Biomedical Imaging Group Rotterdam, Department of Radiology & Nuclear Medicine, Erasmus MC, University Medical Center Rotterdam, the Netherlands.
Biomedical Imaging Group Rotterdam, Department of Radiology & Nuclear Medicine, Erasmus MC, University Medical Center Rotterdam, the Netherlands.
Neuroimage. 2021 Feb 15;227:117646. doi: 10.1016/j.neuroimage.2020.117646. Epub 2020 Dec 16.
Alzheimer's disease (AD) is the most common form of dementia and is phenotypically heterogeneous. APOE is a triallelic gene which correlates with phenotypic heterogeneity in AD. In this work, we determined the effect of APOE alleles on the disease progression timeline of AD using a discriminative event-based model (DEBM). Since DEBM is a data-driven model, stratification into smaller disease subgroups would lead to more inaccurate models as compared to fitting the model on the entire dataset. Hence our secondary aim is to propose and evaluate novel approaches in which we split the different steps of DEBM into group-aspecific and group-specific parts, where the entire dataset is used to train the group-aspecific parts and only the data from a specific group is used to train the group-specific parts of the DEBM. We performed simulation experiments to benchmark the accuracy of the proposed approaches and to select the optimal approach. Subsequently, the chosen approach was applied to the baseline data of 417 cognitively normal, 235 mild cognitively impaired who convert to AD within 3 years, and 342 AD patients from the Alzheimers Disease Neuroimaging Initiative (ADNI) dataset to gain new insights into the effect of APOE carriership on the disease progression timeline of AD. In the ε4 carrier group, the model predicted with high confidence that CSF Amyloidβ and the cognitive score of Alzheimer's Disease Assessment Scale (ADAS) are early biomarkers. Hippocampus was the earliest volumetric biomarker to become abnormal, closely followed by the CSF Phosphorylated Tau (PTAU) biomarker. In the homozygous ε3 carrier group, the model predicted a similar ordering among CSF biomarkers. However, the volume of the fusiform gyrus was identified as one of the earliest volumetric biomarker. While the findings in the ε4 carrier and the homozygous ε3 carrier groups fit the current understanding of progression of AD, the finding in the ε2 carrier group did not. The model predicted, with relatively low confidence, CSF Neurogranin as one of the earliest biomarkers along with cognitive score of Mini-Mental State Examination (MMSE). Amyloid β was found to become abnormal after PTAU. The presented models could aid understanding of the disease, and in selecting homogeneous group of presymptomatic subjects at-risk of developing symptoms for clinical trials.
阿尔茨海默病（AD）是最常见的痴呆症形式，表现型异质性明显。APOE 是一个三等位基因，与 AD 的表型异质性相关。在这项工作中，我们使用判别事件基模型（DEBM）确定 APOE 等位基因对 AD 疾病进展时间线的影响。由于 DEBM 是一种数据驱动的模型，与将模型拟合到整个数据集相比，将其划分为更小的疾病亚组会导致模型不够准确。因此，我们的次要目标是提出并评估新的方法，将 DEBM 的不同步骤分为特定组和特定组部分，使用整个数据集来训练特定组部分，并仅使用特定组的数据来训练 DEBM 的特定组部分。我们进行了模拟实验来评估所提出方法的准确性，并选择最佳方法。随后，将所选方法应用于来自阿尔茨海默病神经影像学倡议（ADNI）数据集的 417 名认知正常、235 名轻度认知障碍（3 年内转化为 AD）和 342 名 AD 患者的基线数据，以深入了解 APOE 携带对 AD 疾病进展时间线的影响。在 ε4 携带者组中，模型高度自信地预测 CSF 淀粉样蛋白β和阿尔茨海默病评估量表（ADAS）的认知评分是早期生物标志物。海马体是最早出现异常的体积生物标志物，紧随其后的是 CSF 磷酸化 Tau（PTAU）生物标志物。在纯合子 ε3 携带者组中，模型预测 CSF 生物标志物的排序相似。然而，梭状回的体积被确定为最早的体积生物标志物之一。虽然 ε4 携带者和纯合子 ε3 携带者组的发现符合 AD 进展的当前认识，但 ε2 携带者组的发现则不然。模型相对低置信度地预测 CSF 神经颗粒蛋白和 Mini-Mental State Examination（MMSE）的认知评分作为最早的生物标志物之一。发现淀粉样蛋白β在 PTAU 之后出现异常。所提出的模型可以帮助理解疾病，并选择有症状的临床前无症状高危人群进行临床试验。
