Thesis (Ph. D.)--University of Sydney, 2007. / Title from title screen (viewed Apr. 12, 2007). Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy to the Faculty of Medicine. Includes bibliography. Also issued in print.

Diss. (sammanfattning) Umeå : Umeå universitet, 2005. / Härtill 6 uppsatser.

Thesis (Ph. D.)--University of Alabama at Birmingham, 2008. / Title from first page of PDF file (viewed Feb 19, 2009). Includes bibliographical references (p. 114-124).

<p>Amyotrofisk lateralskleros och multipel skleros är båda neurologiska sjukdomar som orsakar fysiska begränsningar och påverkar vardagslivet. Syftet med studien var att undersöka hur vardagslivet gestaltar sig för dessa patienter. Studien baseras på en kvalitativ metod utifrån sex självbiografier och en biografi, vilket ger en insyn i patienternas egna upplevelser av hur det är att leva med ALS eller MS. Resultatet består av fyra huvudteman; Relationer, Begränsningar, Psykisk hälsa och Tankar. I samband med sjukdomen blir relationer mer betydelsefulla samtidigt som den för med sig påfrestningar i förhållandet. Begränsningarna kan leda till att den sjuke får allt svårare att klara av sin vardag vad det gäller hemmet, fritiden samt arbete. Den psykiska hälsan kan yttra sig som depression och det blir en daglig kamp där de söker mening med livet och försöker ta kontroll över situationen. Tankarna handlar om nya värderingar i livet och deras ovisshet om framtiden samt att acceptera situationen. Denna studie kan öka sjuksköterskans kunskap och förståelse för patientens situation, samt vara till hjälp vid individanpassningen av omvårdnaden för dessa patienter. Den kan även vara till hjälp för andra personer som vårdar dessa patienter, som till exempel anhöriga och annan ansvarig vårdpersonal.</p> / <p>Amyotrophic lateral sclerosis and multiple sclerosis are both neurological diseases that cause physical limitations and have consequences on daily life. The aim of this study was to clarify how this daily life appears for these patients. The study is based on a qualitative method with six autobiographies and one biography, which gives an insight of their own, lived experiences on how it is to live with ALS or MS. The result contains four main subjects; Relations, Limitations, Psychical health and Thoughts. In sickness relations becomes more of value, but it also cause stress within a relationship. The limitations make life more difficult in different aspects, such as home environment, leisure activities and work. The mental health can develop into a depression and it becomes a daily fight where they seek a meaning with life and try to take control over the situation. Thoughts are about new values in life, an uncertainty about the future and to accept the situation. The findings of this study can give nurses more knowledge and understanding and be helpful when adjusting nursing care for each of these individuals. It can also be a help to other people who take care of these patients, such as family members and other involved care staff.</p>

Amyotrofisk lateralskleros är en sjukdom som drabbar det centrala nervsystemet och orsakar muskelförlamningar. Sjukdomen är obotlig vilket gör att vården endast handlar om att lindra symptom och minska lidande. Syftet med studien var att beskriva patienters upplevelser av att leva med amyotrofisk lateralskleros. Metoden som användes var en allmän litteraturstudie där tio vetenskapliga artiklar valdes ut efter granskning. Med hjälp av en innehållsanalys framkom tio olika subteman och ur dessa abstraherades fyra huvudteman. Dessa fyra huvudteman var; upplevelse av förlust, upplevelse av förändring, upplevelse av beroende och upplevelse av meningen med livet.  Resultatet visade att leva med amyotrofisk lateralskleros upplevdes som att leva ett liv med ständig förlust och förändring vilket påverkade de drabbades identitet och autonomi samt gav en upplevelse av att vara beroende av andra. För att finna styrka att hantera vardagen var upplevelsen av att känna meningsfullhet av betydelse. Det behövs mer omvårdnadsstudier som belyser patienter med amyotrofisk lateralskleros så att sjuksköterskan kan få en bättre förståelse för hur patienterna upplever omvårdnaden och sin sjukdom för att kunna hjälpa dem på bästa sätt. Sjuksköterskeutbildningen bör inkludera hur sjuksköterskan ska stödja och möta denna grupp av patienter och deras anhöriga. Även vidareutbildning för sjuksköterskor bör erbjudas av arbetsgivare.

