The basal ganglia system is directly involved in functions of habitual motor control, organisation and initiation of movement (Redgrave et al., 2010). As decreased dopamine levels debilitate normal motor function, people with Parkinson's disease tend to move 30-40% slower than healthy adults, with a movement range that is often compromised (Stelmach, Teasdale, Philips, & Worringham, 1989). There is lack of consistent evidence as to how well Parkinson's Disease patients are able to temporally control their movements. This thesis reports on work exploring the underpinnings of temporal control of movement in healthy brains and Parkinson's disease patients. Initial investigations suggest that basal ganglia play an important role in sensorimotor synchronisation through error correction and temporal anticipation processes. We demonstrate that progression of the disease has a debilitating impact on the ability to time the movement with regards to an external temporal framework in intercepting beat task and is independent from underscaling of the movement. We further explore ways of enhancement of temporal control in Parkinson's disease by providing an extrinsic kinematic template for the movement. We present novel evidence that enhancement of motor performance in Parkinson's disease (paradoxical kinesia) is triggered by the dynamic temporal information in the environment (moving object, visual and auditory arrays of information). We demonstrate that both healthy controls and patients can exploit the characteristics of specially engineered sensory guides (visual and acoustic) to improve the timing of their movement (finger tracking and ball catching). The findings from this report have both theoretical and practical implications. We propose that ability for sensorimotor synchronisation could be a behavioural marker of Parkinson's disease progression. Finally, we point towards the use of dynamic guides based on biological motion to aid motor planning in daily activities and facilitate exercise in Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative condition with a predilection for the elderly. PD is classically known as a disease of motor debility. However, non-motor symptoms (NMS) in PD are becoming increasingly recognised. Sleep and mood disturbance are commonly encountered as major non-motor issues in clinical practice. These symptoms often cause significant bio-psycho-social impact which can lead to impaired quality of life in the patient and their family. Despite their importance, these symptoms have rarely been studied in incident cohorts of PD. Limited understanding of NMS and their temporal onset was one of the main motivational factors for this study. In addition, there was no prior study of these symptoms in an incident cohort of PD in North East England. This gap in local epidemiological knowledge plus the inherent need to improve our understanding on this subject acted as a catalyst for this project which was executed as part of the Incidence of Cognitive Impairment in a Cohort with Longitudinal Evaluation - Parkinson's Disease (ICICLE-PD) study. The crude incidence of PD in North East England was 17.71 100,000 persons per year. This figure was somewhat higher than most previous studies in the UK. A major finding was the characterisation of NMS onset and frequency in newly diagnosed PD with symptoms of mood and sleep disturbance being prominent. The temporal onset of many NMS, for example mood changes and sleep disturbances, was earlier than motor symptoms, consistent with current pathophysiological models of disease evolution. 28.6% of subjects experienced anxiety and apathy whilst a smaller proportion had symptoms of major depression (13.1%). In terms of sleep disturbance, 56.9% experienced poor sleep quality and excessive daytime somnolence was present in 22.4% of subjects. Almost half the PO cohort (46.0%) had clinically defined REM sleep behaviour disorder. This study confirms the high burden of NMS in incident PD and so the importance of screening for such symptoms in newly diagnosed cases.

Parkinson's disease (PD) is a chronic and progressive neurodegenerative disorder, which is characterised by the degeneration of dopaminergic neurons. The molecular mechanisms that lead to PD are unknown. A number of genes have been identified to be associated with inherited forms of PD, including PINK1 and Parkin, which are linked to autosomal recessive juvenile parkinsonism. It has been demonstrated in the Drosophila melanogaster model system that PINKl and Parkin function in a common pathway. The work of this thesis aims to characterise PINKI molecularly and genetically in Drosophila . One approach that was taken is to conduct an unbiased genetic screen to identify novel genes that interact with PINKl. This screen uses a rough-eye phenotype that is caused by overexpression of PINKl in the eye tissue. Deficiency chromosomes that result in modification to the rough-eye phenotype indicate the deficiency region spans a gene or genes that may be involved in the normal function of PINKl. Another approach is to identify candidate genes that may have a role with PINK1 function. Drosophila PINK1 and Parkin mutants exhibit a distinct set of mutant phenotypes. Similar phenotypes are also seen with Rhomboid-7 mutants, which suggest Rhomboid-7 to be a potential candidate gene. This was tested genetically and biochemically. An alternative approach to understand the way PINK1 functions is based on the fact that there are two forms of PINKl. The functional importance of having two forms of PINK1 and the site of their function is unknown. A putative PINK1 form was designed to mimic the PINKl processed form located to the cytoplasm. This was analysed functionally against PINK1 and Rhomboid-7. The result shows that Rhomboid-7, a mitochondrial intramembrane protease, is required for the processing of PINKl, resulting in two detectable forms. The significance of having two forms ofPINKl is unclear. The processed PINK! in the cytoplasm can rescue PINK! mutant phenotypes but not that of Rhomboid-7. This suggests that processed PINKl has no role in the functionality of Rhomboid-7. In conclusion, Rhomboid-7 was identified as a novel component of the PINK! pathway, which acts to cleave full length PINKl. The putative processed PINK1 form was able to rescue PINK 1 function.

