Matching Items (4)
Description
Parkinson’s disease (PD) is a progressive neurodegenerative disorder, diagnosed late in
the disease by a series of motor deficits that manifest over years or decades. It is characterized by degeneration of mid-brain dopaminergic neurons with a high prevalence of dementia associated with the spread of pathology to cortical regions. Patients exhibiting symptoms have already undergone significant neuronal loss without chance for recovery. Analysis of disease specific changes in gene expression directly from human patients can uncover invaluable clues about a still unknown etiology, the potential of which grows exponentially as additional gene regulatory measures are questioned. Epigenetic mechanisms are emerging as important components of neurodegeneration, including PD; the extent to which methylation changes correlate with disease progression has not yet been reported. This collection of work aims to define multiple layers of PD that will work toward developing biomarkers that not only could improve diagnostic accuracy, but also push the boundaries of the disease detection timeline. I examined changes in gene expression, alternative splicing of those gene products, and the regulatory mechanism of DNA methylation in the Parkinson’s disease system, as well as the pathologically related Alzheimer’s disease (AD). I first used RNA sequencing (RNAseq) to evaluate differential gene expression and alternative splicing in the posterior cingulate cortex of patients with PD and PD with dementia (PDD). Next, I performed a longitudinal genome-wide methylation study surveying ~850K CpG methylation sites in whole blood from 189 PD patients and 191 control individuals obtained at both a baseline and at a follow-up visit after 2 years. I also considered how symptom management medications could affect the regulatory mechanism of DNA methylation. In the last chapter of this work, I intersected RNAseq and DNA methylation array datasets from whole blood patient samples for integrated differential analyses of both PD and AD. Changes in gene expression and DNA methylation reveal clear patterns of pathway dysregulation that can be seen across brain and blood, from one study to the next. I present a thorough survey of molecular changes occurring within the idiopathic Parkinson’s disease patient and propose candidate targets for potential molecular biomarkers.
the disease by a series of motor deficits that manifest over years or decades. It is characterized by degeneration of mid-brain dopaminergic neurons with a high prevalence of dementia associated with the spread of pathology to cortical regions. Patients exhibiting symptoms have already undergone significant neuronal loss without chance for recovery. Analysis of disease specific changes in gene expression directly from human patients can uncover invaluable clues about a still unknown etiology, the potential of which grows exponentially as additional gene regulatory measures are questioned. Epigenetic mechanisms are emerging as important components of neurodegeneration, including PD; the extent to which methylation changes correlate with disease progression has not yet been reported. This collection of work aims to define multiple layers of PD that will work toward developing biomarkers that not only could improve diagnostic accuracy, but also push the boundaries of the disease detection timeline. I examined changes in gene expression, alternative splicing of those gene products, and the regulatory mechanism of DNA methylation in the Parkinson’s disease system, as well as the pathologically related Alzheimer’s disease (AD). I first used RNA sequencing (RNAseq) to evaluate differential gene expression and alternative splicing in the posterior cingulate cortex of patients with PD and PD with dementia (PDD). Next, I performed a longitudinal genome-wide methylation study surveying ~850K CpG methylation sites in whole blood from 189 PD patients and 191 control individuals obtained at both a baseline and at a follow-up visit after 2 years. I also considered how symptom management medications could affect the regulatory mechanism of DNA methylation. In the last chapter of this work, I intersected RNAseq and DNA methylation array datasets from whole blood patient samples for integrated differential analyses of both PD and AD. Changes in gene expression and DNA methylation reveal clear patterns of pathway dysregulation that can be seen across brain and blood, from one study to the next. I present a thorough survey of molecular changes occurring within the idiopathic Parkinson’s disease patient and propose candidate targets for potential molecular biomarkers.
ContributorsHenderson, Adrienne Rose (Author) / Huentelman, Matthew J (Thesis advisor) / Newbern, Jason (Thesis advisor) / Dunckley, Travis L (Committee member) / Jensen, Kendall (Committee member) / Wilson, Melissa (Committee member) / Arizona State University (Publisher)
Created2019
Description
Parkinson’s Disease is one of the most complicated and abundantneurodegenerative diseases in the world. Previous analysis of Parkinson’s disease has
identified both speech and gait deficits throughout progression of the disease. There has
been minimal research looking into the correlation between both the speech and gait
deficits in those diagnosed with Parkinson’s. There is high indication that there is a
correlation between the two given the similar pathology and origins of both deficits. This
exploratory study aims to establish correlation between both the gait and speech deficits
in those diagnosed with Parkinson’s disease. Using previously identified motor and
speech measurements and tasks, I conducted a correlational study of individuals with
Parkinson’s disease at baseline. There were correlations between multiple speech and gait
variability outcomes. The expected correlations ranged from average harmonics-to-noise
ratio values against anticipatory postural adjustments-lateral peak distance to average
shimmer values against anticipatory postural adjustments-lateral peak distance. There
were also unexpected outcomes that ranged from F2 variability against the average
number of steps in a turn to intensity variability against step duration variability. I also
analyzed the speech changes over 1 year as a secondary outcome of the study. Finally, I
found that averages and variabilities increased over 1 year regarding speech primary
outcomes. This study serves as a basis for further treatment that may be able to
simultaneously treat both speech and gait deficits in those diagnosed with Parkinson’s.
