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 阿尔茨海默氏病（AD）通常被认为是一种灰质（GM）疾病，被认为是一种特征 通过病理变化，包括细胞外淀粉样β（Aβ）斑块和神经原纤维缠结（NFTS）。 但是，最近的研究表明，白质中的寡头变性和髓磷脂障碍 （WM）出现在Aβ斑块和NFT之前的临床前AD中。心脏内部髓质损失也是最早的 广告中的事件。髓磷脂可以将大脑“连通性”增加约3000倍。髓鞘损伤会破坏轴突 传输，完整性和可塑性，导致信号传递大量降低。鉴于其必不可少的 在详细的认知功能的发展和维持中的作用，失去髓磷脂可能会起关键作用 在AD的发病机理中。可以准确评估髓磷脂的非侵入性MR成像技术可以 因此，对于准确的AD诊断和监测治疗有效性至关重要。 MRI已被广泛用于AD诊断。结构MRI是临床的组成部分 评估萎缩是关键发现的AD患者。更先进的技术，例如扩散 张量成像（DTI），定量磁化转移（MT），多组分T2，多组分驱动 已经提出了用于定量成像的T1和T2的平衡单脉冲观察（McDespot） GM和WM的广告。但是，所有这些技术均基于Echo的常规数据采集 次数（TES）按几至毫秒数的顺序（TES）。这些TE可以从长T2水中检测信号 成分（细胞内水，CSF和/或髓鞘水），但太长检测来自髓磷脂的信号 T2S极短（<1 ms）。非常需要开发MRI技术来直接成像髓磷脂， 量化髓磷脂含量，并映射其T1和T2。 TES <0.1 ms的Ultrashort Echo时间（UTE）序列允许 直接检测来自Ultrashort T2物种的信号。主要的挑战是选择性，因为长T2水 组件的信号比髓磷脂高得多。绝热倒转恢复（IR）脉冲提供 水分纵向磁化的均匀反转和无效，使其成为可能 有选择地图像髓磷脂。这项研究的最初目标是进一步发展，验证和比较3D双重 回声滑动反转恢复ute（desire-ut）和短tr绝热倒转恢复ute （楼梯）序列，用于直接成像幻影，标本和AD小鼠。最终目标是 在健康志愿者和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和楼梯式插入 序列将在GM和大脑的WM中稳健地检测到髓磷脂的变化，并且髓磷脂的损失更大 将与较差的认知表现有关。 3d Desire-ute和楼梯生物标志物可能 提高MRI的诊断能力，可在窗口内早期识别痴呆症 修改疾病的治疗是有效的，并允许监测治疗的有效性。