Introdução: A instabilidade postural é uma manifestação tardia da doença de Parkinson (DP), sendo incapacitante e um fator de risco para quedas. O comprometimento das respostas posturais na DP é provavelmente a causa mais importante das quedas. Estas respostas posturais dependem de informações vestibulares, somatossensoriais e visuais, que são integradas nos núcleos da base, tronco cerebral e medula espinhal. Este estudo avalia um possível papel do sistema vestibular na fisiopatologia da instabilidade postural através da vertical visual subjetiva (VVS). A VVS avalia o julgamento da vertical gravitacional e é um teste sensível da função otolítica. Objetivo: Analisar a VVS em pacientes com DP e comparar com os controles normais; correlacionar a direção das inclinações da VVS e o lado de maior comprometimento da doença; correlacionar a VVS com as escalas Unified Parkinsons Disease Rating Scale (UPDRS), Hoehn e Yahr (HY); determinar se as inclinações da VVS estão relacionadas à instabilidade postural. Métodos: Pacientes com DP foram submetidos a: exame neurológico completo; escalas UPDRS e HY; teste clínico para avaliação da instabilidade postural e o teste da VVS foi realizado em 45 pacientes e 45 controles normais. Resultados: As inclinações da VVS nos controles tiveram valores entre -2,7º a +2,4º, média +0,18º e DP = 1.17, e entre -6,4º a +5,6º, média -0,50º e DP = 2.89 nos pacientes. Não houve diferença das médias entre pacientes e controles, porém os pacientes tiveram variabilidade maior. A avaliação da variabilidade no grupo dos pacientes utilizou os valores absolutos de cada medida da VVS. As médias dos valores absolutos da VVS nos controles e pacientes foram 1,55º e 3,65º, respectivamente, sendo maiores nos pacientes (p<0,0001). Houve uma fraca correlação positiva entre os resultados da VVS a avaliação motora da escala UPDRS; razoável correlação positiva com a escala HY e uma boa correlação entre a VVS e a severidade da instabilidade postural. Conclusões: Os erros do julgamento da VVS foram significantemente maiores em pacientes comparados aos controles. Além disso, houve uma fraca correlação com as escalas UPDRS e Hoehn e Yahr, e boa correlação da VVS com a instabilidade postural. Estes resultados sugerem que as vias aferentes do sistema vestibular estão comprometidas nos pacientes com DP e poderiam estar envolvidas nos mecanismos que levam à instabilidade postural, indicando que a instabilidade postural não é um fenômeno exclusivamente motor / Introduction: Postural instability is a late manifestation of Parkinsons disease (PD). The impairment of postural responses on PD is probably the most important cause of falls. These postural responses depend on vestibular, somatossensorial and visual inputs, and they are integrated on basal ganglia, brainstem and spinal cord. By use of the subjective visual vertical (SVV), this study evaluates a possible role of the vestibular system on the hysiopathology of postural instability. The SVV makes the judgment of gravitational vertical and is a specific test of otolith function. Objective: To analyze the SVV in patients with PD and to compare with normal controls; to correlate the direction of SVV-inclinations with the side of more impairment disease; to correlate the SVV with the Unified Parkinsons Disease Rating Scale (UPDRS), the Hoehn and Yahr (HY) scales, to determine if the inclination of SVV is related to the postural instability. Methods: Patients with idiopathic PD were submitted to: complete neurological examination; the scales UPDRS and HY; the clinical test to postural instability and the SVV test. The measurement of SVV was performed in 45 patients and 45 normal controls. Results: The SVV-inclination ranged from -2.7º to +2.4º, mean 0.18º and SD = 1.17 in controls, and from -6.4º to +5.6º, mean -0.50º and SD = 2.89 in patients. There was no difference in mean between patients and controls, but patients had a greater deviation. The variability evaluation in patients group used absolute values of SVV. The means of absolute values of SVV in controls and patients were 1.55º and 3.65º, respectively, and were greater in patients (p < 0.0001). There was a weak correlation between SSV and scores in the motor evaluation of UPDRS scale. A reasonable correlation was found between SVV values and scores in the HY scale. There was a good correlation between SVV and severity of postural instability. Conclusions: The error of judgment of SVV was significantly increased in the patients compared to controls. Further, there was a weak correlation with UPDRS and HY scales, and a good correlation of SVV with postural instability. These results suggest that the afferent pathways of vestibular system are impaired in patients with PD and could be involved in mechanisms underlying postural instability; so that, postural instability is not only a motor phenomemon

