Orientador: Lilian Teresa Bucken Gobbi / Banca: Gustavo Christofoletti / Banca: Renato de Moraes / Resumo: Desordens na marcha são identificadas em pacientes com doença de Parkinson (DP), comprometendo a capacidade de locomoção independente e a interação com o ambiente. Irregularidades no ambiente podem desafiar ainda mais o controle motor destes indivíduos para realizar tarefas locomotoras com sucesso. Além do tratamento medicamentoso com levodopa, que provoca melhoras nos parâmetros da marcha, dicas auditivas têm sido utilizadas para auxiliar e modular o padrão locomotor destes indivíduos. Entretanto, pouco se sabe sobre o efeito da dica auditiva durante a locomoção adaptativa, especialmente em associação com os efeitos da levodopa. Ainda, poucos estudos encontrados na literatura comparam os pacientes com idosos sadios na utilização de dica auditiva durante a marcha livre e com obstáculos. Este projeto compreendeu dois estudos: o Estudo 1 objetivou verificar o efeito de dica auditiva na marcha livre de pacientes com DP e idosos sadios; o Estudo 2 objetivou verificar o efeito de dica auditiva nos parâmetros de andar durante a ultrapassagem de obstáculo em pacientes com DP e idosos sadios. Em ambos os estudos, com intuito de investigar o efeito do medicamento na locomoção, os pacientes foram testados nos estados off e on do medicamento. Participaram deste projeto 30 indivíduos, distribuídos em dois grupos (Grupo 1: pacientes com DP e Grupo 2: idosos sadios). Após consentir em participar do projeto, avaliações clínicas do estágio de evolução e do comprometimento da doença foram realizadas por um neuropsiquiatra. Para investigar o padrão locomotor, análises cinemática, cinética e eletromiográfica foram utilizadas em ambos os estudos. Especificamente no Estudo 2, duas alturas de obstáculos foram selecionadas e padronizadas como segue:... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Gait disorders are identified in people with Parkinson's disease (PD). As a result, the capacity of walking independently and the interaction with the environment can be impairment. Uneven environments can challenge even more the motor control of these patients to perform the locomotor tasks successfully. Besides of the levodopa therapy, the auditory cues have also been utilized to improve the gait parameters. However, the effects of auditory cues in gait during obstacle avoidance and the association with the levodopa effects are not known. Yet, few studies in the literature compare the PD patients with the older adults during the locomotor tasks and obstacle avoidance in association with the effects of auditory cues. In order to answer these questions, this project is composed of two studies: Study 1, which aim was to verify the effects of auditory cues in the gait parameters in PD patients and older adults; and Study 2, which aim was to verify the effects of auditory cues during obstacle avoidance in PD patients and older adults. In both studies, the effects of levodopa therapy were also investigated. So, the patients were tested in on and off levodopa states. Thirty subjects distributed in two groups (Group 1, PD patients; Group 2, healthy older adults) participated in this study. After the participation approval, the clinical assessment related to the disease progression was done by a physician. Therefore, kinematic, kinetic and electromiographic analyses were utilized to investigate the locomotor pattern. Specifically in the Study 2, two different obstacle heights were manipulated (high obstacle at half of knee height; low obstacle at ankle height). Mann Whitney and Wilcoxon tests were done for each analysis to verify possible differences between groups and condition, respectively, with... (Complete abstract click electronic access below) / Mestre

No description available.

University of Macau / Institute of Chinese Medical Sciences

No description available.

No description available.

No description available.

In the case of Parkinson’s disease, a common neurodegenerative disorder, the loss of motor function results from the selective degeneration of dopaminergic neurons (DNs) in the brain. Current treatments focus on pharmacological approaches that lose effectiveness over time and produce unwanted side effects. A more complete concept of rehabilitation to improve on current treatments requires the production of DNs to replace those that have been lost. Although pluripotent stem cells (PSCs) are a promising candidate for the source of these replacement neurons, current protocols for the terminal differentiation of DNs require a complicated cocktail of factors. Recently, a naturally occurring steroid called guggulsterone has been shown to be an effective terminal differentiator of DNs and can simplify the method for the production of such neurons. I therefore investigated the potential of long-term guggulsterone release from drug delivery particles in order to provide a proof of concept for producing DNs in a more economical and effective way. Throughout my study I was able to successfully encapsulate guggulsterone in Poly-ε-caprolactone (PCL)-based microspheres and I showed that the drug was capable of being released over 44 days in vitro. These guggulsterone-releasing microspheres were also successfully incorporated in human induced pluripotent stem cell (hiPSC)-derived neural aggregates (NAs), providing the foundation to continue investigating their effectiveness in producing functional and mature DNs. Together, these data suggest that guggulsterone delivery from microspheres may be a promising approach for improving the production of implantable DNs from hiPSCs. / Graduate

