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Ikuta, Toshikazu. "fMRI study of grammar, Parkinson's disease and dopaminergic medication." [Bloomington, Ind.] : Indiana University, 2008. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3337540.
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Thesis (Ph.D.)--Indiana University, Program of Neuroscience and the Dept. of Linguistics, 2008.<br>Title from PDF t.p. (viewed on Jul 27, 2009). Source: Dissertation Abstracts International, Volume: 69-11, Section: B, page: 6602. Adviser: Laura L. Murray.
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Crocker, Stephen J. "Novel therapeutic strategies for the treatment of Parkinson's disease." Thesis, University of Ottawa (Canada), 2001. http://hdl.handle.net/10393/9053.
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Parkinson's disease (PD) is a common neurodegenerative disorder associated with the loss of dopamine neurons located in the substantia nigra pars compacta. Current pharmacological approaches for the treatment of PD are confounded by development of abnormal involuntary movements called dyskinesias, and offer limited long-term utility because they do not stop the disease progression. Accordingly, this thesis addressed two primary issues limiting the present treatments of Parkinson's disease: the molecular basis of dopamine receptor-related dyskinesias, and attenuation of dopamine neuron death. Administration of dopamine receptor agonists to rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway produce changes in the denervated striatum that enable subsequent exposure to dopamine agonists to elicit potentiated circling behaviour, a phenomenon called "priming". Priming is used as a model to study the molecular basis of dyskinesias. Here, I demonstrate that dopamine D1-receptor priming is associated with a profound elevation of the nuclear transcription factor FosB in the denervated striatum. Moreover, intrastriatal delivery of an antisense oligonucleotide to fosB effectively blocked the induction of striatal FosB by dopamine agonist administration and attenuated the circling response elicited by injection of a selective dopamine D1-receptor agonist 3 days later. These findings suggest that dopamine receptor mediated FosB expression in the striatum plays a role in priming. In addition, the results from this study suggest that fosB may be involved the intracellular events which are responsible for the development of dyskinesias following chronic dopamine replacement therapy. The molecular processes which mediate the loss of nigral dopamine neurons in Parkinson's disease are not known. Recently, a novel family of mammalian proteins, called Inhibitor of Apoptosis (IAP) proteins, were cloned and shown to prevent cell death induced by a variety of cytotoxic factors. In two separate studies, I demonstrate that enhanced neuronal expression of two of these IAP proteins, neuronal apoptosis inhibitor protein (NAIP) and X-linked IAP (XIAP), prevents the death of nigral dopamine neurons following exposure to the dopaminergic neurotoxins. In rats, intrastriatal administration of recombinant adenoviruses containing NAIP (Ad.NAIP) was shown to prevent both the cellular and behavioural deficits produced by intrastriatal administration of 6-OHDA when compared to adenovirus control (Ad.lacZ) lesioned animals. Secondly, I describe a novel strain of mice engineered to overexpress XIAP in neurons by using a neuron-specific enolase promoter (NSE-xiap). Moreover, I demonstrate that NSE-xiap mice were profoundly resistant to the deleterious effects of the dopaminergic neurotoxin, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Since administration of MPTP can produce behavioural and neuropathological deficits reminiscent of PD in humans, results from this study suggest that IAP proteins may have utility for the treatment and prevention of cell death in idiopathic PD. Taken together, these studies suggest that neuroprotective strategies based on enhanced neuronal expression of IAP proteins may have novel therapeutic potential for treating neurodegeneration associated with Parkinson's disease.
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Biswas, Amitava. "Perioral sensorimotor integration in Parkinson's disease." [Bloomington, Ind.] : Indiana University, 2005. http://wwwlib.umi.com/dissertations/fullcit/3183913.
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Alexopoulou, Zoi. "The study of the deubiquitinase USP8 in Parkinson's disease pathogenesis." Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:47c2941b-5232-4bd0-92fa-e59aac16af7c.
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Parkinson's disease is the second commonest neurodegenerative disease currently treated symptomatically. It is a multifactorial disease involving mechanisms ranging from protein aggregation to mitochondrial dysfunction, oxidative stress and dopamine dysregulation. The levels of α-synuclein have been causatively linked to the development and progression of Parkinson's disease. Therefore α-synuclein lowering strategies are valid approaches in Parkinson's disease. Neuropathologically, Lewy Bodies in the vulnerable substantia nigra of Parkinson's disease patients are less ubiquitinated and specifically less K-63 ubiquitinated than Lewy bodies in the cortex, suggesting differential activation or regulation of ubiquitin interactors. A targeted screen for such interactors revealed that the Deubiquitinating enzyme Usp8 is upregulated in the substantia nigra of Parkinson's disease brains and is inversely correlated with the degree of total and K-63 ubiquitination. Using genetic knockdown and overexpression techniques, Usp8 was found to colocalize and directly interact with α-synuclein. It was found to de-ubiquitinate α-synuclein and increase its half-life. Its knockdown increased the total and K-63 α-synuclein ubiquitination and decreased its levels by 35% at least partly by increasing its degradation via the lysosome. In vivo in the Drosophila melanogaster, Usp8 knockdown demonstrated protection against α-synuclein toxicity. It rescued in a specific manner the rough eye phenotype, the age-dependent locomotive defect and the loss of dopaminergic neurons caused by the expression of α-synuclein. Specific and effective pharmacological Usp8 inhibition also has the potential to lower α-synuclein levels. Collectively, the evidence produced in my thesis suggests that Usp8 could be a potential target for the future disease-modifying therapies in Parkinson's disease.
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Little, Simon. "Adaptive deep brain stimulation for Parkinson's disease : closed loop stimulation for Parkinson's." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:5b76616a-7d5e-424e-9c66-5d48b19cae1c.
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Our understanding of the pathophysiology Parkinson’s disease has transformed over the last decade as we have come to appreciate the importance of changes in neuronal firing pattern that occur within the motor network in the dopamine deficient state. These changes in firing pattern, particularly increased synchrony result in oscillations that can be recorded as local field potentials. This thesis concerns itself with the study of beta oscillations which are characteristic of Parkinson’s disease. Firstly, I investigate whether beta oscillations play a pathophysiological role in Parkinson’s disease or whether they are purely epiphenomenal by augmenting beta with low frequency deep brain stimulation. In this study I show that rigidity is increased by ~25% with low frequency stimulation providing significant further evidence for a patho-physiological role of beta in Parkinson’s disease. Next I investigate whether beta oscillations correlate with Parkinsonian severity at rest and could therefore potentially be used as a biomarker of clinical state. I demonstrate that the variability of beta amplitude recorded from the subthalamic nucleus strongly correlates with symptom severity at rest and also in response to levodopa administration. I then use beta amplitude as a biomarker for a trial of adaptive deep brain stimulation in Parkinson’s disease. I show that by using beta amplitude to control stimulation, time on stimulation is reduced by >50% but despite this, clinical outcome is improved by 25% relative to conventional continuous high frequency stimulation. Finally, I investigate the bilateral subcortical beta network and its response to levodopa. I report statistically significant bilateral functional connectivity in the beta range which is driven by phase locking and modulated by levodopa in the low beta range with implications for bilateral adaptive deep brain stimulation. These findings further our understanding of the pathophysiological role of beta oscillations in Parkinson’s disease and provide new avenues for treatment development.
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Marshall, Victoria Louise. "Clinical and functional imaging correlates in Parkinson's disease." Thesis, University of Glasgow, 2006. http://theses.gla.ac.uk/7012/.
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Parkinson's disease (PD) is misdiagnosed throughout its disease course for conditions such as essential tremor, drug-induced parkinsonism, vascular pseudo-parkinsonism, Alzheimer's disease and other degenerative parkinsonian diseases. This thesis aims to verify the accuracy of dopaminergic imaging in early and uncertain parkinsonian/tremor disorders through 3 studies. The first is a prospective United Kingdom multicentre assessment of [1231] FP-CIT SPECT use in 190 patients in pre-defined diagnostic categories and with particular focus on clinical features to assess the influence of imaging in routine practice. The second is a 2 year follow-up study of 150 consecutive patients with normal SPECT, with specific attention to clinical progression and antiparkinson medication use, and includes focus on a subgroup who fulfilled PD criteria where successful antiparkinson medication withdrawal was achieved. The third is a multicentre prospective European study of the accuracy of [1231] FP-CIT SPECT in 99 patients that included serial clinical and imaging assessments. Notably, when initial diagnosis/scan mismatch cases occurred, and with awareness of the scan result, the clinician invariably changed the diagnosis in line with the scan result which confirms the considerable influence of imaging on the practising clinician. Parkinson's disease is clinically overdiagnosed early in its disease course, whereas imaging is more specific, in the vast majority of cases with normal dopaminergic imaging, there was no evidence of clinical or imaging progression which would be in keeping with degenerative parkinsonism.
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Kabbach, Ghassan. "Interactions of LRRK2 in a Drosophila melanogaster model of Parkinson's disease." Thesis, University of Ottawa (Canada), 2010. http://hdl.handle.net/10393/28820.
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Parkinson's disease is the most common movement disorder. A complex neurodegenerative disease, its cause and progressive nature are of unknown roots, making a final cure currently unattainable. Recently, mutations in LRRK2 have been deemed the most common cause of both familial and sporadic forms of Parkinson's disease. Itself a mysterious protein, it harbors pathogenic mutations in all of its complex functional domains. Here, we present a Drosophila melanogaster model of LRRK2 by creating four different human LRRK2 transgenic flies. Wild type LRRK2, and LRRK2 mutants I1122V, Y1699C, and I2020T have each demonstrated Dopamine neuron loss, complex behavioral and life span alterations, and a complex eye phenotype. Lastly, we have used the eye phenotype to conduct both a biased screen against recessive Parkinson's disease genes, and an unbiased screen against the Drosophila genome.
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Acosta, Glen Howel G. "Susceptibility of parkinson's disease following mild blast traumatic brain injury." Thesis, Purdue University, 2015. http://pqdtopen.proquest.com/#viewpdf?dispub=1571943.
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<p> Blast injury-induced neurotrauma (BINT) is steadily increasing in prevalence due to escalated terror activity and constitutes the signature injury associated with current military conflicts. BINT produces significant neurological deficiencies and there is a growing concern that the injury may produce long-term consequences that affect the resilience and the performance of soldiers. One of the potential consequences is an increased susceptibility to Parkinson's disease (PD). A vital goal aimed at curtailing the post-deployment long-term consequences of blast injury-induced neurotrauma is to further our knowledge of pathogenic mechanisms responsible for the escalation of post injury diseases. <i> The purpose of this project is to investigate the molecular mechanism underlying the susceptibility of PD in post-blast rats.</i> We have identified acrolein, a highly reactive aldehyde that persists days to weeks following brain-injury and perpetuates oxidative insult, as a potential therapeutic target to curtail chemically mediated damage, a common feature of BINT and PD. <b>Our hypothesis is that acrolein is a key pathological factor linking BINT and the development of PD in our rat model.</b></p>
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Song, Linyang 1978. "The role of astroglial HO-1 in the pathogenesis of Parkinson's disease /." Thesis, McGill University, 2005. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=98803.
