The primary objective of this study was to assess cognitive functioning in participants with relapsing remitting multiple sclerosis (RRMS) using the MicroCog and to compare their performance to that of a demographically matched, healthy control group. It was hypothesized that as a group, participants with RRMS would have worse cognitive function than healthy controls on all Level 1, 2, and 3 Index scores of the MicroCog. Twenty-six participants with RRMS and twenty-nine sex and education matched healthy controls were administered the MicroCog (Standard Form) along with measures of depression and clinical status, and paper-pencil tests of processing speed (Symbol Digit Modalities Test; SDMT and Paced Auditory Serial Addition Test; PASAT). A series of ANCOVAs with depression as a covariate was performed to determine between group differences for each MicroCog Level 3 Index score (General Cognitive Proficiency (GCP) and General Cognitive Functioning (GCF)), Level 2 Index score (Information Processing Accuracy (IPA) and Information Processing Speed (IPS)), and Level 1 Index score (Attention/Mental Control, Memory, Reasoning/Calculation, Spatial Processing, and Reaction Time). Pearson's and point biserial r correlations were calculated in order to assess the degree to which Level 2 and 3 Index scores correlated with clinical and demographic factors (sex, disease duration, depression, and clinical status) and to correlate the MicroCog IPS index score with traditional measures of processing speed. Eight RRMS and two control participants met criteria for cognitive impairment on the MicroCog. ANCOVA results indicated there were significant differences between RRMS and control performance for two MicroCog scores (GCF and IPS). There were not significant differences for GCP, IPS, and all Level 1 scores. A post-hoc analysis performed for the same hypothesis with a group of age equivalent participants suggested a significant RRMS by depression interaction for Level 3 scores. RRMS was not predictive of Level 2 scores after controlling for depression in the age equivalent sample. Correlations for clinical and demographic factors with cognitive outcomes indicated significant relationships for clinical status and depression. There was not a significant relationship detected for disease duration or sex. MicroCog and processing speed measures were significantly related. Post-hoc analyses supported that the criterion validity of the MicroCog is comparable to other cognitive screening tools in RRMS. The results and limitations of our study are discussed, in addition to recommendations for future research.

No description available.

Multiple sclerosis (MS), a demyelinating disorder of the central nervous system (CNS), affects approximately 400,000 individuals in the United States, and 2.5 million people worldwide. It is a leading cause of disability in young adults. Current treatments for MS target the inflammatory aspects of the disease, but do not aid in remyelination. To address remyelination as a therapeutic strategy, it is imperative to identify mechanisms that regulate myelin formation, including epigenetic targets. In this study, we investigate the role of the LMNA, a gene encoding Lamins A and C, intermediate filaments of the nuclear lamina, in regulating oligodendrocyte development and myelination in the CNS. Using electron microscopic analyses, I examined levels of heterochromatin and its distribution in the oligodendrocyte nucleus as an indicator of gene expression, oligodendrocyte maturity, and myelin formation in the absence of A type lamins.. While overall levels of heterochromatin in oligodendrocytes were not altered in the absence of A type lamins, peripherally located heterochromatin was reduced and thinner myelin was observed in the spinal cord. My observations present novel findings for the role of LMNA in oligodendrocytes and myelination.

People with the autoimmune disease multiple sclerosis (MS) have few options for educational activities. Although web-based instruction may be a viable option, little is known about how people with MS perceive this form of learning. The purpose of this qualitative study was to understand the experiences of people with MS regarding web- based instruction. The 3 learning structures--differentiated instruction, collaborative learning, and assistive technology--provided the conceptual framework for this research. Nine volunteers from the Pacific Northwest area of the United States who have MS were individually interviewed for this basic qualitative study. Transcripts were analyzed using open, axial, and selective coding. The results indicated that all participants found personal and professional benefits of their experience with web-based instruction and used course management systems to successfully communicate with instructors or peers. Participants also noted that these management systems did not directly aggravate their MS disease symptoms. Findings from the study may be useful information to individuals with MS for effectively managing their educational choices. This study's results could also be used by learning institutions to improve the access to education and allow individuals with MS to more fully participate in training opportunities.

