Dissertations / Theses on the topic 'Parkinson's disease'

Non-motor symptoms such as dementia and visual hallucinations are key determinants of long-term outcome and quality of life in Parkinson’s disease (PD). Attempting to understand these issues better was the motivation behind this thesis. A major aim of the study was to characterise the visual symptoms experienced by patients with PD and PD dementia, focussing not just on complex visual hallucinations, whose prognostic implications are already well-described, but also on a range of other visual symptoms including illusory misperceptions, sensations of passage and presence and double vision. A major objective was to define key measures of visual exploration strategy during visuocognitive assessment and examine the link between strategy, cognition and visual and motor symptoms. We also set out to examine the utility of retina-specific visual assessment techniques to define the potential role of retinal dysfunction in visual impairment and symptomatology. A major finding of this study was that not all visual symptoms share a common pathophysiological basis. Our results argue in favour of splitting hallucinations into separate phenomenological groups in order to better define causation and predictive value in future longitudinal studies. In addition, exploration strategy on a variety of visual tasks was demonstrated to be significantly less efficient in subjects with perceptual difficulties, providing insight into the interaction between cognition and eye movements in PD. Retinal structure, as assessed by optical coherence tomography, was not significantly altered in PD and our results would caution against the use of this technique as a disease biomarker until more is known about the limitations of this method. Finally, our neurophysiological assessment hints at the retina as the site of diminished visual acuity in PD despite there being no striking differences in central and peripheral retinal responses between control and PD subjects.

Parkinson???s disease (PD) is a progressive neurodegenerative disease characterised pathologically by the selective death of the dopaminergic neurons of the substantia nigra and the appearance of abnormal inclusions in some surviving neurons. A body of evidence from epidemiological, in vitro and in vivo studies suggest that isoprenoids, a lipid family which includes cholesterol, dolichol and ubiquinone, may play a role in PD, although to date the data has been conflicting with little consensus regarding the type or direction of change in isoprenoids in PD. The current study investigated isoprenoids in PD by quantifying a range of isoprenoids in blood sera, brain homogenates and olfactory mucosa derived from PD patients and controls. Further, isoprenoid synthesis pathways were investigated by comparing the activitites and amount of the rate-limiting enzyme for isoprenoid synthesis, HMG CoA reductase, in olfactory mucosal cultures from individuals with sporadic PD and leucine-rich repeat kinase 2 (LRRK2)-PD with those from healthy individuals. Serum levels of total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides and dolichol were unchanged in patients with PD compared with controls. Similarly, total tissue cholesterol was unchanged in degenerating and non-degenerating regions of the PD brain, but tissue dolichol was significantly decreased in the substantia nigra in the PD brain, possibly reflecting a change in the neuron/glia ratio in this brain region. In olfactory mucosa, a significant decrease in cellular cholesterol content was identified in patients with LRRK2-PD compared with patients with sporadic PD or controls. The reduction in cholesterol was similar in two different LRRK2 mutations but was not associated with a change in either the amount or activity of HMG CoA reductase. This study suggests that decreased cholesterol is associated with LRRK2-PD but not with sporadic PD. As cholesterol levels in cells with different LRRK2 mutations were reduced to a similar extent, it is suggested that mutations in this gene result in a loss-of-function of LRRK2 protein. Further it suggests a role for LRRK2 in cholesterol homeostasis independent of HMG-CoA reductase-associated pathways. Recent data has suggested a functional role of LRRK2 in autophagy, a mechanism which may explain the reduction in cholesterol observed in LRRK2-PD.

