Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease caused by the death of motor neurons in the spinal cord and brain. ALS is a genetically complex disease; diverse mutations cause motor neuron death by disrupting various interrelated pathways. To date, no therapy targeting a single factor can rescue motor neuron loss, nor is it known how or why sub-populations of motor neurons are particularly vulnerable in disease. Many studies have pointed to the Transforming Growth Factor Beta (TGF-𝝱) signaling superfamily as a modifier of disease in human patients and in animal models. Here, we have used the SOD1G93A model of ALS to investigate if and how TGF-𝝱 signaling in motor neurons changes pathology in these animals. In the first part of this study we characterize canonical TGF-𝝱 activation in motor neurons in SOD1G93A animals compared to controls. We have found that a vulnerable motor neuron subpopulation upregulates TGF-𝝱RII, a receptor necessary and unique to the classical arm of the TGF-𝝱 signaling family, in a disease dependent manner. Despite the upregulation of TGF-𝝱RII in these cells, there is not a corresponding activation of downstream canonical TGF-𝝱 effectors in diseased motor neurons. Through in vivo genetic manipulation we found that TGF-𝝱RII is dispensable in motor neurons, but that ablation of TGF-𝝱RI, a key receptor in multiple arms of the TGF-𝝱 superfamily, decreases motor neuron survival in SOD1G93A animals. To further understand how this manipulation changes TGF-𝝱 activation in motor neurons, we performed iterative indirect immunoflourescence imaging. We have identified that knocking out TGF-𝝱RI from motor neurons disrupts downstream canonical TGF-𝝱 activation in these cells. To identify how TGF-𝝱 signaling changes gene expression in these cells we have used Visium, a spatial RNAseq method, on lumbar spinal cords from these animals We have identified and are currently investigating potential downstream targets of TGF-𝝱 signaling in motor neurons in SOD1G93A animals. These data suggest that motor neurons rely on TGF-𝝱 signaling for survival in disease and that TGF-𝝱 signaling is important to the biology of a known vulnerable population of motor neurons.

