No description available.

Parkinson’s disease is a common neurodegenerative disorder caused by nigrostriatal dopamine loss, with motor deficiencies as the primary outcome. To increase the striatal dopamine content, patients are treated with 3,4-dihydroxyphenyl-l-alanine (l-DOPA). Beneficial relief of the motor symptoms is achieved initially, although the efficacy is lost with time and severe side effects, referred to as l-DOPA-induced dyskinesia, manifest in the majority of patients. Biological mechanisms responsible for the dopaminergic degeneration and the upcoming of dyskinesia are still unclear, and thus knowledge regarding critical factors for maintenance of the nigrostriatal system as well as neurochemical changes upon chronic l-DOPA is urgent. The present work aims at studying the importance of glial cell line-derived neurotrophic factor (GDNF) for nigrostriatal preservation, and the involvement of the dopaminergic, serotonergic, and glutamatergic systems in l-DOPA-induced dyskinesia. Effects from different levels of GDNF expression were evaluated on fetal mouse nigrostriatal tissue in a grafting study. In GDNF gene-deleted grafts, degeneration of the entire nigrostriatal system was evident at 6 months. In grafts with partial GDNF expression, significant loss of dopamine neurons was observed at later time points, although deviant findings in the dopamine integrity such as reduced innervation capacity and presence of intracellular inclusions-like structures were already present at earlier stages. The results emphasize GDNF as a crucial factor for long-term maintenance of the nigrostriatal system. Furthermore, striatal neurochemical alterations upon chronic l-DOPA treatment were studied in hemiparkinsonian rats using in vivo voltametry. The findings demonstrated impaired dopamine as well as glutamate releases in dyskinetic subjects, with no effects from acute l-DOPA administration. Conversely, in l-DOPA naïve dopamine-lesioned animals, dopamine release was increased and glutamate release attenuated upon a l-DOPA challenge. Moreover, l-DOPA-derived dopamine release was demonstrated to originate from serotonergic nerve fibers in the dopamine-lesioned striatum, an event that contributes significantly to dopamine levels also in intact striatum, and thus, is not a consequence from dopamine depletion. Assessment of serotonergic nerve fibers in l-DOPA treated animals and in a grafting study concluded that nerve fiber density was not affected by chronic l-DOPA treatment, nevertheless, dysfunction of this system can be suspected in dyskinetic animals since dopamine release was impaired and regulation of glutamate release by serotonergic 5-HT1A receptor activation was achieved in normal but not in dyskinetic animals. Furthermore, the selective serotonin reuptake inhibitor, fluoxetine, attenuated l-DOPA-induced dyskientic behavior, an effect that was demonstrated to be mediated via 5-HT1A receptors. In conclusion, dysmodulation of multiple transmitter systems is evident in LID.

