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Gonsalves, Crystal. "Bimanual coordination in Huntington's disease and Parkinson's disease." Thesis, University of Ottawa (Canada), 2008. http://hdl.handle.net/10393/27588.
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Special populations that suffer from Parkinson's disease (PD) and Huntington's disease (HD) display poorer performance in movement and bimanual coordination tasks. Both PD and HD are basal ganglia disorders with neuropathology distinct from one another. The production of internally guided movements is disrupted in PD and HD, therefore utilization of the external pathway may be able to stabilize movements for these groups. The current study examines the effect of auditory cueing for these two populations in timing performance. A total of 10 PD patients, 10 healthy controls (matched for age and gender) and 2 HD patients were examined on a repetitive bimanual finger tapping task. PD patients and healthy controls were asked to perform finger tapping at two different frequencies (1.0 Hz, 2.0 Hz) and two movement types (in-phase, anti-phase). Additionally half of the trials were performed with an external cue (metronome beat), while the other half were not (cue was turned off after 10 metronome heats). Results showed that PD patients were able to effectively use the cue to facilitate bimanual coordination as it was shown that absolute mean timing errors were decreased during the cue trials. PD patients were able to perform both movement types although the more complex mirror asymmetrical anti-phase trials were more difficult to perform. HD patients were not able to achieve the designated fast and slow frequencies that PD and healthy controls performed. The HD patients' movement was highly variable due to tremors and involuntary tics experienced by the patients. Through the examination of raw trajectories and polar plots of phase differences it was concluded that the external cue did not seem to stabilize bimanual coordination for the HD patients.
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Gu, Mei. "Mitochondrial function in Parkinson's disease and other neurodegenerative diseases." Thesis, University College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.322371.
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Underwood, Mandy. "Pain and psychological factors in Huntington's disease and Parkinson's disease." Thesis, University of Leicester, 2015. http://hdl.handle.net/2381/33297.
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Background: Chronic pain is a common aspect of many neurological conditions and often causes psychological distress. A scoping literature search revealed research was lacking in the area of Huntington’s disease (HD) and pain, therefore the empirical work focused on providing data on prevalence of pain and psychological predictors of pain in HD. There was insufficient research on HD and pain to form the basis of a review, however there was a body of literature on Parkinson’s disease (PD). The review focused on the relationship between pain and depression in people with PD. A critical appraisal of the experience of conducting the review and empirical work formed the final part of the thesis. Literature review: Fourteen articles were identified and reviewed in depth. Half of the studies, representing approximately three quarters of the participants in total, found a significant relationship between pain and depression in PD, with increased pain associated with increased depression. There was reasonable evidence to support an association between the severity of depression and the severity of pain in people with PD, although further research was recommended. Empirical report: A data-mining study was undertaken using data from 1474 participants of the European Huntington’s Disease Network (EHDN) REGISTRY study to examine the prevalence of pain in HD and to identify, using ordinal regression analysis, which psychological factors predicted severity of pain in people with HD. The prevalence of pain in HD was found to be 41%. Pain severity in HD was predicted by anxiety, depression and irritability. Caregivers and health professionals should consider the possibility that people with HD might be experiencing pain, particularly if there are signs of anxiety, depression or irritability. Recommendations were made for further research and limitations were discussed. Critical appraisal: The research process, methodology and main learning points were considered.
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Orth, Michael. "Molecular study of cell culture models of Parkinson's disease and Huntington's disease." Thesis, University College London (University of London), 2005. http://discovery.ucl.ac.uk/1445761/.
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The discovery of the genetic basis of neurodegenerative disorders has enabled the generation of models to study their pathogenesis. In part one, human embryonic kidney cells with inducible expression of wild-type or mutant G209A cc-synuclein modelled increased a-synuclein expression and a familial form of Parkinson's disease, respectively. Both wild-type and mutant a- synuclein were localised to vesicles, some of which were catecholaminergic. Over- expression of wild-type or mutant (G209A) a-synuclein alone did not reduce cell viability, cause oxidative stress or impair mitochondrial function. However, mutant a- synuclein expression enhanced the susceptibility to dopamine toxicity causing increased oxidative stress and cell death. This effect was similar to that of reserpine, an inhibitor of vesicular monoamine uptake, in controls. These results suggest that a-synuclein may play a role in dopamine compartmentalisation. Loss of function conferred by the G209A mutation could therefore increase cytoplasmic dopamine concentrations with subsequent cell damage or death. In part two, myoblast cell lines were established, and characterised, from the R6/2 mouse model of Huntington's disease (HD). Mutant N-terminal huntingtin transgene over-expression was associated with significantly greater numbers of myotubes suggesting a role of huntingtin in muscle differentiation. In long-term culture, differentiated R6/2 myotubes, but not controls, formed nuclear huntingtin inclusions. Inclusion number depended upon culture medium conditions suggesting that environmental factors might be relevant. This model of HD in non-neuronal post mitotic cells may be useful to study the pathophysiology of, and possibly the effect of therapeutics on, huntingtin aggregate formation. The third part examined the suggestion that codon 129 homozygosity of the prion protein (PrP) gene may predispose to sporadic inclusion body myositis (sIBM). Codon 129 zygosity in 41 sIBM muscle biopsies was not significantly different to results published in population studies in several Western countries suggesting sIBM is not linked to homozygosity at codon 129 of the PrP gene.
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Pretsell, Douglas Ogilvy. "The role of the dorsal striatum in the control of reaction time performance." Thesis, University of Cambridge, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.261652.
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Keenan, Siobhan Elizabeth. "Language and the basal ganglia : insights from Parkinson's and Huntington's disease." Thesis, University of Cambridge, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.615882.
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Johnson, Katherine A. (Katherine Anne) 1973. "Movement preparation and execution in Huntington's and Parkinson's diseases." Monash University, Dept. of Psychology, 2001. http://arrow.monash.edu.au/hdl/1959.1/9176.
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Antoniades, Chrystalina Andrea. "The development and optimization of biomarkers for Huntington's and Parkinson's disorders." Thesis, University of Cambridge, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609075.
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Ferreira, Danilo Avelar Sampaio. "Avaliação do efeito protetor do beta-cariofileno em modelos celulares de doenças neurodegenerativas." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/60/60134/tde-17042015-093013/.
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As doenças neurodegenerativas (DN) estão entre as principais causas de mortalidade e morbidade nos países ocidentais. Não há ainda um tratamento definitivo para estas neuropatias, mas estudos têm indicado mecanismos comuns de toxicidade que incluem disfunção mitocondrial, estresse oxidativo, apoptose e neuroinflamação. Adicionalmente, o efeito benéfico da neuroplasticidade induzida por fatores neurotróficos no retardamento ou inibição do processo neurodegenerativo também tem sido sugerido por muitos estudos. O beta-cariofileno é um sesquiterpeno bi-cíclico encontrado no óleo essencial de algumas plantas, e que possui efeito anti-inflamatório e antioxidante. Assim, este composto possui características e é capaz de induzir efeitos que o tornam um potencial candidato ao tratamento/prevenção dos processos envolvidos na neurodegeneração. Apesar disso, pouco se sabe sobre os efeitos e os mecanismos de ação do beta-cariofileno no processo de degeneração neuronal. Então, neste estudo, avaliou-se o efeito do beta-cariofileno em modelos celulares (PC 12) de neurotoxicidade que mimetizam in vitro os mecanismos moleculares envolvidos nas doenças de Parkinson, Huntington e Alzheimer, os quais, para efeitos práticos, denominaremos de \"modelos celulares de Parkinson, Huntington e Alzheimer\". Estes modelos são induzidos experimentalmente pela neurotoxina dopaminérgica iodeto de 1-metil 4-fenil piridina (MPP+), pela neurotoxina mitocondrial ácido 3-nitropropiônico (3NP) e pelo peptídeo neurotóxico B-amiloide (AB42), respectivamente. O beta-cariofileno apresentou efeitos benéficos nestes três modelos de neurotoxicidade, e adicionalmente induziu neuritogênese e a expressão de proteínas neurotípicas no modelo neuronal. Este é o primeiro estudo a demonstrar tais efeitos do beta-cariofileno.Neurodegenerative diseases (ND) are among the leading causes of mortality and morbidity in Western countries. There is not a definitive treatment for these neuropathies, but studies have indicated common mechanisms of toxicity that include mitochondrial dysfunction, oxidative stress, neuroinflammation and apoptosis. Additionally, the beneficial effect of the neuroplasticity induced by neurotrophic factors on the retardation or inhibition of neurodegeneration has also been suggested by several studies. Beta-caryophyllene is a bicyclic sesquiterpene found in essential oils of some plants, and possesses anti-inflammatory and antioxidant effects. Thus, this compound has characteristics and is capable of inducing effects that make it a potential candidate for treatment / prevention of the processes involved in neurodegeneration. Despite this, little is known about the effects and mechanisms of action of beta-caryophyllene in the neuronal degeneration process. Then, this study evaluated the effect of beta-caryophyllene in cellular models of neurotoxicity (PC 12) that mimic in vitro the molecular mechanisms involved in Parkinson\'s, Huntington\'s and Alzheimer\'s diseases, which, for practical purposes, we will denominate \"Cellular models of Parkinson\'s, Huntington\'s and Alzheimer\'s diseases.\" These models are experimentally induced by the dopaminergic neurotoxin 1-methyl iodide, 4-phenyl pyridine (MPP+), by the mitochondrial neurotoxin 3-nitropropionic acid (3NP) and the neurotoxic peptide B-amyloid (AB42), respectively. Beta-caryophyllene showed beneficial effects on these three models of neurotoxicity, and additionally induced neuritogenesis and the expression of neurotypic proteins in the neuronal model. This is the first study to demonstrate such effects of beta-caryophyllene.
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Gobbel, John Randall. "The role of the neostriatum in the execution of action sequences /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 1997. http://wwwlib.umi.com/cr/ucsd/fullcit?p9808981.
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Chandrasekaran, Sreedevi. "A Network View on Neurodegenerative Disorders." VCU Scholars Compass, 2013. http://scholarscompass.vcu.edu/etd/3083.
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Neurodegeneration is a chronic, progressive and debilitating condition that affects majority of the World's elderly population who are at greater risk. Numerous scientific studies suggest that there could be a common underlying molecular mechanism that promotes the degeneration and the subsequent neuronal loss, however so far the progress in this direction is rather limited. Abnormal protein misfoldings, as well as protein plaque formations in the brain, are some of the hallmark characteristic features of neurodegenerative disorders (NDDs). Genetic and environmental factors, oxidative stress, excessive reactive oxygen species formation, mitochondrial dysfunction, energy depletion and autophagy disruption etc. are some of the widely suspected mechanisms that manifest the cognitive, motor and emotional symptoms of these NDDs. Motivated by some molecular traits found in common in several NDDs, network-based systems biology tools and techniques were used in this study to identify critical molecular players and underlying biological processes that are common for Parkinson's, Alzheimer's and Huntington's disease. Utilizing multiple microarray gene expression datasets, several biomolecular networks such as direct interaction, shortest path, and microRNA regulatory networks were constructed and analyzed for each of the disease conditions. The network-based analysis revealed 26 genes of potential interest in Parkinson's, 16 in Alzheimer's and 30 in Huntington's disease. Many new microRNA-target regulatory interactions were identified. For each disorder, several routes for possible disease initiation and protection scenarios were uncovered. A unified neurodegeneration mechanism network was constructed by utilizing the significantly differentially expressed genes found in common in Parkinson's, Alzheimer's and Huntington's microarray datasets. In this integrated network many key molecular partakers and several biological processes that were significantly affected in all three NDDs were uncovered. The integrated network also revealed complex dual-level interactions that occur between disease contributing and protecting entities. Possibilities of microRNA-target interactions were explored and many such pairs of potential interest in NDDs were suggested. Investigating the integrated network mechanism, we have identified several routes for disease initiating, as well as alleviating ones that could be utilized in common for Parkinson's, Alzheimer's and Huntington's disease. Finding such crucial and universal molecular players in addition to maintaining a delicate balance between neurodegeneration promoters and protectors is vital for restoring the homeostasis in the three NDDs.