A Doença de Parkinson (DP) é causada pela degeneração progressiva de neurônios no sistema nervoso central, principalmente os neurônios dopaminérgicos nigroestriatais, levando a sintomas motores como a bradicinesia, rigidez e tremor. Os sintomas não motores (SNM), como a dor, estão presentes em muitos doentes e representam um impacto negativo na qualidade de vida. A estimulação encefálica profunda é um tratamento bem estabelecido para o tratamento dos sintomas motores da DP. Entretanto, o seu impacto sobre os sintomas não motores ainda é bastante desconhecido. O objetivo do presente estudo foi avaliar os efeitos da EEP sobre as diferentes características da dor e sensibilidade, e de outros SNM nos indivíduos com DP. Foram avaliados 41 indivíduos com diagnóstico de DP (14 do sexo feminino), idade de 60 ± 10,4 anos, com 15 ± 7,6 anos da duração da doença e estágio intermediário de evolução (Escala de Hoehn & Yahr = 2,80 ± 0,64). Os doentes foram submetidos a implante de sistema de estimulação bilateral do núcleo subtalâmico guiado por eletrofisiologia intraoperatória. Foram avaliados, prospectivamente, antes e um ano após, o procedimento de forma encoberta. O desfecho principal foi a mudança da prevalência da dor após a cirurgia. Os desfechos secundários incluíam mudanças nos sintomas motores (UPDRS parte III), na qualidade de vida (escala SF-36), na avaliação de humor (Escala Hospitalar de Ansiedade e Depressão [EHAD]), nos outros sintomas não motores (Escala dos sintomas não motores [ESNM]) e nas características da dor. Foram avaliadas as dimensões da dor (questionário de McGill), a intensidade e o impacto nas atividades de vida diária da dor (escala visual analógica da dor [EVA], inventário breve da dor [IBD]), a presença de dor neuropática (Douleur Neuropathique-4 Questionnaire [DN-4]) e o perfil dos sintomas neuropáticos (inventário de sintomas de dor neuropática (ISDN), o perfil de catastrofismo da dor (Escala catastrófica da dor [ECD]) e os limiares de sensitivos por meio da análise quantificada dos limiares de sensibilidade. Houve redução de prevalência da dor de 70% para 21% após a cirurgia (p < 0,05). Houve melhora na intensidade (EVA: antes = 80 ± 13,2; depois = 42,2 ± 17,8, p = 0,007) e nos diferentes aspectos da dor, além de outros sintomas não motores (ESNM: antes = 114,80 ± 59,89; depois = 62,68 ± 22,76; p < 0,001), como a cognição, humor, atenção, alucinação e trato gastrointestinal. Houve melhora na detecção de estímulos térmicos e mecânicos após a cirurgia, além de redução da sensibilidade aos limiares de dor (p < 0,05). A melhora na intensidade da dor foi fortemente relacionada com a melhora na qualidade vida (r = 0,708; p < 0,005). Não houve correlação entre a melhora da dor e a resposta à dopamina pré-operatória ou a melhora motora após a cirurgia (r = 0,247; p = 0,197 e r = 0,249; p = 0,193, respectivamente). Concluise que a ECP do núcleo subtalâmico diminui a prevalência e diferentes aspectos da dor após a cirurgia, e essa melhora está diretamente associada à melhora da qualidade de vida. A melhora motora ou dos outros SNM não foi relacionada à melhora da dor, sugerindo que a ECP apresenta diferentes mecanismos de ação sobre os sintomas nos indivíduos com DP / Parkinson disease (PD) is caused by progressive degeneration of neurons throughout the nervous system, especially the dopamine neurons, leading to motor symptoms as bradykinesia, rigidity and tremor. Non-motor symptoms (NMS), such as pain, are present in a large proportion of Parkinson\'s disease patients and have a major negative impact on patients quality of life. Subthalamic deep brain stimulation has gained general use in the management of motor symptoms in these patients. However, its impact on non-motor symptoms remains largely unknown. The aim of this study was to evaluate the effect of subthalamic deep brain stimulation (STN-DBS) on the different characteristics of pain, sensibility and other NMS in patients with PD. Forty-one patients with PD were evaluated (14 female), mean age 60 ± 10,4 years. The mean duration of the disease was 15 ± 7.6 years, and the Hoehn & Yahr off-medication score was 2.80 ± 0.64. The patients underwent stereotactic implantation of bilateral subthalamic nucleus stimulation system guided by intraoperative electrophysiology. They were evaluated before and 01 year after surgery. The primary outcome was change in pain prevalence after surgery. Secondary outcome measures were changes in motor function (PDRS part III), quality of life (SF-36 scale), presence of NMS (Non-motor symptoms scale [NMSS] and Hospital Anxiety and Depression Scale [HADS]), and characteristics of pain. We evaluated pain dimensions (Short Form of McGill Pain Questionnaire [MPQ]), pain intensity and impact of pain in daily activities (Brief Pain Inventory [BPI] and Visual Analogic Scale [VAS]), presence of neuropathic pain (Douleur Neuropathique-4 Questionnaire [DN-4]) and its symptom profile (Neuropathic Pain Symptom