Early imaging markers for elderly individuals with high risk to develop Alzheimer's disease

项目概要/摘要：阿尔茨海默病（AD）的早期诊断很重要， 淀粉样蛋白免疫等干预措施被认为在疾病的这一阶段最为有益。 因此，AD研究的重点正在转向了解高危老年人 个体开始发展大脑异常，而此时他们的认知仍然正常。载脂蛋白E 等位基因4（APOE 4）是散发性阿尔茨海默病的最大已知遗传危险因素。APOE 4载体 携带APOE 4基因的人患AD的风险是不携带APOE 4基因的人的10到30倍。 因此，了解APOE 4携带者和非携带者之间的神经生物学差异将有助于我们了解APOE 4基因的表达。 在这一高风险人群中具有显著的益处，并且还将有助于阐明一般的早期AD机制。 近年来，脑代谢被认为是AD最早的影像学标志物之一。 共识模型迄今为止，AD的脑代谢主要用氟脱氧葡萄糖（FDG）PET测量。 然而，电离辐射的存在和缺乏绝对量化使得该技术 常用于认知正常受试者的研究。我们的实验室最近开发并验证了 一种通过MRI测量大脑氧摄取分数和代谢的技术。这项技术确实 不需要任何外源性示踪剂，在标准3 T上五分钟内即可完成，具有较高的测试性- 重新测试重现性，最近已在多个地点进行了评估。该项目代表了第一个 这种新技术在前驱AD中的应用。该项目的核心假设是， 具有发展AD的高风险的个体，例如APOE 4携带者，将显示异常的脑代谢特征， 这是他们认知能力还正常的早期阶段。 我们有一个成本效益高、时间有限的机会窗口来检验这一假设， NIH资助的“老年痴呆症风险控制的生物标志物（BIOCARD）”研究。的 BIOCARD研究是一项对278名老年人进行的纵向观察性研究。我们已经获得批准 从BIOCARD研究中纳入MRI方案中的脑代谢序列， 研究表明APOE 4具有潜在的作用。因此，我们处于一个独特的位置， 影像学标记物在高危个体神经变性发病中的作用。我们的具体目标是：（1） 认知功能正常老年人脑氧代谢指标与载脂蛋白E 4的关系 2）研究AD高风险和异常脑代谢之间的关联是否可以被认为是一个潜在的问题。 扩展到其他风险因素，如tau蛋白病和淀粉样蛋白。 影响：这项工作的影响是，我们将建立一个早期生物标志物来检测神经变性， 具有发展阿尔茨海默病的高风险的个体，当他们仍然认知正常时， 什么时候干预最有效

Project Summary/Abstract: Early diagnosis of Alzheimer’s disease (AD) is important, as therapeutic interventions such as amyloid immunization are thought to be most beneficial at this stage of the disease. Therefore, the emphasis in AD research is shifting toward understanding the process by which high-risk elderly individuals begin to develop brain abnormality, at a time when they are still cognitively normal. Apolipoprotein E allele 4 (APOE4) is the largest known genetic risk factor for sporadic Alzheimer’s disease. Carriers of APOE4 gene have between 10 and 30 times the risk of developing AD, as compared to those not carrying APOE4. Therefore, understanding neurobiological differences between APOE4 carriers and non-carriers will have a significant benefit in this high-risk population and will also help elucidate early AD mechanisms in general. Brain metabolism has been hypothesized as one of the earliest imaging markers of AD in the recent consensus model. To date, brain metabolism in AD is primarily measured with Fludeoxyglucose (FDG) PET. However, the presence of ionizing radiation and the lack of absolute quantification make the technique less frequently used in studies of cognitively normal subjects. Our laboratory has recently developed and validated a technique to measure the brain’s oxygen extraction fraction and metabolism with MRI. The technique does not require any exogenous tracer, can be completed within five minutes on a standard 3T, has a high test- retest reproducibility, and has recently been evaluated in a multi-site setting. This project represents the first application of this novel technique in prodromal AD. The central hypothesis of this project that elderly individuals with high risk to develop AD, e.g. APOE4 carriers, will show abnormal brain metabolic features, at an early time when their cognition is still normal. We have a cost-effective, time-limited window of opportunity to test this hypothesis, by leveraging rich resources of the NIH-funded “Biomarkers for Older Controls at Risk for Dementia (BIOCARD)” study. The BIOCARD Study is a longitudinal, observational study of 278 elderly individuals. We have obtained approval from the BIOCARD study to include the brain metabolism sequences in the MRI protocol, and the preliminary studies have shown a potential effect of APOE4. Therefore, we are in a unique position to thoroughly examine the role of imaging markers in the onset of neurodegeneration in high-risk individuals. Our Specific Aims are 1) Examine the relationship between brain oxygen metabolic markers and APOE4 in cognitively normal elderly individuals; 2) Investigate whether the association between high AD risk and aberrant brain metabolism can be extended to other risk factors such as tauopathy and amyloid protein. Impact: The impact of this work is that we will establish an early biomarker to detect neurodegeneration in individuals with a high risk to develop Alzheimer’s disease, at a time when they are still cognitively normal and when intervention may be most effective.