Dissertations / Theses on the topic 'Motor neuron disease, MND'
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Watermeyer, Tamlyn Julie. "Emotional processing and social cognition in Amyotrophic Lateral Sclerosis (ALS)/Motor Neuron Disease (MND)." Thesis, King's College London (University of London), 2014. https://kclpure.kcl.ac.uk/portal/en/theses/emotional-processing-and-social-cognition-in-amyotrophic-lateral-sclerosis-als--motor-neuron-disease-mnd(e3552e39-2127-40a8-8035-357b66edd75d).html.
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Amyotrophic Lateral Sclerosis (ALS) is a debilitating and life–limiting neurodegenerative disorder that causes progressive muscle atrophy and spasticity. A small proportion of ALS patients experience co–morbid Frontotemporal Dementia (FTD). Milder cognitive–behavioural changes have been noted in ALS patients without dementia. In these patients, deficits in executive functioning, language, memory and behaviour have been documented. Recently, changes to emotional processing and social cognition (EMOSOC) in ALS have also been reported, albeit with inconsistent findings. The primary aims of the current thesis were i) to delineate the nature and extent of changes in EMOSOC in ALS and ii) to determine the relationship between such changes and interindividual differences in mood, behaviour, personality, empathy and ALS–related executive dysfunction. The results of the study indicate a profile of predominant executive dysfunction, with relative sparing of EMOSOC in non–demented ALS patients. However, the ALS patients did show impaired performance on a task requiring the attribution of thoughts and feelings to characters from cartoons and vignettes. ALS patients’ performance on EMOSOC tasks was predicted by their performance on tests of executive function, above and beyond mood, behaviour, personality and empathy variables. As a secondary aim, the impact of patients’ cognitive and behavioural changes on ALS caregivers’ outcomes (mood, perceived strain, burden and marital satisfaction) were examined. The data indicated patients’ behavioural dysfunction and functional impairment as key predictors of caregivers’ outcomes. Exploratory analyses revealed differences between patients’ and caregivers’ perceptions of patients’ personality, empathy and behaviour; these differences were associated with caregiver outcomes. In summary, the current thesis characterises the profile of EMOSOC changes in non–demented ALS and highlights the role of ALS–related executive dysfunction in these changes. It also assesses the relative impact of patients’ disease, cognitive and behavioural changes on ALS caregivers.
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Gopinath, Sumana. "Finding new genes causing motor neuron diseases." Thesis, The University of Sydney, 2006. http://hdl.handle.net/2123/1624.
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Abstract Neurodegenerative disorders are a diverse group of disorders that affect specific subsets of neurons. Motor neuron diseases, neurodegenerative disorders of motor neurons, are seen commonly as sporadic cases and less frequently as familial disease forms. The familial forms show genetic and phenotypic heterogeneity. Clinically motor neuron diseases may be seen as rapidly progressive disorders like amyotrophic lateral sclerosis, ALS or slowly progressive disorders like hereditary motor neuropathies, HMN. The only proven causes for motor neuron diseases are gene mutations that lead to motor neuron degeneration in familial disease forms. Only some of these genes have been identified and have contributed greatly to our understanding of the neurobiology of familial and sporadic disease forms. Identification of additional disease causing genes would help enhance our knowledge of the pathophysiological mechanisms underlying all forms of motor neuron disorders, which would lead to early diagnoses, effective prophylaxis and efficient therapies for these disorders. This study aimed to find gene mutations that cause rapid and slowly progressive familial motor neuron disorders in Australian families and to determine their relevance to sporadic forms of motor neuron disease. The familial forms of ALS show reduced disease penetrance, that is, not all gene mutation carriers manifest the disease. This study examines ALS penetrance in a group of Australian families. The most frequently observed mutations in ALS families are cytosolic superoxide dismutase/SOD1 gene mutations. In a collection of ALS families in our centre, families without the common SOD1 gene mutations were genotyped for other ALS genes and loci and studied using genetic linkage and haplotype analyses. Studies in a large Australian ALS family further confirmed genetic heterogeneity in non-SOD familial ALS, all known autosomal dominant ALS genes and chromosomal loci were excluded as cause of disease in this family. Such families can be studied further to identify additional disease genes and loci mapped in other ALS families. These families represent powerful resources for identification of additional ALS genes. Identifying the pathogenic genes in families with reduced disease penetrance may be more relevant to sporadic forms of disease. dHMN is a chronic neurodegenerative disorder predominantly affecting motor neurons. In a large Australian dHMN family, all the known dHMN genes and chromosomal loci were excluded as cause of disease. A genome wide microsatellite screen was performed in this family and genetic linkage was established to a novel 12.98 Mb locus on chromosome 7q34.2-q36. Candidate genes in this large interval will be screened based on their function and expression profile. Identification of a new dHMN locus provides the basis for future identification of a novel gene involved in motor neuron degeneration. Genes in dHMN have been shown to be pathogenic in ALS and Charcot Marie Tooth syndromes. The new locus for dHMN mapped in this project would lead to identification of a novel dHMN gene, which may elucidate the pathogenesis underlying a wide range of neurodegenerative disorders.
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Gopinath, Sumana. "Finding new genes causing motor neuron diseases." University of Sydney, 2006. http://hdl.handle.net/2123/1624.
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Doctor of PhilosophyAbstract Neurodegenerative disorders are a diverse group of disorders that affect specific subsets of neurons. Motor neuron diseases, neurodegenerative disorders of motor neurons, are seen commonly as sporadic cases and less frequently as familial disease forms. The familial forms show genetic and phenotypic heterogeneity. Clinically motor neuron diseases may be seen as rapidly progressive disorders like amyotrophic lateral sclerosis, ALS or slowly progressive disorders like hereditary motor neuropathies, HMN. The only proven causes for motor neuron diseases are gene mutations that lead to motor neuron degeneration in familial disease forms. Only some of these genes have been identified and have contributed greatly to our understanding of the neurobiology of familial and sporadic disease forms. Identification of additional disease causing genes would help enhance our knowledge of the pathophysiological mechanisms underlying all forms of motor neuron disorders, which would lead to early diagnoses, effective prophylaxis and efficient therapies for these disorders. This study aimed to find gene mutations that cause rapid and slowly progressive familial motor neuron disorders in Australian families and to determine their relevance to sporadic forms of motor neuron disease. The familial forms of ALS show reduced disease penetrance, that is, not all gene mutation carriers manifest the disease. This study examines ALS penetrance in a group of Australian families. The most frequently observed mutations in ALS families are cytosolic superoxide dismutase/SOD1 gene mutations. In a collection of ALS families in our centre, families without the common SOD1 gene mutations were genotyped for other ALS genes and loci and studied using genetic linkage and haplotype analyses. Studies in a large Australian ALS family further confirmed genetic heterogeneity in non-SOD familial ALS, all known autosomal dominant ALS genes and chromosomal loci were excluded as cause of disease in this family. Such families can be studied further to identify additional disease genes and loci mapped in other ALS families. These families represent powerful resources for identification of additional ALS genes. Identifying the pathogenic genes in families with reduced disease penetrance may be more relevant to sporadic forms of disease. dHMN is a chronic neurodegenerative disorder predominantly affecting motor neurons. In a large Australian dHMN family, all the known dHMN genes and chromosomal loci were excluded as cause of disease. A genome wide microsatellite screen was performed in this family and genetic linkage was established to a novel 12.98 Mb locus on chromosome 7q34.2-q36. Candidate genes in this large interval will be screened based on their function and expression profile. Identification of a new dHMN locus provides the basis for future identification of a novel gene involved in motor neuron degeneration. Genes in dHMN have been shown to be pathogenic in ALS and Charcot Marie Tooth syndromes. The new locus for dHMN mapped in this project would lead to identification of a novel dHMN gene, which may elucidate the pathogenesis underlying a wide range of neurodegenerative disorders.
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Lloyd, Catherine Margaret. "Aspects of cortical function in motor neurone disease." Thesis, Imperial College London, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.243835.
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Rewaj, Phillipa Jane. "Nature of language impairment in motor neurone disease." Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/9744.
