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

改善早期多发性硬化症髓磷脂和轴突完整性的评估

• 批准号: 10662233
• 负责人: Francesca Rosaria Bagnato
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662233
• 关键词: 3-Dimensional; Adult; Affect; Area; Axon; Binding; Biometry; Brain; Central Nervous System; Classification; Clinical; Clinical Trials; Clinical/Radiologic; Cognitive; Contralateral; Data; Demyelinations; Development; Diagnosis; Diffusion; Disease; Disease Progression; Fiber; Foundations; Future; Goals; Health; Health Services; Healthcare; Healthcare Systems; Image; Impaired cognition; Impairment; Individual; Injury; International; Intervention; Investigation; Lesion; Life; Magnetic Resonance Imaging; Measurement; Measures; Methods; Microscopic; Mission; Monitor; Motor; Multiple Sclerosis; Myelin; Nerve Degeneration; Neurologic Dysfunctions; Neurological outcome; Outcome; Pathologic; Pathology; Patients; Personal Satisfaction; Persons; Protons; Proxy; Radiology Specialty; Recovery; Rehabilitation therapy; Research; Risk Factors; Sample Size; Sampling; Specificity; Techniques; Testing; Time; Tissues; Veterans; Veterans Health Administration; Water; Work; axon injury; care burden; cerebral atrophy; disability; disease diagnosis; improved; in vivo; indexing; innovation; magnetic resonance imaging biomarker; military veteran; mortality; multiple sclerosis patient; neuroprotection; novel; predict clinical outcome; repaired; tissue injury; tool

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.

项目概要 以髓磷脂和轴突损伤为特征的神经退行性变是多发性硬化症 (MS) 病理学和 目前，无法在体内评估神经退行性变。 因为没有对髓磷脂和轴突损伤敏感且特异的磁共振成像 (MRI) 生物标志物。 微软国际专家小组将寻找这种生物识别技术作为首要任务，以此作为阻止这种生物识别的途径。 因此，目前的长期目标是治疗多发性硬化症的神经退行性变和促进神经保护。 研究的目的是确定神经退行性变和修复的 MRI 生物标志物，可用于监测疾病和预测 这项工作的总体目标是确定对疾病、神经系统疾病的敏感性。 诊断时患者的两种新型 MRI 方法的功能障碍和结果。 该提案的中心假设是，从选择性反转恢复定量导出的指标 磁化转移成像 (SIR-qMT) 和使用球均值的多室显微扩散成像 技术（SMT）是病程早期髓磷脂和轴突神经退行性组织损伤的敏感标志， 比目前流行的 MRI 测量更准确地关联和预测疾病进展。 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，反映神经功能障碍的横截面，早期 2) 探讨从 SIR-qMT 和 SMT 得出的指标是否可以预测临床结果和放射学结果 纵向进展也将比目前流行的 MRI 测量更准确（目标 3）。 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且新颖的 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病变进展；2) 实现 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，从而更准确地了解退伍军人的多发性硬化症进展； 2) 它将有助于理清可改变和不可改变的退伍军人相关危险因素对疾病进展的影响和 死亡率；3）它有可能支持新的干预措施和治疗方法。

项目成果

White matter tracts that overlap with the thalamus and the putamen are protected against multiple sclerosis pathology.

• DOI: 10.1016/j.msard.2021.103430
• 发表时间: 2022-01
• 期刊: MULTIPLE SCLEROSIS AND RELATED DISORDERS
• 影响因子: 4
• 作者: Clarke, M. A.;Archer, D.;Yoon, K.;Oguz, I;Smith, S. A.;Xu, J.;Cutter, G.;Bagnato, F.
• 通讯作者: Bagnato, F.