Angelman syndrome (AS) is a rare genetic disorder affecting 1/10,000 to 1/20,000 births. This disorder arises through the genetic disruption of the maternal UBE3A allele, which when coupled with epigenetic silencing of the paternal allele UBE3A allele, gives rise to an absence of UBE3A protein in the central nervous system. Clinical manifestations of the syndrome vary in severity and include poor motor function, deficits in language and severe intellectual impairments. Previous research in the Angelman syndrome mouse model revealed abnormalities in dendritic spine density and morphology of hippocampal pyramidal cells. As seen in humans with AS, mice show abnormal behavioral characteristics that include deficits in motor coordination and ability as well as hippocampal dependent associative fear conditioning. Physiologically, these animals exhibit severe deficits in long-term potentiation (LTP) when compared to wildtype littermates. In an attempt to reduce the time from laboratory study to human translation, we began to search a small molecule library for established compounds with the ability to improve the behavioral and physiological defects normally associated with the AS mouse. One compound, minocycline, was found to normalize the density of dendritic spines in the hippocampus as well as recover the associative memory of AS mice. Moreover, a significant increase in LTP after theta-burst stimulation was also observed in area CA1 hippocampal pyramidal neurons of AS mice treated with minocycline when compared to saline vehicle control mice. These results suggest treatment with minocycline improves synaptic function and learning and memory of AS mice and may provide similar improvements to patients with Angelman syndrome. Twenty-five participants ages 4-12 were enrolled in a clinical trial examining the safety and tolerability of minocycline in children with Angelman syndrome. Patients were evaluated at 3 time points, baseline (T1), after 8 weeks of treatment (T2) and again 8 weeks after the drug was discontinued (T3). Each evaluation was identical and included laboratory testing, EEG recording and neuropsychological examination. Results of the study showed minocycline was safe and well tolerated with only minor adverse effects reported. While no change was observed in EEG recordings, significant increases in the mean clinical global impressions severity scale score were observed after treatment with minocycline. Moreover, participants showed significant improvement in the raw scores of the communication and self-care domains of the Bayley Scale of Infant and Toddler Development, 3rd Edition. These results show for the first time, a therapeutic with the ability to improve the characteristic behaviors of Angelman syndrome. Unfortunately, currently available neuropsychological measures were found to be insensitive to the behavioral phenotype of AS. The primary outcome measure, the Bayley Scale of Infant and Toddler Development, 3rd Edition relies on verbal communication and for the examinee to perform specific tasks on command. These testing methods are not compatible with this patient population and resulted in raw scores outside of 2 standard deviations from the mean. The inability of the participants to perform on these exams led us to develop a novel outcome measure; one that relies on observation rather than verbal communication. 9 children with AS and 7 healthy children were enrolled in an observational study in which 30 minutes of free play activity was video recorded. Using behavioral coding software, 3 independent raters quantified stereotypical AS behaviors as well as communication methods. Speech attempts were categorized into five difference types of vocalizations and revealed children with AS used less advance forms of vocalization consisting mostly of phonation control. Phonetic inventories show mostly front or back vowel usage suggesting little tongue movement occurs during speech production. These results suggest deficits in verbal ability may be related to a childhood apraxia of speech. Impairments in balance and motor coordination have been associated with AS. In an attempt to measure gross motor function, spatiotemporal gait parameters were collected using an electronic walkway and gait analysis software. Results show the gait of children with AS most resembles that of patients with ataxia but without cognitive impairment. In an attempt to develop a single quantitative measure able to describe the severity of gait-related disability, statistical methods were used to create a gait index for patients with AS. The results of this study provides AS researchers with the tools necessary to accurately measure changes in behavior and gait during the clinical evaluation of potential therapeutics

The Ataxia-telangiectasia mutated (ATM) protein is regarded as the major regulator of the cellular response to DNA double Strand Breaks (DSBs). In response to DSBs, ATM dimers dissociates into active monomers in a process promoted by Mre11-Rad50-Nbs1 (MRN) complex. ATM-deficient cells exhibit signs of chronic oxidative stress, suggesting that ATM plays an important role in the regulation of reactive oxygen species (ROS). I show for the first time that ATM can be activated by oxidative stress directly in the form of exposure to H₂O₂. In vitro kinase assays with purified ATM suggest that the activation by H₂O₂ is independent of DSBs and the MRN complex. In 293T cells, H₂O₂ induces ATM autophosphorylation on serine 1981. p53 and Chk2 are also phosphorylated by ATM after H₂O₂ treatment but not histone H2AX and heterochromatin protein Kap1, indicating that ATM activation by H₂O₂ in human cells is independent of DNA damage. I also show that the cysteine residue 2991 is critical for ATM activation by H₂O₂ in vitro. / text

No description available.