Inventory [NPSI]), catastrophizing (Pain Catatrosphizing Scale [PCS]) and the sensory thresholds throught the quantitative sensory threshold test. The prevalence of pain changed from 70% to 21% after surgery (p < 0.001). There were also significant improvements in pain intensity (VAS: before = 80 ± 13.2; after = 42.2 ± 17.8, p = 0.007), in different aspects of pain and NMS (before = 114.80 ± 59.89; after = 62.68 ± 22.76; p < 0.001) as cognition, attention, mood and gastrointestinal function. There was improvement on cold and heat detection thresholds (p < 0.05). There was a strong correlation between the change in pain intensity and the improvement in quality of life (r = 0.708; p < 0.005). No correlation was found between pain improvement and preoperative response to levodopa or motor improvement during stimulation (r = 0.247; p = 0.197 and r = 0.249; p = 0.193, respectively) or with changes in other non-motor symptoms. In conclusion, STN-DBS decreased pain intensity. The pain relief was directly associated with improvement in quality of life. Motor and NMS improvements after STN-DBS did not correlate with pain relief, suggesting differents mechanisms of DBS action in PD patients

Orientador: Roger Frigério Castilho / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-24T17:18:02Z (GMT). No. of bitstreams: 1 Michelini_LuizGuilhermeBueno_M.pdf: 1602537 bytes, checksum: f58032fd3eaf359e8f094658a3612c02 (MD5) Previous issue date: 2014 / Resumo: A inibição parcial do Complexo I da cadeia respiratória mitocondrial em ratos tratados cronicamente com rotenona está associada com o desenvolvimento de características neuroquímicas, comportamentais e neuropatológicas da doença de Parkinson. Os objetivos deste trabalho foram (i) caracterizar os efeitos de uma inibição parcial do Complexo I por rotenona na produção de peróxido de hidrogênio (H2O2) por mitocôndrias de cérebro de ratos (MCR) em diferentes estados respiratórios e (ii) avaliar a suscetibilidade de MCR velhos (24 meses) à inibição do consumo de oxigênio (O2) e ao estímulo da produção de H2O2 por rotenona em comparação a MCR adultos (3-4 meses). A análise do potencial de membrana por citometria de fluxo em mitocôndrias isoladas indicou que a adição de rotenona promoveu uma inibição uniforme da respiração mitocondrial nestas organelas. Quando mitocôndrias foram incubadas na presença de uma baixa concentração de rotenona (10 nM) e de substratos geradores de NADH, o consumo de O2 foi reduzido de 45,9±1,0 para 26,4±2,6 nmol O2.mg-1.min-1 e de 7,8±0,3 para 6,3±0,3 nmol O2.mg-1.min-1 nos estados respiratórios 3 (respiração estimulada por ADP) e 4 (respiração de repouso), respectivamente. Nessas condições, a produção mitocondrial de H2O2 foi estimulada de 12,2±1,1 para 21,0±1,2 pmol H2O2.mg-1.min-1 e de 56,5±4,7 para 95,0±11,1 pmol H2O2.mg-1.min-1 nos estados respiratórios 3 e 4, respectivamente. Resultados similares foram observados ao comparar preparações mitocondriais enriquecidas com organelas sinápticas e não-sinápticas ou quando o íon 1-metil-4-fenilpiridina (MPP+) foi utilizado como inibidor de Complexo I mitocondrial. O estímulo da produção de H2O2 por rotenona nos estados respiratórios 3 e 4 foi associado a um aumento do estado reduzido de nucleotídeos de nicotinamida endógenos. Na respiração mitocondrial com succinato, onde a maior parte da produção de H2O2 se origina do fluxo reverso de elétrons do Complexo II para o I, baixas concentrações de rotenona inibiram a produção de H2O2. Rotenona não exerceu efeito sobre a eliminação mitocondrial de concentrações micromolares de H2O2. Em sinaptossomas intactos, observamos que rotenona 10 nM estimulou a liberação de H2O2 em 20,2±3,3% no estado respiratório basal. Ao compararmos MCR adultos e velhos, verificamos que o consumo de O2 no estado respiratório 3 e a atividade da citrato sintase foram 21,0±3,3% e 17,0±5,4% mais baixos em MCR velhos. Experimentos conduzidos na presença de diferentes concentrações de rotenona (5, 10 e 100 nM) demonstraram sensibilidade similar à inibição do consumo de O2 por rotenona no estado respiratório 3, com IC50 de 7,8±0,4 e 6,5±0,5 nM para MCR adultos e velhos, respectivamente. De acordo com esses resultados, o estímulo da produção de H2O2 observado foi similar em MCR adultos e velhos, tratadas com diferentes concentrações de rotenona. Concluímos que, uma inibição parcial do Complexo I pode resultar em uma crise energética e/ou estresse oxidativo mitocondrial, enquanto o primeiro evento predominaria numa situação de alta demanda de fosforilação oxidativa, o segundo ocorreria em condições de respiração de repouso. Em adição, os experimentos com ratos velhos indicaram que rotenona exerce efeitos similares no consumo de O2 e na produção de H2O2 em MCR adultos e velhos / Abstract: Partial inhibition of mitochondrial Complex I is associated with the development of neurochemical, behavioral, and neuropathological features