Regional distribution and maturation of tau pathology among phenotypic variants of Alzheimer's disease.
Regional distribution and maturation of tau pathology among phenotypic variants of Alzheimer's disease.
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DOI：
10.1007/s00401-022-02472-x
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发表时间：
2022-12
影响因子：
12.7
通讯作者：
Irwin DJ
中科院分区：
文献类型：
--
作者：
Arezoumandan S;Xie SX;Cousins KAQ;Mechanic-Hamilton DJ;Peterson CS;Huang CY;Ohm DT;Ittyerah R;McMillan CT;Wolk DA;Yushkevich P;Trojanowski JQ;Lee EB;Grossman M;Phillips JS;Irwin DJ
阿尔茨海默病的神经病理改变（ADNC）在临床上是异质性的，可以表现为典型的多域遗忘综合征或局灶性非遗忘综合征。在这里，我们研究了阿尔茨海默病（AD）表型变异中磷酸化和c端切割的tau病理在海马亚区和皮层区域的分布和负担。本研究将尸检证实的ADNC患者根据临床标准分为遗忘组（aAD， N=40）和非遗忘组（naAD， N=39）。我们对海马亚区和三个皮质区域的磷酸化tau （AT8检测前缠结和成熟缠结）、d421截断tau （TauC3，成熟缠结和鬼缠结的标记）和e391截断tau （MN423，主要检测鬼缠结的标记）的组织切片进行了数字评估。线性混合效应模型用于检验区域和群体差异，同时调整人口统计学。两组海马亚区均显示at8反应性，反映了传统的Braak分期，在Braak分期早期受影响的亚区磷酸化tau负担较高。aAD组和naAD组海马中磷酸化tau蛋白和tauc3免疫反应性tau蛋白的负荷基本相似。naAD组在CA1 （β= - 0.2， SE=0.09, p=0.001）和CA2 （β= - 0.25， SE=0.09, p=0.005）中mn423活性缠结的相对分布低于aAD组。虽然两组在皮层区磷酸化tau病理水平相似，但与aAD相比，naAD在上颞叶/中颞叶皮层中有更高的TauC3反应性负担（β=0.16， SE=0.07, p=0.02）和所有皮层区域的MN423反应性负担（β= 0.4-0.43， SE=0.09, p<0.001）。总之，阿尔茨海默病的临床变异可能在海马体中具有总体磷酸化tau病理的特征分布，反映了传统的Braak分期；然而，与临床失忆性AD患者相比，非失忆性AD患者在新皮层中具有更大的相对成熟缠结病理，在临床失忆性AD患者中，海马具有最大的c端裂解tau反应性的相对负担。因此，不同的神经元对tau介导的神经变性的易感性可能影响ADNC的临床表达。
Alzheimer’s disease neuropathologic change (ADNC) is clinically heterogenous and can present with a classic multidomain amnestic syndrome or focal non-amnestic syndromes. Here, we investigated the distribution and burden of phosphorylated and C-terminally cleaved tau pathologies across hippocampal subfields and cortical regions among phenotypic variants of Alzheimer’s disease (AD). In this study, autopsy-confirmed patients with ADNC, were classified into amnestic (aAD, N=40) and non-amnestic (naAD, N=39) groups based on clinical criteria. We performed digital assessment of tissue sections immunostained for phosphorylated-tau (AT8 detects pretangles and mature tangles), D421-truncated tau (TauC3, a marker for mature tangles and ghost tangles), and E391-truncated tau (MN423, a marker that primarily detects ghost tangles), in hippocampal subfields and three cortical regions. Linear mixed-effect models were used to test regional and group differences while adjusting for demographics. Both groups showed AT8-reactivity across hippocampal subfields that mirrored traditional Braak staging with higher burden of phosphorylated-tau in subregions implicated as affected early in Braak staging. The burden of phosphorylated-tau and TauC3-immunoreactive tau in the hippocampus was largely similar between the aAD and naAD groups. In contrast, the naAD group had lower relative distribution of MN423-reactive tangles in CA1 (β=−0.2, SE=0.09, p=0.001) and CA2 (β=−0.25, SE=0.09, p=0.005) compared to the aAD. While the two groups had similar levels of phosphorylated-tau pathology in cortical regions, there was higher burden of TauC3 reactivity in sup/mid temporal cortex (β=0.16, SE=0.07, p=0.02) and MN423 reactivity in all cortical regions (β=0.4–0.43, SE=0.09, p<0.001) in the naAD compared to aAD. In conclusion, AD clinical variants may have a signature distribution of overall phosphorylated-tau pathology within the hippocampus reflecting traditional Braak staging; however, non-amnestic AD has greater relative mature tangle pathology in the neocortex compared to patients with clinical amnestic AD, where the hippocampus had greatest relative burden of C-terminally cleaved tau reactivity. Thus, varying neuronal susceptibility to tau-mediated neurodegeneration may influence the clinical expression of ADNC.
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影响因子：
2.2
作者：
Khuebachova, M;Verzillo, V;Novak, M
通讯作者：
Novak, M
影响因子：
4.3
作者：
Giannini, Lucia A. A.;Xie, Sharon X.;Irwin, David J.
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影响因子：
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作者：
Irwin, David J.;Byrne, Matthew D.;Trojanowski, John Q.
通讯作者：
Trojanowski, John Q.
影响因子：
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作者：
GOEDERT, M;JAKES, R;VANMECHELEN, E
通讯作者：
VANMECHELEN, E
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2.8
作者：
García-Sierra, F;Wischik, CM;Mena, R
通讯作者：
Mena, R