Assessing skin biomarkers for preclinical diagnosis of PD and non-PD Parkinsonism

评估皮肤生物标志物用于帕金森病和非帕金森病的临床前诊断

• 批准号: 10256807
• 负责人: SHU G. CHEN
• 金额: $ 70.9万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10256807
• 关键词: Address; Affect; Alzheimer' s Disease; Amyloid beta-Protein; Area; Autopsy; Biological Assay; Biological Markers; Biopsy; Biopsy Specimen; Blood; Body Fluids; Brain; Cadaver; Cerebrospinal Fluid; Clinical; Cohort Studies; Creutzfeldt-Jakob Syndrome; Data; Dementia with Lewy Bodies; Deposition; Detection; Diagnosis; Diagnostic; Diagnostic tests; Disease; Exhibits; Formaldehyde; Freezing; Goals; Hypersensitivity skin testing; Immunofluorescence Immunologic; Immunofluorescence Microscopy; Immunohistochemistry; Knowledge; Measures; Medical; Microscopy; Multiple System Atrophy; National Institute of Neurological Disorders and Stroke; Neuraxis; Neurodegenerative Disorders; Parkinson Disease; Parkinsonian Disorders; Pathologic; Patients; Peptides; PrPSc Proteins; Process; Progressive Supranuclear Palsy; Proteins; Sampling; Sensitivity and Specificity; Severity of illness; Site; Skin; Skin Tissue; Specificity; Specimen; Tauopathies; Testing; Therapeutic; Time; Urine; alpha synuclein; base; brain tissue; cohort; corticobasal degeneration; disorder control; insight; misfolded protein; potential biomarker; pre-clinical; programs; protein aggregation; protein misfolding cyclic amplification; synucleinopathy; tau Proteins; tool

ABSTRACT The disease-associated alpha-synuclein (αSynD) that accumulates and deposits as misfolded protein aggregates in the brain is the pathological hallmark of Parkinson disease (PD), and also of other synucleinopathies causing non-PD parkinsonism such as multiple system atrophy (MSA) and dementia with Lewy bodies (DLB). Currently, a definitive diagnosis of these disorders often requires the detection of αSynD in autopsy brain samples. An unmet medical need for PD and non-PD parkinsonism is to identify biomarkers for diagnosis, defining disease severity, and assessing potential neuroprotective therapeutics in easily accessible specimens. Notably, aSynD has been observed in the skin of PD patients by immunohistochemistry or immunofl3`2uorescence microscopy whereas the sensitivity varied dramatically from 0-100%. Remarkably, using the ultrasensitive assay termed real-time quaking-induced conversion (RT-QuIC), our recent preliminary studies have shown that the αSynD-specific seeding activity is readily detectable in autopsy skin tissues of PD patients with 100% specificity and sensitivity. Moreover, the protein misfolding cyclic amplification (PMCA), another highly sensitive assay that detects αSynD seeding activity even in formaldehyde-fixed brain tissue of a MSA patient, is also able to detect skin αSynD seeding activity in PD patients but not in non-PD controls. We hypothesize that RT-QuIC and PMCA are highly sensitive and robust platforms to establish skin αSynD as a biomarker for postmortem and premortem diagnoses of PD. To test this hypothesis, the following three Aims will be pursued: (1) to establish skin aSynD as a biomarker for postmortem diagnosis of PD; (2) Assess skin SynD as a biomarker for premortem diagnosis and defining PD severity using RT-QuIC and PMCA; and (3) Determine skin αSynD as a biomarker for diagnosis of non-PD synucleinopathies such as MSA and DLB as well as differentiate synucleinopathies from tauopathies such as corticobasal degeneration and progressive supranuclear palsy. We believe that new knowledge generated from this study will further apply to other neurodegenerative diseases including the most common neurodegenerative disease Alzheimer's disease, where the disease-specific misfolded proteins such as tau protein and Aβ peptides have been also found in the skin of affected patients.

摘要 疾病相关的α-突触核蛋白（αSynD），以错误折叠的蛋白质形式积累和沉积 脑中的聚集物是帕金森病（PD）的病理标志，也是其他帕金森病的病理标志。 引起非PD帕金森综合征的突触核蛋白病，如多系统萎缩（MSA）和痴呆， 路易小体（DLB）。目前，这些疾病的明确诊断通常需要检测αSynD， 尸检大脑样本PD和非PD帕金森综合征的一个未满足的医学需求是鉴定以下指标的生物标志物： 诊断，确定疾病的严重程度，并评估潜在的神经保护治疗， 标本值得注意的是，已经通过免疫组织化学或免疫组织化学在PD患者的皮肤中观察到aSynD。 免疫荧光显微镜检测灵敏度为0- 100%。值得注意的是， 使用超灵敏的测定称为实时振荡诱导转换（RT-QuIC），我们最近的初步研究 研究表明，α SynD特异性接种活性在PD尸检皮肤组织中很容易检测到， 100%的特异性和敏感性。此外，蛋白质错误折叠循环扩增（PMCA）， 另一种高灵敏度的检测方法，即使在甲醛固定的脑组织中也能检测到αSynD的接种活性。 MSA患者还能够检测到PD患者的皮肤αSynD接种活性，但不能检测到非PD对照。我们 假设RT-QuIC和PMCA是建立皮肤αSynD高度敏感和稳健的平台 作为PD死后和生前诊断的生物标志物。为了验证这一假设， 将追求三个目标：（1）建立皮肤aSynD作为PD死后诊断的生物标志物;（2） 使用RT-QuIC评估皮肤SynD作为生前诊断和定义PD严重程度的生物标志物， PMCA;和（3）确定皮肤αSynD作为诊断非PD突触核蛋白病（如MSA）的生物标志物 和DLB以及区分突触核蛋白病与tau蛋白病，如皮质基底节变性和 进行性核上性麻痹我们相信，这项研究产生的新知识将进一步适用于 其他神经退行性疾病，包括最常见的神经退行性疾病阿尔茨海默氏症 疾病，其中疾病特异性错误折叠的蛋白质如tau蛋白和Aβ肽也已被 在患者的皮肤上发现的。