Development of Resting-State fMRI as a Biomarker for Alzheimers Disease

开发静息态功能磁共振成像作为阿尔茨海默病的生物标志物

• 批准号: 7899707
• 负责人: Michael D Greicius
• 金额: $ 47.67万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-15 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7899707
• 关键词: Address; Adverse effects; Affect; Alzheimer' s Disease; American; Autopsy; Biological Markers; Brain; Brain imaging; Brain region; California; Clinical; Data; Dementia; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Dose; Functional Magnetic Resonance Imaging; Image; Longitudinal Studies; Measures; Medial; Patients; Performance; Pharmaceutical Preparations; Predictive Value; Principal Investigator; Process; Radiation; Reporting; Rest; San Francisco; Scanning; Seasons; Sensitivity and Specificity; Signal Transduction; Site; Staging; Techniques; Temporal Lobe; Testing; Therapeutic; Time; Traction; Training; Universities; Work; cingulate cortex; clinical Diagnosis; cohort; data acquisition; drug development; experience; healthy aging; medical specialties; meetings; mild neurocognitive impairment; novel; public health relevance; response

DESCRIPTION (provided by applicant): More than 100 years after it was first described, Alzheimer's disease (AD) is still diagnosed strictly on clinical criteria that are not sensitive to the early stages of disease and do not adequately distinguish AD from non-AD dementias. When comparing a clinical diagnosis to an autopsy-confirmed diagnosis, even the most seasoned clinicians are wrong 15-20% of the time. This diagnostic inaccuracy is assumed to be considerably worse in non-specialty settings where the initial diagnosis of AD is most often made. With advances in experimental therapeutics and the concomitant reminder that potent treatments may have serious side effects, the need for an accurate, non-invasive AD biomarker is more pressing than ever. Such a biomarker would be useful on several fronts. In the clinical setting it would allow for more diagnostic certainty in trying to distinguish AD from other dementias. An accurate biomarker with sufficient sensitivity should also help predict which patients with mild cognitive impairment (MCI) will go on to develop AD and, just as importantly, which will not. Lastly, an AD biomarker that detects disease in the earliest stages and tracks with clinical status would accelerate drug development by facilitating dose-response studies and enabling more rapid and objective assessment of efficacy. Despite considerable efforts, the field has yet to develop a biomarker that can meet these pressing needs. The current application will examine a relatively novel form of functional MRI (fMRI) as a candidate imaging biomarker in AD. Resting-state fMRI provides a measure of functional connectivity within specific brain networks and has shown promise in preliminary studies as an AD biomarker. The limitations of this approach currently are that it has not yet proven to be reliably interpretable at the single-subject level, its predictive value in MCI remains uncertain, and it has not been examined longitudinally. The current application, drawing on the strengths of a multi-site, longitudinal study, will attempt to address these limitations. The study will involve the acquisition of resting-state fMRI data from Stanford University and the University of California, San Francisco in four large cohorts of subjects: healthy aging, MCI, AD, and non-AD dementia. Subjects will be scanned at baseline and followed longitudinally. A subset of subjects will be scanned again at a 1-year interval. The aims of the study will be a) to enhance the sensitivity and specificity of resting-state functional connectivity measures in distinguishing AD from both healthy aging and non-AD dementia, b) to assess the utility of resting-state fMRI in predicting which patients with MCI subsequently convert to AD over the five-year course of the study and c) to assess the utility of resting-state fMRI in tracking disease progression over time. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is a devastating, fatal illness that will affect more than 10 million Americans by mid-century. The current study will aim to develop a brain imaging test for AD that would allow doctors to diagnose it earlier and more accurately. Such a test would help determine whether experimental drugs were working and would allow drugs to be started early in the course of the illness when they are more likely to be effective.

描述（由申请人提供）：自首次描述以来 100 多年，阿尔茨海默氏病 (AD) 的诊断仍然严格按照临床标准进行，这些标准对疾病的早期阶段不敏感，并且无法充分区分 AD 和非 AD 痴呆。当将临床诊断与尸检确认的诊断进行比较时，即使是最经验丰富的临床医生也有 15-20% 的时间是错误的。在最常做出 AD 初始诊断的非专业环境中，这种诊断不准确性被认为要严重得多。随着实验疗法的进步以及随之而来的提醒，有效的治疗可能会产生严重的副作用，对准确、非侵入性 AD 生物标志物的需求比以往任何时候都更加紧迫。这种生物标记物在多个方面都有用。在临床环境中，它将在尝试区分 AD 和其他痴呆症时提供更多的诊断确定性。具有足够敏感性的准确生物标志物还应有助于预测哪些患有轻度认知障碍 (MCI) 的患者将继续发展为 AD，同样重要的是，哪些患者不会。最后，在最早阶段检测疾病并跟踪临床状态的 AD 生物标志物将通过促进剂量反应研究并实现更快速、客观的疗效评估来加速药物开发。尽管付出了巨大的努力，该领域尚未开发出能够满足这些紧迫需求的生物标记物。当前的申请将检查一种相对新颖的功能 MRI (fMRI) 形式，作为 AD 的候选成像生物标志物。静息态功能磁共振成像提供了特定大脑网络内功能连接的测量，并在初步研究中显示出作为 AD 生物标志物的前景。目前这种方法的局限性在于，它尚未被证明在单个受试者水平上具有可靠的解释性，其在 MCI 中的预测价值仍然不确定，并且尚未经过纵向检验。当前的应用程序利用多地点纵向研究的优势，将尝试解决这些局限性。该研究将涉及从斯坦福大学和加州大学旧金山分校获取四大组受试者的静息态功能磁共振成像数据：健康老龄化、MCI、AD 和非 AD 痴呆。将对受试者进行基线扫描并纵向跟踪。一部分受试者将每隔 1 年再次扫描一次。该研究的目的是：a) 提高静息态功能连接测量的敏感性和特异性，以区分 AD 与健康老龄化和非 AD 痴呆症，b) 评估静息态 fMRI 在预测哪些患者方面的效用在五年的研究过程中，MCI 随后转变为 AD，并且 c) 评估静息态 fMRI 在跟踪疾病进展方面的效用。 公共健康相关性：阿尔茨海默病 (AD) 是一种毁灭性的致命疾病，到本世纪中叶将影响超过 1000 万美国人。目前的研究旨在开发一种针对 AD 的脑成像测试，使医生能够更早、更准确地诊断 AD。这样的测试将有助于确定实验药物是否有效，并允许在疾病早期开始使用药物，此时药物更有可能有效。