Dissertation (Ph.D.) -- University of Texas Southwestern Medical Center at Dallas, 2008. / Vita. Bibliography: p.245-252

Thesis (doctoral)--Lund University, 1994. / Added t.p. with thesis statement inserted.

Thesis (doctoral)--Lund University, 1994. / Added t.p. with thesis statement inserted.

Thesis (Ph.D.)--University of Florida, 2005. / Typescript. Title from title page of source document. Document formatted into pages; contains 143 pages. Includes Vita. Includes bibliographical references.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by dopaminergic cell death in the substantia nigra pars compacta (SNc) and dopamine (DA) depletion in the striatum. Current pharmacological treatments are aimed at the replacement of striatal DA via the administration of levodopa. While this therapy is beneficial initially, long-term treatment is associated with significant side effects, and disease progression continues. The present experiments investigate neuroprotective and neurotransplantation strategies as alternatives to palliative pharmacologic treatments. The optimal therapeutic approach to neurodegenerative diseases would be to protect against cell death and prevent disease progression. PD is well-suited for such neuroprotective strategies as primarily one cell population is affected in this disorder. Neurotrophic factors (NTFs) have been identified which support dopaminergic neuronal survival in vitro. In the present studies, the neuroprotective effects of the neurotrophin brain-derived neurotrophic factor (BDNF) have been evaluated in a 1-methyl-4-phenylpyridinium (MPP+) model of substantia nigra (SN) degeneration. BDNF-secreting fibroblasts were implanted dorsal to the SN prior to the infusion of the mitochondrial complex I inhibitor MPP+. Subsequent histological analysis demonstrated that BDNF is able to attenuate MPP+ induced dopaminergic cell loss in the SNc. Moreover, neurochemical evaluation demonstrated that BDNF is able to enhance DA levels in the remaining SN neurons in this same paradigm. The cause of cell death in neurodegenerative diseases likely involves the interaction of mitochondrial impairment, excitotoxicity, and oxidative stress. In order to evaluate the mechanism of NTF-mediated protection, the ability of nerve growth factor (NGF) to attenuate the production of the oxidant peroxynitrite was evaluated in a model of mitochondrial impairment. NGF was found to decrease the production of 3-nitrotyrosine, the product of peroxynitrite mediated tyrosine nitration. Thus, NTF-mediated neuroprotection may act in part by decreasing reactive oxygen species and oxidative stress. At present, neuroprotective therapies are not clinically available. An alternate therapeutic approach to PD is the replacement of striatal DA and reconstruction of synaptic circuitry via the intrastriatal transplantation of fetal dopaminergic neurons. Current transplantation protocols using human fetal tissue are constrained by limited tissue availability. In order to investigate an alternate cell source for the treatment of PD, fetal porcine dopaminergic neurons were implanted into the DA depleted striatum of 6-OHDA lesioned rats. Amphetamine-induced rotational recovery was monitored, and graft survival was evaluated 19 weeks after grafting. In immunosuppressed rats, porcine dopaminergic neurons were found to attenuate rotational deficits and extensively reinnervate the host striatum. The neuroprotective effects of BDNF suggest that NTFs may be important mediators of dopaminergic neuronal survival and function in the adult brain. However, several conditions including appropriate dosage and delivery need to be determined before clinical applications may be achieved. As an alternative to neuroprotection, neurotransplantation not only restores striatal DA but also reconstructs the synaptic circuitry of the basal ganglia. The finding that porcine dopaminergic neurons survive with in adult host brain, reinnervate the DA depleted striatum, and mediate functional recovery suggests that porcine DA neurons may serve as an alternate cell source for transplantation in PD.

