The effects of dual tasking in Parkinson's disease (PD) have been studied for a number of years. Previous research has generally focused on changes in gait patterns while another task has been performed concurrently. Very few studies have focused on the impact of a concurrent task on speech or language. Language is key for communication: to express wants and needs, to maintain familial relationships, and for social interaction. Thirty-seven individuals participated in the study: 10 with PD, 14 neurologically healthy older (HO) adults, and 13 healthy younger (HY) adults. The participants were given a list of topics to consider and were invited to select several to talk about during the experiment. Their monologues were recorded as they spoke under three conditions: standing still, walking on a treadmill, and walking over randomly presented obstacles on a treadmill. The monologue recordings were transcribed, marked for processing by Systematic Analysis of Language Transcripts (SALT), and analyzed for subordinate clauses by a language expert. The language variables measured were the mean length of utterance in morphemes (MLUm), relative clauses per utterance, adverbial clauses per utterance, noun clauses per utterance, total clauses per utterance, words per minute, different words per minute, relative clauses per minute, adverbial clauses per minute, noun clauses per minute, total clauses per minutes, and utterances per minute. There were significant changes across the conditions of standing, walking, and obstacle in the language variables of words per minute, different words per minute, noun clauses per minute, total clauses per minute, and utterances per minute. A downward trend was noted for adverbial clauses per minute as the gait task became more demanding. The PD and HO groups had less complex language than the HY group, as reflected by the following language variables: adverbial clauses per minute, noun clauses per minute, and total clauses per minute. These findings suggest that as attentional resources used for the production of language are directed to increasing levels of motoric activity, language complexity will significantly decrease across conditions.

The effects of divided attention on speech in Parkinson's disease (PD) have been studied for a variety of tasks in recent years. Much of the previous research studied gait patterns while participants concurrently performed another task. There have been few studies regarding the effects of divided attention on speech in individuals with PD. The ability to communicate effectively relies in part on an appropriate rate of speech, vocal intensity, and fundamental frequency control. This study included 27 participants: 8 with PD, 12 neurologically healthy older (HO) adults, and 7 healthy younger (HY) adults. Each participant was given a list of topics to speak about during the experiment. They produced monologues under three conditions: standing, walking on a treadmill, and walking over obstacles on a treadmill. Each monologue was recorded and trimmed of pauses between topics, experimenter speech, and nonspeech behaviors before analysis. Speech rate, speaking versus pausing time, overall intensity, and intensity and fundamental frequency (F0) variability were analyzed. Median, mean, maximum, and minimum F0 increased as the gait task increased in difficulty. Mean and standard deviation of intensity also increased with gait demands. All groups had increased intensity variability when walking compared to standing. Speaking versus pausing time did not differ significantly as a function of the walking task and the results varied across the groups; the same was true for speech rate. These findings reflect changes in performance during divided attention tasks, with a greater effect on HO adults and individuals with PD than their younger counterparts.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the progressive death of dopaminergic neurons present in the substantia nigra. The clinical presentation of PD includes tremors, slowed movement (bradykinesia), muscle and limb rigidity, and difficulty with walking and balancing. While many environmental factors can affect the onset and progression of the disease, genetic mutations have a large influence. Of the identified PD-linked genetic mutations, mutations in the leucine-rich repeat kinase 2 (LRRK2) are one of the most common genetic causes of PD. Located in endosomes, LRRK2 has been shown to play a role in the sorting and endocytosis of synaptic vesicles, a process that is largely mediated by the retromer complex. Mutations in Vps35, a core component of the retromer cargo-recognition complex, have also been identified as a significant cause of late-onset autosomal dominant familial PD. While the exact molecular mechanisms by which LRRK2 and Vps35 mutations induce PD remain largely unknown, their influence on several cellular processes, including vesicular trafficking and breakdown, and endosomal sorting and recycling, strongly implicate the retromer and autophagy in PD pathology. Recent findings that transgenic expression of Vps35 is able to rescue the PD-related phenotypes caused by LRRK2 mutant forms provide further insight into the interplay of these genes in the context of PD and point to these -genes as potential therapeutic targets. This review outlines the current studies involving these genetic mutations and their interactions with various cellular processes and pathways so as to gain a better understanding of the molecular mechanisms underlying PD pathology for the ultimate purpose of developing safe and effective treatments for PD.