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Yong, Voon Wee. "Neurochemical studies of the pathogenesis of four central nervous system disorders : Parkinson's disease, Huntington's chorea, dialysis encephalopathy, and Hallervorden-Spatz syndrome." Thesis, University of British Columbia, 1986. http://hdl.handle.net/2429/27224.
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My thesis is divided into.4 chapters, each dealing with a particular central nervous system disorder. The first chapter is devoted to the understanding of the pathogenesis of Parkinson's disease (PD). Several studies with living or dead patients with PD were performed. Animal experiments relied heavily on the use of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to create an animal model of PD. Two major conclusions of this chapter are firstly, that patients with PD may be exposed up to the time of death to one or more neurotoxins that may act via reactive free radicals,, and secondly, that antioxidant compounds such as α-tocopherol may be useful in slowing the progression of neuronal loss in PD.
The second chapter in this thesis tested the hypothesis that the premature neuronal death that occurs in Huntington's chorea (HC) may be the result of a genetically-determined enzymatic failure in the degradation of a circulating neurotoxin of either endogenous or exogenous origin. Two main types of studies were performed: an in vivo experiment in which rats were injected repeatedly with serum or serum ultrafiltrate from HC patients or control subjects, and, an in vitro study in which rat striatal explants were exposed in tissue culture to serum or CSF from patients or controls. The results from both types of experiments are suggestive for the presence of a neurotoxin in the serum of patients with HC. This putative neurotoxin may either be a small molecule irreversibly bound to serum proteins, or, a molecule larger than 10000 daltons. The identity of the putative neurotoxin is presently unclear. In the third chapter of this thesis, we examined for neurochemical abnormalities that might be present in the autopsied brains of patients who died with dialysis encephalopathy (DE). A major finding was a deficiency of GABA contents in several regions of autopsied brains of DE patients. Aluminum levels were abnormally high in the frontal cortical gray matter of DE patients. Animal experiments were unsuccessful in clarifying whether or not aluminum is the causative factor in DE, principally because we failed to produce elevation of aluminum content in the brains of rats injected with aluminum hydroxide. The latter was the case even though we employed hemi-nephrectomy, 5/6 nephrectomy, and/or chronic lithium administration in attempts to decrease the renal excretion of aluminum.
Finally, in the fourth chapter, we searched for neurochemical abnormalities in the autopsied brain of 2 patients who died with a rare disease, Hallervorden-Spatz syndrome (HSS). In one patient, contents of cystine and of glutathione-cysteine mixed disulfide in the globus pallidus were elevated 2 SD above those of controls. On the other hand, activity of cysteine dioxygenase, the enzyme that converts cysteine to cysteine sulfinate, was reduced in the globus pallidus of both patients. We propose the hypothesis that cysteine accumulates locally in the globus pallidus in HSS as a result of decreased activity of cysteine dioxygenase. Accumulated cysteine may serve to chelate iron, accounting for the local increase in iron content in the1globus pallidus of HSS. The combination of iron and cysteine may generate free radicals that damage neuronal membranes to cause the typical morphological changes observed in HSS.Medicine, Faculty of
Anesthesiology, Pharmacology and Therapeutics, Department of
Graduate
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Martín, Flores Núria. "Study of the mTOR pathway in neurodegenerative diseases: from synapses to genes." Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/665330.
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Huntington's disease (HD) and Parkinson's disease (PD) are devastating neurodegenerative diseases that progress with the death of selective neuronal subpopulations. Neuronal dysfunction and death are consequence of multiple pathogenic processes which alter signalling cascades. The identification of such molecular pathways is crucial to understand the cellular processes that triggers the symptomatology of diseases. One of the common affected pathways in neurodegeneration is the mTOR pathway. It regulates multiple cellular processes to preserve cellular viability and function. Consequently, to maintain a proper function mTOR activity needs to be fine-tuned. RTP801 is an mTOR negative regulator whose action over this pathway plays a significant role in neurodegeneration. RTP801 protein is induced in an attempt to cope cellular stress. However a sustained RTP801 increase leads to neuronal death by sequentially inactivating first mTOR and then Akt pro-survival kinase. RTP801 pathological increase has been involved in neurodegenerative diseases such as PD. Therefore, identifying RTP801 as a possible new therapeutic target in HD would be highly valuable in designing new pharmacological therapies that block, or at least delay, the neurodegeneration and changes in synaptic plasticity associated with it.
Our results show that the overexpression of pathogenic N-terminal htt increases RTP801 levels by both lengthening the protein half-life and up-regulating its gene expression. Blockade of RTP801 expression prevents mhtt-induced cell death in HD cellular models. Importantly, RTP801 is elevated in HD-iPSC and putamen, caudate nucleus and cerebellum of human HD post-mortem brain. Although total RTP801 levels in the striatum of HD murine models are not altered, RTP801 is increased in the synaptic compartment which contributes to motor learning deficits in the R6/1 model. Downregulation of striatal RTP801 preserves motor learning skills in R6/1 mice. Hence, RTP801 is identified as a novel downstream effector of mhtt which mediates its toxicity.
Recently, exosomes have emerged as a key mechanism to maintain trophic support between neural cells and as vehicle for the clearance of toxic proteins from neurons. Since RTP801 is upregulated under stressful conditions, its propagation by exosomes may allow the neuron-to-neuron spreading of RTP801 toxicity through the modulation of mTOR/Akt pathway.
Our results have elucidated a novel function of RTP801 as an exosomal protein. We demonstrate that both ectopic and endogenous RTP801 can be found in exosomes derived from HEK293 cells. In cortical neurons, exosomal RTP801 elevation is sensitive to PD mimetic 6-OHDA (6-hydroxydopamine) but not to potassium depolarization. Consequently, 6-OHDA exposure induces the loading of RTP801 into exosomes released from cortical neurons. Intriguingly, mhtt does not elevate RTP801 in exosomes obtained from a cellular model. In addition, we demonstrate that exosomes have a protective role promoting the activation of both mTOR complex 1 and 2 in recipient neurons, but increased RTP801 counteracts exosomal mTOR pathway activation suggesting that RTP801 negatively modulates pro-survival signals transneuronally.
Altered protein functions of the mTOR pathway are a common hallmark in many neurodegenerative diseases. However, little is known about the contribution of genetic variants or single nucleotide polymorphisms (SNPs) that belong to the mTOR pathway. As a multifactorial disease, we studied the association of SNPs in genes encoding mTOR pathway protein components with the susceptibility PD and the response to levodopa (L-DOPA) treatment.
The data found indicate that polymorphisms in genetic markers of the mTOR pathway contribute to the susceptibility to PD and the response to L-DOPA treatment in PD patients. We show that these SNPs influence the outcome individually or interacting epistatically with other genetic markers.
Taken together, our findings indicate that deregulation of the mTOR signalling pathway plays an important role in the pathogenesis associated with PE and HD and its regulation is crucial to maintain adequate neuronal function and viability.La enfermedad de Huntington (EH) y la enfermedad de Parkinson (EP) son enfermedades neurodegenerativas devastadoras caracterizadas por la muerte de subpoblaciones neuronales selectivas. La disfunción neuronal y la muerte son consecuencia de múltiples procesos patogénicos que llevan a la alteración de cascadas de señalización. Una de las vías afectadas de forma común en los procesos neurodegenerativos es la vía mTOR. Como modulador de numerosos procesos celulares, la vía de mTOR está regulada para mantener la supervivencia neuronal y la plasticidad sináptica. Una de las proteínas que modula esta cascada de señalización es RTP801. RTP801 se induce en respuesta a factores de estrés celular y su aumento desencadena la muerte neuronal al regular negativamente la vía mTOR/Akt. La implicación de RTP801 en la EP ha sido ampliamente estudiada, sin embargo, su contribución a la patogénesis de la EH nunca antes había sido explorada. Específicamente, nuestros resultados han identificado a RTP801 como un mediador de la toxicidad inducida por huntingtina mutada. El aumento de RTP801 medía la muerte celular inducida por huntingtina mutada y contribuye a la disfunción del aprendizaje motor en el modelo murino R6/1. El silenciamiento de RTP801 en el estriado de los ratones R6/1 contribuye a preservar la plasticidad sináptica de la vía corticoestriatal, y por tanto del aprendizaje motor. Por otra parte, mostramos que los exosomas secretados por neuronas activan la vía de supervivencia mTOR/Akt en neuronas recipientes. Sin embargo, ante un estrés celular, la toxicidad de RTP801 es propagada a través de exosomas que contrarrestan la activación trófica de la vía mTOR/Akt. Finalmente, demostramos que variaciones genéticas en los componentes de la vía de mTOR modulan la susceptibilidad y la edad de inicio de la EP y, contribuyen a la aparición y severidad de la discinesia inducida por levodopa. En conjunto, nuestros hallazgos indican que la desregulación de la vía de mTOR desempeña un papel importante en la patogénesis asociada a la EP y la EH y, su correcta regulación es crucial para mantener la viabilidad y función neuronal.
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Franco, Iborra Sandra. "Mitochondrial quality control in neurodegenerative diseases: focus on Parkinson’s disease and Huntington’s disease." Doctoral thesis, Universitat Autònoma de Barcelona, 2018. http://hdl.handle.net/10803/565668.
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Darrerament s’han produït avanços importants que han contribuït al coneixement dels mecanismes de disfunció cel·lular i mort en la malaltia de Parkinson (MP) i en la malaltia de Huntington (MH). Ambdues malalties són trastorns del moviment que es caracteritzen per la pèrdua específica de neurones dels ganglis basals, les neurones dopaminèrgiques de la substància nigra (SN), en el cas de la MP i les neurones espinoses de l’estriat, en el cas de la MH. Malgrat les diferències, ambdues comparteixen processos patològics comuns com la presència de proteïnes malplegades, l’estrés oxidatiu i disfunció mitocondrial. La mitocòndria és la font d’energia principal en les cèl·lules eucariotes, però també és un orgànul dinàmic relacionat amb una gran quantitat de processos cel·lulars. La disrupció de la homeòstasis mitocondrial i la subseqüent disfunció mitocondrial juguen un paper important en la patofisiologia de les malalties neurodegeneratives. El manteniment de la integritat mitocondrial a través de diferents mecanismes de control és crític per a la superviviència neuronal. Aquesta tesi es centra en l’estudi dels mecanismes de control de qualitat mitocondrial en la MP i la MH, per tal d’entendre millor els mecanismes que duen a la mort cel·lular.
En el primer capítol, he estudiat el transport de proteïnes a la mitocòndria en models in vitro i in vivo de la MP. In vitro, la inhibició del complexe I produeix una alteració del transport de proteïnes a la mitocòndria així com una disminució dels nivells de proteïnes OXPHOS, acumulació de proteïnes agregades i disminució dels nivells de chaperones mitocondrials. Per tal de restablir el transport de proteïnes mitocondrials es van sobreexpressar dos components clau del sistema de translocases: la translocasa de la membrana externa 20 (TOM20) i la translocasa de la membrana interna 23 (TIM23). La sobreexpressió in vitro de TOM20 i TIM23 va restaurar el transport de proteïnes mitocondrials i va alleugerar la disfunció mitocondrial i la mort cel·lular. La inhibició del complexe I en ratolins també dóna lloc a una alteració del transport de proteïnes mitocondrials i produeix neurodegeneració del sistema dopaminèrgic. La sobreexpressió de TIM23 va restaurar parcialment el transport de proteïnes i va protegir lleugerament les neurones dopaminèrgiques de la SN. En canvi, la sobreexpressió de TOM20 va ser incapaç de millorar el transport de proteïnes mitocondrials i, fins i tot, va exacerbar la mort cel·lular. Aquests resultats posen de relleu el paper de la disfunció del transport de proteïnes mitocondrials, en particular de dos dels seus components, en la patogènesis de la MP i suggereixen la necessitat de futurs estudis es centrin en altres elements d’aquest sistema.