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The mechanisms responsible for the progressive loss of dopaminergic neurons and pathological iron deposition in the substania nigra pars compacta of patients with Parkinson disease (PD) remain incompletely understood. Heme oxygenase-1 (HO-1), the rate-limiting enzyme in the degradation of heme to biliverdin, carbon monoxide, and ferrous iron, is up-regulated in affected PD astroglia and may contribute to aberrant mitochondrial iron sequestration in these cells. To determine whether glial HO-1 hyperexpression is inimical to nearby neuronal constituents, we co-cultured dopaminergic PC12 cells atop monolayers of human (h) HO-1 transfected, sham-transfected or non-transfected primary rat astroglia. We observed that PC12 cells grown atop hHO-1 transfected astrocytes, but not the astroglia themselves, were significantly more vulnerable to dopamine (1muM) + H2O2 (1muM)-induced death (measured by nuclear ethidium monoazide bromide staining and anti-TH immunofluorescence microscopy) relative to control preparations. In the experimental group, PC12 cell death was significantly attenuated by the administration of the HO inhibitor, SnMP (1.5muM), the antioxidant, ascorbate (200muM), or the iron chelators, deferoxamine (400muM) and phenanthroline (100muM). Exposure to conditioned media derived from HO-1 transfected astrocytes also augmented PC12 cell killing in response to dopamine (1muM) + H2O2 (1muM) relative to control media. In PD patients, over-expression of HO-1 in nigral astroglia and attendant iron liberation may facilitate the bioactivation of dopamine to neurotoxic free radical intermediates and predispose nearby neuronal constituents to oxidative damage.
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Malek, Naveed. "Variation in Parkinson's disease : age, gender, genotype and phenotype correlations in early onset disease." Thesis, University of Glasgow, 2014. http://theses.gla.ac.uk/5602/.
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There is a wide variation in the phenotypic expression, progression rates, therapy response and complications in Parkinson’s disease (PD). The primary research objective in this thesis was to analyse the variation in the 4 domains of phenotypic expression i.e. motor, non-motor, cognitive, and quality of life in a subset of early onset Parkinson’s disease (EOPD) patients from the PRoBaND study, in the United Kingdom. The secondary objective was to explore the factors responsible for this variation or heterogeneity in the clinical characteristics. Linking genotypes with phenotypes, besides evaluating environmental risk factors and iatrogenic influences, represents one mechanism of understanding this variation in the phenotypic expression of PD. We found subtle but significant variation across all domains of symptoms examined in this thesis by classifying patients into groups according to motor subtype, gender, age at diagnosis and heritability of the parkinsonian trait, despite statistically insignificant differences in risk factors such as head trauma, exposure to pesticides (including herbicides, insecticides, fungicides and fumigants), heavy metals, caffeine and a past history of oophorectomy (in females) with the exception of smoking (p=0.046) and exposure to solvents, which were more common in males compared to females (p<0.001). There were differences in the prevalence of motor symptoms such as balance problems being more prevalent in the postural instability gait difficulty (PIGD) subtype compared to the tremor dominant PD (TDPD) and ‘Mixed’ motor subtypes both subjectively (p<0.001) and objectively (p<0.001). Other axial problems such as speech difficulties and freezing were also more prevalent in those with the PIGD phenotype compared to the other motor subtypes both subjectively (p=0.004, p<0.001) and objectively (p=0.002, p<0.001). There was also variation in the prevalence of motor complications such as dyskinesia (p<0.001) and dystonia (p=0.020), being more prevalent in the PIGD subtype compared to other motor subtypes. 8 The prevalence of certain non-motor symptoms such as pain (p=0.022) and features of gastrointestinal dysfunction e.g. prandial bloating (p=0.024) and constipation (p=0.022) were more commonly reported by females compared to males. There were also differences in the prevalence of cognitive impairment (p=0.049) and neurobehavioural characteristics such as anxiety (p=0.002) and depression (p=0.006), after the diagnosis of PD, being more prevalent in PIGD compared to other motor subtypes. Finally, these differences contributed to the variation in the independence of activities of daily living scores which were lower in those with the PIGD phenotype compared to other motor subtypes (p<0.001). There were some differences in exposure to environmental risk factors for PD but not sufficient to explain all the variation. Iatrogenic influences from drugs contributed in part to the phenotypic variation. 10% of the cases in the EOPD cohort tested positive for mutations in one of three genes screened i.e. LRRK2, GBA and Parkin; their DNA remains banked and there is scope to test these cases for mutations in other genes, relevant to PD, in the future. There were too small numbers of cases in each subgroup to draw definite conclusions about the exact influence of genes on the overall phenotypic variation but differences between Parkin mutation carriers and gene test negative ‘controls’ such as early age of onset and long disease duration were obvious. PRoBaND is linked to other similar research studies in the UK, with the stated aim of sharing datasets, in the hope that larger numbers of patients and their DNA samples will increase the power, in statistical terms, to test hypotheses about the role of genetic markers in influencing the course and expression of symptoms. Our current understanding of PD as a complex trait suggests both genetic and environmental influences (including iatrogenic factors if patients are treated) play a role in the phenotypic expression of this condition. A lot more remains to be explored to improve our understanding of the finer details and molecular mechanisms underlying the variation in this disease.
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Szewczyk-Krolikowski, Konrad. "Clinical and imaging characteristics of early Parkinson's disease." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:c118f620-19a9-4d0c-bcfc-018e3dd9ff3d.
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<strong>Background</strong>. Pathological processes in Parkinson’s disease (PD) start long before the first symptoms appear and by the time the disease is clinically established the results of neurodegeneration may be irreversible. Efforts to prevent or stem disease progression need to start in early disease and good characterization and new markers of early PD are urgently needed. <strong>Objectives</strong>. This thesis aims to characterize early disease stages in three projects. Firstly, clinical features of PD within 3 years of diagnosis will be explored in an incident cohort of patients and controls, using a range of tools to cover the whole breadth of clinical presentation of PD. Secondly, functional imaging studies in PD published so far will be examined through a meta-analysis to identify the most robust functional imaging markers. Thirdly, a functional MRI resting-state study in early PD will be performed to identify reproducible differences between patients and matched control subjects. <strong>Results</strong>. The cohort analysis found that age was a strong predictor of disease severity, independent of disease duration, while gender was seen to affect disease severity depending on the body region. A meta-analysis of all published functional imaging studies across all disease stages showed abnormal activations in the Basal Ganglia but also in a wide range of motor and non-motor brain areas. Dopamine supplementation normalized activations in the Basal Ganglia and some other areas, while other circuits remained resistant to medication suggesting non-dopaminergic abnormality. In the resting-state study, the Basal Ganglia Network showed greatly reduced connectivity in early PD compared to controls, which normalized on administration of dopaminergic medication. Reduced BGN connectivity was also validated on a separate group of PD subjects achieving very good separation of patients from controls. <strong>Conclusions</strong>. The effect of gender and age on early presentation of PD has potential significance for early diagnosis and choice of outcome measures for clinical trials. Within the realm of imaging, traditional task-based fMRI studies fail to show a clear and reproducible pattern of activations making this method unfeasible for early diagnostic testing. In contrast, resting-state fMRI connectivity in the Basal Ganglia Network appears to be a promising and reliable method even in the early stages of PD. Clinical profiling and resting imaging changes offer avenues for developing future biomarkers in early PD.
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Landau, Anne. "A novel neuroprotective role for the Fas molecule in models of Parkinson's disease." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=18289.
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Fas (CD95), a member of the tumor necrosis factor receptor (TNF-R) superfamily, has been extensively studied as a death-inducing receptor in immune cells. However Fas is also widely expressed in a number of other cell-types, including in neurons. We have found that defects in the Fas/Fas Ligand system render mice highly susceptible to neural degeneration in models of Parkinson’s disease (PD). Fas-deficient lpr mice develop a dramatic phenotype resembling clinical PD (i.e., characterized by extensive nigrostriatal degeneration accompanied by tremor, hypokinesia, and loss of motor coordination) upon treatment with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at a dose which causes no neural degeneration nor behavioural impairment in wild-type mice. Moreover, Fas engagement directly protects neuronal cells from MPTP/1-methyl-4-phenylpyridinium ion (MPP+) toxicity in vitro. Our data show that decreased Fas expression renders dopaminergic neurons more prone to degeneration in response to a neurotoxin and imply a neuroprotective role for Fas.Defects in the ubiquitin-proteasome system have been implicated in PD; therefore we investigated the role of the proteasome in Fas-induced neuroprotection. Wild-type and Fas-deficient mice have similar baseline neuronal proteasomal activity. However, lpr mice treated with MPTP demonstrate decreases in proteasomal activity compared with MPTP-treated wild-type mice. To examine these findings in a second model in vivo, we stereotaxically injected adeno-associated viral vectors containing alpha-synuclein or control green fluorescent protein (GFP) into the substantia nigra of lpr and wild-type mice. As seen with the MPTP model, alpha-synuclein-injected lpr mice demonstrate behavioural deficits and nigrostriatal neuropathology compared with lpr mice receiving a control GFP injection or wild-type mice receiving either alpha-synuclein or GFP. This indicates that Fas may be exerting its neuroprotective effect, at le<br>Fas a été principalement étudié dans le système immunitaire pour son rôle de récepteur induisant la mort cellulaire. Pourtant, Fas est également exprimé dans plusieurs autres tissus, dont les neurones. Nous montrons qu’un défaut dans le système Fas/Fas Ligand rend les souris hautement susceptibles à une dégénérescence neuronale dans un modèle de la maladie de Parkinson (MP). Les souris de souche lpr, déficientes en Fas, développent un phénotype similaire à la MP clinique quand elles sont traitées avec des doses de la neurotoxine MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) qui ne causent pas de dégénérescence neuronale ni de déficits comportementaux chez les souris de type sauvage. Nos données démontrent qu’une diminution de l’expression de Fas rend les neurones dopaminergiques plus susceptibles de subir une dégénérescence suite à l’exposition à une neurotoxine, ce qui suggère un rôle neuroprotecteur pour Fas.Un défaut dans le système ubiquitine-protéasome ayant été impliqué dans la MP, nous examinons le rôle du protéasome dans la neuroprotection induite par Fas. Dans les neurones de souris déficientes en Fas et de type sauvage, le niveau d’activité protéasomale de base est similaire. Par contre, les souris lpr traitées avec du MPTP ont un taux d’activité protéasomale plus bas que les souris de type sauvage traitées de la même façon. Afin d’examiner ces résultats dans un deuxième modèle in vivo, nous avons injecté stéréotactiquement, dans la subtantia nigra (substance noire) de souris de type sauvage ou lpr, un vecteur adenoviral-associé contenant le gène de l’alpha-synucléine ou d’une protéine de control fluorescente verte (GFP). Conformément aux résultats du modèle MPTP, les souris lpr, mais non les souris de type sauvage, injectées avec le gène de l’alpha-synucléine accusaient un déficit comportemental et une neuropathologie nigrostriatale. Ces résultats indiquent q
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Frankel, Dov. "The role of astroglial iron in the pathogenesis of Parkinson's disease." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0019/MQ54222.pdf.
