BIOMARKERS AND PATHOGENESIS OF MS: FROM MOUSE TO HUMAN

多发性硬化症的生物标志物和发病机制：从小鼠到人类

基本信息

批准号：
9275041
负责人：
DOROTHY ANNE CROSS
金额：
$ 32.76万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-25 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9275041
关键词：
Acute Advocate Affect Animal Model Area Atlases Autopsy Axon Biological Markers Biological Preservation Biopsy Blood Brain Cellularity Chronic Classification Clinical Clinical Trials Cognitive Data Demyelinations Detection Deterioration Development Diffuse Diffusion Diffusion Magnetic Resonance Imaging Disease Edema Enrollment Evolution Fiber Funding Gadolinium Histologic Histology Histopathology Human Image Imaging Techniques Individual Inflammation Inflammatory Injury Lead Lesion MRI Scans Magnetic Resonance Imaging Measures Methods Modeling Multiple Sclerosis Multiple Sclerosis Lesions Mus Myelin Nerve Fibers Outcome Pathogenesis Pathologic Pathology Patients Play Population Process Relapse Resolution Role Sampling Scanning Severities Specificity Specimen System Techniques Testing Therapeutic Time Tissue Sample Tissues Translating Validation Water axon injury base black hole clinical imaging clinical predictors disability forest imaging approach imaging modality improved in vivo innovation mind control mouse model multiple sclerosis patient neuropathology novel novel therapeutics outcome forecast predict clinical outcome relating to nervous system remyelination repaired spectrograph white matter

项目摘要

During the initial funding period, our group developed a novel Diffusion Basis Spectrum Imaging (DBSI) method to simultaneously detect and quantitate inflammation, demyelination and axon injury in vivo using diffusion imaging (Wang et al. 2011). DBSI has substantially improved the accuracy and specificity of our prior diffusion tensor imaging (DTI) approach, by overcoming the main inadequacies of DTI. We hypothesize that DBSI can quantitate the proportions of axon injury, demyelination, and inflammation in CNS of MS patients. We previously showed using a mouse model that DBSI detects and quantitates axonal and myelin injuries that had escaped detection by standard imaging, and by DTI. Our preliminary data now include validation of DBSI using autopsied and biopsied human specimens, with favorable correlations with human histology. We also now have longitudinal data spanning 1.5 yrs, and comparisons of DBSI with magnetization transfer imaging (MTI). In Project 3, we will apply DBSI to humans with MS, comparing it to standard MRI, DTI and MTI. Project 3 will classify MS lesion subtypes by measures of axon injury, demyelination, and inflammation (cellularity and increased free water due to edema or tissue loss), and follow the patients over 4 years to identify predictors and correlates of clinical deterioration. We expect to achieve this using DBSI by differentiating prominent axonal injury vs. axon preservation, and demyelination vs. myelin preservation/ remyelination. We will examine established persistent black holes (PBHs) (new sub-aim), and perform longitudinal assessments of gadolinium-enhancing (Gd+) MS lesions to determine if DBSI will predict PBH formation, representing severe axon loss. With its ability to profile lesions and normal-appearing CNS, DBSI could help non-invasively elucidate the substrate of MS lesion formation and detect inflammation behind an intact blood-CNS-barrier (not detected by Gd+). DBSI has potential to aid development and testing of new therapies for progressive MS where loss of axons and tissue integrity are believed to play a large role.

在最初的资助期间，我们小组开发了一种新型的扩散基谱成像（DBSI）体内同时检测和定量炎症、脱髓鞘和轴突损伤的方法扩散成像（Wang 等人，2011）。 DBSI 大大提高了我们之前的准确性和特异性扩散张量成像（DTI）方法，克服了DTI的主要不足之处。我们假设 DBSI可以定量MS患者中枢神经系统轴突损伤、脱髓鞘和炎症的比例。我们之前使用小鼠模型展示了 DBSI 检测并定量轴突和髓磷脂损伤，逃脱了标准成像和 DTI 的检测。我们的初步数据现在包括验证 DBSI 使用尸检和活检人体标本，与人类具有良好的相关性组织学。我们现在还有跨越 1.5 年的纵向数据，以及 DBSI 与磁化转移成像（MTI）。在项目 3 中，我们将 DBSI 应用于患有多发性硬化症的人类，并将其与标准 MRI、DTI 和 MTI。项目 3 将通过轴突损伤的测量对 MS 病变亚型进行分类，脱髓鞘和炎症（由于水肿或组织损失导致细胞增多和游离水增加），并遵循对患者进行超过 4 年的研究，以确定临床恶化的预测因素和相关因素。我们期望实现这一目标使用 DBSI 通过区分显着的轴突损伤与轴突保留，以及脱髓鞘与髓磷脂保存/髓鞘再生。我们将检查已建立的持久性黑洞（PBH）（新的子目标），并对钆增强 (Gd+) MS 病变进行纵向评估，以确定 DBSI 是否会预测 PBH 形成，代表严重的轴突损失。具有描绘病变和正常外观的能力 CNS、DBSI 可以帮助非侵入性地阐明 MS 病变形成的底物并检测炎症在完整的血液中枢神经系统屏障后面（Gd+ 未检测到）。 DBSI 有潜力帮助开发和测试进行性多发性硬化症的新疗法中，轴突和组织完整性的丧失被认为起着重要作用。