Over time, reduced hippocampal volume results in an amnestic syndrome, a core feature of Alzheimer’s disease. Damage to the hippocampus is incorporated into the pathological criteria for Alzheimer’s disease, with two regionally separable pathological features required: at least some neurofibrillary tangles in the hippocampus, and β-amyloid deposition and moderate neuritic infiltrate in association cortices. The severity of hippocampal tangle formation at clinical onset can be very variable (from some neurons to nearly all neurons involved). Many studies have shown that it is the severity of neuron loss in the hippocampus, rather than the preceding deposition of tau protein, that is most closely associated with the progressive hippocampal atrophy that accompanies Alzheimer’s disease. The assumption has been that this degenerative process is driven by the redistribution of intracellular tau itself, its interactions at neuronal terminals and dendrites with the β-amyloid protein, or both. Mechanistic studies certainly support the concept of such a pathogenic interaction between these two proteins. In parallel with refining the diagnostic criteria for Alzheimer’s disease, findings of cohort and population-based autopsy studies have shown that a relatively high proportion of the elderly population (aged 80 years or older) have cerebral age-related TAR DNA binding protein 43 (TDP-43) deposition and hippocampal sclerosis. The clinical phenotype of this pathology mimics Alzheimer’s disease through different pathogenic mechanisms. Importantly, TDP43 protein deposition does not usually form amyloid, distinguishing this pathology from that observed for tau and β-amyloid deposition. In addition, the deposition of TDP-43 is usually associated with substantial, focal rapid neuronal death, potentially due to the disruption of its essential RNA binding and transport processes, and its prion-like domains. In The Lancet Neurology, the study by Keith Josephs and colleagues tackles the concept of the pathology responsible for the variable rates of hippocampal atrophy in Alzheimer’s disease. It has been noted that there are four main patterns of atrophy over time in Alzheimer’s disease—59% of patients have typical progressive hippocampal and cortical atrophy, 19% have progressive hippocampal atrophy only, 12% have progressive cortical atrophy only, and 10% have no atrophy in either region over time. These patterns are consistent with those identified previously by Whitwell and colleagues using is promising, fine-tuning of these models and extension of current efforts are key. Although these endeavours are expensive, they are vital in our development of disease-modifying therapies and in the ultimate treatment of Parkinson’s disease.

中文翻译：

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阿尔茨海默病的病理学和海马萎缩

随着时间的推移，海马体积减少会导致遗忘综合征，这是阿尔茨海默病的核心特征。海马体损伤被纳入阿尔茨海默病的病理标准，需要两个区域可分离的病理特征：海马体中至少有一些神经原纤维缠结，以及相关皮质中的 β-淀粉样蛋白沉积和中度神经炎浸润。临床开始时海马缠结形成的严重程度可能非常可变（从一些神经元到几乎所有涉及的神经元）。许多研究表明，海马神经元丢失的严重程度，而不是先前的 tau 蛋白沉积，与伴随阿尔茨海默病的进行性海马萎缩最密切相关。假设这种退化过程是由细胞内 tau 本身的重新分布、其在神经元末梢和树突与 β-淀粉样蛋白的相互作用或两者兼而有之所驱动。机制研究当然支持这两种蛋白质之间这种致病相互作用的概念。在完善阿尔茨海默病诊断标准的同时，队列和基于人群的尸检研究结果表明，相对较高比例的老年人群（80 岁或以上）患有脑年龄相关的 TAR DNA 结合蛋白 43（TDP -43) 沉积与海马硬化。这种病理的临床表型通过不同的致病机制模拟阿尔茨海默病。重要的是，TDP43 蛋白沉积通常不会形成淀粉样蛋白，将这种病理与观察到的 tau 和 β-淀粉样蛋白沉积的病理区分开来。此外，TDP-43 的沉积通常与大量的、局灶性的快速神经元死亡有关，这可能是由于其基本的 RNA 结合和转运过程及其朊病毒样结构域的破坏。在《柳叶刀神经病学》中，Keith Josephs 及其同事的研究解决了导致阿尔茨海默病海马萎缩率可变的病理学概念。已经注意到，随着时间的推移，阿尔茨海默病有四种主要的萎缩模式——59% 的患者有典型的进行性海马和皮质萎缩，19% 仅有进行性海马萎缩，12% 仅有进行性皮质萎缩，10% 有随着时间的推移，这两个区域都没有萎缩。这些模式与 Whitwell 和同事先前确定的模式一致，使用很有希望，对这些模型进行微调并扩展当前的工作是关键。尽管这些努力是昂贵的，但它们对我们开发改善疾病的疗法和最终治疗帕金森病至关重要。