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- Creators: Poulenc, Francis, 1899-1963
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.
Alzheimer’s disease is a disease that can affect cognition, perception and behavior and is currently untreatable. It was discovered in the early 20th century and while significant scientific advancements have occurred, there is ambiguity that remains to be researched and understood. Latinos are the largest ethnic minority in the United States and while data still needs to be uncovered, possible risk factors for developing Alzheimer’s include heart issues, poverty and obesity, age and education level, to name a few. Poverty is linked to obesity, diabetes and a low education level, which in turn have been found to have an impact on Alzheimer’s and all factors impact cardiovascular and vascular health. Due to the collectivistic culture that is deeply rooted in Latinos, there is a strong sense of family that is upheld when caring for relatives who are afflicted and may be hesitant to receive the care that is needed. Other barriers include financial stability, linguistic and cultural barriers, underutilizing resources and health literacy. There are still research gaps that are yet to be filled like brain health and longitudinal studies for Latinos, but current treatments like diet and culturally competent professionals can help with the prognosis. Alzheimer’s is a complex disease, but with the numerous efforts made thus far, such as creating the LatinosAgainstAlzheimer’s Network, it will soon be able to be understood and hopefully eradicated.