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: 9788266
• 负责人: STEVEN E ARNOLD
• 金额: $ 76.14万
• 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/9788266
• 关键词: Address; Adult; Alzheimer' s Disease; Alzheimer’s disease biomarker; 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.

目前还没有实用的阿尔茨海默病（AD）生物标志物，可以常规检测 分期、评估预后和监测治疗反应。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。 在脑脊液中测量的核心AD生物标志物淀粉样蛋白-b和tau（总和磷酸化） 脑脊液（CSF），提供了存在或不存在实质性AD病理的强烈指示， 但还不能很好地反映疾病阶段或进展。为了更早地诊断疾病， 了解并发病理生理学的时间进程，并最大限度地提高 因此，在分期、跟踪和治疗方面，表征更有用的AD生物标志物是至关重要的。 耶鲁大学和马萨诸塞州ADRC之间的合作将利用 这两个中心各自的优势，以发现途径驱动的新的AD生物标志物。 使用大量的临床表征的生物流体样品， 马萨诸塞州ADRC，耶鲁ADRC将利用他们的专业知识，在定量有针对性的LC- MS/MS技术可评估CSF中的100多种分析物， 对血液的信息。LC-MS/MS具有固有的特异性，能够同时检测 小生物流体体积中的许多标记物。使用数据独立采集（DIA）LC- MS/MS技术允许对原始数据进行重新分析，以便对新的 生物标志物，提供可重复但灵活的发现管道。 在目标1中，CSF中涉及AD途径的一组100多种蛋白质 病理生理学将接受全面的技术鉴定。使用来自 在临床试验的安慰剂组中，将检测肽的线性、试验间、试验内 和短期生物时间稳定性。然后将所有高性能肽定量于 60例认知未受损成人（CU-A）和60例AD所致痴呆高对比度样本 例他们将被评估他们的能力，以区分AD从CU-A，并为他们的 与突触功能标志物的相关性。在目标2中，技术上合格的肽将 在3个定制的样本收集中进行定量，以评估其在AD分期、预后 和鉴别诊断。在目标3中，目标1和2中信息量最大的分析物将是 通过LC-MS/MS或灵敏或超灵敏ELISA方法在血液中进行定量。 肽丰度将在生物流体中进行比较，这些标记物的诊断效用 血液评估。