Parkinson’s disease (PD) is the second most common neurodegenerative condition to affect humans, and is characterised by the loss of dopaminergic neurons from the substantia nigra pars compacta (SNpc) in the midbrain along with the deposition of abnormal aggregates of alpha-synuclein protein in the brain which are in the form of Lewy bodies. Dopaminergic neurons from the SNpc project into a large subcortical structure known as the striatum, and positron emission tomography (PET) studies have demonstrated the dysfunction of the dopaminergic system in the striatum of patients with PD. Furthermore, immunohistochemistry studies of the striatum have identified the degeneration of dopaminergic nerve terminals and inclusions of alpha-synuclein. An aggressive and early onset form of familial PD is caused by the G51D point mutation in alpha-synuclein (G51D/+). Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) technology has been used to generate a novel and precise rat model of PD which has the G51D mutation in rat alpha-synuclein. Wild-type (WT) and G51D/+ rats were analysed over the course of ageing (5, 10/11 and 16/17 months of age) using histological experiments and L-3,4-dihydroxy-6-18F-fluorophenylalanine (18FDOPA) PET imaging in order to determine if G51D/+ rats have abnormalities of histological staining and dopaminergic function analogous to those identified in patients with PD. Histological experiments were optimised using WT rat tissue and then used immunohistochemistry for tyrosine hydroxylase (an enzyme involved in the synthesis of dopamine) to evaluate dopamine nerve terminal integrity in the striatum of WT and G51D/+ rats. In addition, immunohistochemistry for alpha-synuclein was used to evaluate staining for alpha-synuclein in cell bodies and the neuropil within the striatum of WT and G51D/+ rats. 18F-DOPA is a well validated PET radiotracer and has been used to investigate dopaminergic function in the striatum of rats. The enzyme aromatic L-amino acid decarboxylase converts 18F-DOPA to 6-18F-fluorodopamine, which is in turn incorporated into presynaptic vesicles, and then released into the synaptic cleft following neuronal activation. PET imaging experiments were first optimised using phantoms and WT rats, then the optimised protocols were applied to studies of WT and G51D/+ rats. Results from tyrosine hydroxylase immunohistochemistry at Bregma 0.00 mm identified a trend for decreased optical density of tyrosine hydroxylase staining in the striatum of 5 month G51D/+ rats compared with age-matched WT controls (p=0.15), and in 17 month G51D/+ rats compared with age-matched WT controls (p=0.10). Semi-quantitative analysis of alpha-synuclein immunohistochemistry indicated an increased abundance of alpha-synuclein positive cell somata in the striatum, and decreased punctate terminal staining in the neuropil of G51D/+ rats compared with age-matched WT rats. 18F-DOPA PET imaging experiments indicated a trend for decreased influx rate constant (Ki) of 18F-DOPA in the striatum of 5 month old G51D/+ rats compared with age-matched WT controls (p=0.08), and a trend for decreased distribution volume ratio (DVR) of 18F-DOPA in the striatum relative to the cerebellum of 16 month old G51D/+ rats when compared with age-matched WT controls (p=0.09). 18F-DOPA PET imaging experiments also identified a trend for a decreased effective distribution volume ratio (EDVR) of 18F-DOPA in the striatum relative to the cerebellum (p=0.09) and in turn indicated increased effective dopamine turnover (EDT) (p=0.13) in the striatum of 16 month old G51D/+ rats compared with age-matched WT rats. Therefore, the results indicated abnormalities of dopaminergic function, as well as tyrosine hydroxylase and alpha-synuclein staining in G51D/+ rats compared with age-matched WT controls, and this appeared to have some features of PD in humans. Indices of EDT indicated compensatory changes in dopaminergic function in the striatum of 16 month old G51D/+ rats compared with age-matched WT rats. Additional compensatory changes in dopaminergic terminal function and tyrosine hydroxylase protein expression may be evident in 11 and 10 month old G51D/+ rats respectively compared with age-matched WT rats. The G51D/+ rat model represents an interesting model for further studies such as the underlying pathophysiology of PD. However, the phenotype observed in G51D/+ rats appeared to be less severe than that which has been observed in humans with G51D type PD.