This thesis examines the clinical and pathological involvement of the olfactory system in Parkinson’s Disease (PD). The main aim is to investigate the practical use of smell identification tests (SITs) in parkinsonism and tremor. A secondary objective is to investigate the pathological involvement of the rhinencephalon. Commercially available SITs were used to differentiate PD patients from control subjects in the UK, Brazil and Sri Lanka, showing SITs have combinations of sensitivity and specificity greater than 80%. Based on the data obtained a traffic light ruler was devised to determine the likelihood of a patient having PD at the time of the initial consultation. This was then used to interpret SITs in 34 patients with possible parkinsonism, showing 86.4% sensitivity and 80.0% specificity of SITs when compared to dopamine transporter imaging using single photon emission computed tomography (SPECT) as the gold-standard for detecting nigrostriatal dopamine denervation. Olfaction was shown to be severely impaired in parkinsonism related to LRRK2 mutations, moderately impaired in subjects with pure autonomic failure, multiple system atrophy and progressive supranuclear palsy (PSP) and normal in patients with essential tremor, dystonia and in subjects who had been diagnosed as having PD, but were found to have normal scans. This indicates that SITs will be more useful in differentiating PD from non-degenerative tremors than from atypical parkinsonism. Neuropathological changes were investigated in the rhinencephalon and it was demonstrated that α-synuclein accumulation in the primary olfactory cortex is heterogeneous, being more severe in the temporal subdivision of the piriform cortex. The piriform cortex had Lewy body pathology in all 10 PD cases studied, as well as in 7 control cases who presented incidental Lewy body pathology and four cases of LRRK2 related parkinsonism. The piriform cortex had abnormal tau accumulation in 6 PSP patients, suggesting tauopathy in the rhinencephalon is a possible substrate for hyposmia in PSP.

Background: Pain is a very common symptom in Parkinson’s disease (PD). The underlying mechanism of pain in PD is poorly understood. Compared to PD, the characteristics of pain in other parkinsonian disorders such as Multiple System Atrophy (MSA) and Progressive Supranuclear Palsy (PSP) have not been studied. Musculoskeletal factors have been implicated in the generation of pain in PD. However, studies in PD have shown impaired central processing of nociceptive inputs. Recently, small fibre neuropathy has also been found to be common in PD with significantly reduced C-fibres density compared to controls. A subclass of C-fibres known as C tactile afferents (CT) mediate the pleasant sensation associated with gentle skin stroking (affective touch). CT afferents have recently been shown to have pain-inhibiting properties. These findings may implicate central sensitisation in pain generation in PD. Objectives: 1) To better understand the mechanisms of pain in PD and study the characteristics of pain in MSA and PSP compared to PD. 2) To quantify small fibre neuropathy in PD and explore its relation to pain utilising a novel diagnostic technique: corneal confocal microscopy (CCM). 3) To assess the perception of affective touch in PD and its relationship to pain. Methods: Four studies were conducted: Study 1: A cross sectional study of pain characteristics in PD, MSA and PSP. Study 2: A descriptive study of pain characteristics in a large cohort of early PD (disease duration < 3 years, n=1763). Study 3: A cross sectional study to quantify small fibre density in PD (n=26) compared to control subjects (n=26) using CCM and skin biopsies. Nerve density was correlated with non-motor symptoms in PD including pain. Study 4: A study to assess the CT-mediated perception of affective touch in PD and correlate it with clinical symptoms such as pain. Results: Study 1: Pain prevalence and intensity was significantly higher in MSA and PD compared to PSP, p < 0.05. Female sex and motor fluctuations but not motor severity were predictors for pain intensity in PD. Study 2: Pain was common in early PD (84.2%). Only a minority of PD patients (19.7%) reported that their pain improved with Levodopa therapy of their motor symptoms. Study 3: PD patients had significantly reduced small fiber nerve density on both CCM and skin biopsies compared to controls. Denervation correlated with autonomic symptoms but not with pain intensity. Study 4: Perception of pleasantness followed a linear relationship with nerve density and was abnormally enhanced in PD compared to control and correlated with pain at a very slow stroking velocity. Conclusions: Pain is common in early PD, does not respond to levodopa treatment and correlates with motor complications but not motor severity favouring central sensitisation. Pain is significantly less common in PSP compared to PD and MSA. Small fibre neuropathy does not appear to be an important cause of pain in PD but small fibre nerve density correlates with affective touch perception, which is enhanced in PD despite peripheral denervation. Corneal confocal microscopy identifies corneal denervation in PD offering a novel non-invasive way of assessing PD pathology.