of Parkinson's disease in rats chronically and systemically treated with rotenone. The aims of this work were (i) to characterize the effects of partial inhibition of respiratory Complex I by rotenone on H2O2 production by rat brain mitochondria in different respiratory states and (ii) to evaluate the susceptibility of brain mitochondria from old rats (24 month-old) to rotenone-induced inhibition of oxygen consumption and increased generation of H2O2 when compared with organelles from adult rats (3-4 month-old). Flow cytometric analysis of membrane potential in isolated mitochondria indicated that rotenone leads to uniform respiratory inhibition when added to a suspension of these organelles. When mitochondria were incubated in the presence of a low concentration of rotenone (10 nM) and NADH-linked substrates, oxygen consumption was reduced from 45.9±1.0 to 26.4±2.6 nmol O2.mg-1.min-1 and from 7.8±0.3 to 6.3±0.3 nmol O2.mg-1.min-1 in respiratory states 3 (ADP-stimulated respiration) and 4 (resting respiration), respectively. Under these conditions, mitochondrial H2O2 production was stimulated from 12.2±1.1 to 21.0±1.2 pmol H2O2.mg-1.min-1 and 56.5±4.7 to 95.0±11.1 pmol H2O2.mg-1.min-1 in respiratory states 3 and 4, respectively. Similar results were observed when comparing mitochondrial preparations enriched with synaptic or nonsynaptic organelles or when 1-methyl-4-phenylpyridinium (MPP+) ion was used as a respiratory Complex I inhibitor. Rotenone-stimulated H2O2 production in respiratory states 3 and 4 was associated with a high reduction state of endogenous nicotinamide nucleotides. In succinate-supported mitochondrial respiration, where most of the mitochondrial H2O2 production relies on electron backflow from Complex II to Complex I, low rotenone concentrations inhibited H2O2 production. Rotenone had no effect on mitochondrial elimination of micromolar concentrations of H2O2. In intact synaptosomes, we observed that 10 nM rotenone stimulated H2O2 release by 20.2 ± 3.3% under basal respiratory state. When comparing isolated brain mitochondria from adult and old rats we observed that oxygen consumption under respiratory state 3 and citrate synthase activity were 21.0±3.3% and 17.0±5.4% lower in mitochondria from old rats. Experiments conducted in the presence of different rotenone concentrations (5, 10 and 100 nM) showed that brain mitochondria from adult and old rats have similar sensitive to rotenone-induced inhibition of oxygen consumption in respiratory state 3, with IC50 of 7.8±0.4 and 6.5±0.5 nM for adult and old rats, respectively. In line with these results, similar stimulations in H2O2 production were observed in mitochondria from adult and old rats treated with different concentrations of rotenone. We conclude that partial Complex I inhibition may result in mitochondrial energy crisis and oxidative stress, the former being predominant under oxidative phosphorylation and the latter under resting respiration conditions. Rotenone exerts similar effects on oxygen consumption and H2O2 production by isolated brain mitochondria from adult and old rats / Mestrado / Biologia Estrutural, Celular, Molecular e do Desenvolvimento / Mestre em Ciências

Orientador: Carlos Arturo Levi D'Ancona / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-22T09:57:34Z (GMT). No. of bitstreams: 1 Perissinotto_MariaCarolinaRamos_D.pdf: 1870557 bytes, checksum: a3f8aae56bf22e41993fdf4017268274 (MD5) Previous issue date: 2013 / Resumo: Introdução: A doença de Parkinson é uma doença neurológica degenerativa de causa desconhecida que leva a alterações motoras em decorrência da diminuição dos neurotransmissores de dopamina na substância nigraestriatal. Distúrbios miccionais acometem de 37% a 70% dos pacientes com esta doença. A eletroestimulação do nervo tibial posterior é uma opção no tratamento dos sintomas do trato urinário inferior. Objetivo: Avaliar a eficácia da referida eletroestimulação na sintomatologia do trato urinário inferior em pacientes com doença de Parkinson. Métodos: A metodologia utilizada foi o estudo controlado randomizado, pela qual foram 96 pacientes com diagnóstico de doença de Parkinson com queixas de sintomas do trato urinário inferior, os quais foram alocados em dois grupos: grupo tratamento e grupo sham. Todos os pacientes foram avaliados através de escalas específicas para a doença de Parkinson, como a Unified Parkinson's Diseases Rating Scale, nos quais preencheram os questionários de qualidade de vida, de incontinência urinária e de bexiga hiperativa, através dos quais foi realizado o estudo urodinâmico. Todas as avaliações foram realizadas pré e pós-tratamento e a técnica utilizada foi a eletroestimulação do nervo tibial posterior durante dez sessões, duas vezes por semana com duração de 30 minutos cada sessão. O grupo de tratamento realizou esta eletroestimulação e o outro grupo, o procedimento sham. Resultados: Os resultados