The logistical complexities of performing multi-site longitudinal diffusion-weighted imaging (DWI) studies requires careful construction of analysis tools and procedures. Proposed clinical trials for therapies in neurodegenerative disease are known to re- quire several hundred subjects, thus mandating multiple site participation to obtain sufficient sample sizes. DWI is an important tool for monitoring diffusivity properties of white matter (WM) in disease progression. The multi-site nature of clinical trials requires new strategies in DWI processing and analysis to reliably measure longitudi- nal WM changes. This work describes the process of developing and validating robust analysis methodologies to process multi-site DWI data in a rare, neurodegenerative disease. Key processing components to accomplish a robust DWI processing system include: DICOM conversion, automated quality control, unbiased atlas construction, fiber tracking, and statistical analysis. Extensive validation studies were performed to characterize methodological results within and across the common confounds inherent in multi-site clinical trials. The conversion and automated quality control tools optimized for this work both enhanced the ability to reliably obtain repeat diffusion tensor image (DTI) scalar measurements in a reliability analysis of healthy controls scanned at multiple sites using multiple scanner vendors. A DTI scalar analysis performed on focused WM regions showed it was possible to detect significant mean differences of DTI scalars among separate groups of a neurodegenerative disease population. The DTI scalar analysis paved the way for an atlas-based cross-sectional fiber tracking analysis. In the cross-sectional fiber tracking analysis, multi-site data was brought into the same space, making major fiber tracts terminating in the focused WM regions of the scalar analysis from all participants comparable. Significant differences in diffusivity were found throughout each tract among separate groups of the neurodegenerative disease population. In addition, multiple neuropsychological cognitive variables that have a documented ability to track disease progression of the neurodegenerative disease, strongly correlated with many of the DTI scalars in each tract. The findings of the cross-sectional fiber tracking analysis were reinforced by similar findings produced by a longitudinal fiber tracking analysis. Collectively, these findings suggest that cogni- tive deficits seen in the neurodegenerative disease population could be explained by changes in diffusivity of the tracts explored in this work. In addition to the longi- tudinal fiber tracking analysis examining diffusivity, methods for a WM morphology analysis using parallel transport to apply longitudinal volume changes to a template was explored.

<p><strong>Objective: </strong>To evaluate the effect of a physiotherapeutic exercise programme for patients with Huntington´s Disease (HD) concerning motor function and disability, balance and fall related self-efficacy, and to investigate the correlation between the seven assessment tools.</p><p><strong>Participants:</strong> Twelve persons with genetically confirmed HD at an early or middle stage of the disease and with a mean age of 52 (16) years.</p><p><strong>Methods:</strong> The intervention comprised physiotherapy (PT) focused on training of transitions, balance and fall-related self efficacy, twice a week for six weeks. Each treatment session lasted for one hour, was individual and took place at an out-patient clinic. Baseline assessments including five clinical tests and two questionnaires were made 6 and 0 weeks prior to the intervention and 0 and 6 weeks after the intervention.</p><p><strong>Outcome measures:</strong> Motor function and disability were measured with the Unified Huntington's disease Rating Scale; the Total Motor Score and the Total Functional Assessment. Static and dynamic balance was measured with the One- leg stance- test, the Timed Up and GO Test, the Figure of Eight-test and the Berg Balance Scale.  Fall-related self-efficacy was measured with the Falls Efficacy Scale.</p><p><strong>Results:</strong> The physiotherapeutic exercise programme demonstrated a significant improvement in balance measured with the Berg Balance Scale (<em>p=.045). </em>The significant correlation coefficients between the different measurements of motor function, disability, balance and fall related self-efficacy ranged from 0.68 to 0.87.</p><p><strong>Conclusions: </strong>The contents of the out-patient clinic physiotherapeutic exercise programme, with a focus on balance and transitions, seemed to have clinical relevance. PT in different kinds of settings should be studied further to get a better knowledge about the effects of PT and physical activity at home, at an out- patient setting or at the hospital for patients with HD.</p><p><strong>Key Words: </strong>Huntington's disease; Physiotherapy; Motor function; Disability; Balance; Fall- related self efficacy.</p>

