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（由适用提供）：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）已被广泛用于评估MS。一种常见的策略是使用T1或T2加权快速回声或梯度回声序列来检测大脑白质中的长T2成分。尽管这些序列在揭示了MS患者大脑的宏观组织异常方面非常敏感，但它们并非特定于MS病变的病理底物，并且预后作用有限。 MS是一种相对特异性地影响髓磷脂的层状膜结构的疾病，该结构由替代蛋白质和脂质层组成，具有超短色T2*，并且未通过常规的临床序列检测到。此外，最近的研究表明，Tysabri促进了基于磁化转移（MT）成像对髓鞘造成的损伤的再生和稳定。但是，MT是评估髓磷脂的间接方法。开发MRI技术是一项主要成就，用于在大脑白质中直接形态和定量成像，直接可视化对其损害的损害，并在治疗过程中监测恢复。我们已经开发了超短回声时间（UTE）序列，其最小标称TE的最低为8 µs，比几毫秒或更长时间的常规TE短100-1000倍。这些序列使使用临床扫描仪直接从髓磷脂中检测信号成为可能。在此提案中，我们将进一步开发用于选择性成像的UTE序列，研究包括单绝热倒转恢复（SIR），双绝热倒转恢复（DIR）和相成像，以及开发定量UTE技术，以测量T1，T2*，相位和Proton和Proton密度（PD）的对比机制。然后，我们将使用标准的Cuprizone小鼠模型比较无需（n = 5）和MS（n = 5）和MS（n = 20）的尸体人大脑的形态和定量评估的UTE和临床序列。我们将将UTE和临床措施与组织病理学进行比较和相关联，并证明UTE可以在小鼠治疗过程中可靠地评估脱髓鞘和脱髓鞘期间的髓鞘蛋白的动态变化（AIM 2）。最后，我们将应用UTE技术来评估MS在三组复发复发的MS（n = 10），原发性MS（n = 10）和继发性MS（n = 10）的纵向研究中，但经过Tysabri治疗（治疗后，6、12和24个月）。一组健康的志愿者（n = 10）也将被招募进行比较。我们将比较髓磷脂横截面和纵向变化的UTE和临床测量与扩展残疾状态量表（EDSS）的神经系统评估（AIM 3）。我们预计UTE技术将对接受Tysabri治疗的MS患者对髓磷脂损伤的损害提供更具体和敏感的评估。该研究可能会提高MRI诊断MS的特异性，了解疾病的自然史以及治疗监测。