Aggleton John P, Pralus Agathe, Nelson Andrew J D, Hornberger Michael
School of Psychology, Cardiff University, Park Place, Cardiff, CF10 3AT, UK
Master of Biosciences, ENS de Lyon, 46 allée d'Italie, 69007 Lyon, France.
Brain. 2016 Jul;139(Pt 7):1877-90. doi: 10.1093/brain/aww083. Epub 2016 Apr 28.
It is widely assumed that incipient protein pathology in the medial temporal lobe instigates the loss of episodic memory in Alzheimer's disease, one of the earliest cognitive deficits in this type of dementia. Within this region, the hippocampus is seen as the most vital for episodic memory. Consequently, research into the causes of memory loss in Alzheimer's disease continues to centre on hippocampal dysfunction and how disease-modifying therapies in this region can potentially alleviate memory symptomology. The present review questions this entrenched notion by bringing together findings from post-mortem studies, non-invasive imaging (including studies of presymptomatic, at-risk cases) and genetically modified animal models. The combined evidence indicates that the loss of episodic memory in early Alzheimer's disease reflects much wider neurodegeneration in an extended mnemonic system (Papez circuit), which critically involves the limbic thalamus. Within this system, the anterior thalamic nuclei are prominent, both for their vital contributions to episodic memory and for how these same nuclei appear vulnerable in prodromal Alzheimer's disease. As thalamic abnormalities occur in some of the earliest stages of the disease, the idea that such changes are merely secondary to medial temporal lobe dysfunctions is challenged. This alternate view is further strengthened by the interdependent relationship between the anterior thalamic nuclei and retrosplenial cortex, given how dysfunctions in the latter cortical area provide some of the earliest in vivo imaging evidence of prodromal Alzheimer's disease. Appreciating the importance of the anterior thalamic nuclei for memory and attention provides a more balanced understanding of Alzheimer's disease. Furthermore, this refocus on the limbic thalamus, as well as the rest of Papez circuit, would have significant implications for the diagnostics, modelling, and experimental treatment of cognitive symptoms in Alzheimer's disease.
人们普遍认为，内侧颞叶早期的蛋白质病变会引发阿尔茨海默病患者情景记忆的丧失，这是这类痴呆症最早出现的认知缺陷之一。在这个区域内，海马体被视为对情景记忆最为关键的部位。因此，对阿尔茨海默病记忆丧失原因的研究仍集中在海马体功能障碍以及该区域的疾病修饰疗法如何潜在地缓解记忆症状上。本综述通过整合尸检研究、非侵入性成像（包括对症状前、有患病风险病例的研究）和转基因动物模型的研究结果，对这一根深蒂固的观念提出了质疑。综合证据表明，早期阿尔茨海默病情景记忆的丧失反映了一个扩展记忆系统（帕佩兹环路）中更广泛的神经退行性变，其中关键涉及边缘丘脑。在这个系统中，丘脑前核很突出，这不仅因为它们对情景记忆有至关重要的贡献，还因为这些核在阿尔茨海默病前驱期似乎很脆弱。由于丘脑异常出现在疾病的一些最早阶段，认为这些变化仅仅是内侧颞叶功能障碍的继发结果这一观点受到了挑战。鉴于后皮质区域的功能障碍提供了一些阿尔茨海默病前驱期最早的体内成像证据，丘脑前核与压后皮质之间的相互依存关系进一步强化了这一不同观点。认识到丘脑前核对记忆和注意力的重要性，能让我们对阿尔茨海默病有更平衡的理解。此外，这种对边缘丘脑以及帕佩兹环路其他部分的重新关注，将对阿尔茨海默病认知症状的诊断、建模和实验性治疗产生重大影响。
