Amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD) represents a spectrum of neurodegenerative disease with clinical presentations ranging from progressive paralysis to cognitive impairment. Approximately 15% of ALS-FTD patients initially presenting with motor symptoms also receive a diagnosis of dementia, but a majority of these patients demonstrate some level of cognitive impairment over the course of disease. Identifying molecular pathways that contribute to the development of cognitive deficits in ALS-FTD has thus far been limited by the quality of clinical information and postmortem tissue preservation as well as available technologies. This thesis aims to investigate early stages of cognitive involvement in ALS-FTD using postmortem tissues from a cohort of non-demented ALS patients who have had cognitive and pathological phenotyping. Spatially resolved transcriptome profiling of prefrontal cortex tissues from this cohort identifies dysregulated pathways in non-motor regions, contributing to our understanding of molecular perturbations underlying cognitive impairment in ALS-FTD.

Bakgrund: ALS är en neurodegenerativ sjukdom som drabbar drygt 300 personer årligen i Sverige. Ofta är det anhöriga till personerna med ALS som sköter omvårdnaden i hemmet. Det har visat sig medföra stora utmaningar och anhöriga som vårdar är därmed en utsatt grupp som kan behöva stöd. Syfte: Syftet var att beskriva anhörigas upplevelser av stöd vid vård av en närstående med Amyotrofisk lateralskleros i hemmet. Metod: Resultatet baserades på 10 empiriska, kvalitativa studier som återfanns i databaserna PubMed och CINAHL. Analys av studiernas resultat inspirerades av Graneheims och Lundmans innehållsanalys för kvalitativa studier. Resultat: Analysen resulterade i två teman - Praktiskt stöd är avgörande för att hantera vardagen och Emotionellt stöd bidrar till trygghet med 8 subteman. Teman och subteman beskriver anhörigas upplevelser av stöd och inom vilka områden de upplevde sig ha behov av stöd, både under sjukdomsförloppet och efter att personen med ALS avlidit. Konklusion: Anhöriga som vårdar en närstående med ALS i hemmet ställs inför komplexa vårdsituationer som medför varierande praktiska och emotionella stödbehov. Det är viktigt att sjukvårdspersonal med ett personcentrerat förhållningssätt regelbundet bedömer anhörigas stödbehov för att säkerställa att anhöriga som vårdar inte drabbas av ohälsa. / Background: ALS is a neurodegenerative disease that annually affects around 300 people in Sweden. Relatives of the people with ALS are often those who provide care at home. This involves major challenges and relatives who provide care are therefore a vulnerable group which may need support. Aim: The aim was to describe relatives’ experiences of support when providing care for a person with Amyotrophic lateral sclerosis at home. Methods: The result was based on 10 empirical, qualitative studies found on the databases PubMed and CINAHL. The analysis of the studies results were inspired by Graneheim’s and Lundman’s content analysis for qualitative studies. Results: The analysis resulted in two themes – Practical support is vital for managing daily life and Emotional support contributes to safety with 8 subthemes. Themes and subthemes describes relatives’ experiences of support and within which aspects they needed support, both during the course of the disease and after the death of the person with ALS. Conclusion: Relatives who provide care for a person with ALS at home faces complex care situations which entails diverse practical and emotional support needs. It is important that healthcare professionals with a person-centered approach regularly assesses relatives' support needs to ensure that relatives who provide care do not suffer from ill health.

No description available.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24839号 / 医博第5007号 / 新制||医||1068(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 井上, 治久, 教授 寺田, 智祐, 教授 林, 康紀 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

As the most common motor neuron disease, Amyotrophic lateral sclerosis (ALS) affects around 4 in every 100,000 people worldwide with reports of increasing prevalence over the years. Characterized by progressive degeneration of motor neurons, ALS patients suffer impairments of movement and typically die from respiratory failure 2-5 years after diagnosis. Curiously, ALS exists on a disease continuum with Frontotemporal Dementia (FTD) where 30-50% of patients will be diagnosed with both diseases. In FTD, degeneration of cortical neurons results in diverse behavioural changes including deficits in executive and social skills as well as language and memory. A central connection between ALS and FTD is TDP-43 (encoded by TARDBP), an essential DNA/RNA binding protein known to serve critical functions in numerous cellular processes. Despite mutations in TARDBP constituting a small percentage of familial cases, TDP 43 nuclear-to-cytoplasmic mislocalization is a pathological hallmark of most ALS-FTD cases. Therefore, therapeutic targets to rectify pathology and disease may be uncovered by identifying factors that regulate TDP-43. While it is currently established TDP-43 is ubiquitinated and phosphorylated in diseased states, our lab recently found TDP-43 is SUMOylated in response to stress. Of note, perturbations in the stress response are becoming increasingly implicated in neurodegenerations. Furthermore, TDP-43 plays critical roles in the stress response which become perturbed in ALS/FTD. We developed a TDP-43 "SUMO dead" mouse allele to gain an understanding of how disrupting this may contribute to the pathogenesis of ALS-FTD. Longitudinal characterization of the model explored behavioural and histological in vivo consequences following loss of TDP-43 SUMOylation. However, the phenotypes observed in the mutant mice were less robust in comparison to established ALS/FTD mouse models. Mutant mice did not have consistent differences in tests for similar outcomes, trials of the same test, or across age. Female mutant mice presented with early hyperactivity and disinhibition along with altered social grooming behaviour. At later age, these female mice developed impairments in spatial working memory. Male mice developed apathetic behaviour and motor deficits at the middle age timepoint. Histologically, various forms of pathological TDP-43 were observed in the absence of neurodegeneration. These data reveal that TDP-43 SUMOylation may play an important role in ALS/FTD pathogenesis.

