Diss. (sammanfattning) Stockholm : Karolinska institutet, 2010.

Thesis (M.Sc.)--Memorial University of Newfoundland, Faculty of Medicine, 1998. / Typescript. Bibliography: leaves 193-209.

More than 50% of people with MS fall in any six-month period. The importance of developing a suitable falls management programme has been identified by people with MS and professionals. This thesis aimed to develop a model for an MS falls intervention. The studies employed a systematic approach to evaluate the risk factors for falls and to identify the optimal programme content, format and structure. Methods The thesis comprises two sections; the first involving a systematic review and an observational study of falls risk factors (n=148). Part two included a second systematic review to inform programme content, and a nominal group study (n=36) to explore approach, format and structure from the perspective of key stakeholders. Results Part one identified the potential target group (people at key mobility transition stages and those with progressive MS), and mechanisms by which the intervention could act (the identification of specific risk factors associated with falls in MS). These include non-modifiable disease and demographic characteristics (e.g. MS classification and gender), and potentially modifiable clinical characteristics (including balance, mobility, continence issues and medication usage). Part two identified that an MS specific falls programme should address falls and participation-related outcomes, incorporating educational activities and a programme of individually tailored gait, balance and functional training. The programme should use a collaborative approach; supporting participants to achieve sufficient intensity and duration of exercise and to integrate falls prevention strategies into their daily lives. The programme should enable participants to engage flexibly according to individual needs and preferences. Conclusions This thesis has identified specific risk factors associated with accidental falls in MS. The evaluation indicates that the success and sustainability of an MS falls programme requires that it is MS specific, employs a collaborative approach and moves away from the group-based, weekly format common to many generic falls programmes.

The human VAMP-associated protein B (hVAPB) has been shown to cause a range of motor neurodegenerative diseases, including amyotrophic lateral sclerosis 8 (ALS8) and spinal muscular atrophy (SMA). However, the molecular mechanisms underlying VAPB-induced neurodegeneration remain elusive. We sought to address this question by identifying VAPB interacting proteins, which may be affected by the disease causative mutations. Using a combination of biochemical and genetic approaches in Drosophila, we confirmed the evolutionarily conserved phosphoinositide phosphatase Sac1 (Suppressor of Actin 1), as a DVAP binding partner and showed that the two proteins colocalise in the endoplasmic reticulum. We also show that DVAP function is required to maintain normal levels of phosphoinositides (PIs) and that downregulation of either Sac1 or DVAP at the larval neuromuscular junction (NMJ) affects a number of synaptic processes, including axonal transport, synaptic growth, microtubule integrity and localisation of several postsynaptic components. We found that double knock down of DVAP and Sac1 induces no further increase in the severity of the mutant phenotypes when compared to either single mutant alone. This, together with the similarity in mutant phenotypes, indicates that the two genes function in a common pathway. In flies carrying the ALS8 mutation (DVAP-P58S), we observed reduced viability, locomotion defects and early death in surviving adults, closely matching the phenotypes of both DVAP and Sac1 downregulation. Additionally, transgenic expression of DVAP-P58S in the motor system elicits synaptic defects similar to those of either Sac1 or DVAP loss-of-function, including an increase in the levels of PtdIns-4-Phosphate (PI4P), the substrate of Sac1. Consistent with these observations, we found that Sac1 is sequestered into DVAP-P58S mediated aggregates and that downregulation of PI4P in neurons rescues the neurodegenerative and the synaptic phenotypes associated with DVAP-P58S transgenic expression. Together our data unveil a previously unknown function for Sac1 in neurodegeneration and synaptic function, as well as provide evidence for a dominant negative mechanism for phosphoinositide-mediated ALS8 pathogenesis. We also highlight a causative role for increased PI4P levels in VAPB-P56S induced neurodegeneration.

Background: The current studies aimed to explore the effects of different variants of multiple sclerosis (MS) on social cognitive skills such as emotion perception, theory of mind (ToM) and empathy. Various aspects of empathy were measured using newly developed video paradigm that generated reliable and consistent responses in study participants. Further, the relationships between social cognition abilities and cognitive functioning, MS severity, mood and age were explored. The final aim was to establish whether difficulties in social cognition predicted restricted social participation and reduced quality of life in MS. Methods: This research measured multi-domain emotion perception, ToM and empathy using more ecologically valid measures than previous studies in participants with relapsing-remitting MS (n = 30), chronic progressive MS (n = 26) and matched healthy controls (n = 31). Executive functioning was measured using verbal fluency, whereas speed of processing was tested with the Digit Symbol Coding Task. Self-report measures were administered to assess of empathy, social participation, MS severity and mood. Results: Both MS groups presented with impairments in emotion perception and ToM but not in empathy. Cognitive functioning was associated with some measures of emotion perception and ToM. Reduced quality of life was inconsistently predicted by personal distress only and some aspects of emotion perception in individuals with MS. No aspects of social cognition were found to be a significant predictor of restricted social engagement in MS. Conclusion: Both MS samples demonstrated similar emotion perception and ToM impairments and no significant empathy impairment, though those with progressive MS reported poorer social participation. Lower levels of emotion perception and personal distress predicted some aspects of quality of life. Since the pattern of these results proved to be inconsistent, it is important to interpret the findings with caution, and to further explore socio-emotional functioning in MS.

published_or_final_version / Anatomy / Doctoral / Doctor of Philosophy

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