A dupla dissociação entre os tipos de prejuízo de memória de longa duração em pacientes amnésicos e parkinsonianos reforça a noção de independência entre os sistemas de memória explícita e implícita. No entanto, apesar de ser amplamente aceito que pacientes com Doença de Parkinson (DP) apresentam prejuízo específico de funções de memória implícita, pelo menos nos estágios iniciais da doença, o grau de comprometimento desse sistema não é utilizado como critério de classificação. A avaliação da progressão da DP e de possíveis tratamentos é feita através de métodos como as escalas de Hoehn e Yahr (HY) e Unified Parkinson’s Disease Rating Scale (UPDRS), que apresentam uma série de fragilidades. Essa falta de instrumentos adequados para a avaliação da DP, gera dificuldades de verificar a eficácia de tratamentos para a doença, como, por exemplo, o tratamento proposto por Coimbra e Junqueira (2003), que consiste na administração de riboflavina e eliminação da carne vermelha da dieta. Assim, os objetivos do presente trabalho são (1) desenvolver uma estratégia de avaliação da progressão da DP e (2) avaliar se o tratamento por riboflavina concomitante à dieta sem carne vermelha de fato determina regressão da doença. O primeiro experimento deste estudo enfocou a primeira questão por meio de treinamento de pacientes com DP na tarefa de tempo de reação serial de oposição de dedos, uma tarefa que requer memória implícita, e outros teste neuropsicológicos, como tarefa de tempo de reação serial de oposição de dedos, tempo de reação simples, “vai-não-vai” e “1- atrás”. Foram observadas incongruências entre o desempenho e a classificação pela escala de Hoehn e Yahr; por outro lado, o índice desenvolvido no trabalho não apresentou incongruências e pareceu ser um bom indicador para classificação da DP. O índice é construído com base em medidas do tempo de reação e taxa de aprendizagem, que parecem apresentar o refinamento necessário para avaliar a progressão da doença e também mudanças em razão de tratamentos. O tratamento por riboflavina e eliminação da carne vermelha da dieta, que reduziria os sintomas motores da DP, foi avaliado utilizando as medidas de desempenho motor e aquisição de habilidade motora; os resultados são apresentados no segundo trabalho. Este estudo não foi suficiente para permitir uma conclusão definitiva sobre a eficácia ou ineficácia do tratamento. No entanto, resultados intrigantes foram obtidos sugerindo a necessidade de uma avaliação mais completa sobre a contribuição desse tratamento para aliviar os prejuízos associados à doença de Parkinson. / The double dissociation between the long-term memory losses in Parkinson’s disease (PD) and amnesic patients strengthens the implicit and explicit memory dissociation. However, although it is widely accepted that patients with PD have specific impairment of implicit memory functions, at least in the initial stages of the disease, the degree of this impairment is not used as criterion of classification. The progression of the PD and possible treatments are evaluated through methods as Hoehn and Yahr Staging of Parkinson’s disease (HY) and Unified Parkinson\'s Disease Rating Scale (UPDRS), that present a series of fragilities. This lack of evaluation instruments adjusted to PD generates difficulties to verify the effectiveness of treatments, for example, the one proposed by Coimbra and Junqueira (2003), which consists in administration of high doses of riboflavin and a red-meat-free diet. Thus, the objectives of the present work are (1) to develop an evaluation strategy of PD progression and (2) to evaluate if riboflavin associated with red-meat-free diet determines regression of the disease. The first experiment of this study focused on the first question by training PD patients in a serial reaction time of fingers-to-thumb task, which requires implicit memory, and other nuropsychological test, as simple reaction time, “go-no-go” and “1-back”. Incongruences between performance and HY classification were observed; on the other hand, the index developed in the work did not present incongruences and seemed to be a good indicator for classification of the PD. The index is based in reaction time measures and learning rate, that seem to present the necessary refinement to evaluate the progression of the disease and changes related to treatments. The treatment of riboflavin associated with red-meat-free diet, which may reduce the motor symptoms of the PD, was evaluated using the measures of motor performance and acquisition of motor skill; the results are presented in the second experiment. This study did not concluded emphatically the effectiveness of the treatment. However, intriguing results suggest the necessity of a more complete evaluation of the treatment’s contribution to reduce impairments associated to Parkinson’s disease.