This thesis deals with a) The investigation of the problem of clumsiness resulting from developmental apraxia and agnosia ; b) the development of effective screening tests particularly suitable for employment by medical practitioners and specialist schoolteachers for the identification of these children. Chapter 2 reports the detailed initial investigation in Great Britain of 21 such clumsy children who had been referred for diagnosis and management. This study in turn stimulated a clinical survey of developmental clumsiness in Western Australian schoolchildren described and analysed in Chapters 3 and 4. It was anticipated that this survey would yield information regarding the magnitude of the problem and would provide normative data regarding motor performance in children. Subsequently these data were to be the basis of a set of standardized tests of motor proficiency in children (Chapter 4). In order to obtain information efficiently and to develop these tests it seemed most rational to commence with a pilot study of a relatively small number of children, when after statistical analysis it would become evident which tests were the most reliable, effective and convenient (Chapter 3). A comprehensive review of the subject of developmental apraxia and agnosia constitutes the final chapter of this thesis (Chapter 5).

Thesis (Ph.D. in Clinical Science) -- University of Colorado Denver, 2008. / Typescript. Includes bibliographical references (leaves 59-67). Free to UCD Anschutz Medical Campus. Online version available via ProQuest Digital Dissertations;

Habilitation - Med. Hochsch., Hannover, 2004.

Orientador: Carlos Augusto Araújo Valadão / Coorientador: André Escobar / Banca: Suzane lilian Beier / Banca: Guilherme de Camargo Ferraz / Resumo: A recuperação é uma fase crítica na anestesia de equinos. Tentativas precoces de retornar à posição quadrupedal são normalmente fracassadas podendo ocasionar quedas, injúrias e até mesmo fraturas. Técnicas para melhorar a qualidade de recuperação incluem o uso de agonistas adrenérgicos do tipo α2, os quais objetivam, neste contexto, a sedação do paciente, aumentando o tempo de decúbito e possibilitando maior tempo de eliminação do anestésico inalatório residual. O doxapram é um fármaco caracterizado por provocar aumento na frequência respiratória e, potencialmente, pode aumentar o clearance dos anestésicos inalatórios. Neste contexto, objetivou-se verificar a influência da administração dos fármacos xilazina e doxapram no tempo e na qualidade da recuperação de equinos submetidos à anestesia geral inalatória com isofluorano. Seis cavalos foram anestesiados durante 90 minutos quatro vezes, com intervalo de duas semanas entre os procedimentos, recebendo aleatoriamente os seguintes tratamentos após a interrupção do anestésico inalatório: xilazina 0,2 mg/kg, ou xilazina e doxapram (0,2 e 0,1 mg/kg, respectivamente), ou xilazina e doxapram (0,2 e 0,2 mg/kg, respectivamente), ou solução NaCl 0,9%. Todas recuperações foram filmadas e avaliadas por dois observadores não cientes dos tratamentos, por meio da escala visual analógica e escala qualitativa descritiva. Os escores foram analisados quanto à concordância por BlandAltman e quanto à diferença pela RM ANOVA, seguido pelo teste de ... