Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.
Brain. 2018 Dec 1;141(12):3443-3456. doi: 10.1093/brain/awy264.
Alzheimer's disease is a heterogeneous disorder. Understanding the biological basis for this heterogeneity is key for developing personalized medicine. We identified atrophy subtypes in Alzheimer's disease dementia and tested whether these subtypes are already present in prodromal Alzheimer's disease and could explain interindividual differences in cognitive decline. First we retrospectively identified atrophy subtypes from structural MRI with a data-driven cluster analysis in three datasets of patients with Alzheimer's disease dementia: discovery data (dataset 1: n = 299, age = 67 ± 8, 50% female), and two independent external validation datasets (dataset 2: n = 181, age = 66 ± 7, 52% female; dataset 3: n = 227, age = 74 ± 8, 44% female). Subtypes were compared on clinical, cognitive and biological characteristics. Next, we classified prodromal Alzheimer's disease participants (n = 603, age = 72 ± 8, 43% female) according to the best matching subtype to their atrophy pattern, and we tested whether subtypes showed cognitive decline in specific domains. In all Alzheimer's disease dementia datasets we consistently identified four atrophy subtypes: (i) medial-temporal predominant atrophy with worst memory and language function, older age, lowest CSF tau levels and highest amount of vascular lesions; (ii) parieto-occipital atrophy with poor executive/attention and visuospatial functioning and high CSF tau; (iii) mild atrophy with best cognitive performance, young age, but highest CSF tau levels; and (iv) diffuse cortical atrophy with intermediate clinical, cognitive and biological features. Prodromal Alzheimer's disease participants classified into one of these subtypes showed similar subtype characteristics at baseline as Alzheimer's disease dementia subtypes. Compared across subtypes in prodromal Alzheimer's disease, the medial-temporal subtype showed fastest decline in memory and language over time; the parieto-occipital subtype declined fastest on executive/attention domain; the diffuse subtype in visuospatial functioning; and the mild subtype showed intermediate decline in all domains. Robust atrophy subtypes exist in Alzheimer's disease with distinct clinical and biological disease expression. Here we observe that these subtypes can already be detected in prodromal Alzheimer's disease, and that these may inform on expected trajectories of cognitive decline.
阿尔茨海默病是一种异质性疾病。了解这种异质性的生物学基础是开发个体化医学的关键。我们在阿尔茨海默病痴呆患者中识别了萎缩亚型，并测试了这些亚型是否已经存在于前驱期阿尔茨海默病中，并可以解释认知能力下降的个体间差异。首先，我们使用数据驱动的聚类分析从结构 MRI 中回顾性地识别了三个阿尔茨海默病痴呆患者数据集的萎缩亚型：发现数据（数据集 1：n = 299，年龄 = 67 ± 8，50%女性），和两个独立的外部验证数据集（数据集 2：n = 181，年龄 = 66 ± 7，52%女性；数据集 3：n = 227，年龄 = 74 ± 8，44%女性）。在临床、认知和生物学特征方面比较了亚型。接下来，我们根据与萎缩模式最佳匹配的亚型对前驱期阿尔茨海默病患者（n = 603，年龄 = 72 ± 8，43%女性）进行分类，并测试了亚型是否在特定领域表现出认知能力下降。在所有阿尔茨海默病痴呆数据集中，我们都一致地识别出四种萎缩亚型：（i）内侧颞叶为主的萎缩，表现为最差的记忆和语言功能，年龄较大，脑脊液 tau 水平最低，血管病变最多；（ii）顶枕叶萎缩，表现为执行/注意力和视空间功能差，脑脊液 tau 水平高；（iii）轻度萎缩，认知表现最佳，年龄较小，但脑脊液 tau 水平最高；和（iv）弥漫性皮质萎缩，具有中间的临床、认知和生物学特征。分类到这些亚型之一的前驱期阿尔茨海默病患者在基线时表现出与阿尔茨海默病痴呆亚型相似的亚型特征。在前驱期阿尔茨海默病患者中，与其他亚型相比，内侧颞叶亚型的记忆和语言随时间下降最快；顶枕叶亚型在执行/注意力域下降最快；弥漫性亚型在视空间功能方面下降最快；而轻度亚型在所有领域的下降速度居中。在阿尔茨海默病中存在具有不同临床和生物学表现的稳健萎缩亚型。在这里，我们观察到这些亚型在前驱期阿尔茨海默病中已经可以检测到，并且这些亚型可能提示认知能力下降的预期轨迹。
