Elhefnawy Marwa E, Patson Noel, Mouksassi Samer, Pillai Goonaseelan, Shcherbinin Sergey, Chigutsa Emmanuel, Gueorguieva Ivelina
Applied Pharmacometrics Training-Africa Program, c/o Pharmacometrics Africa NPC, Cape Town, South Africa.
Pumas-AI, Inc, Dover, Delaware, USA.
J Pharmacokinet Pharmacodyn. 2025 Jan 25;52(1):15. doi: 10.1007/s10928-024-09959-y.
Brain amyloid beta neuritic plaque accumulation is associated with an increased risk of progression to Alzheimer's disease (AD) [Pfeil, J., et al. in Neurobiol Aging 106: 119-129, 2021]. Several studies estimate rates of change in amyloid plaque over time in clinically heterogeneous cohorts with different factors impacting amyloid plaque accumulation from ADNI and AIBL [Laccarino, L., et al. in Annals Clin and Trans Neurol 6: 1113 1120, 2019, Vos, S.J., et al. in Brain 138: 1327-1338, 2015, Lim, Y.Y., et al. in Alzheimer's Dementia 9: 538-545, 2013], but there are no reports using non-linear mixed effect model for amyloid plaque progression over time similar to that existing of disease-modifying biomarkers for other diseases [Cook, S.F. and R.R. Bies in Current Pharmacol Rep 2: 221-230, 2016, Gueorguieva, I., et al. in Alzheimer's Dementia 19: 2253-2264, 2023]. This study describes the natural progression of amyloid accumulation with population mean and between-participant variability for baseline and intrinsic progression rates quantified across the AD spectrum. 1340 ADNI participants were followed over a 10-year period with F-florbetapir PET scans used for amyloid plaque detection. Non-linear mixed effect with stepwise covariate modelling (scm) was used. Change in natural amyloid plaque levels over 10 year period followed an exponential growth model with an intrinsic rate of approx. 3 centiloid units/year. Age, gender, APOE4 genotype and disease stage were important factors on the baseline in the natural amyloid model. In APOE4 homozygous carriers mean baseline amyloid was increased compared to APOE4 non carriers. These results demonstrate natural progression of amyloid plaque in the continuum of AD.
脑淀粉样β神经炎性斑块的积累与患阿尔茨海默病（AD）的进展风险增加相关[Pfeil, J.等人，发表于《神经生物学衰老》106: 119 - 129, 2021]。多项研究估计了临床异质性队列中淀粉样斑块随时间的变化率，这些队列中有来自阿尔茨海默病神经成像计划（ADNI）和澳大利亚成像生物标志物与生活方式研究（AIBL）的不同因素影响淀粉样斑块积累[Laccarino, L.等人，发表于《临床与转化神经病学年鉴》6: 1113 - 1120, 2019；Vos, S.J.等人，发表于《大脑》138: 1327 - 1338, 2015；Lim, Y.Y.等人，发表于《阿尔茨海默病与痴呆》9: 538 - 545, 2013]，但尚无关于使用非线性混合效应模型来研究淀粉样斑块随时间进展的报道，类似研究在其他疾病的疾病修饰生物标志物领域已有[Cook, S.F.和R.R. Bies，发表于《当代药理学报告》2: 221 - 230, 2016；Gueorguieva, I.等人，发表于《阿尔茨海默病与痴呆》19: 2253 - 2264, 2023]。本研究描述了淀粉样蛋白积累的自然进展情况，量化了整个AD谱系中基线和内在进展率的总体均值及个体间变异性。1340名ADNI参与者在10年期间接受随访，使用F - 氟代硼吡咯正电子发射断层扫描（PET）检测淀粉样斑块。采用了带有逐步协变量建模（scm）的非线性混合效应模型。10年期间自然淀粉样斑块水平的变化遵循指数增长模型，内在增长率约为每年3个百分单位。年龄、性别、APOE4基因型和疾病阶段是自然淀粉样模型中基线的重要影响因素。与APOE4非携带者相比，APOE4纯合携带者的平均基线淀粉样蛋白水平升高。这些结果证明了AD连续过程中淀粉样斑块的自然进展情况。