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Recovery is a critical stage on equine anesthesia. Early attempts to assume upright position are seldom successful and frequently result on falls, injuries and even fractures. Techniques to improve anesthetic recovery include the use of α2- adrenergic agonists at recovery in order to increase the recumbency time permitting clearance a broader residual inhalational anesthetic. Doxapram is characterized by increasing respiratory rate. Potentially it can increase inhaled anesthetics clearence. The purpose of the present study was to verify to influence of xylazine and doxapram administration on time and quality of recovery of horses submitted to isoflurane inhalational anesthesia. Six horses were anesthetized four times, with a wash out period of two weeks. Each animal received one of the following randomized treatments following discontinuation of isoflurane anesthesia: xylazine 0.2 mg/kg, or xylazine plus doxapram (0.2 and 0.1 mg/kg, respectively), xylazine plus doxapram (0.2 and 0.2 mg/kg, respectively), or NaCl 0.9% solution. Recovery was filmed and posterior evaluated by two blind observes by a visual analogue scale and a qualitative descriptive scale. The scores were analyzed for agreement by Bland-Altman and for the difference by RM ANOVA followed by Tukey test. The parameters measured were analyzed with RM ANOVA followed by Tukey test (p < 0.05). There was no difference regarding times recovery between groups. The animals who received just xylazine presented better scores on quality analysis, followed by doxapram 0.2 mg/kg group, control group, and 0.1 mg.kg of doxapram group. The use of doxapram to re-sedate horses isoflurane anesthetized does not improve quality neither diminish time of recovery. / Mestre

Submitted by Edileide Reis (leyde-landy@hotmail.com) on 2015-04-09T20:59:45Z No. of bitstreams: 1 André Ferraz de Arruda Musegante.pdf: 704902 bytes, checksum: a90e566c7361d3e37222e3175a6958ac (MD5) / Made available in DSpace on 2015-04-09T20:59:45Z (GMT). No. of bitstreams: 1 André Ferraz de Arruda Musegante.pdf: 704902 bytes, checksum: a90e566c7361d3e37222e3175a6958ac (MD5) Previous issue date: 2013 / Descrever os sintomas urinários e achados urodinâmicos de pacientes com Ataxia de Friedreich (AF) com sintomas do trato urinário inferior (LUTS). Métodos: Estudo prospectivo que avaliou 258 pacientes com diagnósticos de AF confirmados geneticamente. Cento e cinquenta e oito (61%;N258) pacientes responderam a um questionário para avaliar LUTS. Pacientes com LUTS foram convidados à uma investigação com exames de função renal, ultrassonografia e estudo urodinâmico. Resultados: Cento e vinte e nove (82%;N158) pacientes apresentaram LUTS. Apenas 35(22%;N158) pacientes afirmaram que os sintomas urinários interferiam na qualidade de vida, apesar de 40% da amostra referirem alguma forma de incontinência. Vinte e oito (21 mulheres) realizaram estudo urodinâmico. A média de idade e de tempo de início da doença foi de 32 (±11.2) e 16 (±7) anos, respectivamente. O sintoma mais frequente foi urgência, 21 (75%;N28) pacientes. Incontinência foi relatado por 17 pacientes (61%;N28). Estudo urodinâmico foi normal em 4 (14%;N28) pacientes. Hipocontratilidade foi o achado urodinâmico mais comum. Pacientes com urgência, 81% não apresentavam hiperatividade detrusora. Creatinina estava normal em todos os pacientes e ureia estava aumentada em 1 (3%;N28). Ultrassom encontrou discreta/moderada dilatação do trato urinário superior em 4 (14%;N28) pacientes. Em 7 (25%;N28) a bexiga apresentava irregularidade e espessamento da parede. Conclusão: Disfunção do trato urinário baixo foi encontrada em um grande número de pacientes com AF, porem sem interferir na qualidade de vida. O risco para o trato urinário superior é baixo, pois não foi encontrada alteração da complacência e a hiperatividade não possui pressões elevadas.