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Background: Language impairment associated with Motor Neurone Disease (MND) has been documented since the late 19th century, yet little is understood about the pervasiveness or nature of these deficits. The common clinical view among healthcare professionals is that communication difficulties can be attributed solely to the motor speech disorder dysarthria. Recent literature raises the possibility of more central processing deficits. Impairments in naming ability and comprehension of complex grammatical constructs have been frequently reported in some patients with MND. However, there is now growing evidence of spelling impairment, which could suggest the contribution of a more phonologically based deficit. In addition, the close relationship between MND and frontotemporal dementia (FTD) raises questions about the connection between the language impairments seen in MND patients and those documented in patients with the primary progressive aphasia (PPA) syndromes associated with FTD. Aims: This thesis examines the nature of speech and language deficits in people with MND and the extent to which expressive communication impairment can occur above and beyond dysarthria. In particular, the study explores: i) to what extent these language impairments can be attributed to deficits in working memory, executive functioning and/or disease severity; ii) what spelling errors can reveal about the integrity of lexical, phonological and orthographic processing; iii) whether similar patterns of impairment can be seen in PPA syndromes; iv) the relationship between language impairment and bulbar onset; and v) the impact these findings have on clinical management of MND patients. Methods: MND patients from across Scotland with changes in speech and/or language were tested using a neuropsychological battery of experimental and standardised tests of naming, spelling, syntactic comprehension, prosody and phonological and orthographical awareness. Patients were also screened for levels of dysarthria, executive functioning and working memory deficits, and results compared to those of matched controls. Findings: As a group, MND participants performed significantly worse than matched controls on measures of naming, spelling, orthographical awareness, grammatical comprehension, affective prosody and verbal fluency, but not working memory. However, based on patterns of individual impairment, of which spelling impairment formed a distinctive marker, the patient group divided into dichotomous subgroups, with 44% of participants categorised as ‘linguistically impaired’, while the remainder displayed little to no impairment. Those participants identified as linguistically impaired did not differ significantly from other MND participants on measures of disease severity, disease duration or dysarthria severity, although significantly more bulbar onset than limb onset participants were linguistically impaired. Spelling error patterns were suggestive of deficits at both a lexical and sublexical level, and were comparable to those reported in PPA literature. These findings suggest that dysarthria may be masking linguistic deficits in almost half of dysarthric MND patients, and highlight the importance of multidimensional assessment of language for effective clinical management.
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Brown-Wright, Sian Heledd. "Investigating metabotropic glutamate receptor 5 (mGlu5) as a novel therapeutic target in motor neuron disease (MND)." Thesis, University of Sheffield, 2018. http://etheses.whiterose.ac.uk/22583/.
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Wicks, Paul Jon Andrew. "The profile of cognitive, behehavioural and emotional change within MND [motor neurone disease]." Thesis, King's College London (University of London), 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.430936.
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Jones, Ross Alexander. "Comparative anatomy of the human neuromuscular junction." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/29629.
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The neuromuscular junction (NMJ), the synapse formed between lower motor neuron and skeletal muscle fibre, is known to be a target in a number of neurodegenerative conditions, including motor neuron disease (MND). Located in an accessible part of the peripheral nervous system, the NMJ can be used as a ‘model synapse’ in the context of ‘connectomics’ – the study of synaptic connectivity throughout the nervous system as a whole. Although the NMJ has been studied in a number of species, relatively little is known about its structure in humans, complicating the translation of animal models of disease to the human condition. Described here is the first detailed cellular and molecular characterization of the human NMJ. A standardized methodology for comparative morphometric analysis of NMJs was developed and validated (‘NMJ-morph’). NMJ-morph was used to generate baseline data for 2160 NMJs from a single litter of wild type mice, representing 9 distinct muscles across 3 body regions. Principal components analysis (PCA) revealed synaptic size and fragmentation to be the key determinants of synaptic variability. Correlation data revealed the pre-synaptic cell (motor neuron) to be a stronger predictor of synaptic morphology than the post-synaptic cell (muscle fibre). Other factors influencing synaptic variability were in a clear hierarchy: muscle identity accounted for more variation in synaptic form than animal identity, with side having no effect. Human tissue was obtained from 20 patients (aged 34 to 92 years) undergoing lower limb amputation, primarily for the complications of peripheral vascular disease (PVD). Muscle samples were harvested from non-pathological regions of the surgical discard tissue. 2860 human NMJs were analyzed from 4 distinct muscles (extensor digitorum longus, soleus, peroneus longus and peroneus brevis), and compared with equivalent NMJs from wild type mice. Human NMJs displayed unique morphological characteristics, including small size, thin axons, rudimentary nerve terminals and distinctive ‘nummular’ endplates, all of which distinguished them from equivalent mouse NMJs. The previous notion of partial occupancy in human NMJs was disproved. As in mice, the pre-synaptic cell was shown to correlate more strongly with NMJ morphology; in contrast to mice, the human NMJ was found to be relatively stable throughout its 90+ year lifespan. In support of the tissue harvesting procedure, patient co-morbidities (diabetes mellitus and vascular disease) did not significantly impact NMJ morphology. Super-resolution imaging of the NMJ revealed significant differences in the functional architecture of human and mouse active zones. Despite the smaller synaptic size in humans, the total quantity of active zone material was conserved between the species, suggesting a homeostatic mechanism to preserve effective neurotransmission. Parallel proteomic profiling demonstrated further species-specific differences in the broader molecular composition of the NMJ. The cellular and molecular anatomy of the human NMJ is fundamentally different to that of other mammalian species. These differences must be taken into account when translating animal models of disease to the human condition.
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Smith, Hayley-Jane. "The personal experience of carers of individuals with Motor Neurone Disease (MND) and their experiences of services." Thesis, University of Birmingham, 2009. http://etheses.bham.ac.uk//id/eprint/1221/.
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This thesis consists of research and clinical components and is submitted as partial fulfilment of a doctorate degree in Clinical Psychology. Volume 1, the research component, comprises of a literature review, an empirical paper and a public domain paper. The systematic literature review looks at evidence linking attachment and caregiving in adult couples. The empirical paper explores the experiences of individuals with a partners diagnosed with Motor Neurone Disease (MND). Lastly, a public domain provides a summary of the empirical paper. Volume II, the clinical component, contains clinical practice reports conducted within placements from adult, child, learning disability older adult specialities. The first report contains a behavioural and systemic formulation of a 3 year-old who was referred as her mother was having difficulties managing her behaviour. The second report describes an evaluation of the Experiences of practitioners interpreting and delivering Triple P (Positive Parenting Programme) groups in South Asian Community languages. The third report presents a single case experimental design concerning a behavioural approach to challenging behaviour displayed by a 7-year old boy with learning disabilities and autism. The fourth report is a case study of a Cognitive Behavioural approach used with a man diagnosed with Persistent Paranoid Delusional Disorder. Finally, the fifth report is an abstract of an oral case presentation of a small-scale service related project around a multiple family therapy group for adolescents with anorexia nervosa.
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Clabburn, Oliver. "Investigating the use of digital legacies with people affected by Motor Neurone Disease (MND) : an Interpretative Phenomenological Analysis." Thesis, Edge Hill University, 2018. http://repository.edgehill.ac.uk/10255/.
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Background: A video-based 'digital legacy' is a selection of videos which document a person's life, memories, achievements, or special family events. The videos are copied to a digital source to be specifically given to a child or young person to use in the future. A video-based digital legacy may either be purposefully recorded by the person living with MND (plwMND), or, compiled later by bereaved family members. To date, there is little published research about how children and young people are affected when a family member has MND and subsequently dies. As such, there is a dearth of literature on how to best support these young people. Objective: This research is investigating the views, perceptions and experiences of digital legacies with people affected by MND. Methods: The study is underpinned by Interpretative Phenomenological Analysis (IPA) meaning a small homogeneous sample was required using purposive methods of recruitment. Interviews were conducted and audio recorded with four plwMND regarding their experiences of creating a purposeful digital legacy for a child or young person in their family. Interviews were also conducted with three bereaved young people regarding their experiences of using a video legacy of a parent who had died from MND. Also, a sample of twenty healthcare professionals, specialists and experts were interviewed from across the United Kingdom regarding their perceptions on the use of digital legacies with plwMND, and, young people who are bereaved. Ethics: Ethical approvals were obtained from a Faculty of Research Ethics Committee at Edge Hill University (FREC), the Health Research Authority (HRA), and the National Research Service for Scotland. Discussion: 'The Model of Reciprocal Bonds Formation' and coining of the term 'autobiographical chapter' has been developed from this study. Creating a digital legacy provides a number of mutual challenges and benefits for both plwMND, and bereaved young people. Recommendations are provided regarding i) optimal 'windows of opportunity' in which the digital legacy is recorded/used; ii) actionable solutions for current policy/practice; iii) future directions for research.
