Browsing by Subject "Parkinson Disease"
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Item Cognitive and Behavioral Predictors of Fall Risk in Parkinson Disease(2015-07-24) Denney, David Austin; Lacritz, Laura H.; Cullum, C. Munro; Hynan, Linda S.; Patel, Neepa; Ruchinskas, RobertFalls and their related injuries are a significant health issue for individuals with Parkinson disease (PD). Several factors have been identified that increase fall risk, including cognitive impairment, impulsiveness, and lower balance confidence, as well as PD-related characteristics. However, to date, no definitive predictor profile has been identified. As a result, there is a need to develop a comprehensive model incorporating elements from each of the areas known to have a relationship with fall behaviors in PD. Such information could result in improved identification and treatment of PD patients at higher risk of falls. This study used stepwise logistic regression analyses to identify predictors of retrospectively reported falls from four domains, which included separate cognitive, impulsiveness/impulsive-compulsive disorder (ICD) related behaviors, disease characteristics, and balance confidence models. Each stepwise logistic regression yielded significant results (p < .20), and all of the significant predictor variables were included in a fifth combined model. The combined stepwise logistic regression was significant for postural instability (odds ratio = 8.66), verbal learning (California Verbal Learning Test-2 Total Learning T Score [CVLT-II]) (odds ratio = 0.95), and self-reported behavioral impulsiveness (Barratt Impulsiveness Scale-11 [BIS-11]) (odds ratio = 1.10). Model comparisons using net reclassification improvement (NRI) and the Hanley and McNeil (1983) method were conducted to determine if the combined model was significantly better at predicting fall risk than the domain-specific models. The combined model had the highest rate of accurately predicting fall risk (83%); however, the combined model was not significantly better at predicting fall risk than the impulsiveness/ICD or balance confidence models. These results showed that postural instability was the best predictor of fall risk; however, incorporating cognitive and impulsiveness measures improved prediction of fall risk. In light of these findings, screening for impulsiveness and, when possible, verbal learning, could be incorporated into routine clinical PD evaluations for better identification of patients at higher risk of falls.Item A Data-Driven Approach for Deriving Parkinsonâs Disease Subtypes and Related Trajectories of Cognitive and Motor Function(2018-07-27) Dhima, Kaltra; Lacritz, Laura H.; Hynan, Linda S.; McClintock, Shawn Michael; Dewey, Richard B., Jr.; German, DwightParkinson's disease (PD) is a progressive neurological illness that involves a variety of motor and non-motor features, with remarkable heterogeneity in clinical presentation and symptom progression. Previous studies have attempted to identify PD subtypes to better understand the clinical implications of this heterogeneity, though reliable subtypes remain unclear due to inconsistencies across studies, non-generalizable samples, and low subtype stability over time. This study aimed to identify PD subtypes based on motor, cognitive, psychiatric, and functional measures using K-means cluster analysis in a large PD sample (N=683) and explore subtype-specific prognosis. Results yielded a two-cluster solution (Cluster 1 N=457; 2 N=226) at baseline with adequate cluster quality. Cluster 1 exhibited more severe rest tremor but better functioning in all other measures (independence with activities of daily living, daytime sleepiness, depression, anxiety, general non-motor PD symptoms, and postural instability/gait difficulty). Ten half-sample replications of the cluster analysis model and Cohen's kappa revealed excellent model consistency in symptom trends and subjects' cluster membership. Comparison of additional baseline measures using analysis of covariance (ANCOVAs) found that Cluster 1 performed better in overall disease burden, quality of life, motor symptoms, PD medication side effects, mood, sleep dysfunction, compulsive behaviors, psychomotor processing speed, attention, and AÎČ-42. ANCOVAs for annualized change showed Cluster 2 exhibiting greater disease burden over time according to a composite measure, with insignificant cluster differences for all other longitudinal analyses. Replication of the cluster analysis model at last visit revealed consistent cluster differences among model measures, but with suboptimal