Os receptores canabinóides CB1 são abundantemente expressos nos núcleos da base (NB), sugerindo a participação do sistema canabinóide na Doença de Parkinson (DP). Os objetivos deste estudo foram investigar a localização do CB1 nos NB de ratos; avaliar o decurso temporal de sua expressão e de marcadores neuronais em modelo experimental da DP in vivo, e avaliar os efeitos do tratamento com compostos canabinóides em modelos experimentais da DP in vivo e in vitro. Nossos resultados mostraram que o CB1 é predominantemente expresso em neurônios GABAérgicos nos NB. A lesão dopaminérgica produziu mudanças temporais distintas da expressão do CB1 nas estruturas dos NB. O tratamento com o agonista canabinóide ACEA agravou à lesão dopaminérgica e o desempenho comportamental motor. Por outro lado, o tratamento com o antagonista AM 251, embora não tenha gerado diferenças neuroquímicas, gerou melhoras nos testes comportamentais. Por fim, em nosso modelo in vitro, o tratamento com inibidor de recaptação da anandamida AM 404 gerou uma discreta redução dos níveis de morte celular. / Cannabinoid receptors CB1 are abundantly expressed in the basal ganglia (BG), suggesting the involvement of the cannabinoid system in Parkinson\'s disease (PD). The objectives of this study were to investigate the location of CB1 in BG of rats; evaluate the time course expression of CB1 and neuronal markers in an experimental model of PD in vivo, and evaluate the effects of treatment with cannabinoids compounds in experimental models of PD in vivo and in vitro. Our results showed that CB1 is predominantly expressed in GABAergic neurons in BG. The dopamine lesion produced distinct temporal changes in the expression of CB1 in BG structures. Treatment with the cannabinoid agonist ACEA aggravated the dopaminergic lesion and the motor behavioral performance. Moreover, the treatment with the antagonist AM 251, although have not generated neurochemical changes,it promoted improvements in behavioral tests. Finally, in our in vitro model, the treatment with Anandamide transport inhibitor AM 404 led to a slight reduction in the levels of cell death.

O objetivo deste projeto foi investigar as alterações histológicas e comportamentais do exercício físico no modelo da doença de Parkinson (DP) induzida por 6-hidroxidopamina (6-OHDA) em ratos, e o papel do BDNF nas alterações encontradas. O estudo foi dividido em duas etapas, sendo elas voltadas para o efeito neuroprotetor e para o efeito preventivo do exercício. Para analisar o efeito do BDNF realizou-se injeção intraestriatal do bloqueador do receptor de BDNF (K252a). O protocolo de exercício consistiu de treino em esteira (3x/semana; 40 minutos). Realizaram-se testes comportamentais e análises histológicas da substância negra pars compacta e estriado. Os resultados obtidos revelaram, de modo geral, que o exercício foi eficaz na melhora do sistema dopaminérgico e capaz de recuperar o comportamento dos ratos injetados com 6-OHDA. Demonstramos ainda que o beneficio promovido pelo exercício intermitente parece ter o envolvimento do sistema BDNF-TrkB, sugerindo ser esse um importante sistema para prevenção e neuroproteção na DP. / Exercise is known to produce beneficial effects to the nervous system, The objective of this project was to investigate the histological and behavioral changes promoted by physical exercise in the PD model induced by 6-hydroxydopamine (6-OHDA) in rats, and the role of BDNF in the changes. The study was divided into two stages, aimed at evaluating the neuroprotective and the preventive effects of exercise. To analyze the effects of BDNF we used intrastriatal injections of a BDNF receptor blocker (K252a). The exercise protocol consisted of treadmill exercise (3x/week, 40 minutes). We carried out behavioral tests and histological analysis of the substantia nigra pars compacta and the striatum. The results showed, in general, that exercise is effective in improving the dopaminergic system and able to improve the behavior of rats injected with 6-OHDA. We also demonstrated that the positive effects of intermittent exercise appear to involve the BDNF-TrkB system, suggesting this as an important preventive and neuroprotective system in PD.

