The geographic disparity of multiple sclerosis has been noted in the literature for well over a century. The frequency of the disease varies significantly both within countries and in different parts of the world. The goal of this project is to give new insight regarding the etiology of multiple sclerosis. Several theories regarding the etiology of the disease have been reviewed, including a geographic theory, a nutritional theory, and a genetic theory. Although the geographic and nutritional theories have been thoroughly investigated by researchers, neither of them provides a conclusive explanation for the etiology of the disease, and there are discrepancies with respect to both theories. The purpose of this study is to reveal the discrepancies in the epigenetic theories regarding the etiology of multiple sclerosis and to demonstrate the correlation of multiple sclerosis prevalence and the migration and settlement history of Northern Europeans, thus conferring the passage of a genetic susceptibility to the disease.

Multiple sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system. We hypothesize that angiogenesis results in new vessels which serve as a conduit for immune cell recruitment in MS, and contribute to inflammation through the pro-inflammatory properties of angiogenic regulators. This study is one of the first to explore regulation of angiogenesis in a murine model of MS (experimental autoimmune encephalomyelitis, EAE), and its potential as a therapeutic target. Angiogenesis was apparent 21 days following disease induction and correlated with clinical and pathologic scores. We documented alterations in the VEGF and Ang/Tie signaling pathways. Expression of VEGF increased at day 14 then reduced by day 21. At this time point, Ang-2 levels were elevated due to expression by infiltrating macrophages. Ang-1 was significantly reduced at day 14 and increased at day 21 due to expression by CD3+ T-cells. The same expression pattern was validated in inflammatory cells within human MS tissue. Vascular permeability increased at day 14 and returned to control levels at day 21. The volume of permeable tissue weakly correlated with angiogenesis. VEGF blockage with bevacizumab suppressed angiogenesis and reduced clinical scores and vascular permeability. Retention of CD4+ T-cells in peripheral lymph nodes and reduced T-cell proliferation was noted following treatment. Bevacizumab reduced mononuclear cell infiltration into spinal cord. Isolated CD4+ T-cells showed reduced expression of IL-17 and IFN-??. B20-4.1.1 (a monoclonal antibody against murine VEGF) reduced clinical scores and suppressed angiogenesis as did treatment with angiostatin (an inhibitor of endothelial cell proliferation). B20-4.1.1 reduced vascular permeability, induced retention of CD4+ T-cells in peripheral lymph nodes, and inhibited T-cell proliferation, while angiostatin had no effect. Isolated lymphoid cells from mice treated with both agents showed reduced secretion of IL-17, but B20-4.1.1 had no effect on Tcell proliferation or IL-17 secretion when combined with angiostatin. ?? We conclude that these angiogenesis inhibitors are effective in EAE and act by suppressing angiogenesis with a secondary effect on peripheral T-cell activation. To the extent that EAE replicates changes occurring in MS, we have demonstrated that modulation of angiogenesis may represent a promising strategy in the management of disease progression.

Butyrylcholinesterase (BuChE) is a serine hydrolase enzyme that, along with acetylcholinesterase (AChE), catalyzes the hydrolysis of acetylcholine. These enzymes are associated with the pathology of neurologic disorders such as Alzheimer's disease (AD) and multiple sclerosis (MS). In particular, AChE and BuChE accumulate in B- amyloid (AB) plaques and tau neurofibrillary tangles in the AD brain. Thus, imaging cholinesterase activity associated with plaques and tangles in the brain has the potential to provide definitive diagnosis of AD during life. This would be advantageous since, at present, confirmation of AD relies on detecting pathology through post-mortem examination of the brain. In a similar respect, BuChE is associated with the characteristic lesions in MS brain and thus, is a promising target for diagnosis and monitoring of pathology in this disease. It is hypothesized that cholinesterase-binding radiopharmaceuticals can be used in SPECT or PET imaging to visualize these enzymes associated with AD and MS pathology in the living brain. Several classes of cholinesterase ligands were synthesized and exhibited potent binding and specificity towards AChE and BuChE using enzyme kinetic analysis. These compounds were rapidly radiolabelled with 123I and purified. Radiolabelled molecules accumulated in vitro in areas known to contain cholinesterase activity in transgenic AD mice and post-mortem human AD brain tissues, using autoradiography. Furthermore, cholinesterase activity associated with AB plaques was visualized in human and transgenic mouse AD brain tissues. An enzyme kinetic approach was employed to determine critical residues in the BuChE active site gorge for ligand binding. In particular, residues pertaining to the peripheral site of the enzyme were identified and found to be involved in the binding of various ligands. These results are crucial for optimizing the enzyme binding properties of cholinesterase imaging agents. Finally, PET imaging of a transgenic mouse model of AD was performed as a vanguard for pre-clinical evaluation of cholinesterase imaging agents. PET imaging identified similar characteristics between this AD mouse model and the human condition. This is a promising approach for evaluation of cholinesterase imaging agents. Radioligands specific for cholinesterases have the potential to provide a noninvasive means for early diagnosis of neurological diseases using brain scanning.

