Longitudinal Cognitive ERP studies: Advancement for AD Clinical Trials

纵向认知 ERP 研究：AD 临床试验的进展

• 批准号: 9474550
• 负责人: JAMES B BREWER
• 金额: $ 70.92万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9474550
• 关键词: Age; Alzheimer disease prevention; Alzheimer' s Disease; Amyloid; Atrophic; Attention; Biological Markers; Brain; Brain region; Clinical; Clinical Trials; Cognition; Cognitive; Cognitive Therapy; Data; Dementia; Diagnostics Research; Disease; Disease Progression; Early Intervention; Elderly; Electroencephalography; Enrollment; Event; Functional disorder; Impaired cognition; Infrastructure; Intervention Studies; Knowledge; Language; Language Disorders; Left; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Memantine; Memory; Memory Loss; Methodology; Methods; Modality; Modeling; Molecular; Neurons; Neuropsychological Tests; Neuropsychology; Outcome; Outcome Measure; P300 Event-Related Potentials; Participant; Patients; Pharmaceutical Preparations; Physiological; Population; Positron-Emission Tomography; Prevention trial; Primary Prevention; Process; Protocols documentation; Research; Sample Size; Sampling; Short-Term Memory; Specificity; Staging; Structure; Surrogate Markers; Synapses; Techniques; Temporal Lobe; Testing; Time; Validation; Visual; Yang; base; cerebral atrophy; clinically relevant; cognitive change; cost; demented; fluorodeoxyglucose positron emission tomography; high risk; hippocampal atrophy; improved; in vivo; neurotoxicity; potential biomarker; pre-clinical; prognostic; prognostic significance; public health relevance; recruit; treatment response; treatment trial; visual memory

 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.

 描述（由申请人提供）：该提案旨在验证有资格参加 AD 临床药物试验的人群中疾病进展的认知事件相关脑电位 (ERP) 生物标志物。我们将使用全面的 ERP 协议，该协议引发 5 个认知 ERP 组件（P50、P300、N400、LPC 和额叶正性 (FP)），每个组件都对早期阿尔茨海默病 (AD) 表现出高度敏感性。在这个经过验证的淀粉样蛋白生物标志物对早期 AD 敏感的时代，需要进行一项系统研究来比较这些 ERP 成分的相对敏感性和稳定性。我们将对超过 200 名老年参与者（60 名临床前 AD、50 名淀粉样生物标志物 - 正常老年人、50 名遗忘性 MCI 和 40 名轻度 AD 研究完成者）进行纵向认知 ERP/EEG、脑 MRI 和神经心理学测试。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。这项研究将增进我们对如何在 AD 治疗试验中使用 ERP 的了解，例如：用于预防试验中的样本“富集”以及结果衡量。具体目标：1) 验证基线 ERP 在预测认知衰退和脑萎缩纵向轨迹中的效用。 2) 检验我们的综合 ERP 电池将有助于 AD 病理生理过程的体内分期的假设。 3) 检验 ERP 对 AD 病理生理过程随时间变化高度敏感的假设，并将为跟踪疾病进展提供有用的生物标志物。方法：我们将招募老年受试者（年龄 60-90 岁；n = 252，其中 74 名临床前 AD (Pre-AD) 受试者、62 名淀粉样生物标志物阴性正常老年 (NO) 受试者、62 名遗忘性 MCI 受试者和 54 名轻度 AD 痴呆受试者）。所有入组受试者都将接受淀粉样蛋白 PET 研究、纵向 ERP/EEG 和脑 MRI。所有受试者将在基线研究后进行为期 2 年的重复年度 ERP 测试和 MRI 1 年研究，提供纵向 ERP、结构 MRI、神经心理学和功能数据。将使用综合 ERP 电池获得 32 通道 ERP/EEG，该电池评估自动 (P50) 和受控 (P300) 注意力、语言 (N400) 和记忆（语言和视觉，具有 LPC 和 FP 测量）过程。意义：在临床前阶段需要灵敏、可靠的突触功能障碍和早期 AD 标记。该提案通过在与当前 AD 临床药物试验最相关的人群中验证疾病进展的 ERP 生物标志物，将对初级预防试验、疾病缓解和靶向认知治疗具有重要应用。这项研究将允许合理应用特定的 ERP 范式，最适合临床前、前驱和痴呆人群。敏感 ERP/EEG 技术的更广泛应用可能会对减少 AD 治疗试验所需的样本量和成本产生重大影响。