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: 10491802
• 负责人: SHU G. CHEN
• 金额: $ 75.54万
• 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/10491802
• 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.

抽象的 阿尔茨海默病 (AD) 和 AD 相关痴呆 (ADRD)，例如路易体痴呆 (LBD) 都属于 与 AD 和非 AD 患者大脑中错误折叠的蛋白质聚集体沉积相关，包括 tau 蛋白 LBD 中的 tau 蛋白病和 α-突触核蛋白 (αSyn)。目前，这些疾病的明确诊断依赖于 对大脑进行组织学和生化检查以查找错误折叠的蛋白质。开发可靠且 在易于获取的外周样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、确定疾病严重程度以及临床试验中治疗效果的评估。 有趣的是，脑 tau 和 αSyn 聚集体表现出类似朊病毒的聚集播种活性，这可以 通过两种高度灵敏的扩增检测（包括实时震动诱导的转换）专门检测 (RT-QuIC) 和蛋白质错误折叠循环扩增 (PMCA)。事实证明，它们对以下情况高度敏感： 检测朊病毒病 (PrD)、AD 或 PD 中大脑和/或脑脊液中的错误折叠蛋白 (Atarashi 等，2011；佩登等人，2012；富茨等人，2017；奥鲁等人，2015；西条等人，2017；克劳斯等人，2018）。使用 RT-QuIC/PMCA，我们能够检测 PrD 或 PD 患者皮肤中的朊病毒和 αSyn 聚集体 （Orrú 等人，2017 年；Wang 等人，2019 年；2020 年）。值得注意的是，我们的初步结果表明，类朊病毒 tau- RT-QuIC 和 PMCA 可在 AD 患者皮肤中检测到播种活性，但在正常对照中检测不到。因此，我们 假设 RT-QuIC 和 PMCA 检测到的皮肤 tau 播种活性是一种新型生物标志物 诊断、表征和预测 AD 和非 AD tau蛋白病的结果 区分 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 播种活性作为死后诊断和表征的生物标志物 使用 RT-QuIC/PMCA 检测检测 AD； (2) 评估皮肤 tau 播种活性作为 PREMORTEM 的生物标志物 AD 的诊断、特征描述和临床结果预测； (3) 确定皮肤 tau 播种活性 用于区分 AD 与非 AD tau蛋白病以及 LBD（一种常见的 ADRD）的生物标志物； (4) 确定 在动物模型中是否可以通过 RT-QuIC/PMCA 在无症状阶段检测到皮肤 tau 播种活性 AD tau蛋白病。我们相信该项目的成功实施将推动RT-QuIC/PMCA的发展 皮肤 tau 播种活性测定作为诊断测试和评估 AD 临床试验的生物标志物， 非AD tau蛋白病和LBD。