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.

概括 许多帕金森病 (PD) 病例，尤其是非典型帕金森病，都被误诊。 误诊不仅会给患者、家属和护理人员带来巨大的压力和焦虑，而且也是一个重大的问题。 开发针对这些疾病的有效疗法的障碍。最近，我们证明了α- 使用从血清或血浆中免疫沉淀的细胞外囊泡 (EV) 中的突触核蛋白浓度 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 两种类型的电动汽车，为区分帕金森病和多发性痴呆症提供了敏感的生物标志物 系统萎缩（MSA）。这种液体活检方法仅需要微创抽血，并且可能导致 在开发这些疾病的诊断测试方面取得了重大进展。然而，组的定义 是基于临床诊断，这很容易出错，造成了先有鸡还是先有蛋的问题。为了解决这个问题 问题，在这里，我们提出一项试点研究，测试死后收集的血清样本中的生物标志物，其中 诊断经过病理学验证。该策略不适用于总 α-突触核蛋白，具体原因如下： 假设不适用于当前提案中的生物标志物。我们还将测试实用性 每个新生物标志物作为诊断生物标志物组的一部分，用于区分 PD、MSA 和另外两个 非典型帕金森综合征——进行性核上性麻痹和皮质基底节综合征——相互区别 和来自对照样品。试点研究的主要目标是确定是否经过病理学验证 尸检样本可用于帕金森病中枢神经系统电动汽车的生物标志物测量 综合症。第二个目标是测试每个生物标志物对诊断组的贡献。该研究有 未来开发微创生物标记物的潜力，使早期和准确的检测成为可能 帕金森病的诊断。