A Doença de Parkinson é a segunda doença neurodegenerativa mais comum na atualidade. Cerca de 10% dos casos da doença estão relacionados com fatores genéticos e os outros 90% são devido a fatores ambientais e epigenéticos. Evidências indicam alterações na metilação de genes relacionados ao desenvolvimento da doença de Parkinson. No entanto, não se sabe o efeito de inibidores da metilação de DNA sobre a neurotoxicidade induzida por MPP+, uma neurotoxina que mimetiza processos neurodegenerativos associados ao Parkinson in vitro. Portanto, este trabalho teve como objetivo avaliar o efeito dos inibidores da metilação de DNA (RG108, n-ftaloil-l-triptofano e 5azadC, 5-aza-2´-deoxycytidina) e do doador universal de grupamentos metil (SAM, S-adenosilmetionina) sobre neurotoxicidade induzida por MPP+ em cultura de células imortalizadas (PC12), por meio da análise da viabilidade celular avaliada no teste do MTT (3 - [4,5 dimetiltiazol-2-il] -2,5-difenil-tetrazólio); e da análise de neuritogênese, na presença e na ausência de MPP+. Os resultados demonstraram que: 1. o tratamento com DNMTi (inibidor da DNA metiltransferase) ou com SAM induziram efeito per se sobre a viabilidade celular, apenas quando incubados em altas concentrações e em perídos prolongados (24h); 2. não modificaram a morte celular induzida pelo MPP+, em baixas concentrações, mas agravaram a neurotoxicidade quando incubados em altas concentrações ou por períodos prolongados (24h); 3. essas drogas induziram neuritogênese per se e potencializaram a neuritogênese induzida pelo NGF (fator de crescimento neural); 4. protegeram parcialmente contra a diminuição da neuritogênse induzida pelo MPP+. O conjunto de dados sugere que tanto os DNMTi quanto o SAM podem ser citotóxicos, dependen de suas concentrações e do tempo de exposição à droga. No entanto, essas drogas são capazes de aumentar a neuritogênese (diferenciação celular) e proteger contra a neurotoxicidade celular induzida pelo NGF, em células diferenciadas. / Parkinson\'s disease is the second most common neurodegenerative disease nowadays. About 10% of the disease cases are related to genetic factors and the other 90% are due to environmental and epigenetic factors. Evidence indicates changes in DNA methylation in genes related to the development of Parkinson\'s disease. However, the effect of DNA methylation inhibitors on MPP+-induced neurotoxicity, a drug that mimics neurodegenerative processes associated with Parkinson\'s in vitro, is not known. The aim of this study was to evaluate the effect of DNA methylation inhibitors (RG108, N-phthalyl-L-tryptophan and 5azadC, 5-aza-2?-deoxycytidine) and of the universal donor of methyl group (SAM, S-adenosyl methionine) on: 1. MPP+ -induced neurotoxicity in culture of immortalized cells (PC12), by analysis of cell viability in the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium) test; 2. neuritogenesis, in the presence and absence of MPP +. Results indicated that: 1. treatment with DNMTi or SAM induced effects per se on cell viability only at higher concentrations and after prolonged periods of incubation (24h); 2. DNMTi (DNA methyltransferase inhibitors) and SAM increased cell differentiation and neuritogenesis per se, especially when incubated for 30 minutes, as well as they potentiated NGF-induced neurogenesis; 3. the drugs attenuated MPP+-induced effects on neuritogenesis. Altogether, these data suggests short treatment with both DNMTi and SAM do not cause cellular cytotoxicity (cell death), but are able to increase neuritogenesis (cell differentiation) and protect against MPP+-induced neurotoxicity in differentiated cells.

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.

Parkinson‟s disease (PD) is the most common neurodegenerative movement disorder. It is characterized by the progressive degeneration of dopaminergic neurons in substantia nigra pars compacta (SNpc). Although the etiology of PD remains incompletely understood, emerging evidence suggests that iron homeostasis dysregulation may be involved. A pathological hallmark of PD is the formation of Lewy bodies, intra-cytoplasmic inclusions that are major composed of α-synuclein (α-syn). α-synuclein is encoded by the SNCA gene. It is generally believed that α-synuclein aggregation is a main pathogenic feature and the cause of PD. Previous in vitro studies have provided direct evidence showing that iron could interact with α-synuclein and facilitate its aggregation. Nevertheless, the exact role of iron in the pathogenesis of PD is still inconclusive, and so far no studies have proved the interaction between iron and α-synuclein in vivo. / Here, based on a Drosophila model, we tested the hypothesis that the interaction between iron and α-synuclein accumulation accelerates the pathogenesis of PD, and that restoring brain iron homeostasis provides neuroprotective effects against PD. In our present studies, two groups of Drosophila, including w¹¹¹⁸ control