O objetivo principal deste estudo foi investigar a aprendizagem de pacientes com Doença de Parkinson (DP) em 10 jogos do vídeo game Nintendo Wii Fit Plus®, com diferentes demandas motoras e cognitivas, por meio das modificações do desempenho após o treinamento, comparando-a com a aprendizagem de indivíduos saudáveis da mesma faixa etária, em um estudo clínico, longitudinal e controlado. Dezesseis pacientes em estágio inicial da DP e 11 idosos saudáveis participaram de um treinamento que compreendeu 14 sessões de exercícios de aquecimento que precederam o treino no Nintendo Wii Fit Plus®, realizadas 2 vezes por semana. Nessas sessões, duas tentativas em 5 de 10 jogos foram realizadas, sendo que nas sessões pares foram treinados 5 jogos diferentes das sessões ímpares. Uma sessão de treino e avaliação adicional foi feita sessenta dias após o final do treinamento em cada jogo, totalizando 2 sessões adicionais para treino e avaliação da retenção. Ao final do estudo foram realizadas no total 16 sessões de treino. Aprendizado foi a principal medida de resultado sendo baseada nas pontuações obtidas durante todas as sessões, nos 10 jogos. Encontrou-se que os pacientes com DP não mostraram deficiências de aprendizado em 7 dos 10 jogos, embora tenham mostrado desempenho inferior em 5 jogos, quando comparados aos idosos. Os pacientes mostraram importantes deficiências de aprendizado em 3 outros jogos, independentemente do desempenho inicial inferior. Esta deficiência pareceu estar associada às demandas cognitivas desses jogos, que requerem tomadas de decisão rápidas, inibição de resposta, atenção dividida e memória operacional. Concluiu-se que a capacidade de pacientes com DP em melhorar e reter o desempenho após o treinamento no Nintendo Wii Fit Plus® depende grandemente das demandas dos jogos envolvidos, sobretudo as demandas cognitivas, reiterando a importância da seleção adequada dos jogos com proposta de reabilitação / The main objective of this study was to investigate the learning of Parkinson´s Disease (PD) patients in 10 games of the video game Nintendo Wii Fit Plus ® with different motor and cognitive demands, through changes in performance after training, comparing it with health elderly, in a clinical, longitudinal and controlled study. Sixteen patients in early stages of PD and 11 healthy elderly subjects participated in a training program which comprised 14 warm exercises sessions that preceded the Nintendo Wii Fit Plus® training, twice a week. In these sessions, two attempts in 5 of 10 games were held, being that on even sessions were trained 5 different games of odd sessions. A training session and further evaluation was made sixty days after the end of training in each game, totaling two additional sessions to assess retention. At the end of the study were performed, in total, 16 training sessions. Learning was the main outcome measure being based on the scores obtained during all sessions, in 10 games. It was found that PD patients showed no learning impairments in 7 of 10 games, although they have shown a lower performance in 5 games, compared to the elderly. The patients showed significant deficiencies in learning in 3 other games, regardless of the initial performance lower. This deficiency appeared to be related to the cognitive demands of those games that require quick decision making, response inhibition, divided attention and working memory. It was concluded that the ability of PD patients to improve and retain the performance after training on the Nintendo Wii Fit Plus® depends greatly on the demands of the games involved, especially the cognitive demands, reiterating the importance of proper selection of games with proposed rehabilitation

