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: 10685569
• 负责人: Thomas Francis Tropea
• 金额: $ 20.91万
• 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/10685569
• 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 Carriers; Genetic Markers; Genetic Risk; Genetic Variation; Genetic study; Goals; Impaired cognition; Inclusion Bodies; Individual; International; K-Series Research Career Programs; Light; Longitudinal cohort; Medical Care Costs; 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 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; poor health outcome; 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）认知下降的病理机制知之甚少， 尽管阿尔茨海默氏病（AD）的竞争病理学起着重要作用。超过80％的PD患者将 发展痴呆症，导致生活质量较低，护理人员燃烧增加以及健康状况较差。 有症状的疗法仅是最小有效的，并且不存在疾病修改疗法，代表 主要的未满足需求。提高我们对PD痴呆（PDD）神经生物学的理解可以阐明 新型治疗发展的途径。确定AD遗传危险因素在PDD中的作用将扩大 我们对这种疾病的理解。我们假设AD遗传危险因素将预测更快的认知 下降，较大的tau和淀粉样蛋白-β42（Aβ）沉积在分子生物标志物中反映，并且更多的AD共同 PD中的病理学。 Tropea博士将利用宾夕法尼亚大学的多个现有研究队列， 长期以来的Upenn合作者和国际 帕金森的进步标记标记倡议（PPMI）。该提议的目的是测试是否 全基因组与AD风险的遗传变异与1）纵向认知有关 下降，2）反映在分子生物标志物中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。他以前 完成了运动障碍奖学金和Ninds T32支持的转化研究大师。他 在神经科学领域进行了基本和临床研究，有生产力的历史 在PDD上。候选人致力于转化研究的职业，并提出全面的五 心态，正式培训，自我指导学习和研究的年度计划。该K23奖将建立博士 Tropea作为具有专业知识的临床科学家1）发展和执行遗传关联研究；和2） 了解AD和PD之间的常见遗传风险。该职业发展奖将支持博士。 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学结果时多基因风险评分，2）获取技能 分析和解释复杂的临床和遗传数据所必需的； 3）发展分析技能 生物标志物和神经病理学数据。 Tropea博士将在指导的指导下达到这些目标 团队，包括联邦资助的临床科学家爱丽丝·陈·普罗特金（Alice Chen-Plotkin）（主要导师） 导师John Q Trojanowski博士（同事），世界知名的衰老分子病理学专家 和神经变性具有杰出的教师心态记录，Sharon X. Xie博士 神经退行性的生物统计学。该奖项将支持Tropea博士追求发展职业 独立的临床科学家，重点是将生物学见解转化为PD的临床研究。

项目成果

Expediting telehealth use in clinical research studies: recommendations for overcoming barriers in North America.

• DOI: 10.1038/s41531-021-00177-8
• 发表时间: 2021-04-12
• 期刊: NPJ Parkinson's disease
• 作者: Naito A;Wills AM;Tropea TF;Ramirez-Zamora A;Hauser RA;Martino D;Turner TH;Rafferty MR;Afshari M;Williams KL;Vaou O;McKeown MJ;Ginsburg L;Ezra A;Iansek R;Wallock K;Evers C;Schroeder K;DeLeon R;Yarab N;Alcalay RN;Beck JC
• 通讯作者: Beck JC