Brain-computer interfaces (BCIs) might restore communication to people severely disabled by amyotrophic lateral sclerosis (ALS) or other disorders. We sought to: 1) define a protocol for determining whether a person with ALS can use a visual P300-based BCI; 2) determine what proportion of this population can use the BCI; and 3) identify factors affecting BCI performance. Twenty-five individuals with ALS completed an evaluation protocol using a standard 6 × 6 matrix and parameters selected by stepwise linear discrimination. With an 8-channel EEG montage, the subjects fell into two groups in BCI accuracy (chance accuracy 3%). Seventeen averaged 92 (± 3)% (range 71-100%), which is adequate for communication (G70 group). Eight averaged 12 (± 6)% (range 0-36%), inadequate for communication (L40 subject group). Performance did not correlate with disability: 11/17 (65%) of G70 subjects were severely disabled (i.e. ALSFRS-R < 5). All L40 subjects had visual impairments (e.g. nystagmus, diplopia, ptosis). P300 was larger and more anterior in G70 subjects. A 16-channel montage did not significantly improve accuracy. In conclusion, most people severely disabled by ALS could use a visual P300-based BCI for communication. In those who could not, visual impairment was the principal obstacle. For these individuals, auditory P300-based BCIs might be effective.

Evidence from human amyotrophic lateral sclerosis (ALS) patients and ALS-linked Cu/Zn superoxide dismutase (Cu/Zn-SOD) transgenic mice bearing the mutation of glycine to alanine at position 93 (G93A) suggests that the pro-apoptotic protein prostate apoptosis response-4 (Par-4) might be a critical link in the chain of events leading to motor neuron degeneration. We now report that Par-4 is enriched in synaptosomes and post-synaptic density from the ventral horn of the spinal cord. Levels of Par-4 in synaptic compartments increased significantly during rapid and slow declining stages of muscle strength in hSOD1 G93A mutant mice. In the pre-muscle weakness stage, hSOD1 G93A mutation sensitized synaptosomes from the ventral horn of the spinal cord to increased levels of Par-4 expression following excitotoxic and apoptotic insults. In ventral spinal synaptosomes, Par-4-mediated production of pro-apoptotic cytosolic factor(s) was significantly enhanced by the hSOD1 G93A mutation. RNA interference (RNAi) knockdown of Par-4 inhibited mitochondrial dysfunction and caspase-3 activation induced by G93A mutation in synaptosomes from the ventral horn of the spinal cord, and protected spinal motor neurons from apoptosis. These results identify the synapse as a crucial cellular site for the cell death promoting actions of Par-4 in motor neurons, and suggest that targeted inhibition of Par-4 by RNAi may prove to be a neuroprotective strategy for motor neuron degeneration.

A list of genes have been identified to carry mutations causing familial ALS such as SOD1, TARDBP, C9orf72. But for sporadic ALS, which is 90% of all ALS cases, the underlying genetic variants are still largely unknown. There are multiple genome-wide association study (GWAS) for sporadic ALS, but usually a large number nominated SNP can hardly be replicated in larger cohort analysis. Also majority of GWAS SNP lie within noncoding region of genome, imposing a huge challenge to study their biological role in ALS pathology. With the rapid development of next-generation sequencing technology, we are able to sequence exome and whole-genome of a large number of ALS patients to search for novel genetic variants and their potential biological function. Here by analyzing exam data, we discovered two novel or extremely rare missense mutations of DPP6 from a Mestizo Mexican ALS family. We showed the two mutations could exert loss-of-function effect by affecting electrophysiological properties of Potassium channels as well as the membrane localization of DPP6. To our knowledge this is the first report of DPP6 nonsynonymous mutations in familial ALS patients. In addition, by analyzing whole-genome data, we discovered strong linkage disequilibrium between SNP rs12608932, a repeatedly significant ALS GWAS signal, and one polymorphic TGGA tetra-nucleotide tandem repeat, which is further flanked by large TGGA repetitive sequences. We also demonstrated rs12608932 risk allele is associated with reduced UNC13A expression level in human cerebellum and UNC13A knockout could lead to shorter survival in SOD1-G93A ALS mice. Thus the TGGA repeat might be the real underlying genetic variation that confer risk to sporadic ALS.

