Project IV "Tackling Heterogeneity of Cognitive Trajectory in LBD"

项目四“解决LBD认知轨迹的异质性”

• 批准号: 10373923
• 负责人: ALICE S CHEN-PLOTKIN
• 金额: $ 45.27万
• 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: 2019-09-30 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10373923
• 关键词: Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Antibodies; Autopsy; Biochemical; Biologic Characteristic; Biological; Biological Assay; Biological Markers; Cells; Characteristics; Clinical; Clinical Trials; Cognitive; Complement; Complex; Dementia; Dementia with Lewy Bodies; Deposition; Development; Disease; Disease Progression; Enzyme-Linked Immunosorbent Assay; Exhibits; Genetic; Genetic Markers; Genetic Risk; Heterogeneity; Human; Impaired cognition; Individual; Lewy Body Disease; Measures; Mendelian randomization; Methods; Molecular; Molecular Conformation; Motor; Neurobehavioral Manifestations; Neurologic; Neurons; Onset of illness; Outcome; Parkinson Disease; Parkinson' s Dementia; Pathologic; Pathology; Pathway interactions; Patients; Plasma; Plasma Proteins; Process; Proteins; Quantitative Trait Loci; Reporting; Role; Sampling; Scheme; Single Nucleotide Polymorphism; Site; Subgroup; Testing; United States National Institutes of Health; Validation; alpha synuclein; biomarker development; biomarker validation; candidate marker; clinical Diagnosis; cognitive development; cohort; comparison group; endophenotype; follow-up; genome wide association study; genome-wide; improved; molecular phenotype; motor symptom; novel; phenomenological models; predictive marker; programs; recruit; risk variant; screening; symptomatology; synucleinopathy; transmission process

PROJECT SUMMARY/ABSTRACT Project IV: Tackling Heterogeneity of Cognitive Trajectory in Lewy Body Disorders Project IV Leader: Alice Chen-Plotkin; Co-Leaders: Daniel Weintraub, Rizwan Akhtar 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 outcome. 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, some subsequently develop significant cognitive decline and eventual dementia (Parkinson’s Disease with Dementia, or PDD), while others do not. The reasons for these differences in phenomenology among synucleinopathy patients are not well understood. Project IV, like Projects I, II, and III, investigates the role of aSyn in the Alzheimer’s Disease related dementias (ADRD), in the context of living patients who manifest with DLB vs. PD vs. PDD vs. AD. This project aims to define endophenotypes within the LBD vs. AD spectrum using objectively-measured biomarker characteristics. 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 whose baseline levels associate with subsequent cognitive decline. We will validate 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 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 genomewide association with AD risk. These SNPs may then be developed as genetic biomarkers predicting cognitive trajectory in LBD. Specific Aim 3: Define the clinical correlates of different strains of aSyn. We will use enzyme-linked immunosorbent assays (ELISAs) developed with antibodies raised to different conformations of aSyn – “strains” as defined in Project I – to test the hypothesis that different strains of aSyn result in differential development of cognitive features among the synucleinopathies PD without dementia, PDD, and DLB. We will characterize AD and neurological normal controls as comparator groups.

项目摘要/摘要 项目IV：应对路易障碍中认知轨迹的异质性 IV项目负责人：Alice Chen-Plotkin；联合领导者：丹尼尔·温特劳布（Daniel Weintraub），Rizwan Akhtar 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 神经元（或神经元核元病），其中一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，一些患者随后会出现明显的认知下降和最终痴呆症（帕金森氏病 使用痴呆症或PDD），而其他人则没有。这些在现象学上差异的原因 肌醇病患者尚不清楚。 IV项目I，II，II和III，调查了 阿尔茨海默氏病有关的痴呆症（ADRD）中的Asyn，在表现的活着的患者中 DLB与PD与PDD与AD。该项目旨在定义LBD与AD光谱中的内型型 使用客观测量的生物标志物特征。我们使用两种公正的筛选方法， 假设驱动的方法以三个目的开发遗传和生化生物标志物： 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 10个血浆蛋白的候选清单，其基线水平与随后的认知下降相关。我们将 在> 1000个PD主题中验证这些标记，开发多蛋白分类器面板以准确 认知轨迹的预测。我们将在DLB和AD的比较组中表征这些蛋白质 患者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影响LBD中的认知轨迹。为此，我们 将用作MR单核苷酸多态性（SNP）的仪器变量（1） 与蛋白质水平的候选生物化学生物标志物的关系或（2）其全基因组的关联 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。 特定目标3：定义不同菌株ASYN的临床相关性。我们将使用酶连接 免疫吸附剂测定（ELISA）开发，其抗体提出了ASYN的不同考虑的抗体 - “菌株” 正如项目I所定义的那样 - 检验以下假设：ASYN的不同菌株会导致不同的发展 无痴呆症，PDD和DLB的突触核酸PD PD中的认知特征。我们将描述广告 和神经正常对照作为比较组。