Made available in DSpace on 2015-07-22T20:49:50Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-01-28 / Objetivo: verificar a relação entre queixa, aspectos funcionais da deglutição e impacto na qualidade de vida referente à voz e à deglutição, em pacientes portadores da doença de Parkinson, submetidos à administração de riboflavina, no período de um ano. Métodos: participaram do estudo 16 pacientes portadores da Doença de Parkinson, com média de idade de 67,25 anos, média do nível de severidade da doença de II para III e média de tempo de diagnóstico da doença de Parkinson de 3,5 anos. As avaliações videofluoroscópicas da deglutição foram realizadas antes e após um ano da administração de riboflavina e restrição de carne vermelha e de aves. Foram realizadas a análise qualitativa da deglutição, a verificação da presença de queixa com relação à deglutição e aplicação de dois protocolos de qualidade de vida sendo relacionados um com o impacto da alteração vocal, e outro com o impacto da alteração na deglutição. A análise quantitativa compreendeu a realização de medidas de deslocamento do osso hióide, de abertura do esfíncter esofágico superior e de constrição da faringe. Resultados: foram observadas redução da queixa e discreta piora na qualidade de vida relacionada à voz e à deglutição, maior freqüência de ocorrência de deglutição normal, no momento pós-riboflavina. Não foram observadas diferenças significativas entre as medidas quantitativas. Conclusões: Conclui-se neste estudo que: houve melhora, apesar de não significativa, da queixa relacionada à deglutição; não ocorreram pioras significativas na dinâmica da deglutição, com exceção do deslocamento da cartilagem cricóidea na consistência de líquido fino após um ano de estudo; não houve piora com relação ao impacto na qualidade de vida, tanto relacionado à deglutição, quanto ao aspecto vocal; os pacientes que não apresentavam queixas de deglutição no momento pré apresentaram melhora na dinâmica da deglutição, com exceção da constrição da faringe; os pacientes com queixa de deglutição no momento pré apresentaram melhora nos índices de qualidade de vida e na auto-avaliação vocal segundo o QVV, no momento pós. / Objective: to verify the relation between clinical complaint, swallowing functional aspects and the impact on quality of life related to voice and swallowing in patients with Parkinson´s disease submitted to treatment with riboflavin during one year period. Method: sixteen patients with Parkinson´s disease participated in the study; mean age was 67.25 years old, mean degree of disease severity was II to III and mean time of disease diagnosis was 3.5 years. Videofluoroscopic evaluations were performed before and after one year of treatment with riboflavin and restriction diet of read meat and chicken. It were analyzed: qualitative analysis of swallowing, presence of complaints related to swallowing, application of questionnaires related to the impact of voice and swallowing alterations and quantitative analyses of swallowing, which included computerized measurements of hyoid bone and cricoid cartilage displacement, opening of the superior esophageal sphincter and pharyngeal constriction. Results: it were observed: decrease of complaints and slight worsening in quality of life impact regarding voice and swallowing and more frequent normal swallowing post riboflavin; there were no significant changes regarding quantitative measurements. Conclusions: there was a non significant improvement regarding swallowing complaints; it were not observed significant impairments of the swallowing dynamics, except for cricoid cartilage displacement during thin liquid ingestion at the end of the treatment; there was no impairment of quality of life regarding swallowing or voice; patients without swallowing complaints at the beginning of the treatment showed improvement in swallowing dynamics, except for pharyngeal constriction; patients with swallowing complaints at the beginning of the treatment showed improvement regarding quality of life and vocal selfevaluation after treatment. / TEDE / BV UNIFESP: Teses e dissertações

