AD Pilot Clinical Trials: Spatiotemporal Brain ERP Measures

描述(由申请人提供)：为了促进测试阿尔茨海默病(AD)干预措施的临床试验的成功，研究人员必须建立适当的受试者登记并衡量治疗的临床疗效。脑事件相关电位(ERPs)是受试者在完成有设计的知觉/认知需求的任务时获得的，它提供了一种非侵入性的方法来测量受AD影响的大脑活动，一旦开发出来，就可以在没有特殊设备或特殊专业知识的情况下用于临床和研究用途。结合复杂的多变量分析技术，时间事件相关电位已被证明可以检测AD并预测具有临床前疾病形式的个体的AD进展。我们的目标是扩大对事件相关电位的研究，将其时间和空间特性纳入新颖和创新的综合措施中，以：1)定义和细化AD受试者群体，以提高即使在痴呆前期AD患者的临床试验中适当的受试者登记，以及2)开发可以检测受试者随着时间的变化的大脑活动指标，以便衡量AD治疗的效果。使用一种已知的诱发代表记忆编码和提取、刺激预期和执行功能的事件相关电位的认知范式，我们将收集疾病早期的AD患者、MCI患者(其中相当大一部分人在几年内发展为AD)和正常老年人的ERP。然后，我们将应用新的多变量技术，包括两步时空主成分分析和并行因子分析来定义和测量事件相关电位的潜在时空成分，以便将事件相关电位的时间波形及其空间分布合并为有用的综合度量。这些时空事件相关电位测量将被线性组合成判别函数，可用于进行小组分配，并通过小组成员的后验概率对每个受试者的分配进行置信度的定量测量。这项技术也将被研究，以通过纵向重新分析群体安置来检测随时间的变化。如果成功，这些ERP测量和多变量方法将为提高临床试验的有效性提供重要工具，同时解决在整个AD过程中使用经验和定量结合的空间和时间ERP测量的困难障碍。

DESCRIPTION (provided by applicant): To promote the success of clinical trials testing interventions for Alzheimer's disease (AD), it is imperative that researchers establish proper subject enrollment and measure the clinical efficacy of the treatment. Brain Event-Related Potentials (ERPs), which are obtained while subjects do tasks with designed perceptual/cognitive demands, offer a noninvasive method of measuring brain activity affected by AD that, once developed, can be implemented for clinical and research use without special equipment or special expertise. In conjunction with sophisticated multivariate analytic techniques, temporal ERPs have been shown to detect AD and predict AD progression in individuals with pre-clinical form of the disease. Our aim is to expand the study of ERPs to incorporate both their temporal and spatial properties in novel and innovative composite measures to: 1) define and refine the AD subject population to improve proper subject enrollment in clinical trials even in predementia AD, and 2) develop measures of brain activity that can detect change in subjects over time in order to gauge the effects of AD treatments. Using a cognitive paradigm known to elicit ERPs representative of memory encoding and retrieval, stimulus expectancy, and executive functioning, we will collect ERPs from AD patients early in the course of the disorder, MCI patients (a sizeable percentage of whom develop AD within a few years), and normal elderly. We will then apply new multivariate techniques, including Two-step Spatiotemporal Principal Components Analysis and Parallel Factors Analysis to define and measure the underlying spatiotemporal components of the ERPs, in order to combine both the temporal waveforms of the ERPs and their spatial distributions into useful composite measures. These spatiotemporal ERP measures will be linearly combined into discriminant functions that can be used to make group assignments with a quantitative measure of confidence in each subject's assignment through posterior probabilities of group membership. This technique will also be studied to detect change over time by reanalyzing group placements longitudinally. If successful, these ERP measures and multivariate methods will provide important tools for improving the validity of clinical trials while addressing the difficult barrie of empirically and quantitatively combining spatial and temporal ERP measures for use in evaluating AD across its course.