This thesis examines the pathophysiology of motor neurone dysfunction, along with site of disease onset, in amyotrophic lateral sclerosis (ALS). The rationale for this thesis is the "dying forward" hypothesis, which suggests that corticomotoneurons cause anterograde excitotoxic degeneration of motor neurons in ALS. Initially, axonal excitability studies were applied to ALS patients and revealed widespread axonal ion channel dysfunction, with increases in persistent Na+ conductances and reduction in K+ currents. Such changes result in axonal hyperexcitability, thereby resulting in generation of fasciculations and cramps. Subsequently, axonal excitability studies were applied to Kennedy's disease (KD) patients, a pathological control group, revealing similar changes to ALS and suggesting that upregulation of persistent Na+ conductances was responsible for generation of fasciculations. To better understand the mechanisms underlying fatigability and to assess whether Na+/K+ pump dysfunction contributes to neurodegeneration in ALS, activity-dependent changes in axonal excitability were measured after a maximal voluntary contraction. The increase in threshold was more pronounced in ALS patients with predominantly lower motor neuron involvement, suggesting that peripheral factors were responsible for fatigue in ALS and that Na+/K+ pump function was preserved. Having documented abnormalities of axonal excitability, a novel threshold tracking transcranial magnetic stimulation (TMS) technique was developed for assessment of cortical excitability. This technique overcomes the marked variability in the motor evoked potential with consecutive stimuli, a major limitation of the previous "constant stimulus" technique. After establishing normative data, threshold tracking TMS established that cortical hyperexcitability was an early and prominent feature in ALS. Similar changes were found in flail-arm variant ALS, a pure lower motor neuron form of ALS. In KD patients, cortical excitability was normal, thereby suggesting that cortical hyperexcitability is a primary event in ALS rather than a down-regulation of inhibitory control over the motor cortex in order to compensate for anterior horn cell loss. In order to determine whether cortical hyperexcitability underlies motor neurodegeneration, longitudinal studies were undertaken in familial ALS subjects with the copper/zinc superoxide-dismutase-1 gene mutation. These studies established that cortical hyperexcitability precedes the development of clinical ALS, thereby suggesting that cortical hyperexcitability underlies the basis of motor neurodegeneration in familial ALS.

Motor neurone disease (MND) is an uncommon neurodegenerative disease that is terminal and has an insidious onset. With no known cause or cure, the disease triggers progressive death of motor neurones that causes increasing difficulties with mobility, communication, breathing and nutrition. Most research focuses on the disease process, but little is known of the illness experience from the perspective of those diagnosed with the disease. The aim of this study was to explore what it is like to live with MND and how people with the disease negotiate with others to exercise choice over the way they live. A grounded theory methodology was used to explore the life world of people diagnosed and living with MND. Data were collected via in-depth interviews, their stories and photographs, poems and books participants identified as important and fieldnotes. The textual data were analysed using constant comparative analysis. The majority of participants experienced difficulty with verbal communication. Some invited a third person to interpret their speech and others used assistive technologies such as Lightwriters and computers. Analysis revealed three constructs that, together, told the story of the MND illness experience. First, was the “diagnosis story” that described the devastating process of repeated tests had on the participants, shattering their trust in the competence of the health care system. The second construct revealed the process of living with MND as cyclical and repetitive requiring constant decision-making to adapt to the ongoing changes connected with the disease. The core theme and basic social process of “maintaining personal integrity” evolved as the third construct. This process underpinned and explained participants’ decision-making. Finally a substantive theory was conceptualised as the illness experience: “maintaining personal integrity in the face of ongoing change and adaptation”. This theory illustrates that the basic social process of maintaining personal integrity is central to decision and choice making while living with MND. The findings have implications for people with MND, their carers, health professionals and service providers. Recommendations include improved counselling services for people at the time of diagnosis; the introduction of nurse specialists to support health professionals, people diagnosed with the disease and their families; open, accessible, realistic health and funding policies.

