UTE Magnetic Resonance Imaging: New Biomarkers for Multiple Sclerosis

UTE 磁共振成像：多发性硬化症的新生物标志物

• 批准号: 9095465
• 负责人: Jiang Du
• 金额: $ 43.24万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9095465
• 关键词: Achievement; Affect; Aftercare; Animals; Biological Markers; Brain; C57BL/6 Mouse; Cattle; Chronic; Clinical; Clinical Research; Cuprizone; Demyelinating Diseases; Demyelinations; Detection; Development; Diagnosis; Diet; Disease; Early Diagnosis; Early treatment; Edema; Evaluation; Future; Gliosis; Goals; Health; Histopathology; Human; Image; Image Analysis; Imaging Techniques; In Vitro; Inflammatory; Lead; Lipids; Longitudinal Studies; Magnetic Resonance Imaging; Measurement; Measures; Monitor; Multiple Sclerosis; Multiple Sclerosis Lesions; Mus; Myelin; Myelin Sheath; Natural regeneration; Neuraxis; Neurologic; Pathologic; Patients; Phase; Physiologic pulse; Primary Progressive Multiple Sclerosis; Property; Proteins; Protons; Quantitative Evaluations; Recovery; Recruitment Activity; Relapsing-Remitting Multiple Sclerosis; Role; Secondary Progressive Multiple Sclerosis; Signal Transduction; Specificity; Specimen; Staging; Structure; Techniques; Therapeutic; Time; Tissues; Tysabri; Weight; axon injury; base; clinical sequencing; contrast imaging; density; disability; disease natural history; healthy volunteer; improved; in vivo; millisecond; mouse model; multiple sclerosis patient; novel; prognostic; prognostic value; quantitative imaging; remyelination; symptom management; validation studies; white matter

 DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is the most common chronic inflammatory demyelinating disease. Magnetic resonance imaging (MRI) has been widely used for the evaluation of MS. A common strategy is to employ T1- or T2-weighted fast spin echo or gradient echo sequences to detect the long T2 components in white matter of the brain. Although these sequences are highly sensitive in revealing macroscopic tissue abnormalities in the brain of patients with MS, they are not specific to the pathologic substrate of the MS lesion and have a limited prognostic role. MS is a disease that relatively specifically affects the myelin a lamellar membranous structure consisting of alternating protein and lipid layers which has an ultrashort T2*, and is not detected with conventional clinical sequences. Furthermore, recent studies have shown that Tysabri promoted regeneration and stabilization of damage done to the myelin sheath based on magnetization transfer (MT) imaging. However, MT is an indirect approach to assess myelin. It would be a major achievement to develop MRI techniques for direct morphological and quantitative imaging of myelin in white matter of the brain, and directly visualizing damage to it, as well as monitoring recovery during therapeutic treatment. We have developed Ultrashort Echo Time (UTE) sequences with minimum nominal TEs of 8 µs that are 100-1000 times shorter than conventional TEs of several milliseconds or longer. These sequences make it possible to directly detect signal from myelin using clinical scanners. In this proposal, we will further develop UTE sequences for selective imaging of myelin, investigate contrast mechanisms including single adiabatic inversion recovery (SIR), dual adiabatic inversion recovery (DIR) and phase imaging, and develop quantitative UTE techniques to measure T1, T2*, phase and the proton density (PD) of myelin (Aim 1). We will then compare UTE and clinical sequences for morphological and quantitative evaluation of cadaveric human brains without (n=5) and with MS (n=5), and mice (n=20) using a standard cuprizone mouse model. We will compare and correlate the UTE and clinical measures with histopathology, and demonstrate that UTE can reliably assess dynamic changes in myelin during demyelination and remyelination induced by cuprizone treatment in mice (Aim 2). Finally we will apply the UTE techniques to evaluate MS in a longitudinal study of three groups of patients with relapsing-remitting MS (n=10), primary-progressive MS (n=10) and secondary-progressive MS (n=10) subject to Tysabri treatment (pre-, 6, 12 and 24 months post-treatment). A group of healthy volunteers (n=10) will also be recruited for comparison. We will compare UTE and clinical measures of cross-sectional and longitudinal changes in myelin with neurological assessment of expanded disability status scale (EDSS) (Aim 3). We expect that the UTE techniques will provide more specific and sensitive evaluation of the damage to myelin in MS patients subject to Tysabri treatment. The study is likely to improve the specificity of MRI for the diagnosis of MS, understanding of the natural history of the disease, and treatment monitoring.

 描述（由申请人提供）：多发性硬化症（MS）是最常见的慢性炎症性脱髓鞘疾病，磁共振成像（MRI）已广泛用于评估 MS。常见的策略是采用 T1 或 T2 加权快速。自旋回波或梯度回波序列可检测大脑白质中的长 T2 成分，尽管这些序列在揭示 MS 患者大脑中的宏观组织异常方面高度敏感，但它们并不特定于 MS 的病理基础。 MS 是一种相对特异地影响髓磷脂的疾病，髓磷脂是由交替的蛋白质和脂质层组成的层状膜结构，具有超短的 T2*，并且传统的临床序列无法检测到。 Tysabri 基于磁化转移 (MT) 成像促进了髓鞘损伤的再生和稳定，然而，MT 是一种评估髓鞘的间接方法，这将是一项重大成就。 MRI 技术可对大脑白质中的髓磷脂进行直接形态学和成像，并直接定量可视化其损伤，以及监测治疗期间的恢复情况。我们开发了超短回波时间 (UTE) 序列，最小标称 TE 为 8 µs。比传统的几毫秒或更长的 TE 短 100-1000 倍，这些序列使得使用临床扫描仪直接检测髓鞘质信号成为可能。用于髓磷脂选择性成像的序列，研究对比机制，包括单绝热反转恢复 (SIR)、双绝热反转恢复 (DIR) 和相位成像，并开发定量 UTE 技术来测量 T1、T2*、相位和质子密度 (PD)然后，我们将比较 UTE 和临床序列，以对未使用 MS (n=5) 和使用 MS (n=5) 以及小鼠的尸体大脑进行形态学和定量评估。 (n=20) 使用标准的 cuprizone 小鼠模型，我们将比较 UTE 和临床测量与组织病理学，并证明 UTE 可以可靠地评估在小鼠中由 cuprizone 治疗引起的脱髓鞘和髓鞘再生过程中髓鞘质的动态变化（目标 2）。最后，我们将应用 UTE 技术在三组复发缓解型多发性硬化症 (n=10)、原发性进展型多发性硬化症患者的纵向研究中评估多发性硬化症(n=10) 和接受 Tysabri 治疗的继发进展型 MS (n=10)（治疗前、治疗后 6、12 和 24 个月）还将招募一组健康志愿者 (n=10) 进行比较。我们将比较UTE和髓鞘质横截面和纵向变化的临床测量与扩展残疾状态量表（EDSS）的神经学评估（目标3）我们期望UTE技术将为损伤提供更具体和敏感的评估。这项研究可能会提高 MRI 在 MS 诊断、疾病自然史和治疗监测方面的特异性。