Pathological tau deposition in Motor Neurone Disease and frontotemporal lobar degeneration associated with TDP-43 proteinopathy.
Pathological tau deposition in Motor Neurone Disease and frontotemporal lobar degeneration associated with TDP-43 proteinopathy.
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DOI：
10.1186/s40478-016-0301-z
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发表时间：
2016-03-31
影响因子：
7.1
通讯作者：
Mann DM
中科院分区：
文献类型：
--
作者：
Behrouzi R;Liu X;Wu D;Robinson AC;Tanaguchi-Watanabe S;Rollinson S;Shi J;Tian J;Hamdalla HH;Ealing J;Richardson A;Jones M;Pickering-Brown S;Davidson YS;Strong MJ;Hasegawa M;Snowden JS;Mann DM
有研究表明，运动神经元病(MND)和运动神经元病合并行为变异型额颞痴呆(BvFTD， + MND)或单纯行为变异型额颞痴呆(BVFTD)患者可能存在于神经病理和/或遗传风险的共同基础上。此外，有报道称，运动神经元病(MND)患者的TDP-43蛋白异常可伴有神经元和神经胶质细胞的TDP-43蛋白异常，这种异常可能是MND发病机制和临床表型的基础。在这项研究中，我们试图证实后一种发现，并在连续的41例MND患者、16例FTD + MND患者和23例FTD非MND患者中检验这一病理连续体的概念。用抗tau抗体AT8、pThr175和pThr217对额叶、内嗅觉、颞叶和枕叶皮质和海马区的Tau病理进行免疫组织化学染色，用4G8抗体对淀粉样蛋白β蛋白(Aβ)进行免疫组织化学染色。24例(59%)MND患者，7例(44%)FTD + 患者和10例(43%)FTD患者表现出明显的tau病理(即不仅仅是一个孤立的神经纤维缠结或一个或多个大脑区域的几个神经纤维线)。在大多数情况下，这具有阿尔茨海默病过程的组织学特征，累及内嗅皮层、海马体、颞叶皮质、额叶皮质和枕叶皮质的频率递减，并伴随Aβ沉积至Thal 3期，尽管2名MND患者和1名FTD患者确实在Braak III期之后表现出tau病理。另外4名MND患者仅在额叶皮质表现出新的神经元tau病理，由pThr175抗体特异性地检测到，其特征是tau聚集成细小颗粒或更多的聚集，没有神经原纤维缠结或神经枕线。然而，这4名患者中没有一人有临床上明显的认知障碍，这种类型的tau病理在任何一名 + 或FTD患者中都没有看到。最后，两名患者，一名MND患者和一名FTD患者，表现出与嗜银颗粒病(AGD)一致的tau病理。免疫印迹和3-和4-重复tau抗体的使用证实了所有病例中阿尔茨海默病类型病理的组织学解释，除了那些伴有AGD的患者，在这些患者中，Western印迹和免疫组织化学证实了4-重复tau病。在所有3组患者中，淀粉样病变更有可能出现在65岁后死亡的患者中，并且存在载脂蛋白Eε4等位基因。我们得出结论，tau病变在MND、FTD、 + MND和FTD患者中同样常见，尽管在大多数情况下，这些变化的程度有限。在MND患者中，当存在认知障碍时，这最有可能是由于伴随/演变(巧合)阿尔茨海默病的过程，或者像单个病例一样，大脑皮质内的路易小体痴呆，而不是TDP-43蛋白质病的结果。相反，在先天性心脏病和先天性心脏病中， + 痴呆比tau更有可能与Tdp-43蛋白病变有关。因此，目前的研究表明，(Tau)病理的严重程度从MND到 + MND再到FTD没有进展，也不支持这些情况形成临床或病理变化的连续体的概念。本文的在线版本(doi：10.1186/s40478-0160301-z)包含补充材料，授权用户可以使用。
It has been suggested that patients with motor neurone disease (MND) and those with MND combined with behavioural variant frontotemporal dementia (bvFTD) (ie FTD + MND) or with FTD alone might exist on a continuum based on commonalities of neuropathology and/or genetic risk. Moreover, it has been reported that both a neuronal and a glial cell tauopathy can accompany the TDP-43 proteinopathy in patients with motor neurone disease (MND) with cognitive changes, and that the tauopathy may be fundamental to disease pathogenesis and clinical phenotype. In the present study, we sought to substantiate these latter findings, and test this concept of a pathological continuum, in a consecutive series of 41 patients with MND, 16 with FTD + MND and 23 with FTD without MND. Paraffin sections of frontal, entorhinal, temporal and occipital cortex and hippocampus were immunostained for tau pathology using anti-tau antibodies, AT8, pThr175 and pThr217, and for amyloid β protein (Aβ) using 4G8 antibody. Twenty four (59 %) patients with MND, 7 (44 %) patients with FTD + MND and 10 (43 %) patients with FTD showed ‘significant’ tau pathology (ie more than just an isolated neurofibrillary tangle or a few neuropil threads in one or more brain regions examined). In most instances, this bore the histological characteristics of an Alzheimer’s disease process involving entorhinal cortex, hippocampus, temporal cortex, frontal cortex and occipital cortex in decreasing frequency, accompanied by a deposition of Aβ up to Thal phase 3, though 2 patients with MND, and 1 with FTD did show tau pathology beyond Braak stage III. Four other patients with MND showed novel neuronal tau pathology, within the frontal cortex alone, specifically detected by pThr175 antibody, which was characterised by a fine granular or more clumped aggregation of tau without neurofibrillary tangles or neuropil threads. However, none of these 4 patients had clinically evident cognitive disorder, and this type of tau pathology was not seen in any of the FTD + MND or FTD patients. Finally, two patients, one with MND and one with FTD, showed a tau pathology consistent with Argyrophilic Grain Disease (AGD). Western blotting and use of 3- and 4-repeat tau antibodies confirmed the histological interpretation of Alzheimer’s disease type pathology in all instances except for those patients with accompanying AGD where a banding pattern on western blot, and immunohistochemistry, confirmed 4-repeat tauopathy. In all 3 patient groups, amyloid pathology was more likely to be present in patients dying after 65 years of age, and in the presence of APOE ε4 allele. We conclude that tau pathological changes are equally common amongst patients with MND, FTD + MND and FTD though, in most instances, these are limited in extent. In patients with MND, when cognitive impairment is present this is most likely due to an accompanying/evolving (coincidental) Alzheimer’s disease process or, as in a single case, Dementia with Lewy bodies, within the cerebral cortex rather than as a result of TDP-43 proteinopathy. Conversely, in FTD and FTD + MND dementia is more likely to be associated with TDP-43 proteinopathy than tau. Hence, present study shows no progression in severity of (tau) pathology from MND through FTD + MND to FTD, and does not support the concept of these conditions forming a continuum of clinical or pathological change. The online version of this article (doi:10.1186/s40478-016-0301-z) contains supplementary material, which is available to authorized users.