Blood-based biomarkers for early detection of Alzheimer's disease

用于早期检测阿尔茨海默病的血液生物标志物

• 批准号: 9478871
• 负责人: ROBERT G NAGELE
• 金额: $ 68.87万
• 依托单位: ROWAN UNIVERSITY SCHOOL/OSTEOPATHIC MED
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9478871
• 关键词: Affect; Age; Alzheimer disease detection; Alzheimer' s Disease; Amyloid; Autoantibodies; Biological Markers; Blood; Blood Screening; Blood Tests; Brain; Cells; Clear Cell; Clinical Trials; Detection; Development; Diagnosis; Diagnostic tests; Disease; Disease Progression; Early Diagnosis; Early treatment; Enrollment; Gender; Goals; Human; Impaired cognition; Individual; Laboratories; Link; Molecular; Monitor; Neurodegenerative Disorders; Neurologic; Organ; Outcome; Parkinson Disease; Pathogenesis; Pathologic; Pathology; Patients; Physicians; Preclinical Testing; Production; Protein Microchips; Role; Sampling; Sensitivity and Specificity; Serum; Specificity; Staging; Symptoms; Testing; Therapeutic; Time; Tissues; base; biomarker discovery; biomarker panel; blood-based biomarker; cell type; cohort; diagnostic biomarker; disease diagnosis; early detection biomarkers; mild cognitive impairment; molecular marker; novel marker; novel therapeutics; pre-clinical; specific biomarkers; therapy outcome; validation studies

Alzheimer’s disease (AD) is a devastating neurodegenerative disease affecting approximately 5.3 million people in the US. Currently, there are no blood or laboratory tests linked to the pathology that can provide a conclusive early diagnosis of AD. The lack of such tests has hampered the development and successful use of potentially beneficial AD therapies. In view of this, the broad, long-term objective of the proposed study is to develop accurate and reliable blood tests that can be used for detection of preclinical and prodromal AD (i.e., at mild cognitive impairment, MCI) as well as for monitoring AD progression from the preclinical stage to MCI and later AD stages. Our previous studies using human protein microarrays have shown that all humans possess thousands of autoantibodies in their blood and that individual autoantibody profiles are influenced by the presence of disease. We have exploited disease-specific changes in autoantibody profiles to identify biomarkers useful for diagnosing patients with prodromal AD at MCI and mild-moderate disease stages as well as early- and moderate-stage Parkinson’s disease with high sensitivity and specificity. In this proposed study, we will utilize autoantibodies as blood-based biomarkers and human protein microarrays as a testing platform to validate the selected MCI biomarkers with an independent patient cohort to test the ability of these biomarkers to identify patients at MCI and preclinical stages of AD. The following aims are proposed: Specific Aim #1 is to carry out a replication or validation study of early detection of AD at the prodromal (MCI) stage in subjects with low CSF Abeta42 levels and confirm disease stage- and disease-specificity using serum samples from an independent cohort of ADNI MCI subjects who subsequently transitioned to AD. To test the linkage between the efficacy of MCI biomarkers and early AD pathology, Specific Aim #2 will determine the effects of CSF Abeta42 level and cortical amyloid load as pathological indicators of early AD pathology on the overall accuracy, including disease staging and disease specificity, of the MCI biomarker panel. As a result of the high overall accuracy of our MCI biomarker panel in distinguishing MCI subjects with low CSF Abeta42 levels from controls shown in our previous study, Specific Aim #3 is to determine the utility of the prodromal AD (MCI) biomarkers for preclinical detection of AD. Here, the MCI biomarker panel will be probed using sera from subjects who originally enrolled in ADNI as healthy controls, but later transitioned to MCI or full-blown AD. Controls will be ADNI subjects who also enrolled as healthy controls but showed no clear signs of cognitive decline over the same time period. The development of an accurate, relatively noninvasive, inexpensive and early blood-based diagnostic test for AD will be of great benefit to patients afflicted with this disease, since early treatment greatly increases the likelihood of a successful outcome. In addition, it would facilitate earlier enrollment into AD clinical trials, and would enable monitoring of AD progression in patients who are under treatment by their physicians or participating as subjects in clinical trials for new potential therapeutics.

阿尔茨海默病（AD）是一种破坏性的神经退行性疾病，影响约530万人 美国的人。目前，没有血液或实验室检查与病理学相关，可以提供一个 AD的早期诊断。缺乏这种测试阻碍了开发和成功使用 可能有益的AD疗法。有见及此，拟议研究的广泛和长远目标是 开发可用于检测临床前和前驱AD的准确和可靠的血液测试（即， 轻度认知障碍，MCI）以及监测AD从临床前阶段进展为MCI 以及后期AD阶段。我们之前使用人类蛋白质微阵列的研究表明，所有人类 在他们的血液中拥有成千上万的自身抗体，并且个体自身抗体谱受到以下因素的影响： 疾病的存在。我们利用自身抗体谱中的疾病特异性变化来识别 可用于诊断MCI和轻-中度疾病阶段的前驱AD患者的生物标志物 作为早期和中期帕金森病，具有较高的敏感性和特异性。在这项研究中， 我们将利用自身抗体作为基于血液的生物标志物， 用独立的患者队列验证所选MCI生物标志物，以测试这些生物标志物的能力。 生物标志物来识别处于MCI和AD临床前阶段的患者。建议的目标如下： 目的#1是进行在前驱期（MCI）早期检测AD的复制或验证研究， CSF A β 42水平低的受试者，并使用血清样本确认疾病分期和疾病特异性 来自随后转变为AD的ADNI MCI受试者的独立队列。为了测试连接 MCI生物标志物的功效与早期AD病理学之间的关系，具体目标#2将确定 CSF A β 42水平和皮质淀粉样蛋白负荷作为AD早期病理学指标， MCI生物标志物组的准确性，包括疾病分期和疾病特异性。的结果 我们的MCI生物标志物组在区分具有低CSF A β 42水平的MCI受试者方面的较高总体准确性 与我们先前研究中所示的对照相比，具体目标#3是确定前驱AD的效用 (MCI)用于AD临床前检测的生物标志物。在此，MCI生物标志物组将使用来自 受试者最初作为健康对照参加ADNI，但后来转变为MCI或完全AD。 对照将是ADNI受试者，其也作为健康对照入组，但未显示出明显的认知障碍体征。 在同一时期下降。开发一种准确的，相对无创的，廉价的， 早期基于血液的AD诊断测试将对患有这种疾病的患者非常有益，因为 早期治疗大大增加了成功的可能性。此外，它还将有助于更早地 入组AD临床试验，并将能够监测AD患者的进展， 他们可以接受医生的治疗或作为受试者参与新的潜在疗法的临床试验。