En el segon capítol, he estudiat el paper de la proteïna huntingtina en la mitofàgia i com la seva mutació, que dóna lloc a una expansió de glutamines, pot afectar a aquesta funció. Per a tal fi, he treballat en un model in vitro de cèl·lules estriatals ST-Q7 (control) i ST-Q111 (mutant). En condicions fisiològiques, la mitofàgia induïda no es troba mitjançada pel reclutament de parkin als mitocondris despolaritzats. La huntingtina mutada afecta la mitofàgia induïda a través de l’alteració de la seva funció de scaffold en diferents passos del procés de mitofàgia: (i) activació d’ULK1 a través de l’alliberament de mTORC1, (ii) formació del complexe Beclin 1-Vps15,(iii) interacció dels adaptadors de mitofàgia OPTN i NDP52 amb huntingtina i, (iv) amb LC3. Com a resultat, els mitocondris de les cèl·lules ST-Q111 estan més danyats i tenen una respiració mitocondrial deficient. Aquests resultats demostren la presència d’una alteració en la mitofàgia com un mecanisme lligat a la MH. En conclusió, el descobriment de noves dianes mitocondrials en la MP i MH emfatitza el paper important que juga el control de qualitat mitocondrial en la neurodegeneració.In the past years, several important advances have expanded our understanding of the pathways that lead to cell dysfunction and death in Parkinson’s disease (PD) and Huntington’s disease (HD). Both diseases are movement disorders characterized by the loss of a specific subset of neurons within the basal ganglia, dopaminergic neurons in the substantia nigra pars compacta (SNpc), in the case of PD, and medium spiny neurons in the striatum, in the case of HD,. Despite distinct clinical and pathological features, these two neurodegenerative disorders share critical underlying pathogenic mechanisms such as the presence of misfolded and/or aggregated proteins, oxidative stress and mitochondrial anomalies. Mitochondria are the prime energy source in most eukaryotic cells, but these highly dynamic organelles are also involved in a multitude of cellular events. Disruption of mitochondrial homeostasis and the subsequent mitochondrial dysfunction plays a key role in the pathophysiology of neurodegenerative diseases. Therefore, maintenance of mitochondrial integrity through different surveillance mechanisms is critical for neuronal survival. In this thesis I have studied in depth some mitochondrial quality control mechanisms in the context of PD and HD, in order to broaden the knowledge about the pathomechanisms leading to cell death. In the first chapter I have studied mitochondrial protein import in in vitro and in vivo models of PD. In vitro, complex I inhibition, a characteristic pathological hallmark in PD, impaired mitochondrial protein import. This was associated with OXPHOS protein downregulation, accumulation of aggregated proteins inside mitochondria and downregulation of mitochondrial chaperones. Therefore, we aimed to reestablish the mitochondrial protein import by overexpressing two key components of the system: translocase of the outer membrane 20 (TOM20) and translocase of the inner membrane 23 (TIM23). Overexpression of TOM20 and TIM23 in vitro restored protein import into mitochondria and ameliorated mitochondrial dysfunction and cell death. Complex I inhibition also impaired mitochondrial protein import and led to dopaminergic neurodegeneration in vivo. Overexpression of TIM23 partially rescued protein import into mitochondria and slightly protected dopaminergic neurons in the SNpc. On the contrary, TOM20 overexpression did not rescue protein import into mitochondria and exacerbated neurodegeneration in both SNpc and striatum. These results highlight mitochondrial protein import dysfunction and the distinct role of two of their components in the pathogenesis of PD and suggest the need for future studies to target other elements in the system. In the second chapter, I have studied the role of huntingtin in mitophagy and how the polyglutamine expansion present in mutant huntingtin can affect its function. For such, I worked with differentiated striatal ST-Q7 (as control) and ST-Q111 (as mutant) cells, expressing full length huntingtin. In these conditions, induced mitophagy was not mediated by Parkin recruitment into depolarized mitochondria. Mutant huntingtin impaired induced mitophagy by altering wildtype huntingtin scaffolding activity at different steps of mitophagy process: (i) ULK1 activation through its release from the mTORC1, (ii) Beclin1-Vps15 complex formation, (iii) interaction of the mitophagy adapters OPTN and NDP52 with huntingtin and (iv) with LC3. As a result, mitochondria from ST-Q111 cells exhibited increased damage and altered mitochondrial respiration. These results uncover impaired mitophagy as a potential pathological mechanism linked with HD. In conclusion, we have discovered new mitochondrial targets for PD and HD emphasizing the important role that mitochondrial quality control plays in neurodegeneration
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Sacrey, Lori-Ann Rosalind. "Development and degeneration of the sensory control of reach-to-eat behaviour." Thesis, Lethbridge, Alta. : University of Lethbridge, Dept. of Neurosicence, c2012, 2012. http://hdl.handle.net/10133/3259.
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The reach-to-eat movement, in which a hand is advanced towards a food item, shapes to grasp the food item, and withdrawals to place the food item into the mouth for eating, is a behaviour that is performed daily. The movement is controlled by two sensory systems, vision to guide hand advance and grasping, and somatosensation to guide hand withdrawal and mouth placement. The purpose of the present thesis was to examine how the sensory control of reaching-to-eat develops in infancy and degenerates following neurodegenerative disorder. The tight coupling of vision to hand advance and somatosensation to hand withdrawal has a developmental profile from six months to one year of age. That is, six-month-old infants rely on vision to advance their hand, grasp the target, and withdrawal the target to the mouth. By twelve months of age, infants display the adult pattern of coupling vision to hand advance and grasping. The tight coupling of vision to hand advance degenerates with basal ganglia disease, such that subjects with Parkinson’s disease and Huntington’s disease show an overreliance on vision to guide hand advance for grasping and hand withdrawal for mouth placement. The results of the thesis demonstrate that efficient use of sensory control to guide motor behaviour is an important aspect of development that is disrupted by neurodegenerative disease.xiv, 286 leaves : ill. ; 29 cm
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Contreras, López William Omar [Verfasser], and Guido [Akademischer Betreuer] Nikkhah. "Huntington's and Parkinson's disease - clinical and experimental transplantation : : present clinical protocol and recent advances in the use of Adrenal Chromaffin cells as an experimental alternative tissue source = Experimentelle und klinische Hirnzellentransplantation." Freiburg : Universität, 2013. http://d-nb.info/1123479429/34.
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Abrahams-Salaam, Fatima. "A molecular investigation of a mixed ancestry family displaying dementia and movement disorders." Thesis, Stellenbosch : Stellenbosch University, 2008. http://hdl.handle.net/10019.1/2432.
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Thesis (MScMedSc (Biomedical Sciences. Molecular Biology and Human Genetics))--Stellenbosch University, 2008.A South African family of Mixed Ancestry presented with a rapidly progressive dementia and a movement disorder which affected a number of individuals across three generations. The initial symptoms included personality changes and tremors that escalated to severe dementia and eventually a completely bedridden state. It was determined that the mean age at onset was in the third decade of life and affected individuals died within 10-15 years after the onset of symptoms. The aim of the present study was to elucidate the genetic cause of the disorder in this family and to further investigate the patho-biology of the disease. Mutations that could possibly cause the observed phenotype in this family were screened for. These included loci implicated in Huntington’s disease, Parkinson’s disease, Dentatorubral-Pallidoluysian Atrophy, Spinocerebellar ataxias (types 1, 2, 3, 6, and 7), Huntington’s disease-like 2 (HDL2) and several mitochondrial disorders. Single-strand Conformation Polymorphism (SSCP) analysis and direct sequencing were used to detect possible mutations while genotyping on an ABI genetic analyser was used to detect disorders caused by repeat expansions. Haplogroup and Short Tandem Repeats (STRs) analyses of the Y-chromosome and mitochondrial DNA of one affected family member was used to determine the family’s genetic ancestry. Reverse transcriptase polymerase chain reaction (RT- PCR) and complementary DNA (cDNA) analyses of the Junctophlin-3 (JPH3) gene was performed to provide information on the expression profile of this gene. After the exclusion of several genetic loci it was shown that this family had HDL2. This is a rare disease caused by a CAG/CTG repeat expansion in an alternatively spliced version of the JPH3 gene. HDL2 occurs almost exclusively in individuals of Black African ancestry. The genetic ancestry data suggested that the family member was most likely of South African Mixed Ancestry making this the first reported family of South African Mixed Ancestry with HDL2. A pilot study investigated the repeat distribution amongst three South African sub-populations in order to determine whether there was a bias in the repeat distribution that possibly predisposes Black Africans to develop the disease. The results showed a statistically significant difference (P= 0.0014) in the distribution of the repeats between the Black African and Caucasian cohorts. However, no conclusions could be drawn as to whether Black Africans harboured larger repeats that predisposes them to developing HDL2. The expanded repeat is located in an alternatively spliced version of the JPH3 mRNA. Interestingly, this repeat is not present in the mouse homologue of the gene although the rest of the genomic sequence is highly conserved across the human, mouse and chimpanzee genomes. Using foetal brain cDNA and PCR primers designed to be specific for different JPH3 isoforms, independent confirmation of the presence of two JPH3 mRNA transcripts (the full length and a shorter alternatively spliced version) was provided. In the absence of brain tissue from an HDL2-affected individual, it was investigated whether both JPH3 mRNA transcripts could be detected in lymphocytes. Using RNA isolated from the transformed lymphocytes of two HDL2-affected family members, real-time PCR was attempted. These experiments produced inconclusive results and required further optimisation. Further RT-PCR experiments for JHP3 expression in different tissues (brain and other) obtained from HDL2-affected individuals would be of interest. The present study identified the first Mixed Ancestry family with HDL2. This family will now be able to request genetic counselling and pre-symptomatic testing for all at-risk family members. Aspects of this study provided independent confirmation of characteristics of the mutated gene. More research on HDL2 will be crucial in understanding the pathogenesis of this disease.
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Villar, Menéndez Izaskun. "Regulación epigenética de la expresión estriatal del receptor de adenosina A(2A) en enfermedades neurológicas con trastorno motor asociado." Doctoral thesis, Universitat de Barcelona, 2014. http://hdl.handle.net/10803/145900.
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La adenosina es un metabolito presente en todo el organismo con distintas funciones fisiológicas. En el sistema nervioso central, desempeña un importante papel como neuromodulador a través de la interacción con sus receptores de membrana: los receptores de adenosina A(1), A(2A), A(2B) y A(3), siendo los más abundantes en el cerebro el A(1 )y el A(2A).
El receptor de adenosina A(2A) (A(2A)R) presenta una elevada expresión en el estriado, especialmente en las neuronas GABAérgicas medianas espinosas que conforman la vía indirecta de los ganglios basales. La actividad de esta vía está relacionada con la inhibición motora. La actividad del A(2A)R puede modular de hecho la actividad motora. Es bien conocido cómo, tanto en modelos animales como en humanos, los antagonistas del receptor, como la cafeína, estimulan el movimiento, mientras que sus agonistas tienen actividad sedante.
