Parkinson’s Disease (PD) is a neurological disorder affecting the basal ganglia in which the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) manifests as a complex array of motor and non-motor symptoms. Due to the lack of treatment for preventing the neurodegenerative process of PD, the only available therapy options involve managing the clinical symptoms resulting from dopamine (DA) depletion in the basal ganglia. The most widely implemented treatment is the pharmacological agent L-DOPA which serves as the precursor to dopamine. Although L-DOPA administration is initially effective in improving motor function and patient life quality, its therapeutic effect diminishes as PD pathology progressively worsens over time and side effects such as L-DOPA induced dyskinesia become apparent. Researchers are now seeking to alleviate the symptoms of PD on a molecular basis with gene therapy in which the three therapeutic strategies target specific genes involved in either increasing dopamine production, regulating the pathways of the basal ganglia, or protecting dopaminergic neurons of the nigrostriatal pathway. Current research is focused on investigating the efficacy and overall safety of gene therapy through delivery of the genes responsible for aromatic L-acid decarboxylase (AADC), glutamic acid decarboxylase (GAD), glial cell derived neurotrophic factor (GDNF), and neurturin (NRTN). Although these methods of gene therapy are relatively new and still developing, they present a promising direction for PD treatment. In this review, the various gene therapy strategies designed for improving parkinsonism are evaluated for safety and efficacy.

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Thirty-two parkinsonians were compared to 32 age-, sex-, and education-matched healthy controls on measures of depression (Beck Inventory), dementia (Mattis Dementia Rating Scale), and primary and secondary memory components of Free Verbal Recall. Parkinsonians were found to be more depressed, with greater impairment of secondary memory. There were no significant group differences in primary memory or general cognitive functioning. Sub-groups of 41 parkinsonians (including the 32 patients described above) were used to compare the relative contributions of depression, age of onset, and general cognitive decline to the observed secondary memory deficit. Depressed parkinsonians demonstrated more impaired primary memory than did nondepressed parkinsonians, but did not account for the difference in secondary memory. Parkinsonians with later ages of onset demonstrated greater depression and cognitive decline over a shorter length of illness, and parkinsonians with greater cognitive decline performed more poorly on the measure of secondary memory. Comparisons of parkinsonians with predominant unilateral motor symptoms (either right or left) to those with equal bilateral symptoms revealed the bilateral group to be significantly older, with later ages of onset but no difference in length of illness. It is concluded that later age of onset is a critical factor that is more likely to be associated with depression and declines in cognitive functioning than is seen with earlier age of onset. The relationship between age of onset and cognitive decline is not accounted for by age alone, length of illness, nor by the interaction of age with parkinsonian symptoms. Furthermore, the presence of bilateral symptoms may serve as a marker for the cluster of symptoms associated with later ages of symptoms onset.

In an attempt to determine the normative levels in health attribution and emotional, intellectual, and neuromuscular functioning in the parkinsonian population, 31 diagnosed parkinsonian volunteers recruited from exercise classes and/or organizations were tested. Health attribution was measured by the Health Attribution Test (HAT), personality factors by the Clinical Analysis Questionnaire (CAQ), general intellectual level by the Peabody Picture Vocabulary Test- Revised (PPVT-R) and the Intellectual Processes subscale of the Luria-Nebraska Neuropsychological Battery (Luria- Intelligence), and neuromuscular functioning by the McCarron Assessment of Neuromuscular Development (MAND) and Bender- Gestalt (BVMGT). Controls for comparisons were obtained from the clinical ecology population and normals for personality traits and the nonspecific neurologically impaired, healthy aging populations, and normals for intellectual and neuromuscular functionings. Chi-square and t-tests were computed on the data. Results indicated that the parkinsonians manifest less lower body strength (£ < .01), poorer balance with eyes closed (JD < .01), and slower fine motor speed (p < .05) than normals. The parkinsonians function significantly better in areas involving upper body coordination (p < .01, £ < .05) , slow-controlled movements (g.< .001), BVMGT (p < .05), and PPVT-R (p < .01) than the nonspecific neurologically impaired. On the Luria-Intelligence, 21 percent of the parkinsonians compared to eight percent of the healthy aging were within the limits for brain damage (JD < .01) . Although the parkinsonians are internals for health attribution, their internal orientation is lower and external locus of control higher than the clinical ecology population (j> < .01). The parkinsonians' CAQ profile was significantly different in comparison to the clinical ecology patients on the following CAQ factors: F (impulsivity), H (boldness), N (shrewdness), 0 (insecurity), Q2 (self-sufficiency), D4 (anxious depression), Pp (psychotic deviation), As (psychasthenia), IN (independence), and So (socialization). The parkinsonians' CAQ profile was negative for depression. Their CAQ profile can be interpreted as being associated with positive adjustment. The results were interpreted as applying to health care provision for the chronically ill.

