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 病理改变包括细胞外淀粉样蛋白(Aβ，Aβ)斑块和神经原纤维缠结(NFT)。 然而，最近的研究表明，白质中的少突胶质细胞变性和髓鞘损伤 (Wm)在Aβ斑块和NFT出现之前的临床前AD。皮质内髓鞘丢失也是最早的 AD中的事件。髓磷脂可以将大脑的连通性提高约3000倍。髓鞘损伤可扰乱轴突 运输、完整性和可塑性，导致信号转导的大量减少。考虑到它不可或缺的 在复杂的认知功能的发展和维持中的作用，髓鞘的丢失可能起到关键作用 在AD的发病机制中起重要作用。一种可以准确评估髓鞘的非侵入性磁共振成像技术可以 因此，对AD的准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。结构磁共振是临床研究的一个重要组成部分。 评估以萎缩为主要表现的AD患者。更高级的技术，如扩散 张量成像(DTI)、定量磁化转移(MT)、多分量T2、多分量驱动 T1和T2的平衡单脉冲观测(McDESPOT)已被提出用于定量成像 通用汽车和WM在公元。然而，所有这些技术都是基于使用Echo进行的传统数据采集 几毫秒到几十毫秒量级的时间(TES)。这些TES可以探测到来自长T2水的信号 成分(细胞内/细胞外水、脑脊液和/或髓鞘水)，但太长，无法检测到髓鞘信号 具有极短的T2(&lt；1毫秒)。非常希望开发直接成像髓鞘的MRI技术， 量化髓鞘含量，并绘制其T1和T2图。超短回声时间(UTE)序列，允许TES&lt；0.1毫秒 直接探测来自超短T2物种的信号。主要的挑战是选择性，因为长T2水 成分显示的信号比髓鞘高得多。绝热反转恢复(IR)脉冲提供 水组分纵向磁化的均匀反转和零化，使得有可能 选择性地成像髓鞘。本研究的初始目标是进一步开发、验证和比较3D Double 回声滑动反转恢复速度(Desire-Ute)和短时间绝热反转恢复速度 (阶梯)用于在幻影、标本和AD小鼠中直接成像髓鞘的序列。最终目标是 在健康志愿者和轻症患者的横断面研究中评价两种3D UTE序列 认知障碍(MCI)和阿尔茨海默病。我们的中心假设是3D欲望降落伞和楼梯 序列将有力地检测大脑GM和WM中髓鞘的变化，以及更大程度的髓鞘丢失 将与较差的认知表现相关联。3D欲望和阶梯生物标志物可以 提高MRI在一个窗口内早期识别痴呆的诊断能力 疾病修正疗法是有效的，并允许监测治疗的有效性。