Cognitive deficits are highly prevalent in multiple sclerosis (MS) and have a negative impact on daily life. Impairments in information processing speed are among the most commonly reported deficits in MS and are generally assessed by evaluating mean-level performance on time-limited tests. However, this approach to assessing performance ignores potential within-subject differences that may be useful for characterizing cognitive difficulties in MS. An alternative method of measuring performance on timed cognitive tasks is to examine the degree of within-subject variability, termed intraindividual variability (IIV). IIV provides information about the characteristics of an individual’s performance and may provide novel information about cognitive functioning in MS and other neurodegenerative disorders. The research presented in this dissertation examined IIV in performance as an indicator of cognitive functioning in persons with MS and explored the relations of performance variability to measures of neuronal connectivity derived from resting state functional magnetic resonance imaging (rsfMRI). Individuals with MS were found to be both slower and more variable on tests of information processing speed and attention. This variability was observed even when controlling for sensorimotor confounds and other systematic variables that may influence variability, such as practice and learning effects. IIV in performance was found to better distinguish MS patients from matched groups of healthy control subjects when compared to common clinical measures of cognitive performance or average response speed. These differences in IIV were also found consistently across six monthly assessments in a group with MS who remained clinically stable over this period. This stability in IIV suggests its feasibility as a measure of changes in longitudinal cognitive or clinical status. Using rsfMRI, greater stability in performance (i.e., lower IIV) was associated with greater functional connectivity between frontal lobe regions (i.e., ventral medial prefrontal cortex and frontal pole) in persons with MS. This increased connectivity appears to represent potential compensatory processes within mildly affected MS individuals. Together the findings demonstrate that IIV is an important characteristic of cognitive performance that may provide new insights into the cognitive deficits present in MS.

Interactions between the immune system and the nervous system are currently underappreciated, assumed to play minor mechanistic roles in disease pathogenesis. In contrast, our laboratory has demonstrated the importance of this relationship with significant impact, initially in Type 1 Diabetes (T1D). The experiments presented here build on our previous work to provide insights into the etiology of Multiple Sclerosis (MS) and Type 2 Diabetes (T2D). Transient Receptor Potential Vanilloid-1 (TRPV1) is an ion channel expressed on peripheral sensory afferent neurons that fundamentally control T1D pathogenesis. Here we show that mice with genetic ablation of TRPV1 are protected from EAE progression, attributable to reduced central nervous system (CNS) leukocyte passage. The pathogenic role of TRPV1 in permeabilizing the blood-CNS barriers may also translate to MS, as patients with progressive disease show a significant mutation bias within the TRPV1 gene. We were simultaneously intrigued by the growing worldwide obesity epidemic, and we observed that obese mice develop more severe EAE compared to lean mice. This was mechanistically linked to an expansion of TH17 cells, driven by sustained rises of IL-6 in obese mice. This research implies new therapeutic opportunities for the many obese patients with diverse autoimmune diseases. Finally, the immune system, obesity, and T2D are functionally linked, and we contributed to research that uncovered a large presence of immune cells in adipose tissue that drive insulin resistance. Manipulation of T cells and B cells affects local inflammation as well as whole-body insulin resistance and glucose homeostasis. Intriguingly, auto-antibodies in insulin resistant individuals are specific for a number of unique proteins, including glial fibrillary acidic protein (GFAP), initially shown by our laboratory to play a key role in T1D progression. We further characterized the autoimmune and neuronal progression elements that steer disease pathogenesis, and observed that administration of a vaccine containing GFAP is able to dramatically reduce weight gain and insulin resistance in mice. The data presented in this thesis provide a number of novel, mechanistic observations linking the immune and nervous systems in disease, and implies several potential avenues for treatment.

No description available.

