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Genome-wide Prediction of Dementia in Parkinson Disease

帕金森病痴呆的全基因组预测

基本信息

批准号：
10460223
负责人：
CLEMENS R SCHERZER
金额：
$ 32.54万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-20 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10460223
关键词：
Address Alzheimer&apos s disease related dementia Biology Caregiver Burden Case-Control Studies Clinical Clinical Trials Design Cognitive Cross-Sectional Studies Data Dementia Deterioration Dimensions Disease Disease Progression Disease susceptibility Europe Future Genes Genetic Genetic Predisposition to Disease Genome Goals Health Care Costs Healthcare Impaired cognition Individual Medical Memory Loss Modeling North America Parkinson Disease Parkinson&apos s Dementia Patient risk Patients Personal Satisfaction Phase II/III Trial Phase Ib/II Trial Population Precision therapeutics Predictive Value Predisposition Prognosis Quality of life Risk Sample Size Signal Transduction Speed Susceptibility Gene Testing Time Variant Visit cognitive testing cohort cost design functional decline genetic architecture genetic predictors genetic variant genome wide association study genome-wide hazard high risk improved innovation longitudinal analysis motor symptom nervous system disorder novel novel therapeutics patient oriented precision medicine predictive marker prevent prognostication recruit risk prediction symposium

项目摘要

Genome-wide Prediction of Dementia in Parkinson's Disease Progression, not susceptibility, is the major determinant of patients' well-being. Dementia is one of the most debilitating manifestations of disease progression in patients with Parkinson's. It negatively impacts quality of life, burdens caregivers and increases health costs. Existing therapies cannot prevent the decline from initial motor symptoms to cognitive impairment. The pace of deterioration varies dramatically between patients for reasons that are poorly understood. Limited evidence has been found for a proposed association between prognosis and susceptibility variants. Our initial studies provide compelling evidence for distinct genome loci predictive of memory loss. We hypothesize that novel prognosis loci will powerfully predict a patient's risk for developing Parkinson's disease dementia. Previous genome-wide association studies were time-static, cross-sectional, case-control studies that cannot address the time dimension critical for understanding progression. To systematically decode the genetic architecture of cognitive progression in Parkinson's, here we will perform an unbiased, longitudinal genome-wide survival study with deep imputation of nineteen cohorts from North America and Europe. More than six thousand patients with Parkinson’s disease and over fifty thousand cognitive assessments will be analyzed using Cox proportional hazards and mixed random and fixed effect models. In Aim 1, we will discover novel loci associated with progression to Parkinson's disease dementia. In Aim 2, we will replicate and verify forwarded genetic variants in an independent population. In Aim 3, we will build and test a versatile Polygenic Hazard Score to accurately forecast risk of future cognitive decline. This study is poised to elucidate progression loci for Parkinson’s disease dementia, improve clinical prognostication, and transform clinical trial design. The genetic drivers will point to a distinct biology of cognitive decline that could inspire new therapeutic directions.

帕金森病痴呆的全基因组预测疾病进展，而不是易感性，是患者健康的主要决定因素。痴呆症是世界上帕金森病患者疾病进展的衰弱表现。这对质量产生了负面影响，生活，负担照顾者和增加医疗费用。现有的治疗方法不能阻止从最初的下降从运动症状到认知障碍恶化的速度在患者之间差异很大，不太了解的原因。有限的证据表明，预后和易感性变异。我们的初步研究为不同的基因组位点提供了令人信服的证据预示着记忆丧失我们假设新的预后基因座将有力地预测患者发生帕金森病的风险痴呆症以前的全基因组关联研究是时间静态的、横断面的、病例对照的研究不能解决时间维度理解进展的关键。系统地解码帕金森氏症认知进展的遗传结构，在这里，我们将进行一个无偏见的，纵向的全基因组生存研究，对来自北美和欧洲的19个队列进行深度插补。更超过6000名帕金森病患者和超过5000项认知评估将被使用考克斯比例风险和混合随机和固定效应模型进行分析。在目标1中，我们将发现与帕金森病痴呆进展相关的新位点。在目标2中，我们将复制和验证在一个独立的群体中转发遗传变异。在目标3中，我们将构建和测试一个多功能的多基因危险评分可准确预测未来认知能力下降的风险。这项研究有望阐明帕金森病痴呆的进展位点，改善临床表现，简化和改变临床试验设计。遗传驱动因素将指向一种独特的认知生物学，可以激发新的治疗方向。