Bakgrund: Amyotrofisk lateral skleros är en terminal progressiv sjukdom där motoriska nervceller i hjärnan, hjärnstammen och ryggmärgen bryts ner och dör. Musklerna blir därmed understimulerade och förtvinar vilket leder till förlamning. Majoriteten av personerna som insjuknar i amyotrofisk lateral skleros avlider inom fem år. Cirka 10-20 procent lever längre än tio år från sjukdomsdebut. Att diagnostiseras med amyotrofisk lateral skleros innebär en chock och en omfattande livsomställning. Då det inte finns något botemedel är det viktigt att patienten erbjuds individanpassad omvårdnad samt psykosocialt och existentiellt stöd för att lindra symtom och stärka patientens livskvalitet. Syfte: Syftet var att beskriva patienters upplevelser av att leva med Amyotrofisk Lateral Skleros. Metod: Litteraturstudie baserad på befintlig forskning inom området. Tio vårdvetenskapliga artiklar hämtade från databaserna CINAHL Complete och MEDLINE har använts och tillvägagångssättet har utförts enligt Fribergs metod. Resultat: I resultatet framträdde tre teman och fyra subteman som beskrev olika aspekter av att leva med amyotrofisk lateral skleros. De teman som identifierades var: livet faller samman med subtemana förlust av förmågor och förlust av mening, att bygga upp livet på nytt med subtemana acceptans och anpassning och finna mening samt beslut kring vård. Att leva med amyotrofisk lateral skleros innebar sorg, osäkerhet och rädsla samt en känsla av att livet förlorat mening. Sjukdomens progression innebar ett ständigt beslutsfattande kring vård. Familjens delaktighet i vårdbesluten var betydelsefull men gav även upphov till pliktkänslor. Förlusten av fysiska förmågor medförde både rädsla för att helt förlora kontrollen i livet och bli beroende av andra samt rädsla inför döden. Trots detta var det möjligt för deltagarna att acceptera och anpassa sig till sjukdomen samt att hitta ny mening i livet och uppleva livskvalitet. Diskussion: Resultatet diskuterades utifrån ytterligare forskning samt Callista Roys adaptionsmodell som berör människans förmåga till anpassning. De delar som lyftes fram och diskuterades var acceptans, anpassning, autonomi och pliktkänsla. / Background: Amyotrophic Lateral Sclerosis is a terminal progressive disease in which themotor neurons in the brain, brainstem and spinal cord breaks down and dies. As a result of this the muscles becomes under stimulated and atrophies which leads to paralysis. The majority of persons suffering from Amyotrophic Lateral Sclerosis die within five years. Between 10-20 percent live longer than ten years from the onset of the disease. Being diagnosed with Amyotrophic Lateral Sclerosis causes a shock and leads to a sweeping life change. Since there is no cure, it is important that people with Amyotrophic Lateral Sclerosis are offered individualized care as well as psychosocial and existential support in order to relieve symptoms and strengthen the patient’s quality of life. Aim: The aim was to describe patients’ experiences of living with Amyotrophic Lateral Sclerosis. Method: Literature study based on existing research in the field. Ten articles on care science have been used from the databases CINAHL Complete and MEDLINE. The procedure has been carried out according to Friberg's method. Results: The result featured three themes and four subthemes that described different aspects of living with Amyotrophic Lateral Sclerosis. The themes that were identified were: life falls apart with subthemes loss of abilities and loss of meaning, rebuilding life with subthemes acceptance and adaptation and finding meaning and decisions about care. Living with Amyotrophic Lateral Sclerosis meant grief, insecurity and fear as well as a feeling that life had lost meaning. The progression of the disease led to a constant decision-making process regarding care. The family's participation in health care decisions was meaningful, but also caused feelings of duty. The loss of physical abilities led to fear of completely losing control in life and becoming dependent on others but also fear of death itself. Despite this, the participants were able to accept and adapt to the disease allowing them to find new meaning and experience quality of life. Discussion: The results were discussed on the basis of further research and Callista Roy's adaptation model, which is about people's ability to adapt. The parts highlighted in the discussion were acceptance, adaption, autonomy and feelings of duty.

Bakgrund: ALS är en progressiv, ovanlig och obotlig sjukdom. Vuxna personer drabbas främst. Livsstilsförändringar är oundvikliga och eftersom att upplevelsen att leva med denna sjukdom kan variera, är det angeläget att olika upplevelser lyfts i denna studie för att sjukvården kring dessa personer ska kunna vara så personcentrerad som möjligt.   Syfte: Syftet var att beskriva personers upplevelser av att leva med ALS.  Metod: En litteraturöversikt som bygger på sju kvalitativa och tre kvantitativa vetenskapliga artiklar från CINAHL Complete, Academic Search Complete och PsycINFO, dessa var publicerade mellan åren 2010 – 2020.   Resultat: Fem stycken teman identifierades: Ångest; Missuppfattningar; Acceptans; Lidande; och Beröring. Det framkom att de upplevde ett multidimensionellt lidande som förvärras ju mer sjukdomsprogressionen fortlöper. Det framkom även att många personer hade ångest inför när de skulle avlida. I samband med sjukdomslidandet framkom det att många personer upplevde ångest.   Diskussion: I metoddiskussionen diskuterades användningen av vetenskapliga artiklar med samma författare samt hur samspelet mellan författarna varit. I resultatdiskussionen diskuterades två dominerande resultat, att samtliga deltagare upplevde ett multidimensionellt lidande i takt med att sjukdomsprogressionen fortlöpte samt ångest inför när de skulle avlida. / Background: ALS is a progressive, unusual and incurable disease. Adults are primarily affected. Lifestyle changes are inevitable and because the experience of living with this disease may vary, it is important that different experiences are highlighted in this study in order to allow the care of these people to be as person-centered as possible.  Aim: The aim was to describe experiences of people living with ALS.  Method: A literature review based on seven qualitative and three quantitative articles found on CINAHL Complete, Academic Search Complete and PsycINFO, that was published between the years 2010 – 2020.    Results: Five themes were identified: Anxiety; Misconceptions; Acceptance; Suffering; and Touch. It turned out that they experienced a multidimensional suffering that worsened as the disease progression progressed. It also emerged that many people had anxiety when they would die. In connection with the illness suffering, many people experienced anxiety.  Discussion: In the method discussion the use of articles with the same author was discussed and how the interaction between the authors has been. In the results discussion, two dominant outcomes were discussed, that all participants experienced a multidimensional suffering as disease progression progressed and anxiety faced when they were to die.

