Microstructural Characterization of the Optic Nerve in Optic Neuritis

描述(申请人提供)：这项提案的总体目标是在人类视神经中开发和实施新颖的多模式磁共振成像(MRI)，能够理解视神经炎(ON)和视觉(Dys)功能的演变之间的关系，并进行临床评估。我们进一步提出，可以在预测模型中使用对组织微结构(髓鞘和轴突完整性)和生化敏感的定量MRI方法，以洞察多发性硬化症(MS)的最终发展。最近的研究表明，17-25%的MS患者以视神经炎为首发症状，尽管视功能和炎症通常在4-12周内消失。此外，近三分之二的多发性硬化症患者在他们的一生中会经历视神经炎的发作，40%-60% 的多发性硬化症患者的视觉缺陷局限于视神经。眼科和常规MRI评估显示视神经沿线发炎，但长期预后一直具有挑战性。我们假设这一矛盾的原因是常规MRI在整个恢复过程中对组织成分(轴突、髓鞘或神经化学物质)不敏感。虽然先进的MRI方法已经被开发出来用于评估中枢神经系统的大结构，但由于其大小、位置和运动的原因，应用于视神经的相对较少。然而，最近MRI硬件和序列设计的创新为研究视神经的新成像方式提供了机会。重要的是，这些技术提供了前所未有的对整个视神经的非侵入性访问，具有对轴突和髓鞘完整性、大分子排列和神经化学成分敏感的指数。我们推测，确定ON引起的视神经损伤的神经基础特征对于提高我们对ON和MS之间早期关系的理解至关重要。值得注意的是，这些工具可能为早期干预和加强疾病管理提供机会。我们已经证明了新的非侵入性MRI方法定量评估视神经的可行性，我们将首次整合一套对ON患者视神经的微结构整合、髓鞘形成和神经化学组成敏感的工具。我们将利用先进的统计模型来分析这些MRI指数与视觉功能的关系，以及与临床和定量眼科指标的关系。最后，我们将建立预测模型，以确定新的MRI测量方法与从单个事件发展为多发性硬化症的个人风险之间的关系。鉴于K01提供了开发人类视神经的高级MRI的机会，我们现在拥有了一个独特的工具箱，即使在炎症消退后，我们也可以在单个MRI扫描过程中评估ON的多种神经病理底物，我们假设这将为ON的时间演变提供洞察力。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to develop and implement novel, multi-modal magnetic resonance imaging (MRI) in the human optic nerve capable of understanding the relationship between optic neuritis (ON) and the evolution of visual (dys)function and clinical evaluation. We further propose that quantitative MRI methods sensitive to tissue microstructure (myelin and axonal integrity) and biochemistry can be utilized in prediction models to offer insight into the eventual development of multiple sclerosis (MS). Recent studies have shown that optic neuritis is the initial symptom in 17-25% of all MS cases though visual function and inflammation generally resolves in 4 to 12 weeks. Additionally, nearly two thirds of MS patients will experience episodes of optic neuritis in their lifetimes, and 40-60% of MS patients have visual defects localized to the optic nerve. Ophthalmological and conventional MRI evaluation demonstrates inflammation along the optic nerve, but long- term prognosis has been challenging. We hypothesize the reason for this paradox is that conventional MRI is insensitive to tissue composition (axonal, myelin, or neurochemical) throughout the recovery course. While advanced MRI methods have been developed to assess large structures of central nervous system, relatively few have been applied in the optic nerve due to its size, location, and motion. However, recent innovations of MRI hardware and sequence design have yielded an opportunity to study new imaging modalities in the optic nerve. Importantly, these techniques offer unprecedented non-invasive access to the entire optic nerve with indices sensitive to axonal and myelin integrity, macro-molecular arrangement, and neurochemical composition. We hypothesize that characterizing the neurological substrates of optic nerve damage resulting from ON is critical for improving our understanding of the earliest relationships between ON and MS. Significantly, these tools may provide an opportunity for earlier intervention, and enhancing disease management. We have demonstrated the feasibility of new, non-invasive MRI approaches to quantitatively assess the optic nerve and we will integrate for the first time a set of tools that are sensitive to the microstructural integrit, myelination, and neurochemical composition of the optic nerve in patients with ON. We will utilize advanced statistical modeling to parse out the association of these MRI indices to visual function and the relationship to clinical and quantitative ophthalmological measures. Lastly we will build predictive models to determine the relationship between novel MRI measures and the personal risk of developing MS from a single ON event. In appreciation of a K01 which provided the opportunity to develop advanced MRI of the human optic nerve, we now possess a unique toolbox to assess the multiple neuropathological substrates of ON in a single MRI scanning session even after resolution of inflammation, which we hypothesize will offer insight into the temporal evolution of ON.