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：
10022178
负责人：
CLEMENS R SCHERZER
金额：
$ 69.25万
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 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10022178
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 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 outcome forecast patient oriented precision medicine predictive marker prevent prognostic recruit 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痴呆症是影响患者健康的主要决定因素之一，而不是易感性。帕金森病患者疾病进展的衰弱表现会对治疗质量产生负面影响。生命、给护理人员带来负担并增加健康成本，现有疗法无法阻止病情从最初开始的下降。从运动症状到认知障碍，患者之间的恶化速度差异很大。对于两者之间拟议的关联，目前发现的证据有限。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。预示着记忆力减退。我们发现新的预后位点将有力地预测患者患帕金森病的风险先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。无法解决对于理解进展至关重要的时间维度的研究。帕金森氏症认知进展的遗传结构，在这里我们将进行无偏见的纵向研究对来自北美和欧洲的十九个队列进行深度估算的全基因组生存研究更多。超过 6000 名帕金森病患者和超过 5000 项认知评估将被使用 Cox 比例风险以及混合随机和固定效应模型进行分析，我们将发现。在目标 2 中，我们将复制并验证与帕金森病痴呆进展相关的新位点。在目标 3 中，我们将构建并测试一个多功能的多基因变异。危险评分可准确预测未来认知能力下降的风险。这项研究旨在阐明帕金森病痴呆的进展位点，改善临床预测，并改变临床试验设计，遗传驱动因素将指向独特的认知生物学。下降可能会激发新的治疗方向。