and mutant α-synuclein A53T Drosophila were cultured under normal- (normal medium) and high-iron diet (medium added with 30mM ferric ammonium citrate (FAC)) for up to 30 days. During chronic iron treatment, startle-induced negative geotaxis assay was conducted every ten days to test the locomotor ability in the flies. After that, whole-mount immunostaining was used to assess dopaminergic neuronal survival. These flies were also collected and subjected to the quantification of brain iron content for the characterization of the brain iron content status. Furthermore, quantitative real-time PCR and western-blot analysis were conducted to investigate the amount of various α-synuclein conformations. / In the first part, we observed that α-synuclein A53T fly exhibited age-related increase of brain iron content compared with age-matched control. These were accompanied by shorter life-span, locomotor dysfunction, and TH-positive neuronal loss in PPM1/2 and PPM3 cluster. Meanwhile, we have demonstrated that neuronal toxicity and motor deficits were associated with increased proteinase K resistant, insoluble α-synuclein rather than the total amount of protein level. The insoluble α-synuclein was regarded as α-synuclein aggregation. / In the second part, we found that in α-synuclein A53T fly, excessive iron uptake aggravated locomotion defects and led to specific TH positive neuronal loss in cluster PPM3 after 30 days of iron treatment. Moreover, the excessive iron-induced neurological toxicity and motor dysfunction were also associated with increased α-synuclein aggregation. Overall, these two sets of results suggest that abnormal up-regulation of brain iron content may be associated with α-synuclein, and contribute to the pathogenesis of PD through α-synuclein aggregation-dependent mechanisms. / In the third part, we further explored the potential neuroprotective effect of restoring brain iron homeostasis in PD. We made use of genetic modification to manipulate iron-transport protein DMT1 expression, in turn to identify the protective effect of decreasing brain iron content in α-synuclein Drosophila model. Our present results proved that inactivation of Malvolio in α-synuclein A53T fly can suppress the increase of brain iron contents, and can also prolong life span, partially ameliorate locomotion deficits, and attenuate TH positive neuronal loss in α-synuclein A53T fly. In addition, these beneficial effects might occur through the inhibition of α-synuclein aggregation in α-synuclein A53T fly. Consequently, this result implicates that reducing brain iron by inactivation of iron up-take protein DMT1 can inhibit α-synuclein aggregation and provide beneficial effect on DA neuronal survival in PD model. / In conclusion, we demonstrated that : (1) abnormal up-regulation of brain iron content may be associated with α-synuclein and contributes to the pathogenesis of PD through α-synuclein aggregation-dependent mechanisms; (2) iron uptake protein DMT1 may serve as a potential therapeutic target for alleviating aberrant iron accumulation and retards the progression of neurodegeneration in PD. / 帕金森氏病（PD）是最常見的神經退行性疾病之一，其病理學特徵是黑質緻密部（SNpc）的多巴胺能神經元退行性變性。和，其中α-突觸核蛋白（α-synuclein）是Lewy小體的主要成分。雖然帕金森氏病的發病機制仍不十分清楚，隨著研究的進展，越來越多的證據表明鐵穩態失調可能是其中一個重要的致病因素。細胞內Lewy小體聚集物的形成是帕金森病的一個病理標誌物，其主要的成分是α-synuclein蛋白。α-synuclein是由SNCA基因編碼的蛋白。其聚集通常被認為是帕金森病的一個主要的病理特徵，同時也是導致帕金森病的一個原因。之前的研究證據表明，在體外實驗中，鐵能夠與α-synuclein相互作用並促進α-synuclein的聚集。然而，鐵和α-synuclein的相互關係在帕金森病的發病機制中的確切作用仍不十分確定。 / 我們的課題是基於果蠅模型來驗證腦鐵增加導致的α-synuclein聚集加速了帕金森病的病理進程，且恢復腦鐵平衡可以保護帕金森病人多巴胺能神經元的假說。在我們目前的研究中使用了兩組不同基因型的果蠅，其中包括w¹¹¹⁸對照組和突變體α-synA53T果蠅。兩組果蠅分別同時餵養正常食物（正常培養基）和高鐵食物（30mM檸檬酸鐵銨（FAC））。經過30天的慢性鐵處理，分別收集不同組的果蠅並測定其腦鐵含量用於對不同組果蠅的腦鐵含量進行定量分析。在進行鐵處理的30天期間，每隔10天進行一次趨地性行為學實驗用於評價不同組果蠅的運動能力。行為學實驗過後，可使用整腦免疫染色法來觀察果蠅多巴胺能神經元的存活情況。此外，還运用实时定量PCR和蛋白免疫印跡分析法來檢測不同組果蠅體內α-synuclein mRNA和蛋白的表達情況。 / 在第一部分的實驗中我们發現，與年齡相當的對照組相比，α-synA53T果蠅表現為明顯增高的腦鐵含量，並伴隨著壽命短，運動功能障礙以及PPM1/2和PPM3多巴胺能神經元簇的TH-陽性神經元丟失。同時我們發現，α-synA53T果蠅的神經元的毒性和運動障礙與α-synuclein的蛋白總量無關，而可能與在蛋白酶K中穩定的不溶性α-synuclein蛋白的增加相關，這部分α-synuclein的增加被認為與α-synuclein聚集有關。 / 此外在第二部分實驗中我們還發現，α-synA53T果蠅經過30天鐵處理後會加劇其運動功能障礙，並導致更嚴重的PPM3多巴胺能神經元簇的TH-陽性神經元丟失。並且這種由腦鐵含量增加而導致的神經毒性和運動功能障礙也與α-synuclein聚集增加有關。這兩部分的實驗結果表明，腦鐵含量異常增加調節α-synuclein聚集可能與帕金森病的發病機制有關。 / 在第三部分實驗中，我們進一步探討維持腦鐵穩態在PD中潛在的神經元保護作用。我們利用遺傳學手段調節鐵轉運蛋白DMT1的表達來研究腦鐵含量減少對α-synuclein果蠅的保護作用。目前的結果表明，降低α-synA53T果蠅中DMT1同源基因-Malvolio的表達可以抑制隨著年齡增加而顯著增加的腦鐵含量，並且可以延長果蠅的壽命，部分改善α-synA53T果蠅的運動功能障礙，以及完全減輕了TH陽性神經元的丟失。這些保護作用可能是由於抑制了α-synA53T果蠅中α-synuclein的聚集。因此，這些結果顯示，通過降低DMT1的表達來減少腦鐵含量DMT1可以抑制α-synuclein蛋白聚集並對神經元有保護作用。 / 綜上所述，我們的實驗結果證明了：（1）腦鐵含量異常增加調節α-synuclein聚集可能與帕金森病的發病機制有關; （2）鐵攝取蛋白DMT1可作為一個潛在的選擇性鐵螯合劑治療靶標來減緩帕金森病神經退行性進程。 / Zhu, Zhoujing. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2014. / Includes bibliographical references (leaves 155-181). / Abstracts also in Chinese. / Title from PDF title page (viewed on 03, October, 2016). / Zhu, Zhoujing. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only.

