Spread of pathology in amyotrophic lateral sclerosis: assessment of phosphorylated TDP-43 along axonal pathways.
Spread of pathology in amyotrophic lateral sclerosis: assessment of phosphorylated TDP-43 along axonal pathways.
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DOI：
10.1186/s40478-015-0226-y
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发表时间：
2015-07-28
影响因子：
7.1
通讯作者：
Kril JJ
中科院分区：
文献类型：
--
作者：
Fatima M;Tan R;Halliday GM;Kril JJ
肌萎缩侧索硬化症（ALS）的进展，通过大脑最近分期使用独立的神经病理学和神经影像学方式。这两个方案与通过离皮质轴突传递的病理性传播的概念相联系，该轴突传递源于观察到少突胶质细胞pTDP-43聚集体沿着神经元内含物。在这里，我们的目的是通过寻找相关白色物质束中的pTDP-43少突胶质细胞病理来评估沿着轴突途径传播的证据，并首次验证神经病理分期方案。pTDP-43免疫组织化学在尸检证实的ALS病例（N = 34）中的分期方案中选择的白色物质束和灰质区域中进行。进行双标记免疫荧光以确认pTDP-43免疫反应性与少突胶质细胞的共定位。虽然pTDP-43免疫反应性少突胶质细胞在运动和感觉皮质下的白色中频繁出现，但沿着皮质脊髓束以及相同病例的胼胝体和扣带束的白色的类似评估显示没有pTDP-43病理学，质疑少突胶质细胞参与病理学传播。对贝茨细胞损失的评估显示，缺乏深部白色物质pTDP-43少突胶质细胞病理学不是由于缺乏运动轴突。对病理向不同灰质区域传播的评估证实，所有病例均可分为四个神经病理学阶段之一，尽管发现第4期病例在发病年龄（约10岁）和疾病持续时间（持续时间短于第3期，与第2期相似）方面存在显著差异。ALS神经病理学的四个阶段可以一致地确定，尽管连续临床进展的证据需要进一步评估。由于在深部皮质脊髓和运动皮质的其他白色物质束中观察到有限的pTDP-43少突胶质细胞病理学，神经元之间的病理学传播可能不涉及少突胶质细胞，因此应相应修改神经成像上观察到的变化的解释。本文的在线版本（doi：10.1186/s40478-015-0226-y）包含补充材料，可供授权用户使用。
The progression of amyotrophic lateral sclerosis (ALS) through the brain has recently been staged using independent neuropathological and neuroimaging modalities. The two schemes tie into the concept of pathological spread through corticofugal axonal transmission that stems from observation of oligodendrocyte pTDP-43 aggregates along with neuronal inclusions. Here, we aimed to assess evidence of transmission along axonal pathways by looking for pTDP-43 oligodendrocyte pathology in involved white matter tracts, and to present a first validation of the neuropathological staging scheme. pTDP-43 immunohistochemistry was performed in select white matter tracts and grey matter regions from the staging scheme in postmortem-confirmed ALS cases (N = 34). Double-labelling immunofluorescence was performed to confirm co-localisation of pTDP-43 immunoreactivity to oligodendrocytes. While pTDP-43 immunoreactive oligodendrocytes were frequent in the white matter under the motor and sensory cortices, similar assessment of the white matter along the corticospinal tract and in the corpus callosum and cingulum bundle of the same cases revealed no pTDP-43 pathology, questioning the involvement of oligodendrocytes in pathological propagation. The assessment of Betz cell loss revealed that the lack of deep white matter pTDP-43 oligodendrocyte pathology was not due to an absence of motor axons. Assessment of the propagation of pathology to different grey matter regions validated that all cases could be allocated to one of four neuropathological stages, although Stage 4 cases were found to differ significantly in age of onset (~10 years older) and disease duration (shorter duration than Stage 3 and similar to Stage 2). Four stages of ALS neuropathology can be consistently identified, although evidence of sequential clinical progression requires further assessment. As limited pTDP-43 oligodendrocyte pathology in deep corticospinal and other white matter tracts from the motor cortex was observed, the propagation of pathology between neurons may not involve oligodendrocytes and the interpretation of the changes observed on neuroimaging should be modified accordingly. The online version of this article (doi:10.1186/s40478-015-0226-y) contains supplementary material, which is available to authorized users.