stability over time, as over 25% of subjects changed cluster membership from baseline. The current study utilized a large and heterogeneous PD sample and a statistically advanced subtyping approach to derive a two-cluster solution, with one group exhibiting relatively greater severity of rest tremor but better functioning in all other areas used to determine initial group differences, as noted above. Although several significant and clinically manful cluster differences were observed at baseline, longitudinal analyses revealed limited clinical and prognostic usefulness. Future PD subtyping efforts may consider increased variable diversity, novel statistical clustering methodologies, and examining clusters of symptom trajectories rather than baseline symptoms.Item Diffusion Kurtosis Imaging as a Diagnostic Tool for Parkinson's Disease(2015-01-26) Vento, Joseph; Cardoso, Ellison; Otaduy, MariaReliable diagnosis of Parkinson's disease requires long-term assessment of a patient's motor performance tests and response to medication. Though the development of magnetic resonance imaging (MRI) presents an additional tool in making a diagnosis, limited imaging biomarkers have been reported that support a clinical diagnosis of Parkinson's disease or its differentiation from similarly presenting diseases. Diffusion Kurtosis Imaging (DKI) is an MRI method that quantifies deviation of water diffusion from normal Gaussian distribution. DKI is a more sensitive technique than conventional diffusion tensor imaging (DTI) for assessing tissue microstructure. The parameters provided by DKI analysis, particularly the mean kurtosis, reflect structural changes within brain regions and demonstrate potential as a diagnostic tool for Parkinson's disease where the basal ganglia are known to markedly change. Here we examine the DKI maps of 86 patients from Hospital das Clinicas da FMUSP in Sao Paulo, Brazil. 49 patients presented with a previous diagnosis of Parkinson's disease based on the UK Parkinson's Brain Bank criteria (mean age, 65.3 + 8.7 [standard deviation]), 19 patients with a previous diagnosis of essential tremor based on the Movement Disorder Society standards (mean age, 64.7 + 6.7) and 27 patients were age-matched healthy controls (mean age, 64.5 + 10.9). All patients underwent the same 3T MRI procedure, consisting of a DTI scan with 32 different gradient directions and b values of 0, 1000, and 2000 s/mm2, necessary to construct a DKI map. Using a region of interest (ROI) analysis on the substantia nigra (rostral, middle, and caudal) and putamen for each patient and comparing mean kurtosis values, we find no significant differentiation of Parkinson's disease patients in the substantia nigra, but significantly higher mean kurtosis values in the putamen of Parkinson's patients (0.82 + 0.05 [standard deviation]) than healthy controls (0.60 + 0.04, p = 0.0158). Neither analysis demonstrated significant difference from essential tremor patients. Higher mean kurtosis estimates in the basal ganglia of Parkinson's disease patients may reflect changes in the microstructural environment of these structures related to disease progression. Further studies should investigate the histological correlates of these values and the reliability of DKI estimates as a diagnostic tool in various stages of the disease.Item Factors Influencing Quality of Life in Parkinson's Disease(2015-08-31) Chansard, Matthieu; Lacritz, Laura H.; Ringe, Wendy; McClintock, Shawn MichaelBACKGROUND: Parkinsonâs Disease (PD) is a progressive neurodegenerative disease, that encompasses a broad range of motor and non-motor symptoms, each of which has the potential to negatively impact health-related quality of life. Depression, disease duration, and level of disability have been found to significantly influence quality of life in PD. However, there is a paucity of research examining the combined influences of depression, PD motor symptom severity and cognition on overall HRQoL, as well as various domains of HRQoL, in a PD population. SUBJECTS: This study used data collected from 124 participants with PD, aged 50 to 85, who were enrolled in a larger study, and gave informed consent for the parent study, with no knowledge of the current study. Inclusion criteria consisted of a PD diagnosis and a response to levodopa treatment for at least 30 days. Participants meeting DSM-IV-TR criteria for Axis I disorders other than MDD were excluded. METHOD: The current study utilized linear and multiple regression analyses to explore the relationships between HRQoL and depression severity, PD motor symptom severity