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Functional analysis of alpha-synucleinSenior, Steven L. January 2007 (has links)
No description available.
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α-Synuclein Autoimmunity in Parkinson’s DiseaseGarretti, Francesca January 2021 (has links)
Parkinson’s disease (PD) is a multi-organ disorder. It is diagnosed from motor impairments that arise from neurodegeneration in the midbrain. However, the disease begins decades earlier in the gut prior to involvement of the brain. PD is characterized by persistent inflammation, both in the brain and in the periphery in addition to neurodegeneration. Here, I investigate the role of the adaptive immune system in disease pathogenesis and as a driver of prodromal symptoms of PD in both humans and mice.
In Chapter 1, I introduce Parkinson’s disease, its pathological hallmarks and the progression of the symptoms, and discuss genetic and environmental influences. Then, I elaborate on the inflammatory phenotypes observed in the disease and recent work describing the role of inflammation in animal models for PD.
In Chapter 2, I examine the autoimmune features of Parkinson’s disease from analysis of patients’ blood. I found that approximately 40% of PD patients possess aspects of autoimmunity against α-synuclein. By screening peripheral blood mononuclear cells of patients and healthy controls for potential neoantigens derived from α-synuclein protein, I identified two antigenic regions of the protein that elicit an immune response. The immune responses to a specific α-synuclein neo-antigens were linked to unique HLAs that are over-represented in our PD cohort and are associated with PD in genome wide association studies (GWAS).
In Chapters 3 and 4, I describe the effects of recapitulating α-synuclein autoimmunity in a humanized mouse strain expressing the HLA allele risk for PD. In Chapter 3, I show that the humoral and cellular immunity is mounted against α-synuclein in the humanized mice, similar to what is observed in PD patients; however, there is no inflammation or immune response toward the brain. In Chapter 4, I show how the autoimmune response to α-synuclein induces inflammation and neurodegeneration in the gut leading to constipation in mice, recapitulating the prodromal aspects of the human disease.
Finally, in Chapter 5, I discuss the implications of these findings for α-synuclein autoimmunity in the periphery, gut and brain in Parkinson’s disease. I also elaborate on the implications of these findings for potential future diagnostic screening and treatments for Parkinson’s disease.
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Development of an Objective Motor Score for Monitoring the Progression and Severity of Parkinson's DiseaseAlbers, Timothy W. 01 January 2011 (has links)
This thesis describes the development of an objective motor score (OMS) of Parkinson's disease that utilizes the Quantitative Motor Assessment Tool (QMAT) developed through efforts by the Intel Corporation and the Kinetics Foundation. Parkinson's disease (PD) is a movement disorder which is a member of a group of neurodegenerative diseases marked by the depletion or impairment of dopamine-producing cells in the brain. Since PD is chronic and degenerative, treatments are intended to either improve the quality of life for sufferers by superficially treating symptoms or slow and ultimately reverse the progression of the disease. No blood test or biomarker exists, so current assessment of the disease relies on a subjective tool called the Unified Parkinson's disease rating scale (UPDRS) which is a coarse scale that requires costly clinical administration and is subject to rater bias. The objective motor score described in this thesis exhibits excellent clinimetric properties, having demonstrated usability, validity, reliability, and responsiveness. It was calibrated to the motor section of the UPDRS, but in addition to high correlation with the motor UPDRS, it demonstrated an excellent ability to track deep brain stimulation treatment levels and to detect improvement in motor function of subjects due to dopaminergic treatment. With an excellent intraclass correlation coefficient, the OMS is a reliable measure and due to the objective nature of the test, it does not suffer from rater bias. Though these results come from the development phase, they suggest that confirmatory studies will firmly establish the excellent properties of the OMS. While further studies are in motion to improve upon the sensitivity of the OMS by exploring metrics of voice recordings and paced tapping tests, the OMS presented here is a complete and usable tool for assessing the severity of PD-related symptoms. In conjunction with the QMAT, it is ready to be used in clinical trials, clinical practice, and even in the homes of patients who suffer from PD. This makes it an invaluable tool that could begin to replace the UPDRS for use in PD research, reducing costs and confounding factors in studies as well as extending their capabilities into the home.
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Neural vulnerability in models of Parkinson's diseaseMo, Mimi Shin Ning January 2007 (has links)
Parkinson's disease (PD) is a neurodegenerative disorder with no known cure. This thesis explores the degenerative process in two neurotoxin-based models, the 6-hydroxydopamine and the chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)/probenecid mouse models, to yield important information about the pathogenesis of PD. Neuronal survival patterns in Parkinsonian patients and animals are heterogeneous. More dopaminergic neurons are lost from the ventral tier of the substantia nigra (SN) than from the dorsal tier or the adjacent ventral tegmental area, possibly due to differential expression of the calcium-binding protein, calbindin D28K. Brain sections were processed for tyrosine hydroxylase (TH) and calbindin (CB) immunocytochemistry to distinguish the dopaminergic subpopulations. I show that more TH+/CB- and TH-/CB+ than TH+/CB+ neurons are lost in both models, suggesting that CB confers some degree of protection for dopaminergic neurons. With respect to connectivity, I show that both TH+ and CB+ neurons receive striatal and dorsal raphe inputs. I investigated the possibility of a progressive loss in midbrain neurons by prolonging the post-lesion survival period. In both models, there is an irreversible neuronal cell loss of TH+, CB+ and TH+/CB+ neurons but the effects of survival time and lesion treatments differ for the three neuronal types. The lesions also appear to be toxic to GABAergic neurons. I explore whether, once neurodegeneration has started, neurons can be rescued by pharmacological intervention. Salicylic acid appears both to reduce microglial activation and significantly improve TH+, but not CB+ or TH+/CB+ neuronal survival. PD appears multifactorial in origin and may involve complex interactions between genetic and environmental influences. I show that a xenobiotic-metabolising enzyme, arylamine N-acetyltransferase may fulfil a neuroprotective role in the SN by limiting the environmental risks. Taken together, this study provides a body of information on two different mouse PD models and highlights possible genetic predispositions to PD neuropathology.
