Longitudinal Measurement of Neurodegeneration in two Murine Models of Multiple Sclerosis: A Clinical and Histopathologic Validation Study

项目总结 多发性硬化症(MS)是一种中枢神经系统的炎症性和神经退行性疾病 因此，无情的脱髓鞘和神经轴突丢失是不可逆转残疾的主要原因。测试 应对疾病的神经退行性部分的策略，试图阻止疾病的进展和 促进功能恢复，是多发性硬化症翻译研究的一个重要重点，然而，缺乏合适的 监测疾病进展的生物标记物是这一努力的重大障碍。 神经成像的最新进展为开发和验证生物标记物提供了新的机会 神经退行性变作为诊断和监测工具的宝贵辅助工具。为此，最近开展的工作 在范德比尔特大学医学中心引领了两项创新的定量磁学技术的发展 磁共振成像(MRI)技术，即选择性反转恢复定量磁化转移 成像(SIR-QMT)和使用球面平均技术(SMT)的扩散成像。SIRqMT和SMT 为髓鞘和轴突损伤的非侵入性定量提供了一个新的框架。 目前有几种多发性硬化症动物模型可用于研究多发性硬化症的不同临床和生物学特征。 疾病。例如，髓鞘蛋白脂蛋白(PLP)诱导的实验性变态反应性脑脊髓炎 (EAE)类似于复发-缓解型MS表型(R-EAE)，是一种有价值的研究模型。 复发、急性炎症和脱髓鞘/再髓鞘形成。相反，泰勒氏小鼠 脑脊髓炎病毒诱导的脱髓鞘病(TMEV-IDD)小鼠模型独特地复制临床 进展性多发性硬化的病理特征，如脱髓鞘、慢性神经炎和轴突 损害，导致缓慢进展的残疾。这两个模型提供了有关以下方面的补充信息 多发性硬化症的发展和演变，并共同形成一个理想的模型系统，以测试新疗法的潜力。 相应地，我们假设由SIR-QMT得到的油藏饱和度比(PSR)和(表观) 来自SMT的轴突体积分数(VAX)将为髓鞘和轴突提供早期和敏感的生物标志物 分别对两种模型小鼠的脑和脊髓进行损伤。 脑和脊髓磁共振成像将在R-EAE，TMEV-IDD和年龄匹配的SHAM中进行纵向检查。 治疗的小鼠，使用组织学和行为分析来验证成像衍生的生物识别。短期目标 本研究的目的是将SIR-QMT和SMT应用于两种临床上不同的MS小鼠模型，以 将PSR和VAX与组织病理学和临床对照进行验证。我们研究的长期目标是 开发更有效和非侵入性的神经变性和修复生物标记物，可用于 在自然历史研究和实验期间，研究多发性硬化在动物模型和人类中的变化 临床试验。

PROJECT SUMMARY Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system whereby relentless demyelination and neuroaxonal loss are the primary cause of irreversible disability. Testing strategies to address the neurodegenerative component of the disease, in an attempt to halt the progression and promote functional recovery, is a significant focus of translational research in MS. However, a lack of suitable biomarkers to monitor disease progression is a significant impediment to this effort. Recent advances in neuroimaging offer novel opportunities to develop and validate biomarkers of neurodegeneration as valuable adjuncts to diagnostic and monitoring tools. To this end, recent work performed at Vanderbilt University Medical Center led to the technical development of two innovative quantitative magnetic resonance imaging (MRI) techniques, i.e., the selective inversion recovery quantitative magnetization transfer imaging (SIR-qMT) and the diffusion imaging using the spherical mean technique (SMT). SIRqMT and SMT provide a novel framework for non-invasive quantification of myelin and axonal injury, respectively. Several animal models of MS are currently available to study different clinical and biological features of the disease. For example, the myelin proteolipid protein (PLP)-induced experimental allergic encephalomyelitis (EAE) resembles the relapsing-remitting MS phenotype (R-EAE) and serves as a valuable model to study the development of relapses, acute inflammation and demyelination/remyelination. Conversely, the Theiler’s murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) mouse model uniquely reproduces clinical and pathological features of progressive MS, such as demyelination, chronic neuroinflammation, and axonal damage, leading to slowly progressing disability. The two models provide complementary information regarding MS development and evolution and together form an ideal model system to test the potentials of novel therapies. Accordingly, we hypothesize that the pool saturation ratio (PSR) derived from SIR-qMT and the (apparent) axonal volume fraction (Vax) derived from SMT will provide early and sensitive biomarkers of myelin and axonal injury, respectively, in the brain and spinal cord of the two murine models. Brain and spinal cord MRIs will be longitudinally performed in R-EAE, TMEV-IDD and age-matched sham- treated mice, using histology and behavioral analysis to validate imaging derived biometrics. The short-term goal and objective of this study are to apply SIR-qMT and SMT in two clinically distinct mouse models of MS to validate PSR and Vax against histopathologic and clinical counterparts. The long-term goal of our research is to develop more effective and non-invasive biomarkers of neurodegeneration and repair that can be used to investigate changes of MS, both in animal models and humans, during natural history studies and experimental clinical trials.