and global cognitive ability. HRQoL was measured by the Parkinsonâs Disease Questionnaire â 39 Item, a PD specific disease questionnaire designed to assess HRQoL in a variety of domains. Measures included the Quick Inventory of Depressive Symptomatology-Clinician Version, the United Parkinsonâs Disease Rating Scale Part III, selected disease characteristics, and a battery of cognitive tests. RESULTS: Depression severity (QIDS-C16) and PD motor symptom severity (UPDRS) and global cognitive ability accounted for approximately 30% of the variance in PDQ-39 Single Index scores. Depression severity and motor symptom severity were the most significant predictors of HRQoL (PDQ-39). The multiple regression analysis results aligned closely with separate, linear regression analyses designed to control for the redundancy in the independent and dependent variables, which showed that depression severity accounted for 18.7% of the variance in HRQoL, motor severity accounted for 12%, and that global cognitive ability accounted for 3.8%. Depression severity accounted for the greatest amount of variance in all domain scores comprising the PDQ-39 except for Mobility and Activities of Daily Living, of which PD motor symptom severity accounted for the largest amount of variance. Depression severity was significantly correlated with all PDQ-39 domains, (rs=0.22 to 0.48), while PD symptom severity was significantly correlated (rs=0.23 to 0.51) with Mobility, ADL, Cognition, Communication and Bodily Discomfort domains. Global cognitive functioning did not significantly predict overall HRQoL but did significantly influence the Communication domain. The PDQ-39 Single Index score was significantly correlated with measures visual learning and memory (BVMT-R) and processing speed (Trail Making Test Part A and Part B, and Symbol Search). Of all the significant Pearson correlations, Symbol Search scaled scores had the strongest correlation (r=0.29). In an ANCOVA analysis using QIDS-C16 scores as a covariate, verbal learning and memory (RAVLT) achieved statistical significance. When controlling for depression severity and age, no significant differences in HRQoL were found between individuals classified as bradykinetic/rigid motor subtype and those classified as tremor dominant motor subtype. DISCUSSION: The primary aim of the study was to examine the relative influence of depressive symptoms, PD motor symptoms and cognition on HRQoL in individuals with PD. Both depression severity and motor symptom severity significantly influenced HRQoL, while global cognitive ability did not. The influence of depression severity in the sample is impressive, given the low prevalence and severity of depression present. This suggests that although depression severity may be subclinical, early identification and management of these symptoms may positively influence HRQoL. The most frequently reported depressive symptoms included difficulties staying asleep, sad mood and low energy, which indicate that targeting these specific symptoms, even when subclinical, holds potential for improving the HRQoL of individuals with PD. In exploring the relationship between cognition and HRQoL in PD further, Pearson correlational analyses indicated that HRQoL was significantly correlated with measures of visual and verbal learning and memory, working memory and processing speed, even though a global cognition screening measure was not predictive of overall HRQoL. In summary, the collective findings from this study support the influence of motor severity and even subclinical depression on HRQoL in PD, suggesting that interventions designed to improve mood and the capacity to complete activities of daily living may positively impact quality of life.Item Imapct [sic] of Pesticide Exposure on Motor Function and Mortality Among Patients with Parkinson's Disease in Southern Brazil(2020-05-01T05:00:00.000Z) Reddy, Sumanth Palvai; Dewey, Richard B., Jr.; Chang, Mary; Chitnis, ShilpaBACKGROUND: Multiple studies have suggested that various pesticides are associated with a higher risk of developing Parkinson's disease (PD). However, few studies have examined the impact of pesticide exposure on motor impairment and the risk of mortality among patients with PD. This study takes place in the context of growing pesticide use in Brazil as well as many other low- and middle-income countries around the world. OBJECTIVE: This study examines whether occupational pesticide exposure influences motor impairment and the risk of mortality among patients with PD in Southern Brazil, when accounting for socioeconomic status, disease-specific factors, nicotine exposure, and caffeine exposure. METHODS: 150 patients with idiopathic PD in Porto Alegre, Brazil were enrolled from 2008-2013 and followed until 2019. In addition to undergoing a detailed neurologic evaluation, patients completed surveys regarding environmental exposures. 