肌萎缩侧索硬化症中 pTDP-43 病理学的阶段。
Stages of pTDP-43 pathology in amyotrophic lateral sclerosis.
机构信息
Center for Neurodegenerative Disease Research (CNDR), University of Pennsylvania School of Medicine, 3rd Floor Maloney Building, 3600 Spruce Street, Philadelphia, PA 19104, USA.
Clinical Neuroanatomy Section, Department of Neurology, Center for Biomedical Research, University of Ulm, Helmholtzstrasse 8/1, 89081 Ulm, Germany.
出版信息
Ann Neurol. 2013 Jul;74(1):20-38. doi: 10.1002/ana.23937. Epub 2013 Jun 19.
OBJECTIVE
To see whether the distribution patterns of phosphorylated 43kDa TAR DNA-binding protein (pTDP-43) intraneuronal inclusions in amyotrophic lateral sclerosis (ALS) permit recognition of neuropathological stages.
METHODS
pTDP-43 immunohistochemistry was performed on 70 μm sections from ALS autopsy cases (N = 76) classified by clinical phenotype and genetic background.
RESULTS
ALS cases with the lowest burden of pTDP-43 pathology were characterized by lesions in the agranular motor cortex, brainstem motor nuclei of cranial nerves V, VII, and X-XII, and spinal cord α-motoneurons (stage 1). Increasing burdens of pathology showed involvement of the prefrontal neocortex (middle frontal gyrus), brainstem reticular formation, precerebellar nuclei, and the red nucleus (stage 2). In stage 3, pTDP-43 pathology involved the prefrontal (gyrus rectus and orbital gyri) and then postcentral neocortex and striatum. Cases with the greatest burden of pTDP-43 lesions showed pTDP-43 inclusions in anteromedial portions of the temporal lobe, including the hippocampus (stage 4). At all stages, these lesions were accompanied by pTDP-43 oligodendroglial aggregates. Ten cases with C9orf72 repeat expansion displayed the same sequential spreading pattern as nonexpansion cases but a greater regional burden of lesions, indicating a more fulminant dissemination of pTDP-43 pathology.
INTERPRETATION
pTDP-43 pathology in ALS possibly disseminates in a sequential pattern that permits recognition of 4 neuropathological stages consistent with the hypothesis that pTDP-43 pathology is propagated along axonal pathways. Moreover, the finding that pTDP-43 pathology develops in the prefrontal cortex as part of an ongoing disease process could account for the development of executive cognitive deficits in ALS.
目的
观察肌萎缩侧索硬化症（ALS）中磷酸化 43kDa TAR DNA 结合蛋白（pTDP-43）神经元内包涵体的分布模式是否能识别神经病理学阶段。
方法
对经临床表型和遗传背景分类的 76 例 ALS 尸检病例（n=76）的 70μm 切片进行 pTDP-43 免疫组化染色。
结果
pTDP-43 病理负担最低的 ALS 病例表现为颗粒状运动皮层、颅神经 V、VII 和 X-XII 的脑干运动核以及脊髓α运动神经元的病变（1 期）。病理负担增加则表现为额前皮质（额中回）、脑干网状结构、小脑前核和红核受累（2 期）。在 3 期，pTDP-43 病理学累及额前（直回和眶回）和中央后皮质以及纹状体。pTDP-43 病变负担最大的病例表现为颞叶前内侧（包括海马体）有 pTDP-43 包涵体（4 期）。在所有阶段，这些病变都伴有 pTDP-43 少突胶质细胞聚集。10 例 C9orf72 重复扩展病例显示出与非扩展病例相同的连续传播模式，但病变的区域负担更大，这表明 pTDP-43 病理学的传播更迅速。
解释
ALS 中的 pTDP-43 病理学可能以连续的模式传播，这可以识别出与 pTDP-43 病理学沿轴突途径传播的假设一致的 4 个神经病理学阶段。此外，pTDP-43 病理学在前额皮质发展作为疾病进展过程的一部分，这可以解释 ALS 中执行认知功能缺陷的发展。
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