M.A. / Parkinson's disease is a progressive neurological disorder. Symptoms such as tremor, muscular stiffness and slowness of bodily movement are prevalent in the disease. Early research studies have investigated emotional difficulties experienced by Parkinson's disease patients. Most research studies have focused on depression in Parkinson's disease. However few studies have investigated other emotional concomitants of Parkinson's disease, for example anxiety, self-esteem and impulse control. The aim of the present study was to investigate emotional concomitants of Parkinson's disease and to explore problematic emotional symptoms experienced by patients suffering from Parkinson's disease. The aim of the study was to compare a group of 10 male Parkinson's disease patients with a group of 10 healthy males (non-Parkinson's disease males) regarding the six subscales (Thought/Behaviour disorder, Impulse Control, Anxiety, Depression, Low Self-esteem and Total Pathology) of the Emotional Problems Scales (EPS). In the second part of the present study a group of six male Parkinson's disease patients completed the Millon Clinical Multiaxial Inventory (MCMI). The Millon Clinical Multiaxial Inventory consists of 22 clinical scales. The results indicated that there were statistically significant differences between the Parkinson's disease patients and the non-Parkinson's disease males regarding the Anxiety, Depression and Total Pathology subscales of the Emotional Problems Scales. The results further indicated that the Parkinson's disease patients had elevated scores above the 75 and 85 base rate scores of the Millon Clinical Multiaxial Inventory. The elevated scores were on the Schizoid, Compulsive, Self-defeating, Anxiety and Dysthymia scales. The results obtained in the present research study support previous studies regarding emotional concomitants in Parkinson's disease. Although effort has been made to ensure the present research study is methodologically sound, the study had a few shortfalls and limitations. The questionnaires (EPS and MCMI) used in the present study have not been standardised for the South African population. The present research study was interesting but a larger sample would be needed that would be more representative of the South African population. The present study did not discriminate between tremor dominant Parkinson's disease and rigid Parkinson's disease. Incidence of depression seems to be higher in Parkinson's disease patients with prominent features of bradykinesia and gait instability. It is recommended that future research studies distinguish between rigid Parkinson's disease and tremor dominant Parkinson's disease. Future research should also include measuring instruments that have been standardised for the South African population. Combined gender studies regarding emotional concomitants of Parkinson's disease will contribute to understanding the problematic emotional symptoms experienced by patients suffering from Parkinson's disease.