Amyotrophic lateral sclerosis (ALS) is a progressive adult neurodegenerative disease that causes death of both upper and lower motor neurons. Approximately 90 percent of ALS cases are sporadic (SALS), and 10 percent are inherited (FALS). Mutations in the PFN1 gene have been identified as causative for one percent of FALS. PFN1 is a small actin-binding protein that promotes actin polymerization, but how ALS-linked PFN1 mutations affect its cognate functions or acquire gain-of-function toxicity remains largely unknown. To elucidate the contribution of ALS-linked PFN1 mutations to neurodegeneration, we have characterized these mutants in both mammalian cultured cells and Drosophila models. In mammalian neuronal cells, we demonstrate that ALS-linked PFN1 mutants form ubiquitinated aggregates and alter neuronal morphology. We also show that ALS-linked PFN1 mutants have partial loss-of-function effects on actin polymerization in growth cones of mouse primary motor neurons and larval neuromuscular junctions (NMJ) in Drosophila. In Drosophila, we also observe that PFN1 level influences integrity of adult motor neurons, as demonstrated by locomotion, lifespan, and leg NMJ morphology. In sum, the work presented in this dissertation has shed light on PFN1- linked ALS pathogenesis by demonstrating a loss-of-function mechanism. We have also developed a Drosophila PFN1 model that will serve as a valuable tool to further uncover PFN1-associated cellular pathways that mediate motor neuron functions.

No description available.

Background: Air pollution is one of the leading environmental issues in the world today. In 2015, pollution-related diseases accounted for 16% of all deaths worldwide — that is an estimated 9 million premature deaths were linked to air pollution. In addition to the substantial effects on human health, air pollution-related diseases result in productivity losses that reduce countries’ gross domestic product. Although air pollution disproportionately affects middle- and low-income countries, it is still a major issue in high-income countries, such as the United States, where 25% of Americans breath air with pollutant levels above the national regulatory standards. Fine particle matter (particles with diameter ≤ 2.5 μm, PM₂.₅ ) is the most extensively studied air pollutant and it has been causally linked with a wide range of adverse health outcomes, including cardiovascular and pulmonary disease, myocardial infarction, hypertension, congestive heart failure, arrhythmias, chronic obstructive pulmonary disease, and lung cancer. Moreover, recent scientific evidence suggests that PM₂.₅ affects the nervous system and possibly contributes to the development and exacerbation of neurodegenerative diseases. This is increasingly relevant as populations are aging and the number of adults living with neurodegenerative diseases increases, negatively affecting families, communities, and health-care systems around the world. Although millions of people suffer from neurodegenerative diseases, there is currently no treatment that slows the progression of these conditions and no known cure or cause. Thus, determining whether a link exists between air pollution and neurodegenerative diseases is a goal of increasing importance. Objective: The research presented in this dissertation has two main objectives: (1) to characterize the relationship between long-term exposure to PM₂.₅ and disease aggravation in two of the most prevalent neurodegenerative diseases worldwide: Alzheimer’s (AD) and Parkinson’s disease (PD), as well as in the rare and devastating neurodegenerative motor disorder amyotrophic lateral sclerosis (ALS); (2) to identify the specific PM₂.₅ chemical components that are associated with disease aggravation in PD. Methods: We used data from the New York Department of Health Statewide Planning and Research Cooperative System from 2000–2014 to identify patients’ first hospitalization with a primary or secondary diagnosis of AD, PD, or ALS. With these data, we constructed annual AD, PD, and ALS first hospitalization county counts (total and sex- and age-stratified) for all of New York State (NYS). A patient’s first hospital admission was used as a surrogate for disease aggravation, indicating the crossing point into a more severe stage of the disease. We used prediction estimates from well-validated models that incorporate satellite information and ground-based monitoring data to estimate annual PM₂.₅ and PM₂.₅ chemical component (nitrate, sulfate, organic matter, sea salt, black carbon, and soil) concentrations across NYS at a high spatial resolution. In Chapter 2, we used outcome-specific (AD, PD, or ALS) mixed quasi-Poisson models with county-specific random intercepts to assess the relationship between long-term exposure to PM₂.₅ and disease aggravation. In Chapter 3, we used a multi-pollutant mixed quasi-Poisson model with county-specific random intercepts to identify specific PM₂.₅ components associated with disease aggravation in PD. In all analyses, we evaluated potential nonlinear exposure–outcome relationships using penalized splines and accounted for potential confounders. Results: We observed a total of 264,075 AD, 114,514 PD, and 5,569 ALS first admissions between 2000 and 2014. The hospitalization annual average counts per county were 284, 131, and 6 for AD, PD, and ALS, respectively. In Chapter 2, we found a nonlinear association between total PM₂.₅ exposure and PD hospitalizations, which plateaued at higher concentrations of PM₂.₅ (> 13 μg/m³, RR=1.08, 95% CI: 1.04–1.13 for a PM₂.₅ increase from 8 to 10 μg/m³, Figure 2.3). We also found that patients with a first PD hospitalization at age 70 or younger are at slightly higher risk for disease aggravation at lower PM₂.₅ concentrations relative to those age >70. In the case of AD, we observed evidence of a potential association between annual increases in PM₂.₅ exposure and disease aggravation, but only in a sensitivity analysis aiming to decrease outcome misclassification. We found no association for ALS in the main analysis, but we observed an unexpected negative association in those <70 years in the stratified analysis. We found no evidence of effect modification by sex for any of the outcomes. In Chapter 3, we observed a linear association between disease aggravation in PD and long-term exposure to the PM₂.₅ components nitrate (RR = 1.05, 95%CI: 1.02–1.09 per one standard deviation (SD) increase) and organic matter (RR = 1.05, 95%CI: 1.02– 1.07 per one SD increase), and a nonlinear association for black carbon with a negative association above the 96th percentile of the BC concentration distribution (Figure 3.4). We found no evidence of an association with sulfate, sea salt or soil. Conclusion: Overall, our studies provide an analysis of the potential association between long-term exposure to PM₂.₅ , both as an overall pollution mixture and by chem- ical composition, and disease aggravation in AD, PD, and ALS. Our findings suggest that annual increases in county-level PM₂.₅ concentrations are associated with disease aggravation in PD and possibly AD. We found that the PM₂.₅ components organic matter and nitrate are particularly harmful in the association between PM₂.₅ and dis- ease aggravation in PD. Additionally, our results indicate that current national PM₂.₅ standards may not be strict enough to safeguard the population’s neurological health. Specifically, in Chapter 2, we observed that the PM₂.₅ –PD association has a steeper slope at lower concentrations that are well below the current annual National Ambient Air Quality Standards for PM₂.₅ . Thus, our findings warrant further investigation into the potential link between long-term PM₂.₅ exposure and disease aggravation, particularly in the context of PD. Our results also indicate that the chemical composition of PM2.5 affects its neurotoxicity. Further research into how PM₂.₅ composition influences the overall PM₂.₅ adverse effects is needed to fully understand the mechanisms that underlie the association between exposure to PM₂.₅ and aggravation of neurodegenerative diseases.

