Institute of Public Health, University of Cambridge, Cambridge, UK.
Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
Brain Pathol. 2018 Jul;28(4):548-559. doi: 10.1111/bpa.12556. Epub 2017 Sep 25.
Hippocampal neuron loss is a common neuropathological feature in old age with various underlying etiologies. Hippocampal sclerosis of aging (HS-Aging) is neuropathologically characterized by severe CA1 neuronal loss and frequent presence of transactive response DNA-binding protein of 43 kDa (TDP-43) aggregations. Its etiology is unclear and currently no standardized approaches to measure HS-Aging exist. We developed a semi-quantitative protocol, which captures various hippocampal neuron loss patterns, and compared their occurrence in the context of HS-Aging, TDP-43, vascular and tau pathology in 672 brains (TDP-43 staining n = 642/672, 96%) donated for the population-based Cambridge City over-75s Cohort and the Cognitive Function and Ageing Study. HS-Aging was first evaluated independently from the protocol using the most common criteria defined in literature, and then described in detail through examination of neuron loss patterns and associated pathologies. 34 (5%) cases were identified, with a maximum of five pyramidal neurons in each of over half CA1 fields-of-view (x200 magnification), no vascular damage, no neuron loss in CA2-CA4, but consistent TDP-43 neuronal solid inclusions and neurites. We also report focal CA1 neuron loss with vascular pathology to affect predominantly CA1 bordering CA2 (Fisher's exact, P = 0.009), whereas neuron loss in the subicular end of CA1 was associated with TDP-43 inclusions (Fisher's exact, P < 0.001) and high Braak stage (Fisher's exact, P = 0.001). Hippocampal neuron loss in CA4-CA2 was not associated with TDP-43. We conclude that hippocampal neuron loss patterns are associated with different etiologies within CA1, and propose that these patterns can be used to form objective criteria for HS-Aging diagnosis. Finally, based on our results we hypothesize that neuron loss leading to HS-Aging starts from the subicular end of CA1 when it is associated with TDP-43 pathology, and that this neurodegenerative process is likely to be significantly more common than "end-stage" HS-Aging only.
海马体神经元缺失是老年人群中一种常见的神经病理学特征，其病因多种多样。与衰老相关的海马体硬化（HS-Aging）在神经病理学上的特征是严重的 CA1 神经元缺失和频繁出现转激活反应 DNA 结合蛋白 43kDa（TDP-43）聚集物。其病因尚不清楚，目前尚无测量 HS-Aging 的标准化方法。我们开发了一种半定量方案，该方案可捕获各种海马体神经元缺失模式，并将其与 672 例捐赠用于基于人群的剑桥市 75 岁以上人群队列和认知功能与衰老研究的 HS-Aging、TDP-43、血管和 tau 病理学的背景下进行比较（TDP-43 染色 n=642/672，96%）。首先使用文献中定义的最常见标准独立于方案评估 HS-Aging，然后通过检查神经元缺失模式和相关病理学详细描述。确定了 34 例（5%）病例，其中超过一半的 CA1 视野（x200 放大倍数）中每个视野最多有 5 个锥体神经元，没有血管损伤，CA2-CA4 中没有神经元缺失，但存在一致的 TDP-43 神经元固缩物和神经突。我们还报告了以血管病理学为主的 CA1 局灶性神经元缺失，主要影响 CA2 交界的 CA1（Fisher 精确检验，P=0.009），而 CA1 亚区末端的神经元缺失与 TDP-43 包含物相关（Fisher 精确检验，P<0.001）和高 Braak 分期（Fisher 精确检验，P=0.001）。CA4-CA2 中的海马体神经元缺失与 TDP-43 无关。我们得出结论，CA1 内的不同病因与海马体神经元缺失模式相关，并提出这些模式可用于形成 HS-Aging 诊断的客观标准。最后，根据我们的结果，我们假设导致 HS-Aging 的神经元缺失始于与 TDP-43 病理学相关的 CA1 的亚区末端，并且这种神经退行性过程可能比仅“终末期”HS-Aging 更为常见。
