Amyloid precursor protein metabolism and inflammation markers in preclinical Alzheimer disease
Amyloid precursor protein metabolism and inflammation markers in preclinical Alzheimer disease
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DOI：
10.1212/wnl.0000000000001859
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发表时间：
2015-08-18
期刊：
影响因子：
9.9
通讯作者：
Lleo, Alberto
中科院分区：
文献类型：
--
作者：
Alcolea, Daniel;Martinez-Lage, Pablo;Lleo, Alberto
目的：研究阿尔茨海默病(AD)临床前阶段和疑似非阿尔茨海默病(SNAP)患者脑脊液中与淀粉样前体蛋白加工、神经元损伤和神经炎症有关的标志物。方法：收集266名认知正常志愿者的脑脊液，研究淀粉样前体蛋白加工(Aβ42、Sappβ、β-分泌酶活性)、神经元损伤(总tau[t-tau]、p-tau])和神经炎症(YKL-40)。我们分析了生物标记物、临床变量和APOE基因型之间的关系，并比较了国家老年-阿尔茨海默病协会分类的临床前阶段的生物标记物水平：0、1、2、3期和SNAP。结果：整个队列中的中位年龄为58.8岁(范围39.8-81.6)。2-3期和SNAP患者的YKL-40水平高于0期和1期患者。SNAP患者的Sappβ水平高于0期和1期患者。0、1和2-3期患者的Sappβ和脑脊液中β-分泌酶活性无差异。年龄与t-tau、p-tau、YKL-40相关。它也与Aβ42相关，但仅在APOE epsilon 4携带者中相关。在Aβ42正常的受试者中，Aβ42与t-tau、sappβ和YKL-40呈正相关。结论：在AD和SNAP的临床前期，中枢神经系统的炎症反应增加，并与神经退行性改变的标志物密切相关。Sappβ和β-分泌酶活性不是临床前AD的有用诊断或分期标记物。
Objective:To investigate CSF markers involved in amyloid precursor protein processing, neuronal damage, and neuroinflammation in the preclinical stages of Alzheimer disease (AD) and participants with suspected non-Alzheimer pathology (SNAP).Methods:We collected CSF from 266 cognitively normal volunteers participating in a cross-sectional multicenter study (the SIGNAL study) to investigate markers involved in amyloid precursor protein processing (A beta 42, sAPP beta, beta-secretase activity), neuronal damage (total-tau [t-tau], phospho-tau [p-tau]), and neuroinflammation (YKL-40). We analyzed the relationship among biomarkers, clinical variables, and the APOE genotype, and compared biomarker levels across the preclinical stages of the National Institute on Aging-Alzheimer's Association classification: stage 0, 1, 2, 3, and SNAP.Results:The median age in the whole cohort was 58.8 years (range 39.8-81.6). Participants in stages 2-3 and SNAP had higher levels of YKL-40 than those in stages 0 and 1. Participants with SNAP had higher levels of sAPP beta than participants in stage 0 and 1. No differences were found between stages 0, 1, and 2-3 in sAPP beta and beta-secretase activity in CSF. Age correlated with t-tau, p-tau, and YKL-40. It also correlated with A beta 42, but only in APOE epsilon 4 carriers. A beta 42 correlated positively with t-tau, sAPP beta, and YKL-40 in participants with normal A beta 42.Conclusions:Our findings suggest that inflammation in the CNS increases in normal aging and is intimately related to markers of neurodegeneration in the preclinical stages of AD and SNAP. sAPP beta and beta-secretase activity are not useful diagnostic or staging markers in preclinical AD.