A Doença de Parkinson (DP) é uma das doenças degenerativas do Sistema Nervoso Central que mais acomete indivíduos no mundo. Apesar de a DP ser descrita classicamente como desordem do movimento, sintomas não motores também fazem parte da apresentação da doença, como as alterações cognitivas, que podem estar presentes antes mesmo de os sintomas motores serem percebidos. Os principais domínios cognitivos afetados na DP são as funções executivas (FE). Estas consistem num contingente de funções de ordem superior, que são cruciais para cognição, emoção e comportamento. Muitos estudos abordam a influência das FE no controle da marcha, já que esta não é mais considerada como um ato motor puramente automático. De fato, existem componentes cognitivos na generalização e manutenção de um padrão de marcha consistente e normal, o que justifica os prejuízos neste controle interdependente entre FE e marcha na DP. O objetivo deste estudo foi avaliar a eficiência de um treino original de marcha com demandas motoras e cognitivas desafiadoras, integradas em um contexto funcional em pacientes com DP em estágio inicial. Trata-se de um ensaio clínico cego e randomizado realizado na Associação Brasil Parkinson em São Paulo. Participaram do estudo 25 pacientes com DP nos estágios 1 a 2,5 da escala Hoehn & Yahr. Eles foram distribuídos aleatoriamente nos grupos experimental (GE: 13 sujeitos) e controle (GC: 12 sujeitos). Os dois grupos foram submetidos a 10 sessões de treinamento, com duração de 60 minutos cada uma (divididos em 25 minutos de exercícios de mobilidade global e 35 minutos para os treinos específicos), com frequência de duas vezes por semana, por 5 semanas. O treino experimental consistiu em treino de marcha com demandas motoras desafiadoras e demandas cognitivas constituídas por seis tarefas que exigiam as principais FE envolvidas na realização da marcha, que foram integradas em um contexto funcional. O treino 12 controle consistiu apenas de demandas motoras desafiadoras. As principais medidas foram: (1) Dynamic Gait Index (DGI); (2) Montreal Cognitive Assessment (MoCA); (3) teste de marcha em 30 segundos em dupla-tarefa cognitiva; (4) sessão II da Escala Unificada da Doença de Parkinson (UPDRS). Anova de medidas repetidas seguida de teste de Tukey avaliou a existência de diferenças dentro de cada grupo, em avaliações realizadas antes (AT), depois (DT) e após 60 dias do final do treinamento (RET). Resultados mostraram melhora estatisticamente significativa no DGI, MoCA, teste de marcha em dupla tarefa cognitiva, e sessão II da UPDRS. Entretanto, na medida de seguimento após 60 dias, para várias medidas foram observadas diferentes tendências entre os grupos: o GE apresentou uma tendência à manutenção dos ganhos, ao passo que o GC apresentou uma tendência à remissão dos ganhos. Conclui-se que os pacientes com DP lograram melhoras nos âmbitos motor, cognitivo e funcional por meio de um treinamento baseado na associação de tarefas cognitivas à marcha dentro de um contexto funcional, ganhos estes possivelmente mais estáveis em comparação aos oriundos do treino motor isolado / Parkinson\'s disease (PD) is one of the most frequent degenerative diseases of the central nervous system. Despite being classically described as a motor disorder, non-motor symptoms such as cognitive disorders are also part of the disease, and may be present even before patients become aware of their motor disorders. The main cognitive domains that are affected in PD are executive functions (EF). They consist of a number of higher-order functions, which are crucial for cognition, emotion and behavior. Several studies address influence of EF upon gait control, since gait is no longer considered as a purely automatic motor act. In fact, there are cognitive components in the generalization and maintenance of a normal consistent gait pattern. This helps explain why damages in EF affect gait control in PD, and gait affects EF. The study aimed to assess the effectiveness of an original gait training with challenging motor and cognitive demands, which are integrated in a functional context in patients with early PD. It consists of a blind randomized clinical trial, which was conducted at the Brazil Parkinson\'s Association in Sao Paulo. In the procedure 25 patients, with PD in stages 1 to 2.5 on Hoehn & Yahr scale, were randomly assigned to experimental group (13 subjects) and control group (12 subjects). Training consisted of 10 sessions, 60 minutes each. Sessions were divided into global mobility exercises (25 minutes) and training (35 minutes). Sessions occurred twice a week over five weeks. Experimental training consisted of a gait training with challenging motor demands and cognitive demands. There were six tasks that demanded important EF involved in gait performance, which were integrated into a functional context. Control training consisted only of challenging motor demands. Measures included: (1) Dynamic Gait Index (DGI); (2) Montreal Cognitive