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第19003号 / 工博第4045号 / 新制||工||1622(附属図書館) / 31954 / 京都大学大学院工学研究科分子工学専攻 / (主査)教授 白川 昌宏, 教授 佐藤 啓文, 教授 梶 弘典 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DGAM

Bakgrund: ALS är en obotlig neurologisk sjukdom som leder till försvagning av muskler efter en nedbrytande process i nervsystemet. Det finns en ärftlig komponent, men i många fall går det inte att fastställa orsaken bakom sjukdomens uppkomst. Att diagnostiseras med en obotlig sjukdom där kroppsliga funktioner avtar samtidigt som de kognitiva förmågorna och känseln består innebär ofta ett stort lidande för patienterna. Att beskriva patienters erfarenheter av sjukdomen kan öka förståelsen och skapa en möjlighet att närma sig lidandet. Syfte: Syftet var att beskriva patienters upplevelse av att leva med ALS. Metod: Studien är en litteraturöversikt som baserades på 15 vetenskapliga artiklar. Dessa återfanns i databaserna Pubmed och CINAHL. Artiklarna granskades med hjälp av Sophiahemmets Högskolas formulär för kvalitetsgranskning och analyserades genom en integrerad analys. Resultat: Ur analysen framträdde tre kategorier: “Upplevelsen av maktlöshet”, “Upplevelsen av att vara en börda” och “Upplevelsen av att anpassa sig till en ny tillvaro”. I resultatet framkom att patienter med ALS upplevde ett lidande som de själva beskrev i olika termer, men likaså återgav de positiva erfarenheter och hur dem utvecklade strategier för att hantera sin nya tillvaro. Slutsats: Denna litteraturöversikt beskriver hur patienter med ALS hanterar sin verklighet, vilket till viss del skiljer sig åt. Lidandet som patienterna upplever kan bli del av personlig utveckling, samtidigt som risken finns att hela livsperspektivet påverkas negativt om patienterna fastnar i lidandet. Sjuksköterskan har en viktig roll i att lindra patienters lidande och litteraturöversikten upplyser om hur ett personcentrerat förhållningssätt, som bland annat innefattar lyhördhet till hur patienterna upplever sin tillvaro, kan bidra till detta. / Background: ALS is an incurable neurological disease that leads to muscle deterioration following a degrading process in the nervous system. There is a hereditary component, but in many cases it is not possible to determine the cause behind the onset of the disease. Being diagnosed with an incurable disease in which bodily functions decline at the same time as the cognitive abilities and tactile sense remains often results in great suffering for the patients. Describing patients' experiences of the disease can increase understanding and create an opportunity to approach suffering. Aim: The aim was to describe patients' experiences of living with ALS. Method: The study is a literature review based on 15 articles. These were found in the databases PubMed and CINAHL. The articles were reviewed with the use of Sophiahemmets Högskola's form for quality review and were analyzed through integrated analysis. Results: From the analysis three categories appeared: “The experience of powerlessness”, “The experience of being a burden” and “The experience of adapting to a new existence”. The results showed that patients with ALS experienced suffering that they themselves described in different terms, but they also portrayed positive experiences and how they developed strategies to manage their new situation. Conclusions: This literature review describes how patients with ALS manage their reality, which differs to some extent. The suffering that the patients experience may be part of personal development, while there is a risk that the entire life perspective will be adversely affected if the patients become stuck in the suffering. The nurse plays an important role in relieving patients suffering and the literature review informs how a person-centered approach, which includes, among other things, responsiveness to how patients experience their lives, can contribute to this.

