Peripheral Tissue Biomarker for Premortem Diagnosis of Lewy Body Dementia

用于路易体痴呆死前诊断的外周组织生物标志物

• 批准号: 10248548
• 负责人: SHU G. CHEN
• 金额: $ 109.02万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2021-12-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10248548
• 关键词: Affect; Age; Alzheimer' s Disease; Autopsy; Biological Assay; Biological Markers; Biopsy; Biopsy Specimen; Brain; Cadaver; Caring; Cerebrospinal Fluid; Clinical; Clinical Trials; Colon; Colonoscopy; Dementia; Dementia with Lewy Bodies; Deposition; Detection; Diagnosis; Diagnostic; Diagnostic tests; Differential Diagnosis; Disease; Early Diagnosis; Emerging Technologies; Enrollment; Enteric Nervous System; Functional disorder; Goals; Hypersensitivity skin testing; Immunologics; Lewy Body Dementia; Measures; Medical; Methods; Neuraxis; Neurodegenerative Disorders; Nose; Parkinson' s Dementia; Parkinsonian Disorders; Patient Care; Patient Recruitments; Patients; Peripheral; Progressive Supranuclear Palsy; Reporting; Salivary Glands; Sampling; Sensitivity and Specificity; Severity of illness; Sigmoid colon; Sigmoidoscopy; Skin; Specimen; Spinal Puncture; Submandibular gland; Symptoms; Tauopathies; Testing; Time; Tissues; alpha synuclein; atypical parkinsonism; base; cohort; comorbidity; comparison group; corticobasal degeneration; diagnostic biomarker; early detection biomarkers; follow-up; improved; nervous system disorder; patient stratification; prion-like; protein aggregation; synucleinopathy; tau Proteins; tau aggregation; therapeutic development; tissue biomarkers; tool

Abstract The overall goal of our project is to validate a diagnostic tool for dementia with Lewy bodies (DLB), and Parkinson’s disease dementia (PDD), two common neurodegenerative diseases affecting 1.4 million people in the U.S. Currently, definitive diagnosis of DLB and PDD often requires the postmortem detection of disease- associated alpha-synuclein (αSynD) aggregates in the brain. Clinically, DLB and PDD can be easily misdiagnosed with other dementias and parkinsonisms such as Alzheimer’s disease (AD) and tauopathies. An unmet medical need is to identify biomarkers for early and differential diagnosis of DLB and PDD in more easily accessible tissues. We have taken advantage of the emerging technology known as the real-time quaking induced conversion (RT-QuIC) assay to develop a robust platform for ultrasensitive detection of αSynD in peripheral tissues. In preliminary studies, we are able to detect prion-like seeding activity of αSynD in the skin of DLB and PD patients with 100% specificity and sensitivity. In addition, we were remarkably successful in detecting αSynD seeding activity in multiple peripheral tissues including skin, sigmoid colon, and submandibular glands in autopsied specimens. We hypothesize that RT-QuIC of peripheral αSynD is a highly sensitive and robust diagnostic biomarker for premortem diagnoses of DLB and PDD. To test this hypothesis, we propose to pursue the following four Aims: (1) Establish peripheral αSynD as a biomarker for postmortem diagnosis of DLB and PDD using RT-QuIC assay; (2) Assess skin αSynD as a biomarker for premortem diagnosis of DLB and PDD; (3) Determine peripheral αSynD and tau as a biomarker for differentiating DLB and PDD from other dementias and parkinsonisms such as AD and tauopathies; (4) Explore gut αSynD as a biomarker for premortem diagnosis of DLB and PDD using colon biopsy. Successful implementation of this proposal will establish RT- QuIC assay utilization for early diagnosis of DLB and PDD using readily available peripheral specimens.

抽象的 我们项目的总体目标是验证用路易尸体（DLB）和 帕金森氏病痴呆症（PDD），两种常见的神经退行性疾病，影响140万人 美国目前，对DLB和PDD的明确诊断通常需要疾病后检测 - 相关的α-突触核蛋白（αSynd）聚集在大脑中。临床上，DLB和PDD很容易 与其他痴呆症和帕金森氏症（如阿尔茨海默氏病（AD）和陶氏病）误诊。 未满足的医疗需求是更轻松地识别DLB和PDD的早期和差异诊断的生物标志物 可访问的时间。我们利用了新兴技术称为实时震颤 诱导转化率（RT-QUIC）测定，以开发一个可靠的平台，用于超敏检测αSyd 外围组织。在初步研究中，我们能够检测到皮肤中αsyd的prion样播种活性 DLB和PD患者具有100％特异性和灵敏度。此外，我们在 检测包括皮肤，乙状结肠和下颌在内的多个外周组织中的αSyd播种活性 尸体标本中的腺体。我们假设外围αSynd的rt Quic是一种高度敏感的，并且 DLB和PDD的预先诊断诊断的强大诊断生物标志物。为了检验这一假设，我们提出了 追求以下四个目标：（1）建立外围αSynd作为验证后诊断的生物标志物 DLB和PDD使用RT Quic分析； （2）评估皮肤αSyd作为DLB和 PDD; （3）确定外围αSyd和Tau作为将DLB和PDD区分开的生物标志物 痴呆症和帕金森氏症，例如AD和Tauopathies； （4）探索肠道αSyd作为Premortem的生物标志物 使用结肠活检诊断DLB和PDD。该提案的成功实施将建立RT- 使用随时可用的外围标本，用于早期诊断DLB和PDD的QUIC分析利用。