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

项目摘要/摘要：阿尔茨海默病(AD)的早期诊断与治疗一样重要 在疾病的这个阶段，淀粉样蛋白免疫等干预措施被认为是最有益的。 因此，AD研究的重点正在转向了解高危老年人 当个体在认知上仍然正常的时候，他们就开始出现大脑异常。载脂蛋白E 等位基因4(APOE4)是已知的最大的散发性阿尔茨海默病的遗传危险因素。载脂蛋白4携带者 与那些没有携带APOE4的人相比，携带APOE4基因的人患阿尔茨海默病的风险是后者的10到30倍。 因此，了解APOE4携带者和非携带者之间的神经生物学差异将具有 在这些高危人群中显著受益，也将有助于从总体上阐明早期AD的机制。 近年来，脑代谢被认为是阿尔茨海默病最早的影像标志物之一 共识模型。到目前为止，AD患者的脑代谢主要是通过氟脱氧葡萄糖(FDG)PET来测量的。 然而，电离辐射的存在和缺乏绝对量化使这项技术变得不那么 常用于研究认知正常的受试者。我们的实验室最近开发并验证了 一种用核磁共振技术测量大脑氧摄取率和代谢的技术。这项技术做到了 不需要任何外源示踪剂，在标准3T上可以在5分钟内完成，具有很高的测试- 重测重复性，最近在多地点环境中进行了评估。这个项目是第一个 这项新技术在前驱AD中的应用。这个项目的中心假设是老年人 患有AD的高危人群，如APOE4携带者，将显示出异常的大脑代谢特征， 他们的认知还处于正常的早期阶段。 我们有一个经济高效、时间有限的机会窗口来测试这一假设，通过利用RICH NIH资助的“老年痴呆症风险控制生物标记物(BIOCARD)”研究的资源。这个 Biocard研究是对278名老年人进行的纵向观察性研究。我们已获得批准 来自BIOCARD的研究，将大脑代谢序列包括在MRI方案中，以及初步的 研究表明，APOE4具有潜在的作用。因此，我们处于一个独特的地位，可以彻底检查 影像标记物在高危个体神经退行性变发病中的作用。我们的具体目标是1) 认知正常老年人脑氧代谢标志物与载脂蛋白4的关系 2)调查阿尔茨海默病的高风险与大脑代谢异常之间是否存在关联 扩展到其他风险因素，如肌萎缩侧索硬化症和淀粉样蛋白。 影响：这项工作的影响是，我们将建立一个早期生物标记物来检测神经退行性变 患有阿尔茨海默病的高危人群，而此时他们的认知仍然正常， 在干预可能最有效的时候。

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.