Las tres enfermedades abordadas en este trabajo han sido previamente relacionadas con alteraciones del sistema adenosinérgico. En la enfermedad de Parkinson, coincidiendo con una sintomatología hipocinética, se ha descrito una sobreexpresión patológica del A(2A)R en el estriado. La reducción de los niveles del receptor ha sido descrita en la misma región cerebral en el contexto de la enfermedad de Huntington, en la que se da una sintomatología hipercinética. La esquizofrenia, a su vez, ha sido relacionada con una disfunción de los ganglios basales y un déficit en la señalización adenosinérgica.
La línea de investigación en la que se enmarca este trabajo había determinado previamente cómo la expresión tejido específica del A(2A)R en el cerebro está controlada por la metilación de la región 5'UTR de su gen, ADORA2A. A lo largo de la presente tesis se ha investigado si éste u otros mecanismos epigenéticos están implicados en la aparición de niveles anómalos del receptor en las enfermedades de Parkinson y Huntington. Además, se han explorado los niveles de expresión del receptor en el estriado en personas con esquizofrenia. Para todo ello se ha trabajado fundamentalmente con muestras de putamen postmortem, una de las regiones del estriado que ha sido vinculada más estrechamente con el control motor.
Este trabajo ha permitido confirmar que la sobreexpresión patológica del A2A en el estriado en la enfermedad de Parkinson se produce ya en los primeros estadios de la enfermedad (estadios de Braak 1 a 3), coincidiendo con una bajada de los niveles del microARN hsa-miR-34b. El descenso en los niveles de este microARN había sido previamente descrito en cerebros postmortem de personas con Parkinson pero en otras regiones cerebrales, relacionándolo con estrés mitocondrial. En este trabajo se ha validado el A(2A)R como diana para este microARN mediante ensayos funcionales in vitro, por lo que se propone que el descenso del hsa-miR-34b promueve un aumento de los niveles del A(2A)R en el putamen desde las primeras etapas de la progresión patológica.
En cuanto a los resultados en la enfermedad de Huntington, se ha mostrado cómo la reducción de la expresión del A(2A)R en el estriado humano coincide con un incremento en los niveles de metilación y una reducción en los niveles de hidroximetilación de la región 5'UTR del ADORA2A.
El estudio llevado a cabo en la esquizofrenia ha revelado un importante descenso de la expresión del A(2A)R en la mitad de los casos patológicos analizados, coincidiendo con hipermetilación de la región 5'UTR del ADORA2A. Estos casos presentan además una sintomatología motora particular, lo que ha permitido proponer la existencia de un subgrupo de pacientes en esta enfermedad.
Esto resultados ofrecen soporte a ciertas estrategias terapéuticas propuestas para estas enfermedades y basadas en la modulación de la actividad o de la expresión del A(2A)R. Indican además un uso potencial para la medida de los niveles del A(2A)R en los pacientes con trastorno motor. Esta información permitiría una mayor personalización de los tratamientos y una mejora en la interpretación de las respuestas individuales a los fármacos.Adenosine is a metabolite distributed throughout the entire organism with multiple physiological functions. In the central nervous system it plays a main role as neuromodulator, interacting with specific membrane receptors: A(1), A(2A), A(2B) and A(3). The most brain-enriched are A1 and A2A. Adenosine receptor A(2A) (A(2A)R) is highly expressed in the striatum, specially in the GABAergic medium-sized spiny neurons that form the indirect pathway of the basal ganglia, whose activity has been related with motor inhibition. There is evidence for A(2A)R activity involvement in motor behavior: A(2A)R antagonists, as caffeine, stimulate locomotion, while A(2A)R agonists are sedative. The three diseases studied in this work have previously been related to adenosinergic system dysfunction. In Parkinson's disease, characterized by hypokinesia, a pathological overexpression of striatal A(2A)R has been described. In Huntington's disease, characterized by hyperkinesia, striatal A(2A)R expression is reduced. Schizophrenia has been related to basal ganglia dysfunction and reduced adenosinergic signaling. In previous studies, the group described how DNA methylation regulates ADORA2A (A(2A)R gen) basal expression in different cell lines as well as its tissue-specific expression in brain. In the present thesis, it was studied whether this or other epigenetic mechanisms were involved in A(2A)R pathological expression levels detected in Parkinson or Huntington diseases. Besides, A(2A)R levels were analyzed in striatum of schizophrenia patients. The work has been performed mainly using human postmortem putamen samples, a striatal region strongly related to motor control. Overall, the obtained results (i) reinforce the relation between A(2A)R striatal expression and motor control, (ii) demonstrate involvement of epigenetic mechanisms in pathological A(2A)R expression in different neuropathological contexts and (iii) support therapeutic strategies previously proposed based on the modulation of A(2A)R expression, and indicate potential usefulness of A(2A)R levels measure in patients with motor alterations, considering that this information would allow a better personalization of treatments and a better understanding of individual reactions to drugs.
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Ylönen, S. (Susanna). "Genetic risk factors for movement disorders in Finland." Doctoral thesis, Oulun yliopisto, 2019. http://urn.fi/urn:isbn:9789526223988.
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Abstract Parkinson’s disease and Huntington’s disease are progressive neurodegenerative movement disorders that typically manifest in adulthood. In this study, genetic risk factors contributing to these two movement disorders were investigated in Finnish patients. Patients with early-onset or late-onset Parkinson’s disease as well as population controls were examined. The p.L444P mutation in GBA was found to contribute to the risk of Parkinson’s disease. POLG1 compound heterozygous mutations were detected in two patients with Parkinson’s disease and rare length variants in POLG1 were associated with Parkinson’s disease. Variants in SMPD1, LRRK2 or CHCHD10, previously detected in other populations, were not detected, suggesting that they are rare or even absent in the Finnish population. Patients with Huntington’s disease were investigated for HTT gene haplotypes as well as whether these haplotypes alter the stability of the elongated CAG repeat. Haplogroup A was less common in Finns than in other European populations, whereas it was significantly more common in patients with Huntington’s disease than in the general population. Certain HTT haplotypes as well as the parental gender were found to affect the repeat instability. We found that compound heterozygous mutations in POLG1 were causative of Parkinson’s disease, rare length variants in POLG1 were associated with Parkinson’s disease and GBA p.L444P was significantly more frequent in patients than in the controls, which suggests that these mutations are associated with the development of Parkinson’s disease. The low prevalence of Huntington’s disease in Finland correlates with the low frequency of the disease-associated HTT haplogroup A. Paternal inheritance combined with haplotype A1 increased the risk of repeat expansion. Movement disorders in Finland were found to share some of the same genetic risk factors found in other European populations, but some other recognized genetic variants could not be detectedTiivistelmä Parkinsonin tauti ja Huntingtonin tauti ovat hermostoa rappeuttavia eteneviä liikehäiriösairauksia, jotka tyypillisesti ilmenevät aikuisiällä. Tässä tutkimuksessa selvitettiin näiden kahden liikehäiriösairauden geneettisiä riskitekijöitä suomalaisilla potilailla. Tutkimme potilaita, joilla oli varhain alkava Parkinsonin tauti tai myöhään alkava Parkinsonin tauti sekä väestökontrolleja. GBA-geenin p.L444P mutaation havaittiin lisäävän Parkinsonin taudin riskiä. Kaksi Parkinsonin tautia sairastavaa potilasta oli yhdistelmäheterotsygootteja haitallisten POLG1-geenin varianttien suhteen ja harvinaiset POLG1 CAG toistojaksovariantit assosioituivat Parkinsonin tautiin. Tutkittuja variantteja SMPD1-, LRRK2- ja CHCHD10-geeneissä ei löydetty tästä aineistosta lainkaan, mikä viittaa siihen, että ne puuttuvat suomalaisesta väestöstä tai ovat harvinaisia. Huntingtonin tautia sairastavilta potilailta tutkittiin HTT-geenin haploryhmiä ja niiden vaikutusta Huntingtonin tautia aiheuttavan pidentyneen toistojakson epästabiiliuteen. Haploryhmä A oli suomalaisessa väestössä harvinainen verrattuna eurooppalaiseen väestöön ja se oli huomattavasti yleisempi Huntingtonin tautipotilailla kuin väestössä. Toistojakson epästabiiliuteen vaikuttivat tietyt HTT-geenin haplotyypit samoin kuin sen vanhemman sukupuoli, jolta pidentynyt toistojakso periytyy. POLG1 yhdistelmäheterotsygoottien katsottiin aiheuttavat Parkinsonin tautia ja harvinaisten POLG1 CAG toistojaksovarianttien todettiin assosioituvan Parkinsonin tautiin Suomessa. GBA p.L444P mutaatio merkittävästi yleisempi Parkinsonin tautipotilailla kuin kontrolleilla, mikä viittaa siihen, että se on Parkinsonin taudin riskitekijä. Huntingtonin tautiin assosioituvan haploryhmä A:n matala frekvenssi selittää taudin vähäistä esiintyvyyttä Suomessa. Paternaalinen periytyminen ja haplotyyppi A1 lisäsivät HTT-geenin toistojakson pidentymisen riskiä. Liikehäiriösairauksilla todettiin Suomessa osittain samanlaisia riskitekijöitä kuin muualla Euroopassa, mutta kaikkia tutkittuja variantteja emme havainneet
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Bernard, Branka. "Huntington's disease." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2009. http://dx.doi.org/10.18452/15900.
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Die Huntington''sche Krankheit (Huntington''s disease, HD) ist eine tödliche neurodegenerative Erkrankung mit einem extensiven Verlust von Neuronen im Striatum. Die Ursache für HD ist eine genetische Mutation, bei der eine CAG-Wiederholungssequenz verlängert wird. Im resultierenden Protein, das Huntingtin (htt) genannt wurde, diese Mutation führt zur Missfaltung und Aggregation von htt. Ich habe untersucht ob die Bildung von htt-Aggregaten die Transkription von Genen dass sie von HD-assoziierten Transkriptionsfaktoren kontrolliert werden, verändert. Zur Untersuchung der Transkription wurden die zu untersuchenden Gene auf cDNA-Mikroarrays aufgebracht und mit RNA, welche aus den Zellen nach der Induktion der Expression des mutierten htt gewonnen wurde, hybridisiert. Es wurden keine systematischen Veränderungen innerhalb der durch spezifische Transkriptionsfaktoren regulierten Gengruppen gefunden. Ich habe auch mehrere mathematische Modelle erstellt, welche die htt-Aggregation und den Zelltod beschreiben. Die Ergebnisse zeigten, dass eine transiente Dynamik im System und die nicht-monotone Reaktion auf Parameteränderungen zu den nicht-intuitiven Ergebnissen bei Behandlungsansätzen, welche die htt-Aggregation beeinflussen, führen könnten. Für den Fall, dass Aggregate die toxische Form von htt sind, zeigten die numerischen Simulationen dass das Einsetzen der Aggregation, welches durch ein Überschießen der Aggregatkonzentration gekennzeichnet ist, am ehesten zum Zelltod führt. Dieses Phänomen wurde "one-shot"-Modell genannt. Es gibt, auch bei HD-Patienten mit gleicher Länge der CAG-Wiederholungssequenz, eine große Varianz des Alters bei Krankheitsausbruch (age of onset, AO). Ich habe ein stochastisches Modell für den neuronalen Zelltod im Striatum entwickelt. Das Modell zeigte, dass ein signifikanter Anteil der nicht erklärbaren Varianz des AO der intrinsischen Dynamik der Neurodegeneration zugeschrieben werden kann.Huntington''s disease (HD) is a fatal neurodegenerative disorder characterized by a progressive neuronal loss in the striatum of HD patients. HD is caused by a CAG repeat expansion which translates into a polyglutamine stretch at the N-terminus of the huntingtin protein (htt). The polyQ stretch induces misfolding, cleavage and aggregation of htt. To test the hypothesis that the sequestration of transcription factors into the htt aggregates causes transcriptional changes observed in HD models, I compiled lists of genes controlled by the transcription factors associated with HD. These genes were spotted on cDNA microarrays that were later hybridized with RNA extracted from cells expressing a mutant htt fragment. In this study, no systematic changes related to a specific transcription factors were observed. Formation and the accumulation of htt aggregates causes neurotoxicity in different HD model systems. To investigate the consequences of therapeutic strategies targeting aggregation, I derived several mathematical models describing htt aggregation and cell death. The results showed that transient dynamics and the non-monotonic response of cell survival to a change of parameter might lead to the non-intuitive outcome of a treatment that targets htt aggregation. Also, the numerical simulations show that if aggregates are toxic, the onset of aggregation, marked by the overshoot in the concentration of aggregates, is the event most likely to kill the cell. This phenomenon was termed a one-shot model. The principal cause of the variability of the age at onset (AO) is the length of the CAG repeat. Still, there is a great variance in the AO even for the same CAG repeat length. To study the variability of the AO, I developed a stochastic model for clustered neuronal death in the HD striatum. The model showed that a significant part of the unexplained variance can be attributed to the intrinsic stochastic dynamics of neurodegeneration.
