Thesis (Ph. D.)--University of Missouri-Columbia, 2002. / Typescript. Vita. Includes bibliographical references (leaves 66-76). Also available on the Internet.

Thesis (Ph. D.)--Rutgers University, 2008. / "Graduate Program in Toxicology." Includes bibliographical references (p. 253-266).

Thesis (M.S.)--University of Louisville, 2008. / Department of Anatomical Sciences and Neurobiology. Vita. "December 2008." Includes bibliographical references (leaves 27-34).

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.

Deficits of attentional and motor set that are seen in patients with PD were investigated in the research reported in this thesis. A deficit of attentional set is a failure of selective attention to one aspect of a complex stimulus. Deficits of motor set manifest as an inability to form a state of motor 'readiness' that can speed movement initiation. Attentional set was investigated with tasks that require patients to shift attention between perceptual dimensions (extradimensional - ED - shifting tasks), and motor set was studied using reaction time (RT) tasks. Study 1 rejected the hypothesis that the mechanism of 'learned irrelevance' causes ED shift deficits in patients with PD. Studies 2 and 3 confirmed that learned irrelevance also plays no role in determining the difficulty of ED shifts in healthy subjects. The experimental manipulation used in Study 4 succeeded in creating changes in scores that resembled those seen in patients with PD. Thus, it appears that patients with PD may have a deficit similar to that induced by the experimental manipulation - that is, an inability to attend to all dimensions present when hypothesis testing after an ED shift. A quantitative analysis of past RT studies of PD showed that the ability to speed movement initiation when given advance information about an upcoming movement - a form of motor set - is intact in patients with PD. In contrast, the motor set that underlies rapid simple RT performance is consistently dysfunctional in patients with PD. Study 5 investigated temporal and spatial motor set in PD, finding that these two mechanisms are functionally separate and that temporal motor set is intact in PD. A final study (Study 6) investigated the cognitive consequences of a novel neurosurgical treatment for PD, finding it to be largely a neuropsychologically 'safe' procedure.

The purpose of this investigation was to identify the cognitive control operations involved in task switching, and to apply this understanding to a theoretical account of the qualitatively different task-switching deficits associated with aging versus Parkinson's disease (PD). Participants in young (N = 33), elderly (N = 34) and PD ( N = 34) samples switched between color naming and word reading in response to incongruent, neutral, or congruent Stroop stimuli and vocal response time (RT) was recorded. The results suggested that executive processes involved in switching selective attention between object attributes determined a substantial portion of task-switching RT costs. More specifically, these component control processes were identified as: (a) shifting selective attention from the stimulus dimension just attended to on the previous response to the now-relevant stimulus dimension (SHIFT), and (b) a preventative operation characterized by the partial inhibition of selective attention to the now-relevant stimulus dimension, carried out when the probability is high that the now-relevant dimension must be ignored on a future response (MODERATE). A multilayer, linear, parallel distributed processing (PDP) model was presented to demonstrate how these cognitive processes may be implemented by the cognitive system, and how these findings relate to the executive function concepts of the Supervisory Attentional System (SAS) and Contention Scheduling (CS). In addition, a cost associated with responding to the first member of a stimulus pair or triplet was also identified (FIRST); however, this operation appeared to function independently from the executive control operations involved in switching tasks (i.e., FIRST was also present for task repetition trials). Finally, a number of two-way interactions between these three main effects (SHIFT, MODERATE and FIRST) accounted for unique variance in task-switching RTs, such that RT was increased when these effects co-occurred. In the neuropsychological investigation it was demonstrated that the SHIFT and MODERATE effects were significantly greater for an elderly sample compared to a young sample, resulting in an increase in task-switching RT. This deficit was attributed to an inefficient shifts of selective attention. Conversely, PD did not necessarily affect the SHIFT and MODERATE operations, when compared to age-matched controls; however, the disease was associated with difficulty overcoming Stroop interference while switching tasks. This deficit was interpreted as affecting the SHIFT operation under the most taxing conditions, attributable to a central resource deficit in PD. In contrast, no between-group differences on the effect FIRST were observed. / Graduate

