Project IV "Tackling Heterogeneity of Cognitive Trajectory in LBD"

项目概要/摘要 项目四：解决路易体疾病认知轨迹的异质性 项目IV负责人：Alice Chen-Plotkin；联合领导人：Daniel Weintraub、Rizwan Akhtar 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 的人类患者中 神经元（或神经元突触核蛋白病），有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，一些人随后出现显着的认知能力下降并最终患上痴呆症（帕金森病 患有痴呆症（PDD），而其他人则没有。现象学差异的原因 突触核蛋白病患者尚不十分了解。项目 IV 与项目 I、II 和 III 一样，研究了 阿尔茨海默氏病相关痴呆症 (ADRD) 中的 aSyn，在存在以下症状的活着的患者中 DLB、PD、PDD、AD。该项目旨在定义 LBD 与 AD 谱系内的内表型 使用客观测量的生物标志物特征。我们使用公正的筛选方法和 假设驱动的方法开发遗传和生化生物标志物的三个目标： 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 10 种血浆蛋白的候选列表，其基线水平与随后的认知能力下降相关。我们会 在超过 1000 名其他 PD 受试者中验证这些标记，开发多蛋白质分类器面板以实现准确 认知轨迹的预测。我们将在 DLB 和 AD 比较组中表征这些蛋白质 患者以及神经系统正常的对照。 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 相关疾病过程影响 LBD 的认知轨迹。为此，我们 将使用从 (1) 提名的 MR 单核苷酸多态性 (SNP) 作为工具变量 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 广告风险。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：定义不同 aSyn 菌株的临床相关性。我们将使用酶联 使用针对 aSyn 不同构象的抗体开发的免疫吸附测定 (ELISA) - “菌株” 如项目 I 中所定义 - 检验不同 aSyn 菌株导致不同发育的假设 不伴痴呆的突触核蛋白病 PD、PDD 和 DLB 的认知特征。我们将描述AD 和神经系统正常对照作为比较组。

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.