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

• 批准号: 10307911
• 负责人: SHU G. CHEN
• 金额: $ 84.22万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 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/10307911
• 关键词: Age; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' 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; 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; base; brain tissue; corticobasal degeneration; diagnostic biomarker; early detection biomarkers; misfolded protein; mouse model; neurobehavioral; 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

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.

摘要 阿尔茨海默氏病（AD）和AD相关痴呆（ADRD）如路易体痴呆（LBD）都是阿尔茨海默氏病（AD）的一部分。 与AD和非AD患者脑中错误折叠蛋白聚集体（包括tau）的沉积相关 tau蛋白病和LBD中的α-突触核蛋白（αSyn）。目前，这些疾病的明确诊断依赖于 对脑进行组织学和生物化学检查以寻找错误折叠的蛋白质。发展可靠和 在容易获得的外周标本中对这些错误折叠蛋白进行灵敏的检测对于早期或 鉴别诊断、确定疾病严重程度和在临床试验中评价治疗效果。 有趣的是，脑tau蛋白和αSyn聚集体表现出朊病毒样聚集播种活性，这可以被认为是一种新的蛋白质。 通过两种高灵敏度扩增测定法（包括实时振荡诱导转化）特异性检测 （RT-QuIC）和蛋白质错误折叠循环扩增（PMCA）。它们已被证明是高度敏感的， 朊病毒病（PrD）、AD或PD中脑和/或脑脊液中错误折叠蛋白的检测（Atarashi 例如，2011; Peden等人，2012; Foutz等人，2017; Orrú等人，2015;西条等人，2017; Kraus等人，2018年）。使用 RT-QuIC/PMCA，我们能够在PrD或PD患者的皮肤中检测朊病毒和αSyn聚集体 (Orrú等人，2017; Wang等人，2019年; 2020年）。值得注意的是，我们的初步结果表明，朊病毒样tau蛋白- 通过RT-QuIC和PMCA可以在AD患者的皮肤中检测到接种活性，但在正常对照中则无法检测到。因此我们 假设通过RT-QuIC和PMCA检测皮肤tau接种活性是一种新的生物标志物， 诊断、表征和预测AD和非AD tau蛋白病的结果， 区别AD和LBD。为了检验这一假设，将追求以下四个目标：（1）建立 尸检皮肤样本中的tau接种活性作为死后诊断和表征的生物标志物 （2）评估皮肤tau接种活性作为PREMORTEM的生物标志物; AD的诊断、表征和预测临床结果;（3）确定皮肤tau-播种活性作为AD的诊断、表征和预测临床结果。 用于区分AD与非AD tau蛋白病和LBD（一种常见的ADRD）的生物标志物;和（4）确定 在动物模型中，通过RT-QuIC/PMCA在无症状阶段是否可检测到皮肤tau接种活性 AD tau蛋白病我们相信，该项目的成功实施将有助于RT-QuIC/PMCA的发展。 皮肤tau-播种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 tau蛋白病和LBD。