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

7.摘要 阿尔茨海默氏病（AD）通常被认为是灰质（GM）疾病，其特征在于 病理改变包括细胞外β淀粉样蛋白（Aβ）斑块和神经纤维缠结（NFT）。 然而，最近的研究表明，白色物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事件。髓鞘可以将大脑的“连通性”提高3000倍。髓鞘损伤可破坏轴突 运输，完整性和可塑性，导致信号转导的大量减少。鉴于其不可或缺的 在发展和维持复杂的认知功能中的作用，髓鞘的丢失可能起着关键作用。 AD的发病机制。一种非侵入性的磁共振成像技术，可以准确地评估髓鞘， 因此，对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MRI是临床MRI的一个组成部分， 评估AD患者，其中萎缩是关键发现。更先进的技术，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 GM和WM在AD中的作用。然而，所有这些技术都是基于传统的数据采集与回波 时间（TE）的数量级为几毫秒到几十毫秒。这些TE可以检测来自长T2水的信号 在一些实施方案中，所述探针可以检测来自髓磷脂组分（细胞内/细胞外水、CSF和/或髓磷脂水）的信号，但是太长而不能检测来自髓磷脂的信号。 T2 s非常短（< 1 ms）。非常需要开发MRI技术来直接对髓磷脂成像， 量化髓鞘含量，并绘制其T1和T2。TE <0.1 ms的超短回波时间（UTE）序列允许 直接检测来自超短T2种类的信号。主要的挑战是选择性，因为长T2水 组分显示出比髓磷脂高得多的信号。绝热反转恢复（IR）脉冲提供 水组分的纵向磁化的均匀反转和归零，使得有可能 选择性成像髓磷脂。本研究的初步目标是进一步开发、验证和比较3D Double 回波滑动反转再细化UTE（STRE-UTE）和短TR绝热反转恢复UTE （STAIR-UTE）序列，用于对模型、样本和AD小鼠中的髓磷脂进行直接成像。最终目标是 在健康志愿者和轻度脑梗死患者的横断面研究中评价两种3D UTE序列 认知障碍（MCI）和AD。我们的中心假设是，3D楼梯和楼梯 序列将稳健地检测脑的GM和WM中髓磷脂的变化，并且髓磷脂的更大损失 会导致认知能力下降3D STAIR-UTE和STAIR-UTE生物标志物可以 提高MRI的诊断能力，以便在早期阶段在一个窗口内识别痴呆， 改善疾病的治疗是有效的，并允许监测治疗的有效性。

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.