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Chapman, Charlotte. "A qualitative study into the communication surrounding the initiation and withdrawal of non-invasive ventilation (NIV) in people with Motor Neurone Disease." Thesis, Edith Cowan University, Research Online, Perth, Western Australia, 2019. https://ro.ecu.edu.au/theses/2211.
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Introduction
Motor neurone disease (MND) is a degenerative disease that adversely affects the nervous system and muscular control. Eventually respiratory muscles weaken, causing breathing, communication and swallowing difficulties, and ultimately, respiratory failure and death. Improved quality of life and potentially a short extension of life can be provided with non-invasive ventilation (NIV), which is offered to people with MND when symptoms of respiratory distress become evident.
It is recommended that end-of-life communication, encompassing the benefits and burdens of symptom-relieving interventions (NIV and percutaneous gastrostomy tube to assist with nutrition), NIV withdrawal (proposed when continued use is considered futile) and other respiratory distress-relieving interventions (e.g., opioids), is initiated either before respiratory symptoms emerge or at that time. Little is known, however, about whether, when and how this communication occurs.
Methods
This qualitative research sought to address this gap in knowledge by determining the content and timing of end-of-life options clinicians communicate to people with MND and their families. Nineteen clinician participants and six families, all experienced with MND, were interviewed. Clinicians’ accounts of their communication were compared to bereaved families’ recollections of communication by clinicians. A framework incorporating patient-centred care principles and evidence-based medicine was used to link clinicians’ communication to the most recent MND guideline recommendations. The data collected were coded and categorised manually for each participant transcript and again using NVivo 10 software. Trustworthiness was established through independent coding of randomly selected participant interviews by one of the candidate’s supervisors. Symbolic interactionism and interpretive description provided the theoretical lens and methodology, respectively, through which the data were interpreted.
Findings
Despite the existence of comprehensive evidence-based guidelines reflecting international consensus, this research found some clinicians were unaware of the recommended timing and content of end-of-life communication, some chose to depart from or adapt the recommendations and some found the recommendations too difficult to implement. Clinicians stated they had insufficient time to communicate and reiterate the benefits and burdens of care options to ensure understanding. The recommendation to refer people with MND to palliative care soon after diagnosis was reported to happen infrequently. Clinicians stated that they felt discussion recommending early palliative care referral was confrontational for people with MND and their families; family participants confirmed this view.
Recommendations
Despite their ethos of patient-centred care, clinicians were concerned that early end-of-life communication would take away any hope the person with MND and their family may have. Consequently, many of the family participants appeared unprepared for the consequences of NIV, not having understood the potential of NIV withdrawal, with several turning to the Internet for answers. Compounding confusion was the disjointed nature of the care provided to people with MND often involving several health care providers.
This research recommends the establishment of a progressive interactive timeline, incorporating a case manager and reducing the number of external care providers particularly in the terminal phase of the disease.
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Wilson, Deborah. "Motor Neurone Disease : how do we manage? A study focusing on the experiences of people with MND and those involved in their care." Thesis, University of Southampton, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.240975.
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Carina, Engström, Ludvig Fogelström, and Granbom Julia. "ALS-En livsförändring i vardagen : -En litteraturöversikt." Thesis, Hälsohögskolan, Högskolan i Jönköping, HHJ, Avd. för omvårdnad, 2018. http://urn.kb.se/resolve?urn=urn:nbn:se:hj:diva-39580.
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Syfte: Att beskriva närståendes upplevelser av att leva med en person med ALS. Metod: En litteraturöversikt med kvalitativ metod och en induktiv ansats. Resultat: Sjukdomen ALS är ovanlig och de som drabbas av den är i stort behov av omvårdnad. Närstående till en anhörig som har fått diagnosen ALS, upplever att vårdpersonalen har kunskapsbrist angående sjukdomen och vårdandet. De upplever bristande information om sjukdomens förlopp. Egentiden tas ifrån dem, sådant som förr togs förgivet läggs istället åt sidan, då all fokus ligger på den anhöriges omvårdnad. Slutsats: Närstående väljer ofta att vårda den anhöriga i hemmet, trots det snabba sjukdomsförloppet. Vårdandet av den anhöriga leder till känslomässiga påfrestningar hos de närstående, både psykiska och fysiska.Purpose: To describe next of kin experiences of living with person with ALS. Method: A literature review with qualitative method and an inductive approach. Result: The disease ALS is unusual and those who suffer from it are in great need of nursing. The next of kin those who has been diagnosed with ALS, find that healthcare professionals have a lack of knowledge regarding the disease and care. They experience insufficient information about the course of the disease. The true time is taken away from them, as was previously taking for granted, instead being put aside, as all focus is on the patient's nursing. Conclusion: Next of kin often choose to care for their relatives in spite of the progress of the ilness. The care of the relatives leads to emotional stresses of the related, both mental and physical.
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Johansson, Monika, and Carina Thomsen. "Omvårdnad vid andningsproblematik och sväljproblematik hos ALS patienter." Thesis, Högskolan Dalarna, Omvårdnad, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:du-4200.
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Amyotrofisk Lateral Skleros, ALS, är en neurologisk sjukdom vilken leder till att samtliga kroppens muskler förtvinas och dör. Då sjukdomen saknar bot blir all behandling symptomatisk och individuellt anpassad för varje enskild persons behov. I denna systematiska litteraturstudie har det sökts efter olika sätt att stötta denna patientgrupp då syftet att belysa hur vi som personal kan hjälpa och stötta personer med ALS relaterad dysfagi och andningsproblem till en så bra tillvaro som möjligt skulle belysas.Författarna har funnit att omvårdnaden sällan sätts i fokus. Det är istället de lösningar som tar bort symtomet som fått fokus i flertalet av de artiklar som granskats. Att hjälpa dessa personer till trygga och oberoende människor som kan fortsätta att leva istället för som många av artiklarna visade då det gjordes insatser som ledde till att personerna blev mer bundna till sina anhöriga och sina vårdare.
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Zhang, Xuekai. "The role of chaperone proteins in neurodegenerative diseases." Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/the-role-of-chaperone-proteins-in-neurodegenerative-diseases(850af92d-8f30-4e7b-8f6e-1fd9c434dc96).html.
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Many neurodegenerative diseases are characterized by the accumulation of misfolded proteins that often share common morphological and biochemical features, and can similarly co-localize with several other proteins, including various chaperone proteins. Chaperone proteins, like heat shock protein 27 (HSP27), heme oxygenase 1 (HO-1) and clusterin, have been implicated as potent modulators of misfolded proteins, thus may play important roles in the pathogenesis of neurodegenerative diseases. The present study aims to investigate their roles in the pathogenesis of Frontotemporal lobar degeneration (FTLD), Alzheimer's disease (AD), Parkinson's disease (PD), and Motor neuron disease (MND) by determining their distribution and amount via immunohistochemical staining and western blotting in diseased and control subjects.There were distinct patterns of HSP27 and clusterin immunostaining in different brain regions. For HSP27, patients with AD and FTLD were in general more severely affected than were patients with MND and control subjects. For clusterin, patients with AD and FTLD were more severely affected than control subjects where neurons and glial cells were concerned, while patients with AD and control subjects were more severely affected than those with FTLD where diffuse and cored plaques were concerned. However, there were no obvious differences in the pattern of HO-1 immunostaining in various brain regions in patients with AD or FTLD relative to control subjects. Moreover, there was no association between HSP27, HO-1 and clusterin with disease or histological type, and the ‘classic’ neuropathological changes in FTLD, AD and MND were not immunoreactive to any of these proteins. There were significant correlations between the degrees of HO-1 and clusterin immunostaining in many brain areas for both AD and FTLD cases, and for all cases overall, but none between HSP27 and clusterin or HSP27 and HO-1. Present results suggest an involvement with ongoing cellular stress, misfolded or unfolded protein accumulation or the deficits/failure of other relevant protein quality control systems, in the pathogenesis of these neurodegenerative diseases. Present work may therefore have implications for the further development of ideas concerning the cause or treatment of neurodegenerative diseases where there is aberrant accumulation of misfolded, aggregated protein, and perhaps for conformational diseases in general. However, there are still many issues remain to be elucidated. Further research aimed at understanding the function and mechanisms of the chaperone system, and other protein quality control mechanisms, in the pathogenesis of neurodegenerative diseases is still needed.
