The retromer is a protein complex whose function is to mediate the recycling of proteins from the endosome to either the plasma membrane or the trans-Golgi network. A deficit in retromer function has been associated with multiple neurodegenerative disorders, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). In both AD and PD, deficiencies have been found in retromer expression both in patient tissues and in animal models of disease. Furthermore, mutations in the retromer and in retromer-associated genes have been strongly linked with both diseases. Despite ample evidence of the link between the retromer and neurodegeneration, little is known about the retromer in the context of amyotrophic lateral sclerosis (ALS), another common neurodegenerative disorder. ALS is an adult-onset neurodegenerative disorder of the upper and lower motor neurons (MNs) characterized by muscle wasting and weakness leading to death within 3-5 years after diagnosis. To date, the most commonly used model of ALS is a transgenic (Tg) mouse that overexpresses an ALS-causing G93A mutation in the human superoxide dismutase 1 (SOD1) gene. In this study, I first establish a link between the retromer and ALS by showing that cells from ALS patients as well as tissues and cells from SOD1G93A-Tg mice express lower protein levels of the retromer core components—vacuolar protein sorting 35 (Vps35), Vps26a, and Vps29. I then establish that deficiencies in retromer core proteins have functional consequences in an in vitro model of ALS. Having found significant deficiencies in the retromer in SOD1G93A-Tg mice, I then followed the model of studies performed in mouse models of other neurodegenerative disorders by investigating whether repletion of retromer levels, either virally or pharmacologically, in SOD1G93A-Tg mice confers a therapeutic benefit. Surprisingly, I find that rather than ameliorating disease, repletion of retromer levels in SOD1G93A-Tg mice exacerbates it, resulting in a faster decline in motor performance, earlier mortality, and a decrease in MNs in the spinal cord. Finally, since retromer repletion causes deleterious effects on SOD1G93A-Tg mouse disease progression, I study the effect of a single allele deletion of Vps35 in SOD1G93A-Tg mice and find that this depletion of the retromer results in amelioration of disease, including delayed onset of symptomatology, slower decline of motor deficits, delayed mortality, and an increase in MNs in the spinal cord. Altogether, the findings reported herein, support the notion that a mild defect in retromer develops over the course of the disease, which, rather than being deleterious may be therapeutic in mutant SOD1-induced MN degeneration. Perhaps this unexpected outcome may be explained by the fact that the observed mild nature of the defect is not sufficient to kill MNs but enough to alter the trafficking of specific cargos such as AMPA receptors, allowing MNs to better withstand the neurodegenerative process.

Objective. The P300 speller is a brain-computer interface (BCI) that can possibly restore communication abilities to individuals with severe neuromuscular disabilities, such as amyotrophic lateral sclerosis (ALS), by exploiting elicited brain signals in electroencephalography (EEG) data. However, accurate spelling with BCIs is slow due to the need to average data over multiple trials to increase the signal-to-noise ratio (SNR) of the elicited brain signals. Probabilistic approaches to dynamically control data collection have shown improved performance in non-disabled populations; however, validation of these approaches in a target BCI user population has not occurred. Approach. We have developed a data-driven algorithm for the P300 speller based on Bayesian inference that improves spelling time by adaptively selecting the number of trials based on the acute SNR of a user's EEG data. We further enhanced the algorithm by incorporating information about the user's language. In this current study, we test and validate the algorithms online in a target BCI user population, by comparing the performance of the dynamic stopping (DS) (or early stopping) algorithms against the current state-of-the-art method, static data collection, where the amount of data collected is fixed prior to online operation. Main results. Results from online testing of the DS algorithms in participants with ALS demonstrate a significant increase in communication rate as measured in bits/min (100-300%), and theoretical bit rate (100-550%), while maintaining selection accuracy. Participants also overwhelmingly preferred the DS algorithms. Significance. We have developed a viable BCI algorithm that has been tested in a target BCI population which has the potential for translation to improve BCI speller performance towards more practical use for communication.

