Cortical mechanisms of disease progression in early multiple sclerosis

描述(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。免疫组织化学的进展使多发性硬化症的研究从白质(WM)疾病的病理生理学范式转向新皮质灰质(GM)。尸检结果显示，主要累及皮质外层的软膜下病变是最常见的皮质病变类型，尤其是在晚期疾病中。通过皮质层的脱髓鞘有一个梯度的体外观察，其中最显著的变化可见在真皮质膜皮质层，支持的假说的主要致病机制，驱动从软膜表面，皮质变性的MS最近的神经病理学证据，皮质可以是位置的脱髓鞘CLS在发病时间附近，支持存在一个早期的退变过程，主要针对皮质，独立于西医损害。从疾病的早期阶段在体内描述软膜下病变和CLS的发展和演变的能力可以提供更明确的证据，证明它们在MS的发病机制和进展中所起的作用。磁共振成像(MRI)研究虽然对软膜下病变不敏感，但在疾病的早期显示了不同程度的皮质受累。我们在MS的超高场7T MRI上的研究表明，T2*成像比目前可用的临床成像方法检测到更多的CLS，并对软膜下病理具有更高的敏感性。通过对软膜表面特定深度处皮质T2*的表面层状分析，我们发现MS患者的软膜下T2*在整个皮质增加，这可能反映了体外描述的软膜下病变，并与患者的残疾程度相关。我们的数据得到了MS大脑的体外MR检查的支持，这些检查显示了T2*成像在MS中检测CLS的高度敏感性。在这里，我们提出了一项针对非常早期的MS人群的纵向研究，并使用7T和3T MRI的准确和临床可行的采集和处理方法来成像和表征活体皮质病理。我们推测，包括软膜下病理在内的CLS可能是MS的早期事件，独立于WM损害，并构成侵袭性疾病表型的敏感标记。更好地了解多发性硬化症早期阶段皮质疾病进展的体内机制将允许更准确地指示不同多发性硬化症的表型。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，并可能成为制定区分患者和选择适当治疗的循证指南的关键，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.