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Al-Khamees, Inas, and Mary Bilal. "Att leva med ALS : En litteraturstudie ur patienters perspektiv." Thesis, Mälardalens högskola, Akademin för hälsa, vård och välfärd, 2020. http://urn.kb.se/resolve?urn=urn:nbn:se:mdh:diva-52375.
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Bakgrund: Amyotrofisk lateralskleros, ALS, är en fortskridande motorneuronsjukdom som drabbar och bryter ner nervceller som styr skelettmuskulaturen. Sjukdomen orsakar stort lidande för patienter och kan vara snabbt fortskridande och oförutsägbar. Sjuksköterskor upplever att patienter med ALS behöver få adekvat information och stöd för att lindra lidande. Detta sker genom att sjuksköterskor är respektfulla och lyhörda på patientberättelsen. Närstående har också en stödjande funktion i patienters kamp mot sjukdomen genom att vara närvaro i vardagen. Syfte: Att beskriva patienters upplevelser av att leva med ALS. Metod: En kvalitativ litteraturstudie baserad på tretton kvalitativa artiklar. Resultat: Två teman och fem subteman identifierades. Det första temat var en förändrad livssituation genom att uppleva rädsla för framtiden, att vara begränsad i vardagen och att vara beroende av omgivningen. Det andra temat var att anpassa sig till en ny tillvaro genom att leva med acceptans i nuet och att finna mening trots sjukdomen. Slutsats: Patienter med ALS upplever en förändrad livssituation på grund av sjukdomen. Detta krävs en medvetenhet och kunskap om patienters upplevelser hos sjuksköterskor vilken kan bidra till bättre vård och öka anpassning för patienter i livet. Nyckelord: Kvalitativ, Motorneuronsjukdom, Palliativ vård, Patienters perspektiv, Upplevelser.
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Martin, Joanne Elizabeth. "Cellular pathology of the lower motor neuron in motor neuron disease." Thesis, Queen Mary, University of London, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.266426.
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Parton, Matthew James. "Disease-modifying factors in motor neuron disease." Thesis, King's College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.289882.
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Williams, David Bruce. "Genetic factors in motor neuron disease." Thesis, The University of Sydney, 1989. https://hdl.handle.net/2123/26235.
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The term motor neuron disease is used by different authors to designate one or more of a wide variety of disorders whose principal common feature is dysfunction of the motor neuron (MN) or anterior horn cell (AHC). In one convention, the term motor neuron disease is used to denote all such disorders, including both infantile- and juvenile-onset forms of spinal muscular atrophy, and corticospinal degenerations in which the upper motor neuron is prominently affected. At other times the term motor neuron disease refers only to the relatively common and presumably more homogeneous condition which is idiopathic, has its onset in late adult life and is almost inevitably fatal. Often the distinction between these two uses is not clearly stated and must be inferred. In another more recent, but not yet universal convention, the term motor neuron disease designates all disorders of the anterior horn cell and associated motor system, and amyotrophic lateral sclerosis (ALS) is used to indicate the commonest disorder. This is also potentially confusing, as by definition the term ALS is the clinical presentation of a patient with combined upper and lower motor neuron signs in either or both of the bulbar and spinal regions. Therefore its use may implicitly exclude patients with the clinical features of progressive bulbar palsy (PBP) (exclusive lower motor neuron involvement in the bulbar region) or progressive muscular atrophy (PMA) (exclusive lower motor neuron involvement in the spinal region, (also called progressive spinal muscular atrophy (PSMA))). Some authors suggest that PMA has a sufficiently different clinical presentation and prognosis to define it is a different disease (Norris et al, 1978). However, there is poor correlation between the clinical and pathological features of clinically defined cases of ALS and PMA (Chou, 1978), the electrophysiological abnormalities are indistinguishable (Hansen and Ballantyne, 1978), and one clinical form may change into another (Friedman and Freedman, 1950). When patients with either pure PMA or pure PBP are examined repeatedly during the course of their illness, they are often found to develop upper motor neuron signs, so exclusive lower motor neuron syndromes confirmed at autopsy are probably quite rare (cf the Mayo Clinic patients in Juergens et al, 1980). Therefore, a reasonable inference is that ALS, PBP and PMA are clinical variants of one disease. By contrast, most authors are cautious to discuss pure upper motor neuron degeneration, or primary lateral sclerosis (PLS), as a separate entity (Stark and Moersch, 1945; Younger et al, 1988).
In this thesis, the uncapitalised phrase 'motor neuron diseases' will refer to all disorders where loss or degeneration of the AHC is the principal salient feature. The abbreviation MND/ALS will be this author's term for the idiopathic, adult-onset disease which may have the variety of clinical presentations (ALS, PBP, PMA) described above. The terms MND or ALS will be used alone when they refer to a patient or group of patients described by a specific author, so that then the reference will be to the definition utilised by that author. Clinical presentations will be called the ALS, PMA or PBP 'form' of MND/ALS.
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Sargsyan, Siranush Anna. "Microglial activationas a potential contributor to motor neuron injury in motor neuron disease." Thesis, University of Sheffield, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.444237.
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Bäumer, Dirk. "Functional genetic analysis of motor neuron disease." Thesis, University of Oxford, 2010. http://ora.ox.ac.uk/objects/uuid:859016f8-5eff-4a8e-bfda-48afb8695646.
Full textAbstract:
Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are the commonest motor neuron diseases of adult- and childhood onset. Alterations of the RNA binding protein TDP-43 are associated with most cases of ALS, while SMA is caused by deletion of the Survival Motor Neuron (SMN1) gene. SMN has been well characterised in its role in the assembly of the cellular machinery that carries out splicing of pre-mRNA, but is thought to have other functions in RNA metabolism unrelated to pre-mRNA splicing. It is conceivable that specific aspects of RNA handling are disrupted in both SMA and ALS. A variety of genetic, molecular and neuropathological approaches were applied to investigate a potential common pathway in these diseases. The spectrum of genetic mutations underlying motor neuron disorders were explored by screening patient DNA. Cell culture and mouse models were used to test the hypothesis that altered pre-mRNA splicing causes motor neuron death. Human neuropathological specimens were examined for changes in proteins involved in RNA metabolism. The results indicate that altered pre-mRNA splicing is a late occurrence in disease and more likely to be a consequence rather than the cause of motor neuron degeneration. However, the notion that RNA metabolism is highly relevant to motor neuron diseases was strengthened by the discovery of mutations in another RNA binding protein, FUS, in cases of ALS without TDP-43 pathology. Overall the findings highlight the need to consider disruption of mRNA transport and regulation of mRNA translation in future motor neuron disease research.
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Long, Zhe. "Frontotemporal Dementia-Motor Neuron Disease: disease continuum or distinct entity?" Thesis, University of Sydney, 2020. https://hdl.handle.net/2123/23012.
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Frontotemporal dementia-motor neuron disease (FTD-MND) is a rare disease characterised by the simultaneous occurrence of FTD and MND. Clinical, pathological, and genetic investigations have highlighted the association between FTD and MND, but much remains unclear. The experimental studies of this thesis comprehensively and systematically investigate the natural history of cognition and behaviour in FTD-MND and explore whether FTD-MND is distinct from well-recognised FTD phenotypes using clinical, neuropsychological and multimodal neuroimaging analyses. Results arising from two separate studies (Chapters 3 and 4) reveal that the majority of FTD-MND presents with variable combinations of behaviour, language and motor deficits initially, and fulfil FTD-MND diagnosis within 24 months from symptom onset. Heterogenous deficits persist even after meeting FTD-MND diagnostic criteria. Clinical heterogeneity in FTD-MND, highlighted by using a data-driven approach, may reflect variable white matter tract involvement. Language impairment in FTD-MND is highly prevalent, and more mixed than in FTD language phenotypes. The frequency and severity of behavioural and language deficits in FTD-MND lie between that of FTD phenotypes. Over time (Chapter 5), cognition and language deficits progress more rapidly in FTD-MND than bvFTD. Progression in FTD-MND may be driven by left inferior frontal gyrus and anterior temporal lobe involvemeny. Survival in FTD-MND is much shorter than in FTD, despite a similar age at onset. Motor neuron dysfunction may be highly specific for frontotemporal lobar degeneration TAR DNA binding protein 43 kDa (FTLD-TDP, Chapter 6), but the current FTLD-TDP pathological staging scheme may not correlate with clinical progression. These findings demonstrate that FTD-MND is distinct from, rather than simply a later clinical stage of, FTD.
