Background: Research in psychological adjustment to multiple sclerosis (MS) suggests that the way individuals appraise their condition can have an impact upon their psychological well-being and adjustment to their condition. Such research has influenced the development of Cognitive Behavioural Therapy (CBT) interventions in this population. In recent years, Acceptance and Commitment Therapy (ACT) has gathered increasing interest in relation to chronic health conditions. ACT does not target the content of thought, but rather focuses on the contexts in which thought occurs (i.e. how individuals relate to their experiences). Aim and Primary Hypothesis: A cross sectional design was used to compare the extent to which cognitive appraisals and ACT constructs (‘acceptance’ and ‘cognitive fusion’), mediate the relationship between physical symptoms of MS and psychological adjustment outcomes. It was hypothesised that in comparison to cognitive appraisals, ACT constructs would serve as stronger mediators of the relationship between physical symptoms of MS and outcome measures. This study also piloted a newly adapted measure of MS related acceptance, the Multiple Sclerosis Acceptance Questionnaire (MSAQ). Method and Results: Participants (N = 133) completed self-report measures of: MS symptom severity, various cognitive constructs (cognitive appraisals and ACT constructs), symptoms of psychological distress, and satisfaction with life. Multiple mediation analysis was then used to compare competing mediational hypotheses. In comparison to all measures of cognitive appraisals, the ACT constructs tended to be stronger mediators of the relationship between symptoms and outcome measures (both psychological distress, and satisfaction with life). There was also some evidence for appraisals of personal control mediating the relationship between symptoms of MS and psychological distress. Conclusions: This research suggests that ACT constructs may be relevant to the process of psychological adjustment to MS, and that ACT based interventions may be worthy of investigation in this population. The newly adapted MSAQ also shows preliminary promise as a measure of MS related acceptance.

Die Magnetresonanztomographie stellt für die Detektion von zerebralen und spinalen Läsionen bei der Multiplen Sklerose die sensitivste bildgebende Methode dar und ist ein Instrument, die räumliche und zeitliche Dissemination der Erkrankung abbilden zu können. Die Spezifität des Verfahrens ist aber gering und die Applikation von MR-Kontrastmittel bei der Diagnostik zwingend notwendig. Bei der suszeptibilitätsgewichteten Magnetresonanzbildgebung (SWI) handelt sich um ein MR-Verfahren, das Schwankungen der magnetischen Suszeptibilität in der Gradientenechosequenz nutzt, um einen Bildkontrast zu erzeugen. Dadurch ist es möglich, hochaufgelöst und sensitiv Magnetfeldinhomogenitäten zu detektieren. In der vorliegenden prospektiven Studie wurden im Zeitraum von 2010 bis 2013 MRT-Untersuchungen unter Einschluss der suszeptibilitätsgewichteten Bildgebung in einem Kollektiv von 41 Patienten (33 weiblich, 8 männlich;; Durchschnittsalter 40 Jahre) mit gesicherter Multipler Sklerose und einem Vergleichskollektiv von 43 Patienten (28 weiblich, 15 männlich;; Durchschnittsalter 45 Jahre), bei denen weder bildgebend noch klinisch Hinweise auf eine Multiple Sklerose vorlagen, durchgeführt. Die Untersuchung wurde mit einem 1,5-Tesla-Magnetresonanz- tomographen realisiert. Das besondere wissenschaftliche Interesse galt dabei der „normal erscheinenden weißen Substanz“ (NAWM) und den zerebralen Läsionen. In der FLAIR-Sequenz wurden die MS-Läsionen und ROIs detektiert und markiert. Anschließend erfolgte die Übertragung in gleicher Schichthöhe auf die SWI-, T1w- und ADC-Sequenz. Zur Differenzierung von akuten und chronischen Läsionen erfolgte im Untersuchungsablauf die intravenöse Gabe von Gadolinium-DTPA- Kontrastmittel. Schon längere Zeit werden im wissenschaftlichen Diskurs krankheitsspezifische Veränderungen in der NAWM vor Auftreten der MS-Läsionen vermutet. Die Sensitivität der FLAIR-Sequenz ist aber scheinbar unzureichend. Mit der SWI- Bildgebung konnten statistisch signifikante SI-Unterschiede zwischen Referenz- und MS-Gruppe in der NAWM herausgearbeitet werden. Nach Kontrastmittelgabe wurden dabei keine Veränderungen der Signalintensität der NAWM in den beiden Gruppen festgestellt, was gegen die Hypothese einer primären Schrankenstörung in der Pathogenese der Erkrankung spricht. Insgesamt wurden 669 Läsionen identifiziert. Es folgte eine Differenzierung in 11 KM-aufnehmende (ACM-) Läsionen, 546 nicht KM-aufnehmende (NACM-) Läsionen und 112 „black holes“ (BLH). Eine gezielte Auswertung der Phasen- und Magnitudenbilder wurde nicht durchgeführt. Besonders in den KM-anreichernden Läsionen (ACM) sind bereits vor der KM-Gabe statistisch erhöhte Signalintensitäten in der SWI-Sequenz nachweisbar. Dies könnte theoretisch für den Nachweis akuter Läsionen, ohne dass eine KM-Gabe notwendig ist, genutzt werden. Doch ist die Anzahl dieser Läsionen in der Untersuchung zu gering, um verlässliche Aussagen diesbezüglich machen zu können. Dafür sind weitere Studien notwendig. Zusammenfassend betrachtet handelt es sich bei der SWI um ein hoch sensitives bildgebendes Verfahren, welches eine ausgezeichnete Differenzierung von ZNS- Läsionen ermöglicht und Veränderungen der NAWM bei der Enzephalomyelitis disseminata nachweisen kann. Es stellt somit eine sinnvolle Ergänzung zur konventionellen MS-Diagnostik dar und ist ein innovatives bildgebendes In-vivo- Verfahren zur weiteren Erforschung der Multiplen Sklerose.