The present study prospectively examines factors that affect whether self-enhancement exerts favorable or unfavorable effects on both psychological and physical well-being in a context that is less controllable than other contexts in which self-enhancement has been examined (e.g., academic performance), an at risk population of Multiple Sclerosis (MS) patients. In particular, the present study (a) examines whether self-enhancement differentially predicts psychological and physical well-being when self-enhancement is related or unrelated to the well-being outcomes, and (b) whether self-enhancement interacts with severity of circumstances (i.e., course of MS) to predict psychological and physical well-being, as suggested by O’Mara, McNulty, & Karney (2011). In addition to the baseline assessment, participants completed measures of self-enhancement (outcome-related and outcome-unrelated), and psychological and physical well-being every 30 days for 90 days, for a total of four assessments. The pattern of findings suggests that in less controllable contexts, self-enhancement is a doubled-edged sword. Outcome-related self-enhancement was trending towards a positive, cross-sectionally association with physical well-being, and a measure of prior outcome-unrelated self-enhancement (collectivistic tactical self-enhancement) was positively associated with subsequent physical well-being only for individuals with less severe MS. Further, prior outcome-related self-enhancement was associated with better subsequent psychological well-being but worse subsequent physical well-being, and although prior collectivistic tactical self-enhancement is associated with favorable subsequent physical well-being for individuals with less severe MS, it is also associated unfavorable psychological well-being regardless of MS severity. The discussion addresses the contributions of the present study to the literature, strengths and limitations of the present study, and directions for future research.

Theiler's murine encephalomyelitis virus (TMEV) is classified as a Cardiovirus in the Picornaviridae family. An enteric virus, TMEV, spreads within the mouse population by the fecal-oral route. The neurovirulent GDVII strain of Theiler's virus causes a fatal encephalitis in all strains of mice following intra-cranial infection of the virus. Persistent BeAn strain of Theiler's virus causes a demyelinating disease in susceptible strains of mice, which is similar to the human disease - Multiple Sclerosis (MS). Although a well-recognized model for MS, the route of entry of the virus into the central nervous system (CNS) following natural infection has not been well understood. One of the proposed portals of entry includes the blood-brain barrier (BBB). This report indicates the ability of both the neurovirulent and the persistent strains of Theiler's virus to induce apoptosis in the functional units of the BBB - the cerebrovascular endothelial cells (CVE) both in vitro and in vivo. Induction of apoptosis in CVE was demonstrated by Annexin staining, electron microscopy, DNA fragmentation assay, Hoechst staining and by caspase-3 staining. Corresponding to results by other authors, GDVII is a stronger inducer of apoptosis in CVE compared to BeAn. Induction of apoptosis is dependent on the MOI of the virus. UV-inactivated virus is not capable of inducing apoptosis and induction of apoptosis appears to be an internal event not requiring activation of death receptors. Determining the pathway of induction of apoptosis by TMEV in CVE indicated the involvement of a Ca2+ dependent pathway for apoptosis - the calpain pathway. Involvement of calpain in apoptosis has been reported in MS. Induction of apoptosis in CVE in vivo was also demonstrated following the intra-peritoneal inoculation of Theiler's virus. Induction of apoptosis in CVE following Theiler' virus infection could lead to a breach of the BBB and entry of inflammatory cells as well as virus into the central nervous system. This finding could aid understanding the neuropathogenesis of Theiler's virus.