Várias doenças neurológicas que acometem idosos cursam com quadro de disfagia orofaríngea, dentre elas, a doença de Parkinson. Na presença de disfagia orofaríngea neurogênica e mecânica, o biofeedback eletromiográfico (EMG) foi descrito como importante modalidade coadjuvante de tratamento, não tendo sido descrita na literatura a aplicação desse método na reabilitação desta população. O objetivo deste trabalho foi verificar a repercussão ao longo do tempo do uso do biofeedback EMG como método coadjuvante na reabilitação da disfagia orofaríngea em idosos com doença de Parkinson. Seis idosos com doença de Parkinson e com diagnóstico de disfagia orofaríngea submeteram-se à avaliação do nível de ingestão oral com a aplicação da escala funcional de ingestão oral (Functional Oral Intake Scale - FOIS), à avaliação da qualidade de vida por meio da aplicação do protocolo SWAL-QOL, bem como à avaliação videfluoroscópica da deglutição de alimentos nas consistências sólida, pudim e líquida. Para classificação do grau da disfunção da deglutição foi utilizada a escala DOSS, enquanto a escala de Eisenhuber foi aplicada para a análise da estase de alimento em orofaringe. Todos os procedimentos foram realizados antes, após três e seis meses da reabilitação fonoaudiológica. Dos seis indivíduos, três foram reabilitados com terapia convencional e três receberam terapia convencional associada ao biofeedback EMG, num total de 15 sessões (três sessões por semana), seguidas de mais três sessões uma vez por semana para acompanhamento. Para análise estatística foi aplicado o teste de análise de variância de medidas repetidas. Os resultados obtidos mostraram não haver diferença estatisticamente significante para o grau da disfagia entre os grupos reabilitados pelas diferentes modalidades, porém ambos os grupos apresentaram diferença significante (p=0,01) entre os resultados anteriores à reabilitação e após três meses. Não foi encontrada diferença entre os grupos e os períodos avaliados para o nível de resíduo alimentar em orofaringe e o nível de ingestão oral. Para a avaliação da qualidade de vida, foi encontrada diferença estatisticamente significante entre os grupos reabilitados pelas distintas modalidades terapêuticas (p=0,04) e entre os períodos anterior à reabilitação e após três meses (p=0,01). Diante destes achados, conclui-se que ambas as modalidades terapêuticas empregadas resultaram em diminuição do grau da disfagia orofaríngea e melhora da qualidade de vida após três meses da reabilitação, tendo os resultados de qualidade de vida sido superiores para a terapia convencional associada ao biofeedback EMG em todos os períodos. Não foi observado impacto no nível de ingestão oral e na presença de resíduo alimentar em orofaringe. / Several neurological diseases that affect elderly are related with oropharyngeal dysphagia. Parkinsons disease is one of them. The electromyographic (EMG) biofeedback was described as an important adjunctive method in the treatment of neurogenic and mechanical oropharyngeal dysphagia, but there are few studies about the effectiveness of speech therapy treatment in the rehabilitation of this individuals. The objective of this study was verify the influence over the time of EMG biofeedback as an adjunctive method in the treatment of oropharyngeal dysphagia in elderly with Parkinsons disease. Six elderly with Parkinsons disease and oropharyngeal dysphagia were evaluated for the level of oral intake using the Functional Oral Intake Scale (FOIS), for the quality of life using the SWAL-QOL questionnaire and for videofluoroscopy of swallowing of solid, pudding and liquid consistencies. The severity of dysphagia was obtained using the Dysphagia Outcome and Severity Scale DOSS and the level of food residue in oropharynx was obtained using Eisenhuber scale. All procedures were realized before, after three months and after six months of speech therapy treatment for oropharyngeal dysphagia. From the six individuals, three were treated with conventional therapy for oropharyngeal dysphagia and three were treated with conventional therapy using adjunctive EMG biofeedback, in a total of 15 sessions (three times a week), followed by three sessions (once a week) for maintenance. The statistical analysis used was repeated measures analysis of variance test. The results didnt have significant difference for severity of dysphagia between groups treated with different speech therapy, but had significant difference between the times before and after three months of rehabilitation (p=0.01). For the levels of food residue and oral intake were not seen statistical difference between the groups and the different times. The quality of life assessment showed significant difference between the groups treated with different speech therapy (p=0.04) and the times before and after three months of therapy (p=0.01). We concluded that both modalities of therapy resulted in decrease of severity of dysphagia and improve in quality of life after three months of rehabilitation, with the results for quality of life being superior for conventional therapy using adjunctive EMG biofeedback at all times. Impact in the level of oral intake and food residue in oropharynx were not observed.