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Richards, Christopher David. "Electrophysiology and electrochemistry of substantia nigra neurones in vitro." Thesis, University of Oxford, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.259895.
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Dashti, Eman. "Role of receptor mediated endocytosis-8, a novel Parkinson's disease gene, in mitochondrial quality control." Thesis, McGill University, 2014. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=121496.
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Over the past two decades, significant understanding of the pathogenesis of Parkinson's disease (PD) has been attributed to the discovery of genes, that when mutated, are responsible for familial forms of PD. Recently a novel autosomal dominant mutation (AD) causing PD was identified in receptor-mediated endocytosis-8 (RME-8). When mutated, symptoms of PD manifest with an onset ~ 70 years of age. RME-8 is a DnaJ domain containing protein that plays an important role in intercellular trafficking and recycling of retrograde cargo. Loss of function of RME-8 disrupts the endosome to Golgi transport resulting in cargo accumulation in the endosome and its re-routing to the lysosome for degradation. Studies have shown that VPS35 (another AD-PD gene, and part of the retromer that RME-8 interacts with) is involved in the mitochondrial quality control pathway implicated in PD. In addition, recent studies have shown that bec-1, a protein long studied as a regulator of autophagy (part of the mitochondrial quality control pathway), to also be involved in the retrograde trafficking co-localizing with RME-8. These findings suggest a possible new role of RME-8 in the mitochondrial quality control pathway. Here we investigated the possible role of RME-8 in the mitochondrial quality control pathway implicated in PD. Using loss of function approach by knocking-down RME-8 and gain of function approach by overexpressing the mutant form of RME-8 we investigated its role in two pathways involved in mitochondrial quality control: mitophagy and mitochondrial vesicle formation. Our results show that RME-8 is not involved in either pathways and thus the exact role of RME-8 in the pathogenesis of PD has to still be elucidated.<br>Des avancées significatives dans la compréhension de la pathologie propre à la maladie de Parkinson (MP) ont marqués les deux dernières décennies grâce, notamment, à la découverte de mutations génétiques responsables de formes familiales de la MP. Récemment, une mutation autosomale-dominante (AD) dans le gène RME-8 (receptor-mediated endocytosis-8) a été identifiée comme cause de la MP dont les manifestations cliniques associées à cette mutation apparaissent vers 70 ans. La protéine codée par RME-8, contient un domaine DnaJ qui joue un rôle important dans le trafic intracellulaire et le recyclage de cargos rétrogrades. La protéine RME-8 est exprimée dans plusieurs tissus et possède une forte affinité pour la chaperonne HSC70 (heat shock protein 70). RME-8 recrute HSC70 aux membranes couvertes de clathrine et interagit avec le complexe du retromère pour désassembler les triskelions de clathrine. La perte de fonction de RME-8 perturbe le transport de l'endosome au Golgi, ce qui entraîne l'accumulation du cargo dans l'endosome et sa redirection vers le lysosome. De plus, il a été démontré, que VPS35, fait partie du complexe du retromère et interagit avec RME-8, et que BEC-1 est impliquée dans le trafic rétrograde et que l'appauvrissement de RME-8 ou BEC-1 donne des phénotypes similaires. Puisque VPS35 et BEC1 jouent un rôle dans le contrôle de la qualité mitochnodriale, nous avons émis l'hypothèse que RME-8 est aussi impliquée dans ce processus. Ni l'ablation de RME-8 via l'ARN interférence ou sa surexpression n'a permis de montrer un rôle pour RME-8 dans la mitophagie ou la formation de vésicules mitochodriales. Nos données tendent à montrer que RME-8 n'est pas impliquées dans le contrôle de la qualité mitochondriale et que son rôle dans la pathogénèse de la MP demeure obscur.
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Smith, Gaynor. "Optimisation and mechanistic insights of dyskinesia in rodent models of Parkinson's disease." Thesis, Cardiff University, 2011. http://orca.cf.ac.uk/15071/.
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The work presented in herein focuses on the optimisation and use of established animal models to study behavioural, pharmacological, histological and molecular correlates of the debilitating motor side effects of current and future treatments for Parkinson’s disease, namely L-DOPA induced dyskinesia (LID) and graft induced dyskinesia (GID). Chapter 3 optimises the 6-OHDA lesion model in mice, from surgical approaches to behavioural assessment of motor function. The neurotoxin was injected at three different regions along the nigrostriatal tract to produce unique patterns of dopaminergic cell death in the midbrain. The resulting cell loss was correlated to behavioural deficits identified through an extensive battery of motor hand tests. Fully lesioned mice from each of the three models were chosen for chronic L-DOPA treatment, described in Chapter 4, where doses were increased every 1-2 weeks. Behaviour was assessed and correlated to deficits on motor hand tests prior to L-DOPA treatment, cell loss within sub regions of the midbrain, serotonergic density levels and upregulations in ΔFosB and striatal TH cell populations. Chapter 5 uses knowledge gained in previous chapters to use the most appropriate 6-OHDA mouse model of LID for the examination of changes in the Regulators of G-protein Signalling (RGS) following an acute and chronic L-DOPA treatment. RGS2 was the only one to increase significantly following either treatment regime. In Chapter 6 a well established rat model of GID (the induction of dyskinesia in the transplanted 6-OHDA lesioned rat through the administration of amphetamine) was used to assess the use of pharmacological agents known to reduce LID. Changes in locomotor function and abnormal inhibitory movements (AIMs) could be assessed giving an insight into the mechanism and receptors involved. To further the understanding of GID, Chapter 7 examines dopamine receptor levels, RGS transcript expression, and the proportions of dopamine and serotonin cells in the transplanted, 6-OHDA lesioned rodent brain. The aim was to determine any correlation between these parameters and amphetamine induced dyskinesia. Only the number of dopaminergic and serotonin cells could be correlated to dyskinesia and not the proportion of serotonin cells. As no previous mouse model of GID has been established, Chapter 8 demonstrates that transplantation of E12 ventral mesencephalon (VM) grafts can be optimised in the lesioned mouse of C57/Bl6 and CD1 strains to give functional recovery, and amphetamine induced dyskinesia. Both strains were also used to demonstrate that transplants were also able to reduce LID.
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Thiffault, Marie-Christine. "MTTP, L-deprenyl and Parkinson's disease : pharmacological implications of oxidative stress." Thesis, McGill University, 1997. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=34469.
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Excessive free radical formation or antioxidant enzyme deficiency can result in oxidative stress, a mechanism proposed in the toxicity of MPTP and in the etiology of Parkinson's disease (PD). To be effective as a toxin, MPTP must be metabolized by monoamine oxidase-B (MAO-B) to form MPP$ sp+.$ The latter compound leads to the degeneration of the dopaminergic cell bodies of the substantia nigra (SN) and striatal dopamine (DA) depletion that are reminescent of PD. The toxic effects of MPP$ sp+$ are related to the inhibition of NADH dehydrogenase activity in the mitochondrial respiratory chain. This event leads to the rapid depletion of ATP synthesis and loss of membrane potential to further enhance free radical formations. Similar respiratory deficits are reported in PD. The major antioxidant enzymes in the CNS are superoxide dismutase (SOD), glutathione peroxidase (GSH-PX) and catalase (CAT). SOD catalyses the dismutation of superoxide (O$ sb2 sp{ cdot}$) radical into H$ sb2$O$ sb2$, while GSH-PX and CAT convert H$ sb2$O$ sb2$ to H$ sb2$O. Lipid peroxidation and SOD activity are increased in PD brains, whereas CAT and GSH-PX remain unchanged or reduced. This observation is suggestive of a deficiency in dealing with excessive H$ sb2$O$ sb2$ formation which exacerbates iron-catalysed free radical generations. To date however, it is unclear if the alteration in SOD activity observed in PD is sufficient to enhance free radical formation and, consequently, to increase lipid peroxidation. We were able to demonstrate that, despite marked alterations in SOD and CAT activities in the SN and striatum of MPTP-treated mice, lipid peroxidation remained unaffected. These results suggest that factors other than antioxidant enzymes play a pivotal role in the modulation of peroxidative damage to lipids as observed in PD. Surprisingly, L-deprenyl, a potent MAO-B inhibitor known to protect dopaminergic neurons against the deleterious effects of MPTP by blocking MPP$ sp+$ formation,
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Brecknell, John Edward. "The rat nigrostriatal system : regeneration and reconstruction." Thesis, University of Cambridge, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.262821.
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Welleford, Andrew. "Autologous Peripheral Nerve Grafts to the Brain for the Treatment of Parkinson's Disease." UKnowledge, 2019. https://uknowledge.uky.edu/neurobio_etds/23.
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Parkinson’s disease (PD) is a disorder of the nervous system that causes problems with movement (motor symptoms) as well as other problems such as mood disorders, cognitive changes, sleep disorders, constipation, pain, and other non-motor symptoms. The severity of PD symptoms worsens over time as the disease progresses, and while there are treatments for the motor and some non-motor symptoms there is no known cure for PD. Thus there is a high demand for therapies to slow the progressive neurodegeneration observed in PD. Two clinical trials at the University of Kentucky College of Medicine (NCT02369003, NCT01833364) are currently underway that aim to develop a disease-modifying therapy that slows the progression of PD. These clinical trials are evaluating the safety and feasibility of an autologous peripheral nerve graft to the substantia nigra in combination with Deep Brain Stimulation (DBS) for the treatment of PD. By grafting peripheral nerve tissue to the Substantia Nigra, the researchers aim to introduce peripheral nerve tissue, which is capable of functional regeneration after injury, to the degenerating Substantia Nigra of patients with PD. The central hypothesis of these clinical trials is that the grafted tissue will slow degeneration of the target brain region through neural repair actions of Schwann cells as well as other pro-regenerative features of the peripheral nerve tissue.