Background: Levodopa is still thought of as the 'gold standard' symptomatic treatment for Parkinson’s disease. However, after four to five years of treatment, levodopa efficacy tends to decline even if there was a good initial therapeutic response. The ideal treatment of Parkinson’s disease is a much debated issue with a range of guidelines available. Objectives: This study was undertaken to analyse medication use and prescribing patterns as well as to determine the risk factors involved in causing dyskinesias in Parkinson’s sufferers. Methods: The study consisted of two parts, namely a drug utilisation review (DUR) and a questionnaire survey. There were 25 523 antiparkinsonian records consisting of 5 168 patients for the year 2010. The questionnaires were verbally administered to patients diagnosed with Parkinson’s disease. A total of 43 patients were interviewed. Results: The average age of the population was 70.74±10.37 years, with the oldest patient being 100 years. Females constituted 59.17percent (5 168: n = 3 058) of the total number of patients. The most common antiparkinsonian products dispensed were combination drugs containing levodopa with a decarboxylase inhibitor and some with a COMT-inhibitor as well (46.5percent; n = 11 875). Males represented 53.49percent (43: n = 23) of the patients included in the questionnaire survey. A review of the medical records showed that patients with dyskinesias were diagnosed with Parkinson’s disease at a younger age and had experienced longer disease duration. Conclusion: Parkinson’s disease is an under-recognised condition in South Africa. Treatment needs to be individualised and based on evidence-based guidelines. Further studies in South Africa, as well as SSA (sub-Saharan Africa), need to be conducted on both the prevalence as well as the treatment of Parkinson’s disease.

Parkinson’s disease (PD) is a common neurodegenerative disorder symptomatically characterized by motor dysfunction caused by the selective loss of nigral dopamine neurons within midbrain. The pathogenesis of PD remains unclear. Although, originally thought to be sporadic, about ten percent of PD is familial. The recent elucidation of mutations in genes linked to the disease has offered potential for new animal models and understanding of PD pathogenesis. DJ-1 and LRRK2 are genes linked to autosomal recessive juvenile-onset PD and autosomal-dominant late onset PD, respectively. How mutations in these two genes leads to PD remains uncertain and is plagued by poor murine models that do not recapitulate the human condition. The following dissertation attempts to characterize both mouse and fly models of DJ-1 and LRRK2 mediated PD and elucidate other genetic modifiers that may contribute to PD. Firstly, the DJ-1 null mouse model, which lacks cell death, was improved by backcrossing to a pure C57-Bl6 background. These DJ-1 null mice display a robust and progressive unilateral-to-bilateral loss of nigral neurons accompanied by motor deficits in aged mice. Secondly, a large scale screen was performed in Drosophila to determine genes that modify mutant LRRK2 toxicity in both the eye and dopaminergic neurons of the fly. The screen revealed 36 genetic interactors that either suppressed or enhanced LRRK2 induced cell death in the fly. One of these interactors was SCAR (human WAVE-2). Due to the role WAVE-2 is known to have in immune cell phagocytic function, we demonstrate that LRRK2 deficient/G2019S murine myeloid cells have impaired/enhanced phagocytic activity which is correlated with a decrease/increase in WAVE-2 protein, respectively. We furthermore suggest that LRRK2 and WAVE-2 may bind directly and that LRRK2 phosphorylates WAVE-2 to maintain its stability. Finally, as a proof of concept, we constructed a novel animal model of LRRK2 in flies by limiting LRRK2 over expression to central phagocytes of the Drosophila brain. This causes lifespan deficits and motor dysfunction that can be rescued by down-regulation of SCAR. Collectively, this body of work helped create the first germ-line, genetic model of PD that recapitulates nigral loss and elucidated LRRK2 interactors in the fly. Furthermore, we demonstrate that one of these interactors mediated LRRK2’s modulation of phagocytic activity that may contribute to the pathogenesis of PD.

The population of patients with Parkinson's disease, already the second most common neurodegenerative disorder, is continuing to grow. Despite years of research, no cure or clear pathogenic pathway has been discovered. However, the SNCA gene and its protein product, α-synuclein, have emerged as an important focus in both inherited and sporadic Parkinson's disease. Dosage effects created by duplication and triplication of the SNCA locus can cause the death of dopaminergic neurons in the brain. Naturally occurring overexpression of α-synuclein has been found to have the same devastating consequences. Most current drug development has focused on alleviating the overproduction of α-synuclein, instead of stopping it. We have hypothesized that by repressing endogenous SNCA gene expression at the transcription level we can prevent overexpression of α-synuclein and its associated toxicity. The discovery that β2-agonists, specifically clenbuterol hydrochloride, can reduce SNCA mRNA abundance and protein expression has implicated the β2-adrenergic receptor pathway as a potential regulatory target. We have further found that clenbuterol causes hypoaceytlation of histone H3 that may downregulate SNCA expression. Although, the precise mechanism by which β2-agonists are regulating SNCA expression needs to be further explained, our findings present exciting data that could potentially lead to a novel treatment for not just Parkinson's disease, but other synucleinopathies as well. / 2023-04-30