Quantitative UTE MR Imaging of Myelin: Novel Biomarkers for Alzheimer's Disease

髓鞘质的定量 UTE MR 成像：阿尔茨海默病的新型生物标志物

• 批准号: 10525525
• 负责人: Jiang Du
• 金额: $ 231.92万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10525525
• 关键词: 3-Dimensional; Action Potentials; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer’s disease biomarker; Amyloid beta-Protein; Atrophic; Axonal Transport; Biological Markers; Brain; Clinical; Clinical assessments; Cognitive; Cognitive deficits; Complex; Cross-Sectional Studies; Dementia; Detection; Development; Diffusion Magnetic Resonance Imaging; Disease; Disease Progression; Effectiveness; Equilibrium; Event; Generations; Goals; Histologic; Histology; Image; Imaging Techniques; Impairment; Learning; Light; Magnetic Resonance Imaging; Maintenance; Maps; Measures; Mechanics; Memory; Monitor; Motor Skills; Mus; Myelin; Neurofibrillary Tangles; Oligodendroglia; Pathogenesis; Pathologic; Patients; Physiologic pulse; Play; Powder dose form; Property; Protons; Radial; Recovery; Refractory; Registries; Role; Senile Plaques; Serum; Signal Transduction; Slide; Specimen; Speed; Suspensions; Techniques; Testing; Time; Transgenic Mice; Treatment Effectiveness; Vesicle; Water; age group; arm; base; cognitive function; cognitive performance; cognitive testing; data acquisition; density; diagnostic value; extracellular; gray matter; healthy volunteer; human subject; improved; mental state; mild cognitive impairment; millisecond; neurofilament; non-invasive imaging; novel; novel marker; object recognition; pre-clinical; quantitative imaging; sex; tau Proteins; transmission process; water maze; white matter

7. Abstract Alzheimer’s Disease (AD) is typically considered to be a Gray Matter (GM) disease and is characterized by pathological changes including extracellular Amyloid β (Aβ) plaques and NeuroFibrillary Tangles (NFTs). However, recent studies have shown oligodendroglial degeneration and myelin impairment in White Matter (WM) in preclinical AD before Aβ plaques and NFTs appear. Intracortical myelin loss is also among the earliest events in AD. Myelin can increase brain “connectivity” by ~3000-fold. Myelin impairment can disrupt axonal transport, integrity, and plasticity, leading to a massive reduction in signal transduction. Given its indispensable role in the development and maintenance of elaborate cognitive functions, loss of myelin could play a key role in the pathogenesis of AD. A non-invasive MR imaging technique that can accurately evaluate myelin could therefore be of critical importance for precise diagnosis of AD and monitoring the effectiveness of treatment. MRI has been widely used in the diagnosis of AD. Structural MRI is an integral component of the clinical assessment of AD patients in which atrophy is the key finding. More advanced techniques such as Diffusion Tensor Imaging (DTI), quantitative Magnetization Transfer (MT), multi-component T2, multicomponent-Driven Equilibrium Single Pulse Observation of T1 and T2 (mcDESPOT), have been proposed for quantitative imaging of GM and WM in AD. However, all these techniques are based on conventional data acquisitions with Echo Times (TEs) on the order of several to tens of milliseconds. These TEs can detect signal from long T2 water components (intra/extracellular water, CSF, and/or myelin water), but are too long to detect signal from myelin with extremely short T2s (< 1 ms). It is highly desirable to develop MRI techniques to directly image myelin, quantify myelin content, and map its T1 and T2. Ultrashort Echo Time (UTE) sequences with TEs <0.1 ms allow direct detection of signal from ultrashort T2 species. The main challenge is selectivity, because long T2 water components demonstrate far higher signal than myelin. Adiabatic Inversion Recovery (IR) pulses provide uniform inversion and nulling of the longitudinal magnetizations of water components, making it possible to selectively image myelin. The initial goal of this study is to further develop, validate, and compare 3D Double Echo Sliding Inversion REcovery UTE (DESIRE-UTE) and Short TR Adiabatic Inversion Recovery UTE (STAIR-UTE) sequences for direct imaging of myelin in phantoms, specimens, and AD mice. The final goal is to evaluate the two 3D UTE sequences in a cross-sectional study of healthy volunteers and patients with Mild Cognitive Impairment (MCI) and AD. Our central hypothesis is that the 3D DESIRE-UTE and STAIR-UTE sequences will robustly detect changes in myelin in GM and WM of the brain, and that greater loss of myelin will be associated with poorer cognitive performance. The 3D DESIRE-UTE and STAIR-UTE biomarkers may improve the diagnostic capability of MRI for identifying dementia at an early stage within a window where disease-modifying therapy is effective, and allow monitoring the effectiveness of therapy.