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Amyotrophic Lateral Sclerosis is a neurodegenerative disease affecting adults with disease onset averaging between 50-60 years of age. As neurons die, patients experience rapid physical and cognitive decline with death typically following 3-5 years after diagnosis. As there is currently no cure for disease and no treatment to prolong life expectancy, medical management is focused on quality of life. In addition to traditional medical treatments, medical professionals must also consider maximizing autonomy as a way to increase quality of life with a focus on relational and psychological factors. For patients in low-income urban neighborhoods, inequalities affecting agency should be evaluated as part of medical care to increase both autonomy and overall quality of life. / Urban Bioethics

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TAR DNA Binding Protein-43 (TDP-43) proteinopathy is a disease pathology that underlies a broad field of neurodegenerative disorders. Most prominently, TDP-43 aggregates are the hallmark of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). The implication of TDP-43 in ALS, in particular, has helped initiate a cascade of research to determine the properties of the previously obscure protein. From these studies, it is now known that TDP-43 is a DNA and RNA binding protein, important for the splicing and regulation of many transcripts. In the disease state, TDP-43 is modified in a way that fuels its accumulation into cytoplasmic aggregates called inclusions. This paper will delineate the current understanding of the mechanisms behind TDP-43 proteinopathy and the resultant clinical conditions. The body of evidence firmly supports a clinical spectrum of TDP-43 proteinopathy that ranges between pure motor neuron disease (MND) and pure frontotemporal dementia (FTD). It also appears that the root cause of neurodegeneration in these disorders comes about through a combination of a gain of toxic function and a loss of normal TDP-43. Continued research into the molecular processes leading to the capitulation of TDP-43 holds great promise for the development of new drug targets to help treat the spectrum of TDP-43 proteinopathy.

Syftet med denna litteraturstudie var att beskriva existentiella och psykosociala upplevelser hos patienter med ALS. Nio kvalitativa artiklar valdes ut och inkluderades till litteraturstudiens resultat. Artiklarna beskrev upplevelser från patienter i olika kontexter där existentiella och psykosociala aspekter berördes. Det framkom i resultatet att patienter upplevde meningsfullhet och att familjen var betydande för deras välmående, men också hopplöshet och känslan av att vara en börda för andra vilket utgjorde svårigheter att finna mening i livet. Patienter upplevde lidande i flera dimensioner och hanterade sin situation med hjälp av olika strategier, attityder och förhållningssätt. Slutsatser som författarna för denna litteraturstudie kunde dra från resultatet var att patienterna går igenom flera dimensioner av lidande vilket ställer krav på sjuksköterskan att lindra dessa. Sjuksköterskan ska också hjälpa patienten att framhäva sina styrkor och skapa en större förståelse för att patienten skall nå acceptans. En annan slutsats som drogs var att familjens involvering i omvårdnaden kunde vara positiv då de står närmast patienten och det visade sig vara en positiv faktor för att acceptera situationen. ALS är en neurodegenerativ sjukdom som förstör motorneuron i hjärnan. Det leder till att den viljestyrda muskulaturen förlorar sin funktion. Till sist drabbas även muskulaturen kring lungorna som leder till minskad lungkapacitet. Från symtomdebut är överlevnadssikten cirka två till fem år där vanligaste dödsorsaken är koldioxidnarkos. Tidigare forskning har framfört positiva och negativa känslor hos patienter med ALS. Upplevelser att kroppen misslyckas i förtid samt behov av att prata om döden framkom. Kommunikation med vården var viktig för att patienter skulle uppleva att sjukdomen var hanterbar. Litteraturstudien använde bärande begrepp såsom lidande och försoning. En kvalitativ ansats användes då upplevelser skulle undersökas och analysen utgick från Fribergs femstegsmodell. Diskussionen utgick från resultatets huvudteman Främjande aspekter för meningsfullhet samt Utmanande aspekter för livsvillkor. Denna litteraturstudie är viktig då den bidrar till en ökad kunskap och förståelse för hur patienter med ALS upplever existentiella och psykosociala aspekter. Genom kunskap kan vården utvecklasoch främja vårdkvaliteteten för patienterna och samtidigt stärka sjuksköterskan i sin yrkesroll.Främjande och utmanande aspekter som påverkade välbefinnandet hos patienter identifierades och diskussionen ledde således till sjuksköterskans funktion samt litteraturstudiens bärande begrepp, lidande och försoning.