Thesis (M. S.)--Florida State University, 2006. / Advisor: Julie Stierwalt, Florida State University, College of Communication, Dept. of Communication Disorders. Title and description from dissertation home page (viewed Sept. 15, 2006). Document formatted into pages; contains vii, 34 pages. Includes bibliographical references.

Thesis (B.Sc)--University of Hong Kong, 2002. / "A dissertation submitted in partial fulfilment of the requirements for the Bachelor of Science (Speech and Hearing Sciences), The University of Hong Kong, May 10, 2002." Also available in print.

Thesis (Ph.D.) - University of Queensland, 2005. / Includes bibliography.

Thesis (M.S.)--Brock University, 2005. / Includes bibliographical references. Also available online (PDF file) by a subscription to the set or by purchasing the individual file.

Thesis (M.S.)--Brock University, 2005. / Includes bibliographical references.

One of the major hallmarks of Parkinson’s disease (PD) is the deposition of intracellular Lewy body inclusions. α-Synuclein is a small protein that accumulates and aggregates to form Lewy bodies. Recent studies uncovered variation of α-synuclein mRNA 3’ untranslated region (UTR), but the role of this region in regulating the α-synuclein expression is poorly understood. 3’UTR is a target region for RNA binding proteins and microRNAs (miRs) in regulating protein translation from the mRNA transcript. Leucine-rich repeat kinase 2 (LRRK2) is a key regulator of miR-mediated translational repression and is frequently mutated and causally associated with PD. We hypothesize that LRRK2 regulates α-synuclein expression post-transcriptionally via binding of miR to α-synuclein mRNA’s 3’UTR. We have found that α-synuclein mRNA with short 3’UTR has similar protein expression level to that of long 3’UTR in the absence of LRRK2 in both HEK-293 FT cells and primary hippocampal neurons. However, LRRK2 wild-type and disease mutant G2019S increased α-synuclein protein expression. In particular, an increase of 2-fold was observed for the short 3’UTR transcript, which is significantly greater than the increase for the long isoform. These data suggest differential effects of LRRK2 on α-synuclein depending on the length of 3’UTR. The short 3’UTR of the α-synuclein transcript has a binding site for miR-7; whereas, that of the long isoform has binding sites for miR-7 and miR-153. We discovered that these differential effects of LRRK2 on α-synuclein are dependent on the binding of miR-7 and miR-153 to the 3’UTR of the isoforms. Specifically, miR-7 is a stronger mediator in regulating α-synuclein translation compared to miR-153, leading to an approximately 30% inhibition of α-synuclein protein expression. Our studies have also shown that the effects of LRRK2 on regulating α-synuclein protein expression are dependent on LRRK2 kinase activity. Gain-of-kinase-function mutation, G2019S, leads to a greater increase of α-synuclein protein expression compared to wild-type; whereas, inhibition of LRRK2 kinase function decreases its effect on α-synuclein protein expression. These findings highlight novel mechanisms regulating the expression of α-synuclein involving LRRK2, miRs-7 and -153. These results highlight miRs as potential targets for reducing levels of α-synuclein in PD.