The development of neurodegenerative diseases is an ever increasing risk faced by modern society as aging populations rise globally. For complex diseases such as Alzheimer‟s Disease (AD) or Parkinson‟s Disease (PD) the prospect of finding a cure within the immediate future is unlikely. These complexities arise primarily from the interactions of the protein of interest each of the diseases, which in the case of typical and atypical PD is α-synuclein (α-syn). Thought to be involved in neuronal vesicle recycling in its monomeric α-helical state, change to a β-sheet conformation allows α-syn to misfold, creating oligomers and eventually aggregates which form the initial bedrock for inclusion bodies. One of the more fascinating features of pathological α-syn is the difference in inclusion body composition and cell type affected in typical and atypical PD variants. For instance within Multiple System Atrophy (MSA), an atypical PD variant, α-syn aggregates form Glial Cytoplasmic Inclusions (GCIs) the composition of which differs from the Lewy Bodies (LB) formed in PD, and are largely found in oligodendrocytes. Unlike neurons, oligodendrocytes normally express only minimal amounts of α-syn which does not alter even after GCIs are formed, indicating acquisition of α-syn from an external source. How oligodendrocytes acquire pathological α-syn and the mechanisms by which the protein is able to spread within the central nervous system (CNS) are topics currently with more questions than answers. Thus the primary focus of the thesis is to investigate potential models of α-syn spread in order to develop future novel targets to slow disease progression. The investigations within Chapters 2 and 3 focus on exploring microglial cells as a potential vehicle for α-syn migration within the CNS. Along with the presence of α-syn inclusion bodies, part of the degeneration taking place within MSA is due to the chronic inflammatory activation and actions of the CNS resident immune cell, the microglia. Whilst microglial inflammatory responses play a role in PD, the severity of inflammation is greater in MSA. Microglia possess many traits which contribute to their ability to become a potential transporter of α-syn, including the lack of ability to degrade internalised pathological α-syn variants such as oligomers and aggregates. Post-mortem human MSA brain tissues were examined for evidence of microglial interactions with GCI-affected oligodendrocytes. Not only were interactions between these cells noted in a variety of different tissue regions and patients, but qualitative evidence of microglial migration with internalised α-syn distal from GCI-affected cells was obtained. Whilst these findings suggest that microglia could play a potential role in α-syn spread within the CNS and α-syn occurrence within oligodendrocytes, post-mortem examination is limited to detailing what may occur following the observed interactions. An in vitro assay was developed to investigate α-syn uptake and mobilisation by cells from a point source of immobilized protein. In this assay, monomeric and aggregated α-syn uptake and migration were assessed when exposured to THP-1 monocytes and microglial-like differentiated THP-1 cells. Microglial-like differentiated THP-1 cells were found to show uptake and migration with internalised aggregate α-syn to distal regions, not observed with undifferentiated THP-1 monocytes or monomeric protein. This result indicates that microglia/microglial-like cells are more likely to internalise pathological α-syn such as aggregates than the normal, monomeric form. The greater numbers of differentiated THP-1 with internalised aggregated α-syn indicates that once the protein has been taken up by microglia, then it becomes a transported to distal brain regions. The inability of microglia to degrade aggregated α-syn, similar to microglia within the CNS, likely contributes microglial-mediated α-syn spread. Further testing using highly aggressive proliferating immortalised (HAPI) cells, a rat microglial cell line, was conducted which corroborated the previous findings, indicating that microglia take up the pathological variant of α-syn, mobilizing the protein rather than degrading it. Utilising the same α-syn mobilization assay, inhibition of microtubule instability through the use of the microtubule stabilising agent Epothilone D (EpoD) proved successful in lowering both uptake and mobilization of aggregated α-syn, showing promise as a novel therapy against α-syn spread. Inhibition of the microglial inflammatory response through TAK-242 treatment, a Toll-like Receptor 4 (TLR4) inhibitor, was also trialled to investigate if TLR4 plays a significant role with regards to α-syn uptake and mobilisation. However, unlike EpoD, TAK-242 proved ineffective. For Chapter 4 experimentation focussed on investigating the role of intercellular mitochondrial transfer through tunnelling nanotubes (TnTs) as a potential means of α-syn spread. Pathological α-syn species have been described to bind to intercellularly migrating organelles such as lysosomes for spread to adjacent sites. The role of mitochondria in typical and atypical PD has predominantly focussed on their role in degeneration and as such gaps exist as to mitochondrial function in relation to α-syn propagation. Utilising Stimulated Emission Depletion (STED) super resolution microscopy, SH-SY5Y, 1321N1 and differentiated THP-1 monocultures, as models of neurons, astrocytes and microglia, were each inoculated with aggregated α-syn to examine transfer to adjacent cells via TnTs whilst bound to mitochondria. Under each cell culture condition, the formation of TnT-like structures was observed between adjacent cells, each containing migrating mitochondria with α-syn aggregates bound to the outer mitochondrial membrane. Further exploration of this result through 1321N1 / differentiated THP-1 co-culture showed that this mechanism of α-syn spread is not limited to monoculture conditions and may be a potential mechanism relevant to typical and atypical PD. Knockdown of Miro1, a critical protein bridging mitochondria to the motor adaptor complex for intercellular migration, was performed in order to ascertain if its role is significant in the α-syn spread process and a potential therapeutic target. Miro1 silencing however proved qualitatively ineffective in the prevention of α-syn spread mediated by mitochondria, indicating other factors in addition to Miro1 may be involved in bridging mitochondria to intercellular motor complexes. Taken together these results illustrate the great complexity of mechanisms of α-syn spread and the inherent difficulties associated with attempting to combat them.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Medical Science
Griffith Health
Full Text

