Heterogeneity of neuroanatomical patterns in prodromal Alzheimer's disease: links to cognition, progression and biomarkers
Heterogeneity of neuroanatomical patterns in prodromal Alzheimer's disease: links to cognition, progression and biomarkers
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DOI：
10.1093/brain/aww319
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发表时间：
2017-03-01
期刊：
影响因子：
14.5
通讯作者：
Davatzikos, Christos
中科院分区：
文献类型：
--
作者：
Dong, Aoyan;Toledo, Jon B.;Davatzikos, Christos
患有轻度认知障碍和阿尔茨海默病临床诊断的个体可以显示出显著的表型异质性。这种变异性可能反映了潜在的遗传、环境和神经病理学差异。表征这种异质性对于精确诊断、个性化预测和招募相对同质的患者集进入临床试验非常重要。在这项研究中，我们将最先进的半监督机器学习方法应用于阿尔茨海默病神经成像队列（ADNI），以阐明轻度认知障碍（n = 530）和阿尔茨海默病（n = 314）受试者与认知正常个体（n = 399）之间神经解剖学差异的异质性，从而增加了旨在建立阿尔茨海默病及其前驱期的神经解剖学和神经病理学（例如淀粉样蛋白和tau沉积）维度的文献。这些维度方法旨在提供导致认知障碍的异质性潜在病理过程的替代措施。我们将这些神经影像学模式与脑脊液生物标志物、白色高信号、认知和临床测量以及纵向轨迹联系起来。我们确定了四种这样的萎缩模式：（i）具有基本正常的神经解剖学特征的个体，在随访期间，他们也被证明具有最少的异常认知和脑脊液生物标志物特征以及最慢的临床进展;（ii）具有经典阿尔茨海默病神经解剖学、认知、脑脊液生物标志物和临床特征的个体，他们表现出最快的临床进展;（iii）具有弥漫性萎缩模式的个体，其中内侧颞叶的参与相对不太明显，脑脊液淀粉样蛋白β（1-42）值异常，以及成比例地更大的执行障碍;以及（iv）具有明显的内侧颞叶的局灶性参与和缓慢稳定进展的个体，可能代表早期阿尔茨海默病阶段。这四种萎缩模式有效地定义了轻度认知障碍和阿尔茨海默病中神经解剖学改变的4维分类，其可以补充使用各种生物标志物对阿尔茨海默病进行分期的现有维度方法，这提供了实现精确诊断和诊断的可能性，以及针对临床试验的相对同质的受试者亚组的靶向患者招募。
Individuals with mild cognitive impairment and Alzheimer's disease clinical diagnoses can display significant phenotypic heterogeneity. This variability likely reflects underlying genetic, environmental and neuropathological differences. Characterizing this heterogeneity is important for precision diagnostics, personalized predictions, and recruitment of relatively homogeneous sets of patients into clinical trials. In this study, we apply state-of-the-art semi-supervised machine learning methods to the Alzheimer's disease Neuroimaging cohort (ADNI) to elucidate the heterogeneity of neuroanatomical differences between subjects with mild cognitive impairment (n = 530) and Alzheimer's disease (n = 314) and cognitively normal individuals (n = 399), thereby adding to an increasing literature aiming to establish neuroanatomical and neuropathological (e.g. amyloid and tau deposition) dimensions in Alzheimer's disease and its prodromal stages. These dimensional approaches aim to provide surrogate measures of heterogeneous underlying pathologic processes leading to cognitive impairment. We relate these neuroimaging patterns to cerebrospinal fluid biomarkers, white matter hyperintensities, cognitive and clinical measures, and longitudinal trajectories. We identified four such atrophy patterns: (i) individuals with largely normal neuroanatomical profiles, who also turned out to have the least abnormal cognitive and cerebrospinal fluid biomarker profiles and the slowest clinical progression during follow-up; (ii) individuals with classical Alzheimer's disease neuroanatomical, cognitive, cerebrospinal fluid biomarkers and clinical profile, who presented the fastest clinical progression; (iii) individuals with a diffuse pattern of atrophy with relatively less pronounced involvement of the medial temporal lobe, abnormal cerebrospinal fluid amyloid-beta(1-42) values, and proportionally greater executive impairment; and (iv) individuals with notably focal involvement of the medial temporal lobe and a slow steady progression, likely representing in early Alzheimer's disease stages. These four atrophy patterns effectively define a 4-dimensional categorization of neuroanatomical alterations in mild cognitive impairment and Alzheimer's disease that can complement existing dimensional approaches for staging Alzheimer's disease using a variety of biomarkers, which offer the potential for enabling precision diagnostics and prognostics, as well as targeted patient recruitment of relatively homogeneous subgroups of subjects for clinical trials.