Assessment (MoCA); (3) gait test for 30 seconds in dual-cognitive task; (4) session II of the Unified Parkinsons Disease Rating Scale (UPDRS). Repeated measures ANOVA followed by Tukey tests were used to assess the existence of differences 14 within each group, in measures taken before training, after training, and in a follow-up 60 days after training. Both groups showed improvement in DGI, MoCA, gait test in dual-cognitive task, and session II of the UPDRS. However, in the follow-up assessment 60 days after training different trends were observed between the groups: EG showed a tendency to maintain gains, whereas CG showed a tendency to remission of gains. In conclusion, PD patients showed improvements in motor, cognitive and functional areas through a combination of a training based on challenging cognitive tasks on gait integrated in a functional context. Such gains were possibly more stable than those derived from gait training alone

A doença de Parkinson (DP) é a segunda doença neurodegenerativa mais comum do mundo, e seu tratamento atual se baseia principalmente no uso de medicações que facilitam a transmissão dopaminérgica nos núcleos da base. A L-DOPA é a principal medicação usada no tratamento da DP, contudo seu uso crônico está associado ao surgimento de complicações motoras, como as discinesias induzidas por L-DOPA (DIL). As DIL ocorrem em cerca de 50% dos pacientes com DP que usaram LDOPA por cerca de 4 a 6 anos, e podem causar uma série de impactos negativos aos pacientes. Pela incapacidade adicional que esta complicação traz aos pacientes com DP, a definição de fatores que possam predizer o surgimento das DIL é de importância direta para o clínico que prescreve L-DOPA rotineiramente. O objetivo deste estudo foi determinar os principais fatores de risco clínicos e genéticos para o desenvolvimento de DIL em uma casuística de pacientes brasileiros com DP. Um estudo transversal foi realizado em pacientes brasileiros de dois centros (Ribeirão Preto e São Paulo) como parte do projeto \"Latin American Research Consortium on the Genetics of PD\" (LARGE-PD), incluindo apenas pacientes com DP e em uso de L-DOPA. A avaliação foi baseada em um exame neurológico completo e em uma entrevista semi-estruturada feita por um médico neurologista especialista em Distúrbios de Movimentos. A presença de DIL foi considerada se a pontuação fosse >= 1 no item 32 da Parte IV na MDS-UPDRS. Baseados em estudos prévios, nós escolhemos oito polimorfismos tipo single nucleotide polymorphism (SNP) nestes genes: COMT, MAOB, ANKK1, DRD3, DAT1, BDNF, ADORA2A and NOS1. A genotipagem foi realizada através de ensaios TaqMan SNP. Foram realizados modelos de regressão logística e análises de sobrevivência para identificarmos os fatores de risco clínicos e genéticos associados ao surgimento de DIL. Ao todo, foram analisados 199 pacientes (sexo masculino - 59%; idade média 61.8 anos), sendo 96 indivíduos (48.2%) com DIL. Através de um modelo de regressão logística multivariado com 7 variáveis independentes, o fenótipo clínico motor do tipo postural instability with gait disorder (PIGD) (OR 0.17, IC 95% 0.07-0.39; p < 0.001), longos períodos de tratamento com L-DOPA (OR 1.31, IC 95% 1.17-1.47; p < 0.001), altas doses diárias equivalentes de L-DOPA (OR 1.00, IC 95% 1.000-1.002; p = 0.04) e a início precoce dos sintomas da 11 DP (OR 1.04, IC 95% 1.01-1.07; p = 0.009) foram os fatores de risco clínicos mais associados ao surgimento de DIL. Dentre os fatores de risco genéticos, apenas o alelo T do SNP rs1799836 no gene da MAOB esteve associado ao aumento na chance de surgimento de DIL (OR 1.51, IC 95% 1.00-2.28; p = 0.05). Nossos resultados mostraram que a predição de surgimento de DIL em pacientes com DP em uso de L-DOPA pode ser feita através de alguns fatores de risco clínicos (fenótipo clínico motor, duração do tratamento com L-DOPA, dose diária equivalente de L-DOPA e idade de início de sintomas) e genéticos, como o SNPrs1799836 no gene da MAOB. Novos estudos com amostras maiores e desenhos prospectivos longitudinais são necessários para se explorar a associação entre estes preditores e o surgimento de DIL. / Parkinson\'s disease (PD) is the second most common neurodegenerative disease in the world, and its treatment is mainly based on drugs involved on dopaminergic neurotransmission in basal ganglia. L-DOPA is