Submitted by KÉSIA MAÍSA DO AMARAL null (kesinha.m.a@gmail.com) on 2017-01-17T13:17:29Z No. of bitstreams: 1 Defesa_Completo.pdf: 1880504 bytes, checksum: b232b42cdd04a94a74033f8240630862 (MD5) / Approved for entry into archive by LUIZA DE MENEZES ROMANETTO (luizamenezes@reitoria.unesp.br) on 2017-01-17T15:46:54Z (GMT) No. of bitstreams: 1 amaral_km_me_rcla.pdf: 1880504 bytes, checksum: b232b42cdd04a94a74033f8240630862 (MD5) / Made available in DSpace on 2017-01-17T15:46:54Z (GMT). No. of bitstreams: 1 amaral_km_me_rcla.pdf: 1880504 bytes, checksum: b232b42cdd04a94a74033f8240630862 (MD5) Previous issue date: 2016-12-14 / Introdução: Os acidentes de trânsito envolvendo pedestres são responsáveis por muitos casos de lesões graves e óbitos. Os idosos representam 30% das vítimas de atropelamento durante a travessia de rua no Brasil, e, outro grande grupo de risco são os indivíduos com doença de Parkinson, uma vez que esta doença está entre os acometimentos neurológicos que mais causam distúrbios do movimento. Objetivo: Identificar, por meio de parâmetros cinemáticos, alterações na marcha de idosos sem e com doença de Parkinson durante simulação de situações cotidianas de travessia de rua. Método: Participaram do estudo, idosos sem e com doença de Parkinson do sexo feminino e masculino os quais foram divididos em dois grupos: grupo de controle (GC) e grupo de idosos com doença de Parkinson (GIDP). A avaliação da marcha ocorreu sob três condições distintas: marcha habitual, marcha com simulação de travessia de rua e marcha com simulação de travessia de rua com tempo do semáforo de pedestres reduzido. Cada voluntário caminhou sobre a passarela por três vezes consecutivas em cada uma das condições de marcha. A simulação de travessia de rua foi realizada de acordo com as recomendações do Departamento Nacional de Trânsito para a temporização de semáforos. A análise estatística foi realizada utilizando o software PASW statistics 18.0® (SPSS) por meio do teste ANOVA Medidas Repetidas. Em todos os testes estatísticos foi adotado o nível de significância de p<0.05. Resultados: Na comparação intergrupos GIDP apresentou diminuição significativa da velocidade em todas as condições (p=0.002; p=0.008; p=0.001) e do comprimento de passo na condição de marcha habitual e com simulação de travessia de rua (p=0.015; p=0.025 respectivamente), e, aumento do tempo de duplo apoio somente na condição de marcha habitual (p=0.027) quando comparado ao GC. Na comparação intragrupo, ambos os grupos apresentaram diferença significativa entre as condições em todas as variáveis analisadas. Conclusão: Os parâmetros cinemáticos analisados no presente estudo se comportam de modo semelhante entre as condições em ambos os grupos, entretanto, idosos com doença de Parkinson apresentam pior desempenho da marcha. / Introduction: The traffic accidents involving pedestrian are responsible for many cases of serious injuries and deaths. The elderly represent 30% of victims of trampling during the street crossing in Brazil, and other big risk group is the individuals with Parkinson's disease, since this disease is among the neurological events causing more disorders of movements. Objective: Identify, through kinematic parameters, changes in gait of elderly without and with Parkinson's disease during simulation of everyday situations of street crossing. Method: Male and female elderly without and with Parkinson's disease participated in the study, who were divided in two groups: control group (CG) and group of elderly with Parkinson's disease (GEPD). The gait evaluation took place in three different conditions: usual gait, gait with street crossing simulation and gait with street crossing simulation with reduced time of traffic lights pedestrian. Each volunteer walked on the walkway for three consecutive times in each of the gait conditions. The street crossing simulation was realized according with the National Traffic Department recommendations to the timing of traffic lights. The Statistical analysis was realized be software PASW statistics 18.0® (SPSS), using the test ANOVA two way. In all the statistical tests was adopted the significance level p<0.05. Results: In comparison between groups GEPD show significant decrease in velocity in all conditions (p=0.002; p=0.008; p=0.001), and in step length in usual gait condition and street crossing simulation condition (p=0.015; p=0.025 respectively), and, increase of double support time only in usual gait condition (p=0.027) when compared to CG. In comparison of same group, both groups showed significant difference between the conditions in all the variables analyzed. Conclusion: The kinematic parameters analyzed in this study behave similarly between the conditions in both groups, however, elderly patients with Parkinson's disease have worse performance of gait.

No description available.

This work deals with the problem of face parameterization from the video of a speaking person and estimating Parkinson’s disease and the progress of its symptoms based on face parameters. It describes the syntax and function of the program that was created within this work and solves the problem of face parameterization. The program formats the processed data into a time series of parameters in JSON format. From these data, a dataset was created, based on which artificial intelligence models were trained to predict Parkinson’s disease and the progress of its symptoms. The process of model training and their results are documented within this work.

