Can diagnostic biomarkers for parkinsonian syndromes be measured in postmortem blood samples?

可以在死后血液样本中测量帕金森综合症的诊断生物标志物吗？

• 批准号: 10572535
• 负责人: GAL BITAN
• 金额: $ 44.45万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10572535
• 关键词: Address; Affect; Age; Alzheimer' s disease pathology; Anxiety; Autonomic Dysfunction; Autopsy; Biological Markers; Blood; Blood Tests; Blood specimen; Brain; Brain Diseases; Caregivers; Cessation of life; Chickens; Clinical Trials; Confusion; Consult; Data; Dementia; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Early Diagnosis; Enzymes; Erythrocytes; Family; Future; Goals; Health; Hemoglobin; Immunoprecipitation; MM form creatine kinase; Measurement; Measures; Monitor; Movement Disorders; Multiple System Atrophy; Muscle; Muscle Cells; Neurodegenerative Disorders; Neurologist; Neurons; Oligodendroglia; Parkinson Disease; Parkinsonian Disorders; Pathologic; Pathologist; Patients; Persons; Phosphorylation; Pilot Projects; Plasma; Progressive Supranuclear Palsy; Proteins; Public Health; Publishing; Research Institute; Sampling; Serum; Signal Transduction; Source; Specialist; Specificity; Stress; Symptoms; Tauopathies; Testing; Time; Tissues; Validation; accurate diagnosis; alpha synuclein; biobank; biomarker panel; candidate marker; clinical diagnosis; corticobasal degeneration; corticobasal syndrome; diagnostic accuracy; diagnostic biomarker; diagnostic panel; disease diagnosis; effective therapy; egg; extracellular vesicles; improved; liquid biopsy; minimally invasive; neuropathology; patient stratification; prevent; success; synucleinopathy; tau Proteins; tau-1; treatment effect

Summary Many cases of Parkinson’s disease (PD), and even more so atypical parkinsonian disorders, are misdiagnosed. Misdiagnosis not only causes high stress and anxiety to patients, families, and caregivers, but also is a major impediment to developing effective therapy for these diseases. Recently, we have demonstrated that the α- synuclein concentration in extracellular vesicles (EVs) immunoprecipitated from serum or plasma using oligodendroglial and neuronal markers, and in particular the ratio between the α-synuclein concentrations in the two types of EVs, provided a sensitive biomarker for distinguishing between Parkinson’s disease and multiple system atrophy (MSA). This liquid biopsy approach requires only a minimally invasive blood draw and could lead to a major advancement in developing diagnostic tests for these diseases. However, the definition of the groups was based on clinical diagnosis, which is error-prone, creating a chicken-and-egg problem. To address this issue, here we propose a pilot study testing biomarkers in serum samples collected postmortem for which the diagnosis was validated pathologically. This strategy could not work for total α-synuclein for specific reasons that are hypothesized not to be applicable to the biomarkers in the current proposal. We will also test the utility of each of the new biomarkers as part of diagnostic biomarker panel for distinguishing PD, MSA, and two additional atypical parkinsonian syndromes—progressive supranuclear palsy and corticobasal syndrome—from each other and from control samples. The main goal of the pilot study is to determine whether pathologically validated postmortem samples can be used for biomarker measurement in CNS-originating EVs for parkinsonian syndromes. A secondary goal is to test the contribution of each biomarker to the diagnostic panel. The study has the potential to lead to future development of minimally invasive biomarkers allowing early and accurate diagnosis of parkinsonian disorders.

摘要 许多帕金森氏病(PD)病例，尤其是非典型帕金森病，都被误诊了。 误诊不仅会给患者、家属和照顾者带来很大的压力和焦虑，而且是一种主要的 阻碍开发这些疾病的有效治疗方法。最近，我们已经展示了α- 从血清或血浆中免疫沉淀细胞外小泡中突触核蛋白浓度的研究 少突胶质细胞和神经元标记物，特别是α-突触核蛋白浓度之间的比率 两种类型的EVS为区分帕金森氏病和多发性硬化提供了一个敏感的生物标志物 系统萎缩(MSA)。这种液体活组织检查方法只需要微创抽血，并可能导致 在开发这些疾病的诊断测试方面取得了重大进展。然而，对这些群体的定义 是基于临床诊断，这很容易出错，造成了一个鸡和蛋的问题。要解决这个问题 在这里，我们建议进行一项初步研究，测试死后采集的血清样本中的生物标记物 诊断经病理证实。这种策略不能用于总α-突触核蛋白，因为特定的原因 假设不适用于当前提案中的生物标记物。我们还将测试 每个新的生物标记物都是诊断生物标记物小组的一部分，用于区分PD、MSA和另外两个 非典型帕金森综合征-进行性核上性瘫痪和皮质-基底综合征-相互关联 以及对照样本。这项初步研究的主要目标是确定病理上是否有效 帕金森病死后标本可用于中枢神经系统起源的EVS的生物标记物测量 综合症。第二个目标是测试每个生物标记物对诊断小组的贡献。这项研究已经 导致微创生物标记物未来发展的潜力，使早期和准确 帕金森病的诊断。