Orientador: Prof. Dr. Helio Afonso Ghizoni Teive / Coorientador: Profª. Drª. Ana Chrystina de Souza Crippa / Tese (doutorado) - Universidade Federal do Paraná, Setor de Ciências da Saúde, Programa de Pós-Graduação em Medicina Interna. Defesa : Curitiba, 23/12/2016 / Inclui referências : f. 57-65 / Resumo: As principais manifestações clínicas das ataxias espinocerebelares (AEC) resultam a partir do envolvimento do cerebelo e suas conexões aferentes e eferentes. Cursam tanto com sintomas motores como também com sintomas não motores. Evidências têm demonstrado uma frequência elevada de sintomas não motores nas AEC. Dentre os sintomas não motores estão os distúrbios do sono que, muitas vezes, são subdiagnosticados ou pouco valorizados. Os principais distúrbios do sono já relatados em diversos tipos de ataxias cerebelares, foram: transtorno comportamental de sono REM (TCR), síndrome das pernas inquietas(SPI), sonolência diurna excessiva (SDE), insônia e apneia obstrutiva do sono. Todavia, nenhum estudo até o momento relatou sobre o sono e os distúrbios do sono na AEC 10. Neste estudo, investigou-se de forma transversal o sono de 23 pacientes com diagnóstico molecular confirmado de AEC 10 que faziam acompanhamento no Ambulatório de Distúrbios do Movimento do Complexo Hospital de Clínicas da Universidade Federal do Paraná, de janeiro de 2015 a janeiro de 2016. Foram comparados com 23 controles provenientes do ambulatório de polissonografia do mesmo hospital, sem história familiar de AEC, sem queixas de doença pulmonar crônica e ou neurológica, sem história de uso de medicações hipnóticas. Foram coletados dados demográficos e clínico neurológico além da realização de polissonografia para avaliar o sono e os possíveis distúrbios do sono.Foram aplicadas as seguintes escalas: para avaliação e graduação da gravidade da ataxia (SARA), de Hamilton para avaliar ansiedade e inventário de Beck para depressão, de Pittsburgh e de Berlim para avaliar qualidade de sono, Epworth para sonolência diurna (ESS) e escala para síndrome das pernas inquietas. Do grupo com AEC 10, onze (47,8%) eram do sexo feminino, a média de idade era de 47,3 +/-11,6 anos e a média do índice de massa corpórea foi de 25,4 +/- 4,5. Dos pacientes controles, 12 eram mulheres (52,2%), a média de idade foi de 50,7 +/-3,3 anos e o índice de massa corpórea foi de 24,6 +/- 3,0. Em relação aos achados clínicos e polissonográficos que foram positivos neste estudo pode-se destacar que os pacientes com AEC tipo10, comparativamente ao grupo controle, tem maior latência para início de sono REM, maior índice de distúrbios respiratórios e maior índice de despertares em sono REM, e todos estes achados tem significado estatístico.Porem um estudo longitudinal com maior amostra é necessário para acompanhar as modificações clinicas e polissonograficas a medida qua a doença se desenvolve e uma possível relação entre o mecanismo da AEC e o mecanismo dos distúrbios do sono nas AEC tipo 10. Palavras-chave: Ataxia; ataxia espinocerebelar tipo 10, sono e distúrbios do sono. / Abstract: The main clinical manifestations of spinocerebellar ataxias (SCA) result from the involvement of the cerebellum and its afferent and efferent connections with both motor symptoms and non-motor symptoms. Evidence has shown a high frequency of non-motor symptoms in the SCA. Non-motor symptoms include sleep disorders that are often underdiagnosed or undervalued. The main sleep disturbances reported in several types of cerebellar ataxias were: REM sleep behavioral disorder, restless legs syndrome, excessive diurnal somnolence, insomnia, and obstructive sleep apnea. However, no current study has reported on sleep and sleep disorders in SCA 10. In this study, the sleep of 23 patients with a confirmed molecular diagnosis of SCA 10 was investigated in a cross-sectional study, who were monitoring the movement disorders clinic of Federal University of Paraná, from January 2015 to January 2016. They were compared to 23 controls from the polysomnography outpatient clinic of the same hospital with no family history of SCA, with no complaints of chronic and/or neurological lung disease, with no history of hypnotic medication use. Demographic and neurological data were collected in addition to performing polysomnography to evaluate sleep and possible sleep disorders. The following scales were used: severity of the ataxia evaluation and graduation scale (SARA), Hamilton Anxiety Scale (HAM-A) and Beck Depression Inventory (BDI), Pittsburgh and Berlin scale to assess sleep quality, Epworth for diurnal drowsiness and scale for restless legs syndrome. Of the SCA group 10, eleven (47.8%) were female, the average age was 47.3 +/-11.6 years and the average body mass index was of 25.4 +/- 4.5. Of the control patients, 12 were women (52.2%), the average age was 50.7 +/-3.3 and the body mass index was 24.6 +/-3.0. Regarding the clinical polysomnography findings that were positive in this study, it can be pointed out that patients with SCA Type 10, compared to the control group, have a higher latency for REM sleep onset, a higher rate of respiratory disorders and higher REM sleep and all these findings have statistical significance. Nevertheless a longitudinal study with a larger sample is necessary to accompany the clinical and polysomnographic changes as the disease develops and a possible relation between the ACS mechanism and the mechanism of sleep disorders in the ACS Type 10. . Key words: Ataxia; Spinocerebellar Ataxia Type 10, sleep and sleep disorders.

