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

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.

Bakgrund: Amyotrofisk lateralskleros är en fortskridande motorneuronsjukdom som drabbar de nervceller som styr skelettmuskulaturen. Sjukdomen leder till en successivt ökande muskelförsvagning och till sist döden, oftast inom 3-5 år från det att diagnos satts. Sjukdomen orsakar ett stort lidande för patienten och dennes närstående då den kan vara snabbt fortskridande och oförutsägbar. Syfte: Syftet var att beskriva upplevelsen av att leva med ALS. Metod: Studien genomfördes som en kvalitativ litteraturstudie med induktiv ansats och är baserad på 10 kvalitativa originalartiklar. Artiklarna analyserades med hjälp av en manifest innehållsanalys och resulterade i 4 huvudkategorier och 12 underkategorier. Resultat: Resultatet visade att upplevelsen av att leva med ALS är individuell men vissa fynd stack ut mer än andra. Dessa var de ständiga förlusterna sjukdomen medförde, upplevelsen av att vara en börda för andra, sjukdomen gav patienten en ny synvinkel på livet samt att kunna finna mening trots sjukdomen. Slutsats: Upplevelsen av ALS är mångdimensionell och individuell. Sjukdomen innebär svåra prövningar för den drabbade individen men med rätt stöd från anhöriga och sjuksköterskan kan lidandet lindras och meningen i livet bibehållas.

Orientador: Lúcia Figueiredo Mourão / Dissertação (mestrado profissional) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-19T03:46:04Z (GMT). No. of bitstreams: 1 Franceschini_AndressadaCosta_M.pdf: 8732521 bytes, checksum: a9d303e9da9fcd34c31872821d899f4b (MD5) Previous issue date: 2011 / Resumo: Esclerose Lateral Amiotrófica (ELA) é definida como uma doença neurodegenerativa, caracterizada por paralisia muscular progressiva dos membros, orofaringe e musculatura respiratória, com consequente disfagia, disartria e insuficiência respiratória devido a degeneração dos neurônios motores no córtex motor primário, no tronco cerebral e na medula espinhal. As mudanças nos aspectos físicos e funcionais da fonoarticulação e da deglutição na ELA podem trazer consequências em termos sociais e psicossociais, acarretando em impacto a qualidade de vida. Apesar da existência de diversos estudos que caracterizam a qualidade de vida de pacientes com ELA, pouca informação está disponível acerca do impacto especificamente da disfagia na qualidade de vida desses indivíduos. O objetivo geral deste estudo foi analisar a qualidade de vida relacionada às alterações de deglutição em pacientes com ELA de inicio espinhal. Os objetivos específicos foram: verificar se o tempo da doença e do diagnóstico interferem na percepção da qualidade de vida; comparar a qualidade de vida relacionada a deglutição com as queixas de deglutição, com a gravidade da disfagia e com a funcionalidade da deglutição; comparar a gravidade da disartria com a gravidade da disfagia e a funcionalidade da deglutição e verificar o impacto da gravidade da disartria na qualidade de vida. Dezessete pacientes com diagnóstico clínico de ELA com início espinhal os sintomas foram avaliados no Ambulatório de Disfagia/ORL do Hospital das Clinicas a UNICAMP através da aplicação do Questionário de Qualidade de Vida em Deglutição SWAL-QOL; da anamnese, que incluiu a coleta das queixas relacionadas a deglutição; da avaliação fonoaudiológica de rotina, que incluiu a avaliação dos aspectos fonoarticulatórios e da avaliação videoendoscópica da deglutição. A disfagia foi graduada par três escalas: Escala de Gravidade da Disfagia (ALSSS), a Escala da Gravidade da Disfagia, e a Escala de Funcionalidade da Ingestão por Via Oral (FOIS). A disartria foi graduada pela Escala de Gravidade da Disartria (ALSSS). Mais de 70% da amostra apresentou disfagia e disartria e houve predomínio de queixas na fase faríngea da deglutição. Foi observado que as alterações e deglutição apresentaram impacto leve a moderado na qualidade de vida, sendo os domínios mais afetados a Duração da alimentação e a Função social. O tempo da doença e do diagnóstico da ELA não interferiu com significância na percepção da qualidade de vida relacionada à deglutição, exceto para o domínio Sono. A piora da qualidade de vida relacionada à deglutição para os pacientes com ELA esteve diretamente relacionada com o aumento do número de queixas de deglutição, com a gravidade da disfagia e com a funcionalidade da deglutição. A gravidade da disartria apresentou impacto na qualidade de vida relacionada à deglutição, e esta correlacionou-se com a disfagia em pacientes com ELA de inicio espinhal / Abstract: Amyotrophic Lateral Sclerosis (ALS) can be defined as a neurodegenerative disorder characterized by progressive muscular paralysis of members, oropharyngeal and respiratory muscles, with consequent dysphagia, dysarthria and respiratory insufficiency, due to degeneration of motor neurons in the primary motor cortex, brainstem and spinal cord. Changes in physical and functional aspects of speech articulation and swallowing in ALS may have social and psychosocial consequences, decreasing the quality of life. Despite many studies that characterize the quality of life in ALS patients, little information is available about the specific impact of dysphagia on quality of life to these individuals. The aim of this study was to analyse the quality of life related to swallowing problems in patients with spinal onset of ALS; verify if the disease duration and the time of diagnosis change the quality of life perception; to compare the swallow-specific quality of life questionnaire (SWAL-QOL) with dysphagia complaints, dysphagia severity and functional oral intake; to compare the severities of dysarthria and dysphagia and the functional oral intake and verify the impact of severity of dysarthria o quality of life. Seventeen patients diagnosed with ALS with spinal onset were evaluated at the Dysphagia Outpatient Clinic at UNICAMP hospital. All the subjects filled out self-report assessment of the Swallowing Quality of Life (SWAL-QOL), underwent to anamnesis that included swallowing-related complaints; to routine speech. evaluation, including a perceptual analysis of the speech, and to Fiberoptic Endoscopic Evaluation of Swallowing (FEES). The dysphagia severity was graded using the Swallowing Subscale of ALS Severity Scale, the Dysphagia Severity Scale and the Functional Oral Intake Scale (FOIS). The dysarthria severity was graded using the Speech Subscale of ALS Severity Scale. Over 70% of the sample had dysphagia and dysarthria, and predominated complaints in the pharyngeal phase of swallowing. Swallowing problems presented mild to moderate impact on quality of protocol, and the domains of eating duration and social function had the worse scores. Disease duration and time of diagnosis did not impact on SWAL-QOL scores, except for the Sleep domain. The worsening swallowing quality of life for patients with ALS was directly related to the increased number of swallowing complaints, with severity of dysphagia and functinality of swallowing. The severity of dysarthria presented impact on quality of life related to swallowing, and this occurred concomitantly with dysphagia in spinal onset of ALS patients / Mestrado / Interdisciplinaridade e Reabilitação / Mestre em Saúde, Interdisciplinaridade e Reabilitação