obtidos ao final do tratamento foi que o grupo de tratamento relatou melhora significativa nos sintomas urinários de urgência e noctúria em comparação ao grupo sham. Urgência (p=0,0047), entre os grupos (100,0% grupo de tratamento, 12,5% grupo sham) e noctúria no grupo de tratamento entre os tempos pré e pós (p=0,0156) (4,0 pré - 2,0 pós). Na análise da qualidade de vida, ocorreu uma melhora significativa no score total do questionário International Consultation on Incontinence Questionnaire no grupo de tratamento entre os tempos pré e pós (p=0,0191) (7,0 pré - 4,0 pós), e no questionário Overactive Bladder Questionnaire no mesmo grupo entre os tempos (p=0,0144) (29,0 pré - 21,5 pós). No estudo urodinâmico, houve melhora significativa no grupo de tratamento entre o tempo pré e pós no primeiro desejo (mediana 150 pré -185 ml pós) (p=0.0056) e volume urgência (mediana 200 pré -285 ml pós) (p= 0.0014). Conclusão: O tratamento com a eletroestimulação do nervo tibial posterior se mostrou uma técnica capaz de melhoras na sintomatologia do trato urinário inferior em pacientes com doença de Parkinson, tais como a redução da urgência e da noctúria, proporcionando, assim, melhora na qualidade de vida desses pacientes. Novos estudos são necessários para aprofundar a eficácia desta técnica em pacientes com doença de Parkinson / Abstract: Introduction: Parkinson's disease is a neurologic disorder caused by neurodegeneration of the nigrostriatal dopaminergic. Lower urinary tract symptoms, are non-motor symptoms that occur in 37% to 70% of patients throughout the course of the disease and negatively affect the Quality of Life of these patients. Aims: Evaluate the efficacy of transcutaneous posterior tibial nerve stimulation on treatment of lower urinary tract symptoms in patients with Parkinson's disease. Methods: Randomized controlled trial, twenty three patients with a diagnosis of parkinson's disease and lower urinary tract symptoms, were randomized in two groups: PNTS group (GI) and group sham (GII). Evaluation included, urinary symptoms, Unified Parkinson's Diseases Rating Scale, International Consultation on Incontinence Questionnaire, Overactive Bladder Questionnaire questionnaire and the urodynamic study, all evaluation were performed pre and post PNTS. GI intervention consisted on PNTS and GII received a sham treatment with effective stimulation. Results: At the end of the treatment the GI present's significant improvement in storage and voiding symptoms than GII. There were significant differences on the symptoms of urgency (p=0.0047) between group (100.0% GI, 12.5% GII). In nocturia occurs an improvement pre and post PNTS in GI (p=0.0156) (4.0 pre - 2.0 post). Quality of life analyses there were significant differences on questionnaire, International Consultation on Incontinence Questionnaire, GI pre and post PNTS (p=0.0191) (7.0 pre - 4.0 post) and Overactive Bladder Questionnaire, GI pre and post PNTS (p=0.0144) (29.0 pre - 21.5 post). There were statistical difference in the urodynamic study pre and post PNTS in group I in volume stronge desire (median 150 pre -185ml post) (p=0.0056) and volume urgency (Median 200 pre-285 ml post) (p= 0.0014). Conclusion: PNTS is an option in the treatment of Lower urinary tract symptoms in patients with diagnosis of parkinson's disease, contributing to reduce urgency and nocturia and improving Quality of life score. This pilot study shows a good response in treat patients with parkinson's disease and Lower urinary tract symptoms, further study should be perform to provide evidence of the potential therapeutic effects / Doutorado / Fisiopatologia Cirúrgica / Doutora em Ciências

Pacientes com doença de Parkinson (DP) apresentam diversos sintomas não motores, dentre eles, alterações cognitivas. Déficits de função executiva podem ser observados desde os estágios iniciais da DP e impactam na independência funcional e na qualidade de vida. A função executiva é essencial para a realização de atividades de vida diária, que requerem integração cognitivo-motora. A realização de atividades cotidianas depende não só do sistema motor, mas também da interpretação e do processamento sensorial/ perceptual e da seleção e do planejamento da melhor estratégia motora. Sendo assim, um grande número de atividades de vida diária pode ser afetado por déficits na função executiva em pacientes com DP. Nessas tarefas, os componentes cognitivos e motores competem por recursos atencionais, o que pode prejudicar o desempenho em um ou em ambos os componentes. Entretanto, os estudos são muito direcionados para a análise de tarefas-duplas que envolvam equilíbrio em ortostatismo e marcha, mas contemplam pouco outras tarefas motoras. Os objetivos desse estudo foram (1) comparar o desempenho de pacientes com DP com o de um grupo controle nos testes de função executiva (Trail Making Test) e de fluência verbal (fluência semântica e fonêmica e