The research presented in this thesis investigates the motoric versus perceptual basis of bimanual coordination stability. A general introductory section provides an overview of Parkinson's disease, upper limb coordination in healthy younger and healthy older adults and individuals with Parkinson's disease, and the current views of the basis of bimanual coordination stability. Following the general introductory section are two manuscripts for the two experiments. Both experiments followed similar paradigms. Healthy young adults participated in the first experiment and individuals with Parkinson's disease and healthy older adults participated in the second experiment. Following the presentation of the empirical work is a general discussion section. This section is intended to summarize the two experiments, to discuss potential methodological issues and to provide ideas for future experiments. / Thesis / Master of Science (MS)

The research presented in this thesis investigates the motoric versus perceptual basis of bimanual coordination stability. A general introductory section provides an overview of Parkinson's disease, upper limb coordination in healthy younger and healthy older adults and individuals with Parkinson's disease, and the current views of the basis of bimanual coordination stability. Following the general introductory section are two manuscripts for the two experiments. Both experiments followed similar paradigms. Healthy young adult~ participated in the first experiment and individuals with Parkinson's disease and healthy older adults participated in the second experiment. Following the presentation of the empirical work is a general discussion section. This section is intended to summarize the two experiments, to discuss potential methodological issues and to provide ideas for future experiments. / Thesis / Master of Science (MSc)

published_or_final_version / abstract / Medicine / Doctoral / Doctor of Philosophy

Safe and efficient swallowing requires integrity of both motor and sensory systems. Prior studies have established that motor impairment in individuals with PD frequently manifests as abnormalities in swallowing biomechanics. In contrast, very few studies have investigated the contribution of sensory impairment towards pharyngeal biomechanics and airway protection in this patient cohort. This area should be addressed in light of evidence that the severity of limb motor dysfunction in PD does not reliably predict severity of dysphagia. Emerging data suggests that dysphagia in PD cannot be solely attributed to motor impairment, but may also be influenced by deficits in sensory aspects of airway protection. As an example, silent aspiration in up to 100% has been reported in individuals with PD due to laryngopharyngeal sensory deficits have. Even so, current research lacks information on the integration of both motor and sensory components that make up the swallowing process. The aim of this study was to document changes in airway protection with age, in PD and across severity levels of PD. The project was comprised of two parts. In part one, three parallel studies were conducted to assess a series of both motor and sensory airway mechanism (Chapters 4 to 9). In the first study, 16 young (8 males, age range 21.3 - 32.4) and 16 elder adults (8 males, age range 61.5 - 84.7), were assessed to investigate changes in airway protection that accompany ageing. In the second study, data from individuals diagnosed with PD across severity levels (Hoehn-Yahr 1 - 4, age range 64.2 - 84.5) were age and gender-matched to 16 healthy elders in order to examine the effects of PD on airway protection. In the third, the impact of disease severity was studied with data from 16 individuals in the earlier stages (Hoehn-Yahr ≤ 2, 13 males, age range 51.3 - 82.5, ) compared to 16 individuals in the later stages (Hoehn-Yahr ≥ 2.5, 10 males, age range 61.5 - 78.9). In part two of this project, two smaller, pilot studies were completed to probe the influence of pharmacologic and behavioural treatments on airway protection mechanisms. In the first pilot study, the effect of pharmacotherapy on airway protection was investigated in 10 patients 'on' and 'off' levodopa (Chapter 10). In the second study, 5 patients were assessed before and after completing the Lee Silverman Voice Treatment (LSVT) to document effects of speech rehabilitation on airway protection (Chapter 11). Multimodality assessment elicited data from all participants on both motor and sensory components of airway protection (Chapter 3). Specifically, breathing-swallowing coordination (BSC) and swallowing apnoea (SA) were captured using simultaneous directional nasal airflow and surface electromyography (sEMG). Standard, closed-loop spirometry was used to assess pulmonary function. Swallowing biomechanics were screened using a validated timed test of swallowing efficiency and further evaluated using fibreoptic endoscopic evaluation of swallowing (FEES). Finally, chemo-sensation of the laryngopharynx was determined with the administration of the inhalation cough challenge while mechanosensation was examined using FEES. Results suggest that motor control for airway protection is reasonably robust in PD, although