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.

我们提出的研究的总体目标是开发强大的死前生物标志物，以实现准确和 阿尔茨海默病 (AD)、非 AD tau蛋白病、路易体痴呆 (LBD) 及其相关疾病的鉴别诊断 AD 和其他 tau 病的病理特征是 tau 蛋白聚集体的沉积。 在大脑中，而在 LBD 中，α-突触核蛋白 (aSyn) 聚集体的积累量惊人，超过一半。 临床诊断的 AD 或 LBD 患者在尸检时伴有 tau 和 aSyn 共同病理。 此外，目前，患有混合 tau 和 aSyn 病理的患者通常会遭受更差的临床结果。 由于症状重叠，临床区分 AD、LBD 和混合型 AD/LBD 极具挑战性。 此外，aSyn 病理学的共存也经常发生在非 AD tau蛋白病中。 β-淀粉样蛋白和磷酸化 tau (p-tau) 的脑成像和免疫分析极大地促进了诊断 然而，这些检测无法识别非 AD tau蛋白病和混合 AD/LBD。 在易于获取的生物样本中采取替代措施是必要的，特别是如果它们能够同时进行 初步检测混合型 tau 蛋白病和突触核蛋白病患者中的 tau 蛋白和 aSyn 聚集体。 研究中，我们利用了称为实时地震诱导转换的新兴技术 用于特异性检测 AD 和非 AD 患者皮肤中 tau 聚集体的测定 (tau RT-QuIC) 与最近建立的 aSyn RT-QuIC 相结合，我们处于独特的地位，可以准确地 使用易于获取的皮肤标本诊断患有混合 tau 和 aSyn 病理的患者。 RT-QuIC 检测到的皮肤 tau 和 aSyn 是用于早期和鉴别诊断的新型生物标志物 我们建议通过常规临床实践来检验这一假设。 追求三个目标：1) 建立针对混合 tau蛋白病/突触核蛋白病的双皮肤 RT-QuIC 生物标志物检测 使用神经病理学确诊的病例；2) 评估 RT-QuIC 检测到的皮肤 tau 和 aSyn 的可靠性 用于死前诊断混合 tau 病和突触核蛋白病的生物标志物；以及 3) 评估皮肤 tau/aSyn 通过生物标志物测定改善混合 tau蛋白病/突触核蛋白病的鉴别诊断 该转化项目有丰富的临床资源和强大的基础团队支持。 我们的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 和相关痴呆症中常见的混合病理，从而促进更好的患者护理和 疾病修饰疗法的开发。