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: 10653599
• 负责人: SHU G. CHEN
• 金额: $ 198.99万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10653599
• 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 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; Persons; 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; diagnostic strategy; diagnostic tool; early detection biomarkers; follow-up; improved; nervous system disorder; patient stratification; prion-like; protein aggregation; synucleinopathy; tau Proteins; tau aggregation; therapeutic development; tissue biomarkers

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.

摘要 我们项目的总体目标是验证路易体痴呆症（DLB）的诊断工具， 帕金森病痴呆症（PDD）是两种常见的神经退行性疾病，影响着140万人， 目前，DLB和PDD的明确诊断通常需要疾病的尸检检测- 相关的α-突触核蛋白（αSynD）聚集在大脑中。临床上，DLB和PDD可以很容易地 被误诊为其他痴呆症和帕金森症，如阿尔茨海默病（AD）和tau蛋白病。一个 未满足的医疗需求是更容易地鉴定用于DLB和PDD的早期和鉴别诊断的生物标志物， 可获取的组织。我们利用了一种新兴的技术叫做实时震动 诱导转化（RT-QuIC）试验，以开发用于超灵敏检测αSynD的稳健平台。 外周组织在初步研究中，我们能够检测到朊病毒样的αSynD在皮肤中的播种活性， DLB和PD患者的特异性和敏感性均为100%。此外，我们还非常成功地 检测包括皮肤、乙状结肠和下颌下在内的多种外周组织中的αSynD播种活性 尸体解剖标本中的腺体。我们假设外周αSynD的RT-QuIC是一种高度敏感的， 用于DLB和PDD的死前诊断的稳健诊断生物标志物。为了验证这一假设，我们建议 目的：（1）建立外周血αSynD作为尸检诊断的生物标志物， 使用RT-QuIC测定DLB和PDD;（2）评估皮肤αSynD作为DLB死前诊断的生物标志物， （3）检测外周αSynD和tau蛋白作为鉴别DLB和PDD与其他疾病的生物标志物。 痴呆和帕金森病，如AD和tau蛋白病;（4）探索肠道αSynD作为死亡前 使用结肠活检诊断DLB和PDD。成功实施这一建议将建立RT- 利用QuIC检测试剂盒，使用现成的外周血标本早期诊断DLB和PDD。