Orientadores: Fernando Cendes, Iscia Lopes Cendes / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-12T17:57:06Z (GMT). No. of bitstreams: 1 D'Abreu_AnelyssaCysneFrota_D.pdf: 3449847 bytes, checksum: eea5f74252de56c304a925b8900a4cad (MD5) Previous issue date: 2009 / Resumo: A doença de Machado-Joseph ou ataxia espinocerebelar do tipo 3 (MJD/SCA3) é uma ataxia autossômica dominante resultante de uma expansão de tripletos CAG no gene MDJ1 localizado no cromossomo 14q. Clinicamente ela se caracteriza por ataxia cerebelar, neuropatia periférica, síndrome piramidal e extrapiramidal e oftalmoplegia. A idade de início é variável e se correlaciona inversamente com o tamanho da expansão CAG. Pacientes com início de sintomas precoce tendem a apresentar quadro clínico mais severo, e fenômeno de antecipação foi descrito nestes pacientes. MJD/SCA3 é progressiva e não há tratamento específico. Os objetivos deste trabalho foram: 1) Avaliar de forma prospectiva um número significativo de pacientes com MJD, através de questionários padronizados e escalas validadas para o estudo de pacientes com ataxia; 2) Avaliar os atuais instrumentos de avaliação clínica em MJD; 3)Avaliar de forma prospectiva as alterações de neuroimagem apresentadas em MJD, correlacionando-as com marcadores genéticos e manifestações clínicas. Os pacientes foram avaliados de forma sistemática através de ficha clínica padronizada, exame neurológico, escalas ICARS (International cooperative ataxia rating scale) e UMSARS (Unified Multiple System Atrophy Rating Scale), e exame de ressonância magnética do crânio (RM). Em trinta pacientes fomos capazes de repetir a RM após um intervalo aproximado de 12 meses. Inicialmente, investigamos se as escalas ICARS e UMSARS seriam adequadas para a avaliação clínica destes pacientes. Ambas as escalas (ICARS e UMSARS) apresentaram consistência interna adequada com escores a >0.90. No entanto, o subescore oculomotor (ICARS) obteve a=0.08. Coeficiente de correlação intraclasse foi de 0.94 para a ICARS, 0.96 para UMSARS-I, 0.97 para UMSARS-II e 0.94 para UMSARS-IV ("global disability score" (GDS)). Houve uma correlação quase perfeita entre os escores da ICARS e UMARS-II. Houve claramente uma interferência de sintomas que não a ataxia, notadamente distonia, nos escores totais de ambas as escalas. Além disso, o escore total ICARS demonstrou ser sensível a mudança após um período de um ano, mostrando a validade da escala na avaliação longitudinal dos pacientes. Como este projeto estava inserido em um projeto maior, envolvendo avaliação de sintomas não motores, entrevistamos 52 pacientes através de um questionário padronizado de sono e escala Epworth. Destes, 23 apresentaram escores na escala Epworth acima de 10, sugerindo sonolência diurna excessiva. Um achado interessante foi a alta freqüência de pacientes com insônia (19 pacientes), além de onze pacientes com sintomas sugestivos de síndrome das pernas inquietas, e oito com sintomas sugestivos de distúrbio do sono REM (RBD). Dezesseis pacientes utilizavam algum tipo de medicação indutora do sono. A avaliação de neuroimagem envolveu diferentes técnicas de análise. O passo inicial foi a avaliação visual das imagens adquiridas na RM. Observamos atrofia cerebelar em 28 pacientes; atrofia de ponte em 20 e de bulbo em 19; alargamento do 4o ventrículo em 17 e atrofia dos pedúnculos cerebelares em 12. Atrofia cortical difusa leve foi observada em 12 pacientes, enquanto em seis ela estava restrita aos lobos frontais. Doze pacientes apresentaram áreas de lesões hiperintensas não-específicas na substância branca. O segundo passo foi a análise de espectroscopia (MRS). Em um primeiro momento utilizamos a mensuração manual dos picos de metabólitos (NAA, Cr, Cho) e comparamos a razão;NAA/Cr e Cho/Cr do grupo de pacientes com um grupo controle. Nós observamos valores menores de NAA/Cr em MJD quando comparados com controles (1.63+/-0.41 (1.15-2.76) versus 1.9?