This dissertation details analysis of the peripheral nerve tissue used in the above clinical trials with respect to tissue composition and gene expression, both of injury-naive human peripheral nerve as well as the post-conditioning injury nerve tissue used in the grafting procedure. RNA-seq analysis of sural nerve tissue pre and post-conditioning show significant changes in gene expression corresponding with transdifferentiation of Schwann cells from a myelinating to a repair phenotype, release of growth factors, activation of macrophages and other immune cells, and an increase in anti-apoptotic and neuroprotective gene transcripts. These results reveal in vivo gene expression changes involved in the human peripheral nerve injury repair process, which has relevance beyond this clinical trial to the fields of Schwann cell biology and peripheral nerve repair. To assess the neurobiology of the graft post-implantation we developed an animal model of the grafting procedure, termed Neuro-Avatars, which feature human graft tissue implanted into athymic nude rats. Survival and infiltration of human graft cells into the host brain were shown using immunohistochemistry of Human Nuclear Antigen. Surgical methods and outcomes from the ongoing development of this animal model are reported. To connect the results of these laboratory studies to the clinical trial we compared the severity of motor symptoms before surgery to one year post-surgery in patients who received the analyzed graft tissue. Motor symptom severity was assessed using the Unified Parkinson’s Disease Rating Scale Part III. Finally, the implications and future directions of this research is discussed. In summary, this dissertation advances the translational science cycle by using clinical trial findings and samples to answer basic science questions that will in turn guide future clinical trial design.
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Torres, Eduardo. "Improving the survival of dopaminergic grafts in a rat model of Parkinson's disease." Thesis, Cardiff University, 2005. http://orca.cf.ac.uk/55390/.
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The remaining three manuscripts deal with issues directly related to the graft survival and the use of gene therapy and animal models of PD, looking at the dynamics of viral vector gene expression in the pathological brain, an investigation of the two-layer staining obtained on immunohistochemical stained sections, and a re-assessment of the amphetamine induced rotational response of dopamine grafted animals
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Duval, Christian 1963. "The clinical relationship between tremor and voluntary motor behavior in patients with Parkinson's disease /." Thesis, McGill University, 2002. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=82862.
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Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive loss of dopaminergic neurons of the substantia nigra pars compacta. Symptoms usually include akinesia, bradykinesia, muscle rigidity, postural imbalance and tremor. Despite numerous studies on the physiology and pathophysiology of tremor, its influence on voluntary motor behavior remains unclear. Accordingly, the main objectives of the present thesis were to (a) determine if a clinical relationship existed between tremor and performance of voluntary movements, and (b) characterize the impact of ventrolateral (VL) thalamotomy on tremor and voluntary motor behavior. Results indicate that age-related change of the supraspinal component of normal physiological tremor (NPT) has no influence on the performance of healthy elderly subjects making rapid alternating movements (RAM). Our results also show that subsets of patients presenting different tremor amplitudes and/or tremor power characteristics had similar RAM performance, hence negating any direct relationship between the supraspinal oscillator(s) generating tremor and RAM performance. Our results demonstrate that tremor can be detected during manual-tracking movements performed by patients with early PD, but this tremor has little consequence on the accuracy of these patients.<br>As for the impact of VL thalamotomy on tremor, our results show that the thalamic lesion eliminates selectively PD tremor oscillations, in addition to preventing a resurgence of the supraspinal component of physiological tremor. The surgical procedure did not however improve or worsen RAM performance, suggesting that tremor probably plays little role in bradykinesia. Accuracy during the manual-tracking task is nonetheless greatly improved post-surgery, hence confirming the anticipated clinical benefits of the surgical procedure. In conclusion, despite previous evidence that tremor and RAM may share common neural networks and that tremor may be pathophysiologically linked with bradykinesia, the aforementioned results suggest that there is little clinical relationship between tremor and bradykinesia observed in patients with PD making RAM.
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Weiss, Alexander R. "Novel approaches to studying the role of the anterior cingulate cortex in cognition and Parkinson's disease." Thesis, University of Oxford, 2017. https://ora.ox.ac.uk/objects/uuid:c827764b-af3b-4397-90cc-039f40fab460.
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The motor symptoms of Parkinson's disease (PD) have been linked to the emergence of exaggerated oscillatory activity in the 13 - 35 Hz beta range in recordings of the basal ganglia (BG) thalamocortical circuit of PD patients and animal models. PD patients and animal models also express dopamine-dependent cognitive impairments, implying effects of dopamine loss on the function of the anterior cingulate cortex (ACC). This thesis examines the electrophysiological behavior of the BG thalamocortical circuit in PD and dopamine-normal states during cognitive and motor activity. In vivo recordings in the BG of PD and dystonic patients were used to study the influence of dopamine during a test of executive function. Normal executive function was also investigated in the dopamine-healthy ACC of chronic pain patients. Both the BG and ACC exhibited lateralized electrophysiological responses to feedback valence. The BG also exhibited dopamine-sensitive event-related behavior. In additional experiments, chronically implanted recording electrodes in awake, behaving hemiparkinsonian rats were used to examine the transmission of synchronized oscillatory activity from the BG, through the ventral medial (VM) thalamus, to the ACC. Modulation of subthalamic nucleus, VM thalamus, and ACC activity during a simple cognitive/movement task was also investigated in hemiparkinsonian rats. Findings in the rat model suggest that ACC-mediated executive function is dopamine-sensitive and is reflected in the region's electrophysiology. These results may provide further insight into the significance of excessive oscillatory activity in PD and its influence on cognitive systems.
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Podolsky, Eric. "Pharmacological Rescue of Parkinson's Disease Symptoms with Drosophila Larvae." Ohio University Art and Sciences Honors Theses / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ouashonors1429199460.
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Roberts, Rosalind F. "The role of alpha-synuclein oligomers in Parkinson's disease pathophysiology and biology." Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:e13d9429-f2cd-4764-bf8d-d139e71f7711.
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Accumulating evidence links oligomeric species of the protein alpha-synuclein to the neuronal death associated with Parkinson's disease. However, the direct detection of alpha-synuclein oligomers in post-mortem brain has been challenging and this has limited our understanding of their structure, distribution and effects in Parkinson's disease. The work presented in this thesis addresses two aspects of the role of alpha-synuclein oligomers in Parkinson's disease. Firstly, I describe the development of a novel technique, the alpha-synuclein proximity ligation assay (AS-PLA), which specifically detected alpha-synuclein oligomers in vitro and in post-mortem brain tissue. In a blinded study with post-mortem brain tissue from eight Parkinson's disease patients and eight controls, AS-PLA revealed widespread, previously unrecognised pathology in the form of extensive diffuse deposition of alpha-synuclein oligomers. Furthermore, AS-PLA preferentially detected early-stage, loosely compacted Parkinson's disease lesions such as pale bodies, whereas Lewy bodies, considered heavily compacted late lesions were only very exceptionally stained. The oligomeric species detected by AS-PLA displayed a unique, intermediate proteinase K resistance profile, suggesting the detection of a conformer that is different from both physiological pre-synaptic alpha-synuclein (proteinase K sensitive) and highly aggregated alpha-synuclein within Lewy bodies (proteinase K resistant). In addition, AS-PLA revealed the age-dependent accumulation of alpha-synuclein oligomers in the substantia nigra of a BAC transgenic mouse model of Parkinson's disease that overexpresses human wild-type alpha-synuclein, SNCA-OVX. Secondly, the detection of early pathology in Parkinson's disease brain tissue using AS-PLA suggests that oligomeric species of alpha-synuclein could represent a potential target for therapeutic intervention. Therefore, I undertook a screen to identify compounds that can prevent the formation of alpha-synuclein oligomers in vitro. Using bimolecular fluorescence complementation constructs, I identified nine compounds capable of reducing the fluorescence indicative of the formation of alpha-synuclein oligomers. Two of these compounds showed dose-dependent activity. Future work will confirm the hits in vitro before studying whether Parkinson's-like phenotypes in the SNCA-OVX mice can be ameliorated or reversed by treatment with the compounds.
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Keane, Harriet. "Network pharmacology of the MPP+ cellular model of Parkinson's disease." Thesis, University of Oxford, 2015. http://ora.ox.ac.uk/objects/uuid:1e18e521-c1a3-4f1b-9572-9c68e0f16c2f.
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Parkinson's disease (PD) is an incurable neurodegenerative motor disorder caused by the inexorable loss of dopamine neurones from the substantia nigra pars compacta. Cell loss is characterised by the perturbation of multiple physiological processes (including mitochondrial function, autophagy and dopamine homeostasis) and much of this pathophysiology can be reproduced in vitro using the mitochondrial toxin MPP+ (1-methyl-4-phenylpyridinium). It was hypothesised that MPP+ toxicity could be modelled using protein-protein interaction networks (PPIN) in order to better understand the interplay of systems-level processes that result in eventual cell death in MPP+ models and PD. Initially, MPP+ toxicity was characterised in the human, dopamine-producing cell line BE(2)-M17 and it was confirmed that the neurotoxin resulted in time and dose dependent apoptosis. A radio-label pulse-chase assay was developed and demonstrated that MPP+ induced decreased autophagic flux preceded cell death. Autophagic dysfunction was consistent with lysosome deacidification due to cellular ATP depletion. Pertinent PPINs were sampled from publically available data using a seedlist of proteins with validated roles in MPP+ toxicity. These PPINs were subjected to a series of analyses to identify potential therapeutic targets. Two topological methods based on betweenness centrality were used to identify target proteins predicted to be critical for the crosstalk between mitochondrial dysfunction and autophagy in the context of MPP+ toxicity. Combined knockdown of a subset of target proteins potentiated MPP+ toxicity and the combined resulted in cellular rescue. Neither of these effects was observed following single knockdown/overexpression confirming the need for multiple interventions. Cellular rescue occurred via an autophagic mechanism; prominent autophagosomes were formed and it was hypothesised that these structures allowed for the sequestration of damaged proteins. This thesis demonstrates the value of PPINs as a model for Parkinson's disease, from network creation through target identification to phenotypic benefit.
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Hewitt, Sarah. "Stress-Induced Mitochondrial DJ-1: Role of Parkin, Pink1 and VDAC1." Thesis, Université d'Ottawa / University of Ottawa, 2016. http://hdl.handle.net/10393/34341.
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Parkinson’s disease (PD) is the second most common neurodegenerative disease and is characterized by motor symptoms such as tremor, rigidity, akinesia and postural instability. Approximately 90% of the cases are due to unknown causes however a familial inheritance has been shown for about 10% of cases. Loss-of-function mutations in DJ-1 cause early-onset PD. Originally identified as an oncogene, DJ-1 has since had many functions attributed to it but its major role in the cell seems to be oxidative stress handling. We have previously demonstrated that DJ-1 deficiency results in hypersensitivity of cells to oxidative stress. Additionally, mitochondria from DJ-1 null mice are fragmented and produce more ROS. To better understand the relationship between DJ-1, cell survival and mitochondria, we investigated the possible interaction between DJ-1 and the mitochondrial protein voltage dependent anion channel 1 (VDAC1). Here we show mitochondrial translocation of DJ-1 following oxidative stress in murine embryonic fibroblasts (MEFs) and primary cortical neurons, a process dependent on Pink1 and Parkin. Additionally, we confirm that DJ-1 and VDAC1 interact and that stress-induced mitochondrial translocation of DJ-1 depends on VDAC1. Deficiency of VDAC1 in primary cortical neurons results in decreased survival, increased ROS production following extended stress, fragmented mitochondria and decreased mitochondrial ATP production. We also demonstrate that there is substantially less matrix-localized DJ-1 in VDAC1 deficient cells. Finally, we demonstrate that decreased mitochondria ATP production can signal for DJ-1 translocation to mitochondria. Taken together, we suggest that mitochondrial translocation of DJ-1 is a two-step process. First, a signal, perhaps decreased mitochondrial ATP production, induces DJ-1 translocation to mitochondria. Second, DJ-1 localizes to the matrix in a VDAC1-dependent manner. Our work suggests that stress-induced mitochondrial localization of DJ-1, specifically to the matrix, is regulated by VDAC1 to promote survival possibly by promoting ATP production.
