Biomarkers of cognitive decline in Parkinson's Disease

帕金森病认知能力下降的生物标志物

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Alzheimer&apos 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&apos 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&apos 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

项目摘要

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.

项目摘要/摘要：帕金森氏病认知能力下降的生物标志物而Lewy身体疾病（LBD）的患者具有沉积错误折叠α-核蛋白的核心特征（Asyn）进入神经病理学包含，它们在两个初始临床上暴露了明显的异质性现象学，以及结果的轨迹。具体而言，在ASYN夹杂物患者中在神经元（或神经元核元病）中，有些主要表现为认知症状和痴呆从疾病发作中 - 导致对Lewy身体（DLB）的痴呆症的临床诊断。其他人表现出来主要是运动症状 - 导致对帕金森氏病（PD）的临床诊断。在PD中患者，随后大多数患者的认知能力下降和最终痴呆症（患有痴呆症的PD或 PDD），而其他人则没有，而PDD的时间课程差异很大。这些差异的原因突触核苷患者的现象学尚不清楚。该项目旨在定义 LBD光谱中使用客观测量的生物标志物特征，内型型，开发PD认知能力下降并将这些分子信号与发现的预测指标在DLB和阿尔茨海默氏病（AD）患者中。我们使用公正的筛选方法和假设 - 以三个目的开发遗传和生化生物标志物的驱动方法：特定目的1：开发差异PD认知进展的生化生物标志物。通过在来自多个队列的300名PD患者中，无偏筛选> 1000个血浆蛋白，我们衍生了候选10个血浆蛋白的清单，这些等离子体蛋白可以预测未来的认知下降。我们将在> 1000中断言这些标记其他PD受试者，开发多蛋白分类器面板，以准确预测认知轨迹。我们将在DLB和AD患者的比较组中表征这些蛋白质，以及神经学 - 正常对照。特定目的2：研究利用LBD患者对认知轨迹的因果影响孟德尔随机化。我们将使用Mendelian随机化（MR）来测试该候选者的假设生化生物标志物和与广告相关的疾病过程有时会影响LBD的认知轨迹。做这，我们将用作从（1）提名的MR单核苷酸多态性（SNP）的仪器变量它们与蛋白质水平的候选生物化学生物标志物或（2）全基因组关联的关系有广告风险。然后，这些SNP可以作为遗传生物标志物预测LBD中的认知轨迹。特定目的3：确定生化和遗传生物标志物是否可以预测认知能力下降与无GBA突变的PD的差异。我们建议在开发中使用独特的资源宾夕法尼亚大学 - 神经疾病（思维）倡议的分子整合 - 比较生化和遗传生物标志物可预测PD的认知能力下降，而没有GBA突变。