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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：
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