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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要目前，对于认知正常（CN）但认知异常的老年受试者，尚无 FDA 批准的治疗方法。功能连接性和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检验我们的假设，即在临床前认知正常 (CN) 的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），异常的功能亢进可以相关使用低剂量的左乙拉西坦 (LEV) 等扰动可改善情景记忆。具体来说，我们将 1) 确定由于 26- 每周，对 50 名 CN 老年受试者（年龄从 55 岁到 75 岁）进行低剂量 LEV 扰动（125 毫克，每天两次）年）与 APOE 4 等位基因，以及 2）将网络变化与情景记忆的变化相关联在安慰剂或低剂量 LEV 扰动之前和之后 26 周，我们将采用协调的人类。用于成像采集的 Connectome Project 协议和用于确定网络活动的 FIX 方法以下结果测量将用于检验我们提出的假设。结果测量：LEV 后 HFC 双侧感觉运动皮层区域的网络变化扰动（时间范围：26 周）。次要结果指标：情景记忆表现。在基线和扰动后程序以及神经心理学测试电池中进行评估（时间范围：26 周）类似于使用婴儿阿司匹林来预防脑血管中风的风险。希望每天低剂量的LEV能够有效预防或减缓记忆力衰退。