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Baird, Todd B. "Oculomotor Deficits in Diseases of the Basal Ganglia: Parkinson's and Huntington's Diseases." VCU Scholars Compass, 1992. http://scholarscompass.vcu.edu/etd/4344.
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Oculomotor deficits are now recognized as being present in several neurological diseases of the basal ganglia. The present report will focus primarily on those observed in Huntington's and Parkinson's diseases. Neuronal cell loss in the pars compacta of the substantia nigra, degeneration of the nigrostriatal pathway, and consequent depletion of the neurotransmitter dopamine is the most obvious etiological abnormality in Parkinson's disease. Huntington's disease, on the other hand, involves the selective genetically-driven atrophy of the striatum (caudate and putamen). In order to attempt to understand oculomotor dysfunction, as a component of basal ganglia disease, it is necessary to first establish a definition of the basal ganglia, its relevant connections, and their associated neurotransmitters and functions.
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Hurelbrink, Carrie Brienne. "Optimisation of neural transplantation for Parkinson's and Huntington's diseases." Thesis, University of Cambridge, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.431504.
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Archibald, Neil Kenneth. "Visual symptoms in Parkinson's disease and Parkinson's disease dementia." Thesis, University of Newcastle Upon Tyne, 2011. http://hdl.handle.net/10443/1177.
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Non-motor symptoms such as dementia and visual hallucinations are key determinants of long-term outcome and quality of life in Parkinson’s disease (PD). Attempting to understand these issues better was the motivation behind this thesis. A major aim of the study was to characterise the visual symptoms experienced by patients with PD and PD dementia, focussing not just on complex visual hallucinations, whose prognostic implications are already well-described, but also on a range of other visual symptoms including illusory misperceptions, sensations of passage and presence and double vision. A major objective was to define key measures of visual exploration strategy during visuocognitive assessment and examine the link between strategy, cognition and visual and motor symptoms. We also set out to examine the utility of retina-specific visual assessment techniques to define the potential role of retinal dysfunction in visual impairment and symptomatology. A major finding of this study was that not all visual symptoms share a common pathophysiological basis. Our results argue in favour of splitting hallucinations into separate phenomenological groups in order to better define causation and predictive value in future longitudinal studies. In addition, exploration strategy on a variety of visual tasks was demonstrated to be significantly less efficient in subjects with perceptual difficulties, providing insight into the interaction between cognition and eye movements in PD. Retinal structure, as assessed by optical coherence tomography, was not significantly altered in PD and our results would caution against the use of this technique as a disease biomarker until more is known about the limitations of this method. Finally, our neurophysiological assessment hints at the retina as the site of diminished visual acuity in PD despite there being no striking differences in central and peripheral retinal responses between control and PD subjects.
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Thompson, Jennifer Charlotte. "Automaticity in Huntington's disease." Thesis, University of Manchester, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.516828.
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Huntington's disease (HD) is an inherited neurodegenerative disorder. An intriguing observation in the HD literature is that simple psychomotor tasks with low rather than high demands on attention and executive function are the most sensitive markers oflongitudinal chance in HD, and most consistently distinguish pre-manifest carriers of the HD mutation from non-carriers. It has been suggested that this reflects in HD a breakdown in the ability to execute simple tasks automatically. This hypothesis was explored in a series of studies that examined the performance of HD patients and pre-manifest carriers of the HD mutation on a variety of psychomotor tasks using dual-task and procedural learning paradigms. On a simple 'dual-task' paradigm, in which patients were required to perform a simple paced finger-tapping task with one or both hands, patients with early HD showed increased tapping variability and reported greater subjective difficulty for the bimanual 'dual-task' condition compared with controls, suggesting that the simple finger-tapping action was not executed automatically but rather, placed greater demands on HD patients than controls. On a visually cued reaching task in which stimuli were ordered in a highly simple, repeating sequence, HD patients showed slow and minimal motor-skill improvement and, despite extensive practice, failed to reach the level of rapid, efficient performance associated with skill automisation. In a further study it was shown that a subset of patients, who had greater cognitive impairment, failed to acquire any knowledge of the repeating sequence. It was suggested that, in these patients, the performance of the reaching task itself was so demanding that patients lacked the attentional resources required to abstract the sequential pattern. Subtle indications of a breakdown in automaticity could also be detected in premanifest carriers of the HD mutation (P-HD). On a paced finger-tapping task, P-HD participants exhibited greater performance variability, the degree of which was correlated with estimated proximity to disease onset. In a subset ofP-HD participants who were estimated to be close-to-onset, variability was greater still and was disproportionately increased by the performance of a secondary cognitive task, indicating impaired ability to execute the tapping task without directed attention. Taken together, the studies suggest that a breakdown in automaticity is a fundamental feature of HD, reflecting progressive striatal degeneration. The findings have implications for the understanding of attentional impairment in HD. If simple tasks cannot be automated then they will necessarily place greater demands on attentional resources in HD.
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Krench, Megan Attardo. "Investigating toxicity in Drosophila models of Huntington's Disease and Huntington's Disease-Like 2." Thesis, Massachusetts Institute of Technology, 2016. http://hdl.handle.net/1721.1/103211.
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Thesis: Ph. D. in Neuroscience, Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, 2016.Cataloged from PDF version of thesis.
Includes bibliographical references (pages 247-264).
The polyglutamine diseases are the most common form of inherited neurodegenerative disorders. Each of the polyglutamine diseases stems from the same underlying cause: a CAG expansion mutation in the coding region of a gene. This gives rise to a protein with an expanded glutamine repeat stretch. Despite the fact that all polyglutamine diseases are caused by the same type of mutation, the CAG expansion in different genes gives rise to different diseases, with differentially vulnerable neuronal populations and distinct pathologies. One of the most well-known polyglutamine disorders is Huntington's disease (HD), which results from a CAG repeat expansion in the huntingtin (Htt) gene. HD is characterized by psychiatric symptoms, cognitive decline, and movement disturbances, especially chorea. Interestingly, some presumed HD patients exhibited HD-like symptoms and characteristic striatal degeneration, but did not harbor a mutation in Htt. This led to the discovery of the Huntington's disease-like (HDL) disorders. One such disorder is Huntington's disease-like 2 (HDL2). Recent studies identified a specific polyglutamine protein hypothesized to contribute to HDL2 pathology. Given the similarities between HD and HDL2 patients, I used Drosophila to model these two genetically distinct disorders to compare polyglutamine-induced toxicity. This work represents the first time HDL2 has been modeled in Drosophila, and the first characterization of HDL2 polyglutamine protein pathology. My investigation highlights many distinctions between expanded Htt and HDL2 polyglutamine proteins. Importantly, my research demonstrates that nuclear localization of the polyglutamine protein is critical to disease pathogenesis in HDL2, but not HD. I also present the results from an in vivo RNAi screen to search for novel suppressors of toxicity in our HD and HDL2 models. Analyzing top RNAi suppressors from both models indicates different pathogenic pathways are at play in these two polyglutamine diseases, but some mechanisms may be shared. We conclude that while HD and HDL2 have similar clinical profiles, distinct pathogenic mechanisms contribute to the two neurodegenerative disorders.
by Megan Krench.
Ph. D. in Neuroscience
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Runne, Heike. "Transcriptional dysregulation in Huntington's disease /." [S.l.] : [s.n.], 2008. http://library.epfl.ch/theses/?nr=4183.
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Coles, R. "The Huntington's disease gene promoter." Thesis, University of Cambridge, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.597843.
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Recent studies have demonstrated that affected regions of the striatum show increased HD immunoreactivity, suggesting that subtle differences in expression of the HD protein may be relevant to pathogenesis. Current information regarding control of HD gene expression is limited, and to date has been based entirely upon sequence analysis of the promoter region. The overall aim of this thesis, therefore, was to carry out a more detailed analysis of the HD gene promoter, in order to identify its key regulatory elements, and to attempt to determine the relationship between promoter activity and various aspects of HD pathogenesis. Single-stranded conformation polymorphism analysts, heteroduplex and sequencing analyses were used to demonstrate that the HD gene promoter is highly polymorphic. Seven allelic forms were identified. This region of the promoter was found to be highly conserved in non-human primates, which may reflect a common mechanism of gene regulation. Reporter gene assays were used to localise the key regulatory regions, whilst the ability of specific transcription factors to bind the putative sites was studied using the Electrophoretic Mobility Shift Assay. The critical positive-acting region of the HD gene promoter was shown to arise from the synergistic action of two sites in a tandem repeat, which each bind the transcription factor, Sp1. Differences in expression control have been found to exist between a neuronal and a non-neuronal cell line, and the regions of the promoter responsible for these effects have been localised. Both 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and forskolin were found to elicit a cell-type specific response in transcription from the HD gene promoter. The responses to TPA have been mapped in detail in the neuronal SK-N-SH cell line and in HeLa cells. Additional experiments, including a comparison of promoter activity in undifferentiated and differentiated neurons, and a study of the effects of excitotoxins upon activity, have addressed questions regarding temporal patterns and modulations of expression from the HD gene promoter.
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Pearson, Sally Jane. "The neurochemistry of Huntington's disease." Thesis, University of Nottingham, 1992. http://eprints.nottingham.ac.uk/28467/.
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This thesis describes the study of the neurochemistry of Huntington's disease using a large series of post mortem brain tissue taken from patients with Huntington's disease and from matching controls with no previous history of neuropsychiatric disorder. There were two main aims: firstly, to identify and characterise any altered parameters of neurotransmitter systems, especially in relation to the symptomatology of the disease; secondly, to understand the role of neurotoxins in the aetiology of the disease, particularly endogenous compounds that may have derived from aberrant metabolism. Concentrations of the amino acid transmitters, GABA and glutamate, were generally significantly decreased throughout the brain in Huntington's disease, including cortical and limbic regions. Cortical deficits were not associated with the dementia of the disease, whereas caudate levels of GABA and glutamate showed a relationship with the dementia. In patients with severe chorea, the medial pallidum was found to have a relatively smaller GABA deficit than mildly choreic patients. Another novel finding was that 5HT and 5HIAA concentrations were significantly increased in most regions of the brain in Huntington's disease, perhaps reflecting abnormal tryptophan metabolism. Such changes in the cortex provide evidence for a cortical involvement in the disease. Dopamine metabolism appeared to be reduced in Huntington's disease, reflected by the significantly decreased concentrations of its major metabolite, homovanillic acid, in most regions except for the cortex (where it was increased). Neuroactive compounds of the kynurenine pathway of tryptophan metabolism were measured in Huntington's disease. Quinolinic acid concentrations were not significantly altered, however 3- hydroxykynurenine concentrations were significantly increased in the striatum and cortex. This provides the first evidence for increased concentrations of an endogenous neurotoxic compound in the brain in Huntington's disease.