The placebo effect represents a fascinating example of how cognition can influence the physiology of the brain and body. The expectation of therapeutic benefit elicited by a placebo given in the guise of active medication has been proposed to be a form of reward expectation, and is associated with activation of brain reward circuitry. Prominent placebo effects occur in Parkinson’s disease (PD), where the expectation of symptom improvement stimulates dopamine release in the striatum. In the work described in this dissertation, positron emission tomography with [¹¹C] raclopride was used to investigate the relationship between the strength of expectation of benefit and the degree of dopamine release in PD, and how this relationship corresponds to current models of dopamine function in reward. Chapter 3 describes a pilot study conducted in patients who had undergone subthalamic nucleus deep-brain stimulation (STN-DBS) in which we examined how awareness of stimulator status (ON or OFF) affected synaptic dopamine levels compared to when subjects were blind. No difference was detected between conditions; however, it proved to be difficult to maintain blinding due to the profound effects of STN-DBS. Chapter 4 describes the development of the methodology for the analysis of high-resolution PET data, in which we utilized the combined efforts of neuroscience and imaging physics to optimize the analysis of [¹¹C] raclopride PET data. In Chapter 5, I describe the use of verbal instructions to manipulate patients’ expectations in order to investigate how the likelihood of receiving levodopa influenced dopamine release when the patients were in fact given placebo. Placebo-induced dopamine release was differentially modulated by expectation in the dorsal and ventral striatum: dopamine release in the putamen was related monotonically to expected reward value, whereas dopamine released in the ventral striatum reflected the uncertainty of benefit or the salience of the expectation. The placebo effect in PD therefore involves at least two related but separate mechanisms: the expectation of benefit itself, which is scaled to reflect the value of the drug to the patient and is mediated by nigrostriatal dopamine, and the uncertainty or salience of benefit that is mediated by mesolimbic dopamine. / Medicine, Faculty of / Graduate

Psychopharmacological studies have implicated the mesolimbic dopamine (DA) system in the mediation of cost/benefit evaluations about effort-related costs associated with larger rewards. However, the role of DA in risk-based decision making remains relatively unexplored. The present study investigated how systemic manipulations of DA transmission affect risky choice assessed with a probabilistic discounting task. Over discrete trials, rats between two levers; a press on the “small/certain” lever always delivered one reward pellet, whereas a press on the other, “large/risky” lever delivered four pellets, but the probability of receiving reward decreased across the four trial blocks (100%, 50%, 25%, 12.5%). In separate groups of well-trained rats we assessed the effects of the DA releaser amphetamine, as well as receptor selective agonists and antagonists. Amphetamine consistently increased preference for the large/risky lever; an effect that was blocked or attenuated by co-administration of either D₁ (SCH23390) or D₂ (eticlopride) receptors antagonists. Blockade of either of these receptors alone induced risk aversion. Conversely, stimulation of D₁ (SKF81297) or D₂ (bromocriptine) receptors also increased risky choice. In contrast, activation of D₃ receptors with PD128,907 induced risk aversion. Likewise, D₃ antagonism with nafadotride potentiated the amphetamine-induced increase in risky choice. Blockade or stimulation of D₄ receptors did not reliably alter patterns of choice. These findings indicate that DA plays a critical role in mediating risk-based decision making, where increased activation of D₁ and D₂ receptors biases choice towards larger, probabilistic rewards, whereas D₃ receptors appear to exert opposing effects on this form of decision making. / Arts, Faculty of / Psychology, Department of / Graduate

Parkinson’s disease (PD) is the most common movement neurodegenerative disease affecting approximately 1% of the population over 60. Though originally thought to be sporadic in nature, a genetic component is increasingly being linked to the disease. Of these genes, mutations in DJ-1 (PARK7) cause early onset autosomal recessive PD. Initial workup of the DJ-1 protein has suggested that it may act in the cell by combatting oxidative stress though the mechanism by which it does so is unclear. Thus, though much work has attempted to elucidate a function at the biochemical, cellular and organismal level, the overt physiological role of DJ-1 remains elusive. In this dissertation, we explore the mechanisms through which DJ-1 confers neuroprotection, particularly in the case of oxidative stress insult. We demonstrate that DJ-1 acts through the pro-survival protein AKT to accomplish its neuroprotective function. Moreover, we note that DJ-1 likely serves its role as an antioxidant through the NRF2 master antioxidant regulator pathway a pathway that is, itself, likely to be regulated by AKT. Together, our results demonstrate that neuroprotection by DJ-1 is done through a signaling pathway involving both AKT and NRF2 and that disruption of the former in PD likely results in abolishing this signaling pathway. Finally, to generate a better animal model of PD, we demonstrate that backcrossing DJ-1 null mice - which originally did not demonstrate any gross histopathological or behavioral phenotypes – display unilateral dopaminergic degeneration that progresses to bilateral degeneration with aging, a feature reminiscent of classical PD progression. Collectively, this thesis takes a two-sided approach to address the biochemical and physiological functions of DJ-1 within the cell and the mouse in hopes of elucidating mechanisms of neuronal death to devise better translational therapies.