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: 10622565
• 负责人: SHU G. CHEN
• 金额: $ 72.93万
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622565
• 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; Central Nervous System; Cerebrospinal Fluid; Clinical; Cohort Studies; Creutzfeldt-Jakob Syndrome; Data; Dementia with Lewy Bodies; Deposition; Detection; Diagnosis; 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; 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; amplification detection; biomarker identification; brain tissue; cohort; corticobasal degeneration; detection assay; diagnostic tool; disorder control; insight; misfolded protein; neuropathology; neuroprotection; potential biomarker; pre-clinical; programs; protein aggregation; protein misfolding cyclic amplification; synucleinopathy; tau Proteins

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.

抽象的 与疾病相关的α-突触核蛋白（αSynd），积累和沉积物是错误折叠蛋白的 大脑中的骨料是帕金森病（PD）的病理标志，也是其他 引起非PD帕金森氏症（例如多系统萎缩（MSA）和痴呆症）的突触核核病态 路易尸体（DLB）。当前，对这些疾病的明确诊断通常需要检测 尸检大脑样品。对PD和非PD帕金森主义的未满足医疗需求是确定生物标志物 诊断，定义疾病严重程度，并评估易于获得的潜在神经保护疗法 标本。值得注意的是，通过免疫组织化学或PD患者的皮肤观察到异步 免疫3`2构光显微镜，而灵敏度从0-100％差异很大。值得注意的是 使用称为实时Quaking诱导的转换的超敏化测定（RT-Quic），我们最近的初步 研究表明，在PD的尸检皮肤组织中，很容易检测到αSyd特异性的播种活性 具有100％特异性和灵敏度的患者。此外，蛋白质错误折叠环状扩增（PMCA）， 另一个高度敏感的测定法，即使在甲醛固定的脑组织 MSA患者还能够检测PD患者的皮肤αSynd播种活性，但不能检测到非PD对照中的皮肤。我们 假设RT Quic和PMCA是高度敏感且稳健的平台，可以建立皮肤αSynd 作为验尸和PD预先诊断的生物标志物。为了检验这一假设，以下 将追求三个目标：（1）将皮肤与PD验证诊断的生物标志物建立； （2） 评估皮肤联合性作为预先诊断的生物标志物，并使用RT-QUIC定义PD严重程度 PMCA; （3）确定皮肤αSynd作为诊断非PD突触核苷（例如MSA）的生物标志物 和DLB以及与皮质型变性和诸如皮质型疾病的突触核苷不同 进行性上腹部麻痹。我们认为，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病 疾病，疾病特异性错误折叠的蛋白（例如tau蛋白和Aβ肽）也已经存在 在受影响的患者的皮肤中发现。