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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.

摘要阿尔茨海默病(AD)和AD相关痴呆(ADRD)，如路易体痴呆(LBD)都是与脑内错误折叠的蛋白质聚集体的沉积有关，包括AD和非AD患者的tau α-突触核蛋白(α-syn)在腰椎病中的表达。目前，对这些疾病的明确诊断依赖于脑组织的组织学和生化检查错误折叠的蛋白质。开发可靠的和在容易接触到的外周样本中对这些错误折叠的蛋白质进行敏感的检测对于早期或临床试验中的鉴别诊断、疾病严重程度的确定和治疗效果的评估。有趣的是，脑tau和αsyn聚合体显示出类似Pron的聚集种子活性，这可以是通过两种高灵敏的扩增分析进行特异性检测，包括实时抖动诱导转换 (RT-QuIC)和蛋白质错折叠循环扩增(PMCA)。它们已被证明对 Prion病(PRD)、AD或PD(Atarashi)患者脑和/或脑脊液中错误折叠蛋白的检测等人，2011年；Peden等人，2012年；Foutz等人，2017年；Orrú等人，2015年；Saijo等人，2017年；Kraus等人，2018年)。vbl.使用 RT-QuIC/PMCA，我们能够在PRD或PD患者的皮肤中检测到Prion和αSyn聚集体 (Orrú等人，2017；Wang等人，2019；2020)。值得注意的是，我们的初步结果表明，类似普里恩的tau- RT-QuIC和PMCA检测到AD患者皮肤中的种子活性，而正常对照中未检测到种子活性。因此，我们假设RT-QuIC和PMCA检测到的皮肤tau种子活性是一种新的生物标志物诊断、表征和预测阿尔茨海默病和非阿尔茨海默病区分AD和LBD。为了验证这一假设，将追求以下四个目标：(1)建立尸检皮肤标本中tau种子的活性作为尸检诊断和鉴定的生物标志物使用RT-QuIC/PMCA检测AD；(2)评估皮肤tau种子活性作为生前生物标记物 AD的诊断、特征和预测临床结果；(3)确定皮肤tau种子活性作为一种用于区分AD与非AD肌萎缩侧索硬化症和LBD的生物标记物，一种常见的ADRD；以及(4)确定 RT-QuIC/PMCA在动物模型中是否可检测到无症状阶段的皮肤tau种植活性公元十年的变态。我们相信，该项目的成功实施将发展RT-QuIC/PMCA 皮肤tau种子活性的检测作为诊断测试和评估AD临床试验的生物标记物，非AD肌萎缩侧索硬化症和LBD。