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

α-突触核蛋白菌株特性与帕金森病伴痴呆的诊断和进展相关

• 批准号: 10369767
• 负责人: Xiaobo Mao
• 金额: $ 213.33万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10369767
• 关键词: Alzheimer' s Disease; Alzheimer' s disease related dementia; Animals; Automobile Driving; Autopsy; Biochemical; Biological Assay; Biological Markers; Biophysics; Brain; Cerebrospinal Fluid; Clinical; Cognition; Cognitive; Cross-Sectional Studies; Data; Data Set; Delusions; Dementia; Dementia with Lewy Bodies; Deposition; Development; Diagnosis; Disease; Disease Progression; Double-Blind Method; Exhibits; Experimental Models; Fluorescence; Functional disorder; Goals; Hallucinations; Heterogeneity; Human; Impaired cognition; Individual; Longitudinal Studies; Mediating; Methodology; Methods; Midbrain structure; Motor; Mus; Parkinson Disease; Parkinson' s Dementia; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Phenotype; Prions; Process; Property; Protocols documentation; Quality of life; Records; Research Priority; Resources; Role; Sampling; Seeds; Stereotyping; Technology; Therapeutic; Time; Tissues; Validation; alpha synuclein; base; biomarker development; biophysical properties; brain tissue; cognitive impairment in Parkinson' s; cohort; common symptom; cost; demented; follow-up; improved; ineffective therapies; light scattering; mortality; motor symptom; mouse model; neurotoxicity; novel; novel marker; predictive marker; programs; protein misfolding cyclic amplification; synucleinopathy; transmission process

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.

路易体痴呆是仅次于阿尔茨海默病的第二种最常见的痴呆症， 定义与聚集的α-突触核蛋白在皮质中的沉积有关，并被确认为一项研究 阿尔茨海默病相关痴呆症计划的优先事项。帕金森氏病痴呆(PDD)就是其中之一 当一个人在运动发作超过一年后出现痴呆症时，就会被诊断为 帕金森病(PD)的症状。届时多达1/3的帕金森病患者会有认知障碍(PD-CI) 超过80%的人在他们的疾病过程中变得痴呆，从 PD-正常认知(PD-NC)，到PD-MCI(轻度CI)，然后是PDD。然而，这一进程是可变的 15年后患有PD-NC或PD-MCI的20%的人以及那些确实发展为PDD的人的PDD比率 痴呆症，是高度可变的。PDD尤其令人虚弱，因为患者还可以患有妄想症和 幻觉共同导致显著的生活质量成本和比单独帕金森病更高的死亡率。 确定病理标记物与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改善疾病的疗法。 致病的α-SYN传播被强烈地牵涉到介导一种刻板的病理传播 从肠道到大脑的时尚，皮质中的α-SYN病理推动了痴呆症的发展。近期 研究支持这样一种观点，即致病的α-SYN的行为方式类似于菌株特有的普恩病毒 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-突触核病症中，也许在认知的开始和进展中观察到的变异性 帕金森病的损害(CI)。然而，α-SYN株的特性与帕金森病的CI之间的关联是 非常有限。我们建议使用已建立的协议来放大α-SYN聚集体，方法是使用 从我们的PD-NC和PDD患者的脑脊液样本中提取病理性α-SYN的模板，并鉴定、定义和 通过生物物理和生化方法以及细胞和动物试验分离不同的α-SYN菌株。我们 将比较不同认知层在横断面(目标1)和 纵向(目标2)分析，以评估α-SYN株随之变化的程度并预测发展 PD-MCI和PDD。然后，我们将把同样的方法应用于个人的肠道和大脑尸检组织。 帕金森病和肠脑型α-突触核病小鼠模型(目标3)。我们将确定两者之间的关联 帕金森病患者α-SYN特征株及CI的特性该项目的首要目标是确定 PD-MCI和PDD菌株及其菌株转换可作为该病发病和死亡的生物标志物 脑梗塞在帕金森病中的进展。成功完成我们的目标将主要确定预测 PD中CI的发生和发展，但也揭示了PD中痴呆的发病机制，发现有希望 疾病修改和产生新的实验模型的目标。