Mitochondrial respiratory chain deficiency and increased oxidative stress have been closely associated with major age-associated neurodegenerative diseases. I hypothesized that mitochondrial oxidative phosphorylation defects or elevated oxidative stress, which could arise in a stochastic manner during our normal aging process, might modulate the formation of protein aggregates or production of misfolded proteins, contributing to the initiation of these diseases. To test this hypothesis, we (i) have developed and characterized mouse and cellular models of Alzheimer's and Huntington's diseases expressing aggregate-prone pathogenic proteins, beta-amyloid and mutant huntingtin (Chapters 1 and 2), (ii) have developed mouse models that exhibit neuron-specific defects in mitochondrial oxidative phosphorylation (Chapters 2 and 3), and (iii) have evaluated the alterations in the amount of aggregate loads upon genetic and pharmacological manipulations of mitochondrial oxidative phosphorylation activities (Chapters 1 and 2). The evaluation of the impacts of mitochondrial defects on the amount of huntingtin aggregates has revealed that a defect in complex III promotes the accumulation of huntingtin aggregates via the impairment of proteasome activity (Chapter 1). On the other hand, ablation of complex IV activity in a subset of postmitotic neurons revealed that complex IV deficiency does not promote either oxidative stress or the deposition of amyloid plaques in a mouse model of Alzheimer's disease, questioning the mitochondrial origin of Alzheimer's disease (Chapter 2). However, as shown previously, the tight correlation between oxidative stress and accumulation of amyloid plaques was found. Chapter 3 involved the generation of an improved mouse model, in which mitochondrial defects can be induced in a subset of forebrain neurons (cortex, hippocampus, and striatum) in a doxycycline-dependent manner. This system relies on the regulated expression of a mitochondria-targeted restriction enzyme, PstI, which digests mitochondrial DNA and thereby impairs the activity of oxidative phosphorylation. In conclusion, our studies highlighted the disease-specific complex pathways that may modulate the accumulation of misfolded proteins during aging. Future studies employing the newly-developed mouse model may reveal a contribution of age-associated global defects of oxidative phosphorylation to oxidative stress and neurodegenerative diseases.

Objective: To evaluate the effect of a physiotherapeutic exercise programme for patients with Huntington´s Disease (HD) concerning motor function and disability, balance and fall related self-efficacy, and to investigate the correlation between the seven assessment tools. Participants: Twelve persons with genetically confirmed HD at an early or middle stage of the disease and with a mean age of 52 (16) years. Methods: The intervention comprised physiotherapy (PT) focused on training of transitions, balance and fall-related self efficacy, twice a week for six weeks. Each treatment session lasted for one hour, was individual and took place at an out-patient clinic. Baseline assessments including five clinical tests and two questionnaires were made 6 and 0 weeks prior to the intervention and 0 and 6 weeks after the intervention. Outcome measures: Motor function and disability were measured with the Unified Huntington's disease Rating Scale; the Total Motor Score and the Total Functional Assessment. Static and dynamic balance was measured with the One- leg stance- test, the Timed Up and GO Test, the Figure of Eight-test and the Berg Balance Scale.  Fall-related self-efficacy was measured with the Falls Efficacy Scale. Results: The physiotherapeutic exercise programme demonstrated a significant improvement in balance measured with the Berg Balance Scale (p=.045). The significant correlation coefficients between the different measurements of motor function, disability, balance and fall related self-efficacy ranged from 0.68 to 0.87. Conclusions: The contents of the out-patient clinic physiotherapeutic exercise programme, with a focus on balance and transitions, seemed to have clinical relevance. PT in different kinds of settings should be studied further to get a better knowledge about the effects of PT and physical activity at home, at an out- patient setting or at the hospital for patients with HD. Key Words: Huntington's disease; Physiotherapy; Motor function; Disability; Balance; Fall- related self efficacy.