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Brodrick, Paige. "A Composite Review of the Proposed Molecular Mechanisms and Genetic Components Underlying Parkinson’s Disease." Scholarship @ Claremont, 2019. https://scholarship.claremont.edu/scripps_theses/1337.
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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.
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Mecconi, Alessandro. "Dopamine replacement therapy reduces beta band burst duration in Parkinson’s disease." Thesis, KTH, Skolan för teknik och hälsa (STH), 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-215055.
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One of the main characteristics of Parkinson's disease (PD) is an exaggerated oscillatory activity in the beta band (12-30 Hz). This activity has been linked to the rise of symptoms such as bradykinesia and akinesia. Even if dopamine replacement therapy (oral intake of dopamine pro-drug levodopa) reverses these symptoms, the effect of the treatment on the beta band activity has still not been completely understood. Therefore, here the temporal dynamics of beta band activity in human patients affected by PD were characterized with and without levodopa treatment. Local-field-potential (LFP) recordings from five patients undergoing dopamine replacement therapy were used. From the LFPs, the extracted beta epochs with significantly higher power than expected from a comparable noisy signal were analyzed. This analysis showed that beta band activity occurred in bursts meaning that high amplitude oscillation alternated with silenced periods. The pathological state also distinguished itself for longer epochs and with power that increased with the length of the epoch. The administration of levodopa reduced the duration of bursts and decreased the overall mean power of the beta band activity. Finally, epochs with the same number of cycles were compared. The Coefficient of Variation prior such epochs suggested that the ongoing activity might lock into a synchronization process prior the burst. These results provide important information to better understand how levodopa alleviates some of the symptoms of PD and pave the way to develop better computational models for the emergence of beta oscillations.
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Fraraccio, Maria. "Effects of high frequency stimulation of the subthalamic nucleus on cognitive function in Parkinson's disease." Thesis, McGill University, 2005. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=84030.
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Objective. The goal of the present study was to investigate whether high frequency stimulation of the subthalamic nucleus (HFS STN), for the treatment of motor signs and symptoms characteristic of Parkinson disease (PD), has detrimental consequences for cognitive processing. Methods . An extensive battery of neuropsychological tests was administered to 15 PD patients with bilateral implantation of high frequency stimulators of the subthalamic nucleus for the treatment of PD. Patients were tested in two sessions: during one session the stimulator was set to a satisfactory therapeutic level and in the other the stimulator was set to OFF. Results. Statistically significant differences between sessions were not observed on task variables measuring executive function, verbal working memory, attention, language, visuospatial perception and verbal and visuospatial memory. In contrast, significant improvements with stimulation were observed for motor signs and symptoms and on tasks measuring skilled motor function. Conclusion. We investigated the specific cognitive effects of HFS STN in non-demented patients diagnosed with late stage PD. Our findings suggest that in relatively young patients with no symptoms of dementia or psychiatric disorder, the impact on cognitive processing is minimal.
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Thevathasan, Arthur Wesley. "Pedunculopontine nucleus stimulation for gait and postural disorders in Parkinson's disease." Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:b64d5e10-9e22-4c25-8537-5aa4858d77aa.
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The pedunculopontine nucleus (PPN) is a reticular collection of neurons at the junction of midbrain and pons. The PPN in animal models appears topographically organised and functionally related to locomotion and arousal. In Parkinson’s disease, the PPN degenerates and is susceptible to abnormal basal ganglia output. In patients with Parkinson’s disease, low frequency PPN stimulation is proposed to improve gait freezing and postural instability. However, the therapeutic mechanisms, optimal clinical application and precise effects on gait and posture of PPN stimulation are unclear. Here, a topographic arrangement of the PPN was supported by local field potential recordings in parkinsonian patients. In the PPN region, beta oscillations were recorded rostrally and alpha oscillations caudally. Alpha oscillations, consistent with their putative role in allocating attention, correlated with gait performance and attenuated with gait freezing. Thus the caudal PPN subregion may be the most relevant target for gait disorders. Accordingly, an unblinded clinical study suggested that stimulation of the caudal PPN subregion was beneficial for gait freezing, postural instability and falls. In a double-blinded study using spatiotemporal gait analysis, caudal PPN stimulation reduced triggered gait freezing, with bilateral stimulation more effective than unilateral. However, akinesia including akinetic gait did not improve with PPN stimulation. Accordingly, dopaminergic medication requirements did not change. Mechanisms underlying gait freezing and PPN stimulation were explored with reaction time experiments. Parkinsonian patients with severe gait freezing and postural instability demonstrated a ‘block’ to pre-programmed movement. This was evidenced by prolonged simple reaction times and the absence of ‘StartReact’, whereby pre-prepared responses are normally accelerated by loud acoustic stimuli. PPN stimulation improved simple reaction time and restored Startreact. The relief of this ‘motor block’ with PPN stimulation may therefore explain the associated improvement in gait freezing and postural instability, as these tend to occur in circumstances requiring triggered, pre-prepared adjustments.
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Breger, Ludivine. "Parameters impacting the outcome of cell replacement therapy for Parkinson's disease : a preclinical study." Thesis, Cardiff University, 2013. http://orca.cf.ac.uk/49925/.
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Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, currently affecting 6.3 million people worldwide. Although it is associated, in the longterm, with severe complications (dyskinesias), L-DOPA remains the gold standardtreatment. An alternative approach to the treatment of PD is the replacement of the lost striatal dopaminergic innervation by transplantation of foetal ventral mesencephalon (VM) dopaminergic precursor cells. Opened trials have provided the proof of concept that intrastriatal VM transplant can survive, integrate and in some cases, restore motor functions. Nevertheless, later double blind studies reported inconsistent benefit of the therapy and the development of dyskinesias remaining after withdrawal of L-DOPA medication. The failure of the animal models in predicting these problems raises concern about their reliability. Therefore, the global aim of this PhD work was to identify some of the critical factors that can influence the functional outcome of cell therapy for PD, and on the basis of this, to develop an improved 6-OHDA unilaterally lesioned rat model for transplantation. The first step was to determine the most reliable method to assess dyskinesias in rats. The second part of this thesis was set out to determine the effect that chronic L-DOPA treatment, administered at different time could had on the survival and function of immunologically incompatible foetal VM transplant. The results demonstrated that L-DOPA administered chronically post-grafting increases the host immune response around the xenogeneic transplant. Therefore, the last set of experiments were designed to create a model of mixed donors graft to better reproduce the patient situation, where each transplant required up to 8 donors from unknown immunological background. All of these experiments come together to help to develop a rat model that more accurately represents all aspects of patients undergoing transplantation for PD.
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Medicetty, Satish. "Effect of umbilical cord matrix stem cells on Parkinson’s disease model rats." Diss., Kansas State University, 2005. http://hdl.handle.net/2097/127.
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Doctor of Philosophy<br>Department of Anatomy and Physiology<br>Mark L. Weiss<br>Umbilical cord matrix or Wharton’s Jelly is a mucous connective tissue ensheathing the cord blood vessels and contains mesenchymal-like stem cells. Previously, we have shown that pig umbilical cord matrix stem (pUCMS) cells transplanted into normal rat brain were recovered up to 6 weeks post-transplantation, where a sub-population of pUCMS cells exhibited neuronal morphology and expressed a variety of neuronal markers. Here, approximately 150 pUCMS cells were transplanted into non-immunesuppressed rats that previously received a brain lesion by neurotoxin, 6-hydroxydopamine (6-OHDA), which specifically affects midbrain dopaminergic neurons, leading to pathologic findings similar to that of Parkinson’s disease (PD). The pUCMS cells proliferated up to 8 weeks post-transplantation and there was a significant increase in the percentage and number of pUCMS cells expressing tyrosine hydroxylase (TH), which is a marker for dopaminergic cells. We conclude that 1. Xenotransplants of pig UCMS cells are not rejected by rats at least up to 8 weeks after transplantation and 2. The pig UCMS cells proliferate and differentiate after transplantation into PD model rats.
The surface antigen and gene expression profile of human umbilical cord matrix stem (hUCMS) cells resemble that of mesenchymal stem cells. Apomorphine-induced rotatory behavior was used to analyze the motor deficits of the PD model rats. In different experiments 1000, 2500 and 25000 hUCMS cells were transplanted into the brain of non-immunesuppressed PD model rats. There was a dose-dependent decrease in apomorphine-induced rotations; the maximum benefit was found in the rats that received 1000 hUCMS cells. The graft cells were recovered at 2 days and 1 week, but not at 6, 10 or 12 weeks post-transplantation. Quantitative assessment of host TH-positive midbrain dopaminergic neurons revealed a positive correlation between the behavioral improvement and TH-positive cell number in the low-density (1000 cells) transplant group, showing that the hUCMS cells may play a role in rescuing damaged host dopaminergic neurons and promote improvement of motor deficits in PD-model rats. In summary, hUCMS cells appear to be mesenchymal stem cells that can be harvested in great numbers from a non-controversial, inexhaustible source. Human UCMS cells show therapeutic benefit in PD model rats, but the mechanism by which they promote improvement is presently unknown.
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Bélanger, Catherine. "The Parkinson's disease gene, Parkin, ubiquitinates the endocytic accessory protein Eps15 and regulates endocytosis of the epidermal growth factor receptor /." Thesis, McGill University, 2006. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=101705.
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Mutations in the parkin gene are responsible for an early-onset autosomal-recessive form of Parkinson's disease. Parkin is an E3 ubiquitin ligase that acts in the covalent attachment of the small protein ubiquitin to substrate proteins. Although many parkin substrates have been identified, none can fully account for the relatively specific death of the dopaminergic neurons in the substantia nigra that occurs in Parkinson's disease. Using an assay that reconstitutes the ubiquitination reaction completely in vitro, I found that not all disease-associated mutations affected parkin's ligase activity. I used this assay to test a potential parkin substrate identified in our lab, the endocytic accessory protein Eps15, which specifically interacts with parkin in a regulated fashion. I found that parkin directly ubiquitinates Eps15 in vitro. Eps15 ubiquitination is known to occur during the process of ligand-induced downregulation of the epidermal growth factor receptor. I found that overexpressing parkin in COS-7 cells inhibited the first step of this process, namely, receptor internalization. These findings add to the knowledge of how pathogenic mutations affect parkin function, and identify a novel role for parkin as a regulator of ligand-induced downregulation of the epidermal growth factor receptor.