the major medication used on the management of PD, but its chronic use is associated with the onset of motor complications, as L-DOPA-induced dyskinesias (LID). LID occur in approximately 50% of patients using L-DOPA over 4 and 6 years, and they cause negative impacts on the quality of life of patients PD. To predict the onset of LID based on clinical and genetic risk may be an useful tool for clinicians which prescribe L-DOPA. The aim of this study was to determinate the main clinical and genetic risk factors for the onset of LID in Brazilian PD patients. A cross-sectional study was conducted with Brazilian PD patients from two centers (Ribeirao Preto and Sao Paulo) as part of the Latin American Research consortium on the Genetics of PD (LARGE-PD), which enrolled only PD patients using L-DOPA. PD patients were submitted to neurological examination and semi-structured interviews performed by movement disorders specialists. Presence of LID was confirmed if UPDRS Part IV had a score >= 1 on item 32. Based on previous studies, we chose eight Single Nucleotide Polymorphisms (SNP) in the following genes: COMT, MAOB, ANKK1, DRD3, DAT1, BDNF, ADORA2A and NOS1. Genotyping was performed using TaqMan SNP genotyping assays. We performed logistic regression and survival analysis to identify clinical and genetic risk factors associated with LID onset We enrolled 199 PD patients (males - 59%; mean age 61.8 years), and 96 patients (48.2%) had LID. At a multivariate model with 7 independent variables, postural instability with gait disorder (PIGD) clinical phenotype (OR 0.17, CI 95% 0.07-0.39; p < 0.001), longer duration of L-DOPA therapy (OR 1.31, Cl 95% 1.17-1.47; p < 0.001), higher L-DOPA equivalent daily doses (OR 1.00, CI 95% 1.000-1.002; p = 0.04), as also as early onset of PD (OR 1.04, CI 95% 1.01-1.07; p = 0.009) were the clinical risk factor more associated with onset of LID. Regarding genetic risk factors, only MAOB SNP rs1799836 was associated with LID, with the T allele increasing the risk of developing LIDs (OR 1.51, CI 95% 1.00-2.28; p = 0.05). Our results showed onset of LID can be predicted based on some clinical (motor clinical phenotype, duration of L-DOPA therapy, L-DOPA equivalent daily dose and age at PD onset) and genetic risk factors, as MAOB SNP rs1799836. Further studies in larger samples, using longitudinal and prospective designs, are needed to explore the association between these predictors and onset of LID.

The discovery of biomarkers for Parkinson's disease (PD) is challenging due to the heterogeneous nature of this disorder, and a poor correlation between the underlying pathology and the clinically expressed phenotype. An ideal biomarker would inform on PD-relevant pathological changes via an easily assayed biological characteristic, which reliably tracks clinical symptoms. Human dermal (skin) fibroblasts are accessible peripheral cells that constitute a patient-specific system, which potentially recapitulates the PD chronological and epigenetic aging history. Here, we compared primary skin fibroblasts obtained from individuals diagnosed with late-onset sporadic PD, and healthy age-matched controls. These fibroblasts were studied from fundamental viewpoints of growth and morphology, as well as redox, mitochondrial, and autophagic function. It was observed that fibroblasts from PD subjects had higher growth rates, and appeared distinctly different in terms of morphology and spatial organization in culture, compared to control cells. It was also found that the PD fibroblasts exhibited significantly compromised mitochondrial structure and function when assessed via morphological and oxidative phosphorylation assays. Additionally, a striking increase in baseline macroautophagy levels was seen in cells from PD subjects. Exposure of the skin fibroblasts to physiologically relevant stress, specifically ultraviolet irradiation (UVA), further exaggerated the autophagic dysfunction in the PD cells. Moreover, the PD fibroblasts accumulated higher levels of reactive oxygen species (ROS) coupled with lower cell viability upon UVA treatment. In essence, these studies highlight primary skin fibroblasts as a patient-relevant model that captures fundamental PD molecular mechanisms, and supports their potential utility to develop diagnostic and prognostic biomarkers for the disease.

