Lesion Activity and Atrophy in Multiple Sclerosis: Analysis of Multi-center MRI

描述(申请人提供)：炎性病变和萎缩(全局性、组织特异性和区域性)之间的关系被认为代表多发性硬化症(MS)的神经变性，对于了解这种疾病的发病机制至关重要。我们假设病变的活动和空间位置驱动了MS随后的萎缩，这一假设将通过分析在CombiRx队列中获得的MRI数据来验证。CombiRx是一项多中心、双盲临床试验，有1008名登记患者。对患者进行至少3年的随访，所有患者都得到跟踪，直到2012年1月最后一名患者完成，允许长达6.5年的随访期 在一些病人身上。这个队列的MRI数据是通过严格的MRI方案获得的，治疗分配保持不变。这项建议的五个具体目标是：1)自动识别T2高信号、T1低信号和Gd增强的病变及其空间位置，2)确定皮质变薄作为皮质病理的衡量标准，3)基于使用双回波图像逐个体素确定的T2值评估正常外观脑组织的病理，4)确定全脑、组织特异性和区域萎缩，以及5)确定病变活动及其空间位置对区域萎缩的影响，并检查MRI措施作为疾病可能的生物标志物/预测因子的作用。图像分割将结合基于atlas的技术使用多光谱分割进行。T2高信号和T1低信号病变的活动性将通过减去在差异性非线性图像配准后的不同时间点采集的图像来确定。局部萎缩将使用基于张量的形态测量来确定。将使用白质图谱研究病变位置和区域萎缩之间的连通性的影响。最后，综合MRI测量将与扩展残疾状态量表(EDSS)和MS功能量表(MSFC)及其各自的组成部分相关联。这一包括空间信息的战略应该能够确定疾病的强有力的生物标志物/预测因素。这项分析基于大量临床特征良好的队列，跟踪了相对较长的一段时间，以了解炎症和神经退行性变之间的关系是这项建议的一个独特特点。缩写：CNS(中枢神经系统)；DGM(深部灰质结构)；DIR(双倒置恢复)；DSI(骰子相似性指数)；DTI(扩散张量成像)；EDSS(扩展残疾状态量表)；FOE(专家领域)；GM(灰质)；ICBM(国际脑成像联合会)；MNI(蒙特利尔神经研究所)；MRF(马尔可夫随机场)；MRI(磁共振成像)；MRIAP(磁共振自动处理)；MRS(磁共振波谱)；MS(多发性硬化症)；MSFC(MS功能复合体)；MTR(磁化传输率)；NABT(正常脑组织)；NAWM(正常出现的白质)；PD(质子密度)；RGM(区域GM)；RRMS(复发缓解期MS)；RWM(区域白质)；SIENAX(结构图像评估，包括萎缩的正常化)；SPM(统计参数映射)；TBM(基于张量的形态测量)；TOADS(拓扑保持解剖分割)；VBM(基于体素的形态测量)；WM(白质)

DESCRIPTION (provided by applicant): The relation between inflammatory lesions and atrophy (global, tissue-specific, and regional) that is thought to represent neurodegeneration in multiple sclerosis (MS) is of fundamental importance in understanding the pathogenesis of this disease. We hypothesize that the activity and spatial location of the lesions drive the subsequent atrophy in MS. This hypothesis will be verified by analyzing the MRI data acquired on the CombiRx cohort. CombiRx is a multi-center, double blinded clinical trial with 1008 enrolled patients. Patients are being followed over a minimum period of 3 years with all patients followed until the last patient completes in January 2012 allowing for up to 6.5 years of follow up on some patients. MRI data on this cohort is acquired with a rigorous MRI protocol and the treatment assignments have remained constant. The five specific aims of this proposal are: 1) automatic identification of T2-hyperintense, T1- hypointense, and Gd enhancing lesions and their spatial location, 2) determine the cortical thinning that is a measure of cortical pathology,3) assess the pathology in the normal appearing brain tissue based on the T2 values, determined on a voxel-by voxel basis using the dual echo images, 4) determine the whole brain, tissue specific, and regional atrophy, and 5) determine the effect of lesion activity and their spatial location on the regional atrophy and examine the role of MRI measures as possible biomarkers/predictors of the disease. The image segmentation will be performed using the multi- spectral segmentation in combination with the atlas-based techniques. Activity of both T2-hyperintense and T1- hypointense lesions will be determined by subtracting images acquired at different time points following diffeomorphic nonlinear image registration. Regional atrophy will be determined using the tensor based morphometry. The effect of connectivity between the lesion location and regional atrophy will be investigated using the white matter atlas. Finally composite MRI measures will be correlated with both EDSS (extended disability status scale) and MSFC (MS functional scale) and their individual components. This strategy that includes spatial information should allow identification of robust biomarkers/predictors of the disease. The analysis based on a large and clinically well characterized cohort followed over a relatively long period of time to understand the relationship between inflammation and neurodegeneration is a unique feature of this proposal. Abbreviations: CNS (central nervous system); DGM (deep gray matter structures); DIR (double inversion recovery); DSI (Dice similarity index); DTI (diffusion tensor imaging); EDSS (extended disability status scale); FoE (field of expert); GM (gray matter); ICBM (international consortium for brain mapping); MNI (Montreal Neurologic Institute); MRF (Markov random field); MRI (magnetic resonance imaging); MRIAP (MRI Automated Processing); MRS (magnetic resonance spectroscopy); MS (multiple sclerosis); MSFC (MS functional composite); MTR (magnetization transfer ratio); NABT (normal appearing brain tissue); NAWM (normal appearing white matter); PD (proton density); RGM (regional GM); RRMS (relapsing remitting MS); RWM (regional white matter); SIENAX (Structural Image Evaluation, including Normalization, of Atrophy (X-sectional); SPM (statistical parametric mapping); TBM (tensor based morphometry); TOADS (Topology preserving Anatomical Segmentation); VBM (voxel based morphometry); WM (white matter)