No description available.

Fused in Sarcoma (FUS) is a nuclear RNA binding protein functioning in a number of essential cellular processes such as RNA processing and DNA damage response. Mutations in FUS gene contribute to 5% of familial Amyotrophic Lateral Sclerosis (ALS) characterized by FUS protein cytoplasmic aggregation. Despite efforts have been made in the past decade, mechanisms of FUS aggregates to induce cytotoxicity are not fully understood. In addition, wild-type FUS protein has been found mis-localized to cytoplasm in sporadic ALS and Frontotemporal Dementia (FTD) patients with unclear mechanisms. Here, we aimed to address the functional consequences of ALS mutant FUS aggregation and investigate the mechanisms of wild-type FUS cytoplasmic translocation. This dissertation is divided into three parts: In the first part, we review pathophysiological mechanisms of FUS and other ALS mutant genes which induce cell death via disrupting six major cellular processes: mRNA processing, non-sense mediated decay, mitochondrial functions, nucleocytoplasmic transport, autophagy and DNA damage response. In the second part, we aimed to understand the functional consequences of RNA sequestration by FUS aggregates. We performed RNA immunoprecipitation against exogenous or endogenous FUS in the transfected cell lines and mutant FUS ALS patient fibroblasts to isolate RNAs associated with wild-type or ALS mutant FUS. Next, we analyzed the isolated RNAs using poly(A+) RNA-specific sequencing 3’READS and RT-qPCR, and we found many nuclear-encoded respiratory chain complex mRNAs are top-enriched transcripts associated with ALS mutant or overexpressed wild-type FUS. We further demonstrated that respiratory chain complex mRNAs are sequestered in mutant FUS cytoplasmic aggregates and the encoded protein expression levels are suppressed. Finally, we showed that knockdown of respiratory chain complex proteins encoded by FUS-sequestered transcripts can recapitulate mitochondrial dysfunction observed in FUS-transfected cell lines. Our findings in the second part thus provides a novel mechanism by which ALS mutant FUS, as well as overexpressed wild-type FUS, to induce mitochondrial dysfunction via preferential sequestration of respiratory chain complex mRNAs. The third part focuses on understanding pathways affecting FUS nucleocytoplasmic distribution. By using pharmacological treatments and immunofluorescence, we found that nuclear RNA transcription, export and decay substantially modulate nucleocytoplasmic distribution of wild-type FUS protein. Moreover, we report that FUS antibodies used in immunofluorescence significantly affect the results of nucleocytoplasmic ratio quantification. Intriguingly, we observed altered serine-2/-5 phosphorylation on RNAPII CTD as well as reduced number of nascent transcripts in sporadic ALS patient cells, indicating aberrant transcriptional activity related to cytoplasmic accumulation of nuclear RNA binding proteins. Our findings in the third part provide insights to the importance of nuclear RNA metabolism in modulating FUS localization. We also addressed the inconsistent results reported in previous studies regarding FUS nucleocytoplasmic distribution in response to stress. Altogether, these findings suggest proof-of-principle mechanisms of FUS toxic function and aberrant localization linked to ALS and FTD disease spectrum.