diadococinesia oral /pataka/) e (2) investigar possíveis correlações entre função executiva e fluência verbal. O estudo foi realizado de maneira transversal, em uma única sessão, em uma avaliação de cerca de 50 minutos. Quarenta pacientes com DP (idade entre 50 e 79 anos, Hoehn & Yahr entre 2 e 3) e quarenta controles (com idade e escolaridade semelhantes) foram avaliados com o Trail Making Test, a fluência verbal semântica e fonêmica e o teste de diadococinesia oral. Na parte A do TMT, os participantes conectaram círculos numerados de 1 a 25, em sequência. Na parte B, os participantes conectaram círculos alternando números e letras (1-A-2-B-3-C-4-D-5-E-6-F-7-G-8-H-9-I-10-J-11-K-12-L-13). No teste de fluência verbal fonêmica, foi solicitado que os participantes dissessem palavras começando com a letra F. No teste de fluência verbal semântica, os participantes disseram o maior número de animais possível, em 60 segundos. No teste de diadococinesia oral, os participantes repetiram a sequência /pataka/ o mais rápido possível. Os grupos foram comparados por meio de análises de variância e as relações entre as variáveis foram investigadas pelo teste de correlação de Pearson. A análise de variância mostrou diferenças significativas entre grupos (F1,78=10,55; p=0,002) e entre partes do Trail Making Test (F1,78=154,02; p < 0,001). A parte B apresentou tempos maiores que a parte A (p < 0,001). Pacientes com DP disseram menos palavras nos testes de fluência verbal, em comparação aos controles (p < 0,001). Pacientes com DP repetiram a sequência /pataka/ menos vezes que os controles (p=0,019). Houve forte correlação entre o teste de fluência verbal fonêmica e a parte B do Trail Making Test (valor de r=-0,874 e p=0,001) e entre a diadococinesia oral e as partes A e B do Trail Making Test (valor de r=-0,824 e p=0,001). A correlação entre a parte B do Trail Making Test, que é uma medida de função executiva e reflete a habilidade de integração cognitivo-motora e as tarefas de fluência verbal, evidencia a importância do controle motor para as tarefas de fala. A tarefa da fala fornece não somente sobrecarga cognitiva, mas também motora para pacientes com DP. Esse conhecimento é importante para a prática clínica, uma vez que é necessário detectar a natureza do acometimento e da tarefa para usá-las de maneira adequada em programas de reabilitação / Patients with Parkinson´s disease (PD) can present several non-motor symptoms, including cognitive deficits. Executive function deficits can be observed since the early stages of PD and impact on functional independence and quality of life. The executive function is essential to the activities of daily living, which require cognitive-motor integration. The performance of activities of daily living depends not only on the motor system, but also on the sensory/ perceptual interpretation and processing and the selection and planning of the best motor strategy. Therefore, many activities of daily living can be affected by deficits in the executive function in patients with PD. In such tasks, cognitive and motor components compete for attentional resources, which may impair the performance of one or both tasks. However, most studies focus on to the analysis of dual-tasks involving orthostatic balance and gait, but they do not approach other motor tasks. The objectives of this study were (1) to compare the performance of patients with PD with a control group in executive function (Trail Making Test) and verbal fluency tests (semantic and phonemic and oral diadochokinesis /pataka/) and (2) to investigate possible correlations between executive function and verbal fluency. This was a cross-sectional study and the tests were performed individually in a 50-minute single session. Forty people with PD (aged 50 - 79 years, Hoehn & Yahr 2 - 3) and forty controls (with similar age and education) were evaluated with Trail Making Test (TMT, executive function), phonemic/semantic verbal fluency and oral diadochokinesis (/pataka/) tests. In part A of Trail Making Test, participants connected circles with the numbers 1-25, in sequence. In part B, participants connected circles in a sequence with alternated numbers and letters (1-A-2-B-3-C-4-D-5-E-6-F-7-G-8-H-9-I-10-J-11-K-12-L-13). In the phonemic verbal fluency test, participants were instructed to say words beginning with the letter F. In the semantic verbal fluency test, participants were instructed to say out loud as many animals as they could remember, in 60 seconds. In the oral diadochokinesis test, participants were asked to say the /pataka/ sequence as fast as they could. Groups were compared by analyses of variance and the relationships between the variables were investigated by Pearson correlation tests. Analysis of variance showed significant differences between groups (F1,78=10.55; p=0.002) and between Trail Making Test parts (F1,78=154.02; p < 0.001). Part B showed longer times than