α-Synuclein strain properties are associated with diagnosis of and progression to Parkinson's disease with dementia

路易体痴呆症（DLB）是继阿尔茨海默病之后第二大最常见的痴呆症疾病， 定义与皮质中聚集的α-突触核蛋白的沉积有关， 阿尔茨海默病相关痴呆症计划的优先事项。帕金森病痴呆症（PDD）是一种 当一个人在运动开始一年多后患上痴呆症时， 帕金森病（Parkinson's Disease，PD）多达1/3的PD患者在当时将有认知障碍（PD-CI） 超过80%的人在疾病过程中变得痴呆， PD-正常认知（PD-NC），PD-MCI（轻度CI），然后PDD。然而，这一进展随着 15年后，20%的PD-NC或PD-MCI患者以及确实发生PDD的患者中PDD的发生率 老年痴呆症是高度可变的。PDD特别使人衰弱，因为患者还可能患有妄想症， 幻觉，一起导致生活质量的显著成本和死亡率增加。 确定病理标志物和PDD临床表现之间的关联对于 了解发病机制，开发更有效的对症和疾病缓解疗法。 致病性α-syn传递与介导刻板印象中的病理传播密切相关。 从肠道到大脑的时尚，皮质中的α-syn病理学驱动痴呆症的发展。最近 研究支持致病性α-syn可能以类似于菌株特异性朊病毒的方式表现的观点， 表现出不同的生化和病理表型。这些不同的菌株可能是异质性的基础 在α-突触核蛋白病中，也许在认知的发作和进展中观察到的变异性 PD中的损伤（CI）。然而，α-syn菌株的性质与PD中的CI之间的关联是 非常有限。我们建议使用已建立的方案来扩增α-syn聚集体， 来自PD-NC和PDD患者CSF样本的病理性α-syn模板，并识别、定义和 通过生物物理和生物化学方法以及细胞和动物试验分离不同的α-syn菌株。我们 将在横截面（目标1）和 纵向（目标2）分析，以评估α-syn应变随发育变化的程度并预测发育 PD-MCI和PDD。然后，我们将把这些相同的方法应用于个人的肠道和大脑尸检组织， PD和肠脑α-突触核蛋白病小鼠模型（目的3）。我们将确定 PD中表征的α-syn菌株和CI的性质。本项目的首要目标是确定 PD-MCI和PDD菌株以及菌株转化可以被开发为用于发病和 PD中的CI进展。成功完成我们的目标将主要确定新的标志物，用于预测 研究PD患者CI的发病和进展，同时也揭示PD患者痴呆的发病机制， 疾病修饰和产生新的实验模型的目标。

Dementia with Lewy Bodies (DLB) is the 2nd most common dementia illness after Alzheimer’s disease, by definition is associated with deposition of aggregated alpha-synuclein in the cortex and is identified as a research priority under the Alzheimer’s Disease Related Dementia’s program. Parkinson’s disease dementia (PDD) is one of the DLB’s and is diagnosed when an individual develops dementia more than a year after onset of the motor symptoms of Parkinson’s disease (PD). Up to 1/3 PD patients will have cognitive impairment (PD-CI) at the time of diagnosis and more than 80% become demented over the course of their disease, having progressed from PD-normal cognition (PD-NC), to PD-MCI (Mild CI) and then PDD. This progression, however, is variable with 20% of individuals with PD-NC or PD-MCI after 15 years and the rate of PDD, amongst those who do develop dementia, is highly variable. PDD is particularly debilitating because patients can also suffer from delusions and hallucinations, together leading to significant cost in quality of life and increased mortality over PD alone. Determining the association between pathological markers and PDD clinical presentation is crucial for understanding the pathogenesis and developing more effective symptomatic and disease-modifying therapies. Pathogenic α‐syn transmission has been strongly implicated in mediating pathology spread in a stereotyped fashion from the gut to the brain, with α‐syn pathology in the cortex driving development of dementia. Recent studies support the notion that pathogenic α‐syn may behave in manner similar to strain-specific prions that exhibit distinct biochemical and pathologic phenotypes. These different strains may underlie the heterogeneity in α‐synucleinopathies, and perhaps the variability observed in the onset and progression of cognition impairment (CI) in PD. However, the association between the properties of α‐syn strains and CI in PD is significantly limited. We propose to use an established protocol to amplify α‐syn aggregates by using the template of pathological α‐syn from the CSF samples of our PD-NC and PDD patients, and identify, define and segregate different α‐syn strains by biophysical and biochemical methods and cellular and animal assays. We will compare the strain properties between different cognitive strata in both a cross-sectional (Aim 1) and longitudinal (Aim 2) analysis, to evaluate the extent to which α‐syn strains change with and predict development of PD-MCI and PDD. We will then apply these same methods to gut and brain autopsy tissue from individuals with PD and a gut-brain alpha-synucleinopathy mouse model (Aim 3). We will determine the association between the properties of characterized α‐syn strains and CI in PD. The overarching goal of this project is to determine if PD-MCI and PDD strains and the strain conversion can be developed as biomarkers for the onset and progression of CI in PD. Successful completion of our Aims will mainly identify new markers for predicting the onset and progression of CI in PD, but also uncover the pathogenesis of dementia in PD, discover promising targets for disease modifying and generating novel experimental models.