+/-0.51 (1.50-2.92); U test =219.000; p<0.001). Os valores de NAA/Cr não se correlacionaram com nenhuma variável clínica ou tamanho da repetição CAG. Devido à diferença de idade entre controles e pacientes, nós realizamos de forma cega, um pareamento entre o grupo controle e os pacientes, resultando assim em um grupo de 15 pacientes e 15 controles. Nesse subgrupo, as diferenças entre NAA/Cr se mantiveram (U test=44.000; p=0.004). No entanto, uma diferença entre os níveis de Cho/Cr também foi encontrada (0.86+/-0.14 (0.71-1.15) e 0.98+/-0.14 (0.78-1.23); U test=53.000; p=0.014). A análise de morfometria baseada em voxels (VBM) ocorreu em duas etapas. Em um primeiro momento nós avaliamos as imagens dos pacientes em relação ao grupo controle. Na segunda análise nós comparamos de forma pareada as imagens de cada paciente com intervalo médio aproximado de 12 meses entre elas. Nós observamos uma diminuição de densidade de substância cinzenta significativa nas seguintes áreas (p<0,01): lobo frontal (giros pré-central; frontal inferior, superior e médio); lobo parietal (giros pós-central; parietal inferior, superior, angular e supramarginal); giro temporal médio; giro cingulado; putamen. Atrofia de substância branca estava restrita ao cerebelo. Múltiplas áreas demonstraram uma correlação inversa com CAG, idade, idade de início, e duração de doença. A análise longitudinal, no entanto, não demonstrou progressão significativa da patologia cerebral, possivelmente por efeito solo, ou tempo de seguimento curto. A fim de confirmar os achados de VBM, utilizamos um software para análise semi-automática de MRS, nas imagens na avaliação inicial e no exame de seguimento. Não houve novamente diferença significativa na análise longitudinal. Por último, realizamos um estudo comparativo entre a densidade de substância cinzenta e o volume do tálamo entre pacientes com MJD e controles. Houve uma diferença significativa entre a densidade de substância cinzenta de pacientes (130.359 +/-16.758) e controles (153.193 +/- 23.599;p<0.001), assim como no volume do tálamo (7862.5+/- 712.5 mm3 versus controles 8592.3+/-712.5 mm3; p<0.001). O volume talâmico foi menor em pacientes com distonia do que naqueles sem distonia (7456.2+/-814.2 versus 7984.4+/- 644.8 mm3; p=0.0049). Não houve correlação entre o volume talâmico e a tamanho da repetição CAG, duração de doença, idade de início de sintomas e idade do paciente / Abstract: Machado-Joseph disease or spinocerebellar ataxia type 3 (SCA3/MJD) is an autosomal dominant ataxia resulting from an expansion of a CAG triplet at the MDJ1 gene located on chromosome 14q. Clinically, it is characterized by cerebellar ataxia, peripheral neuropathy, pyramidal and extrapyramidal syndrome and ophthalmoplegia. The age of onset is variable and inversely correlated with the size of the CAG expansion. Patients with early symptoms tend to have a more severe clinical picture, and the anticipation phenomenon was described in these patients. MJD/SCA3 is progressive and there is no specific treatment. The objectives of this study were: 1) to prospectively evaluate a significant number of patients with MJD/SCA3, through standardized questionnaires and validated scales; 2) To assess the current clinical tools for the evaluation of patients with MJD/SCA3; 3) To perform a longitudinal neuroimaging study in MJD/SCA3, correlating those findings with genetical and clinical markers. Patients were evaluated in a systematic manner through a standardized clinical form, neurological examination, ICARS (International cooperative ataxia rating scale) and UMSARS (Unified Multiple System Atrophy Rating Scale), and Magnetic Resonance Imaging of the brain (MRI). In thirty patients we were able to repeat the MRI after an interval of approximately 12 months. Initially, we investigated whether the ICARS and UMSARS would be suitable for the clinical evaluation of these patients. Both scales (ICARS and UMSARS) had adequate internal consistency with scores a> 0.90. However, the oculomotor subscore (ICARS) obtained a = 0.08. Intraclass correlation coefficient was 0.94 for ICARS, 0.96 for UMSARS-I-II UMSARS to 0.97 and 0.94 for UMSARS-IV ("global disability score" (GDS)). There was an almost perfect correlation between the scores of ICARS and UMARS-II. There was clearly