Network-Level Mechanisms for Preclinical Alzheimer?s Disease Development

临床前阿尔茨海默病发展的网络级机制

• 批准号: 9371548
• 负责人: Shi-Jiang Li
• 金额: $ 22.7万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-15 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9371548
• 关键词: Age; Alleles; Alzheimer' s Disease; Antiepileptic Agents; Apolipoprotein E; Apolipoproteins; Aspirin; Bilateral; Biological Neural Networks; Brain; Classification; Clinical; Cognitive; Cognitive deficits; Data; Dementia; Development; Disease; Dose; Double-Blind Method; Episodic memory; FDA approved; Foundations; Functional Magnetic Resonance Imaging; Future; Hippocampus (Brain); Human; Hyperactive behavior; Image; Individual; Intervention; Late Onset Alzheimer Disease; Levetiracetam; Link; Measurement; Measures; Memory; Memory Loss; Methods; Motor Cortex; Neuropsychological Tests; Outcome; Outcome Measure; Patients; Pattern; Performance; Phase; Pilot Projects; Placebos; Prevention strategy; Preventive Clinical Trial; Procedures; Protocols documentation; Randomized; Reproducibility; Research; Rest; Risk; Risk Factors; Sensory; Stroke; Symptoms; Synapses; Task Performances; Testing; Time; abeta accumulation; base; brain volume; connectome; high risk; human study; human subject; improved; independent component analysis; mild cognitive impairment; mouse model; network dysfunction; neuroimaging; placebo controlled study; pre-clinical; prevent; primary outcome; relating to nervous system; response; secondary outcome; temporal measurement

PROJECT SUMMARY Currently, no FDA-approved therapy exists for cognitively normal (CN) older subjects who have abnormal functional connectivity and are at increased risk for progression to dementia. To take the full advantage of early disease intervention, we propose a pilot project to test our hypothesis that, during the preclinical Alzheimer's disease developmental phase in cognitively normal (CN) older subjects with the apolipoprotein ε4 allele (APOE 4), decreased abnormal hyperfunctional connectivity can be correlated with improved episodic memory using a perturbation, such as a low dose of levetiracetam (LEV). Specifically, we will 1) determine network-level changes in hippocampal functional connectivity due to a 26- week, low-dose LEV perturbation (125 mg, twice daily) in 50 CN older subjects (ranging in age from 55 to 75 years) with the APOE 4 allele, and 2) correlate the network changes with changes in episodic memory before and after 26 weeks of placebo or low-dose LEV perturbation. We will employ the harmonized Human Connectome Project protocol for imaging acquisition and the FIX method to determine the network activity changes. The following outcome measurements will be used to test our proposed hypothesis. Primary outcome measures: Network changes in the bilateral sensory motor cortex regions of the HFC after LEV perturbation (time frame: 26 weeks). Secondary outcome measures: Episodic memory performance as assessed in the baseline and post-perturbation procedures and in the neuropsychological test battery (time frame: 26 weeks). Analogous to the use of baby aspirin to prevent the risk of cerebrovascular stroke, we hope a daily low dose of LEV will effectively prevent or slow memory decline.

项目总结 目前，没有FDA批准的针对认知正常(CN)老年患者的治疗方法 功能连接，进展为痴呆症的风险增加。充分利用早期的优势 疾病干预，我们提出了一个试点项目来测试我们的假设，在临床前 认知正常(CN)老年受试者中阿尔茨海默病的发展阶段 载脂蛋白ε4等位基因(ApoE 4)与异常功能亢进连接性降低相关 使用诸如低剂量左乙拉西坦(LEV)的扰动来改善情节记忆。 具体地说，我们将1)确定由于26- 每周，低剂量水平扰动(125 mg，每天两次)在50名CN老年人(年龄从55岁到75岁不等)中 年)与APOE 4等位基因有关，以及2)网络变化与情景记忆的变化相关 在26周的安慰剂或低剂量LEV扰动前后。我们将雇佣和谐的人类 用于图像采集的Connectome Project协议和确定网络活动的FIX方法 改变。以下结果测量将用于检验我们提出的假设。主要 观察指标：LEV后双侧HFC感觉运动皮质区的网络变化 扰动(时间范围：26周)。次要结果测量：情景记忆表现为 在基线和扰动后程序以及神经心理测试组合中进行评估 (时间框架：26周)。类似于使用婴儿阿司匹林来预防脑血管中风的风险，我们 希望每天小剂量的利福平能有效防止或延缓记忆力衰退。