Previous studies have shown that the experience of negative emotions is rarer, while experience of positive emotions is more frequent in the elderly, suggesting an overall improvement in emotional well-being as people age. However, most research did not account for the dynamic characteristics of emotions (e.g. peak intensity, latency, duration) and the levels of emotional challenges. In addition, since most previous studies have focused on studying the experience, expression, and psychophysiological response of emotion, it is still not fully understood how performance in cognitive or behavioral tasks (e.g., automobile driving) can be affected by emotions in older age. To address this gap, the current study examined the effect of normal aging on the dynamic processes of emotion during different levels of emotional challenge (aim 1), and the effect of emotion on driving in older adults as compared to middle-aged adults (aim 2). Parkinson’s disease (PD) is an age-related neurodegenerative disease that shares similar pathological characteristics with the process of normal aging (i.e., reduced dopamine), but to a much higher degree. In addition to investigating the effect of normal aging, the current study also examined the effect of “abnormal aging” on emotion and driving using PD as a model (aim 3). Participants included 16 older (65 - 79 years old), 16 middle-aged (38 - 55 years old) neurologically normal adults, and 16 patients with mild PD (56 - 80 years old). This study focused on fear and anger, the two negative emotions that are most likely to be elicited by driving experiences and to disrupt driving behaviors. Low-level and high-level fear and anger challenges were created using simulated driving scenarios: 1) Low fear task, participants drove in fog and frequently encountered static obstacles on the road; 2) High fear task, participants drove at nighttime and frequently encountered deer running across the road; 3) Low anger task, participants drove following a slow-moving vehicle; 4) High anger task, participants followed a slow vehicle and were honked at by a tailgating vehicle. Participants rated the intensity of fear and anger experiences at 1- minute intervals when they were driving. Comparing older adults against middle-aged adults, it was found that 1) fear intensity was lower in older adults in the low fear task. In contrast, latency and duration of fear were similar between groups in both fear tasks. 2) Anger intensity was lower in older adults in both anger tasks. Anger latency and duration were similar between groups in the high anger task, but anger took longer to develop and was of shorter duration in older adults in the low anger task. 3) In the low fear task, older adults exhibited more cautious driving behaviors (e.g., more frequent uses of brake). In the high anger task older adults were less able to control the acceleration and brake pedals smoothly (e.g., higher forces for brake and acceleration). These results suggest that age differences in the dynamic processes of emotion and the effect of emotion on driving may depend on the type of emotion and level of emotional challenge. When comparing PD patients against age- and education-matched neurologically normal participants (n = 18), it was found that the PD patients reported experiencing similar degrees of fear and anger as the normal comparisons. However, in the high fear task PD patients were less responsive to deer running across the road (e.g., mean and variation of force for brake was lower in PD patients). This finding suggests an impaired ability in PD patients to respond to the sudden appearance of driving hazards. Collectively, the findings of this study provide a window into how the moment-to-moment experience of negative emotions in response to environmental challenges may contribute to the overall emotional well-being of older adults. They also suggest that both the type of emotion and the level of challenge may be important factors in determining the experience of emotion and the effect of emotion on driving during “normal” and “abnormal” aging.

Pesticides have been used to control various types of pests, including plants and insects, for thousands of years, however the impact of exposure to these toxic chemicals, with respect to environmental and health consequences, is not fully understood. Two pesticides of interest, molinate and dieldrin, have been shown to cause neurotoxicity in humans, but their mechanisms of toxicity are still unknown. In order to better understand how exposure to these chemicals can cause toxicity, the structure-activity relationship (SAR) was defined to determine how specific changes to the structure of each pesticide affects the toxicity profiles of each of these compounds. Results of this study demonstrated that oxidation of molinate to molinate sulfoxide, and then further to molinate sulfone, a more potent inhibitor of aldehyde dehydrogenase. The sulfone metabolite is capable of covalently modifying the active-site cysteine residue of aldehyde dehydrogenase, accounting for the observed enzyme inhibition. These results indicate that the compound responsible for the toxicity from molinate exposure is not the parent compound, but rather one of the sulfoxidation metabolites. When the SAR of dieldrin was investigated with respect to a Parkinson's disease model, it was determined that the compounds that were previously found to be the least potent insecticides were the most toxic with respect to dopaminergic cells. Each of the compounds tested was observed to disrupt dopamine metabolism in accordance with their toxicity profiles in dopaminergic cells. In combination, these results implicate important structural features responsible for the toxicity with respect to Parkinson's disease. This information is critical for the development of new pesticides, and will be important to increase the selective toxicity for insects while minimizing adverse/off-target effects. This can lead to the development of safer, more effective pesticides that will be essential for future environmental and human health.

