Asymmetric TDP-43 distribution in primary progressive aphasia with progranulin mutation
Asymmetric TDP-43 distribution in primary progressive aphasia with progranulin mutation
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DOI：
10.1212/wnl.0b013e3181df0a1b
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发表时间：
2010-05-18
期刊：
影响因子：
9.9
通讯作者：
Geula, C.
中科院分区：
文献类型：
--
作者：
Gliebus, G.;Bigio, E. H.;Geula, C.
目的：原发性进行性失语症(PPA)是语言占优势(通常为左侧)大脑半球不对称变性的结果，与阿尔茨海默病(AD)或额颞叶变性(FTLD)的病理机制有关。本研究旨在探讨1例伴有原颗粒蛋白基因突变和FTLD病理改变的PPA患者脑组织中TDP-43包涵体的解剖分布是否表现出相应的向左不对称。方法：采用免疫组织化学方法检测1例65岁PPA和前颗粒蛋白突变患者脑组织中TDP-43的表达。分析对象为颞上回、颞下回、顶下小叶、眶前皮质、内嗅皮层和齿状回。用改良的体视学分析方法对神经元核内包涵体、神经元胞浆包涵体和营养不良的轴突进行定量。结果：3种类型的包裹物均以左侧皮质占优势。结论：TDP-43异常包涵体在原发性进行性失语症(PPA)中的分布具有表型一致性。这与患有阿尔茨海默病的PPA病例形成对比，在PPA病例中，尽管萎缩向左不对称，但没有表现出一致的神经纤维变性或淀粉样蛋白沉积的向左不对称，并且尽管主要是失语型，但神经纤维缠结在记忆中显示出比语言区域更高的密度。这一案例表明，与PPA-阿尔茨海默病的神经纤维和淀粉样沉积相比，PPA-额颞叶变性中的TDP-43包涵体与神经元死亡和功能障碍的联系更紧密。神经病学(R)2010；74：1607-1610
Objective: Primary progressive aphasia (PPA) results from an asymmetric degeneration of the language dominant (usually left) hemisphere and can be associated with the pathology of Alzheimer disease (AD) or frontotemporal lobar degeneration (FTLD). This study aimed to investigate whether the anatomic distribution of TDP-43 inclusions displayed a corresponding leftward asymmetry in a patient with PPA with a mutation in the progranulin gene and FTLD pathology.Methods: Brain tissue from a 65-year-old patient with PPA and progranulin mutation was analyzed using immunohistochemical methods for TDP-43. Analysis was performed in the superior temporal gyrus, inferior temporal gyrus, inferior parietal lobule, orbitofrontal cortex, entorhinal cortex, and dentate gyrus. Neuronal intranuclear inclusions, neuronal cytoplasmic inclusions, and dystrophic neurites were quantified using modified stereologic analysis. Analysis of variance was used to determine significant effects.Results: All 3 types of inclusions predominated on the left side of analyzed cortical regions. They were also more frequent in language areas than in memory-related areas.Conclusion: These results demonstrate a phenotypically concordant distribution of abnormal TDP-43 inclusions in primary progressive aphasia (PPA). This contrasts with PPA cases with Alzheimer pathology where no consistent leftward asymmetry of neurofibrillary degeneration or amyloid deposition has been demonstrated despite the leftward asymmetry of the atrophy, and where neurofibrillary tangles show a greater density in memory than language areas despite the predominantly aphasic phenotype. This case suggests that the TDP-43 inclusions in PPA-frontotemporal lobar degeneration are more tightly linked to neuronal death and dysfunction than neurofibrillary and amyloid deposits in PPA-Alzheimer disease. Neurology (R) 2010; 74: 1607-1610