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.

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.

Although it is well-known that motor neuron disease (MND) primarily affects motor neurons, the involvement of sensory pathways in the disease is currently receiving more attention. There is a dearth of information regarding the atypical effects of MND, resulting in limited understanding of the vulnerability of for example the auditory system. The presence of hearing loss negatively impacts on participation across all communicative contexts, stripping individuals of autonomy and self-worth, ultimately resulting in withdrawal and isolation. These factors form the foundation for individual desire to pursue life-prolonging measures. Hearing loss, combined with dysarthria and the use of augmentative and alternative communicative strategies, implies that individuals with MND require additional support to meet their daily communicative needs. This descriptive, exploratory study aimed to identify the prevalence of hearing loss in eight individuals with adult onset MND. In addition, perceptions relating to the implications of auditory impairment and value of auditory diagnosis were explored. An evaluation of auditory function was performed on eight individuals with a neurologist confirmed diagnosis of MND. Auditory function was assessed using a comprehensive audiological test battery including both objective and subjective measures. Perceptions related to auditory impairment were determined using the Hearing Handicap Inventory for Adults (HHIA) and the Hearing Experience Questionnaire. Both individuals with MND and their primary caregivers completed the Hearing Experience Questionnaire. The results of the study indicate that a high frequency sensorineural hearing loss was identified in six participants. Auditory handicap, as measured by the Hearing Handicap Inventory for Adults, was reported in four participants, with social handicaps reported more than emotional handicaps. Individuals with MND and their caregivers identified communication as the most important functional skill. Interestingly, the caregivers related more to the threats auditory impairment than individuals with MND. The nature of hearing loss identified in this study mimics the pattern of a presbycustic (age-related) hearing loss. It is postulated that hearing loss may arise during disease course. Participants‘ limited understanding of the devastating consequences of hearing loss on quality of life highlights the need for inclusion of an audiologist as part of the multidisciplinary management team in MND. Audiological assessment, management, counseling and education will serve to guide the process of sensory regulation and limit psychosocial threats posed by MND. This will in turn promote enhanced quality of life and maintenance of individual autonomy.

No description available.

yes / Despite intense attention from biomedical and chemical researchers, there are few approved treatments for amyotrophic lateral sclerosis (ALS), with only riluzole (Rilutek) and edaravone (Radicava) currently available to patients. Moreover, the mechanistic basis of the activity of these drugs is currently not well-defined, limiting the ability to design new medicines for ALS. This Letter describes the synthesis of triazole-containing riluzole analogues, and their testing in a novel neuroprotective assay. Seven compounds were identified as having neuroprotective activity, with two compounds having similar activity to riluzole.

Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder, which causes dysfunction/loss of lower motor neurons and muscle weakness as well as atrophy. While SMA is primarily considered as a motor neuron disease, recent data suggests that survival motor neuron (SMN) deficiency in muscle causes intrinsic defects. We systematically profiled secreted proteins from control and SMN deficient muscle cells with two combined metabolic labeling methods and mass spectrometry. From the screening, we found lower levels of C1q/TNF-related protein 3 (CTRP3) in the SMA muscle secretome and confirmed that CTRP3 levels are indeed reduced in muscle tissues and serum of an SMA mouse model. We identified that CTRP3 regulates neuronal protein synthesis including SMN via mTOR pathway. Furthermore, CTRP3 enhances axonal outgrowth and protein synthesis rate, which are well-known impaired processes in SMA motor neurons. Our data revealed a new molecular mechanism by which muscles regulate the physiology of motor neurons via secreted molecules. Dysregulation of this mechanism contributes to the pathophysiology of SMA.