Myelination- and immune-mediated MR-based brain network correlates
Myelination- and immune-mediated MR-based brain network correlates
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DOI：
10.1186/s12974-020-01827-z
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发表时间：
2020-06-12
影响因子：
9.3
通讯作者：
Meuth, Sven G.
中科院分区：
文献类型：
--
作者：
Cerina, Manuela;Muthuraman, Muthuraman;Meuth, Sven G.
多发性硬化（MS）是一种以炎症和神经退行性病变为特征的中枢神经系统自身免疫性疾病。尽管脱髓鞘是这种疾病的一个标志，但它与神经变性的关系仍然没有完全解开，研究仍在进行中，以了解如何非侵入性地跟踪这些过程。磁共振成像（MRI）衍生的脑网络特征，密切反映疾病过程，并涉及功能障碍，最近成为表征免疫介导的神经退行性变的重要变量，然而，其组织病理学基础仍不清楚。方法为了确定髓磷脂动力学的MRI衍生相关性，并测试来自扩散张量成像的脑网络特征是否反映了微结构组织重组，我们利用了小鼠一般脱髓鞘的cuprizone模型，并进行了纵向组织学和成像分析与行为测试。通过将cuprizone引入饮食中，我们在5周的时间内诱导少突胶质细胞的靶向和一致的脱髓鞘。随后的髓鞘合成是通过重新引入正常食物来实现的。结果使用特定的免疫组织学标记物，我们证明，2周的cuprizone饮食诱导的髓鞘含量减少52%的胼胝体（CC）和减少35%的新皮质。延长的cuprizone饮食增加髓鞘损失的CC，而髓鞘再生开始在新皮层。这些组织学确定的动力学通过来自扩散张量成像的MRI测量来反映。脱髓鞘与各向异性分数（FA）值降低和网络水平的模块化和聚类增加相关。MRI衍生的脑网络模块化和关键解剖区域（包括海马、丘脑和分析的皮质区）的FA减少与记忆功能受损和焦虑样行为密切相关。结论：神经网络特异性髓鞘再生，通过组织学和MRI指标显示，决定了功能表现和神经精神症状的改善。两者合计，我们说明了MRI驱动的网络反应脱髓鞘，增加模块化导致不断发展的损害和MS的异常行为的组织学基础。在体内髓鞘形成过程的定量信息反映了基于扩散的成像的微观结构的完整性和网络特性。
Background Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), characterized by inflammatory and neurodegenerative processes. Despite demyelination being a hallmark of the disease, how it relates to neurodegeneration has still not been completely unraveled, and research is still ongoing into how these processes can be tracked non-invasively. Magnetic resonance imaging (MRI) derived brain network characteristics, which closely mirror disease processes and relate to functional impairment, recently became important variables for characterizing immune-mediated neurodegeneration; however, their histopathological basis remains unclear. Methods In order to determine the MRI-derived correlates of myelin dynamics and to test if brain network characteristics derived from diffusion tensor imaging reflect microstructural tissue reorganization, we took advantage of the cuprizone model of general demyelination in mice and performed longitudinal histological and imaging analyses with behavioral tests. By introducing cuprizone into the diet, we induced targeted and consistent demyelination of oligodendrocytes, over a period of 5 weeks. Subsequent myelin synthesis was enabled by reintroduction of normal food. Results Using specific immune-histological markers, we demonstrated that 2 weeks of cuprizone diet induced a 52% reduction of myelin content in the corpus callosum (CC) and a 35% reduction in the neocortex. An extended cuprizone diet increased myelin loss in the CC, while remyelination commenced in the neocortex. These histologically determined dynamics were reflected by MRI measurements from diffusion tensor imaging. Demyelination was associated with decreased fractional anisotropy (FA) values and increased modularity and clustering at the network level. MRI-derived modularization of the brain network and FA reduction in key anatomical regions, including the hippocampus, thalamus, and analyzed cortical areas, were closely related to impaired memory function and anxiety-like behavior. Conclusion Network-specific remyelination, shown by histology and MRI metrics, determined amelioration of functional performance and neuropsychiatric symptoms. Taken together, we illustrate the histological basis for the MRI-driven network responses to demyelination, where increased modularity leads to evolving damage and abnormal behavior in MS. Quantitative information about in vivo myelination processes is mirrored by diffusion-based imaging of microstructural integrity and network characteristics.