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: 10254407
• 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/10254407
• 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; 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.

帕金森病（PD）认知能力下降的病理机制尚不清楚， 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 患者会 患上痴呆症，导致生活质量下降、护理人员负担增加以及健康状况恶化。 对症治疗的效果有限，并且不存在缓解疾病的疗法，这代表 主要未满足的需求。提高我们对 PD 痴呆 (PDD) 神经生物学的理解可以阐明 新疗法开发的途径。确定 AD 遗传风险因素在 PDD 中的作用将扩大范围 我们对这种疾病的认识。我们假设 AD 遗传风险因素将预测更快的认知能力 分子生物标志物所反映的 tau 蛋白和淀粉样蛋白 β42 (Aβ) 沉积量增加，以及更多 AD 共存 PD 的病理学。特罗佩博士将利用宾夕法尼亚大学现有的多个研究团队， 太平洋西北尤德尔中心 (PANUC)，他们是宾夕法尼亚大学的长期合作者，以及国际 帕金森病进展标记物倡议 (PPMI)。该提案的目的是测试是否 与 AD 风险相关的全基因组遗传变异与 1) 纵向认知相关 下降，2) 分子生物标志物反映出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 具有生产力的历史，在神经科学领域进行过基础和临床研究，最近专注于 在PDD上。候选人致力于转化研究的职业生涯，并提出了全面的五项建议： 年度指导、正式培训、自主学习和研究计划。该 K23 奖项将确立 Dr. 特罗佩亚作为一名临床医生科学家，在 1) 开发和执行遗传关联研究方面拥有专业知识；和 2) 了解 AD 和 PD 之间的共同遗传风险。该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) 技能获取 分析和解释复杂的临床和遗传数据所必需的； 3）培养分析技能 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 团队成员包括 Alice Chen-Plotkin 博士（主要导师），她是一位联邦资助的临床医生科学家，并建立了 导师：John Q Trojanowski博士（联合导师），世界著名衰老分子病理学专家 Sharon X. Xie 博士是该领域的专家， 神经退行性疾病的生物统计学。该奖项将支持特罗佩亚博士追求作为一名 独立临床医生科学家，专注于将生物学见解转化为帕金森病的临床研究。