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Stephens, Benjamin. "Pathology of spinal interneurons in motor neuron disease." Thesis, Imperial College London, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.251759.
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Blackburn, Daniel J. "The role of glial cells in motor neuron disease." Thesis, University of Sheffield, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.531123.
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Kwok, Alice. "Unfolded protein responses in models of Motor Neuron Disease." Thesis, University of Oxford, 2010. http://ora.ox.ac.uk/objects/uuid:2f3efba7-dce1-4521-bda6-4db8ee81094d.
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Motor neuron disorders are a heterogeneous group of diseases characterized by the selective degeneration of motor neurons leading to muscle wasting and atrophy. Amyotrophic Lateral Sclerosis (ALS) is the most common amongst these disorders and is characterized by the selective loss of both upper and lower motor neurons in the brain and spinal cord. 20% of familial cases of ALS are caused by mutations in the Cu, Zn-superoxide dismutase gene (SOD1), a ubiquitously expressed enzyme responsible for scavenging superoxide radicals. The exact mechanisms underlying mutant SOD1-mediated neurotoxicity are unknown. Misfolded mutant SOD1 accumulates in the cytosol and mitochondrial intermembrane space (IMS) indicating the involvement of unfolded protein responses in ALS pathogenesis. Unfolded protein responses (UPRs) are complex signal transduction cascades which detect perturbations in protein folding and couple them to the expression of protein quality control machinery thereby allowing individual compartments to adapt to stress. In the cytosol, this study has shown that HspB8 was upregulated by SOD1 mutants, where it induced the clearance of aggregates by macroautophagy. This is a protective mechanism, as overexpression of HspB8 suppressed mutant-SOD1 mediated toxicity. In contrast, HspB8 mutants were impaired in macroautophagy and are toxic to NSC-34 cells. The mechanisms for the IMS-UPR have not been previously identified. To address this issue, a model for the accumulation of misfolded mutant SOD1 within the IMS was created and candidate proteins involved in protein quality control within the IMS were explored at the transcriptional level and at the level of protein expression. Preliminary results revealed some possible candidates that may have a role in the adaptation to mitochondrial stress. Interestingly, increased mitophagy was also found in IMS-G93A expressing cells, advocating the central role of macroautophagy in eliminating protein aggregates and damaged mitochondria in SOD1-FALS.
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Shum, Carole Yick Lam. "Modelling motor neuron disease using induced pluripotent stem cells." Thesis, King's College London (University of London), 2016. https://kclpure.kcl.ac.uk/portal/en/theses/modelling-motor-neuron-disease-using-induced-pluripotent-stem-cells(1686136a-d045-4edc-9439-1028b0ea47db).html.
Full textAbstract:
Amyotrophic Lateral Sclerosis (ALS) is the most common adult motor neuron disease. The majority of ALS cases are sporadic (SALS), but 10% of patients have a familial form of ALS (FALS). Mutations in Fused in Sarcoma (FUS) occur in approximately 4% of FALS and less than 1% of SALS. A hallmark feature of ALS is the degeneration of upper and lower motor neurons in the brain and spinal cord; however, the mechanism underlying this loss is not known. Studies of degenerative mechanisms have been impeded by the inaccessibility of human neural tissue. A possible solution is to use induced pluripotent stem cells (iPSCs) derived from patients, which may be differentiated into the cell types affected by disease. To test whether patient-specific stem cells can be used to model aspects of ALS pathogenesis, iPSC lines were generated from a patient carrying the pathogenic FUS R521C mutation. FUS iPSCs derived from patient fibroblasts and WT iPSCs derived from fibroblasts from two healthy controls were differentiated into neural progenitors and motor neurons. FUS iPSC-derived neuronal cells recapitulate key aspects of FUSassociated ALS, including mislocalisation of FUS protein, the redistribution of FUS protein into cytoplasmic stress granules, and increased apoptotic cell death. The second study uses this iPSC model to investigate the effects of mutant FUS on dendritic morphology and synaptic regulation. FUS iPSC-derived neurons display abnormal dendritic morphology, such as reduced neurite outgrowth and reduced density of dendritic protrusions. FUS iPSC-derived neurons also show differences in the localisation of synaptic proteins. This study suggests that physiological levels of mutant FUS protein affect the morphology and synaptic structure of human neurons. These studies validate the stem cell approach to disease modelling and provide support for the use of patient-specific stem cells for the study of disease mechanisms.
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Lyon, Alison Nicole. "Generation and Analysis of Motor Neuron Disease Models in Zebrafish." The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1337276861.
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Witherden, Abigail Sian. "Positional cloning of Loa, a mouse motor deficit mutation." Thesis, Imperial College London, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.248151.
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Garcia-Willingham, Natasha E. "LANGUAGE DYSFUNCTION IN MOTOR NEURON DISEASE: COGNITIVE FEATURES AND SCREENING SENSITIVITY." UKnowledge, 2019. https://uknowledge.uky.edu/psychology_etds/168.
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Motor neuron disease (MND) is a set of neuromuscular diseases that affect the upper and/or lower motor neurons, resulting in progressive disability. Amyotrophic lateral sclerosis (ALS) and Primary lateral sclerosis (PLS) are two forms of MND that both involve upper motor neuron degeneration, which can also accompany extra-motor changes in cognitive, behavioral, and/or emotional functioning for some individuals. Characterization of the cognitive profile of MND is still evolving, with growing interest in cognitive subtypes. The development of cognitive screens targeted to the MND cognitive profile aim to provide efficient and accurate brief assessments. However, empirical evaluation of tailored MND cognitive screens is needed for cross-validation independent of tests’ original developers. The present study addresses the cognitive profile of MND and the utility of brief cognitive screens with a focus on impairments in the language domain. The two primary aims include: (1) comprehensive assessment and characterization of language dysfunction in MND, and (2) empirical evaluation of brief cognitive screens with regard to detecting language impairments.
Forty-one patients with MND (ALS n = 36; PLS n = 5) were administered a comprehensive language battery to classify cognitive impairment (MND/ALSci; Strong et al., 2017) in the language domain and/or verbal fluency. Patients also completed two tailored cognitive screens [ALS Cognitive Behavioral Screen (ALS-CBS), Edinburgh Cognitive and Behavioral ALS Screen (ECAS)] and one general screen (Montreal Cognitive Assessment; MoCA).
The current preliminary results suggest language dysfunction in MND is characterized by prominent difficulties with word retrieval (confrontation naming) and/or syntax comprehension. However, evidence of reduced word production resembling nonfluent/agrammatic aphasia was not found. In total, 19.5% of the sample met criteria for MND/ALSci in the language domain (n = 8, all ALS); 22.0% met criteria for MND/ALSci in the verbal fluency domain (n = 9). Patients were classified into three subgroups, those with broad language impairments (ALSci-L n = 4, 9.8%), phonemic fluency impairments (MNDci-VF n = 5, 12.2%), or both impairments (ALSci-L+VF n = 4, 9.8%). Results also revealed existing challenges in accurately classifying patients with language dysfunction using brief cognitive screens. The ECAS Language subscore offered limited classification of broad language impairments in the present MND sample (sensitivity 50%, specificity 70%). Among the broader cognitive screens, sensitivities to language impairments were: ALS-CBS (100%), ECAS ALS-Specific Score (75%), and MoCA (71%). Convergent validity was demonstrated between outcomes on the ALS-CBS and ECAS ALS-Specific Score (rФ = .59). Discriminant validity was also demonstrated between outcomes on ALS-CBS compared to the MoCA (rФ = .11).