Palliativ vård innebär att förbättra livskvalitet för personer med livshotande kronisk sjukdom och dess närstående. De fyra hörnstenar som den palliativa vården vilar på är symtomkontroll, kommunikation, teamarbete och närståendestöd. Sjuksköterskor inom palliativ vård har till uppgift att tillsammans med teamet förebygga, observera, behandla och lindra symtom för både patient och närstående. Amyotrofisk lateralskleros är en motorneuronsjukdom som påverkar kroppens alla muskler. Nedsatt andningsfunktionen hos personer med ALS leder till hypoventilation vilket kan behandlas med ventilatorstöd med noninvasiv ventilator via näseller helmask och trakeostomiansluten invasiv ventilator. Sjuksköterskan har ett ansvar att stödja personen med ALS att bevara sin autonomi, värdighet och livskvalitet samt stödja närstående som ofta även är vårdare. Behandling för att ersätta livsnödvändiga funktioner, såsom andning, som ges i syfte att bevara liv vid ett livshotande tillstånd innebär en livsuppehållande behandling. Rätten att neka behandling är lagstadgad i Sverige likaväl som rätten att avsäga sig pågående behandling. Studiens resultat diskuteras mot Katie Erikssons teorier om vårdlidande. Syftet med studien var att undersöka sjuksköterskors erfarenheter av avslutande av ventilatorbehandling för personer med amyotrofisk lateralskleros inom palliativ vård Metoden som använts var en intervjustudie med kvalitativ ansats. Tio sjuksköterskor intervjuades med avseende på deras erfarenheter av att avsluta ventilatorbehandling. En kvalitativ analys med induktiv ansats användes för att få fram både latent och manifest data. Resultatet presenteras under två teman. I temat att göra resan från oro och rädsla till trygghet beskrivs att sjuksköterskorna inför att avsluta ventilatorbehandling kunde känna rädsla och oro men att avslutet i de allra flesta fall uppfattades ett värdigt avslut där sjuksköterskan lindrade lidande. Vidare presenteras faktorer som kan minska erfarenheten av oro och rädsla. Under detta tema återfinns kategorierna att praktiskt förbereda inför avslut, att stänga av ventilatorbehandling samt förberedelse och bearbetning. I temat att balansera de egna känslorna som uppstår framkommer sjuksköterskans känslor av ansvar och hur de förhöll sig till detta ansvar. I detta tema belyser sjuksköterskorna vad de upplever är vårdens helhetsansvar, att det finns ett informationsansvar samt att de känner ett personligt ansvar mot personen som vill avsluta ventilatorbehandling. Under detta tema finns kategorierna teamarbete på olika nivåer, att förhålla sig till ansvar och målet med vården. Slutsatser som kan dras är bland annat; att närvara vid avslut av livsuppehållande ventilatorbehandling kan skapa känslor av oro och rädsla men förberedelser och planering kan göra erfarenheten positiv. Det finns en trygghet i rutiner och att använda redan befintlig erfarenhet för att sjuksköterskor ska känna sig trygga i avslutssituationen. / Palliative care means to improve quality of life for people with a life-threatening chronic illness and their family. The four cornerstones on which palliative care rests are symptom control, communication, team work and support for family. Nurses in palliative care have the task, together with the palliative team, to prevent, observe, treat and alleviate symptoms for both patient and their family members. The need for palliative care to be adapted for people with neurological disease, which includes amyotrophic lateral sclerosis (ALS), has only been noticed in recent years. For people with ALS, there can be advantages with an early contact with palliative care providers. Nurses in palliative care has a challenge to support the person with ALS in order to preserve autonomy, dignity and quality of life, and to support relatives. Amyotrophic lateral sclerosis is a collective term for several motor neuronal diseases where the most common form is classical amyotrophic lateral sclerosis. Reduced respiratory function in people with ALS lead to hypoventilation, which van be treated with ventilator support. Treatment may be either non-invasive ventilator via nasal or whole mask and with invasive ventilation via tracheostomy. Life-sustaining treatment means to replace vital functions, such as breathing, to preserve life in a life-threatening condition. The right to refuse treatment is statutory in Sweden as well as the right to renounce ongoing treatment. The results of the study are discussed against Katie Eriksson's theories of suffering of care. The aim of the study was to investigate nurses' experiences of withdrawal of ventilator treatment for patients with amyotrophic lateral sclerosis in palliative care. The method used was an interview study with qualitative approach. Ten nurses were interviewed for their experience regarding withdrawal of ventilator treatment. A qualitative analysis with inductive approach was used to obtain both latent and manifest data. The result is presented under two themes. In the theme of making the journey from worry and fear to security, it is described that the nurses before withdrawal of ventilator treatment could feel fear and anxiety, but that in most cases the conclusion was perceived as a worthy termination of treatment where the nurse alleviated suffering. Furthermore, factors are presented that can reduce the experience of concern and fear. Under this theme are the categories to practically prepare for withdrawal, to turn off ventilator treatment and preparation and processing. In the theme of balancing their own feelings that arise, the nurse's feelings of responsibility emerge and how they relate to this responsibility. In this theme, the nurses highlight what they feel is the overall responsibility of caregivers, that there is an information responsibility and that they feel a personal responsibility towards the person who wants to terminate the ventilator treatment. Under this theme are the categories team work at different levels, to relate to responsibility and the aim of the care. Conclusions that can be drawn include; attending withdrawal of life-sustaining ventilator treatment can create feelings of concern and fear, but preparation and planning can make the experience positive. Security can be found in routines and using already existing experience, which can make nurses feel safe in the withdrawal situation.