Introdução: A doença de Parkinson é uma enfermidade neurodegenerativa decorrente da perda de neurônios dopaminérgicos na substância negra, principalmente, e em outras regiões cerebrais. Caracteriza-se clinicamente por tremor, rigidez, bradicinesia e instabilidade postural. O tratamento é sintomático e consiste essencialmente na reposição da dopamina deficiente. A etiologia da doença de Parkinson ainda não é conhecida, mas os recentes avanços da Neurologia trouxeram novos conhecimentos acerca dos mecanismos fisiopatológicos envolvidos. Disfunção mitocondrial, estresse oxidativo e degradação de proteínas são alguns dos processos celulares que foram relacionados à degeneração dos neurônios dopaminérgicos. O campo da genética da doença de Parkinson tem recebido atenção especial na última década, graças à descoberta de vários genes associados ao desenvolvimento da doença. Um fator de risco genético recentemente descrito é a presença de mutações no gene da glicocerebrosidase, uma enzima lisossomal cuja deficiência resulta na doença de Gaucher. Apesar de a maioria dos estudos já publicados terem confirmado esta associação, um trabalho mais recente da Noruega não encontrou significância estatística ao analisar a presença destas mutações em pacientes com doença de Parkinson, tornando o assunto ainda controverso. Objetivo: Pesquisar a presença de mutações da glicocerebrosidase em pacientes com diagnóstico de doença de Parkinson no Brasil, acompanhados no ambulatório de Distúrbios do Movimento do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo e correlacionar tais achados com estudos recém-publicados que analisaram esta associação em outras populações em âmbito mundial, além de descrever possíveis características dos pacientes portadores de mutações que os diferenciem de não portadores. Métodos: Foram incluídos no estudo 65 pacientes com o diagnóstico de doença de Parkinson e idade de início da doença inferior ou igual a 55 anos e 267 controles sem a doença, emparelhados para sexo e idade. Foi realizada análise genética de material obtido a partir de raspagem da mucosa oral destes indivíduos, tendo sido pesquisadas as três mutações da glicocerebrosidase mais comuns na população brasileira: N370S, L444P e G377S. Resultados: Em dois dos 65 pacientes e em nenhum dos 267 controles foram identificadas mutações no gene da glicocerebrosidase. Os dois pacientes carreadores de mutações (L444P em um e L444P + E326K em outro) apresentavam quadro clínico indistinguível dos demais pacientes com doença de Parkinson não portadores das mutações. Conclusões: Foi observada uma associação estatisticamente significativa (P=0,0379, teste exato de Fisher) entre doença de Parkinson e mutações da glicocerebrosidase na nossa população. A prevalência de mutações da glicocerebrosidase neste grupo de pacientes foi maior do que a esperada para a população geral, porém menor do que a encontrada em estudos internacionais previamente publicados. Espera-se que a identificação desta nova associação permita uma maior compreensão dos mecanismos subjacentes à doença de Parkinson e que em um futuro próximo possa propiciar o desenvolvimento de novas estratégias terapêuticas. / Introduction: Parkinson\'s disease is a neurodegenerative disorder due to the loss of dopaminergic neurons in the substantia nigra, primarily, and in other brain regions. It is clinically characterized by tremor, rigidity, bradykinesia and postural instability. Treatment is symptomatic and consists essentially in replacing the deficient dopamine. The etiology of Parkinson\'s disease remains unknown, but recent advances in Neurology have provided data concerning the pathophysiological mechanisms involved. Mithocondrial dysfunction, oxidative stress and protein degradation are some of the cellular processes that have been linked to dopaminergic neurons degeneration. The field of genetics in Parkinson\'s disease has gained special attention in the past decade, thanks to the discovery of several genes associated with the development of the disease. A recently described genetic risk factor for Parkinson\'s disease is the presence of glucocerebrosidase gene mutations. Glucocerebrosidase is a lysosomal enzyme which is deficient in Gaucher disease. Although most studies published to date have confirmed such association, a recent article from Norway could not find statistical significance when Parkinson\'s disease patients were analyzed for glucocerebrosidase mutations, generating controversy. Objective: To search for glucocerebrosidase mutations in Parkinson\'s disease patients in Brazil, followed at the Movement Disorders Division at Hospital das Clínicas, University of São Paulo Medical School, and correlate these findings with recently published studies which evaluated this association in other populations worldwide, besides describing possible features of patients carrying the mutations that may help differentiating them from non-carriers. Methods: Sixty five patients diagnosed with Parkinson’s disease, with disease onset before age 55, and 267 age and sex-matched controls were included in the study. DNA analysis of the three most common glucocerebrosidase mutations in the Brazilian population, N370S, L444P and G377S, was performed utilizing samples obtained from mouth mucus. Results: Glucocerebrosidase gene mutations were identified in two of the 65 Parkinson\'s disease patients and in none of the 267 controls. The two patients who were carriers of mutations (one of them had L444P and the other L444P+E326K) had a clinical picture indistinguishable from the other Parkinson\'s disease non-carriers patients. Conclusion: A statistically significant association (P=0,0379, Fisher\'s exact test) between Parkinson\'s disease and glucocerebrosidase mutations was observed in our population. The prevalence of glucocerebrosidase mutations was higher than expected for the general population, though lower than reported in previous international studies. It is expected that the finding of this association will allow a better understanding of Parkinson\'s disease mechanisms and that in a near future it may help providing the development of new therapeutic strategies.