Amyotrophic lateral sclerosis (ALS) is a progressive, lethal, degenerative disorder of the CNS. The hallmark of this disease is the premature and selective death of upper and lower motor neurons (MNs) in the brain and spinal cord, leading to fatal paralysis. Although the archetypal vision of neurotoxicity in neurodegenerative diseases is based on the idea that a specific neuronal population is particularly vulnerable to a cumulative toxic event (protein aggregation, mitochondria dysfunction, compromised axonal transport etc…), experimental evidence illustrate that ALS possibly does not arise strictly from damage within MNs. There is now convincing data supporting a non-cell autonomous mechanism in which neurodegeneration is influenced by the toxicity of non-neuronal cells in the vicinity of neurons such as astrocytes and microglia. Considering the accumulation of data implicating astrocytes in the pathogenesis of ALS (loss of GLT-1, secretion of toxic factor, enhanced inflammation, etc…), approaches aiming at replacing astrocytes at site of lesions constitute promising therapeutic strategies. Rapid progresses in the characterization of adult stem cell biology have generated considerable enthusiasm for the development of therapeutic strategies for CNS insults. Several observations support the hypothesis that stem cells may display a valuable influence on diseased host tissues by exerting a protective “chaperone” effect to neurons after differentiation in glial cells. Hence, we decided to study the neuroprotective potential of adult mesenchymal stem cells (MSCs) in ALS. In contrast to neural stem cells (NSCs) which localization in the central nervous system complicates their isolation, MSCs are easily isolated from the bone marrow. The relevance of using on MSCs in stem cell therapies of neurodegenerative disorders is also justified by their capacity to (trans)differentiate into neural cells. For this purpose, we exposed MSCs to growth factors involved in the astroglial differentiation of NSCs. The differentiation of MSCs was characterized by the acquisition of astrocyte morphology in addition to an increased expression of gene related to NSCs (nestin) and astrocytes (glutamine synthetase). The astroglial differentiation of MSCs is associated with the acquisition of a glial-like specific regulation of the production of GDNF, a potent neurotrophic factor for neurons. Then, we characterized the glutamate uptake in differentiated MSCs, a critical function of astrocytes. Our data demonstrate that the differentiation of MSCs is associated with an increased expression of the high affinity glutamate transporter, GLT-1. Thus, our in vitro results confirm the astrocytic differentiation potential of MSCs and we decided to use then in stem cell therapy of ALS. Indeed, we demonstrated that mechanism of stem cell recruitment is present in the spinal cord during the development of the disease by the secretion of stem cell factor (SCF). We injected MSCs derived from healthy animals into the cerebrospinal fluid of a transgenic rat model of familial ALS (expressing a mutated form of the human superoxide dismutase-1, hSOD1G93A) at disease onset. MSCs were found to infiltrate the nervous parenchyma and migrate substantially into the ventral grey matter by interacting with the SCF. At the site of lesion, MSCs differentiated massively into astrocytes around MNs. The intrathecal delivery of MSCs preserved motor functions and extended the survival of hSOD1G93A rats. Investigation of the lumbar spinal cord 35 days after graft demonstrated that the generation of healthy astrocytes from MSCs decreased motor neuron loss. However, this beneficial effect is not related to a decreased excitotoxicity by the rescue of GLT-1 expression but rather a decreased inflammation around MNs. Together, the data presented in this thesis highlight the protective capacity of adult MSC-derived astrocytes in the treatment of ALS.

Ungefär 200 personer insjuknar årligen i sjukdomen amyotrofisk lateralskleros (ALS), vilket ses som en ökning de senaste 30 åren. Att insjukna i en obotlig sjukdom bidrar till både fysiskt och psykiskt lidande. Det är viktigt att förstå patienters upplevelser av sjukdomen vilket det saknas information om. Syftet var att utifrån självbiografier, beskriva patienters upplevelser av att leva med ALS. En kvalitativ innehållsanalys beskriven av Lundman och Hällgren Graneheim gjordes. Datamaterialet bestod av sju självbiografier. Ur datamaterialet urskiljdes patienters känslor och upplevelser kring sjukdomen ALS i form av sex kategorier med tillhörande underkategorier. Kategorierna som framkom var; svårigheter kring den begynnande sjukdomen, tankar kring döden, sorg, bristande självkänsla, att känna sig utlämnad och att få insikt i sin sjukdom. Informanternas beskrev upplevelserna olika eftersom det fanns variationer av varje individs sjukdom. Att slutligen kunna se positiva stunder trots sin sjukdom var betydande. Ingen vet bättre än patienten själv hur den mest uppskattade omvårdnaden kan ges. Därför är det av vikt att lyssna på patienters upplevelser och deras egen berättelse av den upplevda sjukdomen. Erfarenheterna av sjukdomen var av olika karaktär men likheter kunde ses där många upplevelser var återkommande hos de flesta informanterna. / About 200 persons become ill annually with the illness amyotrophic lateral sclerosis (ALS), which can be seen as an increase in the last 30 years. Falling ill in an incurable illness contributes to both physical and psychological suffering. It is important to understand the patient’s experiences of the illness and this is a field where there is little or no information available. The aim of this study was to describe the patients’ experiences of living with ALS from autobiographies. A qualitative content analysis described by Lundman and Hällgren Graneheim was performed. The data material consisted of seven autobiographies. From the data material patient’s feelings and experiences of the illness ALS was discerned in terms of six categories with associated subcategories. The categories were; difficulties of the emerging illness, thoughts about death, sadness, lack of self esteem, to feel deserted and to reach insight into their own illness. The informants described experiences differently due to individual variations of illness. To eventually be able to see positive moments despite the illness was significant. No one knows better than the patient how the most appreciated nursing care should be. Therefore it is of importance to listen to patients’ own experience of the illness. The experiences of the illness varied but similarities could be seen where many experiences were recurrent among most informants.