by Leung, Chi Ting Gideon. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1995. / Includes bibliographical references (leaves 72-86). / Acknowledgement / List of Abbreviations / Abstract --- p.i / Chapter Chapter 1 --- Introduction / Chapter 1.1 --- Parkinson's disease --- p.1 / Chapter 1.1.1 --- Epidemiology --- p.1 / Chapter 1.1.2 --- Symptoms --- p.1 / Chapter 1.1.3 --- Pathology --- p.3 / Chapter 1.1.4 --- Etiology --- p.4 / Chapter 1.2 1 --- "-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP)" --- p.5 / Chapter 1.2.1 --- History --- p.5 / Chapter 1.2.2 --- MPTP induced Parkinson's disease --- p.6 / Chapter 1.2.2.1 --- The metabolism of MPTP --- p.6 / Chapter 1.2.2.2 --- MPTP neurotoxicity --- p.9 / Chapter 1.2.2.3 --- MPTP analogs --- p.11 / Chapter 1.3 --- Factors involved in the degenerative process of Parkinson's disease --- p.12 / Chapter 1.3.1 --- Mitochondrial defect --- p.13 / Chapter 1.3.2 --- Oxidative stress --- p.14 / Chapter 1.3.2.1 --- Free Radicals --- p.14 / Chapter 1.3.2.2 --- Superoxide radicals --- p.14 / Chapter 1.3.2.3 --- Hydrogen peroxide --- p.16 / Chapter 1.3.2.4 --- Hydroxyl radicals --- p.17 / Chapter 1.3.3 --- Lipid peroxidation --- p.18 / Chapter 1.4 --- Antioxidants --- p.22 / Chapter 1.4.1 --- Introduction --- p.22 / Chapter 1.4.2 --- Glutathione and related enzymes --- p.25 / Chapter 1.4.2.1 --- Glutathione --- p.25 / Chapter 1.4.2.2 --- Glutathione peroxidase --- p.29 / Chapter 1.4.2.3 --- Glutathione reductase --- p.30 / Chapter 1.5 --- Astrocytes --- p.31 / Chapter 1.5.1 --- Introduction --- p.31 / Chapter 1.5.2 --- Role of astrocytes in PD --- p.34 / Chapter 1.6 --- Aim of the project --- p.35 / Chapter Chapter 2 --- Materials And Methods / Chapter 2.1 --- Astrocyte cultures --- p.38 / Chapter 2.2 --- MPTP treatment --- p.40 / Chapter 2.3 --- Lactate dehydrogenase (LDH) assay --- p.41 / Chapter 2.4 --- DTNB-GSSG reductase recycling assay for total GSH --- p.43 / Chapter 2.5 --- DTNB-GSSG reductase recycling assay for GSSG --- p.44 / Chapter 2.6 --- Glutathione peroxidase --- p.45 / Chapter 2.7 --- Glutathione reductase --- p.48 / Chapter 2.8 --- Statistics --- p.49 / Chapter Chapter 3 --- Results / Chapter 3.1 --- Change in lactate dehydrogenase (LDH) activities after MPTP treatment --- p.50 / Chapter 3.2 --- Change in total glutathione (GSH+GSSG) levels in astrocytes after different concentrations of MPTP treatment --- p.51 / Chapter 3.3 --- Change in glutathione and related enzyme activities in astrocytes after MPTP treatment --- p.51 / Chapter 3.3.1 --- Change in total glutathione (GSH+GSSG) levels --- p.51 / Chapter 3.3.2 --- Change in oxidized glutathione (GSSG) level in astrocytes after MPTP treatment --- p.54 / Chapter 3.3.3 --- Change in oxidized glutathione and total glutathione ratioin astrocytes after MPTP treatment --- p.56 / Chapter 3.3.4 --- Change in glutathione peroxidase activity after MPTP treatment --- p.57 / Chapter 3.3.5 --- Change in glutathione reductase activity after MPTP treatment --- p.59 / Chapter Chapter 4 --- Discussion And Conclusion --- p.61 / Chapter Chapter 5 --- References --- p.72

Made available in DSpace on 2016-04-27T18:47:18Z (GMT). No. of bitstreams: 1 PedroLodoviciNeto.pdf: 1572071 bytes, checksum: 5c82629bef47821aa9dca3b164807b06 (MD5) Previous issue date: 2006-05-19 / This study is a result of a research in the qualitative approach, in the Gerontology and Musictherapy scenario. It was analyzed the importance of alternative practices like playing an instrument, singing, or practicing a guided musical exercise as a therapy activity for old people with Parkinson Disease. The data collection was based on questionnaires, with recorded and transcript information, obtained from ten individuals: two musictherapeuts (a pianist and a maestro of the therapeutic Chorus), two phonoaudiologists and two physiotherapists, which guide vocal and physical therapy of the patients, and four old people with Parkinson Disease, members of the Association Brazil Parkinson-ABP, located in Sao Paulo, one of them a public person, from which information was collected from a published interview and a published book. The analysis, the systematization and the interpretation of the data were based on the phenomenological paradigm, which pointed: music is an excellent way to improve the life of the patient that becomes more sociable, decreasing physical and psychological symptoms (symptomatology). The singing or playing (piano, violin) act, as therapeutic activity, is a way for the self-expression and self-realization, and the lyrics reveal the intimate subjectivity/existentiality of each patient. The self-reliance of the patient brings positive expectations about the present moment and also about the future. The Musictherapy, as a coadjuvant treatment, can be extended and indicated in others areas of actuation. Finally, Musictherapy seems to contemplate about themes related to life/death, health/disease, besides the relation of the patient with its disease and the sociability with people around / Este trabalho resultou de uma pesquisa com abordagem qualitativa, na interface da Gerontologia e Musicoterapia, ao analisar como o exercício de tocar um instrumento, ou cantar, ou praticar um exercício musical orientado, funciona como uma atividade terapêutica para as pessoas portadoras da Doença de Parkinson. A coleta de dados teve como instrumentos entrevistas baseadas em questionários, com gravação e transcrição, realizadas com dez sujeitos: dois musicoterapeutas (pianista e regente do Coral terapêutico); dois fonoaudiólogos e dois fisioterapeutas que orientam a terapia vocal e corporal dos doentes; quatro idosos portadores da Doença de Parkinson, três membros da Associação Brasil Parkinson (ABP), localizada em São