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Popov, Roman. "Neural Preparation For Step Initiation In Unpredictable Conditions With Age And Parkinson's Disease." ScholarWorks @ UVM, 2018. https://scholarworks.uvm.edu/graddis/952.
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Mobility is essential for the independent lifestyle. However, as the US population ages, challenges to mobility start to arise, among them just the aging itself which leads to decreased postural stability, falls and the second most common neurodegenerative disease, that is Parkinson’s disease (PD). We decided to investigate step initiation as it is crucial to mobility: walking is not possible without the first step.
Step initiation is impaired in PD. However, the impact of PD on the neural mechanisms of step initiation when some of the step parameters are unpredictable remains unexplored. Cortical preparation for step initiation can be assessed by beta event-related desynchronization (ERD) derived from electroencephalography (EEG) recordings. We hypothesized that subjects with PD would exhibit less cortical modulation between conditions of forward step initiation with and without prior knowledge of limb choice. Further, we hypothesized that decreased cortical modulation in PD would associate with a higher impairment of motor performance. Results identified that the group with PD exhibited decreased beta ERD amplitudes that were similar regardless of condition, whereas control subjects modulated beta ERD amplitudes between conditions, particularly in early stages of pre-movement processing in areas overlying sensory cortex. Subjects with PD presented with delayed and reduced postural preparation with increased step target error across both conditions and exhibited a greater incidence of multiple anticipatory postural adjustments (APAs) in the predictable relative to the unpredictable condition. Delayed postural preparation significantly correlated with lower amplitudes of beta ERD. We concluded that diminished early pre-movement processing over sensory cortex was concomitant with poor pre-selection of the stepping limb in predictable conditions and that a generally diminished amplitude of cortical pre-movement processing relates to delayed step initiation in people with PD.
Furthermore, impaired mobility accompanies healthy aging, but there is a need for deeper understanding of how aging changes central control of motor behavior. Using previous study’s method, we compared cortical preparation for step initiation using beta ERD in young and older healthy subjects performing forward steps with and without prior knowledge of limb choice. Our results show that older subjects exhibited increased beta ERD amplitudes before the step regardless of whether they were informed of limb choice or not. Moreover, older subjects exhibited early increases in beta ERD in the “sensory” cluster of electrodes, but only when full limb-choice information was available. Behaviorally, the older subjects also exhibited shortened and increased anticipatory postural adjustments which led to earlier step initiation and similar swing-foot velocities but was also accompanied by greater target step placement errors and decreased postural stability. For the older group, condition-related increases in beta ERD amplitudes and stability correlated with condition-related prolongation of APA durations. We conclude that older subjects exhibited a spectrum across two strategies: (1) a “fast” strategy associated with decreased neural preparation that trades shortened step preparation and higher swing-foot velocity for target step errors and lowered postural stability; and (2) an “accurate” strategy associated with greater neural preparation, longer step-preparation time, and higher stability during step execution.
In conclusion, this thesis provides more support for beta ERD as a useful tool for studying cortical preparation non-invasively. We have also established the importance of the signals recorded by “sensory” clusters: in subjects with PD the absence of beta ERD similar to the control group was associated with impaired motor behavior even when conditions were predictable. Similarly, a part of the older group seemed to pre-potentiate its cortex lying beneath the cluster of “sensory” electrodes which was associated with more safe and accurate steps. Further investigations should focus on the importance of sensorimotor integration and its’ changes due to PD or healthy aging and beta ERD may be an excellent tool for this task.
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Coxon, Anne. "Exploring mechanisms of change in a pilot randomised trial of a distant delivery mindfulness intervention for people with Parkinson's disease." Thesis, City, University of London, 2018. http://openaccess.city.ac.uk/21605/.
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People with Parkinson's disease report high levels of non-motor symptoms, including anxiety and depression, that are difficult to treat pharmacologically. Mindfulness-based interventions have been shown to be effective in other long-term conditions. This pilot study explored how a mindfulness-based intervention may have had an effect and for whom, with a view to informing future studies. Volunteers were randomised to a remote delivery, eight-week mindfulness cognitive behavioural group therapy intervention (n=40) or wait-list (n=38), and measures for psychological outcomes and putative mediators were taken at baseline, 4 weeks, 8 weeks and 20-week follow-up. The study showed that all the outcome measures changed in a positive health direction in the intervention group. The intervention had a small effect on decentering (d=.36) and acceptance (d=.27) by mid-point, before depression at 8 weeks (d=-.28) and anxiety at follow-up (d=-.29), indicating an indirect effect between trial arm and levels of distress. Mediation and moderation analysis were conducted using PROCESS, time-lagging the mediators to the outcome variables, but no combined or individual indirect effects had confidence intervals entirely above or below zero, thus mediation cannot be confirmed. When the end of intervention mediators were analysed with the follow-up levels of anxiety and depression, there is evidence of inconsistent mediation, or possible suppression effects. Moderation analysis revealed that the effect on anxiety levels was moderated by gender, with women benefitting more from the mindfulness intervention. Moderated mediation analysis also indicated that the effect of the trial arm on levels of acceptance was conditional by age and time since diagnosis, and the effect of trial arm on levels of mindfulness skills by age, meaning that younger, newly-diagnosed patients were more able to increase mindfulness skills and acceptance.
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Kosillo, Polina. "Investigating circuits underlying acetylcholine-evoked striatal dopamine release in health and disease." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:1675813e-0b07-4ede-9094-cdc442679394.
Full textAbstract:
Dopamine (DA) is a key striatal neuromodulator central to normal functioning of the basal ganglia. Identifying and characterizing circuits governing striatal DA transmission is necessary for understanding DA involvement in adaptive behaviour and pathology. Properties of evoked striatal DA release can be examined using fast-scan cyclic voltammetry at carbon fibre microelectrodes, a technique enabling live monitoring of transmitter release events with sub-millisecond resolution. Experimental work presented in this thesis employed this approach to study regulation of striatal DA by acetylcholine (ACh) in health and disease in acute brain slices. Synchronous activity in a small population of striatal cholinergic interneurons (ChIs) was previously shown to directly drive striatal DA release. Here using optogenetic approach I explore physiological relevance of ChI-evoked drive of striatal DA by examining whether corticostriatal and thalamostriatal afferents to ChIs can trigger ACh-evoked DA events. Following floxed vector injections in motor cortex or caudal intralaminar thalamus of CaMK2a-Cre mice I examine the properties of evoked DA upon light activation of channelrhodopsin-2-transduced inputs to striatal ChIs. These experiments revealed that both cortical and thalamic afferents are capable of driving ACh-evoked DA release, but operate using a different complement of post-synaptic ionotropic glutamate receptors and display distinct release recovery profiles. I further explore if rebound excitation in a population of striatal ChIs could drive DA events by examining whether ACh-evoked DA release follows optical inhibition of striatal ChIs selectively expressing hyperpolarizing halorhodopsin 3.0 or archaerhodopsin 3.0 in ChAT-Cre mice. This work showed that hyperpolarizing ion pumps were not successful in triggering ChI-evoked DA release. I also investigate whether cholinergic brainstem innervation of striatum could contribute to or drive ACh-evoked striatal DA events in ChAT-Cre rat, concurrently showing that ChI-evoked DA release is not a species artefact, and is present in mouse and rat alike. Current results also suggest that cholinergic brainstem afferents do not drive or contribute to striatal ACh-evoked DA events. Close interaction between DA and ACh systems further indicates that ACh could impact dopaminergic dysfunction. To explore this I examined the state of ACh transmission in a mouse model of Parkinson’s disease overexpressing human wild type alpha–synuclein protein. These animals present with impaired striatal DA release from young age, but DA deficits could be mediated by changes in ACh tone. Here I show that impaired striatal DA release is the results of primary DA axon dysfunction, although in ventral striatum DA release deficits could be partially compensated by increased ACh tone at nicotinic receptors. I further show that the functional state of muscarinic ACh receptors in not altered following decreased DA transmission, although the data from aged animals suggest that alpha–synuclein-dependent changes in vesicle handling could contribute to impaired DA releasability. Finally, I show that vesicle handling may indeed be altered in this mouse model as impaired DA release is evident with short stimulation protocols, while with prolonged depolarization of DA axon terminals alpha–synuclein-overexpressor mice are better able to sustain evoked DA release. Overall, the main body of work presented in this thesis examined the processes regulating striatal DA transmission via ACh system. In particular, I show that ChI-evoked drive of striatal DA release can be recruited physiologically and further establish that changes in ACh transmission are not the primary drivers of impaired DA releasability in a mouse model of Parkinson’s disease overexpressing human alpha–synuclein protein.
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Davies, Sian Elizabeth. "Analysis of SMN function in development and Nedd4, a putative modifier of Parkinson's disease, in Drosophila melanogaster." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:7b02d101-aaa4-4658-834d-06a2bcd56136.
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Neurological diseases are devastating illnesses that affect over one billion people worldwide. Drosophila melanogaster provides a genetically tractable system in which to study gene function and the mechanisms of pathogenesis of neurological diseases. In this study I have investigated the function of survival motor neuron (SMN), the causative gene in the neuromuscular disease spinal muscular atrophy (SMA), in growth and differentiation in Drosophila. In addition, I have used the fruit fly to investigate a putative modifier of a previously characterised Drosophila model of Parkinson's disease. Spinal muscular atrophy is an autosomal recessive neurological disease that is characterised by motor neuron loss resulting in muscle weakness. The disease is caused by the deletion or mutation of the survival motor neuron (SMN) gene. In Drosophila, SMN was found to be highly expressed in dividing tissues and a reduction in SMN levels resulted in growth defects, stem cell defects and developmental delay. SMN was also shown to regulate chromosome morphology of the endocycling nurse cells of the female germline. Therefore it appears that SMN has a role in growth control and development in Drosophila. Parkinson's disease is a common disorder that results in widespread neurodegeneration with a predilection for dopaminergic neuron loss resulting in movement defects. A defining neuropathological feature of the disease is the presence of alpha-synuclein containing inclusions. Using a Drosophila model of PD, I have shown that specific alpha-synuclein-induced phenotypes in the fly can be suppressed by the overexpression of the E3 ubiquitin ligase, Nedd4.
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Stenslik, Mallory J. "The Intranasal Delivery of DNSP-11 and its Effects in Animal Models of Parkinson's Disease." UKnowledge, 2015. https://uknowledge.uky.edu/neurobio_etds/14.
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A major challenge in developing disease altering therapeutics for the treatment of Parkinson’s disease (PD) has been the delivery of compounds across the blood-brain barrier (BBB) to the central nervous system (CNS). While direct surgical infusion has been utilized to deliver compounds to the brain that don’t cross the BBB, issues of poor biodistribution in the CNS due in part to properties of the molecules being delivered and/or infusion device protocols have limited the widespread success of this invasive approach. To avoid the issues of surgically delivering compounds to the CNS, numerous studies have examined the use of intranasal administration as a non-invasive delivery method. The data presented in this dissertation examines intranasal administration of dopamine neuron stimulating peptide-11 (DNSP-11), a small, amidated peptide with neuroprotective and restorative properties, and its effects on the nigrostriatal system in animal models of PD.
