The nonlinear relationship between cerebrospinal fluid Aβ42 and tau in preclinical Alzheimer's disease.
The nonlinear relationship between cerebrospinal fluid Aβ42 and tau in preclinical Alzheimer's disease.
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DOI：
10.1371/journal.pone.0191240
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
National Alzheimer’s Coordinating Center
中科院分区：
文献类型：
--
作者：
de Leon MJ;Pirraglia E;Osorio RS;Glodzik L;Saint-Louis L;Kim HJ;Fortea J;Fossati S;Laska E;Siegel C;Butler T;Li Y;Rusinek H;Zetterberg H;Blennow K;Alzheimer’s Disease Neuroimaging Initiative;National Alzheimer’s Coordinating Center
脑脊液（CSF）研究一致表明，在阿尔茨海默病（AD）相关认知功能减退发作前，CSF中淀粉样蛋白β 1 - 42（A β 42）水平降低，tau水平升高。然而，低CSF A β 42水平（脑A β 42沉积的替代物）的临床前预测准确度不高。此外，病理学数据表明tau蛋白病引发的病程与A β引发级联反应的当代临床观点相矛盾。将3个正常老化队列（45 - 90岁）的CSF A β 42和tau数据合并，以检验横断面（n = 766）和纵向（n = 651）假设：1）CSF A β 42和tau水平之间的关系在成人寿命内不是线性的; 2）非线性模型改善了认知下降的预测。支持假设的结果显示，U形二次拟合（A β 2）最佳描述了CSF A β 42与CSF tau水平的关系。此外，我们还发现A β 42与tau蛋白的关系随年龄而变化，在45~70岁之间呈正线性相关，而在71~90岁之间呈负线性相关。二次效应似乎是A β 42独有的，因为A β 38和A β 40仅与年龄和CSF tau呈正线性关系。重要的是，我们观察到，通过考虑高和低水平的A β 42，认知能力下降的预测得到了改善。总体而言，这些数据表明临床前阶段比目前认识到的更早，以CSF tau升高为标志，并伴有A β 42升高或降低。需要进一步研究以检查潜在机制，例如CSF清除失败是A β 42在脑中沉积前升高CSF A β xx分析物水平的常见因素。
Cerebrospinal fluid (CSF) studies consistently show that CSF levels of amyloid-beta 1–42 (Aβ42) are reduced and tau levels increased prior to the onset of cognitive decline related to Alzheimer’s disease (AD). However, the preclinical prediction accuracy for low CSF Aβ42 levels, a surrogate for brain Aβ42 deposits, is not high. Moreover, the pathology data suggests a course initiated by tauopathy contradicting the contemporary clinical view of an Aβ initiated cascade. CSF Aβ42 and tau data from 3 normal aging cohorts (45–90 years) were combined to test both cross-sectional (n = 766) and longitudinal (n = 651) hypotheses: 1) that the relationship between CSF levels of Aβ42 and tau are not linear over the adult life-span; and 2) that non-linear models improve the prediction of cognitive decline. Supporting the hypotheses, the results showed that a u-shaped quadratic fit (Aβ2) best describes the relationship for CSF Aβ42 with CSF tau levels. Furthermore we found that the relationship between Aβ42 and tau changes with age—between 45 and 70 years there is a positive linear association, whereas between 71 and 90 years there is a negative linear association between Aβ42 and tau. The quadratic effect appears to be unique to Aβ42, as Aβ38 and Aβ40 showed only positive linear relationships with age and CSF tau. Importantly, we observed the prediction of cognitive decline was improved by considering both high and low levels of Aβ42. Overall, these data suggest an earlier preclinical stage than currently appreciated, marked by CSF elevations in tau and accompanied by either elevations or reductions in Aβ42. Future studies are needed to examine potential mechanisms such as failing CSF clearance as a common factor elevating CSF Aβxx analyte levels prior to Aβ42 deposition in brain.
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