This doctoral dissertation presents a series of studies that were conducted to investigate the relationship between morphological, as well as functional, changes and clinical disability in multiple sclerosis (MS) using magnetic resonance imaging (MRI) and functional MRI (fMRI). / The extent of macroscopic brain tissue damage, as seen on T2-weighted MRI scans, is poorly correlated with measures of functional impairment in MS. We hypothesized that this might be due to the failure to take lesion location into account. By combining sophisticated lesion segmentation tools with the statistical and stereotaxic techniques of functional neuroimaging, we have shown a relationship between lesion location and the extent and type of physical and cognitive disability. / Brain atrophy is another manifestation of MS. We conducted the first large-scale study of focal cortical atrophy in MS that uses cortical thickness measurements across the entire cortex. We present evidence that cortical atrophy occurs relatively early in the course of the disease, despite the lack of severe disability in MS patients, as assessed by the Expanded Disability Status Scale (EDSS), and follows a pattern of focal thinning that is more pronounced in areas that are heavily inter-connected with other brain regions, such as anterior cingulate cortex and association areas, suggesting that interruption of white matter tracts by MS plaques might play a causative role in cortical atrophy. / Finally, we conducted an fMRI study of working memory in controls, cognitively unimpaired and impaired MS patients that revealed significant differences in the regions that were activated between the groups. Most interestingly, while both cognitively unimpaired MS patients and control subjects significantly activated the left dorsolateral prefrontal cortex and the left thalamus, cognitively impaired MS patients failed to significantly activate these areas. Levels of deactivation within the medial prefrontal/anterior cingulate cortices and posterior cingulate cortex were inferior in MS patients than in controls. This study suggests that with an increased white matter lesion volume there is an increased damage to a number of afferents and efferents to and from the thalamus (cortico-basal ganglia-thalamo-cortical loops and other thalamo-cortical projections) that ultimately causes the observed cognitive deficits. These cognitive deficits seem also to be dependent on a reduced capacity of MS patients to show task-related deactivations.

Multiple Sclerosis (MS) is an autoimmune demyelination disease of the central nervous system (CNS). The traditional immunotherapies so far have not been able to stop the progression of the disease. Galanin (GAL) is an inducible neuropeptide. It has diverse regulatory effects in the nervous. The expression of galanin is induced by the administration of estrogen and is increased during pregnancy in rodents. In women with MS, pregnancy has a protective effect associated with significant remission of MS symptoms during the second and third trimester. In this study, using the cuprizone (CPZ) demyelination model of MS I demonstrated that GAL has a pronounced neuroprotective effect on demyelination and remyelination, with estrogen the protection was further enhanced. Moreover, I also found differential activation of GAL receptors in the demyelination and remyelination processes. These results suggest GAL alone or combined with estrogen might introduce next generation strategies for the treatment of MS.

Multiple Sclerosis (MS) is an autoimmune demyelination disease of the central nervous system (CNS). The traditional immunotherapies so far have not been able to stop the progression of the disease. Galanin (GAL) is an inducible neuropeptide. It has diverse regulatory effects in the nervous. The expression of galanin is induced by the administration of estrogen and is increased during pregnancy in rodents. In women with MS, pregnancy has a protective effect associated with significant remission of MS symptoms during the second and third trimester. In this study, using the cuprizone (CPZ) demyelination model of MS I demonstrated that GAL has a pronounced neuroprotective effect on demyelination and remyelination, with estrogen the protection was further enhanced. Moreover, I also found differential activation of GAL receptors in the demyelination and remyelination processes. These results suggest GAL alone or combined with estrogen might introduce next generation strategies for the treatment of MS.

Mobility in all of its forms is highly commodified in a globalised system. Much focus on mobility theory has offered a new ‘mobilities turn’. Largely absent from this ‘mobility turn’ is an examination of the relationship between mobility and health. This case study focuses on the Canadian televised and print media attention given to a medically contested procedure: liberation therapy (LT), which emerged as the possible treatment for multiple sclerosis (MS). As a non-insured service, Canadian MS patients wanting access to the procedure must travel to other geographical locations in what is termed as medical tourism. A comprehensive media analysis reveals an overwhelming patient mobility in the hopes of positive outcomes mainly from anecdotal stories. Patients’ advocacy for LT intensified and this pressured governments’ to fund clinical trials. This highlights the influence of the media in mobilizing patients and directing resources for research in the Canadian health care system.