Imaging neurodegeneration in multiple sclerosis

描述(申请人提供)：有新的证据表明，灰质(GM)变性在多发性硬化症(MS)中很常见，与残疾的联系比白质(WM)损伤更密切。事实上，用高分辨率MRI测量的WM体积，作为炎症的反映，而GM萎缩在MS中随着时间的推移而加速，GM变性是否纯粹是WM损伤的结果，或者也可能是MS的主要过程尚不清楚。最近有越来越多的证据表明，MS患者可能会发生皮质和视网膜的初级神经元丢失，与脱髓鞘或轴突损伤无关。视网膜虽然是一种无髓鞘的脑结构，但现在被认为是多发性硬化症患者炎症、血视网膜屏障破坏和神经元丢失的常见部位，强调了视网膜是 这是一个研究炎症直接导致多发性硬化症神经变性的机制的好地方，并将这些过程与大脑中正在发生的事情联系起来。然而，视网膜各层随时间的变化之间的相互作用，以及这些变化与多发性硬化症的脑亚结构变化的关系仍不清楚，我们建议在当前的应用中对此进行研究。在这里，我们假设ONL萎缩是INL炎症的结果，并意味着MS患者由于炎症而增加了全局神经变性的易感性。本申请概述的实验的完成将揭示炎症介导多发性硬化症有髓和无髓脑区神经变性的病理生物学机制。具体地说，我们计划确定主要的神经元病理机制是否在多发性硬化症视网膜中起作用，以及这种原发神经元病变是否预测多发性硬化症的萎缩和临床残疾的增加。这些结果可能为挑战多发性硬化症是髓鞘依赖性疾病的范式提供证据，并直接影响目前关于如何靶向多发性硬化症的变性和疾病进展的概念。

DESCRIPTION (provided by applicant): There is emerging evidence that gray matter (GM) degeneration is common in multiple sclerosis (MS), and more closely linked with disability than white matter (WM) injury. Indeed, WM volumes, as measured by high resolution MRI, wax and wane as a reflection of inflammation, whereas GM atrophy accelerates with time in MS. Whether GM degeneration purely results from WM injury or may also occur as a primary process in MS is unclear. More recently there has been growing evidence that primary neuronal loss in the cortex and retina may occur in MS, independent of demyelination or axonal injury. The retina, although an unmyelinated brain structure, is now recognized to be a frequent site of inflammation, blood-retinal-barrier disruption, and neuronal loss in MS, highlighting the retina as an opportune site to study the mechanisms by which inflammation directly mediates neurodegeneration in MS, and link these processes back to what is occurring in the brain. However, the interplay between changes in retinal layers over time, and the relationships of these changes with brain-substructure changes in MS remains unclear, and we propose to investigate this in the current application. Herein, we hypothesize that ONL atrophy is the consequence of INL inflammation, and signifies increased susceptibility for global neurodegeneration in MS as a consequence of inflammation. The completion of the experiments outlined in this application will reveal novel insights into the pathobiological mechanisms through which inflammation mediates neurodegeneration in myelinated and unmyelinated regions of the brain in MS. Specifically, we plan to determine if primary neuronal mechanisms of pathology are operative in MS retina, and if this primary neuronopathy is predictive of GM atrophy and the accrual of clinical disability in MS. The results could provide evidence to challenge the paradigm that MS is a myelin dependant disorder, and directly impact present concepts of how to target degeneration and disease progression in MS.