Future research is needed to assess whether language dysfunction reflects a distinct MND cognitive phenotype(s) and potential relationships with disease prognosis. Naming and syntax comprehension may be fruitful language screening targets for future research.
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Günther, Rene, Nicole Richter, Anna Sauerbier, Kallol Ray Chaudhuri, Pablo Martinez-Martin, Alexander Storch, and Andreas Hermann. "Non-Motor Symptoms in Patients Suffering from Motor Neuron Diseases." Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2017. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-217311.
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Background
The recently postulated “disease spreading hypothesis” has gained much attention, especially for Parkinson’s disease (PD). The various non-motor symptoms (NMS) in neurodegenerative diseases would be much better explained by this hypothesis than by the degeneration of disease-specific cell populations. Motor neuron disease (MND) is primarily known as a group of diseases with a selective loss of motor function. However, recent evidence suggests disease spreading into non-motor brain regions also in MND. The aim of this study was to comprehensively detect NMS in patients suffering from MND.
Methods
We used a self-rating questionnaire including 30 different items of gastrointestinal, autonomic, neuropsychiatric, and sleep complaints [NMS questionnaire (NMSQuest)], which is an established tool in PD patients. 90 MND patients were included and compared to 96 controls.
Results
In total, MND patients reported significantly higher NMS scores (median: 7 points) in comparison to controls (median: 4 points). Dribbling, impaired taste/smelling, impaired swallowing, weight loss, loss of interest, sad/blues, falling, and insomnia were significantly more prevalent in MND patients compared to controls. Interestingly, excessive sweating was more reported in the MND group. Correlation analysis revealed an increase of total NMS score with disease progression.
Conclusion
NMS in MND patients seemed to increase with disease progression, which would fit with the recently postulated “disease spreading hypothesis.” The total NMS score in the MND group significantly exceeded the score for the control group, but only 8 of the 30 single complaints of the NMSQuest were significantly more often reported by MND patients. Dribbling, impaired swallowing, weight loss, and falling could primarily be connected to motor neuron degeneration and declared as motor symptoms in MND.
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Günther, Rene, Nicole Richter, Anna Sauerbier, Kallol Ray Chaudhuri, Pablo Martinez-Martin, Alexander Storch, and Andreas Hermann. "Non-Motor Symptoms in Patients Suffering from Motor Neuron Diseases." Frontiers Research Foundation, 2016. https://tud.qucosa.de/id/qucosa%3A30109.
Full textAbstract:
Background
The recently postulated “disease spreading hypothesis” has gained much attention, especially for Parkinson’s disease (PD). The various non-motor symptoms (NMS) in neurodegenerative diseases would be much better explained by this hypothesis than by the degeneration of disease-specific cell populations. Motor neuron disease (MND) is primarily known as a group of diseases with a selective loss of motor function. However, recent evidence suggests disease spreading into non-motor brain regions also in MND. The aim of this study was to comprehensively detect NMS in patients suffering from MND.
Methods
We used a self-rating questionnaire including 30 different items of gastrointestinal, autonomic, neuropsychiatric, and sleep complaints [NMS questionnaire (NMSQuest)], which is an established tool in PD patients. 90 MND patients were included and compared to 96 controls.
Results
In total, MND patients reported significantly higher NMS scores (median: 7 points) in comparison to controls (median: 4 points). Dribbling, impaired taste/smelling, impaired swallowing, weight loss, loss of interest, sad/blues, falling, and insomnia were significantly more prevalent in MND patients compared to controls. Interestingly, excessive sweating was more reported in the MND group. Correlation analysis revealed an increase of total NMS score with disease progression.
Conclusion
NMS in MND patients seemed to increase with disease progression, which would fit with the recently postulated “disease spreading hypothesis.” The total NMS score in the MND group significantly exceeded the score for the control group, but only 8 of the 30 single complaints of the NMSQuest were significantly more often reported by MND patients. Dribbling, impaired swallowing, weight loss, and falling could primarily be connected to motor neuron degeneration and declared as motor symptoms in MND.
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Friberg, Danielle. "Nerve lesions in pharynx - an aetiology of obstructive sleep apnoea /." Stockholm, 1997. http://diss.kib.ki.se/1997/91-628-2721-9.
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Bermingham, Nessan Anthony. "Genetic characterisation of the progressive motor neuron degeneration mouse 'Legs as odd angles' (Loa)." Thesis, Imperial College London, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.264956.
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Mather, Mary Srikanti. "Putative protein abnormalities in amyotrophic lateral sclerosis." Thesis, University of Sussex, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.239078.
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Bros, Virginie. "In-situ characterisation of the recessive motor neuron disease protein, ALS2/ALSIN." Thesis, King's College London (University of London), 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.420377.
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Turner, Martin Robert. "Understanding pathophysiologial mechanisms in sporadic and familial cases of motor neuron disease." Thesis, King's College London (University of London), 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.417085.
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Griffiths, Lowri Ann. "Investigating the role of eEF1A2 in motor neuron degeneration." Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/5924.
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Abnormal expression of the eukaryotic translation elongation factor 1A (eEF1A) has been implicated in disease states such as motor neuron degeneration and cancer. Two variants of eEF1A are found in mammals, named eEF1A1 and eEF1A2. These two variants are encoded by different genes, produce proteins which are 92% identical but have very different patterns of expression. eEF1A1 is almost ubiquitously expressed while eEF1A2 is expressed only in specialised cell types such as motor neurons and muscle. A spontaneous mutation in eEF1A2 results in the wasted mouse phenotype which shows similar characteristics in the mouse to those seen in human motor neuron degeneration. This mutation has been shown to be a 15.8kb deletion resulting in the complete loss of the promoter region and first non coding exon of eEF1A2 which completely abolishes protein expression. The main aim of this project was to further investigate the role of eEF1A2 in motor neuron degeneration. Firstly, although the wasted phenotype is considered to be caused by a recessive mutation, I established a cohort of aged heterozygote mice to evaluate whether any changes are seen later in life that might model late onset motor neuron degeneration. A combination of behavioural tests and pathology was used to compare wild type and heterozygous mice up to 21 months of age. Whilst results indicate that there is no significant difference between ageing heterozygotes and wildtype controls, there is an indication that female heterozygote mice perform slightly worse that wildtype controls on the rotarod (a behavioural test for motor function). Secondly, I aimed to investigate the primary cause of the wasted pathology by generating transgenic wasted mice expressing neuronal eEF1A2 only. This would complement previous experiments in the lab which studied transgenic wasted mice expressing eEF1A2 in muscle only. Unfortunately the expression of eEF1A2 in the transgenic animals was not neuronal specific. However a transgenic line with expression of eEF1A2 in neurons and skeletal muscle but not cardiac muscle has been generated which clearly warrants further investigation. Thirdly, I wished to assess whether eEF1A2 has any role in human motor neuron degeneration. To achieve this, eEF1A2 expression was investigated in spinal cords from human motor neuron disease (MND) patients. Preliminary data suggests that motor neurons from some MND patients express significantly less eEF1A2 than motor neurons of control samples. Further work is required to confirm these findings. Finally, I investigated the individual roles of eEF1A1 and eEF1A2 in the heat shock response. I used RNAi to ablate each variant separately in cells and subsequently measured the ability of each variant individually to mount a heat shock response. Results indicate a clear role for eEF1A1 but not eEF1A2 in the induction of heat shock. This may explain in part why motor neurons exhibit a poor heat shock response as they express eEF1A2 and not eEF1A1. These experiments shed light on our understanding of the role of eEF1A2 in motor neuron degeneration and uncover many new avenues of future investigation.
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Sassi, Mohammed M. "Apolipoprotein-E genotype in major neurodegenerative diseases." Thesis, University of Nottingham, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.339716.
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Wagner, Justin. "Whole Exome Sequencing to Identify Disease-Causing Mutations in Lower Motor Neuron Disease and Peripheral Neuropathy." Thesis, Université d'Ottawa / University of Ottawa, 2016. http://hdl.handle.net/10393/34124.