Paulo, e um membro, pessoa pública, cujos dados foram colhidos de entrevista e livro publicados na mídia. A análise, a sistematização e a interpretação dos dados basearam-se no paradigma fenomenológico, e apontam: que a Música é um excelente meio para melhorar a vida do doente, fazendo-o conviver bem melhor com a doença e minimizando seus efeitos motores e não-motores (sintomatologia). O cantar ou o tocar instrumentos musicais (piano, violino...), enquanto atividades músico-terapêuticas, são um meio para a auto-expressão e a auto-realização, com as canções revelando a subjetividade/existencialidade interna de cada idoso. A autoconfiança do idoso participante de tais atividades faz com que ele ganhe expectativas positivas quanto a seu presente e esperança em relação ao futuro. A Musicoterapia enquanto tratamento coadjuvante pode ser estendida e indicada a outras áreas de atuação musicoterapêutica. E, finalmente, considerou-se que a Musicoterapia reflete sobre temas relacionados à vida/morte, à saúde/doença, além de repensar a relação do idoso com sua doença e com as demais pessoas do seu ambiente

Submitted by Filipe dos Santos (fsantos@pucsp.br) on 2016-11-01T17:04:58Z No. of bitstreams: 1 Elthon Gomes Fernandes da Silva.pdf: 1286339 bytes, checksum: 372058115e8489b56fa3ec05b245a749 (MD5) / Made available in DSpace on 2016-11-01T17:04:58Z (GMT). No. of bitstreams: 1 Elthon Gomes Fernandes da Silva.pdf: 1286339 bytes, checksum: 372058115e8489b56fa3ec05b245a749 (MD5) Previous issue date: 2016-08-29 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Therapeutic approaches to speech therapy to patients with Parkinson's disease (PD) prioritize individual therapies, focusing on components such as: voice and breath coordination, increased intensity, vocal projection, improved phonation instability and less emphasis on the expressiveness of speech. However, the literature lacks descriptions of procedures performed in a group of people affected with this disease. However, the literature lacks descriptions of procedures performed in a group of people affected with this disease. Objective: To study the effects of a speech therapy, based on theater games, in the expressiveness of people with PD. Method: to meet this objective were developed three studies. In Study 1 was made theoretical research on vocal and speech found in people with PD and presented considerations on possibilities of using theater games as speech therapy approach for people with PD; in Study 2 was structured a working proposal using theater games as a facilitating mechanism for the rehabilitation of speech expressiveness in people with PD and in Study 3 were observed the effects of speech therapy with theater games in the oral expressiveness subjects with PD, according to the opinion of audiologists future. Conclusion: speech therapy with experience in theater games, developed with four subjects with PD, showed improvement in oral expression of a subject with respect to the category "understandable" when we analyzed the testimony directed the photography show. Considering the "understandable" descriptors, "melodious" and "attractive" for the issue of CAPE-V phrases, improvement was observed in another participant. The "understandable" descriptor received the highest score from the judges / As abordagens terapêuticas da Fonoaudiologia com pacientes com Doença de Parkinson (DP) priorizam terapêuticas individuais, com enfoque em componentes como: coordenação fonorrespiratória, aumento da intensidade, projeção vocal, melhora da instabilidade fonatória e com menor destaque na expressividade de fala. No entanto a literatura carece de descrições sobre procedimentos realizados em grupo de pessoas acometidas com essa doença. Objetivo: estudar as repercussões de uma intervenção fonoaudiológica, apoiada em jogos teatrais, na expressividade de pessoas com DP. Método: para responder a esse objetivo foram desenvolvidos três estudos. No Estudo 1 foi feito levantamento teórico sobre alterações vocais e de fala encontradas em pessoas com DP e apresentou considerações sobre possibilidades do uso de jogos teatrais como abordagem terapêutica fonoaudiológica para pessoas com DP; no Estudo 2 foi estruturada uma proposta de trabalho utilizando jogos teatrais como mecanismo facilitador para a reabilitação da expressividade de fala em pessoas com DP e no Estudo 3 foram observados os efeitos de intervenção fonoaudiológica com jogos teatrais na expressividade oral sujeitos com DP, de acordo com a opinião de futuros fonoaudiólogos. Conclusão: a intervenção fonoaudiológica com vivência em jogos teatrais, desenvolvida com quatro sujeitos com DP, evidenciou melhora na expressividade oral de um sujeito, com relação à categoria “compreensível”, quando foi analisado o depoimento direcionado pela apresentação de fotografia. Considerando os descritores “compreensível”, “melodiosa” e “atrativa” durante a emissão de frases do CAPE-V, foi observada melhora em outro participante. O descritor “compreensível” recebeu maior pontuação entre os juízes

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.

