Blood-based diagnostics for Alzheimer's Disease

阿尔茨海默病的血液诊断

• 批准号: 9231053
• 负责人: CLAUDIO SOTO
• 金额: $ 6.47万
• 依托单位: AMPRION, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9231053
• 关键词: Affect; Age; Alzheimer' s Disease; Amyloid beta-Protein; Animal Model; Biochemical; Biological; Biological Assay; Blinded; Blood; Blood Tests; Brain; Brain Injuries; Businesses; Cause of Death; Cerebrospinal Fluid; Cerebrum; Chemical Structure; Clinical; Correlation Studies; Dementia; Deposition; Detection; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Early Diagnosis; Elderly; Evaluation; Event; Goals; Health; Human; In Vitro; Individual; Institution; Knowledge; Laboratory Diagnosis; Lead; Liquid substance; Medical; Mole the mammal; Monitor; Mutation; Nerve Degeneration; Patients; Persons; Phase; Plasma; Population; Predictive Value; Prion Diseases; Prions; Property; Proteins; Reproducibility; Sampling; Secure; Sensitivity and Specificity; Small Business Technology Transfer Research; Specificity; Staging; Structure; Techniques; Technology; Testing; Time; Tissues; Transgenic Animals; Transgenic Mice; Urine; Validation; Work; abeta accumulation; abeta oligomer; authority; base; clinical Diagnosis; design; disease diagnosis; experience; familial Alzheimer disease; high risk; mild cognitive impairment; mouse model; nervous system disorder; polymerization; pre-clinical; programs; protein misfolding; protein misfolding cyclic amplification; research study

DESCRIPTION (provided by applicant): This proposal is for a phase I/II fast track project for the STTR program with the main goal to develop a blood test for Alzheimer's disease (AD) diagnosis. AD is the most common dementia in the elderly population and one of the leading causes of death in the developed world. One of the main problems in AD is the lack of an early, sensitive and objective laboratory diagnosis to identify individuals that will develop the disease before substantial brain damage. Compelling evidences point that the hallmark event in AD is the misfolding, aggregation and brain accumulation of amyloid-beta (Aβ) protein. Aβ aggregation follows a seeding-nucleation mechanism and involves several intermediates, including soluble oligomers and protofibrils. Recent evidence has shown that Aβ oligomers are circulating in biological fluids and these structures appear to be key for inducing brain degeneration in AD. Our working hypothesis is that detection of misfolded Aβ oligomers circulating in blood may be the basis for an early biochemical diagnosis for AD. Our approach is to use the functional property of misfolded oligomers of being capable to catalyze the polymerization of the monomeric protein as a way to detect them. We have recently invented the protein misfolding cyclic amplification (PMCA), which represent a platform technology to detect very small quantities of seeding-competent misfolded oligomeric proteins associated with various protein misfolding diseases. Currently, PMCA has been adapted to detect misfolded prion protein implicated in prion diseases in various biological fluids, including blood and urine and more recently soluble Aβ oligomers in cerebrospinal fluid of AD patients. The major goal of this project is to adapt the PMCA technology for specific and highly sensitive detection of misfolded Aβ oligomers in human blood, perform studies of specificity and sensitivity using large number of samples and evaluate the utility of Aβ-PMCA for pre-clinical identification of people in the way to develop AD. The results generated in this project may lead to the first biochemical test for blood-based diagnosis of AD. The studies included in this project will constitute the basis for regulatory approval of the test that Amprion will commercialize.

描述(由申请人提供)：这项提案是针对STTR项目的I/II阶段快速通道项目，主要目标是开发用于阿尔茨海默病(AD)诊断的血液测试。AD是老年人口中最常见的痴呆症，也是发达国家的主要死亡原因之一。阿尔茨海默病的主要问题之一是缺乏早期、敏感和客观的实验室诊断，以在大脑实质性损伤之前识别将发展为该病的个体。令人信服的证据表明，AD的标志性事件是淀粉样β蛋白(Aβ)的错误折叠、聚集和脑积聚。β聚集遵循种子成核机制，涉及几个中间体，包括可溶低聚物和原纤维。最近的证据表明，Aβ寡聚体在生物体液中循环，这些结构似乎是诱导AD大脑退化的关键。我们的工作假设是，血液中循环的错误折叠的Aβ寡聚体的检测可能是AD早期生化诊断的基础。我们的方法是利用错误折叠的低聚物能够催化单体蛋白质聚合的功能特性作为检测它们的一种方法。我们最近发明了蛋白质错误折叠循环扩增(PMCA)，它代表了一种平台技术，可以检测与各种蛋白质错误折叠疾病相关的非常少量的种子能力错误折叠低聚蛋白。目前，PMCA已被用于检测各种生物体液中与Pron病有关的错误折叠的Prion蛋白，包括血液和尿液，以及最近在AD患者脑脊液中的可溶性Aβ寡聚体。本项目的主要目标是将该技术应用于人类血液中错误折叠的Aβ寡聚体的特异性和高灵敏检测，使用大量样本进行特异性和敏感性研究，并评估Aβ-PMCA在AD患者临床前鉴定中的应用。该项目产生的结果可能导致第一个基于血液的AD诊断的生化测试。该项目中包括的研究将构成监管部门批准Amprion将商业化的测试的基础。