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

项目总结 以髓鞘和轴突损伤为特征的神经变性是多发性硬化症(MS)病理和 是患者残疾和预后的主要决定因素。目前，还不可能在体内评估神经退行性变。 因为没有对髓鞘和轴突损伤敏感和特异的磁共振成像(MRI)生物标志物。 MS国际专家小组将寻找这种生物特征设置为主要优先事项，以此作为停止的途径 因此，在MS中促进神经退行性变和神经保护，目前的长期目标是 研究是确定神经退行性变和修复的MRI生物标记物，可以用于监测疾病和预测 进展的可能性。这项工作的总体目标是建立对疾病的敏感性，神经学 两种新的磁共振成像方法在患者诊断时的功能障碍和结果。 这一提议的中心假设是，从选择性反转恢复量化得出的指标 利用球面平均的磁化传递成像(SIR-QMT)和多室显微扩散成像 技术(SMT)是疾病病程早期髓鞘和轴突神经变性组织损伤的敏感标志， 并且比目前支持的MRI测量更准确地涉及和预测疾病进展。中心假说 将通过追求三个具体目标进行测试：1)建立源自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，并在早期横断面反映神经功能障碍 病程；2)并探索从SIR-QMT和SMT得出的指标是否可以预测临床结果和放射学 纵向上，比目前流行的MRI测量方法更准确(目标3)。纵向数据也将 用于神经保护和修复的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和新颖的MRI 技术，该项目1)评估和测量患有多发性硬化症的退伍军人的神经退行性变的进展；2)提供 神经保护概念验证临床试验的样本计算。这项拟议的研究具有重要意义，因为 1)它将为未来更大规模的研究奠定基础，提供对退伍军人多发性硬化症进展的更准确的理解； 2)它将有助于理清可改变和不可改变的退伍军人相关风险因素对疾病进展和 死亡率；以及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.