Longitudinal Cognitive ERP studies: Advancement for AD Clinical Trials

纵向认知 ERP 研究：AD 临床试验的进展

基本信息

批准号：
9913431
负责人：
JAMES B BREWER
金额：
$ 66.84万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9913431
关键词：
Age Alzheimer disease prevention Alzheimer&apos 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

项目摘要

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（由适用提供）：该提案旨在验证有资格参加AD临床药物试验的人群中与认知事件相关的大脑潜力（ERP）疾病进展的生物标志物。我们将使用一项全面的ERP方案，该方案引起5个认知ERP成分（P50，P300，N400，LPC和额叶阳性（FP）），每个ERP都对早期阿尔茨海默氏病（AD）表现出很高的敏感性。在对淀粉样生物标志物对早期AD敏感的这个时代，需要比较这些ERP成分的相对灵敏度和稳定性的系统研究。我们将研究> 200名基本参与者（60个临床前AD，50个淀粉样生物标志物 - 正常基本，50个羊膜MCI和40个温和的AD研究完成者），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，开发基础设施，改进方法的可行性，并确定如何最好地使用ERP来检测AD的病理生理过程并随着时间的推移测量变化。这项研究将促进我们对如何在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”，并作为结果度量。具体目的：1）验证基线ERP在预测纵向轨迹的实用性N认知能力下降和脑萎缩。 2）测试我们全面的ERP电池将有助于AD病理生理过程的体内分期的假设。 3）测试ERP对随着时间的变化的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； n = 252，74，具有临床前AD（AD前），62个淀粉样生物标志物阴性正常（NO）旧受试者，62个柔韧性MCI和54个轻度AD痴呆症）。所有注册受试者将接受淀粉样蛋白宠物研究，纵向ERP/EEG和Brain MRI。在基线研究后1年，将对所有受试者进行重复的年度ERP测试，并提供纵向ERP，结构MRI，神经心理学和功能数据。 32通道ERP/EEG将使用全面的ERP电池获得，该电池评估自动（P50）和受控（P300）注意力，语言（N400）和内存（语言和视觉，具有LPC和FP测量）过程。意义：需要在其临床前阶段的突触功能障碍和初期AD的敏感，可靠的标记。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，将在初级预防试验，疾病修饰和靶向认知疗法方面有重要应用。这项研究将允许特定的ERP范式合理地应用，最适合临床前与痴呆种群。更广泛的敏感ERP/EEG技术的应用可能会对减少所需的样本量和AD治疗试验的成本产生重大影响。