The neurodegenerative disorders Alzheimer??s Disease (AD) and Parkinson??s Disease (PD) are characterised by the accumulation of misfolded amyloid beta 1-42 peptide (Aβ1-42) or α-synuclein, respectively. In both cases, there is extensive evidence to support a central role for these aggregation-prone molecules in the progression of disease pathology. However, the precise mechanisms through which Aβ1-42 and α-synuclein contribute to neurodegeneration remain unclear. Organismal, cellular and in vitro models are under development to allow elucidation of these mechanisms. A cellular system for the study of intracellular Aβ1-42 misfolding and localisation was developed, based on expression of an Aβ1-42-GFP fusion protein in the model eukaryote Saccharomyces cerevisiae. This system relies on the known inverse relationship between GFP fluorescence, and the propensity to misfold of an N-terminal fusion domain. To discover cellular processes that may affect the misfolding and localisation of intracellular Aβ1-42, the Aβ1-42-GFP reporter was transformed into the S. cerevisiae genome deletion mutant collection and screened for fluorescence. 94 deletion mutants exhibited increased Aβ1-42-GFP fluorescence, indicative of altered Aβ1-42 misfolding. These mutants were involved in a number of cellular processes with suspected relationships to AD, including the tricarboxylic acid cycle, chromatin remodelling and phospholipid metabolism. Detailed examination of mutants involved in phosphatidylcholine synthesis revealed the potential for phospholipid composition to influence the intracellular aggregation and localisation of Aβ1-42. In addition, an existing S. cerevisiae model of α-synuclein pathobiology was extended to study the effects of compounds that have been hypothesized to be environmental risk factors leading to increased risk of developing PD. Exposure of cells to aluminium, dieldrin and compounds generating reactive oxygen species enhanced the toxicity of α- synuclein expression, supporting suggested roles for these agents in the onset and development of PD. Expression of α-synuclein-GFP in phosphatidylcholine synthesis mutants identified in the Aβ1-42-GFP fluorescence screen resulted in dramatic alteration of α-synuclein localisation, indicating a common involvement of phospholipid metabolism and composition in modulating the behaviours of these two aggregation-prone proteins.

Abstract not available

This dissertation is the documentation for a Doctoral research program undertaken at the Industrial Research Institute of the Swinburne University of Technology (IRIS), in collaboration with the School of Biophysical Sciences and Electrical Engineering (BSEE), between the years of 2000 and 2004. The objective of the research work that was undertaken was to study the auditory brainstem response (ABR) characteristics of people with Parkinson�s Disease (PD) to determine whether or not these characteristics could form the basis of a tool for determining the presence of PD; the performance of medication, and disease progression. Prior to the commencement of this research, the gold-standard for PD diagnostics was considered to be autopsy, and the only tools available for assessment of living patients were fluoro-deoxyglucose (FDG) / fluoroDopa (FDopa)-based positron emission tomography (PET) or conventional (subjective) clinical testing. The use of PET was costly and impractical for monitoring disease progression. Clinical testing approaches, on the other hand, had a degree of subjectivity, leading to potential misdiagnoses with inadequately trained clinicians. It was therefore postulated that a low-cost technique based on conventional ABR testing equipment, which was readily available within the medical environment, could provide considerable benefits. In order to be useful as a tool, ABR would ultimately need to identify uniquely the presence of PD from other potential disorders, most notably multiple system atrophy (MSA) which was sometimes confused with PD. At the time this research was conducted, the prevailing method of differentiating PD from MSA was based upon magnetic resonance imaging (MRI). This research was only concerned with the first stage of such a research process � that is, determining whether the ABR of PD patients was fundamentally different to that of a control group. In undertaking the investigation, a significant component of the research involved drawing together research literature from a large number of sources in order to present a case that could present a reasonable research path for experimentation. The next stage of the research involved developing an experimentation program that could be used to compare the ABR characteristics of people with PD against a control group and, further, to compare the ABR characteristics of PD participants against their level of impairment, as measured on a conventional mobility test. In summary, the outcomes of the experimental process that was undertaken, and the statistical analysis of the outcomes, suggested that: (1) People with mild manifestations of PD, who were in an unmedicated state, had marked abnormalities in the amplitude of Wave III of their ABR waveform. (2) The amplitude of Wave III of the ABR waveform was sensitive to variations in PD medication levels. (3) The amplitude of Wave V of the ABR waveform was, to a lesser extent than Wave III, affected by the presence of PD and medication levels. (4) The latencies of Waves III and V of the ABR waveforms did not appear to be affected by the presence of PD or by variations in medication levels. This thesis presents the results of the experimental study, together with a statistical analysis of the significance of the outcomes and an evaluation of the limitations of the work that was carried out. The recommendations arising from the research outcomes suggest ways for extending the work that has been completed in this program.