The exploratory study also indicates multiple targets for further investigation to better
understand cohesive and compensatory mechanisms.
ContributorsBelnavis, Alexander Salvador (Author) / Peterson, Daniel (Thesis advisor) / Daliri, Ayoub (Committee member) / Berisha, Visar (Committee member) / Arizona State University (Publisher)
Created2022
Description
INTRODUCTION: As people age, they become increasingly susceptible to falls, particularly when their attention is divided. Cognitive domains such as executive functioning and processing speed also decline over time and are associated with falls. A critical aspect to reducing falls are reactive steps, which are used to recover balance after a perturbation. Characterizing the relationship between cognition, dual tasking, and prioritization is necessary in order to decrease fall risk in older adults. Thus, the purpose of this analysis was to determine the effects of baseline cognitive status on dual task interference and prioritization of postural and cognitive tasks while reactive stepping. METHODS: 30 participants (Parkinson's disease (PD) n=16, healthy controls (HC) n=14) were divided into two groups based on their baseline cognitive status: the high-cog group (n=18) or the low-cog group (n=12). All participants experienced 7 perturbation trials where they were solely tasked with reactive stepping, 2 cognitive trials where they were solely tasked with verbally responding to an auditory Stroop test, and 7 trials that combined the two tasks. Cognitive and protective stepping performance was calculated for dual task interference and prioritization across groups. RESULTS: There were no outcome variables that showed the log-cog group performing worse than the high-cog group from single to dual task conditions. While examining the dual task interference between groups, the only significant outcome was that the low-cog group exhibited a subtle improvement in their step length performance under dual task conditions while the high-cog group did not. When comparing the prioritization scores, there was no statistically significant difference in prioritization between the high-cog and low-cog group. Albeit not significant across groups, the prioritization score for all outcomes was negative, indicating a stepping prioritization under dual task conditions for both groups. This analysis provides preliminary evidence that baseline cognitive status does not significantly affect dual task interference nor prioritization while reactive step dual tasking. While these effects should be treated with caution, these results would suggest that baseline cognitive status may not play a critical role in dual task interference or attentional allocation in both people with PD and healthy older adults.
ContributorsBarajas, Jordan (Author) / Peterson, Daniel S (Thesis advisor) / Schaefer, Sydney (Committee member) / Ofori, Edward (Committee member) / Arizona State University (Publisher)
Created2020
Description
The presence of pesticide contaminants in cannabis, such as organophosphate and pyrethroid pesticides, has resulted in multiple recalls by manufacturers in the U.S. There are no national guidelines to mitigate the health risk of pesticide exposure in cannabis because it is an illicit Schedule I substance under federal law. Here, we reviewed the state-level regulations of organophosphate and pyrethroid pesticides in cannabis between 2019 and 2023 and found that 14 more jurisdictions (for a total of 29) are regulating organophosphate or pyrethroid pesticides in the U.S. We evaluated the potential connections between pyrethroids, organophosphates, cannabinoids, and Parkinson’s disease using the Comparative Toxicogenomics Database (CTD). 10 pyrethroids, 27 organophosphates, and 15 cannabinoids were associated with 68 genes to form 2,320 inferred and curated Chemical-Gene-Phenotype-Disease tetramers. Exposure to chlorpyrifos and permethrin, but not Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), results in dose-dependent effects on 1-nonanol repulsive behaviors in Caenorhabditis elegans, indicating dopaminergic neurotoxicity (p < 0.01). Dose-dependent effects of chlorpyrifos, but not permethrin, are different in the presence of Δ9-THC and CBD (p < 0.001). Our findings show that (1) U.S. states are reaching a consensus on pesticide regulation in cannabis and (2) regulators need to consider the mechanistic interaction of pesticides and cannabinoids. Further research should apply new approach methodologies such as C. elegans and CTD can help inform pesticide regulation in cannabis by chemical class.
ContributorsRivera, Albert (Author) / Leung, Maxwell (Thesis director) / Neisewander, Janet (Committee member) / Barrett, The Honors College (Contributor) / Department of Psychology (Contributor)
Created2023-12