Network-Level Mechanisms for Preclinical Alzheimer?s Disease Development

项目摘要 目前，没有FDA批准的治疗存在认知正常（CN）的老年受试者，他们有异常的认知障碍。 功能性连接，并且进展为痴呆症的风险增加。充分利用早期 疾病干预，我们提出了一个试点项目，以测试我们的假设，在临床前， 认知正常（CN）老年受试者的阿尔茨海默病发展阶段 载脂蛋白ε4等位基因（APOE 4），异常高功能连接减少可能与 使用扰动，如低剂量的左乙拉西坦（LEV），改善情景记忆。 具体来说，我们将1）确定海马功能连接的网络水平变化，由于26- 在50名CN老年受试者（年龄范围从55岁至75岁）中，低剂量LEV扰动（125 mg，每日两次 年龄）与APOE 4等位基因，和2）相关的网络变化与情节记忆的变化 在安慰剂或低剂量LEV扰动26周之前和之后。我们将雇用和谐的人类 用于成像采集的Connectome Project协议和确定网络活动的FIX方法 变化以下结果测量将用于测试我们提出的假设。初级 观察指标：左心室后HFC双侧感觉运动皮质区的网络变化 扰动（时间范围：26周）。次要结局指标：情景记忆表现， 在基线和扰动后程序以及神经心理学成套测试中进行评估 (time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， 希望每天低剂量LEV能有效预防或减缓记忆衰退。

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.