Chronic Traumatic Encephalopathy (CTE) is a neurodegenerative disease caused by repetitive head trauma and mild traumatic brain injuries (mTBIs) and has been associated with contact sports such as football, boxing, and ice hockey. CTE is a slowly progressing neurological disease that is often clinically associated with symptoms of memory loss, decline in cognitive function, behavioral changes such as increased impulsivity and aggression, and/or suicidal thoughts. Advanced stages of the disease present with more severe neurological changes such as dementia, speech and gait abnormalities, and parkinsonism. Amyotrophic Lateral Sclerosis (ALS, also known as Lou Gehrig Disease) is a progressive and fatal neurodegenerative disease characterized by motor neuron loss and corticospinal tract degeneration. While 90-95% of ALS cases are sporadic in nature, many genetic mutations have been identified that contribute to familial forms of the disease. The etiology of sporadic ALS is unknown but it is likely caused by a complex interaction of various genetic and environmental risk factors. Epidemiological evidence suggests that one such risk factor is brain trauma, the main risk factor associated with the development of CTE. In this study the spinal cord tissue of twelve athletes diagnosed with CTE who also developed a progressive motor neuron disease and showed symptoms of profound muscle weakness, atrophy, spasticity, and fasciculations several years before death was examined. The spinal cord tissue from these 12 CTE cases with motor neuron disease (CTE+MND) was compared to the spinal cord tissue of 10 sporadic ALS control cases. Results showed a difference in frequency of tau pathology between the two disease cohorts, as one-third of CTE+MND cases and none of the ALS cases showed tau immunoreactivity. In addition, TDP-43 immunoreactivity was present in every CTE+MND case but one and was present in all ALS cases. Motor neuron inclusions were positive for both FUS and p62 in both cohorts, and no distinct differences were observed cystatin C pathology. Overall, this suggests that the spinal cord inclusions in CTE+MND have a similar composition to sporadic ALS. However, there is an increased frequency of tau pathology in CTE+MND though this result did not reach statistical significance in this study.

It has been postulated that there could be a connection between traumatic brain injury (TBI) and motor neuron disease (MND), including amyotrophic lateral sclerosis (ALS). As chronic traumatic encephalopathy (CTE) is caused by repeated TBI and is a newly examined disease, there has been little evaluation of the potential relationship between CTE and ALS. It was proposed that CTE is a risk factor for not only MND, but also ALS. There is significant evidence that even a single TBI is a risk factor for Parkinson's disease (PD), thought to be invoked by the inflammatory process that the brain undergoes following a TBI. General rigorous physical activity with trauma to the trunk or extremities does not appear to be a risk factor for ALS. However, physical activity with associated head traumas, especially repeated head traumas, does seem to increase the likelihood of developing ALS. The biological mechanism for this is suspected to be increase in free radicals during exercise in individuals who are predisposed to decreased antioxidant function. Additionally, individuals who have suffered repeated head trauma, even amongst the general population in a non-athletic setting, has been shown to drastically increase the individual's chance of developing ALS. CTE, which is most common in athletes, is speculated to be caused by TAR DNA-binding protein 43 (TDP-43), tau neurofibrillary tangle (NFT), and beta-amyloid (A-Beta) protein inclusions in brain tissue following a multitude of TBI during high level sport activity. There are individuals who suffer initially CTE, followed by ALS, indicating CTE is clearly a risk factor for ALS. Anatomically, the TDP-43, NTF, and A-Beta; inclusions are present in the brain tissue of both individuals with CTE alone as well as the individuals with CTE and ALS. The anatomic difference between these two pathologies is the inclusion of these three proteins in the spinal cord of ALS patients as well. Unfortunately, there are indications that previous studies of professional athletes and their development of ALS have presented with significant issues including confounding factors of the subpopulation and sample sizing. Additionally, the anatomical cause of TBI leading to ALS is still unknown. Further evaluation on the relationship between head injury and ALS must be dedicated to investigating the mechanism involved in developed PD versus ALS following TBI. The biologic sequence following TBI that leads to ALS must be examined and compared to individuals whom develop ALS but did not suffer TBI. Moreover, an assessment must be made to determine what causes some individuals to develop protein inclusions solely in the brain tissue, leading to CTE, and some individuals to have an advancement of the protein inclusions into the spinal cord, leading additionally to CTE followed by ALS.