Orientador: Elizabeth Maria Aparecida Barasnevicius Quagliato / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-22T20:16:26Z (GMT). No. of bitstreams: 1 Sousa_RaimundoNonatoCampos_D.pdf: 2351873 bytes, checksum: aa05f2a60629deedfa05db1c8ace9d8b (MD5) Previous issue date: 2013 / Resumo: Objetivos: Avaliar em mulheres com doença de Parkinson e disfunções urinárias as correlações dos sintomas urinários com os sintomas motores e disfunções mentais. Verificar a prevalência de hiper-reflexia detrusora (HD), bem como analisar em longo prazo a gravidade do desempenho motor, estadiamento de Hoenh-Yahr, habilidades funcionais, funções neuropsicológicas e a magnitude da progressão desses aspectos clínicos e do declínio cognitivo em pacientes com HD. Sujeitos e Métodos: Estudamos uma coorte ambulatorial de sessenta e três (63) pacientes com DP cujos aspectos neurológicos foram avaliados com a utilização das escalas Unified Parkinson's Disease Rating Scale (UPDRS) e a escala de Hoehn-Yahr. As habilidades funcionais foram avaliadas pela escala Schwab & England e a função urológica foi quantificada pela International Prostatic Symptom Scale (IPSS) e qualificada pelo estudo urodinâmico. Foram então categorizados dois grupos: pacientes com e sem HD. Após sete anos os mesmos parâmetros foram reavaliados e a escala Montreal Cognitive Assessment (MoCA)-versão brasileira foi utilizada para o rastreamento neuropsicológico. Resultados: Na avaliação inicial foi constatada correlação positiva entre os sintomas urinários e a gravidade da doença, porém não havia correlação entre a sintomatologia urinária e os sintomas mentais. Sintomas motores, estágio de gravidade da doença e habilidades funcionais eram mais graves em pacientes com HD. Na reavaliação, os grupos não apresentavam diferença quanto à magnitude da progressão dos sintomas motores, do estadiamento da doença e das inabilidades funcionais. Foi observado no grupo com HD maior declínio cognitivo e uma nítida progressão dos escores mentais com risco aumentado para demência. Conclusão: Hiper-reflexia detrusora é um achado urodinâmico frequente em mulheres com DP e embora esteja associada à pior desempenho motor, estágios de maior gravidade da doença e inabilidades funcionais, não é um fator de maior progressão desses aspectos clínicos. Por outro lado as pacientes com HD tiveram, em longa duração, significante progressão da sintomatologia neuropsicológica.O perfil do declínio cognitivo e o risco para demência necessitam ser confirmados em estudos posteriores / Abstract: Objectives: This long-term study in women with Parkinson's disease (PD) and lower urinary tract dysfunctions aimed to verify the correlation of urinary symptoms with the severity of the disease and mental functions. Verify the prevalence of detrusor hiper-reflexia (DH) and analyze the severity of motor symptoms, Hoehn and Yahr stage, functional abilities and neuropsychological functions, as well as analyze the progression of these clinical aspects and cognitive decline in patients with DH. Subjects and Methods: We studied a cohort of sixty-three (63) PD patients whose neurological aspects were evaluated with the Unified Parkinson's Disease Rating Scale (UPDRS) and Hoehn-Yahr scale. Functional abilities were evaluated by Schwab and England scale and the urological function was quantified by International Prostatic Symptom Scale (IPSS) and qualified by urodynamic study. Two groups were then categorized: patients with and without HD. After seven years the same parameters were re-evaluated and the cognitive functions were assessed with the Montreal Cognitive Assessment (MoCA). Results: At baseline a correlation between urinary symptoms and motor dysfunction was verified but no correlation between urinary symptoms and mental symptoms was observed. The severity of