Thesis (Ph. D.)--University of Sydney, 2006.
Title from title screen (viewed May 1, 2007). Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy to the School of Occupation and Leisure Sciences. Includes bibliographical references. Also issued in print.

Thesis (Ph.D.)--University of Cincinnati, 2009.
Advisor: Kathy Steece-Collier. Title from electronic thesis title page (viewed Apr. 26, 2010). Keywords: Parkinson; dopamine; dyskinesia; levodopa; dendritic spine; medium spiny neuron. Includes abstract. Includes bibliographical references.

Parkinson�s disease is a neurodegenerative disorder, which is typically characterised in terms of its debilitating effects on motor function. However, ubiquitous neuropsychological deficits are also an integral feature of the progression of this disease. This thesis investigated these cognitive deficits as they manifest in language, with the overarching goal being to elucidate the word-finding problems that are associated with Parkinson�s disease. Making semantic judgements and identifying semantic relations are two processes that are particularly germane to word-finding. Therefore, the present thesis examined: 1) the ability of people with Parkinson�s disease to make judgements about semantic categories, and 2) the integrity of associative semantic networks in Parkinson�s disease. In the first series of studies, Cups and Bowls, a novel semantic categorisation task was used to investigate the ability of people with Parkinson�s disease to consistently categorise common kitchen items across a number of trials. The Parkinson�s group was impaired relative to an age-matched control group on this task. This inconsistent categorisation was particularly apparent for the less typical category exemplars at the category boundaries, suggesting that the Parkinson�s group had less salient or less elaborated semantic categories, which particularly compromised categorisation of the less typical category exemplars. This finding is discussed in terms of selective attention deficits and inappropriate weightings of semantic features. In the second series of studies, Verbal Memory, the structure of the semantic network and access to the semantic system were further investigated using a verbal memory task, which required participants to recall word lists. These word lists consisted of semantically associated words and were designed to elicit false recall of another, non-presented, close semantic associate (the critical lure). The results of this second series of studies, particularly the fact that the Parkinson�s group recalled more of the false critical lures than the control group, suggested an intact semantic network in Parkinson�s disease and normal saliency of semantic categories. The potentiated false recall effect in the Parkinson�s group is discussed in terms of poor modulation of attention in Parkinson�s disease, both as the result of an executive deficit leading to poor controlled processing and in terms of a dopamine-modulated decrease in the signal-to-noise ratio leading to impaired automatic processing. Taken together, the results reported in the present thesis suggest that basal ganglia pathology and striatofrontal deafferentation in Parkinson�s disease do not diminish the integrity of semantic memory, but do compromise operation of semantic memory due to impaired modulation of activation/inhibition mechanisms. This finding of a selective attention deficit has implications for word-finding, suggesting that the word-finding difficulties associated with Parkinson�s disease are the result of impaired lexical access. In particular, retrieval of specific lexical items from semantic memory is impeded because of failure to modulate activation/inhibition mechanisms effectively for the target word to be distinguished from close semantic associates. An intact semantic checking mechanism in anterior language cortex prevents the production of semantic paraphasias, and results in the tip-of-the-tongue word-finding problems displayed by some people with Parkinson�s disease.