Parkinson’s disease is a neurodegenerative disease caused by a loss of dopamine-producing neurons in the basal ganglia. Primary motor deficits include resting tremor, bradykinesia, muscular rigidity, and postural instability. Most importantly, patients have difficulty both initiating movements and performing well-timed movements. This study explored the effect of rhythm on the timing of upper extremity movements in patients with Parkinson’s disease. Comparisons were made between an external rhythmic cue, an external rhythmic cue in combination with auditory feedback, and no cue. Fifteen participants performed a simple reaching task in each of the four cueing conditions with the use of an interactive touch table. Condition 1 consisted of no cue. Condition 2 included a metronome set to the participant’s baseline tempo. Condition 3 included a metronome set to the participant’s baseline tempo, and a synthesized tone that occurred as a result of contact with the table. Finally, Condition 4 included no cue, similar to Condition 1. Participants were placed into either a mild/moderate level of impairment group, or a severe level of impairment group. Data were collected for total movement time, initiation time, and delta time for each participant in all four conditions. Results of the study did not reveal a main effect of condition on total movement time, initiation time or delta time. However, post-hoc pair-wise comparisons revealed significant decreases between Condition 1 and Condition 4, which were both uncued conditions, for both total movement time and delta time. In addition, for total movement time, a significant decrease was found between Condition 2 (external rhythmic cue) and Condition 4 (no cue). An immediate effect of cueing was found for initiation time and delta time, but did not reach a level of significance. An immediate effect of cueing on total movement time was not evident. Overall, from Condition 1 to Condition 2 as well as Condition 1 to Condition 3, initiation time and delta time decreased, but total movement time did not. Further analysis of level of impairment could not be conducted because of the small number of participants in the severe level of impairment group. The results suggest that one auditory cue was not more beneficial than the other for improving total movement time, initiation time, or delta time. In addition, the improvement from Condition 1 to Condition 4 for total movement time and delta time suggests that a practice effect was evident for the participants. The results of the study suggest that long-term training of either auditory cue can be an effective rehabilitation technique for patients with Parkinson’s disease to improve the timing of upper extremity movements.

A model with human melanoma xenografts transplanted to athymic mice has been adopted for in vivo studies of 5-S-cysteinyldopa (an intermediate pigment metabolite), glutathione, and cysteine. L-Dopa is an intermediate metabolite in pigment formation and is also important in the treatment of Parkinson's disease, and therefore 1 have also studied the pharmacokinetics of this compound. We were first to describe in vivo microdialysis in melanoma tissue and showed that dialysis membranes of cuprophane or polyamide are suitable for studies of interstitial 5-S-cysteinyldopa and selected thiols. Analytical procedures were also improved for quantitation of 5-S-cysteinyldopa, L-dopa, glutathione, cysteine, and N-acetylcysteine (NAC). In the melanoma xenografts the interstitial concentration of 5-S-cysteinyldopa reflected the high intracellular production of this intermediate metabolite. For in vivo manipulation of glutathione in the melanoma tissue we gave intraperitoneal injection of buthionine sulphoximine to the animals and thus reduced the glutathione concentrations substantially. We showed that restitution of glutathione in melanoma tissue occurs spontaneously and is not much improved by treatment with the cysteine deliverers NAC and L-2-oxothiazolidine-4-carboxylate (OTC). 5-S-Cysteinyldopa was not substantially affected by great variations in glutathione concentrations. Transport of NAC from intraperitoneal injection to melanoma tissue occurred rapidly and deacetylation to cysteine in vivo could be detected soon after NAC injection. In vivo formation of cysteine was slower from OTC than from NAC. Pharmacokinetic studies of L-dopa in human subjects indicated a slight to moderate protein binding. Plasma free L-dopa had similar elimination T½ as interstitial L-dopa, but in some cases the elimination of total L-dopa was slower. Difficulties in intestinal absorption of L-dopa were revealed by microdialysis in blood and subcutaneous tissue. Studies showed that this was due to delayed emptying of the stomach. L-Dopa intake increased 5-S-cysteinyldopa concentrations in blood within 30 min in patients with Parkinson's disease and a history of melanoma. No melanoma activation occurred during long-term treatment with L-dopa. Microdialysis is thus a safe and easily applied method for in vivo studies of both pigment metabolites from human melanoma tissue transplanted to nude mice and for pharmacokinetic studies of L-dopa. / On the day of the public defence the status of the articles IV, V and VI was: Submitted.