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Mantell, Andrew Roy. "Huntington's Disease : the carer's story." Thesis, University of Sussex, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.426281.
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Simpson, Sheila. "Huntington's disease in Grampian region." Thesis, University of Aberdeen, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.305088.
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A description of the application of recombinant DNA technology to Huntington's disease is given, and the research for the gene described. The presymptomatic predictive test programme in Grampian region is presented, and a proposal made for the management of high risk individuals. The prevalence study of Grampian region is described; this shows the region to have a very high prevalence of the disease, and the possible reasons for this are explored.
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Freese, Andrew. "Excitotoxic mechanisms in Huntington's disease." Thesis, Massachusetts Institute of Technology, 1991. http://hdl.handle.net/1721.1/17295.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Whitaker College of Health Sciences and Technology, 1992.Includes bibliographical references (leaves 191-250).
by Andrew Freese.
Ph.D.
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Blackmore, Louise. "Cognitive deficits in Huntington's disease." Thesis, University of Aberdeen, 1993. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU059308.
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This thesis presents and discusses the pattern of neuropsychological deficits in subjects affected by Huntington's Disease. Dysfunction is assessed in the area of general intelligence, as measured by the WAIS-R, in mnestic tasks, in visuospatial and motoric tasks and in skills associated with frontal lobe pathology. Affected subjects are compared with controls, individually matched for age, sex and years of education. Cognitive deficits in the at-risk population are also discussed and a comparison made between at-risk gene carriers and their non affected siblings. Findings from the WAIS-R demonstrated severe intellectual impairment, with affected subjects achieving significantly lower scores than their individually matched controls on all three IQ measures. The assessment of premorbid intelligence demonstrated that NART performance in Huntington's Disease declines. It is suggested that demographic variables may provide a more suitable method for predicting premorbid ability in this subject group. Investigation of mnestic skills in affected subjects indicated impairment on a wide range of tasks, including those assessing memory for verbal, numerical, spatial and pictorial information. The thesis also considers implicit memory systems in Huntington's Disease and a dissociation is noted, with intact implicit memory for verbal material and impairment of skill learning. The presence of cognitive deficits resembling those seen in frontal lobe damaged patients is also apparent. Affected subjects demonstrate severe impairment on the Modified Wisconsin Card Sorting Test, assessment of Verbal Fluency and the Cognitive Estimation Task, all tasks which rely on Supervisory Attentional System integrity. Visuospatial and motor functioning are shown to be severely compromised in Huntington's Disease and high correlations between tests of voluntary movement and assessment of cognitive ability are presented. The Comparison of at-risk gene carriers and non gene carriers indicated that although overall at-risk gene carriers performed more poorly than non gene carriers no one cognitive test significantly reflected this difference.
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Michell, Andrew William. "Parkinson's disease : α-synuclein and disease markers." Thesis, University of Cambridge, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.613821.
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Ng, Khuen Yen Prince of Wales Medical Research Institute Faculty of Medicine UNSW. "Isoprenoids in Parkinson's disease." Awarded by:University of New South Wales. Prince of Wales Medical Research Institute, 2009. http://handle.unsw.edu.au/1959.4/44827.
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Parkinson???s disease (PD) is a progressive neurodegenerative disease characterised pathologically by the selective death of the dopaminergic neurons of the substantia nigra and the appearance of abnormal inclusions in some surviving neurons. A body of evidence from epidemiological, in vitro and in vivo studies suggest that isoprenoids, a lipid family which includes cholesterol, dolichol and ubiquinone, may play a role in PD, although to date the data has been conflicting with little consensus regarding the type or direction of change in isoprenoids in PD. The current study investigated isoprenoids in PD by quantifying a range of isoprenoids in blood sera, brain homogenates and olfactory mucosa derived from PD patients and controls. Further, isoprenoid synthesis pathways were investigated by comparing the activitites and amount of the rate-limiting enzyme for isoprenoid synthesis, HMG CoA reductase, in olfactory mucosal cultures from individuals with sporadic PD and leucine-rich repeat kinase 2 (LRRK2)-PD with those from healthy individuals. Serum levels of total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides and dolichol were unchanged in patients with PD compared with controls. Similarly, total tissue cholesterol was unchanged in degenerating and non-degenerating regions of the PD brain, but tissue dolichol was significantly decreased in the substantia nigra in the PD brain, possibly reflecting a change in the neuron/glia ratio in this brain region. In olfactory mucosa, a significant decrease in cellular cholesterol content was identified in patients with LRRK2-PD compared with patients with sporadic PD or controls. The reduction in cholesterol was similar in two different LRRK2 mutations but was not associated with a change in either the amount or activity of HMG CoA reductase. This study suggests that decreased cholesterol is associated with LRRK2-PD but not with sporadic PD. As cholesterol levels in cells with different LRRK2 mutations were reduced to a similar extent, it is suggested that mutations in this gene result in a loss-of-function of LRRK2 protein. Further it suggests a role for LRRK2 in cholesterol homeostasis independent of HMG-CoA reductase-associated pathways. Recent data has suggested a functional role of LRRK2 in autophagy, a mechanism which may explain the reduction in cholesterol observed in LRRK2-PD.
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Silveira, Moriyama L. "Olfaction in Parkinson's Disease." Thesis, University College London (University of London), 2009. http://discovery.ucl.ac.uk/18728/.
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This thesis examines the clinical and pathological involvement of the olfactory system in Parkinson’s Disease (PD). The main aim is to investigate the practical use of smell identification tests (SITs) in parkinsonism and tremor. A secondary objective is to investigate the pathological involvement of the rhinencephalon. Commercially available SITs were used to differentiate PD patients from control subjects in the UK, Brazil and Sri Lanka, showing SITs have combinations of sensitivity and specificity greater than 80%. Based on the data obtained a traffic light ruler was devised to determine the likelihood of a patient having PD at the time of the initial consultation. This was then used to interpret SITs in 34 patients with possible parkinsonism, showing 86.4% sensitivity and 80.0% specificity of SITs when compared to dopamine transporter imaging using single photon emission computed tomography (SPECT) as the gold-standard for detecting nigrostriatal dopamine denervation. Olfaction was shown to be severely impaired in parkinsonism related to LRRK2 mutations, moderately impaired in subjects with pure autonomic failure, multiple system atrophy and progressive supranuclear palsy (PSP) and normal in patients with essential tremor, dystonia and in subjects who had been diagnosed as having PD, but were found to have normal scans. This indicates that SITs will be more useful in differentiating PD from non-degenerative tremors than from atypical parkinsonism. Neuropathological changes were investigated in the rhinencephalon and it was demonstrated that α-synuclein accumulation in the primary olfactory cortex is heterogeneous, being more severe in the temporal subdivision of the piriform cortex. The piriform cortex had Lewy body pathology in all 10 PD cases studied, as well as in 7 control cases who presented incidental Lewy body pathology and four cases of LRRK2 related parkinsonism. The piriform cortex had abnormal tau accumulation in 6 PSP patients, suggesting tauopathy in the rhinencephalon is a possible substrate for hyposmia in PSP.
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Marinus, Johan. "Clinimetrics in Parkinson's disease /." Leiden : Marinus, 2003. http://catalogue.bnf.fr/ark:/12148/cb402330919.
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Kass-Iliyya, Lewis. "Pain in Parkinson's disease." Thesis, University of Manchester, 2017. https://www.research.manchester.ac.uk/portal/en/theses/pain-in-parkinsons-disease(2c746ce7-5ff0-4852-9a55-851ef0f5543c).html.
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Background: Pain is a very common symptom in Parkinson’s disease (PD). The underlying mechanism of pain in PD is poorly understood. Compared to PD, the characteristics of pain in other parkinsonian disorders such as Multiple System Atrophy (MSA) and Progressive Supranuclear Palsy (PSP) have not been studied. Musculoskeletal factors have been implicated in the generation of pain in PD. However, studies in PD have shown impaired central processing of nociceptive inputs. Recently, small fibre neuropathy has also been found to be common in PD with significantly reduced C-fibres density compared to controls. A subclass of C-fibres known as C tactile afferents (CT) mediate the pleasant sensation associated with gentle skin stroking (affective touch). CT afferents have recently been shown to have pain-inhibiting properties. These findings may implicate central sensitisation in pain generation in PD. Objectives: 1) To better understand the mechanisms of pain in PD and study the characteristics of pain in MSA and PSP compared to PD. 2) To quantify small fibre neuropathy in PD and explore its relation to pain utilising a novel diagnostic technique: corneal confocal microscopy (CCM). 3) To assess the perception of affective touch in PD and its relationship to pain. Methods: Four studies were conducted: Study 1: A cross sectional study of pain characteristics in PD, MSA and PSP. Study 2: A descriptive study of pain characteristics in a large cohort of early PD (disease duration < 3 years, n=1763). Study 3: A cross sectional study to quantify small fibre density in PD (n=26) compared to control subjects (n=26) using CCM and skin biopsies. Nerve density was correlated with non-motor symptoms in PD including pain. Study 4: A study to assess the CT-mediated perception of affective touch in PD and correlate it with clinical symptoms such as pain. Results: Study 1: Pain prevalence and intensity was significantly higher in MSA and PD compared to PSP, p < 0.05. Female sex and motor fluctuations but not motor severity were predictors for pain intensity in PD. Study 2: Pain was common in early PD (84.2%). Only a minority of PD patients (19.7%) reported that their pain improved with Levodopa therapy of their motor symptoms. Study 3: PD patients had significantly reduced small fiber nerve density on both CCM and skin biopsies compared to controls. Denervation correlated with autonomic symptoms but not with pain intensity. Study 4: Perception of pleasantness followed a linear relationship with nerve density and was abnormally enhanced in PD compared to control and correlated with pain at a very slow stroking velocity. Conclusions: Pain is common in early PD, does not respond to levodopa treatment and correlates with motor complications but not motor severity favouring central sensitisation. Pain is significantly less common in PSP compared to PD and MSA. Small fibre neuropathy does not appear to be an important cause of pain in PD but small fibre nerve density correlates with affective touch perception, which is enhanced in PD despite peripheral denervation. Corneal confocal microscopy identifies corneal denervation in PD offering a novel non-invasive way of assessing PD pathology.
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Wang, Juelu. "Selective neurodegeneration in Alzheimer's disease and Parkinson's disease." Thesis, University of British Columbia, 2017. http://hdl.handle.net/2429/63267.
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Alzheimer’s disease (AD) and Parkinson’s disease (PD) are featured by cholinergic and dopaminergic neuron loss, respectively. As a unique pathological hallmark of AD, neuritic plaques contain aggregated amyloid β protein (Aβ), generated from amyloid β precursor protein (APP). APP mutations cause familial AD; mutations in the alpha-synuclein (SNCA) and leucine-rich repeat kinase 2 (LRRK2) genes are associated with PD.
Recent studies suggest that the level of LRRK2 affects its toxicity in neurons. Therefore, understanding the mechanisms underlying LRRK2 expression would help to examine its pathogenic effects on PD. However, the features of the LRRK2 promoter remain elusive. In the first project, we cloned and characterized the LRRK2 promoter. There were two functional cis-acting specificity protein 1(Sp1)-responsive elements in its promoter. Our study demonstrates that LRRK2 transcription and translation were facilitated by Sp1 overexpression and blocked by an Sp1 inhibitor in vitro.