Parkinson’s disease (PD) is a common movement disorder, affecting 1% of the population over the age of 65. Pathologically, PD results from degeneration of nigral dopaminergic neurons, however symptoms do not appear until an estimated 50% of these cells are lost, suggesting compensatory mechanisms exist which mask disease onset, and may later delay progression of the disease. Compensation may take place over various spatial and temporal scales, from changes in synaptic dopamine release and synthesis that take place over a period of minutes, to recruitment of novel, widespread networks of brain regions for a specific task, which may require formation of new connections over an extended period of time. Neuroimaging techniques have recently allowed the investigation of regional and network changes in activation related to motor performance in PD, however the question of whether such changes represent a downstream effect of basal ganglia degeneration, or a compensatory change, remains difficult to determine. Here, we applied an approach from research into Alzheimer’s Disease, where abnormal activation patterns are studied in the context of tasks of increasing difficulty, such that inferences regarding their compensatory nature can be made. We show that individuals with PD are able to increase the recruitment of normal networks for a motor task (motor reserve) as a form of compensation, in addition to compensatory recruitment of novel networks to accomplish the same task as healthy controls. In particular, we observe a switch from striato-thalamo-cortical (STC) motor loops to cerebello-thalamo-cortical (CTC) loops as a compensatory strategy. This compensatory recruitment involves changes in the amplitude, spatial extent, and connectivity of regions within the CTC pathway. However, this compensation does not come without a price, since we show that compensatory CTC recruitment involving disconnection between the STC and CTC loops occurs in subjects with tremor-dominant PD, but not akinetic-rigidity-dominant PD, supporting a growing body of evidence that suggests the cerebellum plays an important role in the generation of PD tremor. Together, this body of research has implications for treatments that target the symptom of tremor in PD, as therapies which minimize tremor might also reduce beneficial aspects of compensation.

Parkinson’s Disease (PD) is a common neurodegenerative condition characterised pathologically by progressive dopaminergic cell loss in the substantia nigra pars compacta, dopamine depletion and resulting cortico- basal ganglia circuit dysfunction. There is a considerable variation in symptoms and treatment response between patients and therefore a need to individualise treatments, such as dopamine replacement therapy, and deep brain stimulation (DBS). We therefore require a better understanding of how different motor and non-motor symptoms emerge from the cortico-basal ganglia dysfunction characteristic of PD. In this thesis, I investigated the hypothesis that distinct symptoms in PD may be due to the dysfunction of distinct cortico-basal ganglia circuits. I characterised cortico-basal ganglia coupling by simultaneously recording cortical activity with magnetoencephalography (MEG) and basal ganglia activity from intracranial electrodes placed during DBS surgery for PD. Coupling was measured in terms of coherence – a frequency specific measure of coupling. I found that resting cortico-basal ganglia networks had distinct cortical topographies at different frequencies. Frontal regions coupled to both the subthalamic nucleus (STN) and the pedunculopontine nucleus region (PPNR) in the beta frequency band whilst temporal, parietal and cerebellar areas coupled in the alpha range. I hypothesised that activity in the frontal beta network may relate to executive function, and found that local synchronisation in two frontal cortical hubs was related to stopping an on-going movement – a crucial executive function. In a related experiment in PD patients, transient frontal – basal ganglia coupling was again apparent during motor inhibition, but how this is related to behavioural performance needs further investigation. These results are useful in highlighting how cortico-basal ganglia networks can be separated both spatially and spectrally and how the function and dysfunction of these networks can be interrogated in PD patients. Future work should determine how different stimulation parameters differentially affect these distinct circuits.

