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，是年轻人残疾的主要非创伤性原因。最近，免疫组织化学的进展使MS研究的注意力从白质（WM）疾病的病理生理范式重新集中到新皮质灰质（GM）。尸检结果显示，主要累及皮层外层的基底下病变是最常见的皮层病变（CLs）类型，尤其是在疾病晚期。离体观察发现，在皮层层中有一个脱髓鞘的梯度，在脑膜皮层中看到最显著的变化，这支持了ms皮层变性的一种主要致病机制的假设，这种机制是由脑脊膜表面驱动的，最近的神经病理学证据表明，在疾病发病时，皮层可能是脱髓鞘细胞的部位。支持早期退行性过程的存在，主要针对皮层，独立于WM病变。从疾病早期开始，在体内描述脑膜下病理和慢性淋巴细胞的发展和演变的能力，可以为它们在ms发病和进展中的作用提供更明确的证据。磁共振成像（MRI）研究虽然对脑膜下病变不敏感，但已经证明在疾病早期有不同程度的皮层受累。我们对MS超高场7 T MRI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，并且对基底下病理具有更高的敏感性。通过对皮质T2*进行基于表面的层流分析，我们发现多发性硬化症患者的皮质下T2*增加可能反映了体外描述的皮质下病变，并与患者的残疾水平相关。我们的数据得到了MS大脑离体MR检查的支持，这些检查显示T2*成像对MS中CLs的检测具有很高的敏感性。在这里，我们提出了一项针对早期MS人群的纵向研究，并使用准确且临床可行的7 T和3 T MRI采集和处理方法来成像和表征体内皮层病理。我们假设包括基底下病理在内的CLs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。更好地了解从MS早期开始的皮质疾病进展的体内机制将允许更准确的MS表型指标。反过来，这可能有助于指导未来的表型-基因型相关性，评估对特定治疗的治疗反应，并可能成为制定基于证据的指导方针的关键，以区分患者和选择适当的治疗方法，以及促进新治疗方法的发展。

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.