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

基本信息

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
项目类别：
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&apos 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

项目摘要

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) 以错误折叠蛋白的形式积累和沉积大脑中的聚集物是帕金森病 (PD) 以及其他疾病的病理标志导致非 PD 帕金森病的突触核蛋白病，例如多系统萎缩 (MSA) 和痴呆目前，这些疾病的明确诊断通常需要检测 αSynD。尸检大脑样本。帕金森病和非帕金森病的未满足的医疗需求是确定生物标志物。诊断、确定疾病严重程度并评估潜在的神经保护疗法值得注意的是，通过免疫组织化学或方法在 PD 患者的皮肤中观察到了 aSynD。免疫荧光显微镜的灵敏度在 0-100% 之间变化很大，使用称为实时震动诱导转换（RT-QuIC）的超灵敏测定，我们最近的初步研究研究表明，在 PD 尸检皮肤组织中很容易检测到 αSynD 特异性播种活性此外，蛋白质错误折叠循环扩增 (PMCA) 具有 100% 的特异性和敏感性。另一种高度灵敏的检测方法，即使在甲醛固定的脑组织中也能检测 αSynD 播种活性。 MSA 患者也能够检测到 PD 患者的皮肤 αSynD 播种活性，但不能检测到非 PD 对照。寻求 RT-QuIC 和 PMCA 是建立皮肤 αSynD 的高度敏感且强大的平台作为 PD 死后和死前诊断的生物标志物为了检验这一假设，如下所述。我们将追求三个目标：(1) 建立皮肤 aSynD 作为 PD 死后诊断的生物标志物；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；以及 (3) 确定皮肤 αSynD 作为诊断非 PD 突触核蛋白病（例如 MSA）的生物标志物和 DLB 以及区分突触核蛋白病和 tau 蛋白病，例如皮质基底节变性和我们相信这项研究产生的新知识将进一步应用于治疗。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病疾病特异性的错误折叠蛋白，如 tau 蛋白和 Aβ 肽也被在受影响患者的皮肤中发现。