The Lewy bodies primarily consist of α-synuclein protein, encoded by SNCA, and SNCAA₅₃T mutation promotes α-synuclein aggregation. The Swedish APP mutation (APPSWE) promotes Aβ generation and AD pathogenesis. However, the mechanisms underlying selective neurodegeneration in AD and PD are still unknown. In the second project, we stably overexpressed wildtype and mutated APP and SNCA genes in cholinergic SN56 and dopaminergic MN9D cells. APPSWE and SNCAA₅₃T mutations enhanced Aβ generation and α-synuclein inclusion formation in SN56 and MN9D cells, respectively. Aβ₄₂ and mutant α-synuclein oligomers caused severe cell death in SN56-APPSWE and MN9D-SNCAA53T cells, respectively. Furthermore, syndecan 3 (SDC3) and fibroblast growth factor receptor like 1 (FGFRL1) genes were identified as two of the differentially expressed genes in APP- and SNCA- related stable cells by microarrays. SDC3 was increased in the cholinergic nucleus of APPSWE knock-in mouse brains, whereas FGFRL1 was elevated in dopaminergic neurons in SNCAA₅₃T transgenic mice. Finally, knockdown of SDC3 and FGFRL1 attenuated oxidative stress-induced cell death in SN56-APPSWE and MN9D-SNCAA₅₃T cells. Overall, these demonstrate that SDC3 and FGFRL1 mediated the specific effects of APPSWE and SNCAA₅₃T on cholinergic and dopaminergic neurodegeneration in AD and PD, respectively. Our study suggests that SDC3 and FGFRL1 could be potential targets to alleviate the selective neurodegeneration in AD and PD.Medicine, Faculty of
Graduate
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McGlynn, Susan Mary 1960. "Unawareness of deficits in Huntington's disease." Thesis, The University of Arizona, 1989. http://hdl.handle.net/10150/277038.
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Several new techniques were developed to assess quantitatively the degree to which patients with Huntington's disease (HD) are aware of their deficits, to evaluate the relation between cognitive impairment and unawareness of deficits, and to determine whether patients exhibit differential awareness of their motor disturbance and cognitive deficits. Results of a questionnaire measure indicated that HD patients rated their own difficulties with motor and cognitive activities of daily life significantly lower than relatives rated patients' problems, and this discrepancy was related to patients' level of cognitive impairment. In contrast, patients were reasonably accurate when predicting their performance on specific motor and cognitive tasks when compared to both their actual performance and relatives' predictions. Several interpretations of these findings are discussed, and the role of frontal lobe dysfunction in the awareness problems characterizing dementia is considered.
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Gong, B. "Inclusion formation in Huntington's disease models." Thesis, University of Cambridge, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.599486.
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Huntington's disease (HD) is a progressive genetic neurodegenerative disease caused by the expansion of the CAG repeat in the HD gene and by the expression of pathological polyglutamine tracts in the huntingtin protein. Abnormal aggregates of protein (known as neuronal intranuclear inclusions) are found in the brains of HD patients and mouse models of HD. However, the role of inclusions in HD is controversial. To understand better the role of inclusions in HD, aggregate formation was studied using two well-established transgenic models of HD: an in vitro PCI 2 cell model carrying inducible transgenes with normal or pathological length CAG repeats and a transgenic mouse model, the R6/2 line. For the first time, time-lapse microscopy of inducible transgenic HD cells made it possible to visualise a disease-associated process in living cells. The experiments described in Chapter 3 showed that HD aggregate formation was dynamic, complicated and inversely related to cell death. Further investigations with these cells in Chapters 4-7 showed that some mechanisms underlying HD aggregate formation include proteasome dysfunction, calcineurin inhibition and cell differentiation. HD aggregate formation was also studied in R6/2 mouse brain. The experiments described in Chapter 8 showed that in vivo aggregate formation was dynamic and strikingly similar to that seen in vitro. Huntingtin aggregation was an early and ordered event that could occur as early as two weeks after birth, considerably earlier than that reported previously and well before any observable R6/2 phenotype. Huntingtin aggregation preceded ubiquitin labelling in vitro and in vivo, suggesting that the timing of ubiquitin labelling may be a determinant in the onset of HD pathology. Together, the work presented here suggests that aggregating huntingtin may not be immediately recognised by HD cells as 'toxic'. Thus, these studies support the idea that aggregate formation may have bimodal effects in HD, by being protective and toxic at different stages of aggregate development.
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Goodman, A. O. G. "Non-classical symptoms in Huntington's disease." Thesis, University of Cambridge, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.599513.
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This Ph.D. aimed to investigate some of the non-classical features in HD, focusing in detail on weight loss and metabolism by means of whole body indirect calorimetry in both early stage human patients, as well as in the R6/2 transgenic mouse model of HD. In addition, circadian rhythms and sleep disturbances were investigated in the same patient cohort using actigraphy and polysomnography. Pilot studies on zerostomia, cholesterol levels, olfaction, gestation and orthostatic hypotension were also briefly examined in order to identify further, possible non-classical symptoms. I found that patients had a trend towards elevated total energy expenditure, a finding which was significant in 14 week old R6/2 mice. I also found that patients had an overall loss of form and definition in their rest-activity actograms, suggesting a disturbed circadian rhythm. Sleep cycles were poorly consolidated, fragmented and irregular and the majority of patients had longer sleep latencies, reduced sleep efficiency, more time spent awake during the sleep period, frequent arousals and apnoeas, and reduced slow wave and rapid eye movement sleep. Pilot studies revealed that patients also have significant problems of xerostomia, olfaction and gestation. These investigations will help to define the extent and nature of non-classical abnormalities in this condition more thoroughly, thus providing a better profile of problems and deficits in HD. Future longitudinal studies involving pre-symptomatic patients will help to provide possible biomarkers for disease therapy and could ultimately contribute towards reducing morbidity and mortality in patients, as well as to provide insight into common degenerative pathways of other neurodegenerative diseases.
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Traeger, U. "Myeloid cell function in Huntington's disease." Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1390626/.
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Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene. The peripheral innate immune system contributes to HD pathogenesis and has been targeted successfully to modulate disease progression, but mechanistic understanding relating this to mutant (m)HTT expression in immune cells has been lacking. This thesis demonstrates that human HD myeloid cells produce excessive inflammatory cytokines due to cell-intrinsic effects of mHTT expression on the NFkB pathway, whereby mHTT interacts with IKK, leading to increased degradation of IkB and subsequent nuclear translocation of RelA. Transcriptional alterations in intracellular immune signaling pathways were also observed. Using a novel method of siRNA delivery to lower HTT expression, this thesis shows a reversal of disease-associated alterations in cellular function - the first time this has been demonstrated in human cells. Glucan-encapsulated siRNA particles (GeRPs) were used to lower HTT levels in human HD monocytes/macrophages, resulting in reversal of HTT-induced elevated cytokine production and transcriptional changes. These findings improve our understanding of the role of innate immunity in neurodegeneration, introduce GeRPs as a tool for studying cellular pathogenesis ex vivo in human cells and raise the prospect of HTT lowering in immune cells as a therapeutic in HD. Evaluating immune function in different mouse models of HD, blood and splenic monocytes replicated the hyper-reactive phenotype seen in HD patients demonstrating that HD mouse models can be of use to understanding HD immune pathology and to test immune modulatory therapies. Furthermore, human HD myeloid cells demonstrated a striking defect in migration towards different chemokines. Looking at the cell’s ability to form filopodia, it became apparent that actin-remodelling is reduced and causes decreased migration. Work performed in collaboration with Novartis revealed that mHTT levels in immune cell subsets differ significantly between disease stages. Monocyte and T cell mHTT levels were significantly associated with disease burden scores and caudate atrophy rates in HD patients. mHTT fragments detected in HD immune cells may explain the progressive increase in mHTT levels. These findings indicate that quantification of mHTT holds significant promise as a non-invasive disease biomarker.
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Turner, C. "The molecular pathogenesis of Huntington's disease." Thesis, University College London (University of London), 2009. http://discovery.ucl.ac.uk/19056/.
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Huntington’s Disease (HD) is caused by an expansion in the CAG repeats of the huntingtin gene. This thesis describes an Ecdysone cell model which expressed inducible wild type (WT) and mutant (MT) N-terminal huntingtin (htt) in HEK 293 cells and constitutive EYFP full length (FL) htt in SH-SY5Y cells. WT and MT EYFP FL htt was diffusely localised to the cytoplasm whereas endogenous FL htt and N-terminal htt localised to the nucleus and cytoplasm suggesting that htt has a role both in the nucleus and cytoplasm and EYFP inhibited nuclear translocation. Nterminal htt partially colocalised with vesicular and mitochondrial markers suggesting that N-terminal htt may be involved in vesicle trafficking and mitochondrial function. The decrease in mitochondrial complex IV activity in MT FL htt cells supported previous reports that a complex IV defect is an early event in the pathogenesis of HD. Normal mitochondrial respiratory chain activities in cells expressing N-terminal htt contrasted with some cells models demonstrating a complex II/III defect when highly expanded CAG repeats were expressed. This suggested that a detectable complex II/III defect is not an early feature in the pathogenesis of HD. Muscle biopsies from HD patients revealed a relationship between clinical progression, CAGs and a decrease in complex II/III:CS ratio, consistent with the defect in HD brains and cell models and suggested that muscle may be a useful tissue to study the disease. Decreased aconitase activity with MT FL htt expression and increased sensitivity to paraquat with MT N-terminal htt expression demonstrated that MT htt was associated with increased oxidative stress or compromised antioxidant defences. There was evidence of proteasomal dysfunction in the MT FL htt clones and inhibition of the proteosome by lactacystin caused the formation of perinuclear "aggresome-like" inclusions in both WT and MT FL htt clones. These inclusions contained FL htt which suggested that the proteasome was necessary for processing of FL WT and MT htt. Under normal conditions there was no evidence of cleavage of WT or MT FL htt, however following treatment with lactacystin, an additional 11 kDa N-terminal htt fragment was present in most MT FL htt clones representing a novel mutation-specific cleavage product which may play an important role in the toxicity of MT htt. This thesis has demonstrated several defects in cellular function in the absence of gross cell death and htt inclusion formation. These findings expand on previous hypotheses in the pathogenesis of HD involving abnormal MT htt cleavage, oxidative stress, mitochondrial dysfunction and proteasomal inhibition.
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Southwell, Amber L. Schuman Erin Margaret Patterson Paul H. "Intrabodies as therapeutics for Huntington's disease /." Diss., Pasadena, Calif. : California Institute of Technology, 2009. http://resolver.caltech.edu/CaltechETD:etd-06082009-164212.
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De, Souza Jennifer Charlotte. "The psychiatric phenotype in Huntington's disease." Thesis, University of Birmingham, 2015. http://etheses.bham.ac.uk//id/eprint/5875/.
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Psychiatric symptoms are more prevalent in Huntington's disease (HD) than the general population, but reasons for this are unknown. The primary aim of this research was to investigate possible familial influences on the psychiatric phenotype in HD. 96 gene positive and 5 gene negative siblings were recruited from 50 HD families throughout the UK and underwent a lifetime psychiatric history assessment using semi-structured interview and case-note review. Gene positive index individuals had high lifetime rates of depressive (56%) and anxiety (38%) disorders. Their depressive episodes were less severe and more frequent with an older age of onset and fewer biological symptoms than individuals with depression without HD. Within gene positive sibling-pairs (n=53), there was significant familial aggregation of the presence (ĸ=0.46, \(p\)=0.004) and course (ICC=0.47, \(p\)=0.002) of depressive disorders and the presence of irritability (ĸ=0.357, \(p\)=0.024) and aggression (ĸ=OJ84, \(p\)=O.Ol6). Two gene negative siblings had lifetime psychiatric diagnoses. The high prevalence of psychiatric co-morbidity in HD cannot be entirely explained by the HD gene. Familial factors, most likely other genetic factors, are likely to play a role. Further research into the contribution of biological and environmental factors to the psychiatric phenotype in large samples of individuals with HD is warranted.
