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

MRI 评估内侧颞叶脑氧提取分数 (OEF) 作为阿尔茨海默病的生物标志物

• 批准号: 10523185
• 负责人: Dengrong Jiang
• 金额: $ 45.03万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10523185
• 关键词: Accounting; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease risk; Alzheimer’s disease biomarker; American; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Anatomy; Atrophic; Award; Benchmarking; Biological Assay; Biological Markers; Blood; Brain; Caffeine; Cerebrospinal Fluid; Cerebrum; Classification; Clinical; Cognitive; Complement; Consumption; Coupled; Cross-Sectional Studies; Dementia; Development; Disease; Early Diagnosis; Elderly; Energy Metabolism; Episodic memory; Foundations; Gases; Genes; Genetic Risk; Goals; Human; Image; Impaired cognition; Impairment; Individual; Ingestion; Inhalation; Intervention; Lead; Magnetic Resonance Imaging; Measurement; Measures; Medial; Memory; Methods; Modeling; Morphologic artifacts; Oxygen; Pathologic; Patients; Persons; Physiologic pulse; Physiological; Plasma; Play; Positron-Emission Tomography; Predisposition; Procedures; Radiation; Reproducibility; Research Personnel; Resolution; Role; Scanning; Sensitivity and Specificity; Side; Site; Structure; System; Techniques; Temporal Lobe; Testing; Time; Tissues; Variant; Veins; Venous; Work; accurate diagnosis; apolipoprotein E-4; base; cerebral atrophy; cognitive function; early detection biomarkers; healthy volunteer; indexing; mild cognitive impairment; novel; novel marker; relating to nervous system; sex; tau Proteins; tau-1; tool; treatment trial; β-amyloid burden

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.

项目概要/摘要 阿尔茨海默病 (AD) 是最常见的痴呆症类型，影响美国约 570 万人。 独自的。 AD 的早期、准确诊断对其治疗至关重要。 MRI一直在发挥 在AD的诊断中具有重要作用。然而，目前主要的基于 MRI 的生物标志物是结构性的。 MRI 测量，特别是内侧颞叶 (MTL) 的萎缩，该区域是记忆的关键区域 形成。不幸的是，结构性萎缩代表 MTL 损伤的晚期阶段，并且通常是 被认为是不可逆转的。因此，非常需要开发基于功能的生物标志物，而不是 MTL 的结构，可能为 AD 提供早期诊断工具。脑氧提取分数 (OEF)是大脑能量代谢的重要指标。因为神经活动与 大脑的能量消耗，内侧颞叶的 OEF 测量（MTL-OEF）被认为是 提供对这一关键区域的大脑功能的评估，并可能作为 AD 的新型生物标志物。在 事实上，之前的研究表明，即使仅在全球范围内测量，OEF 对 AD 也很敏感。 由于 MTL 是 AD 病理受累的早期部位，局部 MTL-OEF 预计具有优越性 与之前的全球 OEF 测量相比，敏感性和特异性更高。然而，定量 由于宏观等技术问题，MTL-OEF 的测量仍然是 MRI 领域的一个挑战 磁化率伪影和部分体积效应。因此，目前探索/发展的目标 （R21）研究旨在开发一种新型非侵入性 MRI 技术来测量 MTL-OEF，然后将其应用于 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标。目标1 是技术的发展。我们将开发一种新颖的 MRI 脉冲序列和相关扫描程序 专门测量 MTL 组织引流静脉（即 Rosenthal 基底静脉）的血氧饱和度， 这样MTL-OEF就可以计算为动静脉氧合差。这个目标也将比较 这项新技术与 15O-PET 验证的 TRUST MRI 技术相结合，并将确定 技术，例如 OEF 量化的准确性、重测重现性以及对已知数据的敏感性 通过生理挑战改变 OEF。目标 2 是评估 MTL-OEF 作为治疗方法的初步临床效用 MCI 患者的功能性生物标志物。这项研究的重点是 MCI 而不是全面的 AD，因为它是一个 该疾病的早期形式和大多数治疗试验都是针对这个阶段的。 MTL-OEF将进行比较 MCI 患者和认知正常的老年对照之间的比较。 MTL-OEF 与血浆 AD 的关联 生物标志物（包括 β-淀粉样蛋白和磷酸化 tau）和认知功能（尤其是偶发性 记忆）将被检查。 MTL-OEF 将与 MTL 体积（通过 MRI 体积法测量）进行比较 AD 早期阶段认知能力下降的敏感性。