帕金森病（PD）是一種常見的神經退行性疾病，其特徵性的癥狀是運動功能減弱，常伴有認知障礙如工作記憶缺陷。大多數癥狀源於中腦多巴胺神經元的進行性缺失。目前的治療常隨時間進展誘發嚴重的副反應，促使我們進一步研究PD的病理生理學機制。一般認為基底神經節直接和間接通路不平衡的活動導致PD的運動缺陷，但目前關於基底神經節環路突觸特性改變的研究還很少。對PD認知障礙機制的研究則更為少見。 / 本研究中，我們首先關注在對基底神經節提供主要輸入的皮質紋狀體通路。應用全細胞膜片鉗技術結合皮質刺激，并利用在D2受體表達神經元表達綠色螢光蛋白的轉基因小鼠，我們發現PD狀態下，在間接通路表達D2受體的中型多棘神經元（D2 MSN）上記到的皮質紋狀體通路AMPA受體介導電流的成對脉沖比值（PPR）以及NMDA受體介導電流的PPR均降低。此外皮質至D2 MSN突觸間隙的谷氨酸水平也增加而不伴有谷氨酸轉運體的功能異常。這些結果證明PD狀態下皮質至間接通路D2 MSN的谷氨酸釋放選擇性增加。結合基底神經節的功能環路考慮，至間接通路紋狀體投射神經元的皮質谷氨酸釋放增加可能參與了PD的運動癥狀。 / 我們接下來研究了皮質-D2 MSN通路的下游環節即紋狀體至蒼白球通路傳遞的改變。在蒼白球（GP）神經元上應用全細胞膜片鉗記錄結合紋狀體刺激，我們發現在6-羥多巴損毀之後，紋狀體蒼白球通路的PPR降低，GP神經元記到的紋狀體刺激誘發的抑制性突觸后電流（eIPSC）的變異係數降低,以及GP神經元記到的微型IPSC的頻率增加，這些結果證明紋狀體至蒼白球的GABA釋放增加。突觸前III型代謝型谷氨酸受體介導的對紋狀體蒼白球傳遞的抑制作用消失導致了紋狀體蒼白球通路GABA釋放的增加。這一增加，通過影響間接通路的下游環節，也可能參與了PD的運動癥狀。 / 為探討認知障礙的機制，我們研究了參與工作記憶功能的邊緣前皮質至伏核（NAc）的投射。應用與第一部份相似的研究方法，我們發現多巴胺受體對邊緣前皮質NAc通路的傳遞存在高度精確和補償性的調節。在邊緣前皮質-NAc D1 MSN通路，D1和D2受體突觸前分別介導對該傳遞的抑制性和易化性調節。然而，在D2 MSN相關的邊緣前皮質-NAc通路，上述作用發生了反轉。在耗竭NAc多巴胺之後，D2 MSN上誘發到的興奮性突觸后電流增加，提示邊緣前皮質-NAc D2 MSN傳遞增加。此外，在多巴胺損毀的情況下，激活D1和D2受體不再調節邊緣前皮質NAc通路的傳遞。結合邊緣環路考慮，邊緣前皮質至D2 MSN的谷氨酸釋放增加可能參與了PD的認知障礙。 / 綜上所述，PD狀態下，繼多巴胺缺失之後，多條通路發生可塑性改變，這些改變可能參與PD的運動和認知癥狀。 / Parkinson’s disease (PD) is a common neurodegenerative disease with characteristic hypokinetic motor symptoms and cognitive impairments like working memory deficits. Most of the symptoms are derived from progressive loss of dopaminergic neurons in the midbrain. Current therapies often induce severe side effects with time, which promotes us to further investigate the pathophysiological mechanism of PD. It is generally thought that the imbalanced activity between direct and indirect pathways of the basal ganglia underlies the motor deficits in PD, but little is studied about the changes in synaptic properties of the sub-circuits. Even less is known about the mechanism responsible for the cognitive dysfunctions in PD. / In our study, we first focused on the corticostriatal pathway that provides a major input to the basal ganglia. Employing whole-cell patch-clamp recordings with cortical stimulation as well as by taking advantage of transgenic mice with green fluorescent protein co-expressed in the D2 receptor-expressing neurons, we found a selective increase in cortical glutamate release onto indirect-pathway D2 receptor-expressing medium-sized spiny neurons (D2 MSNs), as indicated by reduced corticostriatal AMPA paired-pulse ratios (PPRs) and NMDA PPRs in D2 MSNs as well as increased glutamate level in cortex-D2 MSN synaptic cleft without malfunction in glutamate transporters in parkinsonian states. Considering from the functional organization of the basal ganglia circuits, the increased corticostriatal glutamate release onto indirect-pathway striatal projection neurons may contribute to the motor symptoms of PD. / We next studied whether the striatopallidal transmission, downstream to the cortex-D2 MSNs pathway, is also altered in parkinsonian states. Combining whole-cell patch-clamp recordings in globus pallidus (GP) neurons with striatal stimulation, we demonstrated that the striatopallidal GABA release was increased following 6-hydroxydopamine lesion, as indicated by decreased striatopallidal PPRs, reduced coefficient of variation of striatally evoked inhibitory postsynaptic currents (eIPSCs) and elevated frequency of miniature IPSCs in GP neurons. The loss of tonic presynaptic group III metabotropic glutamate receptors-mediated inhibition on striatopallidal transmission accounted for the increased striatopallidal GABA release. The increase in the striatopallidal GABA release, through affecting the downstream of the indirect pathway, would also contribute to the motor symptoms in PD. / To investigate the underlying mechanism of cognitive deficits, we targeted the prelimbic cortex-nucleus accumbens (NAc) projection that is critical for working memory function. Using similar approaches as the first part, we observed highly precise and complementary modulations by dopamine receptors, with D1 and D2 receptors presynaptically mediating the inhibition and facilitation of the prelimbic cortex-NAc D1 MSN transmission, respectively, and reversed effects in D2 MSN-associated pathway. Following dopamine depletion in NAc, an enhanced prelimbic cortex-NAc D2 MSN transmission was indicated by selectively increased excitatory postsynaptic current evoked in D2 MSNs. Moreover, in the dopamine-depleted state, activating D1 and D2 receptors failed to modulate the prelimbic cortex-NAc transmission. Considering from the information flow in the limbic loop, the increased prelimbic cortical glutamate release onto D2 MSNs may contribute to the cognitive impairments in PD. / In conclusion, in the parkinsonian states, multiple pathways undergo plasticity changes subsequent to dopamine depletion, which may underlie the motor and cognitive symptoms in PD. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Cui, Qiaoling. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 160-191). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese. / Chapter Chapter 1 --- General introduction --- p.1 / Chapter 1.1 --- Parkinson’s disease --- p.1 / Chapter 1.1.1 --- Symptoms --- p.1 / Chapter 1.1.2 --- Etiology --- p.1 / Chapter 1.1.3 --- Pathology and pathophysiology --- p.2 / Chapter 1.1.4 --- Therapy --- p.5 / Chapter 1.1.4.1 --- L-DOPA and dopamine receptor agonists treatments --- p.5 / Chapter 1.1.4.2 --- Deep brain stimulation (DBS) and lesional surgery treatments --- p.6 / Chapter 1.1.4.3 --- Neural transplantation --- p.7 / Chapter 1.1.4.4 --- Treatment of nonmotor symptoms --- p.8 / Chapter 1.2 --- Basal ganglia --- p.8 / Chapter 1.2.1 --- Components of basal ganglia --- p.8 / Chapter 1.2.2 --- Pathways in basal ganglia --- p.8 / Chapter 1.2.2.1 --- Anatomical organization of the basal ganglia pathways --- p.8 / Chapter 1.2.2.2 --- Functional consequences of the basal ganglia pathways --- p.10 / Chapter 1.3 --- Striatum --- p.11 / Chapter 1.3.1 --- Anatomy of the striatum --- p.11 / Chapter 1.3.1.1 --- Cellular heterogeneity in the striatum --- p.12 / Chapter 1.3.1.1.1 --- MSNs --- p.12 / Chapter 1.3.1.1.1.1 --- Subpopulations --- p.13 / Chapter 1.3.1.1.1.2 --- Morphology --- p.13 / Chapter 1.3.1.1.1.3 --- Electrophysiological properties --- p.14 / Chapter 1.3.1.1.2 --- Cholinergic interneurons --- p.15 / Chapter 1.3.1.1.3 --- GABAergic interneurons --- p.17 / Chapter 1.3.1.2 --- Innervation of the striatum --- p.18 / Chapter 1.3.1.3 --- Output