A hexanucleotide repeat expansion in the C9orf72 gene is the most common cause of familial amyotrophic lateral sclerosis and frontotemporal dementia. Genetic testing for this pathogenic mutation is challenging due to its GC rich, repetitive nature. I developed PCR based assays to detect the presence of the pathogenic variant, which were used in screening an archival cohort of Scottish ALS patients, and have also been implemented within a diagnostic setting. These PCR assays allow amplification of larger repeat expansions than have previously been reported, and can determine whether a C9orf72 expansion of greater than 100 repeats is present or not. It is not well understood how the repeat expansion leads to disease, but several potential mechanisms have been hypothesised, including reduced expression, RNA toxicity and protein toxicity via dipeptide repeat proteins produced through repeat associated non-AUG translation. Motor neurons are an understandably well studied target in amyotrophic lateral sclerosis, however the role of glia, particularly oligodendrocytes, in the pathogenesis of the disease has recently been highlighted from studies on rodent models and post mortem tissue. To investigate the effect of the C9orf72 repeat expansion on oligodendrocytes, we have applied a differentiation protocol to hiPSCs with the expansion and controls, including an isogenic control which has been generated in the lab. There was no difference in the production of neuronal and glial cell types between these cell lines. I went on to look for evidence of the main proposed pathological mechanisms of C9orf72 repeat expansions: loss of function or gain of function through either RNA or protein toxicity. hiPSC derived oligodendrocytes from both carrier and control showed low expression of C9orf72 mRNA, and there was no difference due to the presence of a repeat expansion. Carrier hiPSC derived oligodendrocytes displayed sense RNA foci, which did not appear to have an effect on cellular morphology. The detection of dipeptide repeat proteins proved challenging, and the results were inconclusive as to their presence in hiPSC derived oligodendrocytes. I went on to show there was no evidence of mislocalisation of TDP-43 in C9orf72 carrier oligodendrocytes. Finally, the study showed similar levels of cell death in basal conditions in carrier and control cells, and no clear difference in the response to endoplasmic reticulum stress. Further research will be required to elucidate the role of oligodendrocytes in C9orf72 related amyotrophic lateral sclerosis.

No description available.

abstract: Exome sequencing was used to identify novel variants linked to amyotrophic lateral sclerosis (ALS), in a family without mutations in genes previously linked to ALS. A F115C mutation in the gene MATR3 was identified, and further examination of other ALS kindreds identified an additional three mutations in MATR3; S85C, P154S and T622A. Matrin 3 is an RNA/DNA binding protein as well as part of the nuclear matrix. Matrin 3 interacts with TDP-43, a protein that is both mutated in some forms of ALS, and found in pathological inclusions in most ALS patients. Matrin 3 pathology, including mislocalization and rare cytoplasmic inclusions, was identified in spinal cord tissue from a patient carrying a mutation in Matrin 3, as well as sporadic ALS patients. In an effort to determine the mechanism of Matrin 3 linked ALS, the protein interactome of wild-type and ALS-linked MATR3 mutations was examined. Immunoprecipitation followed by mass spectrometry experiments were performed using NSC-34 cells expressing human wild-type or mutant Matrin 3. Gene ontology analysis identified a novel role for Matrin 3 in mRNA transport centered on proteins in the TRanscription and EXport (TREX) complex, known to function in mRNA biogenesis and nuclear export. ALS-linked mutations in Matrin 3 led to its re-distribution within the nucleus, decreased co-localization with endogenous Matrin 3 and increased co-localization with specific TREX components. Expression of disease-causing Matrin 3 mutations led to nuclear mRNA export defects of both global mRNA and more specifically the mRNA of TDP-43 and FUS. Our findings identify ALS-causing mutations in the gene MATR3, as well as a potential pathogenic mechanism attributable to MATR3 mutations and further link cellular transport defects to ALS. / Dissertation/Thesis / Doctoral Dissertation Neuroscience 2018