Biomarkers of cognitive decline in Parkinson's Disease

项目摘要/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 (ASyn)进入神经病理包涵体，它们在最初的临床上表现出明显的异质性 现象学，以及结果的轨迹。具体地说，在有aSyn包涵体的人类患者中 在神经元(或神经元突触核素病)中，一些主要表现为认知症状和痴呆症 从疾病开始-导致临床诊断为路易体痴呆(DLB)。其他人则表现得 主要表现为运动症状--导致临床诊断为帕金森氏病(PD)。在帕金森州 大多数患者随后出现明显的认知能力下降和最终的痴呆(PD伴痴呆，或 PDD)，而其他人则不是，而PDD的时间进程差异很大。造成这些差异的原因是 联核症患者中的现象学还没有得到很好的理解。该项目旨在定义 使用客观测量的生物标记物特征的LBD谱内的内表型， 开发帕金森病认知功能下降的预测因子，并将这些分子信号与已发现的分子信号进行比较 在DLB和阿尔茨海默病(AD)患者中。我们使用无偏见的筛选方法和假设- 推动开发遗传和生化生物标记物的方法有三个目标： 具体目标1：开发帕金森病认知进展的生化标志物。穿过 从多个队列的&gt；300名PD患者中无偏筛查&gt；1000血浆蛋白，我们得出了一个 候选的10种预测未来认知能力下降的血浆蛋白。我们将在&gt；1000中检测这些标记 其他帕金森病受试者，开发用于准确预测认知轨迹的多蛋白质分类器面板。 我们将在DLB和AD患者的对照组中表征这些蛋白质，以及神经学上的- 正常对照组。 具体目标2：调查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 生化标志物和AD相关疾病过程影响LBD的认知轨迹。去做 这一点，我们将使用作为工具变量的MR单核苷酸多态(SNPs)提名从(1) 它们与候选生化标志物的蛋白质水平的关系或(2)它们在全基因组范围内的关联 有老年痴呆症的风险。然后，这些SNP可能被开发为预测LBD认知轨迹的遗传生物标记物。 具体目标3：确定生化和遗传生物标记物是否预示认知功能减退 有GBA突变和无GBA突变的帕金森病患者不同。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(精神)中的分子集成倡议-比较 生化和遗传生物标记物预测有无GBA突变的帕金森病患者的认知功能下降。

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.