Expanded polyglutamine proteins are known to be the causative agents of a number of human neurodegenerative diseases but the molecular basis of their cytoxicity is still poorly understood. Polyglutamine tracts may impede the activity of the proteasome, and evidence from single cell imaging suggests that the sequestration of polyglutamine proteins into inclusion bodies can reduce the proteasomal burden and promote cell survival, at least in the short term. The presence of misfolded protein also leads to activation of stress kinases such as p38MAPK, which can be cytotoxic. The relationships of these systems are not well understood. We have used fluorescent reporter systems imaged in living cells, and stochastic computer modeling to explore the relationships of expanded polyglutamine proteins, p38MAPK activation, generation of reactive oxygen species (ROS), proteasome inhibition, and inclusion body formation. In cells expressing a polyglutamine protein, inclusion body formation was preceded by proteasome inhibition but cytotoxicity was greatly reduced by administration of a p38MAPK inhibitor. Computer simulations suggested that without the generation of ROS, the proteasome inhibition and activation of p38MAPK would have significantly reduced toxicity. Our data suggest a vicious cycle of stress kinase activation and proteasome inhibition that is ultimately lethal to cells. There was close agreement between experimental data and the predictions of a stochastic computer model, supporting a central role for proteasome inhibition and p38MAPK activation in inclusion body formation and ROS-mediated cell death.

Expanded polyglutamine proteins are known to be the causative agents of a number of human neurodegenerative diseases but the molecular basis of their cytoxicity is still poorly understood. Polyglutamine tracts may impede the activity of the proteasome, and evidence from single cell imaging suggests that the sequestration of polyglutamine proteins into inclusion bodies can reduce the proteasomal burden and promote cell survival, at least in the short term. The presence of misfolded protein also leads to activation of stress kinases such as p38MAPK, which can be cytotoxic. The relationships of these systems are not well understood. We have used fluorescent reporter systems imaged in living cells, and stochastic computer modeling to explore the relationships of expanded polyglutamine proteins, p38MAPK activation, generation of reactive oxygen species (ROS), proteasome inhibition, and inclusion body formation. In cells expressing a polyglutamine protein, inclusion body formation was preceded by proteasome inhibition but cytotoxicity was greatly reduced by administration of a p38MAPK inhibitor. Computer simulations suggested that without the generation of ROS, the proteasome inhibition and activation of p38MAPK would have significantly reduced toxicity. Our data suggest a vicious cycle of stress kinase activation and proteasome inhibition that is ultimately lethal to cells. There was close agreement between experimental data and the predictions of a stochastic computer model, supporting a central role for proteasome inhibition and p38MAPK activation in inclusion body formation and ROS-mediated cell death.

Huntington's disease (HD) is a rare, dominantly inherited neurodegenerative disorder characterized by progressive chorea, emotional and behavioral disturbances, and cognitive decline. The single, causative mutation is an expanded trinucleotide repeat of cytosine, adenosine, and guanine (CAG) of more than 37 residues in the HD gene (currently referred to as HTT). Genetic evidence suggests that the CAG repeat expansion results in a gain of huntingtin function. While huntingtin and its numerous interactors have been implicated in a variety of essential cellular processes, the role of the full-length, endogenous protein remains unclear. Multiple studies have implicated huntingtin in processes related to cytoskeletal structure and dynamics in HD patients and model organisms. However, alterations in cellular dynamics related to the cytoskeleton &mdash; including cell adhesion &mdash; have not been characterized in a comprehensive, rigorous manner. Using Mus musculus genetic models of the HD mutation and/or deficiency and a Dictyostelium discoideum genetic deficiency model, I have undertaken an investigation of evolutionarily conserved huntingtin function in the cytoskeleton and cell adhesion. The results of these studies support a role for huntingtin in cell-cell and cell-substrate adhesion, as well as maintaining actin cytoskeletal structure. Furthermore, my thesis research sets the stage for future work to elucidate the molecular mechanism by which huntingtin is acting and determine the effect of the CAG repeat expansion on huntingtin function. Evolutionary conservation affords an invaluable tool to identify crucial function(s) of the huntingtin molecule and the effect of the pathogenic HD mutation on function, enabling therapeutic development while providing novel insights into cytoskeletal biology and cell adhesion.

