Comparison of direct and indirect magnetic resonance imaging of myelin in Alzheimer's disease

项目总结/摘要 阿尔茨海默病（AD）是以进行性认知功能下降为特征的痴呆的主要原因。 经过几十年的努力，对根本原因仍然知之甚少，这种疾病仍然无法治愈， 被阻止或严重延迟。髓鞘损伤可破坏轴突运输、完整性和可塑性， 导致信号传导的大量减少。鉴于其在发展和维护方面的重要作用， 高级认知功能中，髓鞘的缺失可能在AD的发病机制中起关键作用。非侵入性MR 因此，能够准确评估髓磷脂的成像技术对于精确的 AD的诊断合成MRI（SyMRI）已被提议通过评估脑组织来间接映射髓鞘。 脑实质部分（BPF）和髓磷脂脑实质部分（MyPF）。然而，髓磷脂具有非常短的T2（<<1 ms），并且对于诸如与SyMRI一起使用的常规序列是不可见的。因此，SyMRI仅 通过测量水信号间接评估髓鞘，并且不能使用T1和T2* 评估髓鞘质量 放松时间超短回波时间（UTE）序列，回波时间（TE）约为8µs，范围为100-1000 比常规序列的TE短5倍，使得可以直接检测来自髓鞘的信号 质子，因此避免了与SyMRI相关的问题。UTE方法的主要挑战是 同时检测来自各种水组分的高信号。三维短TR绝热反演恢复 UTE（STAIR-UTE）序列采用绝热反转脉冲来均匀反转长T2组织， 与短TR和高翻转角一起，允许以宽的 T1值的范围，从而选择性髓鞘映射。本研究的第一个目的是验证和比较3D STAIR-UTE和SyMRI序列用于来自供体的髓磷脂和脑标本的髓鞘成像， （n=20）和AD（n=20），使用组织学作为参考标准。第二个目的是评估STAIR-UTE 和SyMRI序列用于轻度认知功能障碍（MCI）（n=40）和AD（n=40）患者的髓鞘定位 以及健康对照组（n=40）。参与者是杜博士新资助的R 01赠款的一部分。我们将把 SyMRI指标（BPF、MyPF）和STAIR-UTE指标（髓鞘PD、T1、T2*），以及认知评估，包括 简易精神状态检查（MMSE），建立痴呆症登记处联盟（CERAD）和临床 痴呆评定（CDR）量表。我们的中心假设是3D STAIR-UTE序列将稳健地检测 髓鞘的数量与髓鞘PD以及髓鞘T1和T2* 的质量的映射将 提供更具体的髓鞘损伤评估，并更好地与残疾和疾病进展相关 比从SyMRI方法获得的指标更准确。Athertya博士和她的导师Du博士设计了一个 详细的培训计划，并组建了一个强大的研究团队，以指导博士Athertya通过她的奖学金期间 为她在AD翻译研究方面的富有成效的职业生涯做好准备。

PROJECT SUMMARY/ABSTRACT Alzheimer’s Disease (AD) is the leading cause of dementia characterized by progressive cognitive decline. The underlying causes remain poorly understood after decades of efforts, and the disease still cannot be cured, prevented, or significantly delayed. Myelin impairment can disrupt axonal transport, integrity, and plasticity, leading to a massive reduction in signal transduction. Given its essential role in development and maintenance of higher 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. Synthetic MRI (SyMRI) has been proposed to indirectly map myelin by assessing brain parenchymal fraction (BPF) and myelin parenchymal fraction (MyPF). However, myelin has a very short T2 (<<1 ms) and is invisible with conventional sequences such as those used with SyMRI. As a result, SyMRI only indirectly evaluates myelin via measuring water signals, and cannot evaluate myelin quality using the T1 and T2* relaxation times. Ultrashort echo time (UTE) sequences with echo times (TEs) of ~8µs, which are 100-1000 times shorter than the TEs of conventional sequences, make it possible to directly detect signal from myelin protons and so circumvent problems associated with SyMRI. The major challenge with UTE approach is the concurrent detection of high signal from various water components. The 3D short TR adiabatic inversion recovery UTE (STAIR-UTE) sequence employs an adiabatic inversion pulse for uniform inversion of long-T2 tissues, which together with a short TR and a high flip angle allow robust suppression of all water components with a wide range of T1 values, thereby selective myelin mapping. The first aim of this study is to validate and compare 3D STAIR-UTE and SyMRI sequences for myelin imaging in phantoms and brain specimens from donors without (n=20), and with AD (n=20) using histology as reference standard. The second aim is to evaluate STAIR-UTE and SyMRI sequences for myelin mapping in patients with mild cognitive impairment (MCI) (n=40) and AD (n=40) as well as healthy controls (n=40). The participants are part of Dr. Du’s newly funded R01 grant. We will correlate SyMRI metrics (BPF, MyPF) and STAIR-UTE metrics (myelin PD, T1, T2*) with cognitive assessments including Mini-Mental State Examination (MMSE), Consortium to Establish a Registry of Dementia (CERAD), and Clinical Dementia Rating (CDR) scales. Our central hypothesis is that 3D STAIR-UTE sequence will robustly detect changes in myelin, and that mapping of myelin quantity with myelin PD and quality with myelin T1 and T2* will provide more specific evaluation of myelin damage and correlate better with disability and disease progression in AD than metrics derived from the SyMRI approach. Dr. Athertya and her mentor, Dr Du, have designed a detailed training plan and assembled a strong research team to guide Dr. Athertya through her fellowship period towards preparing her for a productive career in translational research for AD.