Immune-mediated inflammatory diseases (IMID) represent a group of ostensibly unrelated, chronic and highly disabling diseases that preferentially affect different organ systems. IMID are assumed to manifest as a result of the accumulation of genetic, environmental and immunological factors. A fundamental commonality between IMID is the idiopathic nature of disease, and moreover, substantial similarities are apparent in disease etiopathogenesis. The complex assemblage of microbes and their genes that exists within and on the human body, collectively known as the microbiome has emerged as a critical factor in human health and, altered microbial populations within the gastrointestinal tract lumen and mucosa have been linked to several IMID. Accordingly, we conducted several studies investigating the association of the gut microbiome with IMID. Our main study investigated differences in the microbial profile and functional potential of multiple IMID utilizing 16S rDNA amplicon sequencing and analysis of stool. We also investigated the mucosal-associated microbiome in IBD to characterize the microbial populations and their functions residing in distinct gastrointestinal compartments from inflamed and noninflamed mucosa. We also explored a potential environmental factor; specifically assessing whether microbes present in drinking water in low or high incidence areas of IBD might contribute to disease etiology. The findings of these studies are manifold. First, we show important differences of the stool microbial profile in IMID. In doing so, we were able to identify distinct states of gut dysbiosis and have revealed numerous microbes that are consistently or uniquely disproportionate between IMID. Second, we have shown the microbial profile associated with inflamed and noninflamed mucosa and have reported that a localized dysbiosis is not observed in the presence of inflammation. Third, we have revealed that distinct gastrointestinal compartments are comprised of similar microbial communities. Lastly, we have reported the drinking water microbiome to differ between low and high incidence areas of IBD, thus suggesting a potential role in IBD etiology. Understanding the role of the gut microbiome in human disease will enable the development and application of more appropriate therapeutic strategies that specifically target microbes within the gut. / May 2017

No description available.

No description available.

By using a pragmatic paradigm, different research methodologies were employed in this thesis. MS-related symptoms may be exaggerated due to heatsensitivity and it is supposed that cooling garments relieve the symptoms. The effects of wearing a Rehband® vest were evaluated in a sample of 42 persons with MS in a randomised controlled crossover study. Both objective and subjective statistically significant improvements were found when a cooled Rehband® vest was worn compared to the wearing of a room-tempered vest. Using a repeated-measures design, 10m and 30m timed walks and Timed Up and Go were studied in 42 persons with MS. Reproducibility was investigated within and between test points. High reproducibility was found both within (r=0.97–0.98) and between measure points (r=0.91–0.93). The correlation between the three tests was high (r=0.85). Differences at –23% to +40% were established as being needed to detect genuine changes. Severity of MS infl uenced the size of the differences, especially for the 30m timed walk test. The 12-item MS Walking Scale was translated and used in a cross-sectional study. Out of 81 persons with MS, 89–96% perceived limitations in standing or walking. The internal consistency of the scale was acceptable for nine items (0.69–0.84). The concurrent validity between the 12-item MS Walking Scale and the investigated objective tests was low: Berg Balance Scale (r=–0.368**), Four Square Step Test (r=0.338**) and Timed Up and Gocognitive (r=0.319*). A prevalence of falling was found at 63% in a longitudinal cohort study with prospectively registered falls including 76 persons with MS. The odds of falling were fi ve fold when there was a reported need of using a walking aid indoors and outdoors and by 2.5 to 15.6 times while there was disturbed proprioception, depending on severity. The highest sensitivity was found for the Berg Balance Scale (94%) and the highest specifi city was found for the 12-item MS Walking Scale (82%). Positive predictive values at 70–83% were found for the Berg Balance Scale, Timed Up and Gocognitive, the Four Square Step Test and the 12-item MS Walking Scale. Finally, we explored and described factors that persons with MS perceive as related to accidental falls. A content analysis with a deductive approach was chosen. By conducting interviews, we found previously untargeted factors: divided attention, reduced muscular endurance, fatigue and heat-sensitivity. The content of the interviews also gave support to previously reported risk factors such as changes in gait pattern, walking disability, impaired proprioception and vision, and spasticity.

