Parkinson’s disease (PD) is a common neurodegenerative disorder that is characterised by akinesia, muscular rigidity, and postural instability, due primarily to the loss of dopaminergic neurons in the substantia nigra and depletion of upstream dopamine in the striatum. Current dopaminergic treatments reduce motor symptoms, but have diminishing benefits as the disease progresses. Treatment with the neuroactive steroid natural progesterone (PROG) improves outcomes in many experimental models of brain injury due to its pleiotropic mechanisms of neuroprotection, many of which may also benefit PD. This thesis investigated the influence of PROG on motor impairments in the unilateral intrastriatal 6-hydroxydopamine (6-OHDA) lesion model of PD in rats. We established a PD-like impairment with a d-amphetamine induced rotation test at day 7 after large lesions and then administered PROG (4 mg/kg or 8 mg/kg) once daily for 7 days starting at day 8. Both PROG doses markedly improved the primary outcome measure, forelimb akinesia on the adjusting steps test, with improvement sustained for six weeks after treatment had stopped. In a second study the beneficial influence of PROG (8 mg/kg) on akinesia was replicated for rats with large lesions and was extended to rats with small lesions so that the latter rats were now similar to sham operated controls. We also found that PROG modestly improved postural instability of the ipsilateral forelimb on the postural instability test, and sensorimotor integration on the whisker test, but did not improve skilled reaching accuracy on a single-pellet reaching task, forelimb use asymmetry on the cylinder test, sensory neglect on the corridor test, or rotation bias after apomorphine. Furthermore, PROG did not change striatal tyrosine hydroxylase density when assessed in rats with large lesions. This study has provided the most thorough examination to date regarding PROG’s influence on motor skills in an animal model of PD. Furthermore, this study has produced novel evidence of the beneficial effects of PROG treatment on forelimb akinesia. These initial promising findings suggest that PROG is an effective therapy for akinesia and thus provides an impetus to further investigate PROG’s efficacy for the treatment of PD.

Damage to the adult mammalian central nervous system (CNS), either by traumatic injury or disease, usually results in permanent sensory and/or motor deficits. Regeneration of neural circuits is limited both by the lack of growthpromoting molecules and by the presence of growth-inhibitory molecules in the mature brain and spinal cord. The research described here examines the therapeutic potential of viral vectors and neuronal transplants to reconstruct damaged neural pathways in the CNS. Experimental neural transplantation techniques often fall short of expectations because of limited transplant survival and insufficient neurite outgrowth to repair connections and induce behavioral recovery. These shortcomings are addressed in the current studies by virus-mediated expression of cell-specific neurotrophic and guidance molecules in the host brain prior to cell transplantation. The initial proof-of-principle studies show that viral vectors can be used to create axon-guidance pathways in the adult mammalian brain. With such pathways in place, subsequent transplantation of neurons leads to longdistance, targeted outgrowth of neurites. Application of this technique to a rat model of Parkinsons disease demonstrates that circuit reconstruction leads to functional recovery. For this study, rats were lesioned on one side of their brain with 6-hydroxydopamine to produce a hemiparkinsonian state. The motor deficit was confirmed by amphetamine-induced rotation testing and spontaneous motor asymmetry testing. The rats were then divided into experimental groups to receive lentivirus injections along a path between the substantia nigra (SN) and the striatum to express glial cell-line derived neurotrophic factor (GDNF), GDNF family receptor alpha-1 (GFR1), netrin-1 or green fluorescent protein (GFP, control). One group received combination injections of lenti-GDNF and lenti-GFR1. One week after virus injections, animals received transplants of embryonic midbrain dopaminergic neurons into their SNs. They were tested for motor asymmetry every two weeks for a total of eight weeks and then brain tissue was harvested for immunohistochemical analysis. Results demonstrate that virus-induced expression of GDNF and GFR1 supports growth of dopaminergic fibers from cells transplanted into the SN all the way to the striatum, and these animals have a significant reduction in both drug-induced and spontaneous motor asymmetry.

Several tasks examined implicit and explicit memory in matched samples of Alzheimer's (AD) and Parkinson's disease (PD) patients, and healthy elderly subjects. Lexical priming, pursuit-rotor tracking, and a fragmented pictures test, followed by explicit memory tests, were given. AD patients were impaired on all explicit tests and on lexical priming, but were intact on pursuit-rotor tracking and the procedural learning (PL) component of the fragmented pictures test. PD patients were significantly better than AD patients on all explicit memory tests, but were selectively impaired on the PL component of the fragmented pictures test. Finally, a mirror reading test was given to the PD patients and matched control subjects, with no significant differences in performance between the two groups demonstrated. Results are discussed in terms of hypothetical cognitive processes and brain circuits underlying different explicit and implicit memory domains.

