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.

我们拟议的研究的总体目标是开发出可靠的预典型生物标志物，以进行准确和 阿尔茨海默氏病（AD），非AD tauopathies，Lewy身体痴呆症（LBD）及其鉴别诊断 合并症。 AD和其他Tauopathies的病理标志是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。令人惊讶的是，一半以上 在临床诊断为AD或LBD的患者中，尸检时具有伴随的TAU和ASYN副病理。 此外，混合TAU和ASYN病理的患者通常患有较差的临床结果。目前，它 由于症状重叠，对临床区分AD，LBD和混合AD/LBD的挑战高度挑战。 此外，ASYN病理的共存也经常发生在非AD tauopathies中。最近的进步 淀粉样蛋白β和磷酸化tau（p-tau）的脑成像和免疫测定已有大量准备的诊断 典型广告。但是，这些测定方法无法识别非AD tauopathies和混合AD/LBD。所以， 有必要采取易于访问的生物测量中的替代措施，尤其是在同时启用的情况下 在混合呼吸病和突触核酸的患者中检测TAU和ASYN聚集体。在初步 研究，我们利用了新出现的技术，称为实时Quaking引起的转换 分析（tau rt Quic）用于特异性检测AD和非AD患者皮肤中的Tau骨料 tauopathies。结合最近建立的Asyn Rt-Quic，我们处于一个独特的位置，可以准确地 使用易于访问的皮肤标本诊断混合TAU和ASYN病理的患者。我们假设 RT Quic检测到的皮肤Tau和Asyn是早期和差异诊断的新型生物标志物 常规临床实践中的混合陶氏病/突触核病。我们建议通过 追求三个目的：1）建立双皮肤RT Quic生物标志物分析混合呼吸疾病/突触核酸 使用神经病理学确认的病例； 2）评估由RT Quic检测到的皮肤Tau和Asyn可靠 混合陶氏病和突触核酸疾病的预先诊断的生物标志物； 3）评估皮肤tau/asyn 生物标志物测定法改善混合呼吸疾病/突触核酸的鉴别诊断方法 纵向随访。这个翻译项目得到丰富的临床资源和强大的基本团队的支持 和临床神经科学家。我们建议的成功结果将建立一个基于皮肤的强大诊断 测试在AD和相关痴呆症中普遍存在的混合病理，从而促进了更好的患者护理和 疾病改良疗法的发展。