part A (p < 0.001). People with PD said fewer words in both fluency tests, compared to controls (p < 0.001). People with PD repeated the sequence /pataka/ less times than controls (p=0.019). There was a strong correlation between the phonemic verbal fluency test and the part B of Trail Making Test (r=-0.874 and p=0.001) and between the oral diadochokinesis test and both parts of the Trail Making Test (r=-0.824 e p=0.001). The correlation between the part B of Trail Making Test, which is an executive function measure and reflects the cognitive-motor integration ability, and the verbal fluency tests, evidences the importance of motor control for speech tasks. Speech tasks not only provide cognitive overload, but also motor overload in patients with PD. This knowledge is important in clinical practice, in which therapists must detect the nature of the disability and the task to use this information properly in rehabilitation programs

In patients with Parkinson's disease (PD), the associated pathology follows a characteristic pattern involving inter alia the enteric nervous system (ENS), the dorsal motor nucleus of the vagus (DMV), the intermediolateral nucleus of the spinal cord and the substantia nigra, providing the basis for the neuropathological staging of the disease. Here we report that intragastrically administered rotenone, a commonly used pesticide that inhibits Complex I of the mitochondrial respiratory chain, is able to reproduce PD pathological staging as found in patients. Our results show that low doses of chronically and intragastrically administered rotenone induce alpha-synuclein accumulation in all the above-mentioned nervous system structures of wild-type mice. Moreover, we also observed inflammation and alpha-synuclein phosphorylation in the ENS and DMV. HPLC analysis showed no rotenone levels in the systemic blood or the central nervous system (detection limit [rotenone]<20 nM) and mitochondrial Complex I measurements showed no systemic Complex I inhibition after 1.5 months of treatment. These alterations are sequential, appearing only in synaptically connected nervous structures, treatment time-dependent and accompanied by inflammatory signs and motor dysfunctions. These results strongly suggest that the local effect of pesticides on the ENS might be sufficient to induce PD-like progression and to reproduce the neuroanatomical and neurochemical features of PD staging. It provides new insight into how environmental factors could trigger PD and suggests a transsynaptic mechanism by which PD might spread throughout the central nervous system.

Background: Parkinson disease (PD) is a neurodegenerative disorder with a variety of motor and nonmotor symptoms. Many of these symptoms can be monitored by eHealth solutions, including smartphone apps, wearable sensors, and camera systems. The usability of such systems is a key factor in long-term use, but not much is known about the predictors of successful use and preferable methods to assess usability in patients with PD. Objective: This study tested methods to assess usability and determined prerequisites for successful use in patients with PD. - Methods: We performed comprehensive usability assessments with 18 patients with PD using a mixed methods usability battery containing the System Usability Scale, a rater-based evaluation of device-specific tasks, and qualitative interviews. Each patient performed the usability battery with 2 of 3 randomly assigned devices: a tablet app, wearable sensors, and a camera system. The usability battery was administered at the beginning and at the end of a 4-day testing period. Between usability batteries, the systems were used by the patients during 3 sessions of motor assessments (wearable sensors and camera system) and at the movement disorder ward (tablet app). - Results: In this study, the rater-based evaluation of tasks discriminated the best between the 3 eHealth solutions, whereas subjective modalities such as the System Usability Scale were not able to distinguish between the systems. Successful use was associated with different clinical characteristics for each system: eHealth literacy and cognitive function predicted successful use of the tablet app, and bettermotor function and lower age correlated with the independent use of the camera system. The successful use of the wearable sensors was independent of clinical characteristics. Unfortunately, patients who were not able to use the devices well provided few improvement suggestions in qualitative interviews. Conclusions: eHealth solutions should be developed with a specific set of patients in mind and subsequently tested in this cohort. For a complete picture, usability assessments should include a rater-based evaluation of task performance, and there is a need to develop strategies to circumvent the underrepresentation of poorly performing patients in qualitative usability research.