No description available.

Vascular endothelial growth factor-B (VEGF-B), when initially discovered, was thought to be an angiogenic factor, due to its intimate sequence homology and receptor binding similarity to the prototype angiogenic factor, VEGF-A. Studies demonstrated VEGF-B, unlike VEGF-A, did not play a significant role in angiogenesis or vascular permeability and has become an active area of interest because of its role as a survival factor in pathological processes in a multitude of systems, including the brain. By characterization of important downstream targets of VEGF-B that regulate different cellular processes in the nervous system and cardiovascular system, it may be possible to develop more effective clinical interventions in diseases such as Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS) and ischemic heart disease, which all share mitochondrial dysfunction as part of the disease. Here we summarize what is currently known about VEGF-B function in pathological processes, compare probable mechanisms of action and elude to its potential as a homeostatic protective factor to increase mitochondrial function in the setting of neurological disease and cardiovascular disease.

There has been growing support for the idea that complicated grief symptoms following bereavement are independent of symptoms of depression and anxiety. However, the loss of a loved one is not the only or the most frequent type of loss to be encountered. The onset of an insidious medical illness may trigger a mourning process for the lost function or body part that is posited to also involve feelings of grief. While the risk of depression is high among a medical or rehabilitative population, the impact of grief over functional losses has never been empirically investigated as a contributing factor in the patient's emotional and physical functioning following illness. Currently, many assume that grief and depression are part of the same condition within the medical context. However, it may be that symptoms conceptualized as grief in the bereavement literature can be identified and distinguished from depressive symptoms within a medically ill population.The aims of the current study were to: (1) investigate the reliability and validity of the Loss Inventory (Niemeier, Kennedy, McKinley, & Cifu, 2004), a newly-developed measure used to assess intrapersonal grief, (2) explore the relationship between grief and depression, and their distinction from one another, using principal components analysis among their respective symptom items, and (3) examine the unique and added contribution of grief on concurrent and prospective emotional and physical health outcomes (i.e. self-esteem, intrusive thoughts and avoidant behavior, global well-being, sleep quality, state anxiety, activities of daily living, and number/severity of co-morbid illnesses).Two hundred and ten Parkinson's disease and Essential Tremor patients recruited from a VAMC Hospital completed questionnaires at baseline and five to six months later. The Loss Inventory proved to be a reliable and a valid measure of intrapersonal grief. Principal components analysis supported the distinction between intrapersonal grief and depression symptoms as measured by symptoms from the Loss Inventory and Zung SDS. Finally, grief symptoms significantly predicted several concurrent and prospective emotional and physical health outcomes after controlling for disease stage, disability, and depression. In sum, the present findings lend support to the hypothesis that bereavement-related symptoms can occur and are meaningful after functional losses from medical illness.

Parkinson's disease is a neurodegenerative disease characterized by the buildup of aggregated and spread of misfolded alpha-synuclein. How the misfolded alpha-synuclein contributing to the toxicity and death of neuronal cells has been the focal point of research. The spread of alpha-synuclein has been attributed to many mechanisms, one of which is via cell-derived vesicles called exosomes. This project aims to examine the controllability of exosome release. SH-SY5Y, MCF-7 and CHO-K1 cells were transfected with dopamine receptor 3-green fluorescent protein, G-protein receptor 143 or green fluorescent protein and treated with either dopamine or L-DOPA. Medium was harvested and subjected to ultracentrifugation and a silver stain and western blot were performed. There was no significant difference in the total protein in the exosome fraction lanes between the treatment groups or within them. Another aim was to test the specificity of exosomes. Exosomes isolated from SH-SY5Y or MCF-7 were labeled with Exo-Red dye and introduced to wells containing SH-SY5Y, MCF-7 and CHO-K1 cells at room temperature and -4C. At room temperature, exosomes were observed intercellular in all of the cell lines, however, they did not deliver their content. At -4C exosome uptake was halted and they remained on the surface of the cells. Exo-Red labeled SH-SY5Y exosomes were treated with proteinase K and were introduced to CHO-K1 cells at -4C and room temperature. CHO-K1 did not take up exosomes, suggesting exosomes contain one or more necessary proteins needed to interact with the cellular membrane to initiate internalization. CHO-K1 cells were treated with versene to examine the involvement of integrin proteins. Exo-Red labeled SH-SY5Y exosomes were trapped on the surface of CHO-K1 after versene treatment. Lastly, Exo-Red labeled SH-SY5Y exosomes were biotinylated and magnetically captured then introduced to SH-SY5Y and MCF-7 cells and a silver stain and a biotinylated blot were performed. MCF-7 bound more Exo-Red labeled SH-SY5Y exosomes.