Huntington’s disease (HD) is caused by expression of the huntingtin gene containing an expanded CAG repeat. N-terminal mutant huntingtin protein (N-mHtt) accumulates in the nucleus and impairs transcription of a subset of genes through incorporation into transcriptional complexes or sequestration of proteins away from the promoter. CREB-binding protein (CBP) is a transcriptional co-activator and acetyltransferase (AT) that binds to N-mHtt. We hypothesized that overexpressing CBP fragments that lack a promoter association domain would block N-mHtt-mediated transcriptional dysregulation and toxicity. We found that overexpressing full-length CBP or CBP fragments did not reverse transcriptional dysregulation, but did decrease toxicity in a cell model of HD. Overexpressing fragments of CBP containing the AT domain increased toxicity in wild-type cells, while overexpressing a fragment lacking this domain had no effect. We conclude that excess AT activity was detrimental in wild-type cells, while overexpressing CBP or CBP fragments was protective in HD cells.

Huntingtons sjukdom är en ärftlig degenerativ sjukdom som förekommer hos 800-1000 personer i Sverige. Tidigare forskning visar på bristfällig kunskap om sjukdomen hos vårdpersonal vilket innebär ett stort lidande för de drabbade. För att skapa en djupare kunskap krävs att vårdpersonal lyssnar till personers upplevelser. Syftet med studien var att belysa personers upplevelse av att leva med Huntingtons sjukdom. För att få en överblick av forskningsläget genomfördes en systematisk sökordsbaserad litteraturstudie. Totalt elva artiklar granskades och kodades. Resultatet presenteras i tre huvudrubriker: upplevelser i relation till sjukdomen, upplevelser i relation till vården och upplevelser i relation till livet. Resultatet visade att lidande var centralt i samtliga upplevelser. Resultatet diskuteras mot bakgrund av Katie Erikssons lidandeteori. Avslutningsvis belyses betydelsen av fördjupad kunskap från vårdpersonal för att minska vårdlidandet och därmed minska livslidandet. Ytterligare forskning inom ämnet krävs för att vårdpersonal ska kunna bemöta personer med Huntingtons sjukdom på bästa möjliga sätt. / Huntington’s disease (HD) is a genetic degenerative disease affecting 800-1000 persons in Sweden. Previous research indicate that lack of knowledge about the disease among health care professionals adds to the suffering of persons with HD. Knowledge about the experiences of people living with the disease is required to improve the care. The aim of this study was to examine peoples´ experiences of living with Huntington’s disease. In order to get insights on the actual situation a systematic literature review was conducted. A total sample of eleven articles was reviewed and coded, resulting in three main themes: Experiences regarding the disease, Experiences regarding care and Experiences regarding life. The result showed that suffering was key to understanding the experience of living with the disease. The result of this study is discussed with reference to Katie Eriksson’s theory of suffering. Further research is required in order to improve the care for people with HD. By listening to the experiences of people affected by HD, health care professionals can learn how to create the best encounter possible and thus relieve some aspects of suffering.

Expanded polyglutamine proteins are known to be the causative agents of a number of human neurodegenerative diseases but the molecular basis of their cytoxicity is still poorly understood. Polyglutamine tracts may impede the activity of the proteasome, and evidence from single cell imaging suggests that the sequestration of polyglutamine proteins into inclusion bodies can reduce the proteasomal burden and promote cell survival, at least in the short term. The presence of misfolded protein also leads to activation of stress kinases such as p38MAPK, which can be cytotoxic. The relationships of these systems are not well understood. We have used fluorescent reporter systems imaged in living cells, and stochastic computer modeling to explore the relationships of expanded polyglutamine proteins, p38MAPK activation, generation of reactive oxygen species (ROS), proteasome inhibition, and inclusion body formation. In cells expressing a polyglutamine protein, inclusion body formation was preceded by proteasome inhibition but cytotoxicity was greatly reduced by administration of a p38MAPK inhibitor. Computer simulations suggested that without the generation of ROS, the proteasome inhibition and activation of p38MAPK would have significantly reduced toxicity. Our data suggest a vicious cycle of stress kinase activation and proteasome inhibition that is ultimately lethal to cells. There was close agreement between experimental data and the predictions of a stochastic computer model, supporting a central role for proteasome inhibition and p38MAPK activation in inclusion body formation and ROS-mediated cell death.