Charles F. and Joanne Knight Alzheimer's disease Research Center, Washington University School of Medicine, St. Louis, MO, USA.
Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
Brain. 2018 Nov 1;141(11):3233-3248. doi: 10.1093/brain/awy244.
Longer periods are needed to examine how biomarker changes occur relative to incident sporadic cognitive impairment. We evaluated molecular (CSF and imaging), structural, and cognitive biomarkers to predict incident cognitive impairment and examined longitudinal biomarker changes before and after symptomatic onset. Data from participants who were cognitively normal, underwent amyloid imaging using Pittsburgh compound B and/or CSF studies, and at least two clinical assessments were used. Stepwise Cox proportional hazards models tested associations of molecular (Pittsburgh compound B; CSF amyloid-β42, tau, ptau181, tau/amyloid-β42, ptau181/amyloid-β42), structural (normalized hippocampal volume, normalized whole brain volume), and cognitive (Animal Naming, Trail Making A, Trail Making B, Selective Reminding Test - Free Recall) biomarkers with time to Clinical Dementia Rating (CDR) > 0. Cognitively normal participants (n = 664), aged 42 to 90 years (mean ± standard deviation = 71.4 ± 9.2) were followed for up to 16.9 years (mean ± standard deviation = 6.2 ± 3.5 years). Of these, 145 (21.8%) participants developed a CDR > 0. At time of incident cognitive impairment, molecular, structural, and cognitive markers were abnormal for CDR > 0 compared to CDR = 0. Linear mixed models indicated rates of change in molecular biomarkers were similar for CDR = 0 and CDR > 0, suggesting that the separation in values between CDR = 0 and CDR > 0 must have occurred prior to the observation period. Rate of decline for structural and cognitive biomarkers was faster for CDR > 0 compared to CDR = 0 (P < 0.0001). Structural and cognitive biomarkers for CDR > 0 diverged from CDR 0 at 9 and 12 years before incident cognitive impairment, respectively. Within those who developed CDR > 0, a natural separation occurred for Pittsburgh compound B values. In particular, CDR > 0 who had at least one APOE ɛ4 allele had higher, and more rapid increase in Pittsburgh compound B, while APOE ɛ2 was observed to have slower increases in Pittsburgh compound B. Of molecular biomarker-positive participants followed for at least 10 years (n = 16-23), ∼70% remained CDR = 0 over the follow-up period. In conclusion, conversion from cognitively normal to CDR > 0 is characterized by not only the magnitude of molecular biomarkers but also rate of change in cognitive and structural biomarkers. Findings support theoretical models of biomarker changes seen during transition to cognitive impairment using longitudinal data and provide a potential time for changes seen during this transition. These findings support the use of molecular biomarkers for trial inclusion and cognitive/structural biomarkers for evaluating trial outcomes. Finally, results support a potential role for APOE ɛ in modulating amyloid accumulation in CDR > 0 with APOE ɛ4 being deleterious and APOE ɛ2 protective.
需要更长的时间来研究生物标志物的变化与偶发性认知障碍事件的发生相对应的情况。我们评估了分子（CSF 和成像）、结构和认知生物标志物，以预测认知障碍事件的发生，并检查了症状出现前后的纵向生物标志物变化。使用匹兹堡化合物 B 进行淀粉样蛋白成像和/或 CSF 研究的认知正常参与者的数据，并至少进行了两次临床评估。逐步 Cox 比例风险模型测试了分子（匹兹堡化合物 B；CSF 淀粉样蛋白-β42、tau、ptau181、tau/淀粉样蛋白-β42、ptau181/淀粉样蛋白-β42）、结构（标准化海马体积、标准化全脑体积）和认知（动物命名、轨迹制作 A、轨迹制作 B、选择性回忆测试-自由回忆）生物标志物与临床痴呆评分（CDR）>0 的时间之间的关联。认知正常参与者（n=664）年龄在 42 至 90 岁之间（平均值±标准差=71.4±9.2），随访时间长达 16.9 年（平均值±标准差=6.2±3.5 年）。其中，145（21.8%）名参与者的 CDR>0。在认知障碍事件发生时，与 CDR=0 相比，CDR>0 的分子、结构和认知标志物异常。线性混合模型表明，CDR=0 和 CDR>0 的分子生物标志物的变化率相似，这表明 CDR=0 和 CDR>0 之间的数值差异必须在观察期之前发生。与 CDR=0 相比，CDR>0 的结构和认知生物标志物的下降速度更快（P<0.0001）。与 CDR=0 相比，结构和认知生物标志物的 CDR>0 在认知障碍事件发生前 9 年和 12 年分别出现偏离。在发展为 CDR>0 的参与者中，匹兹堡化合物 B 值出现了自然分离。特别是，至少有一个 APOE ε4 等位基因的 CDR>0 者具有更高且更快速的匹兹堡化合物 B 增加，而 APOE ε2 则观察到匹兹堡化合物 B 增加缓慢。在至少随访 10 年的分子生物标志物阳性参与者中（n=16-23），在随访期间，约 70%的参与者仍保持 CDR=0。总之，从认知正常到 CDR>0 的转变不仅以分子生物标志物的幅度为特征，而且以认知和结构生物标志物的变化率为特征。这些发现支持使用纵向数据观察到的认知障碍过渡期间的生物标志物变化的理论模型，并为观察到的过渡期间的变化提供了一个潜在的时间点。这些发现支持使用分子生物标志物进行试验纳入和使用认知/结构生物标志物评估试验结果。最后，结果支持 APOE ε 在调节 CDR>0 中的淀粉样蛋白积累方面的潜在作用，其中 APOE ε4 具有有害作用，而 APOE ε2 具有保护作用。