105 of these patients also completed an additional survey regarding socioeconomic factors. The primary outcomes were whether occupational pesticide exposure was associated with motor impairment (as measured by linear regression with UPDRS-III score) and mortality (as determined by the log-rank test and Kaplan-Meier testing). Secondary analyses included models that accounted for relevant socioeconomic and disease specific characteristics (multiple linear regression for motor function, and multivariate cox proportionate hazards regressions for mortality). RESULTS: Of the 150 patients in this prospective cohort, 20 (13.3%) reported a history of occupational pesticide exposure, with an average duration of exposure of 14.3 years (SD = 10.6, median = 10). In the univariate analysis, occupational pesticide exposure was associated with a 16.10 point increase in the UPDRS-III (motor function) score (95% CI: [7.11, 25.02], p < 0.001). Similarly, in the multiple linear regression which controlled for several socioeconomic and disease-related covariates, pesticide exposure was associated with a 16.84 point increase in the UPDRS-III score (95% CI: [8.84, 24.85], p < 0.001). Patients with occupational pesticide exposure were more than two times as likely to die than their unexposed PD counterparts (HR = 2.32, 95% CI [1.15, 4.66], p = 0.22). This was significant when controlling for smoking history, caffeine intake, and socioeconomic factors such as historical monthly income, education, and a history of working predominately in agricultural professions. Patients with 10 or more years of occupational pesticide exposure had a significantly elevated risk of mortality (HR = 2.81, 95% CI [1.17, 6.73], p = 0.02), in contrast to patients with fewer than 10 years of exposure. CONCLUSION: In addition to providing a broad overview of the socioeconomic breakdown of a contemporary cohort of patients with PD in South America, this study implicates occupational pesticide exposure as an independent risk factor for poor motor function and mortality among patients with PD when controlling for disease-specific and socioeconomic confounding factors. This is especially important in the Brazilian market, and perhaps in other developing countries, where new pesticides continue to be introduced without the corresponding research output necessary to understand the impact on human health.Item Metabolism of Alpha-Synuclein by the 20S Proteasome(2009-06-18) Lewis, Karen Adell; Rizo-Rey, JosĂ©Parkinson's disease is one of several common neurodegenerative disorders that are related by the intracellular aggregation of the neuronal protein alpha-synuclein (alphaSyn) that normally associates with synaptic vesicles. Within the aggregates, a fraction of alphaSyn is truncated at the C-termini, and these truncations are hypothesized to participate in disease pathogenesis. The prevailing model for cytotoxicity of the aggregated protein proposes that oligomeric forms cause dysfunction of the ubiquitin-proteasome pathway of protein degradation, thereby enhancing an alternative pathway that involves ubiquitin-independent degradation by the 20S core particle of the proteasome. The 20S proteasome is known to degrade proteins with regions of intrinsic disorder, which figure prominently in a wide range of neurodegenerative disorders, including alphaSyn in Parkinson's disease. Importantly, some forms of 20S exert an endoproteolytic activity that produces highly amyloidogenic truncations of alphaSyn. An in vitro system containing liposomes and the 20S proteasome was developed to identify the mechanism by which the three point mutations in alphaSyn associated with familial Parkinson's disease exert cytotoxicity. The proteasome produced truncations from all three mutants in the presence of liposomes, but not wildtype alphaSyn. Additionally, the putative cytotoxic oligomer was formed most rapidly in the presence of both 20S proteasome and liposomes. Polyclonal antibodies specific for the C-termini of a set of truncated alphaSyn proteins were successfully developed to detect cleavage products of alphaSyn in vitro and in vivo. To better understand the physiological role of 20S-mediated degradation of intrinsically disordered proteins, the mechanism of recognition and interaction between substrate and enzyme was studied. While