Longitudinal Cognitive ERP studies: Advancement for AD Clinical Trials

 描述（由申请方提供）：本提案旨在验证符合入组AD临床药物试验条件的人群中疾病进展的认知事件相关脑电位（ERP）生物标志物。我们将使用一个全面的ERP协议，其中包括5个认知ERP组件（P50，P300，N400，LPC和额叶阳性（FP）），每一个都表现出对早期阿尔茨海默病（AD）的高敏感性。在这个对早期AD敏感的经验证的淀粉样蛋白生物标志物的时代，需要比较这些ERP组分的相对敏感性和稳定性的系统研究。我们将用纵向认知ERP/EEG、脑MRI和神经心理学测试研究>200名老年参与者（60名临床前AD、50名淀粉样蛋白生物标志物-正常老年人、50名遗忘型MCI和40名轻度AD研究完成者）。该项目将测试多中心ERP研究的可行性，开发基础设施，完善方法，并确定如何最好地使用ERP来检测AD病理生理过程并测量随时间的变化。这项研究将推进我们如何在AD治疗试验中使用ERPs的知识，例如在预防试验中用于样本“富集”，以及作为结果测量。具体目的：1）验证基线ERP在预测认知下降和脑萎缩纵向轨迹中的效用。2)为了检验我们的综合ERP组合将有助于AD病理生理过程的体内分期的假设。3)为了检验这一假设，即ERP是高度敏感的变化，在AD病理生理过程中随着时间的推移，并将提供有用的生物标志物跟踪疾病的进展。研究方法：我们将招募老年受试者（年龄60-90岁; n =252，74例临床前AD（Pre-AD），62例淀粉样蛋白生物标记物阴性正常老年（NO）受试者，62例遗忘型MCI和54例轻度AD痴呆）。所有入组受试者将接受淀粉样蛋白PET研究、纵向ERP/EEG和脑部MRI。所有受试者将接受为期2年的重复年度ERP测试和基线研究后1年的MRI研究，提供纵向ERP、结构MRI、神经心理学和功能数据。将使用综合ERP组合获得32通道ERP/EEG，该组合评估自动（P50）和控制（P300）注意力、语言（N400）和记忆（言语和视觉，LPC和FP测量）过程。意义：需要敏感、可靠的突触功能障碍和早期AD临床前阶段的标志物。该提案通过验证与当前AD临床药物试验最相关的人群中疾病进展的ERP生物标志物，将对一级预防试验，疾病修饰和靶向认知治疗具有重要应用。本研究将允许合理应用特定的ERP范例，最适合临床前与前驱与痴呆人群。更广泛地应用敏感的ERP/EEG技术可能会对减少AD治疗试验所需的样本量和成本产生重大影响。

 DESCRIPTION (provided by applicant): This proposal aims to validate cognitive event-related brain potential (ERP) biomarkers of disease progression in populations eligible to enroll in AD clinical drug trials. We will use a comprehensive ERP protocol which elicits 5 cognitive ERP components (P50, P300, N400, LPC and Frontal Positivity (FP)), each with demonstrated high sensitivity to early Alzheimer disease (AD). A systematic study which compares the relative sensitivity and stability of these ERP components is needed, in this era of validated amyloid biomarkers sensitive to early AD. We will study >200 elderly participants (60 pre-clinical AD, 50 amyloid biomarker - normal elderly, 50 amnestic MCI & 40 mild AD study completers) with longitudinal cognitive ERP/EEG, brain MRI and neuropsychological testing. The project will test the feasibility of multicenter ERP studies, develop infrastructure, refine methodology, and determine how ERPs can be best used to detect the AD pathophysiologic process and to measure changes over time. This study will advance our knowledge of how to use ERPs in AD treatment trials, e.g. for sample "enrichment" in prevention trials, and as outcome measures. Specific Aims: 1) To validate the utility of baseline ERPs in predicting longitudinal trajectories n cognitive decline and brain atrophy. 2) To test the hypothesis that our comprehensive ERP battery will assist the in vivo staging of the AD pathophysiologic process. 3) To test the hypothesis that ERPs are highly sensitive to changes in the AD pathophysiologic process over time and will provide useful biomarkers for tracking disease progression. Methods: We will recruit elderly subjects (age 60-90; n =252, 74 with Preclinical AD (Pre-AD), 62 amyloid biomarker-negative Normal Old (NO) subjects, 62 amnestic MCI, and 54 mild AD dementia). All enrolled subjects will receive an amyloid PET study, longitudinal ERP/EEG and brain MRI. All subjects will be studied with repeat annual ERP testing for 2 years and MRI 1 year after the baseline study, providing longitudinal ERP, structural MRI, neuropsychological and functional data. 32 channel ERP/EEG will be obtained using a comprehensive ERP battery which assesses automatic (P50) and controlled (P300) attention, language (N400) and memory (verbal and visual, with LPC and FP measures) processes. Significance: Sensitive, reliable markers of synaptic dysfunction and incipient AD in its preclinical stages are needed. This proposal, by validating ERP biomarkers of disease progression in populations most relevant to current AD clinical drug trials, will have important applications to primary prevention trials, disease-modifying and targeted cognitive therapies. This study will allow the rational application of specific ERP paradigms, best suited to preclinical vs. prodromal vs. demented populations. More wide application of sensitive ERP/EEG techniques could have major impact on reducing the requisite sample sizes and costs of AD treatment trials.