The Role of Alzheimer's Disease Genetic Risk in Predicting Parkinson's Disease Dementia

帕金森病（PD）认知功能下降的病理机制知之甚少， 尽管阿尔茨海默病（AD）的共同病理学起着重要作用。超过80%的PD患者 患上痴呆症，导致生活质量下降，增加照顾者的负担，以及更糟糕的健康结果。 症状治疗仅是最低限度有效的，并且不存在疾病修饰疗法，这代表了 未满足的主要需求。提高我们对PD痴呆（PDD）神经生物学的理解可以阐明 开发新的治疗途径。确定AD遗传风险因素在PDD中的作用将扩大 我们对这种疾病的理解。我们假设AD遗传风险因素将预测更快的认知能力， 下降，分子生物标志物中反映的tau和淀粉样蛋白-β42（Aβ）沉积增加， 病理学特罗佩亚博士将利用宾夕法尼亚大学现有的多个研究群体， 太平洋西北尤德尔中心（PANUC）是宾夕法尼亚大学的长期合作者，而国际 帕金森病进展标志物标志物倡议（PPMI）。这项建议的目的是测试是否 与AD风险相关的全基因组遗传变异与1）纵向认知 下降，2）分子生物标志物中反映的更大程度的神经变性、tau和Aβ沉积，3） PD中的AD神经病理学。 K23候选人是宾夕法尼亚大学神经病学助理教授。他此前 完成了运动障碍奖学金和NINDS T32支持的转化研究硕士学位。他 有生产力的历史，进行了神经科学的基础和临床研究，最近专注于 关于PDD候选人致力于翻译研究的职业生涯，并提出了全面的五个- 导师制、正规培训、自主学习和研究的一年计划。这个K23奖将建立博士。 特罗佩亚是一名临床科学家，擅长1）开发和执行遗传关联研究;以及2） 了解AD和PD之间的共同遗传风险。这个职业发展奖将支持博士。 特罗佩亚的短期目标包括：1）详细了解遗传关联研究， 预测临床、生物标志物和神经病理学结果的多基因风险评分，2）获得技能 分析和解释复杂的临床和遗传数据所必需的;和3）培养分析和解释复杂的临床和遗传数据的技能 生物标志物和神经病理学数据。特罗佩亚博士将在导师的指导下实现这些目标 团队，包括Alice Chen-Plotkin博士（主要导师），一位联邦政府资助的临床科学家， 导师John Q Trojanowski博士（共同导师），世界知名的衰老分子病理学专家 和神经退行性疾病，拥有杰出的教师指导记录，以及Sharon X博士。谢，一个专家， 神经退化的生物统计学该奖项将支持特罗佩亚博士在他的追求，发展职业生涯作为一个 独立临床医生-科学家，专注于将生物学见解转化为PD临床研究。

The pathologic mechanisms of cognitive decline in Parkinson's disease (PD) are poorly understood, although Alzheimer's disease (AD) co-pathology plays an important role. Over 80% of people with PD will develop dementia, causing lower quality of life, increased caregiver burden, and worse health outcomes. Symptomatic therapies are only minimally effective, and no disease-modifying therapies exist, which represent major unmet needs. Improving our understanding of the neurobiology of PD dementia (PDD) can elucidate pathways for novel treatment development. Identifying the role of AD genetic risk factors in PDD will broaden our understanding of this disease. We hypothesize that AD genetic risk factors will predict faster cognitive decline, greater tau and amyloid-β42 (Aβ) deposition as reflected in molecular biomarkers, and more AD co- pathology in PD. Dr. Tropea will leverage multiple existing research cohorts at the University of Pennsylvania, the Pacific Northwest Udall Center (PANUC), who are longstanding UPenn collaborators, and the international Parkinson's Progression Markers marker Initiative (PPMI). The aims of this proposal are to test whether genetic variants in genome-wide association with risk of AD are associated with 1) longitudinal cognitive decline, 2) a greater degree of neurodegeneration, tau and Aβ deposition reflected in molecular biomarkers, 3) AD neuropathology in PD. The K23 candidate is an Assistant Professor of Neurology at The University of Pennsylvania. He previously completed a movement disorders fellowship and NINDS T32-supported Masters of Translational Research. He has a history of productivity, having conducted basic and clinical research in neuroscience, recently focusing on PDD. The candidate is committed to a career in translational research and proposes a comprehensive five- year plan of mentorship, formal training, self-directed learning, and research. This K23 award will establish Dr. Tropea as a clinician-scientist with expertise in 1) developing and executing genetic association studies; and 2) understanding common genetic risk between AD and PD. This career development award will support Dr. Tropea's short-term goals, including 1) developing a detailed understanding of genetic association studies and polygenic risk scores in predicting clinical, biomarker, and neuropathological outcomes, 2) acquisition of skills necessary to analyze and interpret complex clinical and genetic data; and 3) developing skills for analyzing biomarker and neuropathology data. Dr. Tropea will meet these objectives under the guidance of a Mentorship Team, including Dr. Alice Chen-Plotkin (primary mentor), a federally-funded clinician-scientist and established mentor, Dr. John Q Trojanowski (co-mentor), a world-renowned expert in the molecular pathology of ageing and neurodegeneration with a distinguished record of faculty mentorship, and Dr Sharon X. Xie, an expert in biostatistics in neurodegeneration. This Award will support Dr. Tropea in his pursuit to develop a career as an independent clinician-scientist, focused on translating biological insights into clinical studies in PD.