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: 10020338
• 负责人: ALICE S CHEN-PLOTKIN
• 金额: $ 51.85万
• 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/10020338
• 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; Deposition; Development; Disease; Disease Progression; Enzyme-Linked Immunosorbent Assay; Exhibits; Genetic; Genetic Markers; Genetic Risk; Heterogeneity; Human; Impaired cognition; Individual; Lewy Body Dementia; Lewy Body Disease; Measures; 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; Randomized; 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.

项目总结/摘要 项目四：解决路易体障碍认知轨迹的异质性 项目四负责人：Alice Chen-Plotkin;共同负责人：丹尼尔温特劳布、Rizwan Akhtar 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。具体地，在患有aSyn包涵体的人类患者中， 神经元（或神经元突触核蛋白病），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 患者中，一些随后发展为显著的认知能力下降和最终的痴呆（帕金森病 有痴呆症或PDD），而其他人则没有。这些现象学差异的原因， 对突触核蛋白病患者的了解还不多。项目四与项目一、二和三一样，调查了 aSyn在阿尔茨海默病相关痴呆（ADRD）中的应用，在表现为 DLB与PD与PDD与AD。该项目旨在确定LBD与AD谱内的内表型 使用客观测量的生物标志物特征。我们使用无偏筛选方法， 假设驱动的方法来开发遗传和生物化学生物标志物，有三个目的： 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 10种血浆蛋白的候选列表，其基线水平与随后的认知下降相关。我们将 在>1000名额外的PD受试者中验证这些标志物，开发多蛋白质分类器组， 认知轨迹的预测我们将在DLB和AD的对照组中表征这些蛋白质 患者以及神经学正常对照。 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相关疾病过程影响LBD的认知轨迹。为此我们 将用作MR单核苷酸多态性（SNP）的工具变量，从（1） 与候选生物化学生物标志物的蛋白质水平的关系，或（2）它们与 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：确定不同aSyn菌株的临床相关性。我们将使用酶联 用针对不同构象的aSyn -“菌株”产生的抗体开发的免疫吸附测定（ELISA） 如项目I中所定义的-检验不同的aSyn菌株导致 突触核蛋白病PD无痴呆、PDD和DLB的认知特征。我们将描述AD 和神经学正常对照作为比较组。