of the striatum --- p.21 / Chapter 1.3.2 --- Function of the striatum --- p.21 / Chapter 1.3.2.1 --- Function of the associative striatum --- p.22 / Chapter 1.3.2.2 --- Function of the sensorimotor striatum --- p.22 / Chapter 1.3.3 --- The corticostriatal system --- p.23 / Chapter 1.3.3.1 --- Anatomy of the corticostriatal system --- p.24 / Chapter 1.3.3.2 --- Physiology of the corticostriatal system --- p.25 / Chapter 1.3.3.3 --- Function of the corticostriatal system --- p.26 / Chapter 1.3.4 --- Striatum, corticostriatal system and PD --- p.26 / Chapter 1.4 --- GPe --- p.29 / Chapter 1.4.1 --- Anatomy of GPe --- p.29 / Chapter 1.4.1.1 --- Cellular heterogeneity in GPe --- p.29 / Chapter 1.4.1.2 --- Innervation of GPe --- p.31 / Chapter 1.4.1.3 --- Output of GPe --- p.33 / Chapter 1.4.2 --- Neurotransmission in GPe --- p.34 / Chapter 1.4.2.1 --- GABAA receptors in GPe --- p.34 / Chapter 1.4.2.2 --- GABAB receptors in GPe --- p.35 / Chapter 1.4.2.3 --- Evoked responses in GPe from direct striatal and pallidal stimulations --- p.37 / Chapter 1.4.3 --- GPe, striatopallidal system and PD --- p.38 / Chapter 1.5 --- NAc --- p.40 / Chapter 1.5.1 --- Anatomy of NAc --- p.40 / Chapter 1.5.1.1 --- Subregions --- p.40 / Chapter 1.5.1.2 --- Cell heterogeneity in NAc --- p.42 / Chapter 1.5.1.2.1 --- MSNs --- p.42 / Chapter 1.5.1.2.2 --- Interneurons --- p.42 / Chapter 1.5.1.3 --- Inervation of NAc --- p.43 / Chapter 1.5.1.4 --- Output of NAc --- p.43 / Chapter 1.5.2 --- Function of NAc --- p.43 / Chapter 1.5.3 --- The prefrontal cortex (PFC)-NAc system --- p.43 / Chapter 1.5.4 --- NAc, PFC-NAc system and PD --- p.44 / Chapter 1.6 --- Objectives --- p.45 / Chapter Chapter 2 --- General methods --- p.51 / Chapter 2.1 --- Electrophysiological experiments --- p.51 / Chapter 2.1.1 --- Slice preparation --- p.51 / Chapter 2.1.2 --- Whole-cell patch-clamp recordings --- p.52 / Chapter 2.1.3 --- Uncaging experiment --- p.54 / Chapter 2.1.4 --- Data analysis and statistics --- p.54 / Chapter 2.2 --- Dopamine depletion --- p.55 / Chapter 2.2.1 --- 6-hydroxydopamine (6-OHDA) injection into medial forebrain bundle (MFB) --- p.55 / Chapter 2.2.2 --- 6-OHDA injection into NAc --- p.56 / Chapter 2.2.3 --- Reserpine treatment --- p.56 / Chapter 2.3 --- Limb-use asymmetry test (cylinder test) --- p.57 / Chapter 2.4 --- Tyrosine hydroxylase (TH) immunohistochemistry and analysis --- p.57 / Chapter 2.4.1 --- TH immunohistochemistry of SNc and striatal slices --- p.57 / Chapter 2.4.2 --- TH immunohistochemistry and analysis of NAc slices --- p.58 / Chapter 2.5 --- Tracing study --- p.59 / Chapter 2.6 --- Genotyping and quantitative polymerase chain reaction (qPCR) --- p.60 / Chapter Chapter 3 --- Alteration of corticostriatal glutamatergic transmission onto D2 MSNs in PD models --- p.62 / Chapter 3.1 --- Summary --- p.62 / Chapter 3.2 --- Introduction --- p.63 / Chapter 3.3 --- Materials --- p.65 / Chapter 3.3.1 --- Animals --- p.65 / Chapter 3.3.2 --- Chemicals --- p.66 / Chapter 3.4 --- Results --- p.66 / Chapter 3.4.1 --- Comparison of corticostriatal paired-pulse ratios (PPRs) between hemizygotes and homozygotes of D2-EGFP BAC transgenic mice --- p.66 / Chapter 3.4.2 --- Corticostriatal AMPA PPR was specifically decreased in D2 MSNs following dopamine depletion --- p.67 / Chapter 3.4.2.1 --- Corticostriatal AMPA PPR was specifically decreased in D2 MSNs following reserpine treatment --- p.67 / Chapter 3.4.2.2 --- Corticostriatal AMPA PPR was specifically decreased in D2 MSNs following 6-OHDA lesion --- p.68 / Chapter 3.4.3 --- Increased glutamate release underlying reduction of corticostriatal PPR in D2 MSNs in parkinsonian states --- p.69 / Chapter 3.4.3.1 --- Effect of γ-DGG on the corticostriatal eEPSCs of D2 MSNs --- p.70 / Chapter 3.4.3.2 --- Effect of γ-DGG on the corticostriatal eEPSCs of D2 MSNs in the presence of CTZ --- p.70 / Chapter 3.4.3.3 --- Decay kinetics of eEPSCs of D2 MSNs in the presence of CTZ or PEPA were not consistently altered following dopamine depletion --- p.71 / Chapter 3.4.3.4 --- Corticostriatal NMDA PPR was decreased in D2 MSNs following dopamine depletion --- p.72 / Chapter 3.4.4 --- AMPA receptor occupancy was increased in D2 MSNs following dopamine depletion --- p.73 / Chapter 3.4.5 --- Increased postsynaptic AMPA receptor desensitization contributing to the reduction of corticostriatal PPR in D2 MSNs of parkinsonian states --- p.74 / Chapter 3.4.5.1 --- Effect of CTZ on the corticostriatal AMPA PPR of D2 MSNs --- p.74 / Chapter 3.4.5.2 --- Effect of PEPA on the corticostriatal AMPA PPR of D2 MSNs --- p.75 / Chapter 3.4.6 --- Loss of dopamine D2 receptor activation did not contribute to the increased corticostriatal glutamate release onto D2 MSNs in the parkinsonian states --- p.75 / Chapter 3.4.7 --- Postsynaptic Ca2+ involved in the modification of the corticostriatal transmission in D2 MSNs of parkinsonian state --- p.77 / Chapter 3.5 --- Discussion --- p.78 / Chapter 3.5.1 --- Corticostriatal glutamate release onto D2 MSNs was increased in the parkinsonian states --- p.78 / Chapter 3.5.2 --- AMPA receptor occupancy was increased in D2 MSNs following dopamine depletion --- p.80 / Chapter 3.5.3 --- Postsynaptic AMPA receptor desensitization was increased in D2 MSNs following dopamine depletion --- p.81 / Chapter 3.5.4 --- Loss of dopamine D2 receptor activation did not contribute to the increased corticostriatal glutamate release onto D2 MSNs in the parkinsonian states --- p.81 / Chapter 3.5.5 --- Postsynaptic Ca2+ involved in the modification of the corticostriatal transmission in D2 MSNs of parkinsonian state --- p.82 / Chapter 3.5.6 --- The increased corticostriatal glutamate release onto D2 MSNs and PD --- p.83 / Chapter Chapter 4 --- Alteration of striatopallidal