Multiple Sclerosis (MS) is the most common demyelinating disease affecting the central nervous system. Over 80% of MS patients are in the relapsing remitting stage. Symptoms range from fever, fatigue, emotional distress, tingling, numbness, optic neuritis, spasticity, muscle weakness, impaired coordination, to other abnormal neurological problems. Expression of symptoms is known as a relapse or exacerbation. The cause of relapses is unknown, but multiple factors seem to play a significant role. Possible factors that may influence MS onset and relapse consist of a genetic association, viruses, disruption of the blood-brain barrier, and stress. Stress has shown to have negative implications and may stimulate relapses. Thus, this study examined a possible stress intervention that most people already had available to them, companion animals. Companion animals have been shown to lower blood pressure, decrease heart rate, provide social support, and reduce stress. The main hypothesis was to evaluate whether or not pet ownership and/or attachment influenced the perceived stress level and number of negative life events experienced by MS patients in the relapsing remitting stage. Participants were given a questionnaire that consisted of 7 surveys. The questionnaire accessed quality of life, disease severity, number of negative life events, perceived stress level, level of depression, social support, and pet ownership and attachment level. Our sample population consisted of MS patients seen at the University of Texas Southwestern Neurology clinic from February 23rd to May 21st, 2004. One hundred and forty seven relapsing remitting MS patients were included in the study. Multiple linear regression was used to compare the relationship of stress and number of negative life events to pet ownership and attachment. Results revealed that pet ownership and attachment levels did not affect the stress level and number of negative life events of MS patients. No confounders were identified. Interaction terms with disease severity as the dependent variable, pet ownership and perceived stress level or negative life events as the independent variables were not significant. The type of pet owned did not influence the attachment level of the MS patient. In conclusion, the results of this study did not support the hypothesis.

Stressful life events have been associated with the onset and/or exacerbation of multiple sclerosis (MS). To investigate the effects of stress on the pathogenesis of MS, we employed restraint stress (RST) in the Theiler’s virus-induced demyelination (TVID) model, an animal model for human MS. Intracerebral inoculation of susceptible strain of mice with Theiler’s murine encephalomyelitis virus (TMEV) results in a biphasic disease – an acute encephalomyelitis and chronic demyelination. The establishment of persistent viral infection is critical in inducing immune-mediated demyelination during the chronic disease. The exposure of mice to RST prior to viral infection produced a stress response as evidenced by elevated circulating corticosterone (CORT). To further study the effect of stress on the immune response to TMEV infection and demyelination, we first examined the cytokine and chemokine response during the acute TMEV infection. We demonstrated that RST down-regulated the virus-induced expression of chemokines, Ltn, IP-10, RANTES, and pro-inflammatory cytokines, TNF, IFN and LT in both the brain and spleen during early infection. Histologically, a decreased pattern of inflammation was observed in the brain of restrained mice as compared to non-restrained mice. The increased viral titer was noted in the CNS of restrained mice and was correlated with the decreased production of pro-inflammatory cytokine, suggesting an impaired immune response by RST. Secondly, the duration of stress on the late demyelination was investigated. Repeated and chronically stressed SJL/J mice developed an early onset of clinical signs and a delayed onset was observed in acutely stressed mice. Both acute and chronic RST suppressed the antibody response to TMEV and stressed displayed a higher incidence of demyelination than non-restrained mice. Axonal loss was also noted in chronic stressed mice. Additionally, RST caused an increased systemic viral infection in extraneural organs during the acute infection and cardiotropic TMEV was isolated from the heart of stressed mice. Taken together, stress resulted in profound immunsuppression during acute infection, which may consequently increase the incidence of demyelination. The present study may be generalized in human MS which is potentially triggered by viral infection.

Thesis (Ph. D.)--Ohio State University, 2009. / Title from first page of PDF file. Includes vita. Includes bibliographical references (p. 119-139).

No description available.