the presence of disorder appears to be necessary for 20S degradation, it was found to be insufficient to define a protein as a 20S substrate. Furthermore, a novel correlation was identified between the endoproteolytic activity of 20S and a modification of the alpha6 subunit. The data support a role for the 20S proteasome in Lewy body disease pathogenesis, where it accelerates the formation of cytotoxic species by endoproteolysis of an intrinsically disordered protein. In that regard, a form of the 20S proteasome was identified that may be responsible for the endoproteolytic cleavage of intrinsically disordered proteins in vivo.Item Neuroinflammation, TNF, and Ceramide Signaling: Putative Pathways for Neurotoxicity in Parkinson's Disease(2010-05-14) Martinez, Terina Nichole; Tansey, MalĂș G.Parkinsonâs disease is a progressive neurodegenerative disorder that is characterized by the loss of dopaminergic neurons in the substantia nigra that innervate the striatum, and it is the loss of these neurons that causes the motor dysfunction that is associated with the disease. However, the mechanisms that contribute to the induction and perpetuation of dopaminergic neuronal cell death in Parkinsonâs disease are multifaceted and poorly understood. Inflammation has been shown to contribute to cytotoxicity in animal models of Parkinsonâs disease, and increased levels of inflammatory cytokines have been observed in the cerebral spinal fluid and striatum of Parkinsonâs disease patients. We have previously demonstrated that blocking soluble tumor necrosis factor (TNF) signaling with dominant-negative TNF inhibitors attenuates the loss of dopaminergic neurons in models of Parkinsonâs disease, but which signaling pathways downstream of TNF mediate this effect remain undetermined. Here, I show that TNF-dependent ceramide signaling contributes to dopamine neuron cytotoxicity by compromising mitochondrial membrane potential, inducing endoplasmic reticulum stress and activating caspase signaling in vitro. My data demonstrate that TNF-induced cytotoxicity is partially ceramide-dependent, as TNF-induced cytotoxic effects are attenuated with two different pharmacological inhibitors of sphingomyelinase, an enzyme that hydrolyzes active ceramide from inactive sphingomyelin pools. Collectively, my data support a model whereby low-dose TNF and concomitant low TNF receptor1 occupancy activates downstream ceramide signaling and metabolism, culminating in caspasedependent cytotoxic cell death of dopaminergic neurons. My data and the data associating ceramide biology and metabolism with Parkinsonâs disease warrants future studies examining the potential neuroprotective effects of inhibition of sphingomyelinase in animal models of Parkinsonâs disease, and may eventually lead to improved therapy for patients who suffer from Parkinsonâs disease.Item [News Release](1969-03-05) Chappell, Frank W., Jr.; Weeks, JohnItem [News](1981-05-08) Rutherford, SusanItem [News](1973-05-16) Weeks, JohnItem Role for Lipids in the Cellular Transmission of α-Synuclein(2015-07-30) Peres, Yair; Michaely, Peter A.; Thomas, Philip J.; DeBose-Boyd, Russell A.; Albanesi, Joseph P.The presynaptic protein α-Synuclein (α-Syn) abnormally aggregates in the brains of Parkinson's Disease patients. Evidence suggest a transcellular transfer of an oligomeric form of the protein (seed) in a prion-like fashion. The mechanism underlying cell entry is unclear, but studies have implicated the cell surface glycan HSPG followed by macropinocytosis, as a possible uptake route. Secretion and uptake of aggregated α-Syn was reported to be associated with lipid vesicles in cells. Monomeric α-Syn was found to tubulate membranes in-vitro. This work aims to study the significance of membrane association and tubulation by α-Syn to its effect on uptake by cells. Uptake of lipid-associated α-Syn seeds was significantly more efficient than lipid-free uptake. Furthermore, seeds in the presence of monomers and lipids, which formed tubules in-vitro, were more readily internalized than seeds and lipids in the absence of monomers. Lipid associated α-Syn was internalized by cells in an HSPG dependent manner as evident from competitive inhibition and enzymatic digestion experiments. Tubule associated seeds may constitute an efficient mechanism of pathological propagation of synucleinopathies. This mechanism should be considered in any therapeutic approach targeting the inhibition of α-Syn intercellular transfer.Item The Role of Tumor Necrosis Factor (TNF) in Microglial Activation and Progressive Degeneration of Dopaminergic