A doença de Parkinson (DP) é uma patologia neurodegenerativa progressiva de causa desconhecida. A degeneração neuronal afeta vários grupos de neurônios no sistema nervoso central, mas de longe afeta muito mais os neurônios dopaminérgicos da pars compacta da substância nigra (SNc). Caracterizada por sintomas motores como bradicinesia, rigidez, tremor e instabilidade postural e sintomas não motores como depressão, ansiedade. O tratamento com o medicamento Levodopa está associado a efeitos colaterais, de ordem motora e não motora, em pacientes que o utilizam a longo prazo. Tais efeitos reduzem a qualidade de vida dos pacientes. Portanto esse estudo tem como principal objetivo analisar os sintomas de ansiedade em pacientes com DP idiopático que apresentavam flutuação motora (wearing - off, on e off), em tratamento com Levodopa, avaliar os sintomas da DP, principalmente o tremor e associar a ele a diminuição da ansiedade do paciente no momento em que se administra a medicação. Portanto, a coleta de dados ocorreu num primeiro contato com o paciente em off, ou seja, sem a Levodopa, em outros 3 momentos com o paciente em on. Foram aplicados a escala da Escala Analógica do Humor (VAMS), a Escala Unificada de Avaliação da Doença de Parkinson (UPDRS), Escala de Hoehn & Yahr (H&Y) e dois testes de Bradicinesia (Tapping, Pronação e supinação) para comparação evolutiva das atividades motoras e ansiedade do paciente em on e off. Concluímos que é comum a ocorrência de ansiedade em DP, que os níveis de ansiedade e a dificuldade motora são maiores quando o paciente está em off e que a administração do medicamento (Prolopa) reduz a ansiedade e melhora a função motora dos pacientes com DP. Esta melhora foi evidente nos testes de bradicinesia e na escala VAMS. / Parkinson\'s disease (PD) is a progressive neurodegenerative disease of unknown cause. The neuronal degeneration affects several groups of neurons in the central nervous system, but by far much more affects the dopaminergic neurons of the substance nigra pars compacta (SNc). Characterized by motor symptoms such as bradykinesia, rigidity, tremor and postural instability and non-motor symptoms such as depression, anxiety. Treatment with levodopa is associated with side effects, order motor and non - motor in patients who use the long term. These effects reduce the quality of life of patients. Therefore this study is meant to examine the anxiety symptoms in patients with idiopathic PD who had motor fluctuations (wearing - off, on and off), on treatment with levodopa, to assess the symptoms of PD, especially tremor and associate with it the decreased patient anxiety at the time administering the medication. Therefore, data collection occurred in a first contact with the patient off, without levodopa, 3 other times with the patient on. We applied the scale of the Analog Mood Scale (VAMS), the Unified Parkinson\'s Disease Rating Scale (UPDRS), Degree of Disability Scale of Hoehn & Yahr (H&Y) and two tests Bradykinesia (Tapping, pronation and supination) for comparison of evolutionary motor activity and anxiety of the patient on and off. Conclude that it is a common occurrence of anxiety in PD, levels of anxiety and motor difficulties are greater when the patient is off and that the drug (Prolopa) reduces anxiety and improves motor function of patients with PD. This improvement was evident in tests of bradykinesia and the VAMS scale.

