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: 8465920
• 负责人: Michael D Greicius
• 金额: $ 43.49万
• 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/8465920
• 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; meetings; mild cognitive 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.

描述（由申请人提供）：首次描述了100年以上，阿尔茨海默氏病（AD）仍严格诊断出对疾病早期不敏感的临床标准，并且不能充分地将AD与非AD痴呆症区分开。当将临床诊断与尸检确认的诊断进行比较时，即使是经验丰富的临床医生，也有15-20％的时间错误。假定这种诊断性不准确率在最初对AD的初始诊断的非专业环境中差得多。随着实验疗法的进步以及伴随的提醒，有效的治疗可能会产生严重的副作用，因此需要准确，无创的AD生物标志物的需求比以往任何时候都更加紧迫。这样的生物标志物在几个方面都会有用。在临床环境中，它可以在试图将AD与其他痴呆症区分开来时获得更多的诊断确定性。具有足够敏感性的准确生物标志物还应有助于预测哪些轻度认知障碍患者（MCI）将继续发展AD，并且同样重要的是，这不会。最后，在最早的阶段和临床状态的轨道上检测疾病的AD生物标志物将通过促进剂量反应研究加速药物的发育，并使功效更快，客观地评估。尽管做出了巨大的努力，但该领域尚未开发出可以满足这些紧迫需求的生物标志物。当前的应用将研究一种相对新的功能性MRI（fMRI）形式，作为AD中的候选成像生物标志物。静止状态fMRI提供了特定大脑网络中功能连通性的量度，并在初步研究中以AD生物标志物显示了希望。这种方法的局限性目前尚未证明在单个主体级别可靠地可靠地解释，其在MCI中的预测价值尚不确定，并且尚未纵向检查。当前的应用借鉴了多站点纵向研究的优势，将试图解决这些局限性。这项研究将涉及从斯坦福大学和加利福尼亚大学，旧金山获得静止状态的FMRI数据，包括四个大型主题：健康衰老，MCI，AD和非AD痴呆症。受试者将在基线时进行扫描，并纵向遵循。一部分受试者将以1年的间隔再次扫描。该研究的目的将是a）提高静止状态功能连通性测量的灵敏度和特异性，以区分AD和健康衰老和非AD痴呆症，b）评估静息状态fMRI的效用，以预测哪些患者随后MCI随后在研究的五年过程中转换为AD，并且c）评估静止状态fMRI在跟踪疾病进展中的效用。