Objectives - Gaucher disease (GD) is caused by bi-allelic mutations in the glucocerebrosidase gene (GBA). GD and heterozygous carriage of GBA mutations significantly increase the risk of developing Parkinson's disease (PD). Here we studied GD patients and carriers to identify a cohort of individuals with clinical signs of prodromal PD and generated fibroblast lines from them to study why GBA mutations cause PD. Methods - 83 patients with Type I GD and 41 of their heterozygous carrier relatives were recruited from lysosomal storage disorder clinics at the Royal Free Hospital and Addenbrooke's Hospital Cambridge, along with 30 mutation negative matched controls. They were clinically screened for hyposmia (University of Pennsylvania Smell Identification Test), cognitive impairment (Montreal Cognitive Assessment), autonomic dysfunction, REM sleep behaviour disorder and motor signs of PD. Two hundred and thirty cases of sporadic PD were screened for GBA gene mutations. Fibroblasts were generated from skin biopsies taken from a selection of patients. GBA metabolism (Western blotting for protein levels, enzyme activity, immunofluorescent localisation), mitochodrial metabolism, endoplasmic reticulum and oxidative stress markers were assayed in the cell lines. Results – GD patients and heterozygous carriers had significantly lower olfactory and cognitive function scores than controls. Several GD patients and carriers had motor signs of PD (e.g. rest tremor) while controls did not. Thirteen PD patients with heterozygous GBA mutations were identified. Their clinical phenotype was similar to mutation negative PD cases. GD fibroblast lines (n=5), and lines from heterozygous GBA mutation carriers with (n=4) and without PD (n=2) had reduced GBA enzyme activity due to endoplasmic reticulum retention of GBA protein. This was associated with upregulation of endoplasmic reticulum stress markers and oxidative stress (increased rate of dihydroethidium oxidation). Conclusions – a subset of GD patients and carriers express clinical markers of prodromal PD. Study of fibroblasts from these individuals indicates that endoplasmic reticulum and oxidative stress may contribute to increased PD risk in these individuals.

Introduction Falls are a frequent and serious complication of Parkinson's disease (PD) in part related to an underlying cholinergic deficit that contributes to both gait and cognitive dysfunction. There is an urgent need to identify strategies that will effectively prevent falls and the consequences thereof. This thesis aims to assess whether ameliorating the cholinergic deficit with the cholinesterase inhibitor rivastigmine will reduce gait variability and the frequency of falls. Methods This phase II randomised double blind placebo controlled trial recruited PD patients, who had fallen in the past year; were able to walk 18 metres without an aid; had no exposure to a cholinesterase inhibitor, and did not have dementia. Patients were randomly assigned (1:1) to rivastigmine (target dose 12mg per day) or placebo by central allocation. The primary outcome measure was step time variability, a marker of gait stability, assessed at 32 weeks employing an intention-to-treat analysis. Step-time variability was assessed in three different walking paradigms combining tasks of increasing attentional demand. Results We recruited 130 patients who were randomly assigned to rivastigmine or placebo and 120 (92.3%) completed the study. Rivastigmine improved step time variability in all three walking conditions with the most significant benefit for normal walking; ratio of geometric means in normal walking 0.72 (95% CI 0.58 to 0.88, p=0.002); simple dual task 0.79 (95% CI 0.62 to 0.99, p=0.05), and complex dual task 0.81 (95% CI 0.60 to 1.09, p=0.17). There was a 45% (95%CI 19% to 62%, p=0.002) reduction in the rate of falls per month during the treatment period. Gastrointestinal side effects were more common on rivastigmine (p