Parkinson’s disease (PD) is a neurodegenerative disorder commonly presenting with perceptual and cognitive dysfunction. Whereas previous work in PD suggests that abnormal basal ganglia activity has profound effects on integrated functioning of widespread cortical networks, the relation of specific network functions to the perceptual and cognitive impairments is still poorly understood. Here, I present a series of fMRI investigations of network-level functioning in non-demented individuals with PD with the aim of elucidating these associations. Study 1 examined the neural correlates of optic flow processing in 23 individuals with PD and 17 age-matched control participants (MC). An optic flow network comprising visual motion areas V6, V3A, MT+ and visuo-vestibular areas PIVC and CSv is known to be important for parsing egomotion depth cues in humans. The hypothesis was that individuals with PD would show less activation in these regions than MC when processing optic flow. While MC participants showed robust activation in this network, PD participants showed diminished activity within MT+ and CSv. Diminished CSv activity also correlated with greater disease severity. Study 2 investigated intrinsic network organization in PD with a focus on the functional coupling among three neurocognitive networks: the default-mode network (DMN), the salience network (SN), and the central executive network (CEN). Twenty-four individuals with PD and 20 MC participants were scanned at rest. The hypothesis was that PD participants would demonstrate dysfunctional SN coupling with the DMN and CEN. Relative to MC, in PD the CEN was less positively coupled with the SN and less anti-correlated with the DMN. Study 3 investigated the association between functional coupling and cognition in the same group that participated in Study 2. As hypothesized, anti-correlated functional coupling between the SN and DMN was related to successful performance on tests of executive function, psychomotor speed, and memory retrieval in MC but not in PD, suggesting that dysfunction within these networks could underlie early cognitive deficits in PD. Together, the results from the three studies suggest that dysfunctional activity in cortical networks important for visual motion processing and neurocognitive efficiency may underlie aspects of perceptual and cognitive impairment in PD. / 2017-12-06T00:00:00Z

The striatum is the major input structure of the basal ganglia, and is composed of two major populations of spiny projection neurons (MSNs), which give rise to the socalled direct and indirect pathways, and several types of interneuron. Dopaminergic inputs to striatum are critical for its proper function. Indeed, loss of dopaminergic neurons in Parkinsonism leads to motor disturbances, grossly disturbs striatal activity, and is associated with the emergence of excessively-synchronized network oscillations at beta frequencies (15-30 Hz) throughout the basal ganglia. How the distinct structural, neurochemical and other properties of striatal neurons are reflected in their firing rates and patterns in vivo is poorly defined, as are their possible cell-type-selective contributions to the aberrant oscillations arising in the Parkinsonian brain. To address these issues, I first used multi-electrode arrays to record the spontaneous firing of ensembles of neurons in dorsal striatum in both anaesthetised dopamine-intact and Parkinsonian (6-hydroxydopamine-lesioned) rats during two well-defined brain states, slow-wave activity (SWA) and spontaneous activation. The chronic loss of dopamine led to an overall increase in the average firing rates of striatal neurons, irrespective of brain state. However, many neurons in the Parkinsonian striatum still exhibited the low firing rates and irregular firing patterns typical of neurons in the dopamine-intact striatum. During SWA in Parkinsonian rats, the firing of striatal neurons was more strongly synchronized at low frequencies, in time with cortical slow (~1 Hz) oscillations. During spontaneous cortical activation in Parkinsonian rats, more striatal neurons engaged in synchronized firing in time with cortical beta oscillations. Under the same experimental conditions, I then recorded the spontaneous firing of individual striatal neurons and juxtacellularly labelled the same neurons to verify their cell types, and locations; indirect pathway and direct pathway MSNs were distinguished by the expression (and lack of expression respectively), of the neuropeptide precursor preproenkephalin (PPE). After chronic dopamine loss, and on average, only indirect pathway (PPE+) MSNs significantly increased their firing rates during both brain states, and engaged in widespread, synchronized firing in the beta-frequency range. This did not hold true for all PPE+ MSNs; the Parkinsonian striatum contained many MSNs that were virtually quiescent, which were just as likely to belong to the indirect pathway as the direct pathway. Direct pathway (PPE-) MSNs increased their firing only during SWA after chronic dopamine loss and rarely engaged in aberrant beta oscillations. Taken together, these data suggest that (1) the firing patterns, as well as the firing rates of many striatal neurons are grossly disturbed by chronic loss of dopamine and (2) that the pathological synchronization of the rhythmic firing of a subpopulation of indirect pathway MSNs could contribute to the propagation of aberrant beta-frequency oscillations to downstream basal ganglia nuclei in Parkinsonism.

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Made available in DSpace on 2014-06-11T19:22:53Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-11-21Bitstream added on 2014-06-13T18:49:49Z : No. of bitstreams: 1 rinaldi_nm_me_rcla.pdf: 1320654 bytes, checksum: 85f4c34f2cf7fab579aef086c08ffb05 (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / 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:... / 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)