7. 摘要 阿尔茨海默病 (AD) 通常被认为是一种灰质 (GM) 疾病，其特征是 病理变化包括细胞外淀粉样蛋白 β (Aβ) 斑块和神经原纤维缠结 (NFT)。 然而，最近的研究表明白质中存在少突胶质细胞变性和髓鞘质损伤 (WM) 在 Aβ 斑块和 NFT 出现之前的临床前 AD 中。皮质内髓磷脂丢失也是最早发生的之一 公元中的事件。髓磷脂可以将大脑的“连接性”提高约 3000 倍。髓磷脂损伤会破坏轴突 运输、完整性和可塑性，导致信号转导大量减少。鉴于其不可或缺 在复杂认知功能的发展和维持中发挥作用，髓鞘质的丧失可能发挥关键作用 在 AD 的发病机制中。一种可以准确评估髓磷脂的非侵入性磁共振成像技术 因此，对于 AD 的精确诊断和监测治疗效果至关重要。 MRI已广泛应用于AD的诊断。结构性 MRI 是临床诊断的重要组成部分 对 AD 患者的评估，其中萎缩是关键发现。更先进的技术，例如扩散 张量成像 (DTI)、定量磁化传递 (MT)、多分量 T2、多分量驱动 T1 和 T2 的平衡单脉冲观测 (mcDESPOT) 已被提议用于定量成像 AD 中的 GM 和 WM。然而，所有这些技术都是基于 Echo 的传统数据采集 时间（TE）大约为几毫秒到几十毫秒。这些 TE 可以检测来自长 T2 水的信号 成分（细胞内/外水、脑脊液和/或髓磷脂水），但太长而无法检测髓磷脂的信号 T2 极短（< 1 ms）。非常需要开发 MRI 技术来直接对髓磷脂进行成像， 量化髓磷脂含量，并绘制其 T1 和 T2 图。允许 TE <0.1 ms 的超短回波时间 (UTE) 序列 直接检测超短 T2 物种的信号。主要挑战是选择性，因为长 T2 水 成分表现出比髓磷脂高得多的信号。绝热反转恢复 (IR) 脉冲提供 水成分纵向磁化强度的均匀反转和归零，从而可以 选择性地成像髓磷脂。本研究的最初目标是进一步开发、验证和比较 3D Double 回波滑动反转恢复 UTE (DESIRE-UTE) 和短 TR 绝热反转恢复 UTE (STAIR-UTE) 序列，用于直接对模型、标本和 AD 小鼠中的髓磷脂进行成像。最终目标是 在健康志愿者和轻度轻度患者的横断面研究中评估两个 3D UTE 序列 认知障碍 (MCI) 和 AD。我们的中心假设是 3D DESIRE-UTE 和 STAIR-UTE 序列将有力地检测大脑 GM 和 WM 中髓磷脂的变化，并且髓磷脂的更大损失 与较差的认知表现有关。 3D DESIRE-UTE 和 STAIR-UTE 生物标志物可能 提高 MRI 的诊断能力，以便在早期阶段识别痴呆症，其中 疾病缓解治疗是有效的，并且可以监测治疗的有效性。