A Novel Multiparameter Blood Test for Early Detection of Alzheimer's Disease

一种用于早期检测阿尔茨海默病的新型多参数血液测试

• 批准号: 10384224
• 负责人: Neil A Fanger
• 金额: $ 41.25万
• 依托单位: VIRTICI, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10384224
• 关键词: Affect; Age; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease blood test; Alzheimer' s disease brain; Alzheimer' s disease diagnosis; Alzheimer' s disease diagnostic; Alzheimer' s disease patient; Alzheimer' s disease related dementia; American; Amyloid beta-42; Amyloid beta-Protein; Antibodies; Autopsy; Binding; Biological Assay; Biological Markers; Blinded; Blood; Blood Tests; Brain; Brain imaging; Caregivers; Caring; Clinical stratification; Cognitive; Collection; Complex; Consensus; Consumption; Data Set; Decision Making; Dementia; Detection; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Disease Progression; Early Diagnosis; Enzyme-Linked Immunosorbent Assay; Goals; Health; Immunoassay; Immunoglobulin Fragments; Immunoglobulin G; Impaired cognition; Investigational Therapies; Length; Light; Longitudinal Studies; Measures; Methods; Modeling; N-terminal; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nutritional; Pain; Pathologic; Pathology; Patients; Performance; Pharmaceutical Preparations; Phase; Physical Examination; Plasma; Plasma Proteins; Positioning Attribute; Procedures; Production; Proteins; Research; Research Institute; Retrospective Studies; Sampling; Sensitivity and Specificity; Source; Standardization; Symptoms; Technology; Testing; The Sun; Therapeutic Clinical Trial; Time; Training; Treatment outcome; Variant; Work; aging population; alpha synuclein; antibody diagnostic; assay development; base; biomarker panel; cognitive testing; cost; cost estimate; design; economic cost; ineffective therapies; mild cognitive impairment; neurofilament; novel; patient stratification; patient subsets; performance tests; protein TDP-43; protein aggregation; repository; stem; tau Proteins; tau-1; tool; validation studies

Project Summary Our objective is to develop a blood-based diagnostic for Pre-symptomatic detection of Alzheimer's disease (AD) based on a Multiparameter Profiling (PreAMP). Currently there are over 18 million cases of AD worldwide, with the number of cases expected to nearly double over the next 15 years. In the US alone, total economic costs are estimated at nearly $200 billion per year1. Diagnosis is complex, costly and time-consuming. In part because of the lack of diagnostic tools and because AD represents a continuum of neurodegenerative disorders that share overlapping symptoms and protein pathologies. For these reasons, ~58% of dementia is thought to be undiagnosed altogether, which result that many patients do not receive adequate, timely care or treatment2. Recent work has revealed that forms of the aggregated proteins commonly found in the brains of AD patients can also be detected in the blood, showing promise for the development of a blood-based diagnostic. So far, however, different studies have emphasized single markers over a multiparameter approach, with no consensus as to which marker is superior3-9. Therefore, a multiparameter biomarker assay may prove to be extremely valuable for early diagnosis of a diverse range of patients against a continuum of dementias. The vast majority of biomarker efforts have focused on detection of non-toxic variants rather than the actual toxic aggregated protein species involved in neurodegeneration. Recently, our project team has developed novel biopanning technologies that enabled us to generate single chain antibody variable domain antibodies (scFvs) that bind to disease-specific variants of four key neuronal proteins implicated in AD and Related Dementias (ADRD): tau, Aβ, TDP-43, and α-syn. Our scFvs react only to the variants found in brain and plasma samples from ADRD patients but not cognitively normal controls10-12. Levels of Aβ and TDP-43 oligomers recognized by four of our scFvs were significantly elevated years before an initial diagnosis of mild cognitive impairment (MCI)9. During disease progression, we found that biomarker profiles change, so our antibody-based diagnostic could also be used to stage progression of AD from pre-symptomatic through late stage, permitting clinical stratification of patients to support experimental therapy decision-making for ADRD9. Building from this work, this proposal is designed to develop a blood-based diagnostic for AD called PreAMP. The specific aims are to: 1) develop a low-volume, multiplex antibody assay for quantitation of plasma protein variants. 2) determine the optimal biomarker set for pre-symptomatic diagnosis of AD, 3) validate the assay performance in a blinded retrospective study of longitudinal AD patient samples.

项目概要 我们的目标是开发一种基于血液的诊断方法，用于阿尔茨海默病的症状前检测 (AD) 基于多参数分析 (PreAMP)。 目前全球有超过 1800 万例 AD 病例，预计病例数将增加近一倍 未来 15 年，仅在美国，每年的总经济成本预计就接近 2000 亿美元1。 诊断过程复杂、昂贵且耗时，部分原因是缺乏诊断工具。 AD 代表一系列具有重叠症状和蛋白质的神经退行性疾病 由于这些原因，大约 58% 的痴呆症被认为没有被完全诊断出来，这导致 最近的研究表明，许多患者没有得到充分、及时的护理或治疗2。 AD 患者大脑中常见的聚集蛋白也可以在血液中检测到，这表明 然而，到目前为止，不同的研究都强调了开发基于血液的诊断的前景。 单一标记优于多参数方法，但对于哪个标记更优越尚未达成共识3-9。 因此，多参数生物标志物测定可能被证明对于早期诊断非常有价值 不同类型的患者对抗一系列痴呆症。 绝大多数生物标志物的工作都集中在检测无毒变异而不是实际的变异上。 最近，我们的项目团队开发了参与神经变性的有毒聚集蛋白种类。 新颖的生物淘选技术使我们能够生成单链抗体可变域抗体 (scFv) 与 AD 及相关疾病相关的四种关键神经元蛋白的疾病特异性变体结合 痴呆症 (ADRD)：tau、Aβ、TDP-43 和 α-syn 我们的 scFv 仅对大脑中发现的变异做出反应。 来自 ADRD 患者而非认知正常对照的血浆样本10-12 Aβ 和 TDP-43 水平。 我们的四个 scFv 识别的寡聚体在初次诊断为轻度症状前几年就显着升高 认知障碍（MCI）9。在疾病进展过程中，我们发现生物标志物谱发生变化，因此我们的 基于抗体的诊断还可用于对 AD 从症状前到晚期的进展进行分期 阶段，允许对患者进行临床分层，以支持 ADRD9 的实验治疗决策。 在这项工作的基础上，该提案旨在开发一种基于血液的 AD 诊断方法，称为 PreAMP。 具体目标是：1) 开发一种低容量、多重抗体测定法，用于血浆蛋白定量 2) 确定 AD 症状前诊断的最佳生物标志物集，3) 验证检测 纵向 AD 患者样本的盲法回顾性研究中的表现。