The Massachusetts and Yale ADRC Collaborative Proteomic Biofluid Biomarker Discovery Program

马萨诸塞州和耶鲁大学 ADRC 合作蛋白质组生物流体生物标志物发现计划

• 批准号: 9687770
• 负责人: STEVEN E ARNOLD
• 金额: $ 77.52万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9687770
• 关键词: Address; Adult; Alzheimer' s Disease; Amyloid beta-Protein; Biological; Biological Assay; Biological Markers; Blood; Brain; Cerebrospinal Fluid; Chitinase; Clinical; Clinical Trials; Cognitive; Collaborations; Collection; Complex; Data; Dementia; Diagnosis; Diagnostic; Differential Diagnosis; Disease; Disease Marker; Disease Progression; Early Diagnosis; Enzyme-Linked Immunosorbent Assay; Extracellular Matrix; Functional disorder; Goals; Immunity; Impaired cognition; Individual; Inflammation; Investigation; Lead; Learning; Light; Liquid substance; Longitudinal cohort; Mass Spectrum Analysis; Massachusetts; Measurement; Measures; Methods; Monitor; Neurodegenerative Disorders; Neuropeptides; Oxidative Stress; Pathologic; Pathology; Pathway interactions; Peptides; Performance; Placebos; Plasma; Positron-Emission Tomography; Process; Proteins; Proteomics; Reproducibility; Research; Sampling; Signal Transduction; Specialized Center; Staging; Synapses; Techniques; Technology; Testing; Time; TimeLine; arm; base; biological adaptation to stress; biomarker discovery; biomarker-driven; clinical biomarkers; cohort; comparative; disease diagnosis; fatty acid-binding proteins; flexibility; functional disability; improved; insight; lipid metabolism; lipid transport; liquid chromatography mass spectrometry; nerve injury; neurofilament; neuroimaging; novel; novel marker; outcome forecast; pre-clinical; predictive marker; predictive modeling; programs; protein biomarkers; sample collection; specific biomarkers; synaptic function; tau Proteins; treatment response

There are currently no practical biomarkers for Alzheimer’s Disease (AD) that can routinely stage, assess prognosis, and monitor treatment response. AD is a complex disease of overlapping pathophysiologies that lead to eventual synapse loss and progressive dementia. The core AD biomarkers, amyloid-b and tau (total and phospho-) measured in cerebrospinal fluid (CSF), provide a strong indication of the presence or absence of substantial AD pathology, but as yet poorly reflect disease stage or progression. In order to diagnose the disease earlier, learn about the time-course of concurrent pathophysiologies, and maximize the potential for staging, tracking and treatment, it is critical that more useful AD biomarkers are characterized. A collaboration is proposed between the Yale and Massachusetts ADRCs that will leverage the individual strengths of these two centers to discover pathway driven novel biomarkers of AD. Using the large numbers of clinically characterized biofluid samples available from the Massachusetts ADRC, the Yale ADRC will employ their expertise in quantitative targeted LC- MS/MS technology to assess over one hundred analytes in CSF, with an extension of the most informative to blood. LC-MS/MS is inherently specific, and enables simultaneous testing of many markers from a small biofluid volume. Use of Data-Independent-Acquisition (DIA) LC- MS/MS techniques allows for primary data to be reanalyzed for retrospective analysis of new biomarkers, providing a reproducible yet flexible discovery pipeline. In Aim 1, a panel of over 100 proteins in CSF from pathways involved in AD pathophysiology will be subjected to comprehensive technical qualification. Using samples from the placebo arm of a clinical trial, peptides will be tested for linearity, inter-assay, intra-assay and short term biotemporal stability. All high performing peptides will then be quantified in a high contrast sample of 60 Cognitively unimpaired-adults (CU-A) and 60 dementia due to AD cases. They will be assessed for their ability to distinguish AD from CU-A, and for their correlation with markers of synaptic function. In Aim 2, technically qualified peptides will be quantified in 3 tailored sample collections to assess their performance in AD staging, prognosis and differential diagnosis. In Aim 3, the most informative analytes from Aims 1 & 2 will be quantified in blood, either by LC-MS/MS, or by sensitive or ultra-sensitive ELISA approaches. Peptide abundance will be compared across biofluids, and the diagnostic utility of these markers in blood assessed.

目前尚无可常规用于阿尔茨海默病 (AD) 的实用生物标志物 AD 是一种复杂的疾病。 重叠的病理生理学导致最终的突触丧失和进行性痴呆。 AD 核心生物标志物，在脑脊液中测量的淀粉样蛋白-b 和 tau（总淀粉样蛋白和磷酸化蛋白） 液体（CSF），提供是否存在实质性 AD 病理的有力指示， 但迄今为止还不能很好地反映疾病的阶段或进展，以便更早地诊断疾病， 了解并发病理生理学的时间进程，并最大限度地发挥潜力 分期、追踪和治疗，表征更有用的 AD 生物标志物至关重要。 耶鲁大学和马萨诸塞州 ADRC 之间提议开展合作，利用 这两个中心各自的优势在于发现 AD 途径驱动的新型生物标志物。 使用可从以下机构获得的大量临床特征生物流体样本 马萨诸塞州 ADRC 和耶鲁 ADRC 将利用其在定量目标 LC 方面的专业知识 MS/MS 技术可评估脑脊液中的一百多种分析物，并扩展了最 LC-MS/MS 本质上具有特异性，可以同时检测血液。 使用数据独立采集 (DIA) LC- 从少量生物流体中提取许多标记物。 MS/MS 技术允许重新分析原始数据，以便对新数据进行回顾性分析 生物标志物，提供可重复且灵活的发现管道。 在目标 1 中，一组涉及 AD 的 CSF 通路中的 100 多种蛋白质 病理生理学将使用来自的样本进行全面的技术鉴定。 在临床试验的安慰剂组中，将对肽进行线性、测定间、测定内测试 然后，所有高性能肽都将在短期生物时间稳定性中进行量化。 60 名认知未受损成人 (CU-A) 和 60 名 AD 痴呆症患者的高对比度样本 将评估他们区分 AD 和 CU-A 的能力以及他们的情况。 在目标 2 中，将获得技术上合格的肽。 在 3 个定制样本集合中进行量化，以评估其在 AD 分期、预后方面的表现 在目标 3 中，来自目标 1 和 2 的信息最丰富的分析师将是 通过 LC-MS/MS 或通过灵敏或超灵敏 ELISA 方法对血液中的蛋白质进行定量。 将比较生物体液中的肽丰度以及这些标记物的诊断效用 在血液评估中。