Department of Nuclear Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany.
School of Mathematics and Natural Science, University of Wuppertal, Wuppertal, Germany.
J Alzheimers Dis. 2018;61(1):373-388. doi: 10.3233/JAD-170705.
The aim of this study was to evaluate the incremental benefit of biomarkers for prediction of Alzheimer's disease dementia (ADD) in patients with mild cognitive impairment (MCI) when added stepwise in the order of their collection in clinical routine. The model started with cognitive status characterized by the ADAS-13 score. Hippocampus volume (HV), cerebrospinal fluid (CSF) phospho-tau (pTau), and the FDG t-sum score in an AD meta-region-of-interest were compared as neurodegeneration markers. CSF-Aβ1-42 was used as amyloidosis marker. The incremental prognostic benefit from these markers was assessed by stepwise Kaplan-Meier survival analysis in 402 ADNI MCI subjects. Predefined cutoffs were used to dichotomize patients as 'negative' or 'positive' for AD characteristic alteration with respect to each marker. Among the neurodegeneration markers, CSF-pTau provided the best incremental risk stratification when added to ADAS-13. FDG PET outperformed HV only in MCI subjects with relatively preserved cognition. Adding CSF-Aβ provided further risk stratification in pTau-positive subjects, independent of their cognitive status. Stepwise integration of biomarkers allows stepwise refinement of risk estimates for MCI-to-ADD progression. Incremental benefit strongly depends on the patient's status according to the preceding diagnostic steps. The stepwise Kaplan-Meier curves might be useful to optimize diagnostic workflow in individual patients.
本研究旨在评估当按照临床常规采集顺序逐步添加生物标志物时，其对轻度认知障碍（MCI）患者阿尔茨海默病痴呆（ADD）预测的增量获益。该模型以 ADAS-13 评分所描述的认知状态为起点。将海马体积（HV）、脑脊液（CSF）磷酸化tau（pTau）和 AD 感兴趣区的 FDG t 总和评分作为神经退行性变标志物进行比较。CSF-Aβ1-42 被用作淀粉样变性标志物。通过对 402 名 ADNI MCI 受试者进行逐步 Kaplan-Meier 生存分析，评估这些标志物的增量预后获益。使用预定义的截止值将患者分为 AD 特征改变的“阴性”或“阳性”，以评估每个标志物的改变。在神经退行性变标志物中，当添加到 ADAS-13 时，CSF-pTau 提供了最佳的增量风险分层。仅在认知相对保留的 MCI 受试者中，FDG PET 优于 HV。在 pTau 阳性患者中，添加 CSF-Aβ 可进一步进行风险分层，而与认知状态无关。生物标志物的逐步整合允许逐步细化 MCI 向 ADD 进展的风险估计。增量获益强烈依赖于患者根据先前诊断步骤的状态。逐步 Kaplan-Meier 曲线可能有助于优化个体患者的诊断工作流程。