Here we demonstrate that severely lesioned 6-hydroxydopamine (6-OHDA) F344 rats repeatedly administered DNSP-11 intranasally exhibited a decrease in damphetamine- induced rotation, dopamine (DA) turnover, and an increase in tyrosine hydroxylase positive neuronal sparing. Additionally, tracer studies indicated rapid distributed throughout the CNS and CSF following a one-time bilateral intranasal dose of 125I-labeled DNSP-11. These results demonstrate that DNSP-11 can be delivered to the CNS intranasally, and maintains its neuroactive properties on the nigrostriatal system in a rat model of PD.
In a dose escalation study of DNSP-11, we evaluated the efficacy of repeated intranasal administration in awake, vertically chaired trained, 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) hemiparkinsonian rhesus macaques using an atomizer system over a 10-week period. Here we report that animals did not exhibit observable adverse effects at the DNSP-11 concentrations examined, bilateral increases in fine motor performance of the upper limbs, and changes in tissue levels of DA and its metabolites. Finally, tracer studies indicated signal present throughout the CNS and CSF following a one-time bilateral intranasal dose of 125I-labeled DNSP-11. These studies support the efficacy of the repeated intranasal administration of DNSP-11 in awake Rhesus macaques over 10-weeks, while also enhancing motor performance and striatal neurochemistry in a non-human primate model of PD.
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Ahmad, Rufai. "Whole-body coordination when turning on-the-spot in people with stroke and Parkinson's disease : a comparison with healthy controls." Thesis, University of Southampton, 2012. https://eprints.soton.ac.uk/345342/.
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Turning around to interact with the environment is a common activity of daily living. The location of a target for interaction may be known or unknown prior to turning and the angle of a turn may vary depending on the task to be carried out. Stroke and Parkinson’s disease could compromise coordination of body movement during turning which may pose a risk for instability and subsequent falls. The sequence of onset latency, peak velocity and timing of peak velocity of body segments (eye, head, shoulder, pelvis and foot) while turning on-the-spot were investigated in people with stroke and age-matched healthy controls (study 1) and in people with Parkinson’s disease and age-matched healthy controls (study 2). The effect of target predictability, turn angle and turn direction on the sequence of the movement of the body segments were also investigated. Participants were asked to stand in front of a light and either turn to a specific light (predictable condition) or locate and turn to a random light (unpredictable condition) placed at 45°, 90° or 135° to the right or left when the light in front extinguished. The results showed that the people with stroke and Parkinson’s disease (PD) initiated the movement of the segments later, had lower peak velocities and attained the peak velocities later than their control counterparts. People with PD showed more simultaneous onset of rotation of body segments as compared to their age-matched control when turning to 135°. The sequence of onset of rotation of the body segments was similar between the people with PD and their age-matched controls for all the other turning tasks. People with stroke also had comparable sequence of onset of rotation of body segments with their age-matched controls for all the turning tasks. While people with stroke presented with consistent pattern of peak velocity of the body segments for all the turning tasks, their control counterparts showed differences in the pattern of the peak velocities when turning to dominant and non-dominant sides. People with PD showed similar peak velocities of pelvis and foot when turning 45° to initially affected side as compared to separate peak velocities of the pelvis and foot in the stroke and control groups. The peak velocities of the segments (head, shoulder, pelvis and foot) occurred at more or less the same time for most of the turning tasks. Impairment of the relative movement of body segments during functional tasks could challenge the balance of an individual. The sequence of movement of body segments in the different tasks could therefore be related to balance during turning to identify which of the strategies of turning could present with risk of falls. Predictability of a target, turn angle and turn direction should be considered when developing interventions to avoid falls during turning and strategies for improving speed of reacting to perturbations should be developed for people with stroke and Parkinson’s disease.
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Janezic, Stephanie. "Molecular and behavioural characterisation of novel α-synuclein BAC transgenic mouse models of Parkinson's disease". Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:2f43c3ba-5665-46fe-a6b1-d48c059ba2d5.
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Alterations in the expression levels of α-synuclein (SNCA) provide an important link between familial and sporadic forms of Parkinson’s disease (PD). Multiplications of the human wild-type SNCA locus give rise to early-onset autosomal-dominant forms of PD and elevated α-synuclein expression has been linked to an increased risk for late-onset sporadic PD. The identification of α-synuclein’s physiological and pathophysiological functions has been hindered by a lack of animal models that accurately recapitulate the key disease features. Traditional cDNA-based transgenic models fail to correctly reflect the spatiotemporal expression pattern of α-synuclein and consequently do not accurately model the disease. Bacterial artificial chromosome (BAC) technology allows transgene expression from the entire genomic locus under the control of native regulatory elements and therefore allows improved modelling of disease mechanisms and phenotypes. This thesis describes a longitudinal characterisation of the molecular and behavioural effects of overexpressing human wild-type α-synuclein in a novel BAC transgenic PD mouse model, the SNCA-OVX model. Firstly, the work investigates transgene expression and localisation, dopamine neuron loss, synaptic function and PD-related motor and non-motor phenotypes. At 3 months of age, deficits in gastrointestinal function were observed while normal levels of dopaminergic markers and neurons were maintained. At 18 months, mice displayed a 30% decrease in nigrostriatal dopamine neurons, accompanied by reduced motor coordination and function. This novel PD model, which reflects accurate transgene expression and displays progressive dopamine neuron loss accompanied by characteristic behavioural PD phenotypes, will aid the investigation of molecular disease mechanisms and the development of novel therapies. Secondly, this thesis describes the generation of Translating Ribosome Affinity Purification (TRAP) transgenic mice, which express an EGFP-tagged ribosomal protein L10a transgene under the control of the tyrosine hydroxylase promoter. Finally, double transgenic TH bacTRAP SNCA-OVX mice were generated to investigate changes in genome-wide gene expression in dopaminergic cell populations of SNCA-OVX mice to identify novel drug targets.
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Chen, Kuan-Hua. "Dynamic characteristics of emotion and effects of emotion on driving in normal aging and Parkinson’s disease." Diss., University of Iowa, 2015. https://ir.uiowa.edu/etd/1958.
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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.
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Merrison-Hort, Robert. "Computational study of the mechanisms underlying oscillation in neuronal locomotor circuits." Thesis, University of Plymouth, 2014. http://hdl.handle.net/10026.1/3107.
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In this thesis we model two very different movement-related neuronal circuits, both of which produce oscillatory patterns of activity. In one case we study oscillatory activity in the basal ganglia under both normal and Parkinsonian conditions. First, we used a detailed Hodgkin-Huxley type spiking model to investigate the activity patterns that arise when oscillatory cortical input is transmitted to the globus pallidus via the subthalamic nucleus. Our model reproduced a result from rodent studies which shows that two anti-phase oscillatory groups of pallidal neurons appear under Parkinsonian conditions. Secondly, we used a population model of the basal ganglia to study whether oscillations could be locally generated. The basal ganglia are thought to be organised into multiple parallel channels. In our model, isolated channels could not generate oscillations, but if the lateral inhibition between channels is sufficiently strong then the network can act as a rhythm-generating ``pacemaker'' circuit. This was particularly true when we used a set of connection strength parameters that represent the basal ganglia under Parkinsonian conditions. Since many things are not known about the anatomy and electrophysiology of the basal ganglia, we also studied oscillatory activity in another, much simpler, movement-related neuronal system: the spinal cord of the Xenopus tadpole. We built a computational model of the spinal cord containing approximately 1,500 biologically realistic Hodgkin-Huxley neurons, with synaptic connectivity derived from a computational model of axon growth. The model produced physiological swimming behaviour and was used to investigate which aspects of axon growth and neuron dynamics are behaviourally important. We found that the oscillatory attractor associated with swimming was remarkably stable, which suggests that, surprisingly, many features of axonal growth and synapse formation are not necessary for swimming to emerge. We also studied how the same spinal cord network can generate a different oscillatory pattern in which neurons on both sides of the body fire synchronously. Our results here suggest that under normal conditions the synchronous state is unstable or weakly stable, but that even small increases in spike transmission delays act to stabilise it. Finally, we found that although the basal ganglia and the tadpole spinal cord are very different systems, the underlying mechanism by which they can produce oscillations may be remarkably similar. Insights from the tadpole model allow us to predict how the basal ganglia model may be capable of producing multiple patterns of oscillatory activity.
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Heideman, Simone. "Dynamics of temporal anticipation in perception and action." Thesis, University of Oxford, 2017. https://ora.ox.ac.uk/objects/uuid:98dde64e-11ea-4516-af8c-5f4707d52907.
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The selective deployment of attention over time optimises our perception and action at the moments when relevant events are expected to happen. Such "temporal orienting" to moments when something is going to happen is especially useful when this information can be combined with predictions about where and what events are likely to occur. A large body of research has already established how temporal predictions dynamically influence our perception and action, but questions remain regarding the neural bases of these attentional mechanisms. In this thesis I present three magnetoencephalography (MEG) studies that I conducted to investigate anticipatory neural dynamics associated with spatial-temporal orienting of attention for perception and action. I also investigate and discuss how such anticipatory dynamics change with ageing and neurodegeneration in Parkinson's disease (PD), and how these anticipatory neural dynamics behave in situations where a complex, hidden spatial-temporal structure is present. In Chapter 1, I introduce the topic of this thesis by reviewing the literature on temporal orienting of attention and by introducing my specific research questions. In Chapter 2, I present an MEG study on anticipatory neural dynamics of joint spatial-temporal orienting of attention in the visual domain, in younger and older adults. This study shows that neural dynamics with spatial, temporal and spatial-temporal orienting are all differentially affected by ageing. In Chapter 3, I describe an MEG experiment that investigates anticipatory neural dynamics during spatial-temporal motor preparation and compares PD participants to healthy control participants. This study reveals that both behavioural and neural dynamics with temporal orienting are affected in PD. In Chapter 4, I describe an experiment that explores how an implicit spatial-temporal structure is utilised to predict and prepare for upcoming actions. This study shows that motor cortical excitability is dynamically modulated in anticipation of the location and timing of events, even when such expectations are hidden in complex visual-motor sequences that remain largely implicit. In Chapter 5, the General discussion, I place these results in their wider context and discuss limitations and future directions.
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Chaudhry, Zahara Latif. "Examining the impact of caspase activities in PD animal model & differentiated ReNcell VM." Thesis, University of Bedfordshire, 2015. http://hdl.handle.net/10547/601101.
