Imaging neurodegeneration in multiple sclerosis

项目摘要 治疗多发性硬化症(MS)面临的重大挑战之一是确定 他们个人进展的可能性，因为这些信息将显著影响治疗类型 被选中了。因此，开发特定的工具来监控和预测病情进展对于更好地管理患者至关重要 护理和了解疾病的机制。我们一直在开发一种多方面的方法来实现更多 容易监测(通过成像)和预测(通过成像和基因分析)疾病进展 以实时的方式。在这笔赠款的上一个周期中，我们演示了高分辨率光谱的用途。 域光学相干断层扫描(SD-OCT)和磁共振成像(3T MRI)在评估中的应用 不同中枢神经系统的疾病负担。我们发现视网膜退行性变发生在 病程与大脑灰质室萎缩相对应。一项关键的发现证实了 这种方法的临床效用是，在对汇集数据的多中心分析中，基线的单个OCT 预测5年后残疾进展的风险。因为多发性硬化症被认为有很强的遗传 成分，我们试图调查是否存在潜在的遗传易感性 进度，这是因为能够实时利用OCT进行监控 退行性变与临床转归相关。因此，我们扩大了成像研究的范围，包括一种基因 我们在其中进行了一个基因阵列，以评估患有糖尿病的人的遗传变异 多发性硬化症的异质性病程，并初步发现了网络通路中的几种基因变异 似乎与视网膜神经退行性变的速度更快有关。大型数据集将是 从这些研究中产生的结果也将允许我们进行推论分析，在此分析中我们可以开始开发风险概况 已知与疾病相关的其他人口特征，如性别和种族 可以合并在一起。拟议研究的中心假设是：视网膜神经节层厚度， 丘脑和GM体积预测MS亚型的10年残疾，高遗传负荷的患者 因为特定网络通路中的基因变异经历了更快的神经退化，并且 OCT、MRI和遗传负荷测量可用于开发具有临床意义的个体预测评分 为了精准的医学。 目的1：确定基线视网膜神经节层厚度与丘脑和GM体积之间的关系 10年疾病转归。 目的2：确定遗传变异、性别和种族是否影响GCIP、丘脑、GM的发生率 萎缩和残疾累积。 目的3：开发一种用于预测疾病结局的算法疾病进展模型。

Project Summary One of the significant challenges facing treatment of people with multiple sclerosis (MS) is determining their individual likelihood of progression, as this information would significantly influence the type of therapy selected. Thus, developing specific tools to monitor and predict progression is critical to better manage patient care and to understand mechanisms of disease. We have been developing a multi-faceted approach to more readily monitor (through imaging) and predict (through both imaging and genetic analysis) disease progression in a real-time fashion. In the past cycle of this grant we demonstrated the utility of high resolution spectral domain optical coherence tomography (SD-OCT) and magnetic resonance imaging (3T MRI) in estimating disease burden in different CNS compartments. We showed that retinal degeneration occurs throughout the disease course and mirrors grey matter compartment atrophy in the cerebrum. A critical finding validating the clinical utility of this approach was that in a multicenter analysis of pooled data, a single OCT at baseline predicted risk of disability progression at 5 years of follow up. As MS is thought to have a strong genetic component, we sought to investigate whether there was an underlying genetic predisposition towards progression, which was made possible by the ability to utilize OCT in a real-time fashion to monitor degeneration and correlate with clinical outcome. We thus expanded the imaging study to include a genetic component in which we conducted a gene array to evaluate genetic variation among people with heterogeneous courses of MS and have preliminarily found that several gene variants in network pathways appear to be associated with more rapid rates of retinal neurodegeneration. The large data set that will be generated from these studies will also allow a corollary analysis in which we can begin to develop a risk profile model in which other population characteristics known to be associated with disease such as sex and ethnicity can be incorporated. The central hypotheses of the proposed studies are; that retinal ganglion layer thickness, thalamic and GM volumes predict 10 year disability across MS subtypes, that patients with high genetic load for gene variants in specific network pathways undergo faster neurodegeneration, and that combinations of OCT, MRI and genetic load measures may be used to develop clinically meaningful individual predictive scores for precision medicine. Aim 1: To determine whether baseline retinal ganglion layer thickness and thalamic and GM volumes predict 10 year disease outcomes. Aim 2: To determine whether genetic variation, sex and ethnicity influence rates of GCIP, thalamic, GM atrophy, and disability accumulation. Aim 3: To develop an algorithm disease progression model to predict disease outcome.