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

用于早期检测阿尔茨海默病的新型多参数血液测试

基本信息

批准号：
10570790
负责人：
Neil A Fanger
金额：
$ 3.05万
依托单位：
VIRTICI, LLC
依托单位国家：
美国
项目类别：
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/10570790
关键词：
Affect Alzheimer disease detection Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease diagnosis Alzheimer&apos s disease diagnostic Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia American Amyloid beta-Protein Antibodies Binding Biological Assay Biological Markers Blinded Blood Blood Tests Brain Caregivers Caring Clinical stratification Complex Consensus Consumption Decision Making Dementia Detection Development Diagnosis Diagnostic Disease Disease Progression Early Diagnosis Investigational Therapies Longitudinal Studies Methods Nerve Degeneration Neurodegenerative Disorders Neurons Pathology Patients Performance Plasma Plasma Proteins Proteins Retrospective Studies Sampling Symptoms Technology Therapeutic Clinical Trial Time Variant Work alpha synuclein antibody diagnostic antibody test base cost cost estimate design diagnostic tool economic cost mild cognitive impairment novel patient stratification patient subsets protein TDP-43 protein aggregation tau Proteins

Affect Alzheimer disease detection Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease diagnosis Alzheimer&apos s disease diagnostic Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia American Amyloid beta-Protein Antibodies Binding Biological Assay Biological Markers Blinded Blood Blood Tests Brain Caregivers Caring Clinical stratification Complex Consensus Consumption Decision Making Dementia Detection Development Diagnosis Diagnostic Disease Disease Progression Early Diagnosis Investigational Therapies Longitudinal Studies Methods Nerve Degeneration Neurodegenerative Disorders Neurons Pathology Patients Performance Plasma Plasma Proteins Proteins Retrospective Studies Sampling Symptoms Technology Therapeutic Clinical Trial Time Variant Work alpha synuclein antibody diagnostic antibody test base cost cost estimate design diagnostic tool economic cost mild cognitive impairment novel patient stratification patient subsets protein TDP-43 protein aggregation tau Proteins

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项目摘要

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.

项目摘要我们的目标是开发基于血液的诊断，以预先对称阿尔茨海默氏病。（AD）基于多参数分析（前置放大器）。目前，全球有超过1800万例广告案例，预计案件的数量将几乎翻一番在接下来的15年中。仅在美国，总经济成本估计为每年近2000亿美元。诊断很复杂，昂贵且耗时。部分原因是缺乏诊断工具，并且是因为广告代表共享重叠症状和蛋白质的神经退行性疾病的连续群病理。由于这些原因，约有58％的痴呆症被认为完全被诊断许多患者没有接受足够的及时护理或治疗2。最近的工作表明在血液中也可以检测到在AD患者大脑中常见的汇总蛋白质，显示有望发展基于血液的诊断。然而，到目前为止，已经强调了不同的研究在多参数方法上的单个标记，对哪个标记为superior3-9没有共识。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与痴呆症连续体的患者不同。绝大多数生物标志物的努力都集中在发现无毒变体上，而不是实际与神经变性有关的有毒聚集蛋白质。最近，我们的项目团队已经发展新型的生物综合技术使我们能够生成单链抗体可变域抗体（SCFV）与AD和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仅对在大脑中发现的变体做出反应来自ADRD患者的血浆样品，但不认知正常对照10-12。 Aβ和TDP-43的水平在最初诊断中期之前，我们四个SCFV认识的低聚物显着升高认知障碍（MCI）9。在疾病进展过程中，我们发现生物标志物谱发生变化，因此我们基于抗体的诊断也可用于从症状到晚期的AD进行阶段阶段，允许患者的临床分层支持ADRD9的实验治疗决策。根据这项工作的建立，该提案旨在为AD开发一个名为PREAMP的基于血液的诊断。具体目的是：1）开发用于定量血浆蛋白的小体积，多抗体测定变体。 2）确定用于AD预症状诊断的最佳生物标志物，3）验证测定法在纵向AD患者样品的盲目回顾性研究中表现。