Background Multiple sclerosis (MS) is an autoimmune disease characterised by inflammatory damage to the central nervous system (CNS). Accumulated CNS injury can be quantified as brain atrophy, definable as a reduction in brain parenchymal fraction (BPF). BPF correlate with disability in MS and is used routinely as an endpoint in clinical trials. In 2009/2010, a new MS clinical care program, that includes follow-up of BPF, was introduced at Umeå University Hospital (NUS). Levels of neurofilament light polypetide (NFL) and glial fibrillary acidic protein (GFAP) in cerebrospinal fluid (CSF) are markers of axonal and astrocytic injury, respectively, and also potential surrogate biomarkers for BPF decline. The goals of this thesis were to establish age-adjusted values of BPF in healthy individuals and to relate these to the BPF values from individuals with MS as well as to the levels of NFL and GFAP in CSF. Another goal was to investigate if expanded disability status scale (EDSS)-worsening could be predicted in a clinical MS cohort and if BPF measurements could contribute to such predictions. Methods A group of 111 healthy individuals volunteered to participate in the studies. A total of 106 of these underwent MRI with BPF measurements, 53 underwent lumbar puncture (LP) with measurement of NFL and GFAP and 48 underwent both MRI and LP. Three different automatic and one manual method were utilised to determine BPF. A literature search on BPF in healthy individuals was performed for the purpose of a systematic review. For studying disability progression in MS, all individuals with MS followed at NUS and included in the Swedish MS registry were included if they had matched data on BPF, EDSS and lesion load as part of clinical follow-up (n=278). Results BPF as well as NFL and GFAP levels in CSF were all associated with age. NFL was associated with BPF and GFAP, but only the association with GFAP was retained when adjusting for age. Significant differences were found between different methods for BPF determination. In the MS population, BPF was associated with EDSS. Only progressive disease course could predict EDSS worsening. Conclusion The data on BPF and levels of NFL and GFAP in CSF of healthy individuals can aid in the interpretation of these variables in the setting of MS. Knowledge on differences in BPF data from different methods for BPF determination can be useful in comparing data across studies, but also highlights the need for a commonly accepted gold standard. The correlation between GFAP and NFL levels in CSF may indicate an association between glial and axonal turnover that is independent of the aging effect on the brain. However, the low number of volunteers for LP precluded clear conclusions. An association between BPF and EDSS was seen in the MS group. The ability to predict EDSS worsening in the clinical MS cohort was limited.

