Swanson Ashley, Willette A A
Department of Food Science and Human Nutrition, Iowa State University, Ames, IA, United States.
Department of Food Science and Human Nutrition, Iowa State University, Ames, IA, United States; Department of Psychology, Iowa State University, Ames, IA, United States; Aging Mind and Brain Institute, University of Iowa, Iowa City, IA, United States.
Brain Behav Immun. 2016 Nov;58:201-208. doi: 10.1016/j.bbi.2016.07.148. Epub 2016 Jul 18.
Chronic neuroinflammation is thought to potentiate medial temporal lobe (MTL) atrophy and memory decline in Alzheimer's disease (AD). It has become increasingly important to find novel immunological biomarkers of neuroinflammation or other processes that can track AD development and progression. Our study explored which pro- or anti-inflammatory cerebrospinal fluid (CSF) biomarkers best predicted AD neuropathology over 24months. Using Alzheimer's Disease Neuroimaging Initiative data (N=285), CSF inflammatory biomarkers from mass spectrometry and multiplex panels were screened using stepwise regression, followed up with 50%/50% model retests for validation. Neuronal Pentraxin 2 (NPTX2) and Chitinase-3-like-protein-1 (C3LP1), biomarkers of glutamatergic synaptic plasticity and microglial activation respectively, were the only consistently significant biomarkers selected. Once these biomarkers were selected, linear mixed models were used to analyze their baseline and longitudinal associations with bilateral MTL volume, memory decline, global cognition, and established AD biomarkers including CSF amyloid and tau. Higher baseline NPTX2 levels corresponded to less MTL atrophy [R=0.287, p<0.001] and substantially less memory decline [R=0.560, p<0.001] by month 24. Conversely, higher C3LP1 modestly predicted more MTL atrophy [R=0.083, p<0.001], yet did not significantly track memory decline over time. In conclusion, NPTX2 is a novel pro-inflammatory cytokine that predicts AD-related outcomes better than any immunological biomarker to date, substantially accounting for brain atrophy and especially memory decline. C3LP1 as the microglial biomarker, by contrast, performed modestly and did not predict longitudinal memory decline. This research may advance the current understanding of AD etiopathogenesis, while expanding early diagnostic techniques through the use of novel pro-inflammatory biomarkers, such as NPTX2. Future studies should also see if NPTX2 causally affects MTL morphometry and memory performance.
慢性神经炎症被认为会加剧阿尔茨海默病（AD）患者的内侧颞叶（MTL）萎缩和记忆衰退。寻找能够追踪AD发展和进程的神经炎症或其他过程的新型免疫生物标志物变得越来越重要。我们的研究探讨了哪些促炎或抗炎脑脊液（CSF）生物标志物能在24个月内最佳预测AD神经病理学。利用阿尔茨海默病神经影像学倡议数据（N = 285），通过逐步回归筛选了来自质谱和多重检测板的CSF炎症生物标志物，并进行50%/50%模型重测以进行验证。分别作为谷氨酸能突触可塑性和小胶质细胞激活生物标志物的神经元五聚体蛋白2（NPTX2）和几丁质酶3样蛋白1（C3LP1）是唯一一致显著的入选生物标志物。一旦选定这些生物标志物，就使用线性混合模型分析它们与双侧MTL体积、记忆衰退、整体认知以及包括CSF淀粉样蛋白和tau在内的既定AD生物标志物的基线和纵向关联。较高的基线NPTX2水平对应较少的MTL萎缩[R = 0.287，p < 0.001]，到第24个月时记忆衰退也显著较少[R = 0.560，p < 0.001]。相反，较高的C3LP1适度预测了更多的MTL萎缩[R = 0.083，p < 0.001]，但随着时间推移并未显著追踪记忆衰退。总之，NPTX2是一种新型促炎细胞因子，比迄今为止的任何免疫生物标志物都能更好地预测AD相关结果，在很大程度上解释了脑萎缩，尤其是记忆衰退。相比之下，作为小胶质细胞生物标志物的C3LP1表现一般，并未预测纵向记忆衰退。这项研究可能会推进目前对AD病因发病机制的理解，同时通过使用新型促炎生物标志物（如NPTX2）扩展早期诊断技术。未来的研究还应探究NPTX2是否对MTL形态测量和记忆表现有因果影响。
