Peripheral Biomarkers for Early Diagnosis of Mixed Pathologies in AD/ADRD

用于 AD/ADRD 混合病理早期诊断的外周生物标志物

• 批准号: 10669877
• 负责人: SHU G. CHEN
• 金额: $ 75.6万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10669877
• 关键词: Affect; Age; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Amyloid beta-Protein; Autopsy; Biological Assay; Biological Markers; Biopsy; Biopsy Specimen; Brain; Brain imaging; Cadaver; Clinic; Clinical; Collection; Consensus; Dementia; Dementia with Lewy Bodies; Deposition; Detection; Development; Diagnosis; Diagnostic tests; Differential Diagnosis; Disease; Disease Progression; Early Diagnosis; Emerging Technologies; Goals; Immunoassay; Lewy Body Dementia; Measures; Memory; Outcome; Outcome Study; Parkinson Disease; Parkinson' s Dementia; Participant; Pathologic; Pathology; Patient Care; Patients; Peripheral; Persons; Positioning Attribute; Probability; Progressive Supranuclear Palsy; Registries; Research; Resources; Sampling; Severity of illness; Skin; Specimen; Symptoms; Tauopathies; Testing; Time; Validation; Visit; accurate diagnosis; alpha synuclein; biobank; brain tissue; clinical diagnosis; clinical practice; comorbidity; corticobasal degeneration; corticobasal syndrome; diagnostic assay; diagnostic biomarker; diagnostic tool; early detection biomarkers; follow-up; illness length; improved; neuropathology; new technology; novel marker; prion-like; prospective; protein aggregation; recruit; sex; success; synucleinopathy; tau Proteins; tau aggregation; tau-1; therapeutic development

The overall goal of our proposed research is to develop robust premortem biomarkers for accurate and differential diagnosis of Alzheimer's disease (AD), non-AD tauopathies, Lewy body dementia (LBD), and their comorbidities. A pathological hallmark of AD and other tauopathies is the deposition of tau protein aggregates in the brain, whereas in LBD there is accumulation of α-synuclein (aSyn) aggregates. Strikingly, more than half of patients with clinically diagnosed AD or LBD have concomitant tau and aSyn co-pathologies at autopsy. Moreover, patients with mixed tau and aSyn pathologies often suffer from worse clinical outcomes. Currently, it is highly challenging to clinically differentiate AD, LBD, and mixed AD/LBD due to overlapping symptoms. Moreover, co-existence of aSyn pathology also occurs frequently in non-AD tauopathies. Recent advances in brain imaging and immunoassays of amyloid-β and phosphorylated tau (p-tau) have greatly facilitated diagnosis of typical AD. However, these assays fail to identify non-AD tauopathies and mixed AD/LBD. Therefore, alternative measures in easily accessible biospecimens are warranted, especially if they enable simultaneous detection of tau and aSyn aggregates in patients with mixed tauopathies and synucleinopathies. In preliminary studies, we have leveraged the newly emerged technology known as the real-time quaking-induced conversion assay (tau RT-QuIC) for specific detection of tau aggregates in the skin of patients with AD and non-AD tauopathies. In conjunction with recently established aSyn RT-QuIC, we are in a unique position to accurately diagnose patients with mixed tau and aSyn pathologies using easily accessible skin specimens. We hypothesize that skin tau and aSyn detected by RT-QuIC are novel biomarkers for early and differential diagnosis of mixed tauopathies/synucleinopathies in routine clinical practice. We propose to test this hypothesis by pursuing three Aims: 1) Establish dual skin RT-QuIC biomarker assays for mixed tauopathies/synucleinopathies using neuropathologically confirmed cases; 2) Assess skin tau and aSyn detected by RT-QuIC as reliable biomarkers for premortem diagnosis of mixed tauopathies and synucleinopathies; and 3) Evaluate skin tau/aSyn biomarker assays for improving the differential diagnosis of mixed tauopathies/synucleinopathies through longitudinal follow-up. This translational project is supported by rich clinical resources and a strong team of basic and clinical neuroscientists. The successful outcome of our proposal will establish a robust skin-based diagnostic test for mixed pathologies that is prevalent in AD and related dementias, thus facilitating better patient care and development of disease-modifying therapies.

我们建议的研究的总体目标是开发强大的死前生物标志物，以准确和 阿尔茨海默病(AD)、非AD脑病、路易体痴呆(LBD)及其相关疾病的鉴别诊断 合并症。AD和其他tau病的一个病理特征是tau蛋白聚集物的沉积 在大脑中，而在LBD中，有α-突触核蛋白(ASyn)聚集体的积累。引人注目的是，超过一半的人 临床诊断为AD或LBD的患者在尸检时伴有tau和aSyn共同病理。 此外，tau和aSyn混合病理的患者往往临床结果较差。目前，它 由于症状重叠，在临床上区分AD、LBD和混合型AD/LBD具有很高的挑战性。 此外，aSyn病理的共存也经常出现在非AD的tauopathy中。的最新进展 淀粉样蛋白-β和磷酸化tau(p-tau)的脑成像和免疫分析极大地促进了诊断 典型的AD的特征。然而，这些检测方法无法识别非AD患者和混合性AD/LBD。因此， 在易于获取的生物检疫中采取替代措施是有必要的，特别是如果它们能够同时 混合性肌萎缩侧索硬化症和联体核病患者中tau和aSyn聚合体的检测。在预赛中 研究中，我们利用了一种名为实时震动诱导转换的新技术 特异性检测AD和非AD患者皮肤中tau聚集体的方法(tau RT-QuIC) 紧张症。与最近成立的aSyn RT-QuIC相结合，我们处于独特的地位，能够准确地 使用易于获取的皮肤样本诊断患有tau和aSyn混合病变的患者。我们假设 RT-QuIC检测皮肤tau和aSyn是早期诊断和鉴别诊断的新的生物标志物 常规临床实践中的混合变态/并核变态。我们建议通过以下方式来检验这一假设 追求三个目标：1)建立双皮肤RT-QuIC生物标记物检测混合性皮肤病变/并核病 使用神经病理确诊的病例；2)评估RT-QuIC检测的皮肤tau和aSyn的可靠性 生前诊断混合性tau病和突触核病的生物标志物；以及3)评估皮肤tau/aSyn 通过生物标记物检测提高混合性结缔组织病/并核病的鉴别诊断 纵向随访。这个翻译项目有丰富的临床资源和强大的基础团队支持 和临床神经学家。我们建议的成功结果将建立一个强大的基于皮肤的诊断 测试AD和相关痴呆中普遍存在的混合病理，从而促进更好的患者护理和 疾病修正疗法的发展。