Background: Previous studies have addressed multiple sclerosis (MS) symptom management and improved health-related quality of life (HrQOL). Yet lowered estrogen levels in post-menopasual women with MS may further worsen physical function and symptomology and not all types of pain management have been examined. Objectives: For post-menopausal women with MS, we evaluated the extent to which smoking is associated with worsened health outcomes and HrQOL, and the extent to which menopausal hormone treatment (MHT) improves health outcomes and HrQOL. For all adult men and women with clinically diagnosed MS, we systematically reviewed pharmacological and non-pharmacological strategies for the reduction of pain. Methods: We identified 256 post-menopausal women with MS in the Women's Health Initiative Observational Study and examined changes from baseline to 3 years in activities of daily living, physical activity, SF-36 mental and physical component scales (MCS, PCS), and menopausal symptoms. In all adults, experimental studies published after 1965 were included if the sample was not restricted to participants with spasticity or trigeminal neuralgia and participant-reported pain was a primary or secondary outcome. Pain scores were reported as Cohen’s d. Results: Nine percent of post-menopausal women with MS were current smokers and 51% reported current MHT use. Smoking and MHT use had no effect on physical functioning, activities of daily living, or menopausal symptoms. Women with early age at smoking initiation experienced declines in MCS (adjusted β <20 vs. ≥ 25 years: -10.50, 95% Confidence Interval (CI) -2.1 to -18.1; adjusted β 20-24 vs. ≥ 25 years: -8.81, 95% CI: 0.6 to -17.4), but not in PCS. Relative to never MHT users, ever MHT users had higher MCS scores at year 3 compared to baseline (adjusted β: 3.0, 95% CI: 0.4 to 5.6), but no change in PCS. For all adults, transcutaneous electrical nerve stimulation (TENS; Cohen’s d: -3.34), nabixomols (Cohen’s d: -0.61), and dextromethorphan/quinidine (Cohen’s d: -0.22) were reported effective in reducing pain. Conclusions: Smoking prevention efforts should be increased for women with MS. Women with MS may also experience HrQOL gains with MHT, but contemporaneous data on MHT use is needed. TENS may be more effective than pharmacological methods in reducing MS pain.

Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) characterized by demyelination and loss of oligodendrocytes (OLGs), the CNS myelin-producing cells. Thus, understanding the mechanisms that control OLG development can provide valuable knowledge regarding remyelination therapies for MS. This disease is thought to result from an autoimmune attack towards myelin. FTY720, an immunomodulator under evaluation for MS treatment is a sphingosine-1-phosphate (S1P) analog. We found before that S1P plays a crucial role in the NT-3-mediated survival of OLGs, an observation that led us to investigate whether FTY720 could have any effect on these cells. Our studies demonstrate that FTY720 indeed has a direct effect on OLG progenitors, protecting them from apoptotic death through a mechanism involving ERK1/2 and Akt activation. However, another key finding of our study was that this drug arrested OLG differentiation, an effect counteracted by NT-3 which not only enhanced the survival of OLG progenitors but also stimulated their maturation. Furthermore, NT-3 induced an increase in myelin basic protein (MBP) levels in the absence of effects on MBP gene promoter activation or mRNA expression. These observations suggested that NT-3 up-regulated MBP levels by a posttranscriptional mechanism raising the question of whether this neurotrophin could have a more general positive effect on the expression of other OLG proteins. In agreement with this idea, we found that NT-3 also induced the expression of the myelin proteins MAG and MOG. Additionally, [35S]-Methionine labeling indicated a 50% increase in de novo protein synthesis following only a 15 min exposure to NT-3. Such a rapid increase in protein synthesis reinforced the idea that NT-3 plays a crucial role regulating protein expression by posttranscriptional mechanisms. In support of this possibility, we found that NT-3 stimulated the phosphorylation of the initiation factor eIF4E and its inhibitory partner 4EBP1, both essential players in mediating cap-dependent protein synthesis. This stimulation involved the activation of ERK1/2 and PI3K/mTOR mediated signaling pathways. To our knowledge, this is the first study on the regulation of translation initiation in OLGs and the first report describing the potential role of NT-3 as an activator of initiation.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system characterized by inflammation and demyelination. In addition to these hallmark features, MS also presents with axonal pathology, which is likely responsible for the signs and symptoms of the disease. Although prominent in MS, axonal pathology is frequently considered a consequence of demyelination and not a primary event. This conclusion is consistent with demyelination inducing the loss of specific axonal domains, known as the nodes of Ranvier that are responsible for the propagation of action potentials along the axon. In contrast, we propose that axonal pathology associated with MS is a primary pathological event, independent of demyelination, and not a product of it. In support of our hypothesis, we have analyzed a different axonal domain known as the axon initial segment. Whereas a single axon has numerous nodes of Ranvier uniformly distributed along the axon, each axon contains only a single axon initial segment that is positioned immediately distal to the neuronal cell body. The axon initial segment is responsible for action potential generation and modulation, and hence is essential for normal neuronal function. Background studies conducted by our lab, employing a murine model of demyelination/remyelination, revealed no correlation between axon initial segment stability and myelin integrity. Here we investigate the fate of the axon initial segment in human multiple sclerosis. While not statistically significant, we provide data demonstrating an apparent 40% reduction in AIS numbers in MS. We further provide qualitative evidence that AIS integrity in MS is not dependent on myelination suggestive that axonal pathology may be a primary event in MS, independent of demyelination. Our current findings are intriguing, but unfortunately this study is underpowered, and more samples will be required to determine whether this apparent reduction is statistically significant.