Parkinson’s disease (PD) is a common neurodegenerative disorder associated with dysfunction of the basal ganglia, which contributes to a range of motor, cognitive, and affective symptoms. Striatal dopaminergic deficits are one of the core pathological mechanisms thought to contribute to the extra-motor (i.e., cognitive and affective) symptoms in early PD. The present study investigated the relationship between striatal dopaminergic integrity and cognition in 21 patients with PD and 21 age and education matched controls. Each individual underwent dopamine transporter (DaT) imaging with single photon emission computed tomography (SPECT) (i.e., DaTscan) and standardized neuropsychological testing. Strong positive associations were found between DaT availability in the striatum and verbal memory (r = .52-.61) and problem solving/set-shifting (r = .55) in patients with PD. Additional moderate to strong positive associations (r = .49-.56) between DaT concentrations and visuospatial functions in patients with PD were found. However, similar significant associations between DaT and cognition were observed in age and education matched controls. Clinically, it is important for health care professionals to consider the role of both striatal and extra-striatal mechanisms as they relate to cognition in PD. Future studies examining the full range of pathological mechanisms that contribute to cognitive dysfunction in PD over time are warranted in order to inform more effective and targeted interventions.

Parkinson’s disease (PD) impairs the quality of life of patients and causes substantial social and economic burden. However the currently available symptomatic treatments, although initially effective, do not satisfactorily control the progressive disability experienced by patients with PD in the long run. In order to develop effective treatments for patients that aim to attain the desired effect with as few adverse events as possible, it is crucial to be able to follow and understand the biological mechanisms underlying the continued neural degeneration and treatment failure. The efforts to understand the precise pathway by which neurodegenerative processes proceed and the development of approaches to modulate them offers the promise to eventually enable the prevention of these neurodegenerative diseases. This dissertation focused on two potential synthetic methods to produce pharmaceutical grade Fluorodopa, ultimately to be able to produce positron emitting 18Fluorodopa in South Africa with its potential for studying neuronal mechanisms in the brain. 18Fluorodopa allows a unique almost non-invasive in vivo approach to the evaluation of neurochemical function in the human brain and its local introduction will be a valuable addition to medical research within South Africa’s borders. The successful implementation of safe and efficient non-radioactive models for Fluorodopa synthesis was achieved. The successful demonstration of locally synthesised Fluorodopa safety, as well as a low toxicity profile, both in vitro using cell cultures and in vivo in mouse models was achieved. These were both positive outcomes of objectives set out for this study. Copyright / Dissertation (MSc)--University of Pretoria, 2010. / Pharmacology / unrestricted

Physical exercise offers a highly effective health-endowering activity as has been evidence using rodent models of Parkinson’s disease (PD). It is a particularly useful intervention in individuals employed in sedentary occupations or afflicted by a neurodegenerative disorder, such as PD. The several links between exercise and quality-of-life, disorder progression and staging, risk factors and symptoms-biomarkers in PD all endower a promise for improved prognosis. Nutrition provides a strong determinant for disorder vulnerability and prognosis with fish oils and vegetables with a mediterranean diet offering both protection and resistance. Three factors determining the effects of exercise on disorder severity of patients may be presented: (i) Exercise effects upon motor impairment, gait, posture and balance, (ii) Exercise reduction of oxidative stress, stimulation of mitochondrial biogenesis and up-regulation of autophagy, and (iii) Exercise stimulation of dopamine (DA) neurochemistry and trophic factors. Running-wheel performance, as measured by distance run by individual mice from different treatment groups, was related to DA-integrity, indexed by striatal DA levels. Finally, both nutrition and exercise may facilitate positive epigenetic outcomes, such as lowering the dosage of L-Dopa required for a therapeutic effect.

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13463号 / 論医博第2250号 / 新制||医||1055(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 高橋 淳, 教授 稲垣 暢也, 教授 萩原 正敏 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM