Cortical mechanisms of disease progression in early multiple sclerosis

描述（由申请人提供）：多发性硬化症（MS）是一种中枢神经系统脱髓鞘和神经退行性疾病，是导致年轻人残疾的主要非创伤性原因。 免疫组化的进展最近重新集中注意力的MS研究从病理生理范例的白色物质（WM）疾病的新皮质灰质（GM）。尸检结果显示，软膜下病变，主要涉及皮层的外层，是最常见的皮质病变（CL）类型，特别是在疾病的晚期。 通过皮质层存在脱髓鞘梯度的离体观察，其中在软脑膜皮质层内观察到最显著的变化，这支持了MS中皮质变性的主要致病机制的假设，其来自软脑膜表面。最近的神经病理学证据表明，皮质可以是疾病发作时附近的脱髓鞘CL的部位，支持早期退行性过程的存在，主要针对皮质，独立于WM病变。在体内的软膜下病变和CL的发展和演变的能力，从最早的疾病阶段，可以提供更明确的证据，其作用的发病机制和MS的进展。磁共振成像（MRI）的研究，虽然不敏感软膜下病变，已经证明了不同程度的皮质参与早期的疾病。我们在MS中的超高场7 T MRI的研究表明，T2* 成像检测到更多的CL，并且比目前可用的临床成像方法对软膜下病理具有更高的灵敏度。使用基于表面的皮层T2* 分层分析，从软膜表面给定的深度，我们证明了在MS患者软膜下T2* 增加的皮质，可能反映了体外描述的软膜下病变，并与患者的残疾水平。我们的数据得到了MS大脑的离体MR检查的支持，这些检查显示了T2* 成像检测MS中CL的极大灵敏度。在这里，我们提出了一项针对极早期MS人群的纵向研究，并在7 T和3 T MRI下使用准确且临床可行的采集和处理方法来成像和表征体内皮质病理。我们假设，包括软膜下病变在内的CL可能是MS的早期事件，独立于WM损伤，并构成侵袭性疾病表型的敏感标志物。 更好地了解皮质疾病进展的体内机制，从MS的最早阶段将允许更准确的指标不同MS表型。这反过来可能有助于指导未来的表型-基因型相关性，用于评估对特定治疗的治疗反应，并可能成为制定循证指南的关键，用于区分患者和选择适当的治疗方法，以及促进新治疗方法的开发。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a demyelinating and neurodegenerative disorder of the central nervous system, and the leading non-traumatic cause of disability in young adults. Advances in immunohistochemistry have recently refocused the attention of MS research from a pathophysiologic paradigm of white matter (WM) disease to the neocortical gray matter (GM). Post-mortem findings show that subpial lesions, which mainly involve the outer layers of the cortex, are the most common type of cortical lesions (CLs), especially in late stage disease. The ex vivo observation that there is a gradient of demyelination through the cortical laminae, with the most dramatic changes seen within the iuxtameningeal cortical layers, supports the hypothesis of a primary pathogenic mechanism, driven from the pial surface, for cortical degeneration in MS. Recent neuropathological evidence that the cortex can be the site of demyelinating CLs near the time of disease onset, supports the presence of an early degenerative process that primarily targets the cortex, independent from WM lesions. The ability to characterize in vivo the development and evolution of subpial pathology and CLs from the earliest disease stages can provide more definitive evidence of their role in the pathogenesis and progression of MS. Magnetic resonance imaging (MRI) studies, although insensitive to subpial lesions, have demonstrated a variable degree of cortical involvement early in the disease. Our studies at ultra-high field 7 T MRI in MS show that T2* imaging detects more CLs and has greater sensitivity to subpial pathology than currently available clinical imaging methods. Using a surface-based laminar analysis of cortical T2* at a given depth from pial surface, we demonstrated in patients with MS subpial T2* increases across the cortex that may reflect subpial lesions described ex vivo, and that correlate with patients level of disability. Our data are supported by ex vivo- MR examinations of MS brains, which have shown the great sensitivity of T2* imaging to detect CLs in MS. Here, we propose a longitudinal study targeted to a very early MS population, and the use of accurate and clinically feasible acquisition and processing methods at 7 T and 3 T MRI to image and characterize cortical pathology in vivo. We hypothesize that CLs including subpial pathology can be an early event in MS, are independent from WM damage, and constitute a sensitive marker of an aggressive disease phenotype. A better understanding of the in vivo mechanisms of cortical disease progression from the earliest stages of MS would allow for more accurate indicators of different MS phenotypes. This in turn could be useful in directing future phenotype-genotype correlations, for evaluating the therapeutic response to specific treatment, and could potentially be the key to developing evidence-based guidelines for differentiating patients and selecting appropriate treatments, as well as facilitating development of novel therapeutic approaches.