Neurons(2010-05-14) Harms, Ashley Nicole Simpson; Tansey, MalĂș G.Parkinsonâs disease (PD) is a progressive neurodegenerative disorder characterized by a loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). A number of studies have implicated chronic inflammation in the pathophysiology of PD; however, it is unclear which inflammatory mechanisms directly contribute to neuronal loss in PD. A number of cytokines, including TNF, are elevated in post-mortem brain and cerebrospinal fluid of patients with PD. Previous studies from our group have shown that blocking solTNF signaling at the time of a unilateral 6-OHDA striatal lesion attenuated behavioral deficits and the acute loss of dopaminergic neuron loss by 50%. However, a critical question of clinical relevance is whether delayed solTNF signaling inhibition can prevent the progressive loss of DA neurons that occurs after a CNS insult. I report here that a single intranigral injection of a lentivirus encoding a dominant negative TNF inhibitor delivered 2 weeks after an intrastriatal 6-OHDA lesion attenuated microgliosis in SNpc and halted the progressive loss of nigral DA neurons and the associated locomotor deficits. Given the potential contribution of microglial activation to PD and the suggestion that anti-TNF therapies in the CNS may exert neuroprotective effects on vulnerable dopaminergic neuron populations, I also investigated the role of TNF in regulating microglia effector functions to gauge the potential detrimental effects of anti-TNF therapies on the microglia functional response. I found that microglia from TNF-null mice produced reduced protein levels of cytokines and chemokines in response to LPS stimulation and they displayed no cytotoxic effects on dopaminergic neuroblastoma MN9D cells when activated in vitro. I also demonstrated that microglia isolated from TNF-null mice failed to display the expected morphological changes in response to LPS stimulation, including enhanced perinuclear expression of the activation marker CD45. My results suggest that TNF plays a critical role in microglia activation, regulation of several microglia effector functions and is the primary microglia-derived inflammatory factor that compromises survival of dopaminergic neurons. Furthermore, these studies suggest that TNF-dependent neuroinflammation directly contributes to the delayed and progressive degeneration of nigral DA neurons after neurotoxic injury and further validates solTNF as a potential therapeutic target in PD.Item [Southwestern News](2000-03-13) Baxter, MindyItem [Southwestern News](2004-03-02) Horton, RachelItem [Southwestern News](2005-06-21) McKenzie, AlineItem [Southwestern News](2005-11-02) McKenzie, AlineItem Surprising Behavioral and Neurochemical Enhancements in Mice with Combined Mutations Linked to Parkinson's Disease(2013-11-29) Hennis, Meghan Reilly; Yu, Gang; Goldberg, Matthew S.; Eisch, Amelia J.; Hsieh, Jenny; Johnson, Jane E.Parkinsonâs disease (PD) is the second most common neurodegenerative disease, after Alzheimerâs disease, afflicting over a million people in the United States alone. PD is an age-dependent disease that causes progressive death of dopamine-producing neurons in the substrantia nigra and depleted dopamine in the striatum. Loss of striatal dopamine results in locomotor symptoms such as bradykinesia, tremor, rigidity and postural instability. Although most forms of the disease are spontaneous, a subset of cases are genetic and humans lacking expression of either Parkin or DJ-1 develop PD. However, one limitation to studying PD is a lack of rodent models that recapitulate both the dopaminergic and motor symptoms as well as the age-dependent development of this disease. In fact, mice deficient for either one or both Parkin and DJ-1 genes have no dopaminergic neuron loss or deficiency in motor abilities. Therefore, I aimed to develop a rodent model of Parkinsonâs disease that mimics the progressive symptoms observed in humans by crossing mice deficient for two genes causative for PD, Parkin and DJ-1. I also crossed mice deficient for Parkin and DJ-1 with mice deficient for glutathione peroxidase 1 (Gpx1), an antioxidant that is decreased in the brains of PD patients and increased in aged DJ-1 deficient mouse brains. Instead of the expected loss of dopamine, Parkin-/-DJ-1-/-Gpx1-/- mice exhibit increased striatal dopamine while Parkin-/-DJ-1-/- mice have increased serotonin in multiple brain regions. Additionally, motor phenotypes in these mice do not replicate symptoms observed in PD because Parkin-/-DJ-1-/- mice have an unexpected increase in latency to fall from the rotarod