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Noninvasive Quantification of Axon Damage in EAE and MS

EAE 和 MS 中轴突损伤的无创定量

基本信息

批准号：
7755369
负责人：
SHENG-KWEI SONG
金额：
$ 36.53万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-15 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7755369
关键词：
Active Immunization Acute Affect Amino Acids Amyloid beta-Protein Precursor Animal Model Animals Anisotropy Attention Autopsy Axon Biological Preservation Brain Brain imaging C57BL/6 Mouse Central Nervous System Diseases Cessation of life Chronic Clinical Clinical Markers Data Defect Demyelinations Detection Diagnosis Diffusion Magnetic Resonance Imaging Disease Disease Management Disease remission Dose Effectiveness Electron Microscopy Encephalomyelitis Evaluation Event Exhibits Experimental Autoimmune Encephalomyelitis Financial compensation Formalin Functional disorder Future Hematoxylin and Eosin Staining Method Heterogeneity Histology Hour Human Image Immersion Investigative Technique Impairment Inflammation Inflammatory Inflammatory Response Injury Ink Knock-out Lesion Literature Luxol Fast Blue MBS Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Measurement Methods Modeling Mouse Strains Multiple Sclerosis Mus Myelin Myelin Basic Proteins Myelin Sheath N-acetylaspartate Nature Neuraxis Neurologic Neurological outcome Neurons Outcome Outcome Assessment Pathologic Pathology Patients Peptides Phase Phenytoin Proteins Proteolipids Protocols documentation Protons Radial Recovery Recovery of Function Relapsing-Remitting Multiple Sclerosis Relative (related person)Reporting Research Design Research Personnel SJL Mouse Severities Signal Transduction Specimen Speed Spinal Cord Staining method Stains System Testing Therapeutic Therapeutic Intervention Time Tissues Translations Treatment Efficacy Validation Water Movements Weight axonal degeneration base diffusion anisotropy disability drug discovery human tissue improved in vivo indexing inflammatory marker injured mouse model neurofilament oligodendrocyte-myelin glycoprotein outcome forecast programs prospective sample fixation translational study white matter white matter injury

项目摘要

MS is a chronic inflammatory disease of the CNS with primary destruction of myelin sheaths. It has been known for decades that axonal loss also occurs in MS. In principle, the functional deficit induced by inflammation and demyelination may be reversible. In contrast, the damage to axons and neurons is likely to be irreversible once the threshold of compensation is exceeded. Thus, it has been widely speculated that axonal loss is the pathologic correlate of irreversible neurological impairment in MS. However, axonal loss is not always evident in lesions from patients who are severely affected. The complexity and heterogeneity of the underlying mechanisms of MS require new para-clinical markers for more accurate diagnosis and more precise therapeutic management of the disease. In the proposed studies, a new diffusion tensor imaging (DTI) based method for noninvasive detection of axonal damage in central nervous system (CNS) white matter will be presented and evaluated using animal models of MS. Pre-translational validation will employ human autopsy CNS tissues. The directional diffusivities derived by diffusion tensor imaging describe water movement parallel to (k\\, axial diffusivity) and perpendicular to (A,i, radial diffusivity) axonal tracts. We have previously proposed and validated that decreasedXy is associated with axonal injury and dysfunction, and increased^ is associated with myelin injury in mouse models of white matter injury. Therefore, a significant reduction inK\\ in CNS white matter in MS patients or in mice with experimental autoimmune encephalomyelitis (EAE) will be suggestive of axonal degeneration and a poor long-term prognosis. To test our hypothesis, EAE will be induced by active immunization in two mouse strains to mimic progressive, non-remitting forms of MS (C57BL/6 mice) and relapsing-remitting MS (RRMS; SJL mice). We predict that axonal damage will be associated with non-remitting neurological defects. This will occur early in C57BL/6 mice reflecting this model's non-remitting nature. In SJL mice, early axonal damage will correlate with incomplete remission following acute peaking of neurological deficits, whereas axonal integrity will be retained with full remissions. In both strains, the extent of axonal damage will closely relate to the duration of the acute peaking of neurological deficits - presumably caused by acute inflammatory responses.

MS是一种中枢神经系统的慢性炎症性疾病，主要破坏髓鞘。它有几十年来，人们已经知道，轴突损失也发生在MS中。炎症和脱髓鞘可能是可逆的。相比之下，轴突和神经元的损伤可能会一旦超过赔偿的门槛，就不可逆转。因此，人们普遍推测，轴突丢失是MS中不可逆神经损伤的病理相关性。在严重受累患者的病变中并不总是明显的。的复杂性和异构性 MS的潜在机制需要新的准临床标志物来进行更准确的诊断，对疾病进行精确的治疗管理。在拟议的研究中，一种新的扩散张量成像， (DTI)用于中枢神经系统（CNS）中轴突损伤的非侵入性检测的基于方法白色将使用MS的动物模型提出和评估问题。翻译前验证将采用人类尸检中枢神经系统组织。由扩散张量成像导出的定向扩散率描述了平行于轴向扩散率）和垂直于（A，i，径向扩散率）轴突束。我们之前提出并验证了Xy降低与轴突损伤和功能障碍相关，而Xy增加与轴突损伤和功能障碍相关。与小鼠白色物质损伤模型中的髓鞘损伤相关。因此，K\\ 在MS患者或患有实验性自身免疫性脑脊髓炎（EAE）小鼠的CNS白色物质中，提示轴突变性和不良的长期预后。为了验证我们的假设，将通过主动免疫诱导EAE在两个小鼠品系中模拟进行性非缓解型MS（C57 BL/6小鼠）和复发-缓解型MS（RRMS; SJL小鼠）。我们预测轴突损伤将与非缓解性神经缺陷相关。这将发生在早期在C57 BL/6小鼠中的表达反映了该模型的非缓解性质。在SJL小鼠中，早期轴突损伤将与神经功能缺损急性高峰后不完全缓解，而轴突完整性将保持完全缓解。在两种菌株中，轴突损伤的程度将与持续时间密切相关。神经功能缺损的急性高峰-可能由急性炎症反应引起。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Optic nerve diffusion tensor imaging parameters and their correlation with optic disc topography and disease severity in adult glaucoma patients and controls.

成人青光眼患者和对照组中视神经扩散量张量参数及其与视盘形态和疾病严重程度的相关性。

DOI：
10.1097/ijg.0b013e318294861d
发表时间：
2014-10
期刊：
Journal of glaucoma
影响因子：
2
作者：
Chang ST;Xu J;Trinkaus K;Pekmezci M;Arthur SN;Song SK;Barnett EM
通讯作者：
Barnett EM

Radial diffusivity predicts demyelination in ex vivo multiple sclerosis spinal cords.

DOI：
10.1016/j.neuroimage.2011.01.007
发表时间：
2011-04-15
期刊：
NEUROIMAGE
影响因子：
5.7
作者：
Klawiter, Eric C.;Schmidt, Robert E.;Trinkaus, Kathryn;Liang, Hsiao-Fang;Budde, Matthew D.;Naismith, Robert T.;Song, Sheng-Kwei;Cross, Anne H.;Benzinger, Tammie L.
通讯作者：
Benzinger, Tammie L.

Delayed axonal degeneration in slow Wallerian degeneration mutant mice detected using diffusion tensor imaging.

使用扩散张量成像检测缓慢沃勒变性突变小鼠的延迟轴突变性。