Les neurones dopaminergiques (DA) du mésencéphale jouent un rôle clé dans le contrôle moteur, les comportements motivés et la cognition. Les neurones dopaminergiques peuvent libérer la DA non seulement à partir de leurs terminaisons axonales, mais également à partir de leur compartiment somatodendritique (STD). Une partie de cette libération dépend de l’activité électrique des neurones (libération phasique de DA), de l’influx de calcium et de l’activation de senseurs calciques, tandis que d’autres formes de libération impliquent l’activation locale d’afférences synaptiques en provenance d’autres neurones ou survient de manière spontanée. Les mécanismes et rôles physiologiques de ces différentes formes de libération sont encore méconnus. Dans cette thèse, je me suis intéressé spécifiquement à la libération phasique de dopamine et au rôle joué par les senseurs calciques régulateurs de l’exocytose de la famille des synaptotagmines (Syts). En utilisant des modèles in vivo de souris knock-out de certaines isoformes de cette famille, j’ai ainsi démontré que Syt1 est la principale isoforme impliquée dans la libération phasique de dopamine au niveau des terminaisons axonales, tandis que les isoformes Syt4 et Syt7 jouent un rôle plus spécifique dans la libération au niveau du soma et des dendrites. La souris Syt1 cKODA a par ailleurs révélé l’exceptionnelle résilience de certaines fonctions dopamino-dépendantes, notamment dans le contrôle de la locomotion spontanée et induites par des drogues, qui sont surprenamment conservées dans un contexte de quasi-abolition de la libération phasique de DA. Des adaptations importantes du système DA ont été observées chez les souris Syt1 cKO et sont comparables à celles observées dans les stages précoces de la maladie de Parkinson. Ces travaux apportent ainsi un nouvel éclairage sur pourquoi une perte drastique de l’innervation dopaminergique est requise pour aboutir aux symptômes moteurs typiques de cette maladie. Ils apportent également de nouvelles perspectives et modèles à l’étude des mécanismes et fonctions de la libération tonique (spontanée) de DA dans le cerveau. / Dopaminergic (DA) neurons in the midbrain play a key role in motor control, motivated behaviors and cognition. Dopaminergic neurons can release DA not only from axon terminals, but also from their somatodendritic compartment (STD). Part of this release depends on electrical activity (phasic release of DA), calcium influx and activation of calcium sensors, while other forms of release involve local activation of synaptic inputs from other neurons or occurs spontaneously. The mechanisms and physiological roles of these different forms of release are still poorly understood. In this thesis, I focused on the phasic release of DA and the role played by calcium sensors from the synaptotagmin (Syt) family regulating exocytosis. By using in vivo knockout mouse models of isoforms from this family, I demonstrated that Syt1 is the main calcium sensor involved in phasic DA release at axonal endings, while the Syt4 and Syt7 isoforms play a more specific role in the release at the level of the soma and dendrites. Syt1 cKODA model also revealed the exceptional resilience of certain DA-dependent functions such as spontaneous and drug-induced locomotion, which are surprisingly preserved in a context of a near abolition of phasic DA release. Important adaptations in the DA system were observed in Syt1 cKO mice and are comparable to those seen at early stages of Parkinson's disease. This work thus sheds new light on why a drastic loss of dopaminergic innervation is required to lead to the motor symptoms typical of this disease. They also bring new perspectives and models to the study of the mechanisms and functions of tonic (spontaneous) DA release in the brain.

OBJECTIVE: Metamemory is integral for strategizing about memory intentions. This study investigated the prospective memory (PM) deficit in Parkinson's disease (PD) from a metamemory viewpoint, with the aim of examining whether metamemory deficits might contribute to PM deficits in PD. METHOD: Sixteen patients with PD and 16 healthy older adult controls completed a time-based PM task (initiating a key press at two specified times during an ongoing task), and an event-based PM task (initiating a key press in response to animal words during an ongoing task). To measure metamemory participants were asked to predict and postdict their memory performance before and after completing the tasks, as well as complete a self-report questionnaire regarding their everyday memory function. RESULTS: The PD group had no impairment, relative to controls, on the event-based task, but had prospective (initiating the key press) and retrospective (recalling the instructions) impairments on the time-based task. The PD group also had metamemory impairments on the time-based task; they were inaccurate at predicting their performance before doing the task but, became accurate when making postdictions. This suggests impaired metamemory knowledge but preserved metamemory monitoring. There were no group differences regarding PD patients' self-reported PM performance on the questionnaire. CONCLUSIONS: These results reinforce previous findings that PM impairments in PD are dependent on task type. Several accounts of PM failures in time-based tasks are presented, in particular, ways in which mnemonic and metacognitive deficits may contribute to the difficulties observed on the time-based task.

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