this method. Approximately 20% of acute lesion voxels show some repair over the initial 7 months. In subsequent months, there is little further repair, but some increases in the lesion volume undergoing demyelination. / Although less conspicuous on conventional MRI, there is considerable MS pathology in the brain tissue outside of white-matter lesions. An image-processing methodology was developed to obtain accurate metrics that quantify change over time in whole-brain MTR (associated with changes in myelin-density) and in T2 relaxation time (associated with changes in inflammatory edema). These metrics, in addition to metrics of brain atrophy and axonal integrity, were used to quantify brain injury and degeneration following immunoablation and autologous hematopoietic stem cell transplantation therapy for MS. Pronounced brain volume loss was detected immediately following therapy, associated with decreased myelin density and not resolution of edema. / Post-mortem histopathology has revealed abnormalities in the cortical grey-matter of MS patients that appear to be independent of white-matter lesions. A methodology to quantify neocortical injury and degeneration that yields cross-sectional and longitudinal metrics of cortical thickness and grey-matter/white-matter interface integrity both globally and regionally is presented and validated. MS patients with progressive disability showed greater decreases in cortical metrics compared to MS patients with stable disability. / The quantitative MRI analysis methods presented in this thesis are applicable to MRI data obtained in clinical trials of therapies for MS, have the necessary sensitivity and specificity to assess therapeutic efficacy, and provide new insights into disease pathogenesis and evolution.

Water is known to take on highly organized structures to influence the reactivity of chemical and biological systems; despite this, water is often only implicitly or approximately included in theoretical studies of biochemical systems, if not omitted entirely. Many of the current models for biological processes predate an understanding of the complex behaviour of water, yet these models have not been updated. This thesis presents an exploration of how a better of water might affect the models used to describe neurotransmission. Two classes of systems are investigated, representing the two main categories of neurotransmission: that which occurs along the length of a neuron, and that which occurs between one neuron and another cell. Lipid bilayers are studied using molecular dynamics, and neurotransmitters are studied using Car-Parrinello molecular dynamics. The results indicate that water structures may play a more specific role in neurotransmission than was previously thought.