An electroencephalographic-based brain-computer interface (BCI) can provide a non-muscular method of communication. A general model for P300-based BCI stimulus presentations is introduced - the "m choose n" or C(m (number of flashes per sequence), n (number of flashes per item)) paradigm, which is a universal extension of the previously reported checkerboard paradigm (CBP). C(m,n) captures all possible (unconstrained) ways to flash target items, and then applies constraints to enhance ERP's produced by attended matrix items. We explore a C(36,5) instance of C(m,n) called the "five flash paradigm" (FFP) and compare its performance to the CBP. Eight subjects were tested in each paradigm, counter-balanced. Twelve minutes of calibration data were used as input to a stepwise linear discriminant analysis to derive classification coefficients used for online classification. Accuracy was consistently high for FFP (88%) and CBP (90%); information transfer rate was significantly higher for the FFP (63 bpm) than the CBP (48 bpm). The C(m,n) is a novel and effective general strategy for organizing stimulus groups. Appropriate choices for "m," "n," and specific constraints can improve presentation paradigms by adjusting the parameters in a subject specific manner. This may be especially important for people with neuromuscular disabilities.

BCI can provide communication for people locked in by amyotrophic lateral sclerosis (ALS). Empirical examination of how disease progression affects brain-computer interface (BCI) performance has not been investigated. This pilot study uses a longitudinal design to investigate changes in P300-BCI use as ALS disability increases. We aimed to (a) examine the relationship between BCI accuracy and the ALS/Functional Rating Scale and (b) examine changes in the event-related potential (ERP) components across time. Eight subjects have been enrolled in the study. BCI accuracy was measured and ERP components were assessed by a principal component analysis (PCA). Two subjects have been followed for an average of nine-months, and BCI accuracy is 99.6%. While many research obstacles remain, these preliminary data help elucidate the relationship between BCI performance and disease progression.

Our objective was to develop and validate a new brain-computer interface (BCI) system suitable for long-term independent home use by people with severe motor disabilities. The BCI was used by a 51-year-old male with ALS who could no longer use conventional assistive devices. Caregivers learned to place the electrode cap, add electrode gel, and turn on the BCI. After calibration, the system allowed the user to communicate via EEG. Re-calibration was performed remotely (via the internet), and BCI accuracy assessed in periodic tests. Reports of BCI usefulness by the user and the family were also recorded. Results showed that BCI accuracy remained at 83% (r -.07, n.s.) for over 2.5 years (1.4% expected by chance). The BCI user and his family state that the BCI had restored his independence in social interactions and at work. He uses the BCI to run his NIH-funded research laboratory and to communicate via e-mail with family, friends, and colleagues. In addition to this first user, several other similarly disabled people are now using the BCI in their daily lives. In conclusion, long-term independent home use of this BCI system is practical for severely disabled people, and can contribute significantly to quality of life and productivity.

A brain-computer interface is a device that uses signals recorded from the brain to directly control a computer. In the last few years, P300-based brain-computer interfaces (BCIs) have proven an effective and reliable means of communication for people with severe motor disabilities such as amyotrophic lateral sclerosis (ALS). Despite this fact, relatively few individuals have benefited from currently available BCI technology. Independent BCI use requires easily acquired, good-quality electroencephalographic (EEG) signals maintained over long periods in less-than-ideal electrical environments. Conventional, wet-sensor, electrodes require careful application. Faulty or inadequate preparation, noisy environments, or gel evaporation can result in poor signal quality. Poor signal quality produces poor user performance, system downtime, and user and caregiver frustration. This study demonstrates that a hybrid dry electrode sensor array (HESA) performs as well as traditional wet electrodes and may help propel BCI technology to a widely accepted alternative mode of communication.

The cyanobacterial toxin β-N-methylamino-l-alanine (BMAA) now appears to be a cause of Guamanian amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC). Its production by cyanobacteria throughout the world combined with multiple mechanisms of BMAA neurotoxicity, particularly to vulnerable subpopulations of motor neurons, has significantly increased interest in investigating exposure to this non-protein amino acid as a possible risk factor for other forms of neurodegenerative illness. We here provide a brief overview of BMAA studies and provide an introduction to this collection of scientific manuscripts in this special issue on BMAA.