Abstract Parkinson's disease (PD) is known to affect both the extrapyramidal system and the autonomic nervous system even in the early phases of the disease. This study was designed to evaluate cardiovascular autonomic regulation in early PD by measuring heart rate (HR) variability from 24-hour ECG recordings. The dynamics of blood pressure (BP), HR and sweating in patients with and without wearing-off were assessed during clinical observations after a morning dose of levodopa. In patients with wearing-off the tests were repeated after selegiline withdrawal. The power spectral components of HR variability and the SD1 value of the Poincaré analysis that quantifies the short-term beat-to-beat variability were suppressed at night in the PD patients. During the daytime only the SD1 of the Poincaré was suppressed. The results indicate impairment of parasympathetic cardiovascular regulation in untreated patients with PD. The dysfunction was more pronounced at night and in patients with more severe PD. The patients with wearing-off had fluctuation of BP during the observation period, BP increasing when the motor performance worsened and vice versa (p &lt; 0.001). The patients without wearing-off did not show fluctuation of BP. Sweating increased during the observation period, and reached its maximum level at the time of the highest UPDRS motor score phase (off-stage) in patients with wearing-off, but in the patients without wearing-off no changes in sweating were observed. Sweating of the hands was significantly higher in PD patients with motor fluctuations than in those without. Selegiline withdrawal decreased systolic BP significantly during the on-stage in a supine position as well as during the orthostatic test. The initial drop of BP in the orthostatic test was significantly smaller after selegiline withdrawal. The HR and sweating remained unaffected. The results show that the autonomic nervous system is affected in the early phases of PD. The dysfunction becomes more pronounced with the disease progression. Wearing-off type motor fluctuations are associated with fluctuation of BP and sweating and these fluctuations may represent autonomic dysfunction caused by PD, the effect of PD medication, or both. Selegiline withdrawal seems to alleviate the orthostatic reaction in patients with advanced PD.

Parkinson's disease (PD) is a neurodegenerative disorder that is characterised by uncontrollable shaking, muscular rigidity and cognitive impairment, due to low levels of dopamine caused by loss of dopamine containing neurons (DCN). The loss of DCN has been strongly associated with Caspase mediated apoptotic death. At present there are many studies that indicate exercise is beneficial in PD treatment, but there is a lack of research exploring the potential pathways, which exercise can activate and suppress to provide such positive and even negative effects. This study is the first to explore the effect of treadmill exercise on the level of Caspases, along with CAMK-IV protein in different brain regions of MPTP-treated rat model, using WB analysis. The results of this research has demonstrated reduction or completely suppression of some active Caspases, as well as, elevated amount of CAMK-IV in different brain regions of exercised PD animal model. To determine how exercise is reducing and inhibiting activation of Caspases, the first step was to identify how Caspases are stimulated, using ReNcell VM stem cell line that had been differentiated and treated with 6OHDA. The results of the study demonstrated 6OHDA triggered Caspase mediated apoptotic death of dDCN via PERK ER stress and NFκB classical pathway. IF, WB and cell viability analysis, using a wide range of inhibitors, showed that Caspase-2 is activated by the PERK pathway of ER stress and NFB classical pathway in 6OHDA treated dDCN. 6OHDA triggered activation of Caspase- 8 by the classical pathway in NFB mediated death of dDCN. 6OHDA triggered Caspase-4 activation but the exact mechanism involved remains to be identified. Only through understanding the molecular pathways regulating death of DCN in PD, new potential targets for therapy may be identified, which may ultimately reduce further death of DCN and slow PD progression. This proposed study has the potential to seek for more efficient drugs, which can suppress Caspase activation by targeting key targets in the pathways that the Caspases follow. These new specific targeted drugs could be used with treadmill exercise to achieve maximum effect, by slowing down or inhibiting further death of DCN.

No description available.