GABAergic transmission in 6-OHDA lesioned PD model --- p.98 / Chapter 4.1 --- Summary --- p.98 / Chapter 4.2 --- Introduction --- p.99 / Chapter 4.3 --- Materials --- p.101 / Chapter 4.3.1 --- Animals --- p.101 / Chapter 4.3.2 --- Chemicals --- p.101 / Chapter 4.4 --- Results --- p.101 / Chapter 4.4.1 --- Striatopallidal paired-pulse ratio (PPR) was decreased following 6-OHDA lesion --- p.101 / Chapter 4.4.1.1 --- Striatopallidal PPR was unchanged following reserpine treatment --- p.102 / Chapter 4.4.1.2 --- Striatopallidal PPR was decreased following 6-OHDA lesion --- p.102 / Chapter 4.4.2 --- Increased striatopallidal GABA release underlying the reduction of striatopallidal PPR following 6-OHDA lesion --- p.103 / Chapter 4.4.2.1 --- CV of eIPSC1 in GP neurons was reduced following 6-OHDA lesion --- p.103 / Chapter 4.4.2.2 --- mIPSCs frequency was increased in GP neurons following 6-OHDA lesion --- p.104 / Chapter 4.4.3 --- Mechanism for the increased striatopallidal GABA release following 6-OHDA lesion --- p.105 / Chapter 4.4.3.1 --- Loss of dopamine D2 receptor activation did not contribute to the increased striatopallidal GABA release following 6-OHDA lesion --- p.105 / Chapter 4.4.3.2 --- GABAB receptor modulation did not contribute to the increased striatopallidal GABA release following 6-OHDA lesion --- p.106 / Chapter 4.4.3.3 --- Loss of presynaptic tonic group III mGluR inhibition accounted for the increased striatopallidal GABA release following 6-OHDA lesion --- p.107 / Chapter 4.5 --- Discussion --- p.109 / Chapter 4.5.1 --- Striatopallidal GABA release was increased in the parkinsonian state --- p.109 / Chapter 4.5.2 --- Mechanism underlying the increased striatopallidal GABA release in the parkinsonian state --- p.111 / Chapter 4.5.2.1 --- Loss of dopamine D2 receptor activation did not contribute to the increased striatopallidal GABA release following 6-OHDA lesion --- p.111 / Chapter 4.5.2.2 --- GABAB receptor modulation did not contribute to the increased striatopallidal GABA release following 6-OHDA lesion --- p.112 / Chapter 4.5.2.3 --- Loss of presynaptic tonic group III mGluR inhibition accounted for the increased striatopallidal GABA release following 6-OHDA lesion --- p.113 / Chapter 4.5.3 --- The increased striatopallidal GABA release and PD --- p.114 / Chapter 4.5.4 --- The striatopallidal group III mGluR system and PD --- p.116 / Chapter Chapter 5 --- Role of D1 and D2 receptors in prelimbic cortex-nucleus acumbens transmission in normal and parkinsonian states --- p.128 / Chapter 5.1 --- Summary --- p.128 / Chapter 5.2 --- Introduction --- p.129 / Chapter 5.3 --- Materials --- p.131 / Chapter 5.3.1 --- Animals --- p.131 / Chapter 5.3.2 --- Chemicals --- p.131 / Chapter 5.4 --- Results --- p.132 / Chapter 5.4.1 --- Prelimbic cortex innervated both D1 MSNs and D2 MSNs in core subregion of NAc- --- p.132 / Chapter 5.4.2 --- D1 and D2 receptors presynaptically modulated the D1 MSN-associated prelimbic cortex-NAc transmission in opposite manner --- p.133 / Chapter 5.4.3 --- D1 and D2 receptors presynaptically modulated the D2 MSN-associated prelimbic cortex-NAc transmission in a reverse manner --- p.134 / Chapter 5.4.4 --- Effects of D1 and D2 receptor antagonists on the prelimbic cortex-Nac transmission --- p.135 / Chapter 5.4.5 --- Basal synaptic transmission was enhanced in D2 MSN-associated prelimbic cortex-NAc pathway following NAc dopamine depletion --- p.136 / Chapter 5.4.6 --- D1 and D2 receptor modulation of the prelimbic cortex-NAc transmission disappeared following dopamine depletion --- p.137 / Chapter 5.5 --- Discussion --- p.138 / Chapter 5.5.1 --- Prelimbic cortex innervated both D1 MSNs and D2 MSNs in core subregion of NAc- --- p.138 / Chapter 5.5.2 --- Prelimbic cortex-NAc projections were presynaptically modulated by D1 and D2 receptors in a highly precise and complementary pattern --- p.138 / Chapter 5.5.3 --- Glutamatergic transmission was selectively enhanced in D2 MSN-associated prelimbic cortex-NAc pathway following NAc dopamine depletion --- p.140 / Chapter 5.5.4 --- D1 and D2 receptor modulation of the prelimbic cortex-NAc transmission was lost following dopamine depletion --- p.142 / Chapter Chapter 6 --- General discussion --- p.154 / Chapter 6.1 --- Enhanced corticostriatal glutamate release, enhanced striatopallidal GABA release and motor deficits in PD --- p.154 / Chapter 6.2 --- Enhanced prelimbic cortical glutamate release onto accumbal D2 MSNs and cognitive deficits in PD --- p.155 / Abbreviations --- p.158 / References --- p.160

Raymond Hiu Yeung, Li. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1997. / Includes bibliographical references (leaves 51-69). / Acknowledgment --- p.iii / Abstract --- p.iv / List of Abbreviations --- p.vii / Chapter CHAPTER ONE: --- INTRODUCTION / Chapter 1.1. --- Parkinson's Disease --- p.1 / Chapter 1.1.1 --- Epidemiology --- p.1 / Chapter 1.1.2 --- Clinical symptoms --- p.2 / Chapter 1.1.3 --- Neuropathology --- p.3 / Chapter 1.2 --- Proposed mechanisms of Neuronal Cell Death in PD / Chapter 1.2.1 --- Oxidative Stress --- p.4 / Chapter 1.2.2 --- Mitochondrial Dysfunction --- p.5 / Chapter 1.2.3 --- Excitotoxicity --- p.6 / Chapter 1.2.4 --- Genetic Factor --- p.8 / Chapter 1.2.5 --- Aging --- p.9 / Chapter 1.3 --- "1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine as a PD model" / Chapter 1.3.1 --- The discovery of MPTP --- p.10 / Chapter 1.3.2 --- The mechanism of MPTP toxicity --- p.10 / Chapter 1.4 --- Reactive Oxygen Species (ROS) and Antioxidants in CNS / Chapter 1.4.1 --- Superoxide and Superoxide Dismutases --- p.13 / Chapter 1.4.2 --- "Hydrogen Peroxide, Catalase and Glutathione System" --- p.14 / Chapter 1.4.3 --- Hydroxyl Radicals --- p.15 / Chapter 1.4.4 --- Nitric