The co-existence of multiple pathologies and proteins is a common feature in the brains of cognitively impaired elderly individuals. Transactive response DNA-binding protein (TDP-43) has been discovered to accumulate in limbic brain regions of a portion of late-onset Alzheimer's disease (AD) patients, in addition to amyloid-β and τ protein. However, it is not yet known whether the TDP-43 species in the AD brain differ in their composition, when compared among different AD cases and to frontotemporal lobar degeneration cases with TDP-43 inclusions (FTLD-TDP). Furthermore, it is not known whether TDP-43 pathology in AD is related to symptoms of the frontotemporal dementia (FTD) spectrum. In this study, we investigated the molecular pattern of TDP-43 lesions with five different antibodies against different phosphorylated (pTDP-43) and non-phosphorylated TDP-43 epitopes. We analyzed a cohort of 97 autopsy cases, including brains from 20 non-demented individuals, 16 cognitively normal pathologically-defined preclinical AD (p-preAD), 51 neuropathologically-confirmed AD cases and 10 FTLD-TDP cases as positive controls. We observed distinct neuropathological patterns of TDP-43 among AD cases. In 11 neuropathologically-confirmed AD cases we found dystrophic neurites (DNs), neuronal cytoplasmic inclusions (NCIs) and/or neurofibrillary tangle (NFT)-like lesions not only positive for pTDP-43409/410, but also for pTDP-43 phosphorylated at serines 403/404 (pTDP-43403/404) and non-phosphorylated, full-length TDP-43, as seen with antibodies against C-terminal TDP-43 and N-terminal TDP-43. These cases were referred to as ADTDP + FL because full-length TDP-43 was presumably present in the aggregates. FTLD-TDP cases showed a similar molecular TDP-43 pattern. A second pattern, which was not seen in FTLD-TDP, was observed in most of p-preAD, as well as 30 neuropathologically-confirmed AD cases, which mainly exhibited NFTs and NCIs stained with antibodies against TDP-43 phosphorylated at serines 409/410 (pTDP-43409, pTDP-43409/410). Because only phosphorylated C-terminal species of TDP-43 could be detected in the lesions we designated these AD cases as ADTDP + CTF. Ten AD cases did not contain any TDP-43 pathology and were referred to as ADTDP-. The different TDP-43 patterns were associated with clinically typical AD symptoms in 80% of ADTDP + CTF cases, 63,6% of ADTDP + FL and 100% of the ADTDP- cases. On the other hand, clinical symptoms characteristic for FTD were observed in 36,4% of ADTDP + FL, in 16,6% of the ADTDP + CTF, and in none of the ADTDP- cases. Our findings provide evidence that TDP-43 aggregates occurring in AD cases vary in their composition, suggesting the distinction of different molecular patterns of TDP-43 pathology ranging from ADTDP- to ADTDP + CTF and ADTDP + FL with possible impact on their clinical picture, i.e. a higher chance for FTD-like symptoms in ADTDP + FL cases.

中文翻译：

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阿尔茨海默氏病 TDP-43 病理学的独特分子模式：与临床表型的关系。

多种病理和蛋白质的共存是认知障碍老年人大脑的一个共同特征。研究发现，除了β-淀粉样蛋白和τ蛋白外，部分迟发性阿尔茨海默病(AD)患者的边缘脑区域还积聚了反应反应DNA结合蛋白(TDP-43)。然而，与不同 AD 病例以及具有 TDP-43 包涵体的额颞叶变性病例 (FTLD-TDP) 相比，AD 大脑中 TDP-43 种类的组成是否存在差异尚不清楚。此外，尚不清楚 AD 中的 TDP-43 病理学是否与额颞叶痴呆 (FTD) 谱系的症状有关。在本研究中，我们使用针对不同磷酸化 (pTDP-43) 和非磷酸化 TDP-43 表位的五种不同抗体研究了 TDP-43 病变的分子模式。我们分析了 97 例尸检病例，包括 20 例非痴呆个体的大脑、16 例认知正常、病理学定义的临床前 AD (p-preAD)、51 例神经病理学确诊的 AD 病例和 10 例 FTLD-TDP 病例作为阳性对照。我们观察到 AD 病例中 TDP-43 的不同神经病理学模式。在 11 例神经病理学确诊的 AD 病例中，我们发现营养不良性神经突 (DN)、神经元细胞质内含物 (NCI) 和/或神经原纤维缠结 (NFT) 样病变，不仅 pTDP-43409/410 呈阳性，而且 pTDP-43 磷酸化也呈阳性。丝氨酸 403/404 (pTDP-43403/404) 和非磷酸化全长 TDP-43，如针对 C 端 TDP-43 和 N 端 TDP-43 的抗体所见。这些病例被称为 ADTDP + FL，因为全长 TDP-43 可能存在于聚集体中。FTLD-TDP 病例表现出相似的分子 TDP-43 模式。第二种模式在 FTLD-TDP 中未见，但在大多数 p-preAD 以及 30 例神经病理学确诊的 AD 病例中观察到，这些病例主要表现出用丝氨酸 409/ 磷酸化的 TDP-43 抗体染色的 NFT 和 NCI。 410（pTDP-43409、pTDP-43409/410）。因为在病变中只能检测到磷酸化的 TDP-43 C 端物种，所以我们将这些 AD 病例指定为 ADTDP + CTF。十个 AD 病例不包含任何 TDP-43 病理学，被称为 ADTDP-。不同的 TDP-43 模式与 80% 的 ADTDP + CTF 病例、63.6% 的 ADTDP + FL 病例和 100% 的 ADTDP- 病例中的临床典型 AD 症状相关。另一方面，在 36.4% 的 ADTDP + FL 病例中观察到 FTD 特征的临床症状，在 16.6% 的 ADTDP + CTF 病例中观察到 FTD 特征，而在 ADTDP- 病例中则没有观察到。我们的研究结果提供了证据，表明 AD 病例中出现的 TDP-43 聚集体的组成有所不同，这表明 TDP-43 病理学的不同分子模式（从 ADTDP- 到 ADTDP + CTF 和 ADTDP + FL）的区别，可能对其临床表现产生影响，即 ADTDP + FL 病例中出现 FTD 样症状的可能性更高。