an interference of symptoms other than ataxia in total scores of both scales. Especially patients with dystonia, regardless of clinical subtype, showed the highest scores. Moreover, the total ICARS score showed to be sensitive to change after a period of one year, demonstrating the validity of the scale in the longitudinal evaluation of patients. As this project was inserted into a larger project, involving the evaluation of non-motor symptoms, we evaluated 52 patients for the presence of sleep related complains. We interviewed all patients through a standardized sleep questionnaire and performed the Epworth Sleepiness Scale (ESS). Of these, 23 had ESS scores above 10, suggesting excessive daytime sleepiness. An interesting finding was the high frequency of patients with insomnia (19 patients). We also observed eleven patients with symptoms suggestive of restless legs syndrome, and eight with symptoms suggestive of REM behavior disorder (RBD). Sixteen patients used some kind of sleep inducing medication. The neuroimaging evaluation involved different analysis techniques. The initial step was the visual evaluation of the MRI sequences. We observed cerebellar atrophy in 28 patients; atrophy of the pons in 20 and atrophy of the medulla in 19; enlargement of the 4th ventricle in 17 and atrophy of the cerebellar peduncles on 12. Mild diffuse cortical atrophy was observed in 12 patients, while in six it was restricted to the frontal lobes. Twelve patients had areas of non-specific hyperintense lesions in the deep white matter. The second step was the analysis of the spectroscopy (MRS) data. We performed manual measurements of the peak area for NAA, Cr and Cho and compared NAA/Cr and Cho/Cr ratios between patients and control groups. We observed lower values of NAA / Cr in MJD when compared to controls (1.63 +/-0.41 (1.15-2.76) vs. 1.97+/-0.51 (1.50-2.92); U test = 219,000, p <0.001). The values of NAA/Cr did not correlate with any clinical variable or CAG repeat size. Due to the difference in age between controls and patients, we performed in a blinded fashion, a pairing between both groups, which resulted in a group of 15 patients and 15 controls. In this subgroup, the differences between NAA/Cr remained (U test = 44,000, p = 0.004). However, a difference between the levels of Cho/Cr was also found (0.86 + / -0.14 (0.71-1.15) and 0.98 + / -0.14 (0.78-1.23); U test = 53,000, p = 0014). Voxel-based morphometry (VBM) analysis occurred in two stages. At first, we compared patients to a control group. In the second analysis, we compare paired images of each patient with an approximate average interval of 12 months. We observed significant grey matter atrophy (p<0.01) at: frontal lobes (precentral, inferior, superior, middle frontal gyrus); parietal lobes (postcentral, inferior, superior, angular, supramarginal gyrus); middle temporal gyrus; cingulate gyrus; putamen. White matter atrophy was restricted to the cerebellum. Multiple areas showed an inverse correlation with CAG, age, age of onset and duration of illness. The longitudinal analysis, however, did not show a significant progression of brain pathology; possibly due to floor effect or the short follow-up interval. In order to confirm the VBM findings, we use a software for semi-automatic MRS analysis to compare MRS results from the first and second MRS failed to demonstrate a significant change in this interval. At last, we performed a comparative study between thalamic grey matter density and thalamic volume between patients and controls. There was a significant difference between grey matter density in patients (130.359 +/-16.758) and controls (153.193 +/- 23.599; p<0.001); as well as thalamic volumes (7862.5+/- 712.5 mm3 versus 8592.3+/-712.5 mm3; p<0.001). Thalamic volumes were significantly smaller in patients with dystonia when compared to patients without dystonia (7456.2+/-814.2 versus 7984.4+/- 644.8 mm3; p=0.0049). There was no significant correlation between thalamic volume and CAG repeat length, disease duration, age of onset and age / Doutorado / Neurociencias / Doutor em Fisiopatologia Medica