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：应对路易身体障碍认知轨迹的异质性 项目IV负责人：Alice Chen-Plotkin；联合负责人：Daniel Wetraub，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 (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，在患有aSyn包涵体的人类患者中 神经元(或神经元性突触核素病)，有些主要表现为认知症状和痴呆 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 患者，其中一些人随后出现明显的认知能力下降和最终的痴呆(帕金森氏病 患有痴呆症或PDD)，而其他人则没有。这些现象学差异的原因是 联核症患者并没有得到很好的理解。项目IV与项目I、II和III一样，调查了 在阿尔茨海默病相关痴呆(ADRD)中的ASyn，在活着的患者中表现为 DLB与PD、PDD与AD。该项目旨在定义LBD与AD谱系内的内表型 利用客观测量的生物标志物特征。我们使用无偏见的筛选方法和 开发遗传和生化生物标记物的假设驱动方法有三个目标： 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种血浆蛋白，其基线水平与随后的认知能力下降有关。我们会 在&gt；1000名额外的PD受试者中验证这些标记，开发多蛋白质分类器面板以获得准确的 认知轨迹的预测。我们将在DLB和AD的比较组中对这些蛋白质进行表征 患者，以及神经学正常的对照组。 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。为了做到这一点，我们 将用作(1)其提名的MR单核苷酸多态(SNPs)的工具变量 与候选生化标志物的蛋白质水平的关系或(2)它们与 广告风险。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：确定不同aSyn菌株的临床相关性。我们将使用酶联法 用针对不同构象的aSyn-“菌株”的抗体建立的免疫吸附试验(ELISA) 正如项目I中所定义的--测试不同的aSyn菌株导致不同的 不伴痴呆的PD、PDD和DLB型联核病患者的认知特征。我们将描述AD的特征 并以神经科正常对照组为对照组。