阿尔茨海默病的分期 - 认知障碍

临床分期体系的演进

传统上，阿尔茨海默病（AD）分期基于临床因素，如认知障碍程度。痴呆被定义为足以导致独立社会或职业功能丧失的获得性认知障碍，可由多种疾病或其他医疗状况引起。

在20世纪后期，患者被诊断为"可能的AD痴呆"，并根据症状对日常功能的影响被分类为轻度、中度或重度痴呆。在21世纪初，轻度认知障碍（MCI）概念被提出，认识到部分患者在轻度痴呆阶段之前已存在认知障碍症状，此时测试显示一个或多个认知领域出现症状和损害证据，但日常功能仍保持正常。

与痴呆类似，多种脑部疾病或其他状况可导致MCI。在21世纪的第一个十年，脑脊液和正电子发射断层扫描（PET）分子生物标志物（针对β-淀粉样蛋白和过度磷酸化tau蛋白）的出现，促使2011年提出了阿尔茨海默病的三个主要阶段：临床前AD（脑内有AD生物标志物证据但认知正常的个体，或部分个体可能注意到主观认知下降）、可能由AD引起的MCI（AD的前驱阶段）和AD痴呆阶段（再次包括轻度、中度和重度痴呆）。这一基本框架在2011年被国家老龄化研究所-阿尔茨海默病协会（NIA-AA）指南推荐，区别在于"认知正常"阶段被称为"临床前"。国际工作组（IWG）在2014年也支持了类似的分期系统。

目前，这些2011年针对可能由AD引起的MCI或痴呆的诊断标准是临床实践中用于诊断AD的主要依据。临床前AD的概念目前仍仅限于研究使用。

当前国家老龄化研究所-阿尔茨海默病协会临床分期

2018年，NIA-AA提出了六个临床阶段（前三个仅限于研究），并在2024年进行了更新，如表1-1所示。作者澄清指出，其中许多元素目前主要用于研究标准（特别是关注临床前AD和新生物标志物的部分），但最终可能为临床实践提供指导。2024年的更新引发了一些争议（见参考文献），国际工作组提出了反建议。

生物学分期系统

β-淀粉样蛋白扩散分期

随着技术进步和对β-淀粉样蛋白及tau蛋白病理生理学的深入理解，平行的生物学分期系统被开发出来。Thal及其同事在2002年基于尸检脑组织开发了一个基于β-淀粉样蛋白扩散的生物学分期系统，包括以下五个阶段：

1期：新皮质中早期β-淀粉样蛋白沉积；
2期：扩散到边缘区域（内嗅皮质、下托、杏仁核和扣带回）；
3期：扩散到皮质下区域（基底神经节和丘脑）；
4期：扩散到脑干（中脑、桥脑和延髓）；以及
5期：扩散到小脑。

tau神经纤维缠结扩散分期

Braak和Braak在1991年开发了一个类似的tau蛋白（神经纤维缠结）在尸检脑组织中的分期方案，包括以下六个阶段：

1期：海马形成中转内嗅区域早期神经纤维缠结；
2期：扩散到海马锥体细胞层的下托区域；
3期：扩散到内嗅皮质和海马锥体细胞层的CA1区；
4期：现有区域神经纤维缠结信号增强，并扩散到海马锥体细胞层的其他区域、颞下皮质、颞上皮质和额皮质；以及
5-6期：海马区域神经纤维缠结持续增强，并扩散到新皮质的其他区域，包括次级联合区和初级皮质区（5期定义为枕叶皮质周纹区出现神经纤维缠结，6期定义为纹状区出现神经纤维缠结）。

生物学阶段最初基于尸检脑组织定义，但如今可通过PET成像测量β-淀粉样蛋白和tau蛋白的位置和数量。

2024年国家老龄化研究所-阿尔茨海默病协会生物学分期

作为2024年拟议AD诊断标准更新的一部分，根据PET成像和/或异常的"核心1"液体生物标志物，定义了AD的四个生物学阶段。此生物学分期如表1-2所示。

临床-生物学综合分期

在同一2024年出版物中，提出了一个综合分期方案，将临床和生物学分期结合起来，同时指出临床和生物学成分可以相互独立。此综合系统如表1-3所示。

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