Oxide (NO) --- p.16 / Chapter 1.5 --- Astrocytes / Chapter 1.5.1 --- Characteristics of astrocytes --- p.20 / Chapter 1.5.2 --- The role of astrocytes in PD --- p.21 / Chapter 1.6 --- The aim of this project --- p.24 / Chapter CHAPTER 2: --- MATERIALS AND METHODS / Chapter 2.1 --- Astrocyte cultures --- p.27 / Chapter 2.2 --- MPTP treatment --- p.28 / Chapter 2.3 --- Lactate Dehydrogenase Assay --- p.29 / Chapter 2.4 --- Determination of nitrite and nitrate levels in cultured astrocytes --- p.30 / Chapter 2.5 --- Assay for Cyclic GMP production --- p.32 / Chapter 2.6 --- Inhibition of NO by L-NAME and Dexamethasone --- p.33 / Chapter 2.7 --- NFkB immunostaining --- p.33 / Chapter 2.8 --- Superoxide Dismutase Assay --- p.34 / Chapter 2.9 --- Statistics --- p.36 / Chapter CHAPTER 3: --- RESULTS / Chapter 3.1 --- Lactate dehydrogenase (LDH) activities after MPTP treatment --- p.37 / Chapter 3.2 --- The effects of MPTP on nitrite levels --- p.37 / Chapter 3.2.1 --- Mesencephalic astrocytes --- p.37 / Chapter 3.2.2 --- Striatal astrocytes --- p.38 / Chapter 3.2.3 --- Cortical astrocytes --- p.38 / Chapter 3.3 --- The effects of L-NAME on nitrite levels after MPTP treatment --- p.38 / Chapter 3.4 --- The effects of dexamethasone on nitrite levels after MPTP treatment --- p.39 / Chapter 3.5 --- Change in intracellular cyclic GMP in astrocytes after MPTP treatment --- p.40 / Chapter 3.6 --- The effects of MPTP on NFkB distribution in astrocytes --- p.40 / Chapter 3.7 --- The effects of MPTP on SOD activity in astrocytes --- p.41 / Chapter 3.7.1 --- Mesencephalic astrocytes --- p.41 / Chapter 3.7.2 --- Striatal astrocytes --- p.41 / Chapter 3.7.3 --- Cortical astrocytes --- p.42 / Chapter CHAPTER 4: --- DISCUSSION AND CONCLUSION --- p.43 / REFERENCES --- p.51

Submitted by Carvalho Dias João Paulo (joao.dias@famerp.br) on 2018-04-12T17:42:05Z No. of bitstreams: 1 karinakellyborges_tese.pdf: 4166303 bytes, checksum: 6285f0b896e90ee79617143e2fd72af2 (MD5) / Made available in DSpace on 2018-04-12T17:42:05Z (GMT). No. of bitstreams: 1 karinakellyborges_tese.pdf: 4166303 bytes, checksum: 6285f0b896e90ee79617143e2fd72af2 (MD5) Previous issue date: 2016-11-24 / Introduction: Parkinson's disease (PD) is a chronic progressive disease that affects physical, cognitive and emotional aspects. Objective: The aim of this study was to evaluate the occurrence of changes in cognition and symptoms of mental disorders pre and post implant DBS (Deep Brain Stimulation) through a Neuropsychological Assessment (NA). Casuistics and Method: This is a descriptive study in which patients with PD, candidates and submitted to implantation of DBS have participated. NA was performed in these patients before and after implantation of DBS with the following instruments: Wechsler Adult Intelligence Scale; Trail Making Test - Form A and B; Stroop Test; Boston Naming Test; Hooper Visual Organization Test; Wechsler Memory Scale-Revised (WMS-R); Rey Complex Figure; Rey Auditory Verbal Learning Test (RAVLT); Wisconsin Card Sorting Test (WCST) and Beck´s Depression and Anxiety Inventory . Results: From the 29 patients evaluated; the mean age was 60.2 (± 9.35) years , mainly males (n = 19), married (n = 21), with complete primary education (n = 22) and retired ( n = 24). The average time of diagnosis was 11.37 years (± 5.47), the mean age of onset 48.63 (± 7.36). The stage of PD was light to moderate. Clinical evaluation showed significant differences pre and post DBS, with improvement in symptoms. The NA has identified improvement after DBS overall intelligence quotient (p = 0.0022), in activities related to processing speed, and symptoms of mental disorders: depression (p <0.0001), anxiety (p = 0.0038) and apathy (p <0.001). Worsening after DBS was Identified in executive function, memory and verbal fluency. Conclusions: After DBS implantation, there was improvement in symptoms of depression, anxiety and apathy. In general, there was no improvement in cognitive function. / Introdução: Doença de Parkinson (DP) é uma doença crônica progressiva, que compromete aspectos físicos, cognitivos e emocionais. Objetivo: O objetivo deste estudo foi avaliar a ocorrência de alterações na cognição e nos sintomas de transtornos mentais pré e pós implante de DBS (Deep Brain Stimulation) por meio de uma avaliação neuropsicológica (AN). Casuística e Método: Estudo descritivo, no qual participaram pacientes com DP, candidatos e submetidos ao implante de DBS. Foi realizada AN nos pacientes pré e pós implante de DBS com os seguintes instrumentos: Wechsler Adult Intelligence Scale; Trail Making Test - Forma A e B; Stroop Test; Boston Naming Test; Hooper Visual Organization Test; Wechsler Memory Scale- Revised (WMS-R); Figura Complexa de Rey; Rey Auditory Verbal Learning Test (RAVLT); Wisconsin Cards Sorting Test (WCST) e Escalas de Depressão e de Ansiedade de Beck. Resultados: Dos 29 pacientes avaliados, a média de idade foi 60,2 (± 9,35) anos, eram principalmente do sexo masculino (n=19), casados (n=21), com ensino fundamental completo (n=22) e aposentados (n=24). O tempo médio de diagnóstico da doença foi 11,37 anos (± 5,47), a média de idade de início 48,63 (± 7,36). O estágio da DP era leve a moderado. A avaliação clínica indicou diferença significante pré e pós DBS, com melhora dos sintomas. A AN identificou melhora pós DBS no quociente intelectual geral (p=0,0022), nas atividades relacionadas à velocidade de processamento, e nos sintomas de transtornos mentais: depressão (p<0,0001), ansiedade (p=0,0038) e apatia (p<0,001). Identificou piora pós DBS na função executiva, memória e fluência verbal. Conclusões: Após o implante de DBS houve melhora dos sintomas de depressão, ansiedade e apatia. Não houve melhora da função cognitiva em geral.