motor symptoms, stage of the disease and functional disabilities were significant in patients with DH. In the follow up, the groups were similar in regards to progression of motor symptoms, Hoehn and Yahr stage and functional disabilities. On the other hand, decline in cognitive function and clear progression of mental scores and risk for dementia was observed in the group with DH. Conclusion: Urinary symptoms are correlated with the severity of the Parkinson's disease. Detrusor hyper-reflexia is a frequent urodynamic finding in women with DP and although it is associated with worse motor performance, stage of the disease and functional disabilities, it is not a factor of greater progression of these clinical aspects of the disease. On the other hand, patients with DH had a significant progression of the neuropsychological symptoms and risk of dementia. The profile of cognitive decline and dementia risk need to be confirmed in subsequent prospective studies / Doutorado / Neurologia / Doutor em Ciências Médicas

Abstract Patients with idiopathic Parkinson's disease (PD) may suffer from autonomic nervous system dysfunction even in the early phase of the disease. We assessed the autonomic cardiovascular and sudomotor regulation in de novo PD patients with and without medication. We also measured the dopamine (DAT) and serotonin transporter (SERT) uptake in the PD patients using 2β-carboxymethoxy-3β-(4-iodophenyl)tropane (β-CIT) SPECT and studied the clinical correlates of the uptake. Sixty PD patients were included in the study and randomised to receive levodopa, bromocriptine or selegiline (n=20 in each) as their treatment. Thirty patients were examined with β-CIT SPECT. The results of the patients were compared with those of healthy controls and within the subgroups at different time points. Cardiovascular autonomic regulation was assessed using standard cardiovascular reflex tests at baseline, after six months' medication and following a 6-week washout period. The heart rate (HR) and blood pressure (BP) regulation was impaired in PD patients at baseline, and PD medications modified the responses further. Bromocriptine and selegiline, in contrast to levodopa, increased the orthostatic BP fall and suppressed the BP response to isometric exercise. The long-term cardiovascular autonomic function was evaluated from ambulatory ECG recordings by analysis of traditional spectral and non-spectral components of HR fluctuation together with two-dimensional vector analysis and power-law relationship analysis of the HR dynamics. All spectral measures and the slope of the power-law relationship demonstrated impaired tonic cardiovascular regulation in the PD patients. Sympathetic sudomotor activity was evaluated using the sympathetic skin response (SSR). The major finding was suppression of the SSR amplitudes with an inverse correlation to clinical disability, whereas PD medication seemed to have only minor effects. The changes in amplitude and repetitiveness of the SSRs with normal adaptation suggest deficits at several levels of the SSR reflex arc. DAT uptake, assessed by β-CIT SPECT, was diminished in the striatum and especially the putamen of the PD patients, and correlated with the results of the cardiovascular reflex tests and ambulatory ECG recordings. Simultaneous measurement of SERT binding demonstrated decreased SERT availability in the thalamic and frontal areas. The results demonstrate disturbances of the reflectory and tonic cardiovascular autonomic regulation caused by PD itself. PD medications further modify the reflectory responses. The degenerative process in PD also involves the sympathetic sudomotor pathway. β-CIT SPECT provides a useful method for simultaneous assessment of DAT and SERT binding, demonstrating the deficit of serotonin metabolism in PD.