Skin biomarkers for diagnosing and characterizing AD and ADRD

用于诊断和表征 AD 和 ADRD 的皮肤生物标志物

基本信息

批准号：
10673714
负责人：
SHU G. CHEN
金额：
$ 75.78万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10673714
关键词：
Age Alzheimer&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Amyloid beta-Protein Animal Model Animals Area Autopsy Biochemical Biological Assay Biological Markers Biopsy Biopsy Specimen Blinded Brain Brain Injuries Brain imaging Cadaver Cerebrospinal Fluid Clinical Clinical Trials Creutzfeldt-Jakob Syndrome Dementia Deposition Detection Development Diagnosis Diagnostic tests Differential Diagnosis Disease Disease Progression Early Diagnosis Exhibits Goals Histologic Human Hypersensitivity skin testing Immunoassay Individual Lewy Body Dementia Measures Mutation Neurodegenerative Disorders Outcome Study Parkinson Disease Pathologic Patients Peripheral Pick Disease of the Brain PrP PrPSc Proteins Prion Diseases Prions Progressive Supranuclear Palsy Protein Isoforms Radioactivity Recombinants Sampling Severity of illness Site Skin Skin Tissue Specimen Spinal Puncture Tauopathies Technology Testing Time Treatment Efficacy alpha synuclein brain tissue corticobasal degeneration diagnostic biomarker early detection biomarkers misfolded protein mouse model neurobehavioral neuropathology novel marker outcome prediction potential biomarker pre-clinical predict clinical outcome prion-like protein aggregation protein misfolding cyclic amplification sex tau Proteins tau aggregation therapeutic evaluation

项目摘要

ABSTRACT Alzheimer's disease (AD) and AD-related dementias (ADRD) such as Lewy body dementia (LBD) are all associated with deposition of misfolded protein aggregates in the brain including tau in AD and non-AD tauopathies, and α-synuclein (αSyn) in LBD. Currently, a definite diagnosis of these disorders relies on the histological and biochemical examination of the brain for the misfolded proteins. Development of reliable and sensitive assays for these misfolded proteins in easily accessible peripheral specimens is critical for early or differential diagnosis, determination of disease severity, and evaluation of therapeutic efficacy in clinical trials. Interestingly, brain tau and αSyn aggregates exhibit prion-like aggregation seeding activity, which can be specifically detected by two highly sensitive amplification assays including real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA). They have been proved to be highly sensitive for detection of misfolded proteins in the brain and/or cerebrospinal fluid in prion disease (PrD), AD, or PD (Atarashi et al., 2011; Peden et al., 2012; Foutz et al., 2017; Orrú et al., 2015; Saijo et al., 2017; Kraus et al., 2018). Using RT-QuIC/PMCA, we were able to detect prion and αSyn aggregates in the skin of individuals with PrD or PD (Orrú et al., 2017; Wang et al., 2019; 2020). Remarkably, our preliminary results have shown that prions-like tau- seeding activity is detectable by RT-QuIC and PMCA in skin of AD patients but not in normal controls. Thus, we hypothesize that skin tau-seeding activity detected by RT-QuIC and PMCA is a novel biomarker for diagnosing, characterizing, and predicting outcomes of AD and non-AD tauopathies and for differentiating AD from LBD. To test this hypothesis, the following four Aims will be pursued: (1) Establish the tau-seeding activity in autopsied skin samples as a biomarker for POSTMORTEM diagnosis and characterization of AD using RT-QuIC/PMCA assays; (2) Assess skin tau-seeding activity as a biomarker for PREMORTEM diagnosis, characterization, and predicting clinical outcomes of AD; (3) Determine skin tau-seeding activity as a biomarker for differentiating AD from non-AD tauopathies, and from LBD, a common ADRD; and (4) Determine whether skin tau-seeding activity is detectable at an asymptomatic stage by RT-QuIC/PMCA in animal models of AD tauopathies. We believe that the successful implementation of this project will develop RT-QuIC/PMCA assays of skin tau-seeding activity as a biomarker for diagnostic testing and evaluating clinical trials across AD, non-AD tauopathies, and LBD.

抽象的阿尔茨海默氏病（AD）和与AD相关的痴呆症（ADRD），例如Lewy身体痴呆症（LBD）都是与大脑中错误折叠蛋白聚集体的沉积有关，包括AD和非AD LBD中的tauopathies和α-突触核蛋白（αSyn）。目前，这些疾病的定义诊断依赖于对错误折叠蛋白的大脑的组织学和生化检查。开发可靠和这些错误折叠蛋白在易于访问的外围样品中的敏感测定对于早期或在临床试验中，鉴别诊断，疾病严重程度的确定以及对治疗效率的评估。有趣的是，脑tau和αSyn聚集体表现出类似prion的聚集活性，这可以是由两个高度敏感的扩增测定法特别检测（RT-Quic）和蛋白质错误折叠环状扩增（PMCA）。事实证明它们对检测大脑中错误折叠的蛋白质和/或脑脊液中的脑脊液（PRD），AD或PD（Atarashi）（Atarashi）等，2011； Peden等人，2012年； Foutz等人，2017年； Orrú等，2015； Saijo等人，2017年； Kraus等，2018）。使用 rt-Quic/pmca，我们能够检测到具有PRD或PD的个体皮肤中的Prion和αSyn骨料（Orrú等，2017; Wang等，2019; 2020）。值得注意的是，我们的初步结果表明，像王子一样在AD患者的皮肤中，RT-Quic和PMCA可以检测到播种活性，但在正常对照组中不能检测到。那，我们假设RT-Quic和PMCA检测到的皮肤tau种子活性是一种新颖的生物标志物诊断，表征和预测AD和非AD tauopathies的结果以及将广告与LBD区分开。为了检验这一假设，将追求以下四个目标：（1）确定尸体式皮肤样品中的tau种子活性是验尸诊断和表征的生物标志物使用RT-QUIC/PMCA分析的AD；（2）评估皮肤tau种子活性作为Premortem的生物标志物诊断，表征和预测AD的临床结果；（3）确定皮肤tau种子活性生物标志物用于将广告与非AD tauopathies区分开，而LBD是常见的ADRD；（4）确定在动物模型中，RT-Quic/PMCA是否可以在不对称阶段检测到皮肤tau播种活性广告tauopathies。我们认为，该项目的成功实施将开发RT-Quic/PMCA 皮肤tau种子活性作为诊断测试和评估AD临床试验的生物标志物的测定非AD tauopathies和LBD。