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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：
10435485
负责人：
ALICE S CHEN-PLOTKIN
金额：
$ 71.61万
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/10435485
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：帕金森病认知能力下降的生物标志物路易体疾病 (LBD) 患者的核心特征是错误折叠的 α-突触核蛋白沉积 (aSyn) 到神经病理学包涵体中，它们在初始临床中表现出明显的异质性现象学以及结果的轨迹。具体来说，在含有 aSyn 夹杂物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开始 – 导致路易体痴呆 (DLB) 的临床诊断。其他表现主要表现为运动症状——导致帕金森病 (PD) 的临床诊断。其中PD 患者中，大多数随后出现显着的认知能力下降并最终发生痴呆（PD伴痴呆，或 PDD），而其他人则没有，并且 PDD 的时间进程差异很大。造成这些差异的原因突触核蛋白病患者的现象学尚不清楚。该项目旨在定义使用客观测量的生物标志物特征来确定 LBD 谱系内的内表型，开发帕金森病认知能力下降的预测因子，并将这些分子信号与发现的信号进行比较 DLB 和阿尔茨海默病 (AD) 患者。我们使用无偏见的筛选方法和假设- 开发遗传和生化生物标志物的驱动方法有以下三个目标：具体目标 1：开发差异性 PD 认知进展的生化生物标志物。通过对来自多个队列的 >300 名 PD 患者中的 >1000 种血浆蛋白进行公正筛查，我们得出了预测未来认知能力下降的 10 种血浆蛋白候选列表。我们将在 >1000 个中检测这些标记其他 PD 受试者，开发多蛋白质分类器面板以准确预测认知轨迹。我们将在 DLB 和 AD 患者以及神经学方面的比较组中表征这些蛋白质正常控制。具体目标 2：使用以下方法研究对 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) 来检验候选者的假设生化生物标志物和 AD 相关疾病过程会影响 LBD 的认知轨迹。要做的事我们将使用 (1) 中指定的 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有 AD 风险。然后可以将这些 SNP 开发为预测 LBD 认知轨迹的遗传生物标志物。具体目标 3：确定生化和遗传生物标志物是否可预测认知能力下降具有 GBA 突变与不具有 GBA 突变的 PD 存在差异。我们建议在开发中使用独特的资源宾夕法尼亚大学 – 神经疾病分子整合 (MIND) 计划 – 比较生化和遗传生物标志物可预测有 GBA 突变与无 GBA 突变的 PD 认知能力下降。