Indiana University-Purdue University Indianapolis (IUPUI) / The main, underlying cause of neurodegenerative disease is the progressive loss of neuronal structure or function, whereby central and/or peripheral nervous system circuitry is severely and irreversibly damaged, resulting in the manifestation of clinical symptoms and signs. Neurodegenerative research has revealed many similarities among these diseases: although their clinical presentation and outcomes may differ, many parallels in their pathological mechanisms can be found. Unraveling these relationships and similarities could provide the potential for the discovery of therapeutic advances such that a treatment for one neurologic disease may also be effective for several other neurodegenerative disorders. There is growing awareness that due to the complexity of pathophysiological processes in human disease, specifically targeting or inactivating a single degenerative process or a discrete cellular molecular pathway may be ineffective in the treatment of these multifaceted disorders. Rather, potential therapeutics with a multi-target approach may be required to successfully and effectively control disease progression. Recent advances in neurodegenerative research involve the creation of animal disease models that closely mimic their human counterparts. The use of both toxin- exposure and genetic animal models in combination may give insight into the underlying pathologic mechanisms of neurodegenerative disorders (target identification) leading to the development and screening of prospective treatments and determination of their neuroprotective mechanism (target validation). Taken together, ideal candidates for the treatment of neurodegenerative disease would need to exert their neuroprotective effect on multiple pathological pathways. Previous studies from this laboratory and collaborators have shown that the naturally-occurring compound, caffeic acid phenethyl ester (CAPE), is efficacious for the treatment against neurodegeneration. Because of its versatile abilities, CAPE was chosen for this study as this compound may be able to target the pathogenic pathways shared by two different animal models of neurodegeneration and may exhibit neuroprotection. In addition, adipose-derived stem cell conditioned media (ASC-CM), a biologically-derived reagent containing a multitude of neuroprotective and neurotrophic factors, was selected as ASC-CM has been previously shown to be neuroprotective by using both animal and cell culture models of neurodegeneration.