Imaging neurodegeneration in multiple sclerosis

描述（由申请人提供）：有新的证据表明，灰质（GM）变性在多发性硬化症（MS）中很常见，与白色物质（WM）损伤相比，与残疾的关系更密切。事实上，WM体积，如通过高分辨率MRI测量的，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变性是否纯粹由WM损伤引起或也可能作为MS中的主要过程而发生尚不清楚。最近有越来越多的证据表明，原发性神经元的损失，在皮质和视网膜可能发生在MS，独立脱髓鞘或轴突损伤。视网膜，虽然是无髓鞘的脑结构，但现在被认为是MS中炎症、血视网膜屏障破坏和神经元损失的常见部位，突出了视网膜作为MS的一部分。 这是一个研究炎症直接介导多发性硬化症神经退行性变的机制的合适场所，并将这些过程与大脑中发生的事情联系起来。然而，随着时间的推移，视网膜层的变化之间的相互作用，以及这些变化与MS中的脑结构变化的关系仍然不清楚，我们建议在当前的应用中对此进行研究。在此，我们假设ONL萎缩是INL炎症的结果，并且表明作为炎症结果的MS中的整体神经变性的易感性增加。本申请中概述的实验的完成将揭示对病理生物学机制的新见解，炎症通过该病理生物学机制介导MS中脑的有髓鞘和无髓鞘区域中的神经变性。具体地，我们计划确定病理学的初级神经元机制是否在MS视网膜中起作用，并且如果这种原发性神经元病是GM萎缩和MS中临床残疾的累积的预测。该结果可以提供证据来挑战MS是髓鞘依赖性疾病的范例，并直接影响目前如何靶向MS中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.