University of Macau / Institute of Chinese Medical Sciences

O objetivo do presente estudo foi elaborar um teste de divisão de atenção envolvendo tarefas funcionais da marcha, controle postural estático e dinâmico e controle manual e aplicar este teste em adultos jovens, idosos e indivíduos com DP em estágio iniciais e moderados de evolução da doença. Trata-se de um estudo transversal realizado na Associação Brasil Parkinson, São Paulo. Participaram do estudo 20 adultos jovens, 17 idosos e 47 indivíduos com diagnóstico de DP, 16 no estágio I na escala de estadiamento de Hoehn Yahr, 15 no estágio II e 16 no estágio III. O desempenho dos 84 participantes foi verificado durante a execução de quatro tarefas denominadas de funcionais: marcha, controle postural dinâmico, controle postural estático e uma de controle manual. Também foi analisado o desempenho de oito tarefas específicas, quatro de características motoras e quatro cognitivas. As doze tarefas, funcionais e específicas, foram avaliadas quando executadas isoladamente (condição chamada de tarefa simples (TS), e também em dupla tarefa, quando uma tarefa funcional foi executada simultaneamente a uma tarefa específica motora (dupla tarefa motora (DTM) e também associada a uma tarefa específica cognitiva (dupla tarefa cognitiva (DTC). Nas condições de dupla tarefa o desempenho de ambas as tarefas foi mensurado. A análise estatística foi realizada por meio de ANOVA de medidas repetidas e pós hoc teste de Tukey para a verificação de possíveis diferenças de desempenho entre jovens e idosos, idosos e pacientes com DP, e entre pacientes nos diferentes estágios da DP. Na comparação entre jovens e idosos, as quatro tarefas funcionais propostas mostraram-se sensíveis para identificar as diferenças associadas ao processo de envelhecimento, em especial a marcha e a tarefa de controle manual. Já entre idosos e indivíduos com DP, a tarefa mais sensível para identificar diferenças foi a de controle manual, onde os indivíduos com DP apresentaram desempenho inferior em todas as condições. Na comparação entre os indivíduos com DP no estágio I, II e III a menos sensível foi a de controle manual, que não identificou prejuízos entre os estágios iniciais da doença (I e II). Com intuito de verificar o impacto global da associação de tarefas, foi analisada a soma dos prejuízos da divisão da atenção para a tarefa funcional e a tarefa específica motora e cognitiva, chamado de custo total motor e custo total cognitivo. Observamos diferentes padrões de resultados: a combinação entre a tarefa de controle postural estático e uma tarefa motora foi a condição mais sensível para identificar as alterações do processo de envelhecimento na habilidade de dividir a atenção, entre idosos e indivíduos com DP nenhuma das condições foi capaz de identificar diferenças e entre os estágios da DP, o custo da divisão da atenção entre a tarefa de controle postural estático e uma tarefa cognitiva foi a condição mais sensível. Conclui-se que o teste de avaliação em divisão de atenção proposta mostrou ser um instrumento de boa aplicabilidade, baixo custo e sensível para a identificação de alterações decorrentes do processo de envelhecimento, prejuízos associados à DP e sua progressão / The aim of this study was to develop a testing division of tasks involving attention functional gait, postural control static and dynamic control manual and apply this test in young adults, seniors and individuals with PD in early and moderate stage of the disease. This is a cross-sectional study in Associação Brasil Parkinson, São Paulo. Study participants were 20 young adults, 17 seniors and 47 individuals diagnosed with PD, 16 in stage I in the scale of Hoehn Yahr staging, 15 in stage II, 16 stage III. The performance of 84 participants was observed during the execution of four functional tasks named: gait, postural control, dynamic, static postural control and manual control. We also analyzed the performance of eight specific tasks, four motor and four cognitive characteristics. The twelve tasks, and specific functional, were evaluated when performed alone (called simple task (ST), and also in dual task, when a functional task was performed simultaneously with a specific motor task (dual motor task (DMT) and also associated with a specific cognitive task (dual cognitive task (DCT). Under the conditions of dual task performance of both tasks was measured. Statistical analysis was performed using repeated measures ANOVA and post hoc Tukey test for checking possible performance differences between young and old, elderly and PD patients, and between patients in different stages of PD. Comparing young and old, the four functional tasks proposals were sensitive to identify differences associated with aging, particularly walking and manual control task. Among elderly and individuals with PD, the most sensitive task was to identify differences in manual control, where individuals with PD showed poorer performance in all conditions. Comparing individuals with DP in stage I, II and III was the least sensitive to manual control, which did not identify losses from the early stages of the disease (I and II). Aiming to verify the impact of the global association task, we analyzed the sum of losses of the division of attention to the task and the task specific functional motor and cognitive, called the total cost of motor and cognitive total cost. observed different patterns of results: the combination of static postural control task and a motor task was the most sensitive condition to identify the changes of aging on the ability to divide attention among elderly individuals with PD and none of the conditions was able to identify and differences between stages of PD, the cost of the division of attention between the task of static postural control and a cognitive task was the most sensitive condition. As conclusion that the assessment test in proposed division of attention shown to be an instrument of good applicability, inexpensive and sensitive for identifying changes resulting from the aging process, and losses associated with DP its progression