Improving the Assessment of Myelin and Axonal Integrity in Early Multiple Sclerosis

项目摘要 以髓鞘和轴突损伤为特征的神经变性是多发性硬化症（MS）病理学的关键驱动因素， 患者残疾和预后的主要决定因素。目前，不可能在体内评估神经变性 因为没有对髓鞘和轴突损伤敏感和特异的磁共振成像（MRI）生物标记物。 找到这种生物特征被MS国际专家小组设定为一个主要优先事项， 因此，目前的治疗方案的长期目标是改善MS中的神经变性和促进神经保护。 研究的目的是确定神经变性和修复的MRI生物标志物，可用于监测疾病和预测 进步的可能性。这项工作的总体目标是建立对疾病的敏感性，神经系统， 功能障碍和结果，两种新的MRI方法在患者诊断时。 该建议的中心假设是，从选择性反转恢复定量导出的度量 磁化传递成像（SIR-qMT）和使用球面平均值的多室显微扩散成像 技术（SMT）是疾病过程早期髓鞘和轴突神经退行性组织损伤的敏感标志， 并且比当前受欢迎的MRI测量更准确地与疾病进展相关并预测疾病进展。核心假设 将通过追求三个具体目标进行测试：1）建立来自SIR-qMT（目标1）和SMT（目标2）的指标 是神经退行性损伤的敏感标志，并反映了神经功能障碍的横断面，在早期， 疾病过程; 2）并探索来自SIR-qMT和SMT的指标是否可预测临床结局和放射学结果 进展，纵向，更准确地比目前青睐的MRI措施（目标3）。纵向数据也将 用于神经保护和修复概念验证临床试验的样本量计算（推论分析）。 本申请中提出的研究具有创新性，因为通过使用两种先进的新型MRI， 技术，该项目1）评估和测量MS退伍军人神经退行性疾病的进展; 2）提供 用于神经保护概念临床试验的样本计算。这项研究意义重大，因为 1)它将为未来更大规模的研究奠定基础，为退伍军人提供更准确的MS进展理解; 2)它将有助于解开可改变和不可改变的退伍军人相关风险因素对疾病进展的影响， 死亡率; 3）它有可能支持新的干预和治疗。

PROJECT SUMMARY Neurodegeneration, characterized by myelin and axonal injury, is a key driver in multiple sclerosis (MS) pathology and a major determinant of patients’ disability and outcome. Currently, it is not possible to assess neurodegeneration in vivo because there are no magnetic resonance imaging (MRI) biomarkers sensitive and specific to myelin and axonal injury. Finding this biometric is set as a major priority by an MS International Panel of Experts, as a path toward halting neurodegeneration and promoting neuroprotection in MS. Accordingly, the long-term goal of the current lines of investigations is to identify MRI biomarkers of neurodegeneration and repair that can be used to monitor disease and predict likelihood of progression. The overall objective of this work is to establish the sensitivity to disease, neurological dysfunction and outcome, of two novel MRI methods in patients at the time of diagnosis. The central hypothesis of this proposal is that metrics derived from selective inversion recovery quantitative magnetization transfer imaging (SIR-qMT) and multi-compartment microscopic diffusion imaging using the spherical mean technique (SMT) are sensitive hallmarks of myelin and axonal neurodegenerative tissue injury early in the disease course, and relate to and predict disease progression more accurately than currently favored MRI measures. The central hypothesis will be tested by pursuing three specific aims: 1) Establish that metrics derived from SIR-qMT (Aim 1) and SMT (Aim 2) are sensitive hallmarks of neurodegenerative injury and reflect neurological dysfunction cross-sectionally, early in the disease course; 2) and explore if metrics derived from SIR-qMT and SMT predict clinical outcome and radiological progression, longitudinally, more accurately than currently favored MRI measures (Aim 3). Longitudinal data will also be used for sample size computations for proof of concept clinical trials on neuroprotection and repair (corollary analysis). The research proposed in this application is innovative because, through the use of two advanced and novel MRI techniques, this project 1) assesses and measures progression of neurodegeneration in Veterans with MS; and 2) delivers sample computations for proof of concept clinical trials on neuroprotection. The proposed research is significant because 1) it will lay the foundation for future larger studies providing a more accurate understanding of MS progression in Veterans; 2) it will help untangle the effects of modifiable and non-modifiable Veteran-related risk factors on disease progression and mortality; and 3) it has the potential to support new interventions and treatments.