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Lower motor neuron diseases and peripheral neuropathies are two groups of diseases that include multiple rare disorders where many causes are unknown and definitive treatments are unavailable. Understanding the molecular etiology of these genetic diseases provides an opportunity for rapid diagnosis, preconception genetic counseling and, in a subset, direction for the development of future treatment options. The recent introduction of whole exome sequencing (WES) marks a new era in Mendelian genetic disease research as the majority of the coding region of the genome can be sequenced in a timely and cost-effective manner. In this study, WES was used to investigate the molecular etiology of a cohort of 37 patients presenting with lower motor neuron disease or peripheral neuropathy. A molecular diagnosis was determined for seven patients informing the diagnostic utility of WES. Novel phenotypes were found for three genes originally associated with a different disorder. Finally, the foundation has been laid, through the use of functional studies and large scale data-sharing, to identify novel disease-causing genes for lower motor neuron disease and peripheral neuropathy.
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Christou, Yiota Apostolou. "Generation of motor neurons from embryonic stem cells : application in studies of the motor neuron disease mechanism." Thesis, University of Sheffield, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.505426.
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Embryonic stem cells are pluripotent cells with the potential to differentiate into any cell type in the presence of appropriate stimulatory factors and environmental cues. Their broad developmental potential has led to the proposal that in the future, the use of human embryonic stem cells or their differentiated progeny may be beneficial in regenerative medicine. In particular, a current goal in the field of clinical neurology is to use stem cells in cell-based therapies for motor neuron disease (MND) or amyotrophic lateral ~clerosis. MND is a progressive neurodegenerative disease that specifically affects upper and lower motor neurons and leads ultimately to death from respiratory failure. Stem cellderived motor neurons could conceivably be used to replace the degenerated cells, to provide authentic substrates for drug development and screening and for furthering our understanding of disease mechanisms. However, to reliably and accurately culture motor neurons, the complex pathways by which differentiation occurs in vivo must be understood and reiterated in vitro to direct embryonic stem cells towards motor neurons. This thesis presents the work I have performed on the directed differentiation of embryonic stem cells towards motor neuron fates. I describe the various experimental approaches I took in attempts to produce motor neurons in vitro. My studies reveal that it is possible to deploy the signals used during normal development to direct the differentiation of both human and mouse embryonic stem cells into neural and neuronal cells, including motor neurons. Two major limitations precluded my analysis of pure motor neuron cultures: first, the high concentrations of the ventralising morphogen, SHH, apparently required to direct embryonic stem cells towards motor neuron fates, and second, the difficulties encountered in culturing purified motor neurons. However, using a mixed culture, I obtained evidence that motor neurons and their progenitors fail to survive in medium conditioned by mutant SOD1-G93A astrocytes.
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Couillard-Despres, Sebastien. "Transgenic mouse models to study the role of neurofilaments in motor neuron disease." Thesis, McGill University, 2001. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=37882.
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Neurofilaments are the major type of intermediate filaments found in the adult nervous system of mammalians. Abnormalities of the neurofilament network constitute a common finding of many neurological disorders. For instance depositions of neurofilament aggregates in the perikarya and axons of motor neurons are observed in most amyotrophic lateral sclerosis (ALS) cases, sporadic and familial. The impact of such accumulation of neurofilaments on the course of motor neuron disease remains to be fully elucidated.In order to investigate the role of neurofilaments in motor neuron disease, transgenic mice expressing a mutant form of the Cu,Zn superoxide dismutase (SOD1) were used as an animal model of familial ALS. Increasing the perikaryal neurofilament content in these mutant SOD1 mice slowed down the motor neuron disease progression and increased their life span by up to 65%. To date, this approach constitutes the most efficient way to increase the life span of mutant SOD1 mice. Moreover, increasing the axonal neurofilament content in mutant SOD1 mice by human neurofilament-light subunit (hNF-L) overexpression demonstrated that axonal neurofilaments do not constitute an exacerbating factor in the neurodegeneration caused by mutant SOD1.
The pathogenicity of human neurofilament-heavy (hNF-H) proteins expressed in transgenic mice was also investigated. Two alleles of the NF-H gene are present in the normal human population. Expression of both alleles in transgenic mice provoked motor neuron dysfunction. The adverse property of NF-H overexpression is the result of an improper stoichiometry between the NF-L and the NF-H subunits. Restoration of an adequate stoichiometry, via the co-expression of NF-L and NF-H subunits, rescued mice from the motor neuron dysfunction. Finally, expression of the allele called NFH43, bearing less phosphorylation sites than the other allele called NFH44, was shown to be more pathogenic in transgenic mice.
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Larivière, Roxanne. "Transgenic approach to study the role of intermediate filaments in motor neuron disease." Thesis, McGill University, 2003. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=84279.
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Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder characterized by the loss of upper and lower motor neurons. Many reports lead to the hypothesis that a high axonal neurofilament burden and a large axonal caliber account for the selective vulnerability of motor neurons affected in ALS (Kawamura et al., 1981; Sobue et al., 1981; 1987). Transgenic mice expressing a mutant form of SOD1-linked to familial ALS and having one disrupted allele for each neurofilament gene were generated to address this issue. Despite a 40% reduction in neurofilament content and a decrease of large axonal caliber from 5--9 mum to 1--5 mum, these mice did not show an extended life span, nor did they display an alleviated loss of motor axons. These results do not support the idea that high neurofilament content and large axonal caliber are responsible for the selective vulnerability of motor neurons in ALS.Peripherin, a type III intermediate filament (IF) protein is also expressed in spinal motor neurons, and is present together with neurofilaments in axonal spheroids of ALS patients, suggesting that this protein could be involved in the pathogenesis of ALS. Moreover, mice overexpressing a peripherin transgene develop a late-onset motor neuron death characterized by the presence of IF inclusion bodies (Beaulieu et al., 1999a). In a first attempt to clarify the role of peripherin in ALS, peripherin knockout mice were generated. Peripherin null mice were viable, reproduce normally and did not exhibit overt phenotype. However, they did show a 34% reduction in the number of L5 unmyelinated sensory fibers demonstrating a requirement of peripherin for the proper development of a subset of sensory neurons.
Finally, in order to investigate whether peripherin contributes to the pathogenesis of ALS, mutant SOD1 mice were generated in a peripherin overexpressing background and a peripherin depleted background. Unexpectedly, upregulation or suppression of peripherin expression had no effect on disease onset, mortality and motor neuron loss in mutant SOD1 mice. Taken together, these results provide compelling evidence that peripherin is not a key contributor of motor neuron degeneration associated with toxicity of mutant SOD1.
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Nicholson, Sharon Joycelyn. "Mapping of Loa : a mouse motor deficit gene." Thesis, Imperial College London, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.344089.
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Sandoe, Jackson L. "Developing Human Stem Cell Derived Motor Neuron Models of Amyotrophic Lateral Sclerosis." Thesis, Harvard University, 2014. http://nrs.harvard.edu/urn-3:HUL.InstRepos:13070028.
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Human neurodegenerative disorders are among the most difficult to study. In particular, the inability to readily obtain the faulty cell types most relevant to these diseases has impeded progress for decades. Amyotrophic lateral sclerosis is a late onset neurodegenerative disease in which the upper and lower motor neurons degenerate, leading to paralysis and eventually death. Recent advances in pluripotent stem cell technology now grant access to significant quantities of disease pertinent neurons both with and without predisposing mutations. The two studies described in this thesis demonstrate the feasibility of using MNs, generated from pluripotent stem cell lines harboring known ALS mutations, to establish in-vitro models of the disease. Specifically, we first used gene targeting to establish genetically controlled systems, able to identify causal relationships between a familial ALS mutation and in vitro phenotypes. Next, using transcriptional profiling, we identified novel pathways altered by the mutation and demonstrated functional consequences of these pathways' misregulation. Furthermore, by monitoring the physiology of the pluripotent stem cell derived MNs, we discovered an increased firing rate in the mutant MNs, and identified an FDA-approved drug, retigabine, capable of rescuing this defect. Lastly, to aid in the discovery of additional therapeutic compounds, we combined gene targeting, transcriptional profiling, and a fluorescent reporter human embryonic stem cell line to establish a well-controlled in vitro system capable of identifying genetic modifiers of the phenotypes described herein.