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Eye movement control and cognition in Parkinson's diseasevan Stockum, Eva Saskia January 2006 (has links)
Many studies have found evidence of abnormal eye movement control in Parkinson's disease. Deficits in the inhibition of unintended saccades and slowed initiation of intentional saccades have been reported in some, but not all, investigations. Also over recent years the presence of cognitive impairment in a proportion of patients with Parkinson's disease has been highlighted. Efficient use of working memory resources is thought to be involved in the performance of tasks in both domains. With a comprehensive selection of saccadic and neuropsychological tasks, the current study investigated whether aspects of abnormal oculomotor control are associated with impairment of cognitive functions. Nineteen Parkinson's disease patients and eighteen healthy age matched control subjects performed six eye movement tasks and completed a neuropsychological test battery assessing five different aspects of cognitive functioning. Deficits were found in both the oculomotor and the cognitive domain in the group of patients. As a group, the patients made more reflexive errors in antisaccade tasks, more inhibition errors in a delayed response task, and were slower to initiate intentional saccades. The three measures of abnormal oculomotor control were not consistently associated with cognitive impairments or with each other. Longer latencies of correct antisaccades and increased number of errors in a delayed response task were associated with lower scores in different cognitive tests. Reflexive errors in the antisaccade task were not associated with cognitive deficits, but with the tendency to produce very fast visually triggered responses. The results suggest that, at least in Parkinson's disease, different neural mechanisms may be involved in specific aspects of abnormal oculomotor control.
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The rat nigrostriatal system : regeneration and reconstructionBrecknell, John Edward January 1995 (has links)
No description available.
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The role of the dorsal striatum in the control of reaction time performancePretsell, Douglas Ogilvy January 1994 (has links)
No description available.
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MEMORY FUNCTIONING IN PARKINSON'S DISEASE: THE EFFECT OF AGE OF ONSET ON HIGH SPEED MEMORY SCANNING.STEBBINS, GLENN THURSTON, III. January 1987 (has links)
A sample of 25 idiopathic Parkinson's disease subjects and 25 age and education matched elderly healthy control subjects were assessed for their speed of primary memory scanning speed using the Sternberg memory scanning paradigm. In addition, all patients were assessed for cognitive functioning as measured by the Mattis Dementia Rating Scale and the Wechsler Memory Scale. Significant differences were found between Parkinson's disease subjects and control subjects on speed of primary memory scanning, with the parkinsonian subjects performing significantly slower than the control subjects. Increased variability in the measure of memory scanning speed was noted for the parkinsonian subjects as compared to control subjects and different variables associated with increased cognitive disturbances in parkinsonian subjects were investigated as possible sources of this variability. It was found that the majority of variance could be accounted for by the parkinsonian subjects' age of symptom onset. Parkinsonian subjects who developed the disease later in life were significantly slower at primary memory scanning speed than were either parkinsonian subjects who developed the disease earlier in life, or than healthy control subjects. Cognitive variables measuring initiation and perseveration, construction and attention were found to be highly associated with increased primary memory scanning time. The relationship between these cognitive abilities and frontal lobe dysfunction is discussed. Also, the possible relationship between slowing of memory scanning and dopamine depletion is presented.
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The Effect of Frontal Lobe Function on Proverb Interpretation in Parkinson's DiseaseGutmann, Michelle January 2009 (has links)
The cognitive impairment associated with PD involves a broad range of deficits including difficulty with executive functions such as working memory, inhibition, decision-making, and cognitive multitasking, learning, and visuoperceptual skills. Even early in the disease, when motor symptoms tend to predominate, there is evidence that cognitive functions can be compromised. Owing to the presence of executive-type dysfunction in PD, some researchers likened the cognitive deficit of PD to that seen with frontal lobe damage. The anatomical basis of PD, however, suggests otherwise. Dopamine depletion in the basal ganglia, and the downstream depletion of dopamine in the frontostriatal circuitry is often thought to be the foundation of the cognitive deficits associated with PD.In addition to cognitive impairments, a language deficit attends Parkinson's disease (PD) alongside the other motor and non-motor aspects of the disease. This language deficit is characterized by difficulty processing various types of figurative language, and has been associated with various PD-related cognitive deficits, such as deficits in working memory (WM). Varied assessment tools have been used to characterize the neuropsychological functions associated with this language deficit, most of which involve some measure of frontally-based cognitive skills.The purpose of this study was to examine the influence of frontal lobe function on higher-level language function in the non-demented PD (NDPD) population. To investigate this influence, the performance of two groups of participants (i.e., one NDPD group and one control group) was compared on both a proverb interpretation task and on a statistically derived measure of frontal lobe function.Results indicated a relation between performance on the measure of frontal lobe function and performance on the proverb interpretation task in the PD group only. Significant findings are discussed in relation to the neuropsychological underpinnings of the figurative language deficit in PD.
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The debrisoquine 4-hydroxylase gene locus and inherited cancer susceptibilityGough, Alan Charles January 1994 (has links)
No description available.
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