published_or_final_version / Anatomy / Doctoral / Doctor of Philosophy

The purpose of this secondary analysis was to test a multivariate model of disability separately in women with two different conditions, multiple sclerosis (MS) and fibromyalgia syndrome (FMS), and to compare respective models across groups. Guided by the Disablement Process Model, this study examined the influences of functional limitations, depressive symptoms, economic adequacy, and social support on disability by use of two-group structural equation modeling (SEM). Nonprobability samples of women with MS (N = 118) and women with FMS (N = 197) were recruited for separate health promotion intervention studies. Baseline data collection occurred between 1997 and 1998 for women with MS enrolled in the Wellness Intervention and between 2004 and 2006 for women with FMS enrolled in the Lifestyle Counts Intervention. Participants in both samples were largely married, well-educated, middle-age, and Caucasian. Descriptive statistics, bivariate correlations, and SEM were conducted with the Statistical Package for the Social Sciences 15.0 and Amos 7.0 software programs. Mean scores of the major study variables indicated poorer physical and mental health for the sample of women with FMS compared to that with MS. Controlling for age, duration of illness, and education, greater functional limitations predicted greater SFdisability and Role Physical (RP)-disability in both groups. The influence of Functional Limitations on both SF-disability and RP-disability was greater for women with FMS than MS. The effect of Depressive Symptoms on SF-disability was equivalent across groups. Feeling depressed significantly impacted RP-disability, although these effects were not equal across groups. Depressive Symptoms played a larger role than did Functional Limitations in explaining SF- and RP-disability in women with MS. Social Support affected Depressive Symptoms equally for both groups. For women with MS, compared to women with FMS, Economic Adequacy had greater detrimental effects on Depressive Symptoms and both measures of disability. Social Support and Depressive Symptoms mediated the effect of Functional Limitations on disability. Adjustment to life with a chronic illness depends on, at the very least, individual physical, social, and psychological capacities. Practitioners should be sensitive to depressive symptoms and availability of social support in women with MS or FMS. / text

No description available.

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.

Recent reviews (Peyser & Poser, 1986; Rao, 1986) suggest that Multiple Sclerosis results in cognitive impairments in the areas of learning and memory, abstract reasoning, information processing efficiency, and, often, visual-spatial ability. Whether this pattern applies to the individual with MS is unclear. Due to the disseminated distribution of MS neuropathology, patients may undergo idiosyncratic cognitive changes dependent upon the site of white matter lesions. The present study explored this question using cluster analysis on the neuropsychological data from a group of mildly disabled MS patients (n = 177) and a well-matched control group (n=89). In a group of MS patients who were identified with unequivocal cognitive impairment, the resultant clusters indicated that MS does not result in a characteristic pattern of impairment. Two clusters were obtained that resembled the pattern described in the literature, while the majority of patients clustered into groups with specific deficits in one or two areas, with normal performance in others. In order to identify associations between cluster groups and lesion sites, frequency tables were constructed for the presence of a lesion on Magnetic Resonance Imaging in 24 brain sites. An association was obtained between two lesion sites and two cognitive tests. Visual-spatial impairment, as assessed by the Benton Visual Retention test, was associated with lesions in the genu of the corpus callosum and with more lesions throughout the corpus callosum. Impaired performance on Paired Associates, a test of learning and memory for novel verbal associations, was associated with a lesion in the deep white matter of the left parietal lobe. The results support the hypothesis that MS results in multiple patterns of cognitive impairment depending on the individual placement of white matter lesions. Identifying and characterizing the heterogeneity of the impairment may greatly increase our understanding of the role of myelin in cognition and the functions of white matter tracts in the brain.

T2 relaxation imaging can be used to measure signal from water trapped between myelin bilayers; the ratio of myelin water signal to total water is termed the myelin water fraction (MWF). First, results from multi-component T2 relaxation and diffusion tensor imaging (DTI) were compared for 19 multiple sclerosis (MS) subjects at 1.5 T to better understand how each measure is affected by pathology. In particular, it was determined that the detection of a long-T2 signal within an MS lesion may be indicative of a different underlying pathology than is present in lesions without long-T2 signal. Next, the single-slice T2 relaxation measurement was implemented, refined, and validated at 3.0 T. Scan parameters were varied for phantoms and in-vivo brain, and changes in multi-exponential fit residuals and T2 distribution-derived parameters such as MWF were monitored to determine which scan parameters minimized artifacts. Measurements were compared between 1.5 T and 3.0 T for 10 healthy volunteers. MWF maps were qualitatively similar between field strengths. MWFs were significantly higher at 3.0 T than at 1.5 T, but with a strong correlation between measurements at the different field strengths. Due to long acquisition times, multi-component T2 relaxation has thus far been clinically infeasible. The next study aimed to validate a new 3D multi-component T2 relaxation imaging technique against the 2D single-slice technique most commonly used. Ten healthy volunteers were scanned with both the 2D single-slice and 3D techniques. MWF maps were qualitatively similar between scans. MWF values were highly correlated between the acquisition methods. Although MWF values were generally lower using the 3D technique, they were only significantly so for peripheral brain structures, likely due to increased sensitivity of slab-selective refocusing pulses used for the 3D approach. The 3D T2 relaxation sequence was then applied to the study of MS to take advantage of the increased brain coverage. Thirteen MS subjects and 11 controls underwent T2 relaxation and DTI examinations to produce histograms of MWF and several DTI-derived metrics. MS MWF histograms differed considerably from those of controls, and differences in MS MWF histograms did not mirror differences in DTI histograms relative to matched controls.