TDP-43 and tau concurrence in the entorhinal subfields in primary age-related tauopathy and preclinical Alzheimer's disease.
TDP-43 and tau concurrence in the entorhinal subfields in primary age-related tauopathy and preclinical Alzheimer's disease.
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DOI：
10.1111/bpa.13159
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发表时间：
2023-07
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影响因子：
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磷酸化tau（p-tau）病理与认知能力下降密切相关，是阿尔茨海默病（AD）的病理标志。近年来，磷酸化反式反应DNA结合蛋白（pTDP-43）已成为常见的合并症，在高达70%的所有AD病例中发现（Josephs et al.，Acta Neuropathol，131（4），571-585; Josephs，Whitwell等人，Acta Neuropathol，127（6），811-824）。AD和原发性年龄相关性tau蛋白病（PART）中pTDP-43的当前分期方案跟踪其在整个大脑中的进展，但尚未研究pTDP-43在最早期内嗅皮质（EC）中的分布。此外，p-tau和pTDP-43共定位的确切性质存在争议。我们研究了在临床前AD和PART死后组织中内嗅子场对磷酸化pTDP-43病理学的选择性脆弱性。在EC内，后外侧子野显示出最高的半定量pTDP-43密度评分，而前内侧子野的评分最低。在吻尾轴上，pTDP-43评分向后高于向前（p < 0.010），在最后节段达到峰值（p < 0.050）。此外，我们在病理阳性但临床无症状阶段显示了这些区域中pTDP-43和p-tau之间的关系。P-tau和pTDP-43在受累亚区的模式相似（p < 0.0001），但密度大小不同（p < 0.0001）。在每个前后节段和大多数EC子场中，P‐tau负荷始终高于pTDP‐43。这些结果强调了EC和后外侧子野内的pTDP-43负荷异质性，这是AD和PART当前pTDP-43分期方案II期内最脆弱的区域。EC是p-tau和pTDP-43的汇聚点，识别其最脆弱的神经元群体将证明是早期诊断和疾病干预的关键。
Phosphorylated tau (p‐tau) pathology correlates strongly with cognitive decline and is a pathological hallmark of Alzheimer's Disease (AD). In recent years, phosphorylated transactive response DNA‐binding protein (pTDP‐43) has emerged as a common comorbidity, found in up to 70% of all AD cases (Josephs et al., Acta Neuropathol, 131(4), 571–585; Josephs, Whitwell, et al., Acta Neuropathol, 127(6), 811–824). Current staging schemes for pTDP‐43 in AD and primary age‐related tauopathy (PART) track its progression throughout the brain, but the distribution of pTDP‐43 within the entorhinal cortex (EC) at the earliest stages has not been studied. Moreover, the exact nature of p‐tau and pTDP‐43 co‐localization is debated. We investigated the selective vulnerability of the entorhinal subfields to phosphorylated pTDP‐43 pathology in preclinical AD and PART postmortem tissue. Within the EC, posterior‐lateral subfields showed the highest semi‐quantitative pTDP‐43 density scores, while the anterior‐medial subfields had the lowest. On the rostrocaudal axis, pTDP‐43 scores were higher posteriorly than anteriorly (p < 0.010), peaking at the posterior‐most level (p < 0.050). Further, we showed the relationship between pTDP‐43 and p‐tau in these regions at pathology‐positive but clinically silent stages. P‐tau and pTDP‐43 presented a similar pattern of affected subregions (p < 0.0001) but differed in density magnitude (p < 0.0001). P‐tau burden was consistently higher than pTDP‐43 at every anterior–posterior level and in most EC subfields. These findings highlight pTDP‐43 burden heterogeneity within the EC and the posterior‐lateral subfields as the most vulnerable regions within stage II of the current pTDP‐43 staging schemes for AD and PART. The EC is a point of convergence for p‐tau and pTDP‐43 and identifying its most vulnerable neuronal populations will prove key for early diagnosis and disease intervention.
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影响因子：
25
作者：
Khan, Usman A.;Liu, Li;Provenzano, Frank A.;Berman, Diego E.;Profaci, Caterina P.;Sloan, Richard;Mayeux, Richard;Duff, Karen E.;Small, Scott A.
通讯作者：
Small, Scott A.
影响因子：
12.7
作者：
Josephs KA;Murray ME;Whitwell JL;Tosakulwong N;Weigand SD;Petrucelli L;Liesinger AM;Petersen RC;Parisi JE;Dickson DW
通讯作者：
Dickson DW
影响因子：
12.7
作者：
Arai, Tetsuaki;Mackenzie, Ian R. A.;Akiyama, Haruhiko
通讯作者：
Akiyama, Haruhiko
影响因子：
2.9
作者：
Higashi, Shinji;Iseki, Eizo;Arai, Heii
通讯作者：
Arai, Heii
影响因子：
12.7
作者：
Augustinack, Jean C.;Huber, Kristen E.;Fischl, Bruce
通讯作者：
Fischl, Bruce