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Lee, John Hung. "Altered mTOR signaling in Huntington's Disease." Diss., University of Iowa, 2015. https://ir.uiowa.edu/etd/5547.
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Huntington's Disease (HD) is caused by a polyglutamine tract expansion in huntingtin (HTT). Despite HTTs ubiquitous expression, there is selective vulnerability in a specific brain region known as the striatum, the cause of which is poorly understood. Here, we provide evidence that impaired striatal mTORC1 activity underlies varied metabolic and degenerative phenotypes in striatal tissues from HD mouse models and patients, and show that further mTORC1 impairment in mouse models, achieved through the knockdown of Rhes, a striatum-enriched mTORC1 activator, exacerbates disease phenotypes. In contrast, exogenous addition of Rhes or the constitutively active form of the mTORC1 regulator, Rheb, into HD mouse brain, alleviates mitochondrial dysfunction, aberrant cholesterol homeostasis, striatal atrophy, and elicits increased autophagy, and reverses impaired dopamine signaling. Furthermore, while HD has been considered primarily a neurological disease, organs with high metabolic demand, such as heart, are also severely affected. The mechanism by which mHTT disrupts cardiac function remains unknown. I provide evidence that mTORC1 is impaired in HD mouse model hearts, causing hyperactive FoxO1 signaling which may render HD hearts vulnerable to stress induced cardiomyopathy. In sum, my combined work indicates impaired mTORC1 signaling as a primary mechanism underlying the neurodegenerative and heart-related disease phenotypes in HD, and thus presents a rational therapeutic target.
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Lahiri, N. "Identification of markers of disease onset and progression in Huntington's Disease." Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1415654/.
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Huntington’s Disease is a progressive, adult onset, neurodegenerative disease. It is inherited in an autosomal dominant fashion and is caused by a trinucleotide repeat expansion in huntingtin, which encodes the protein huntingtin. The length of the expanded trinucleotide repeats accounts for some, but not all of the age of onset of the condition. Despite the monogenic basis of Huntington’s disease, the clinical features display marked variability within families and between those who carry the same length expansion. The variability in age of onset and in clinical features is likely to be due to a number of environmental and other genetic factors. Identification of these factors may lead to novel therapeutic approaches. A number of potential disease modifying agents have been elucidated and are approaching clinical trials. Robust ‘biomarkers’ of disease onset and progression are essential for developing a framework for future clinical trials that have the ability to judge the efficacy of any therapeutic intervention. In this thesis I will present work arising from TRACK-HD, an international observational biomarker study of Huntington’s Disease which has identified a panel of biomarkers for use in future clinical trials. A number of subs-studies arising from TRACK-HD are also presented here. Firstly, a study investigating the use of Positron Emission Tomography and peripheral immune markers as biomarkers of disease progression followed by a candidate genetic modifier study focusing on immune pathways as genetic modifiers of age of onset in Huntington’s Disease.
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Francelle, Laetitia. "A Study of Striatal Markers as Disease Modifiers in Huntington's Disease." Thesis, Paris 11, 2014. http://www.theses.fr/2014PA11T070/document.
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La maladie de Huntington (MH) est une affection neurodégénérative héréditaire dont la mutation conduit à une expansion anormale d’un segment polyglutamine dans la protéine Huntingtine (Htt). La Htt mutée, bien qu’ubiquitaire dans le cerveau, conduit à une neurodégénérescence préférentielle du striatum. Cette atteinte pourrait en partie s’expliquer par la présence de produits de gènes sélectivement exprimés dans le striatum. Le laboratoire étudie depuis plusieurs années l’implication potentielle de marqueurs moléculaires du striatum dans la vulnérabilité des neurones de cette structure cérébrale vis-à-vis de la Htt mutée. Durant ma thèse, j’ai étudié plus spécifiquement trois de ces marqueurs du striatum: l’ARN long intergénique non-codant Abhd11os et les protéines µ-crystalline (CRYM) et doublecortin-like kinase 3 (DCLK3). Une étude préliminaire avait montré l’effet neuroprotecteur de ces marqueurs du striatum contre la toxicité induite par un fragment court de la Htt mutée dans un modèle murin aigu de la MH. J’ai donc étudié plus en détails les caractéristiques de ces "modificateurs" de la MH, ainsi que les mécanismes moléculaires potentiels permettant d’expliquer leur effet neuroprotecteur dans un contexte de la MH. J’ai également mené une expérience de thérapie génique en surexprimant le marqueur striatal DCLK3 dans un modèle transgénique de la MH. Cette étude nous a permis de valider le haut potentiel thérapeutique de cette protéine.L’élucidation précise des mécanismes d’action de ces modificateurs de la MH reste encore à résoudre, mais plusieurs pistes sont maintenant possiblement envisagées par rapport à leurs caractéristiques moléculaires. Outre la découverte de candidats neuroprotecteurs qui pourrait permettre de développer de nouvelles cibles thérapeutiques, cette étude a permis d’envisager de nouvelles hypothèses permettant d’expliquer la vulnérabilité striatale dans la MH et de donner une vue d’ensemble des voies sur lesquelles il serait possible d’agir pour induire des effets neuroprotecteurs dans ce contexteHuntington’s disease (HD) is a neurodegenerative disorder caused by the mutation of huntingtin (Htt) gene, which leads to an abnormal polyglutamine expansion in the Htt protein.Whereas mutant Htt (mHtt) is ubiquitously expressed in the brain, it preferentially affects the striatum. Our hypothesis is that genes products selectively expressed in the striatum could be involved in the high vulnerability of the striatum. From this hypothesis, numerous teams studied “markers of the striatum”, that are genes product enriched in the striatum whose expression are up- or down-regulated in HD compared to healthy condition.During my thesis, I studied three of these striatal markers: the long intergenic non-coding RNA Abhd11os, and the two proteins µ-crystallin (CRYM) and doublecortin-like kinase 3 (DCLK3). A preliminary study from the laboratory has shown that these three markers have neuroprotective effects against a toxic fragment of mHtt in vivo. So, the aims of my thesis were to further characterize these three ill-defined disease modifiers and to better understand the putative molecular mechanisms underlying their neuroprotective effects against mHtt.I also conducted a translational study on DCLK3, whose results validate the high therapeutic potential of this protein.The elucidation of the mechanisms underlying the neuroprotective effects of these disease modifiers against mHtt toxicity will require further studies, but new trails can be envisioned, according to their characteristics. My study has enlightened new therapeutic targets and more globally gives an overview of molecular mechanisms to modulate to induce neuroprotective effects in this context, leading to new hypothesis explaining striatal vulnerability in HD
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Palmer, Samantha Jane. "Compensatory mechanisms in Parkinson's disease." Thesis, University of British Columbia, 2010. http://hdl.handle.net/2429/22661.
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Parkinson’s disease (PD) is a common movement disorder, affecting 1% of the population over the age of 65. Pathologically, PD results from degeneration of nigral dopaminergic neurons, however symptoms do not appear until an estimated 50% of these cells are lost, suggesting compensatory mechanisms exist which mask disease onset, and may later delay progression of the disease. Compensation may take place over various spatial and temporal scales, from changes in synaptic dopamine release and synthesis that take place over a period of minutes, to recruitment of novel, widespread networks of brain regions for a specific task, which may require formation of new connections over an extended period of time. Neuroimaging techniques have recently allowed the investigation of regional and network changes in activation related to motor performance in PD, however the question of whether such changes represent a downstream effect of basal ganglia degeneration, or a compensatory change, remains difficult to determine. Here, we applied an approach from research into Alzheimer’s Disease, where abnormal activation patterns are studied in the context of tasks of increasing difficulty, such that inferences regarding their compensatory nature can be made. We show that individuals with PD are able to increase the recruitment of normal networks for a motor task (motor reserve) as a form of compensation, in addition to compensatory recruitment of novel networks to accomplish the same task as healthy controls. In particular, we observe a switch from striato-thalamo-cortical (STC) motor loops to cerebello-thalamo-cortical (CTC) loops as a compensatory strategy. This compensatory recruitment involves changes in the amplitude, spatial extent, and connectivity of regions within the CTC pathway. However, this compensation does not come without a price, since we show that compensatory CTC recruitment involving disconnection between the STC and CTC loops occurs in subjects with tremor-dominant PD, but not akinetic-rigidity-dominant PD, supporting a growing body of evidence that suggests the cerebellum plays an important role in the generation of PD tremor. Together, this body of research has implications for treatments that target the symptom of tremor in PD, as therapies which minimize tremor might also reduce beneficial aspects of compensation.
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Saunders, Vickie Ellen, and n/a. "Semantic processing in Parkinson's disease." University of Otago. Department of Psychology, 2006. http://adt.otago.ac.nz./public/adt-NZDU20061024.112547.
Full textAbstract:
Parkinson�s disease is a neurodegenerative disorder, which is typically characterised in terms of its debilitating effects on motor function. However, ubiquitous neuropsychological deficits are also an integral feature of the progression of this disease. This thesis investigated these cognitive deficits as they manifest in language, with the overarching goal being to elucidate the word-finding problems that are associated with Parkinson�s disease. Making semantic judgements and identifying semantic relations are two processes that are particularly germane to word-finding. Therefore, the present thesis examined: 1) the ability of people with Parkinson�s disease to make judgements about semantic categories, and 2) the integrity of associative semantic networks in Parkinson�s disease. In the first series of studies, Cups and Bowls, a novel semantic categorisation task was used to investigate the ability of people with Parkinson�s disease to consistently categorise common kitchen items across a number of trials. The Parkinson�s group was impaired relative to an age-matched control group on this task. This inconsistent categorisation was particularly apparent for the less typical category exemplars at the category boundaries, suggesting that the Parkinson�s group had less salient or less elaborated semantic categories, which particularly compromised categorisation of the less typical category exemplars. This finding is discussed in terms of selective attention deficits and inappropriate weightings of semantic features.
In the second series of studies, Verbal Memory, the structure of the semantic network and access to the semantic system were further investigated using a verbal memory task, which required participants to recall word lists. These word lists consisted of semantically associated words and were designed to elicit false recall of another, non-presented, close semantic associate (the critical lure). The results of this second series of studies, particularly the fact that the Parkinson�s group recalled more of the false critical lures than the control group, suggested an intact semantic network in Parkinson�s disease and normal saliency of semantic categories. The potentiated false recall effect in the Parkinson�s group is discussed in terms of poor modulation of attention in Parkinson�s disease, both as the result of an executive deficit leading to poor controlled processing and in terms of a dopamine-modulated decrease in the signal-to-noise ratio leading to impaired automatic processing. Taken together, the results reported in the present thesis suggest that basal ganglia pathology and striatofrontal deafferentation in Parkinson�s disease do not diminish the integrity of semantic memory, but do compromise operation of semantic memory due to impaired modulation of activation/inhibition mechanisms. This finding of a selective attention deficit has implications for word-finding, suggesting that the word-finding difficulties associated with Parkinson�s disease are the result of impaired lexical access. In particular, retrieval of specific lexical items from semantic memory is impeded because of failure to modulate activation/inhibition mechanisms effectively for the target word to be distinguished from close semantic associates. An intact semantic checking mechanism in anterior language cortex prevents the production of semantic paraphasias, and results in the tip-of-the-tongue word-finding problems displayed by some people with Parkinson�s disease.