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Parkinson's disease (PD) is a neurodegenerative disorder that is characterised by uncontrollable shaking, muscular rigidity and cognitive impairment, due to low levels of dopamine caused by loss of dopamine containing neurons (DCN). The loss of DCN has been strongly associated with Caspase mediated apoptotic death. At present there are many studies that indicate exercise is beneficial in PD treatment, but there is a lack of research exploring the potential pathways, which exercise can activate and suppress to provide such positive and even negative effects. This study is the first to explore the effect of treadmill exercise on the level of Caspases, along with CAMK-IV protein in different brain regions of MPTP-treated rat model, using WB analysis. The results of this research has demonstrated reduction or completely suppression of some active Caspases, as well as, elevated amount of CAMK-IV in different brain regions of exercised PD animal model. To determine how exercise is reducing and inhibiting activation of Caspases, the first step was to identify how Caspases are stimulated, using ReNcell VM stem cell line that had been differentiated and treated with 6OHDA. The results of the study demonstrated 6OHDA triggered Caspase mediated apoptotic death of dDCN via PERK ER stress and NFκB classical pathway. IF, WB and cell viability analysis, using a wide range of inhibitors, showed that Caspase-2 is activated by the PERK pathway of ER stress and NFB classical pathway in 6OHDA treated dDCN. 6OHDA triggered activation of Caspase- 8 by the classical pathway in NFB mediated death of dDCN. 6OHDA triggered Caspase-4 activation but the exact mechanism involved remains to be identified. Only through understanding the molecular pathways regulating death of DCN in PD, new potential targets for therapy may be identified, which may ultimately reduce further death of DCN and slow PD progression. This proposed study has the potential to seek for more efficient drugs, which can suppress Caspase activation by targeting key targets in the pathways that the Caspases follow. These new specific targeted drugs could be used with treadmill exercise to achieve maximum effect, by slowing down or inhibiting further death of DCN.
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Ribeiro, Fernandes Hugo José. "Elucidating the role of GBA in the pathology of Parkinson's disease using patient derived dopaminergic neurons differentiated from induced pluripotent stem cells." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:7027574c-dda4-4752-9010-4c573bd0b2aa.
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Heterozygous mutations in the glucocerebrosidase (GBA) gene represent the most common risk factor for Parkinson’s disease (PD), a disease in which midbrain dopaminergic neurons are preferentially vulnerable. However, the mechanisms underlying this association are still unknown, mostly due to the lack of an appropriate model of study. In this thesis, we aimed at elucidating the role of heterozygous GBA mutations in PD using a specific human induced pluripotent stem cell (hiPSC)-based model of disease. First we developed a protocol for the efficient differentiation of hiPSCs into dopaminergic cultures, and extensively characterized the derived dopaminergic neurons which expressed multiple midbrain relevant markers and produced dopamine. Next we screened a clinical cohort of PD patients to identify carriers of GBA mutations of interest. Using for the first time hiPSCs generated from PD patients heterozygous for a GBA mutation (together with idiopathic cases and control individuals) we were able to efficiently derive dopaminergic cultures and identify relevant disease mechanisms. Upon differentiation into dopaminergic neuronal cultures, we observed retention of mutant glucocerebrosidase (GCase) protein in the endoplasmic reticulum (ER) with no change in protein levels, leading to upregulation of ER stress machinery and resulting in increased autophagic demand. At the lysosomal level, we found a reduction of GCase activity in dopaminergic neuronal cultures, and the enlargement of the lysosomal compartment in identified dopaminergic neurons suggesting a decreased capacity for protein clearance. Together, these perturbations of cellular homeostasis resulted in increased release of α-synuclein and could likely represent critical early cellular phenotypes of Parkinson's disease and explain the high risk of heterozygous GBA mutations for PD.
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Chamoun, Mario-Christofer. "An Alzheimer-type cerebrospinal fluid profile in early Parkinson's disease." Thesis, Umeå universitet, Institutionen för psykologi, 2019. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-167374.
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In recent years, several studies have discovered traces of Alzheimer's (AD) biomarkers in a large portion of patients with Parkinson's disease (PD), which have been associated with subsequent dementia (PDD). However, the manifestation of AD biomarkers in PD is not fully understood. At present, few studies have investigated how common AD biomarkers are in newly diagnosed and unmedicated patients with PD. This cross-sectional cohort study investigated whether AD biomarkers were present in unmedicated and newly diagnosed patients with PD and patients with PD and overlapping clinical symptoms (cognitive impairment, depression, olfactory dysfunction). Cerebrospinal fluid (CSF) levels of AD biomarkers Amyloid-β-42 (Aβ42), phosphorylated-tau (p-tau), and total-tau (t-tau) were assessed in 343 patients with the mean age of 68,69 (SD=9,60), including 31 healthy controls with the mean age of 68,90 (SD=5,64). The participants were recruited from The New Parkinson Patient in Umea (NYPUM & PARKNY). The results showed a significant difference in CSF AD biomarkers between patients with PD and healthy controls, but not in patients with PD and overlapping clinical symptoms. The results point to the presence of AD pathology in early PD; however, the presence of AD pathology could not be further strengthened by the clinical overlapping symptoms. More prospective studies on newly diagnosed patients with PD need to be carried out to investigate the prognostic values of the presence of AD pathology found in PD.
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Gitchel, George Thomas Jr. "Development of an Accurate Differential Diagnostic Tool for Neurological Movement Disorders Utilizing Eye Movements." VCU Scholars Compass, 2015. http://scholarscompass.vcu.edu/etd/4109.
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Parkinson’s disease and Essential tremor are the two most prevalent movement disorders in the world, but due to overlapping clinical symptoms, accurate differential diagnosis is difficult. As a result, approximately 60% of patients with movement disorders symptoms will have their diagnosis changed at least once before death. By their subjective nature, clinical exams are inherently imprecise, leading to the desire to create an objective, quantifiable test for movement disorders; a test that currently is elusive. Eye movements have been studied for a century, and are widely appreciated to be quantifiably affected in those with neurological disease. Through a collaborative effort between the VA hospital and VCU, over 1,000 movement disorder subjects had their eye movements recorded, utilizing an SR Research Eyelink 2. Patients with Parkinson’s disease exhibited an ocular gaze tremor during fixation, normal reflexive saccades, and reduced blink rate. Subjects with Essential tremor exhibited slowed saccadic dynamics, with increased latencies, in addition to a larger number of square wave jerk interruptions of otherwise stable fixation. After diagnostic features of each disorder were identified, prospective data collection could occur in a blinded fashion, and oculomotor features used to predict clinical diagnoses. It was determined that measures of fixation stability were capable of almost perfectly differentiating subjects with PD, and a novel, combined parameter was capable of similar results in ET. As a group, it appears as if these symptoms do not progress as the disease does, but subanalyses show that individual patients on constant pharmaceutical doses tracked over time do slightly change and progress. The near perfect separation of disease states suggest the ability of oculomotor recording to be a powerful biomarker to be used for the differential diagnosis of movement disorders. This tool could potentially impact and improve the lives of millions of people the world over.
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Pierson, Johan. "Development of Methods for Protein and Peptide Analysis Applied in Neuroscience Utilizing Mass Spectrometry." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4685.
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Aravamuthan, Bhooma Rajagopalan. "Comparing the radiological anatomy, electrophysiology, and behavioral roles of the pedunculopontine and subthalamic nuclei in the normal and parkinsonian brain." Thesis, University of Oxford, 2008. http://ora.ox.ac.uk/objects/uuid:9a735b39-c1fe-4d5f-b05f-3385f27e6e58.
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Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and DBS of the pedunculopontine nucleus (PPN) have been shown to be effective surgical therapies for Parkinson’s disease (PD). To better understand the PPN and STN as DBS targets for PD, this research compares the anatomy, electrophysiology, and motor control roles of these nuclei. PPN and STN connections were examined in vivo in human subjects and in the non-human primate using probabilistic diffusion tractography. Both the PPN and STN were connected with each other and with the motor cortex (M1) and basal ganglia. After studying these anatomical connections in primates, their functional significance was further explored in an anesthetized rat model of PD. Examination of the electrophysiological relationship between the PPN and basal ganglia in the presence of slow cortical oscillatory activity suggested that excitatory input from the STN may normally modulate PPN spike timing but that inhibitory oscillatory input from the basal ganglia output nuclei has a greater effect on PPN spike timing in the parkinsonian brain. To examine transmission and modulation of oscillatory activity between these structures at higher frequencies, LFP activity was recorded from the PPN and STN in PD patients performing simple voluntary movements. Movement-related modulation of oscillatory activity predominantly occurred in the α (8-12 Hz) and low β (12-20 Hz) frequencies in the STN but in the high β (20-35 Hz) frequencies in the PPN, supporting observations from rodent studies suggesting that oscillatory activity is not directly transmitted from the STN to the PPN in PD. Finally, to better understand the roles of the STN and PPN in large-scale movement, the effects of STN and PPN DBS on gait abnormalities in PD patients were studied. DBS of the STN appeared to improve gait by optimising executive gait control while DBS of the PPN appeared to restore autonomic gait control. These results have several implications for DBS patient selection, surgical targeting, and for understanding the mechanisms underlying DBS efficacy.
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Cooper, Jason Fisk. "Aging, Stress, and Pathogenesis of Parkinson's Disease| Studies Using C. elegans." Thesis, Van Andel Research Institute, 2018. http://pqdtopen.proquest.com/#viewpdf?dispub=10747486.
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<p> Parkinson’s disease (PD) is an adult onset neurodegenerative disease that is characterized by deficiencies in movement, cognition, and Lewy body neuropathology within the brain. Motor and cognitive deficiencies progressively worsen through the course of disease concurrent with increasing neuropathology and neurodegeneration. Approximately 10–15% of PD patients have a family history of PD with a confirmed genetic cause. Presently PD pathogenesis is incompletely understood and there are no treatments capable of halting or reversing this disease. The extended disease-course and age-dependent nature of PD, especially in genetic cases where a mutation is present from birth, affirm that aging itself is the most important risk factor for disease. We hypothesize that specific cellular changes that occur during the normal process of aging confer susceptibility to disease-causing mutations which, while tolerated at younger ages, contribute to disease with age. Accurate animal models of PD and aging provide the ability to elucidate disease mechanisms and explore novel strategies targeting the aging process. To test the role of aging in PD we utilize the nematode <i>Caenorhabditis elegans</i> because this animal has been used extensively to study animal aging at a cellular level. We confirm that disease phenotypes in genetic <i>C. elegans</i> models of PD such as neurodegeneration, protein aggregation, and mitochondrial deficits are proportional to this organism’s brief lifespan. This indicates that PD progresses according to biological age and not merely to chronological time. As a proof-of-principle we also show that delaying aging by mutation of the gene encoding the insulin-IGF receptor, <i>daf-2</i>, can rescue multiple deficits present in nematode models of PD. Overall we demonstrate that biological aging is a crucial for the development of various PD associated phenotypes and that delaying aging is sufficient to delay these phenotypes. Therefore targeting aging itself may be a sound strategy for the halting or the prevention of PD.</p><p>