Biomarkers of cognitive decline in Parkinson's Disease

帕金森病认知能力下降的生物标志物

• 批准号: 10224754
• 负责人: ALICE S CHEN-PLOTKIN
• 金额: $ 71.23万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-19 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224754
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Autopsy; Biochemical; Biochemical Genetics; Biologic Characteristic; Biological; Biological Assay; Biological Markers; Cells; Characteristics; Clinical; Clinical Trials; Cognition; Cognitive; Complex; Dementia; Dementia with Lewy Bodies; Deposition; Development; Disease; Disease Progression; Exhibits; Future; Genetic; Genetic Markers; Genetic Polymorphism; Genetic Risk; Heterogeneity; Human; IgE; Impaired cognition; Individual; Investigation; Lewy Body Disease; Measures; Mendelian randomization; Methods; Modification; Molecular; Mutation; Neurobehavioral Manifestations; Neurologic; Neurons; Onset of illness; Outcome; Parkinson Disease; Parkinson' s Dementia; Pathology; Pathway interactions; Patients; Pennsylvania; Plasma; Plasma Proteins; Process; Proteins; Quantitative Trait Loci; Reporting; Resources; Sampling; Scheme; Signal Transduction; Single Nucleotide Polymorphism; Site; Subgroup; Testing; Time; United States National Institutes of Health; Universities; Validation; alpha synuclein; biomarker development; biomarker validation; blood-based biomarker; candidate marker; clinical Diagnosis; cognitive development; cognitive impairment in Parkinson' s; cohort; comparison group; endophenotype; genetic variant; genome wide association study; improved; in vivo; loss of function; loss of function mutation; molecular phenotype; motor symptom; nervous system disorder; novel; patient subsets; phenomenological models; predictive marker; programs; risk variant; screening; symptomatology; synucleinopathy

PROJECT SUMMARY/ABSTRACT: Biomarkers of Cognitive Decline in Parkinson's Disease While patients with Lewy body disorders (LBD) share the core feature of deposition of misfolded alpha-synuclein (aSyn) into neuropathological inclusions, they exhibit pronounced heterogeneity in both initial clinical phenomenology, as well as in trajectory of outcomes. Specifically, among human patients with aSyn inclusions in neurons (or neuronal synucleinopathy), some manifest predominantly with cognitive symptoms and dementia from disease onset – resulting in a clinical diagnosis of dementia with Lewy bodies (DLB). Others manifest predominantly with motor symptoms – resulting in a clinical diagnosis of Parkinson’s disease (PD). Among PD patients, most subsequently develop significant cognitive decline and eventual dementia (PD with dementia, or PDD), while others do not, and the time course to PDD varies widely. The reasons for these differences in phenomenology among synucleinopathy patients are not well understood. This project aims to define endophenotypes within the LBD spectrum using objectively-measured biomarker characteristics, developing predictors of cognitive decline in PD and comparing these molecular signals to those found in DLB and Alzheimer’s disease (AD) patients. We use both unbiased screening approaches and hypothesis- driven approaches to develop genetic and biochemical biomarkers in three Aims: Specific Aim 1: Develop biochemical biomarkers of differential PD cognitive progression. Through unbiased screening of >1000 plasma proteins in >300 PD patients from multiple cohorts, we have derived a candidate list of 10 plasma proteins that predict future cognitive decline. We will assay these markers in >1000 additional PD subjects, developing multi-protein classifier panels for accurate prediction of cognitive trajectory. We will characterize these proteins in comparator groups of DLB and AD patients, as well as neurologically- normal controls. Specific Aim 2: Investigate causal influences on cognitive trajectory among LBD patients using Mendelian randomization. We will use Mendelian randomization (MR) to test the hypotheses that candidate biochemical biomarkers and AD-related disease processes causally influence cognitive trajectory in LBD. To do this, we will use as instrumental variables for MR single nucleotide polymorphisms (SNPs) nominated from (1) their relationships with protein levels of candidate biochemical biomarkers or (2) their genome-wide association with AD risk. These SNPs may then be developed as genetic biomarkers predicting cognitive trajectory in LBD. Specific Aim 3: Determine whether biochemical and genetic biomarkers predictive of cognitive decline differ for PD with vs. without GBA mutations. We propose to use a unique resource in development at the University of Pennsylvania – the Molecular Integration in Neurological Disease (MIND) Initiative – to compare biochemical and genetic biomarkers predictive of cognitive decline in PD with vs. without GBA mutations.

项目总结/摘要：帕金森病认知功能下降的生物标志物 而路易体病（LBD）患者的核心特征是错误折叠的α-突触核蛋白沉积， 在神经病理学包涵体中，它们在两种初始临床表现中表现出明显的异质性。 现象学，以及结果的轨迹。具体而言，在患有aSyn包涵体的人类患者中， 在神经元（或神经元突触核蛋白病）中，一些主要表现为认知症状和痴呆 从疾病发作-导致路易体痴呆症（DLB）的临床诊断。其他人表现出 主要伴有运动症状-导致帕金森病（PD）的临床诊断。PD中 患者，大多数随后发展为显著的认知下降和最终的痴呆（PD伴痴呆，或 PDD），而其他人则没有，PDD的时间过程差异很大。这些差异的原因是， 突触核蛋白病患者中的现象学尚不清楚。该项目旨在定义 使用客观测量的生物标志物特征确定LBD谱内的内表型， 开发PD认知功能下降的预测因子，并将这些分子信号与发现的信号进行比较。 在DLB和阿尔茨海默病（AD）患者中。我们使用无偏的筛选方法和假设- 开发遗传和生物化学生物标志物的驱动方法有三个目标： 具体目标1：开发不同PD认知进展的生物化学生物标志物。通过 在来自多个队列的>300名PD患者中进行>1000种血浆蛋白的无偏筛选，我们得出了一个 预测未来认知能力下降的10种血浆蛋白的候选名单。我们将在>1000个样本中检测这些标记物， 额外的PD受试者，开发多蛋白质分类器面板，用于准确预测认知轨迹。 我们将在DLB和AD患者的对照组中表征这些蛋白质，以及在神经学上- 正常对照者 具体目标2：研究使用以下方法对LBD患者认知轨迹的因果影响： 孟德尔随机化。我们将使用孟德尔随机化（MR）来检验候选人的假设， 生化生物标志物和AD相关疾病过程因果地影响LBD的认知轨迹。做 因此，我们将使用从（1）中提名的MR单核苷酸多态性（SNP）作为工具变量。 它们与候选生化生物标志物的蛋白质水平的关系，或（2）它们的全基因组关联 AD风险。这些SNPs可以作为预测LBD认知轨迹的遗传生物标志物。 具体目标3：确定生物化学和遗传生物标志物是否可预测认知能力下降 有GBA突变的PD与无GBA突变的PD不同。我们建议在开发中使用一种独特的资源， 宾夕法尼亚大学-神经疾病分子整合（MIND）倡议-比较 生物化学和遗传生物标志物预测具有与不具有GBA突变的PD中的认知下降。