sensory response is impaired. The predominant pattern for swallowing respiratory coordination was mid-expiration for all participants regardless of age and disease severity (Chapter 4). Individuals with PD demonstrated a reduction in average time and volume per swallow, leading to an overall decrease in swallowing capacity (Chapter 5). No difference was found for swallowing efficiency between those in early and later stages of PD. Pulmonary function measures were not significantly different as a function of age, PD or PD severity (Chapter 6). In summary, results from motor assessments contributing to airway protection support the robustness of breathing-swallowing coordination (BSC) and pulmonary function across research groups, but identify a reduction in overall swallowing efficiency in PD. Results from sensory assessments contributing to airway protection revealed that chemosensation was not different between age groups but base of tongue mechano-sensation was diminished in individuals with PD. Natural cough thresholds did not differ between young adults and elders but when asked to stifle coughing, elders were less able to do so compared to young adults (Chapter 7). For the first time, a reduction in mechano-reception at the base of tongue was recorded in individuals with PD (Chapter 8). These patients also demonstrated increased post swallow residual (Chapter 5), which offers an explanation for the complaint of globus in this population. These assessments highlight some compromise to sensory aspects of airway protection in PD. Overall, dysphagia had a negative impact on the quality of life of individuals with PD and even more as disease severity progresses (Chapter 9). Results from part two of the study looking at the effects of therapeutic interventions on airway protection revealed some unexpected findings. In chapter 10, results showed a reduction in pulmonary function when 'on' levodopa, but no differences in swallowing efficiency, BSC, or laryngopharyngeal chemo- and mechano-reception were observed. These results suggested a reduction in pulmonary function with levodopa without any increase in risk of airway protection compromise1. Unexpectedly and documented for the first time, the percentage of post swallow inspiration increased after LSVT (Chapter 11) but as with the levodopa study, this was also not accompanied by any apparent increase in aspiration risk. An increase in submental surface electromyography (sEMG) amplitude across all 5 participants may serve as a proxy measure of improvement in hyolaryngeal excursion. Finally, participants reported an overall improvement in social functioning and communication after LSVT. In conclusion, this study provided evidence that mechano-sensory aspect of airway protection is diminished in individuals with PD, possibly compromising airway protection. Patients not only demonstrated increased residue but the lack of sensation may prevent clearing or spontaneous multiple swallows. Overall, airway protection is maintained in ageing but swallowing efficiency declines in the presence of PD. This study contributes significantly to current research efforts in PD by expanding on existing reports regarding motor aspects of airway protection. Specifically, BSC, swallowing efficiency and evaluation of biomechanics using FEES research have never before been investigated exclusively in the PD population. Finally, the chemo- and mechano-sensation evaluated in this study are an important addition to the limited evidence that sensory impairment in individuals with PD potentially compromises airway protection. Results of the present study will serve as a platform upon which future studies may compare and expand.

Speech breathing was investigated in 14 men with Parkinson disease (PD) and 14 healthy control (HC) subjects. Kinematic, spirometric, acoustic, and pressure data were used to assess speech breathing control during resting tidal breathing, reading aloud, and monologue production. In addition, information regarding the subjects' speech was obtained through perceptual analyses. To address the issue of fluctuations in motor signs data were collected at two times during the drug cycle for subjects with Parkinson disease. During resting tidal breathing, PD subjects, on average, had a faster breathing rate, greater minute ventilation, and lower relative contribution of the rib cage to lung volume excursion than did the HC subjects. During speech breathing, rib cage volume was smaller and abdominal volume was larger at initiation of the breath groups for the PD subjects than the HC subjects. PD subjects produced fewer words and spent less time producing speech per breath group, and tended to have a faster interpause speech rate than did the HC subjects. There was no difference between groups for the duration of inspirations between speech breath groups. Oral pressure was lower for the subjects with Parkinson disease, but tracheal pressure did not differ between the two subject groups. Few differences were found between the two times in the drug cycle for resting breathing and speech breathing. One remarkable finding was the presence of rib cage paradoxing in two subjects when data were collected from the mid-portion of the drug cycle.