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(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)已被广泛用于MS的评估。一种常见的策略是使用T1或T2加权快速自旋回波或梯度回波序列来检测大脑白质中的长T2分量。虽然这些序列对揭示MS患者脑组织的宏观异常高度敏感，但它们不是MS病变的病理基础，对预后的预测作用有限。MS是一种相对特异地影响髓鞘的疾病，它是一种由交替的蛋白质和脂层组成的板层膜性结构，具有超短的T2*，在传统的临床序列中不能检测到。此外，最近的研究表明，Tysabri促进了基于磁化转移(MT)成像的髓鞘损伤的再生和稳定。然而，MT是一种间接评估髓鞘的方法。发展MRI技术，直接对脑白质髓鞘进行形态和定量成像，并直接显示脑白质的损伤，以及监测治疗过程中的恢复，将是一项重大成就。我们开发的超短回波时间(UTE)序列的最小标称TES为8微米S，比传统的几毫秒或更长的TES短100-1000倍。这些序列使得使用临床扫描仪直接检测髓鞘信号成为可能。在这个计划中，我们将进一步开发用于髓鞘选择性成像的UTE序列，研究包括单绝热反转恢复(SIR)、双绝热反转恢复(DIR)和相位成像在内的对比机制，并开发定量UTE技术来测量髓鞘的T1、T2*、相位和质子密度(PD)(目标1)。然后，我们将比较UTE和临床序列，对没有(n=5)和有MS(n=5)的身体人脑，以及使用标准的Cuprizone小鼠模型(n=20)的小鼠进行形态和定量评估。我们将UTE和临床措施与组织病理学进行比较和关联，并证明UTE可以可靠地评估小鼠脱髓鞘和铜酮治疗诱导的再髓鞘形成过程中髓鞘的动态变化(目标2)。最后，我们将应用UTE技术对接受Tysabri治疗(治疗前、治疗后6个月、12个月和24个月)的3组复发-缓解MS(n=10)、原发-进展型MS(n=10)和继发性-进展型MS(n=10)患者进行纵向研究，以评估MS。还将招募一组健康志愿者(n=10)进行比较。我们将比较UTE和临床测量髓鞘的横截面和纵向变化与扩展残疾状态量表(EDSS)的神经学评估(目标3)。我们期望UTE技术将对接受Tysabri治疗的MS患者的髓鞘损害提供更具体和更敏感的评估。这项研究可能会提高MRI诊断多发性硬化症的特异性，了解疾病的自然病史，并监测治疗情况。