in the absence of other significant behavioral phenotypes. These results led me to examine the levels of proteins related to neurotransmitter synthesis and transport and to test non-motor behaviors in Parkin-/-DJ-1-/- mice. Behavior tests suggest that Parkin-/-DJ-1-/- mice have improved rotarod performance due to cognitive, rather than motor changes.Item Tower of California Performance Early in Parkinson's Disease(2008-09-19) Vega, Martin C.; Silver, Cheryl H.Cognitive impairment associated with Parkinson's disease (PD) is widely described in the literature. Executive dysfunction has been reported even when the patients are not experiencing dementia. A significant (24% - 50+%) number of PD patients display cognitive impairment from the onset of the disease and progressively worsen. However, executive dysfunction in newly diagnosed patients often escapes clinical detection. This paper describes a study designed to test both early and late PD patients (0-5 years disease duration and 5-10 years disease duration, respectively) vs. controls on a novel tower task, the Tower of California (TOC, Delis, Kaplan,&Kramer, 2001). Use of the TOC with PD patients has not been published. The TOC is designed to be more difficult and may be more sensitive to subtle executive impairment, specifically in the areas of planning and spatial working memory. It is predicted that the early PD group will perform worse than the control group but better than the late PD group in the number of successful towers (ST) built. The early PD group is also expected to have a longer time to first move on ST built even when corrected for bradykinesia, but not as long as the late PD group, which is anticipated to be the slowest. Implications of the possible outcomes of this study are then discussed.Item Tumor Necrosis Factor Dependent Mechanisms and Neuroprotective Strategies in Models of Parkinson's Disease(2008-05-13) McCoy, Melissa Kay; Tansey, MalĂș G.Parkinson's disease is a chronic, progressive, neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra that innervate the striatum. Although the nigral cell loss that causes motor dysfunction in Parkinson's disease has been identified for some time, the mechanisms that lead to this dopaminergic neuron loss are unclear. Elevated levels of the cytokine tumor necrosis factor in cerebrospinal fluid and postmortem brains of Parkinson's patients and in animal models of the disease implicate tumor necrosis factor in contributing to disease pathology; but a specific role for this cytokine in mediating loss of dopaminergic neurons in Parkinson's disease has not been clearly established. Here I demonstrate that neutralization of soluble tumor necrosis factor in vivo with a recombinant dominant-negative tumor necrosis factor inhibitor reduced 6-hydroxydopamine-induced nigral degeneration by 50% and attenuated amphetamine-induced rotational behavior, indicative of striatal dopamine preservation in a rodent model of Parkinson's disease. Similar protective effects were observed with in vivo chronic co-infusion of dominant-negative tumor necrosis factor inhibitor with a proinflammatory initiator, low-dose lipopolysaccharide, into the substantia nigra of rodents, confirming a role for soluble tumor necrosis factor inhibitor-dependent neuroinflammation in contributing to nigral degeneration. In rat embryonic midbrain neuron/glia mixed cell cultures exposed to lipopolysaccharide, delayed administration of dominant-negative tumor necrosis factor inhibitor prevented degeneration of dopaminergic neurons despite sustained microglia activation. Addition of a dominant-negative tumor necrosis factor inhibitor also attenuated 6-hydroxydopamine-induced dopaminergic neuron toxicity in vitro. In this dissertation the ability of lentiviral-encoded dominant-negative tumor necrosis factor inhibitor to provide neuroprotection was also investigated. Intranigral delivery of lentiviral dominant-negative tumor necrosis factor inhibitor in a hemiparkinsonian rat 6-hydroxydopamine model attenuated nigral dopaminergic neuron loss and reduced behavior deficits when compared to control lentiviral-infected animals. Collectively, these data identify tumor necrosis factor signaling in contributing to dopaminergic neuron loss in vitro and in vivo in two chronic rat models of Parkinson's disease, and provide evidence that delaying the progressive degeneration of the nigrostriatal pathway in the early stages of Parkinson's disease in humans may be therapeutically feasible with agents that block soluble tumor necrosis factor signaling.Item [UT News](1986-12-12) Rutherford, Susan