No description available.

The aim of the present study was threefold. First, to examine the incidence of dysarthria in patients in the beginning of Parkinson's disease by using a standardised test (Frenchay Dysarthria Assessment/FDA) and an intelligibility assessment tool. Second, to identify differences in speech and in measures of phonation between the Parkinsonian group and a matched control geriatric group using the FDA and electrolaryngography. Finally, to identify the effect of medication on speech and phonation in the dysarthric Parkinsonian group. The results showed that 8 out of 12 (66%) Parkinsonian subjects exhibited lower scores in the FDA compared to controls. Qualitative differences between the two groups were found in the isolated movements of the articulators but not in running speech and speech intelligibility. An improvement in the FDA scoring was found 3-3.5 months after medication. This improvement focused on the areas of tongue and lips and was accompanied with significant increases in intelligibility. No differences in measures of phonation were found either between the two groups or in the same group after medication. The above results suggest that in the beginning of Parkinson's disease, dysarthria is expressed as slowness and may be related to the primary diagnostic symptom of bradykinesia. Due to the small sample and the lack of dosage control, the significance of these findings appears to be inconclusive and warrants further investigation. Future research should employ instrumental quantitative measures on isolated movements of the articulators that may correlate with running speech and will aim to find clinical markers of speech in the diagnosis of Parkinson's disease.

Parkinson’s disease is the second most common neurodegenerative disease in the world. The initial motor symptoms are well controlled with replacement therapy with levodopa. Slowly over time the patients run into problems both due to the inexorable progression of the disease and also due to complications of the drugs itself. The two most common disabling complications that are difficult to treat are levodopa-induced-dyskinesias and dementia. Although there have been extensive research, the pathophysiology of both these conditions are still unclear. Unsurprisingly treatment options are limited for both these conditions. From the dyskinesia research, studies with animal models of Parkinsonism have shown abnormalities in glutamate neurotransmission but the role of glutamate in causing dyskinesias in PD patients in still unclear. Using a novel PET tracer [11C]CNS-5161 we demonstrated in vivo an increased activity of NMDA-glutamate receptors specifically in the motor areas when levodopa was administered to dyskinetic PD patients. On the other hand non-dyskinetic PD patients had the opposite effect i.e. reduction of glutamate channel opening with levodopa administration. Our study implicates glutamate overactivity to be a major factor in causing LID and supports the use of anti-glutamate agents in PD dyskinesias. In PD Dementia patients the pathophysiological basis of the disease is still unknown. Concomitant AD type amyloid pathology, cortical Lewy disease , inflammation and biochemical neurotransmitter defects have all been thought to cause the disease. Using specific PET tracers, [11C]-PIB which bind to amyloid , [11C]-PK11195 which bind to activated microglia associated with inflammation and [18F] FDG which measure neuronal dysfunction we showed increased cortical microglial activation and glucose utilisation in both PDD and PD patients but more so in PDD patients implying ongoing disease activity with inflammation playing an important role relatively early in the disease. The conspicuous absence of [11C]-PIB uptake in the majority of PD patients makes amyloid pathology quite unlikely in causing the disease. Our study favours treatment strategies to reduce microglial activation relatively early in the disease compared to anti-amyloid therapy in PDD. Thus this research provides a pathophysiological basis for both PD dyskinesias and dementia and does open up avenues for further treatment strategies.

No description available.

No description available.

No description available.

In this study I investigated the mechanisms of neuronal network oscillatory activity in rat M1 using pharmacological manipulations and electrical stimulation protocols, employing the in vitro brain slice technique in rat and magnetoencephalography (MEG) in man. Co-application of kainic acid and carbachol generated in vitro beta oscillatory activity in all layers in M1. Analyses indicated that oscillations originated from deep layers and indicated significant involvement of GABAA receptors and gap junctions. A modulatory role of GABAB, NMDA, and dopamine receptors was also evident. Intracellular recordings from fast-spiking (FS) GABAergic inhibitory cells revealed phase-locked action potentials (APs) on every beta cycle. Glutamatergic excitatory regular-spiking (RS) and intrinsically-bursting (IB) cells both received phase locked inhibitory postsynaptic potentials, but did not fire APs on every cycle, suggesting the dynamic involvement of different pools of neurones in the overall population oscillations. Stimulation evoked activity at high frequency (HFS; 125Hz) evoked gamma oscillations and reduced ongoing beta activity. 20Hz stimulation promoted theta or gamma oscillations whilst 4Hz stimulation enhanced beta power at theta frequency. I also investigated the modulation of pathological slow wave (theta and beta) oscillatory activity using magnetoencephalography. Abnormal activity was suppressed by sub-sedative doses of GABAA receptor modulator zolpidem and the observed desynchronising effect correlated well with improved sensorimotor function. These studies indicate a fundamental role for inhibitory neuronal networks in the patterning beta activity and suggest that cortical HFS in PD re-patterns abnormally enhanced M1 network activity by modulating the activity of FS cells. Furthermore, pathological oscillation may be common to many neuropathologies and may be an important future therapeutic target.