Human microglia play a pivotal role in neurological diseases, but few targeted therapies that directly modulate microglial state or function exist due to an incomplete understanding of microglial heterogeneity. This thesis aims to advance our understanding of microglial heterogeneity by using single-cell RNA sequencing to profile live human microglia from autopsies or surgical resections across diverse neurological diseases and using computational tools to infer chemical and genetic regulators of specific microglial substates. Chapter 1 provides an overview of microglial ontogeny, function, and known heterogeneity, especially in disease contexts. It also describes the steadily increasing disease burden seen in neurological disease as well as the lack of efficacious treatments and future directions for microglia-targeted therapies. Chapter 2 focuses on microglial heterogeneity in an understudied disease, ALS, describing population structure shifts seen in ALS across cortex and spinal cord. Chapter 3 instead focuses on exploring underlying cross-disease microglial population structure, identifying subsets with metabolic and functional properties, as well as subsets enriched in susceptibility genes for neurodegenerative disease. We then demonstrate applications of this type of data by using our resource to annotate other datasets. Chapter 4 leverages this data in another way, by identifying and validating candidates for chemically and genetically inducing subtype-specific states in vitro. Notably, we show that Camptothecin downregulates the transcriptional signature of disease-enriched subsets and upregulates a signature previously shown to be depleted in Alzheimer’s. Finally, I review our findings and discuss future directions for the field.

No description available.

No description available.

No description available.

Background: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motor neurons. Preference-based measures (PBMs) of health-related quality of life (HRQL) can be utilized for cost-effectiveness analyses of interventions in individuals with ALS. However, current measures are generic (GPBMs) and the psychometric properties of these measures have not yet been evaluated in ALS. Purpose: The purpose of this thesis was to evaluate the psychometric properties of GPBMs in ALS by 1) conducting a systematic review of the psychometric properties of GPBMs, and 2) assessing the content and convergent validity of GPBMs in ALS. Methods: Two studies were conducted. First, a systematic review was performed, and four databases were searched to identify studies that used and reported on the psychometric properties of GPBMs in ALS. Second, participants were recruited from three clinical sites across Canada and outcome measures were administered through an online or hardcopy survey. Areas of importance to the HRQL of individuals with ALS were identified using the Patient Generated Index (PGI), mapped against GPBMs to determine their coverage and scores were compared to determine convergent validity. Results: For the first study, the EQ-5D-3L was found to be the most commonly used GPBMs in ALS. It demonstrated convergent and known-groups validity however, significant floor effects were observed. For the second study, results indicated that the majority of GPBMs identified approximately half of the areas impacted by ALS. In addition, there were several domains not identified by GPBMs. Conclusion: This thesis highlights the importance of complete psychometric evaluation of measures in ALS. There is the need for the development of an ALS specific preference-based measures that reflects the health concerns of individuals with ALS; as GPBMs used in ALS were evaluated and deemed to be lacking in support for their usage in ALS. / Thesis / Master of Science Rehabilitation Science (MSc) / Amyotrophic Lateral Sclerosis (ALS) is a fatal disease that causes individuals to lose their strength and eventually the ability to speak, eat, move and breathe. Questionnaires can be used to understand the health-related quality of life (HRQL) of individuals with ALS however these measures do not always reflect the experiences of these individuals. The goal of this dissertation was to identify whether measures truly capture areas important to individuals with ALS. In our studies, we found that there is little proof in the accuracy of measures used. In addition, the measures do not fully capture the areas of life important to individuals with ALS. This is important to help researchers and health care professionals understand the effects of ALS on HRQL. These results will help them determine which treatments are worthwhile and the best to use in practice and provide recommendations for future research.