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Richardson, Katie. "The investigation of oxidative damage to nucleic acids during ageing and motor neuron disease." Thesis, University of Sheffield, 2013. http://etheses.whiterose.ac.uk/5720/.
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Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disorder, characterised by the degeneration of upper and lower motor neurons. Multiple mechanisms have been associated with ALS pathology, however the precise molecular events leading to selective motor neuron degeneration have yet to be understood. Prominent neuronal RNA oxidation has been reported during ageing and presymptomatic stage of ALS, with specific transcripts selectively modified during disease, which may contribute towards selective cellular degeneration. Gene expression changes using microarray technology has been widely used to investigate pathways underlying ageing and neurodegenerative disease. The aim of our study was to investigate the gene expression profile of an oxidised fraction of RNA extracted from the anterior spinal cord of normal mice aged six, twelve, and eighteen months. In data presented here, we identify specific classes of genes to be enriched within the oxidised fraction at each age. Furthermore, genes previously linked to the pathogenesis of ALS and normal ageing, such as those involved in RNA processing and transcriptional regulation, are identified as being differentially oxidised in the anterior spinal cord. The presence and distribution of oxidative damage to nucleic acids within an in vivo model of familial ALS and age-matched controls is demonstrated. The predominance of cytoplasmic 8-hydroxyguanosine reactivity within motor neurons supports previous data of RNA susceptibility to oxidative modification in neurodegenerative disease. Investigation of RNA oxidation in an in vitro model of fALS harbouring G93A and H48Q human SOD1 mutations identified prominent levels of RNA oxidation in comparison to controls, which correlated with a reduction in human SOD1 protein expression within these cells. Subsequent work demonstrated the G93A mutation to be the most susceptible to oxidative stress related cellular decline, in terms of mitochondrial bioenergetics, mitochondrial morphology, and cell viability. The heterogeneity of various SOD1 mutations on cellular function is demonstrated.
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Valdmanis, Paul Nils. "Genetic analysis of amyotrophic lateral sclerosis and other motor neuron disorders." Thesis, McGill University, 2009. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111916.
Full textAbstract:
Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease which results from the degeneration of upper and lower motor neurons in the brainstem, spinal cord and motor cortex. Tragically there is no treatment to prevent ALS. The drug Riluzole acts to delay progression, but only by a month or so in this disease that has a survival length of three to five years. The identification of genes that are mutated in patients with ALS would help devise novel therapeutic strategies as much remains to be discovered about the genetics of ALS. Familial forms of the disease account for only 5-10% of patients. Among these familial cases, about 15-20% are caused by mutations in the zinc/copper superoxide dismutase gene, but the genetic basis of the remaining familial cases and the many sporadic cases continues to be largely unknown.Altogether, the results presented in this thesis came from the use of several strategies to establish the genetic cause of ALS and the related motor neuron disorders like hereditary spastic paraplegia (HSP) and primary lateral sclerosis (PLS). A concerted and collaborative effort was put forth to identify the gene causative for ALS3 on chromosome 18. In addition, a recently reported locus has been confirmed on chromosome 9p for patients that present both ALS and frontotemporal dementia. The major finding involves the discovery of eight mutations in the TARDBP gene in nine patients with sporadic and familial ALS. Furthermore, a large association study evaluated the role of common polymorphisms in the paraoxonase gene cluster in susceptibility to the development of ALS. In the analysis of upper motor neuron diseases, mutations in a novel gene, KIAA0196, were identified for the HSP locus SPG8 on chromosome 8. Finally, the first locus for PLS was discovered on the p-arm of chromosome 4 following genome scan analysis of a large Quebec family with PLS.
These genetic discoveries all contributed novel advances to the field of motor neuron disorders. As more is elucidated regarding the biochemical function of these the proteins encoded by these genes, a more comprehensive picture of ALS and other motor neuron disorders will hopefully emerge.
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Fong, Chung-yan Gardian. "A study of motor neuron disease in the community and in a large multigenerational kindred." Click to view the E-thesis via HKUTO, 2006. http://sunzi.lib.hku.hk/hkuto/record/B37602263.
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Fong, Chung-yan Gardian, and 方頌恩. "A study of motor neuron disease in the community and in a large multigenerational kindred." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B37602263.
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Yazdani, Armin A. "The Smn-Independent Beneficial Effects of Trichostatin A on an Intermediate Mouse Model of Spinal Muscular Atrophy." Thèse, Université d'Ottawa / University of Ottawa, 2014. http://hdl.handle.net/10393/30703.
Full textAbstract:
Trichostatin A (TSA) is a histone deacetylase inhibitor with beneficial effects in spinal muscular atrophy mouse models that carry the human SMN2 transgene. Whether TSA specifically targets the upregulation of the SMN2 gene or whether other genes respond to TSA and in turn provide neuroprotection in SMA mice is unclear. We have taken advantage of the Smn2B/- mouse model that does not harbor the human SMN2 transgene, to test the hypothesis that TSA has its beneficial effects through a non-Smn mediated pathway. Daily intraperitoneal injection of TSA from postnatal day 12 to 25 was performed in the Smn2B/- mice and littermate controls. Previous work from our laboratory demonstrated that treatment with TSA increased the median lifespan of Smn2B/- mice from twenty days to eight weeks. As well, there was a significant attenuation of weight loss and improved motor behavior. Pen test and righting reflex both showed significant improvement, and motor neurons in the spinal cord of Smn2B/-mice were protected from degeneration. Both the size and maturity of neuromuscular junctions were significantly improved in TSA treated Smn2B/- mice. Here, we have shown that TSA treatment does not increase the levels of Smn protein in mouse embryonic fibroblasts or myoblasts obtained from the Smn2B/- mice. Further, qPCR analysis revealed no changes in the level of Smn transcripts in the brain or spinal cord of TSA-treated SMA mice. Similarly, western blot analysis revealed no significant increase in Smn protein levels in the brain, spinal cord, hind limb muscle, heart muscle, or the liver of TSA treated Smn2B/- mice. However, TSA has beneficial effects in the muscles of Smn2B/- mice and improves motor behavior and myofiber size. TSA improves muscle development by enhancing the activity of myogenic regulatory factors independent of the Smn gene. The beneficial effect of TSA is therefore likely through an Smn-independent manner. Identification of these protective pathways will be of therapeutic value for the treatment of SMA.
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Oosthuizen, Imke. "Message banking : comparing perceptions of persons with motor neuron disease significant others and speech language pathologists." Diss., University of Pretoria, 2015. http://hdl.handle.net/2263/53453.
Full textAbstract:
Facing the reality of a diagnosis of Motor Neuron Disease (MND) and preparing for the
possibility of losing one s ability to speak is extremely challenging. The aim of this study
was to determine and compare the perceptions of ten persons with MND (PMNDs), 11
significant others (SOs) and 17 speech-language pathologists (SLPs) about message
banking, a process where messages are pre-recorded so as to use them in a speechgenerating
device. A quantitative, non-experimental, multi-group, posttest-only survey
design was used. The 38 participants listened to a short presentation of what message
banking entails and how it is done and then individually completed a questionnaire
about their perceptions. Data was compared between the three participant groups to
investigate the similarities and differences between them. Results indicated that most
PMNDs and SOs reported they had never heard of AAC or message banking. SLPs knew
only a little about AAC. Only 43% of SLPs were currently using AAC strategies for
PMNDs. AAC methods that were most recommended for PMNDs were gestures, letter
boards or communication boards. Participants agreed most with the statement that
message banking was a good idea for PMNDs in general, although only 80% of PMNDs
and 36% of SOs showed an interest in doing message banking for themselves or their
loved one with MND. SLPs showed 100% interest in doing message banking with their
patients with MND. PMNDs ranked messages important for message banking in
descending order namely: social closeness, needs and wants, social etiquette and
sharing information. SOs mostly agreed but thought that messages about needs and
wants were more important to bank than were messages about social closeness. The
SOs also thought that sharing information was more important than social etiquette,
which was different to what PMNDs thought. In conclusion, all participants confirmed
an awareness of AAC and message banking, although participants perception about
AAC and message banking differed somewhat. They also had slightly differing views
about the categories of messages that were important to bank during message banking.Dissertation (MA)--University of Pretoria, 2015.
Centre for Augmentative and Alternative Communication (CAAC)
MA
Unrestricted