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

阿尔茨海默病遗传风险在预测帕金森病痴呆中的作用

• 批准号: 10475679
• 负责人: Thomas Francis Tropea
• 金额: $ 18.77万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10475679
• 关键词: Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid beta-42; Autopsy; Award; Basic Science; Bioinformatics; Biological; Biological Markers; Biometry; Brain; Brain Diseases; Caregiver Burden; Cerebrum; Clinical; Clinical Research; Clinical Trials; Clinical dementia rating scale; Cognition; Complex; Data; Data Set; Databases; Dementia; Deposition; Deterioration; Disease; Early identification; Faculty; Fellowship; Five-Year Plans; Funding; Future; General Population; Genetic; Genetic Markers; Genetic Risk; Genetic Variation; Genetic study; Goals; Health; Impaired cognition; Inclusion Bodies; Individual; International; K-Series Research Career Programs; Lead; Light; Longitudinal cohort; Medical Care Costs; Medical Genetics; Memory; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Molecular; Movement Disorders; National Institute of Neurological Disorders and Stroke; Nerve Degeneration; Neurobiology; Neurofibrillary Tangles; Neurology; Neuronal Dysfunction; Neurosciences; Outcome; Pacific Northwest; Parkinson Disease; Parkinson' s Dementia; Pathologic; Pathology; Pathway interactions; Patients; Pennsylvania; Persons; Phenotype; Play; Population; Predictive Value; Prevalence; Productivity; Proteins; Quality of life; Recording of previous events; Research; Risk; Role; Scientist; Severities; Sum; Testing; Therapeutic; Training; Translating; Translational Research; Universities; Variant; Work; alpha synuclein; axonal degeneration; care providers; career; clinical biomarkers; clinical predictors; cognitive impairment in Parkinson' s; cognitive performance; cohort; dementia risk; disorder control; genetic association; genetic risk factor; genetic variant; genome wide association study; genome-wide; genomic locus; high risk; high risk population; improved; insight; molecular marker; molecular pathology; neurofilament; neuron loss; neuropathology; non-demented; novel; polygenic risk score; predictive modeling; professor; progression marker; risk prediction; risk variant; self-directed learning; skill acquisition; skills; tau Proteins; tau-1; therapy development

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.

帕金森氏病(PD)认知功能减退的病理机制尚不清楚。 虽然阿尔茨海默病(AD)的共同病理起着重要作用。超过80%的帕金森病患者会 罹患痴呆症，导致生活质量降低，照顾者负担加重，健康状况更差。 对症治疗只有最低限度的有效，并且不存在改变疾病的治疗方法，这代表了 未得到满足的主要需求。提高我们对帕金森氏病痴呆(PDD)的神经生物学的理解可以阐明 开发新的治疗方法的途径。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。我们假设阿尔茨海默病的遗传风险因素会预测更快的认知能力 下降，分子生物标记物中反映的tau和淀粉样蛋白β42(Aβ)沉积增加，以及更多的AD共同- 帕金森病的病理学。特罗皮亚博士将利用宾夕法尼亚大学现有的多个研究队列， 太平洋西北Udall中心(PANUC)，他们是宾夕法尼亚大学的长期合作者，以及国际 帕金森进展标记物倡议(PPMI)。这项提议的目的是测试 全基因组中与阿尔茨海默病风险相关的基因变异与1)纵向认知相关 下降，2)更大程度的神经变性，tau和Aβ沉积反映在分子生物标志物中，3) 帕金森病患者的AD神经病理改变。 这位K23候选人是宾夕法尼亚大学的神经学助理教授。他之前 完成了运动障碍奖学金和NINDS T32支持的翻译研究硕士学位。他 有生产力的历史，在神经科学方面进行过基础和临床研究，最近专注于 在PDD上。候选人致力于翻译研究的职业生涯，并提出了全面的五项- 指导、正式培训、自我指导学习和研究的年度计划。这项K23奖项将确立Dr。 TROPEA作为临床医生-科学家，具有1)开发和执行遗传关联研究的专业知识；以及2) 了解AD和PD之间的共同遗传风险。这一职业发展奖将支持Dr。 Tropea的短期目标，包括1)对遗传关联研究和 预测临床、生物标志物和神经病理结果的多基因风险评分，2)获得技能 需要分析和解释复杂的临床和基因数据；以及3)发展分析技能 生物标记物和神经病理学数据。特罗皮亚博士将在导师的指导下实现这些目标 团队，包括爱丽丝·陈-普洛特金博士(主要导师)，联邦资助的临床医生兼科学家，并建立了 导师，John Q Trojanowski博士(共同导师)，世界著名的衰老分子病理学专家 和神经退行性变，有杰出的教师指导记录，和Sharon X.X.谢博士， 神经退行性变的生物统计学。这一奖项将支持特罗皮亚博士发展他的职业生涯 独立的临床医生和科学家，专注于将生物学见解转化为帕金森病的临床研究。