MRI assessment of cerebral oxygen extraction fraction (OEF) in the medial temporal lobe as a biomarker in Alzheimer's disease

项目摘要/摘要 阿尔茨海默病(AD)是最常见的痴呆症类型，在美国约有570万人受到影响。 独自一人。AD的早期、准确诊断对其治疗至关重要。核磁共振一直在发挥作用 在阿尔茨海默病诊断中的重要作用。然而，目前主要的基于MRI的生物标记物是结构性的 MRI测量，特别是内侧颞叶(MTL)的萎缩，这是记忆的关键区域 队形。不幸的是，结构性萎缩是MTL损害的晚期，通常 被认为是不可逆转的。因此，开发基于功能的生物标记物是非常必要的，而不是 MTL可能为AD的早期诊断提供一种新的工具。脑氧提取分数 (OEF)是衡量大脑能量代谢的重要指标。因为神经活动与 大脑能量消耗，内侧颞叶OEF的测量(MTL-OEF)被认为是 对这一关键区域的脑功能进行评估，并可能作为AD的一个新的生物标志物。在……里面 事实上，以前的研究表明，即使只在全球水平上测量，OEF对AD也是敏感的。 由于MTL是AD的早期病理受累部位，局限性MTL-OEF有望有更好的疗效。 与以前的全球OEF测量相比，具有更高的灵敏度和特异度。然而，量化的 由于宏观等技术问题，MTL-OEF的测量在MRI领域仍然是一个挑战 磁化率伪影和部分体积效应。因此，目前探索性/发展性的目标是 (R21)研究旨在开发一种新的无创性MRI技术来测量MTL-OEF，并将其应用于 轻度认知障碍(MCI)的研究，这是AD的一种早期形式。这项研究有两个具体目的。目标1 是技术的发展。我们将开发一种新的MRI脉冲序列和相关的扫描程序来 具体测量引流MTL组织的静脉(即，罗森塔尔的基底静脉)中的血氧含量， 因此，MTL-OEF可以作为动-静脉氧合差值来计算。这一目标也将与 这项新技术与150-PET验证的TRUST MRI技术相结合，将确定 技术，如OEF量化的准确性、重测重复性和对已知信息的敏感性 通过生理挑战引起的OEF改变。目的2评估MTL-OEF作为一种 MCI患者的功能性生物标记物。这项研究关注的是MCI而不是成熟的AD，因为它是一种 这种疾病的早期形式和大多数治疗试验都针对这一阶段。MTL-OEF将进行比较 MCI患者和认知正常的老年对照组之间的差异。MTL-OEF与血浆AD的关系 生物标志物(包括β-淀粉样蛋白和磷酸化tau)和认知功能(特别是发作性 存储器)将被检查。年，MTL-OEF将与MTL容量(通过MRI容量测量)进行比较 阿尔茨海默病早期对认知功能下降的敏感度。

Project summary/Abstract Alzheimer's disease (AD) is the most common type of dementia, affecting ~5.7 million people in the U.S. alone. Early and accurate diagnosis of AD are critically important in its management. MRI has been playing an important role in the diagnosis of AD. However, currently the primary MRI-based biomarker has been structural MRI measures, specifically atrophy in medial temporal lobe (MTL), which is a crucial region for memory formation. Unfortunately, structural atrophy represents a late stage of MTL impairment and is generally considered irreversible. Therefore, it is highly desirable to develop a biomarker based on the function, rather than structure, of MTL, which may provide an early-diagnosis tool in AD. Cerebral oxygen extraction fraction (OEF) is an important index of the brain's energy metabolism. Because neural activity is tightly coupled to the brain's energy consumption, measurement of OEF in the medial temporal lobe (MTL-OEF) is thought to provide an assessment of brain function in this critical region and may serve as a novel biomarker in AD. In fact, previous studies have demonstrated that OEF, even only measured at a global level, is sensitive to AD. Since MTL is an early site of pathological involvement in AD, localized MTL-OEF is expected to have superior sensitivity and specificity compared to previous global OEF measurements. However, quantitative measurement of MTL-OEF remains a challenge in the MRI field, due to technical issues such as macroscopic susceptibility artifacts and partial volume effects. Therefore, the goals of the present exploratory/developmental (R21) study are to develop a novel non-invasive MRI technique to measure MTL-OEF and then apply it to the study of mild cognitive impairment (MCI), which is an early form of AD. This study has two specific aims. Aim 1 is the technical development. We will develop a novel MRI pulse sequence and related scan procedures to specifically measure the blood oxygenation in veins draining the MTL tissue (i.e., the basal veins of Rosenthal), so that MTL-OEF can calculated as the arterio-venous difference in oxygenation. This Aim will also compare this new technique to a 15O-PET-validated TRUST MRI technique and will determine benchmarks of the technique such as the accuracy of OEF quantification, test-retest reproducibility and the sensitivity to known alterations in OEF via physiological challenges. Aim 2 is to evaluate the initial clinical utility of MTL-OEF as a functional biomarker in MCI patients. This study focuses on MCI rather than full-blown AD because it is an early form of the disease and most treatment trials are aimed at this stage. MTL-OEF will be compared between MCI patients and cognitively normal elderly controls. Associations of MTL-OEF with blood plasma AD biomarkers (including beta-amyloid and phosphorylated tau) and cognitive function (especially episodic memory) will be examined. MTL-OEF will be compared with MTL volume (measured by MRI volumetry) in terms of the sensitivity to cognitive decline at this early stage of AD.