In Vivo Macromolecular and Protein-Based MRI in the Spinal Cord of MS Patients

项目概述本提案的总体目标是在临床场强（3T）下开发和实施新型、多模态、定量的人类脊髓（SC）磁共振成像（MRI），以定量评估多发性硬化症（MS）中SC病理与神经功能障碍之间的关系。我们建议，对组织微观结构（髓鞘）和生物化学敏感的定量MRI方法可以发展到对ms中存在的亚体素病理敏感。然而，SC是一个具有挑战性的环境，从中获得高分辨率，定量MRI数据。重要的是，先进的MRI方法主要用于评估中枢神经系统的大型结构，由于其大小，位置和运动，相对较少应用于SC。然而，我们必须开始这项研究，因为人们假设MS的大部分临床缺陷是SC损伤而不是大脑损伤的结果。事实上，临床放射学上存在一个悖论，即多发性硬化症患者的神经学表现并不总是与放射学表现的严重程度相符。我们认为这是由于缺乏定量和敏感的标记物来衡量SC经历的损伤程度。其次，由于脊髓是体位组织，如果获得足够高质量的MRI数据，我们可以直接探索结构-功能关系。我们建议开发、实施和评估SC健康的两种定量MRI测量方法，这两种方法都没有针对3T的SC开发。首先，我们将开发一种高分辨率，快速，多点和单点定量磁化转移（qMT）实验来推导池大小比（PSR），它已被证明与髓磷脂密度直接相关。其次，我们发现酰胺质子转移(APT) -化学交换饱和转移（CEST）对高场下正常显现白质的最早变化较为敏感。然而，为了使其在临床上可行，它必须过渡到低分辨率并应用于SC。因此，我们建议在SC中开发和实施高分辨率，强大的APT-CEST，以评估病变和其他正常白质中可能发生的变化。总之，该提案的成功将取决于两种新的MS患者宫颈SC MRI测量方法的开发、验证和应用，其潜在的回报是对晚期MS病理（即qMT引起的脱髓鞘）和潜在的早期MS病理（即CEST引起的蛋白质积累）的敏感性。如果成功，我们还将开发并验证SC工具箱，以定量评估影响SC的各种疾病中的髓磷脂变化、蛋白质（和pH值）变化。不应忽视的是，延伸到视神经、周围神经和胸/腰椎脊髓都在本提案的结果范围内。

DESCRIPTION (provided by applicant): Project Summary The overall goal of this proposal is to develop and implement novel, multi-modal, quantitative magnetic resonance imaging (MRI) in the human spinal cord (SC) at clinical field strengths (3T) to quantitatively assess the relationship between SC pathology and neurological deficit in multiple sclerosis (MS). We propose that quantitative MRI methods sensitive to tissue microstructure (myelin) and biochemistry can be developed to be sensitive to sub-voxel pathology that is present in MS. However, the SC is a challenging environment from which to obtain high-resolution, quantitative MRI data. Importantly, advanced MRI methods have mainly been developed to assess large structures of central nervous system and relatively few have been applied in the SC due to its size, location, and motion. Yet it is imperative that we embark on this study as it has been hypothesized that the bulk of clinical deficit in MS comes as a result of lesions in the SC rather than the brain. In fact, a clinical radiological paradox exists in that the neurological presentatin in patients with MS does not always match the severity of radiological findings. We propose that this is due to the lack of quantitative and sensitive markers for the magnitude of damage that the SC experiences. Secondly, since the spinal cord is somatotopically organized, if sufficient quality MRI data are obtained, we can directly probe the structure- function relationship. We propose to develop, implement and evaluate two quantitative MRI measures of the health of the SC, neither of which have been developed for the SC at 3T. First, we will develop a high- resolution, rapid, multi- and single-point quantitative magnetization transfer (qMT) experiment to derive the pool size ratio (PSR), which has been shown to be directly correlated with myelin density. Secondly, we have shown that amide proton transfer (APT) - chemical exchange saturation transfer (CEST) is sensitive to the earliest changes in normal appearing white matter at high field. Nevertheless, for this to be clinically viable, it must be transitioned to lower fied and applied to the SC. Thus, we propose to develop and implement high- resolution, robust APT-CEST in the SC to assess the changes that may occur in lesions and in otherwise normal appearing white matter. Together, the success of this proposal will be determined by the development, validation, and application of two novel MRI measures to the cervical SC of patients with MS with the potential pay-off being sensitivity to late-stage MS pathology (i.e. demyelination from qMT) and potentially early stage MS pathology (i.e. protein accumulation from CEST). If successful, we will also have developed and validated a SC toolbox to quantitatively assess myelin changes, protein (and pH) changes in a variety of diseases that affect the SC. It should not go with out notice that extensions to the optic nerve, peripheral nerves, and thoracic/lumbar spinal cord are well within the scope of the results of this proposal.