Parkinson Disease: Predicting the Future

帕金森病：预测未来

• 批准号: 9215383
• 负责人: CLEMENS R SCHERZER
• 金额: $ 70.52万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9215383
• 关键词: Address; Aggressive course; Alzheimer' s Disease; Anguish; Binding; Biological Markers; Caregivers; Clinical; Clinical Trials; Clinical Trials Design; Clinical assessments; Code; Cognitive; Conduct Clinical Trials; Data; Dementia; Disease; Disease Progression; Europe; Future; Genes; Genetic; Healthcare; Individual; Link; Maps; Memory Loss; Modeling; Molecular; Motor; Neurodegenerative Disorders; Noise; North America; Parkinson Disease; Parkinson' s Dementia; Patients; Pharmaceutical Preparations; Phase II/III Trial; Population; Precision therapeutics; Recommendation; Recruitment Activity; Research; Research Personnel; Resources; Sample Size; Shapes; Source; Speed; Susceptibility Gene; Therapeutic Trials; United States National Institutes of Health; Variant; Wheelchairs; Work; clinical phenotype; clinical risk; cohort; cost; data management; design; exome; functional decline; genetic predictors; genetic variant; genome wide association study; innovation; novel; novel strategies; outcome forecast; patient stratification; precision medicine; protein function; rare variant; targeted sequencing

Parkinson’s Disease: Predicting the Future It is poorly understood why some patients with Parkinson’s have an aggressive disease course. The pace of progression varies considerably, ranging from a manageable functional decline to an accelerated course that leaves patients rapidly wheelchair bound or with dementia. This is a source of anguish for patients and caregivers. In clinical trials, this variation obfuscates drug effects. Many genetic variants have been linked to susceptibility, but the genes modulating disease progression have not been well established. Our initial studies indicate multiple coding and noncoding variants predictive of a hyper-accelerated motor or memory decline. We hypothesize that genetic variants will powerfully predict the progression of Parkinson’s. We will directly address this question through high coverage, massively parallel, targeted sequencing of ten cohorts from North America and Europe that were longitudinal characterized with exceptional granularity over the course of up to twelve years. 3,939 patients with Parkinson’s disease and over thirty thousand clinical assessments will be analyzed using Cox and mixed random and fixed effect models. In Aim 1, we will identify genetic variants in susceptibility loci and familial genes that predict cognitive or motor progression. Furthermore, novel putative progression loci emerging from our exome-scale search will be evaluated. In Aim 2, we will replicate and verify forwarded genetic variants in independent populations. This study will establish the first progression genes for Parkinson’s disease, clarify prognosis, and shift the way we design clinical trials. Rare variants that disrupt protein function will inform on the underlying mechanism and reveal clues for therapies. More generally, these data will contribute towards a precision medicine poised to transform healthcare.

帕金森病：预测未来 目前还不清楚为什么一些帕金森病患者有一个侵略性的疾病过程。的步伐 进展变化很大，从可管理的功能下降到加速过程， 使患者迅速坐轮椅或患痴呆症。这是病人痛苦的根源， 照顾者在临床试验中，这种变异混淆了药物的作用。许多遗传变异与 易感性，但调节疾病进展的基因尚未得到很好的建立。我们最初的研究 表明多个编码和非编码变体预示着超加速运动或记忆衰退。 我们假设遗传变异将有力地预测帕金森病的进展。我们将 通过对10个队列进行高覆盖率、大规模平行、有针对性的测序， 来自北美和欧洲的纵向特征是在 长达12年的课程。3，939例帕金森病患者和3万多名临床 将使用考克斯和混合随机和固定效应模型分析评估。在目标1中，我们将确定 易感基因座的遗传变异和预测认知或运动进展的家族基因。 此外，将评估从我们的外显子组规模搜索中出现的新的推定进展位点。在目标2中， 我们将在独立群体中复制和验证转发的遗传变异。 这项研究将建立帕金森病的第一个进展基因，阐明预后，并改变 我们设计临床试验的方式。破坏蛋白质功能的罕见变异将告知潜在的 并揭示治疗的线索。更一般地说，这些数据将有助于精确 医学有望改变医疗保健。