Novel CSF biomarkers for Alzheimer's disease and mild cognitive impairment
Novel CSF biomarkers for Alzheimer's disease and mild cognitive impairment
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DOI：
10.1007/s00401-010-0667-0
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发表时间：
2010-06-01
影响因子：
12.7
通讯作者：
Trojanowski, John Q.
中科院分区：
文献类型：
--
作者：
Hu, William T.;Chen-Plotkin, Alice;Trojanowski, John Q.
与阿尔茨海默病（AD）相关的脑脊液（CSF）肽水平的改变与病理AD诊断相关，尽管认知正常的受试者也可能具有这些AD生物标志物的异常水平。为了确定新的CSF生物标志物，区分病理证实的AD认知正常的受试者和其他神经退行性疾病的患者，我们收集了66例AD患者和25例其他神经退行性痴呆患者的死前CSF样本，随后纵向神经病理学确认，加上33名认知正常的受试者的CSF。我们通过富含细胞因子、趋化因子和生长因子的靶向多重组以及已建立的AD CSF生物标志物（A β 42、tau和p-tau水平）测量了151种新型分析物的水平（181）。鉴定了两类生物标志物：（1）特异性区分AD（尤其是CSF A β 42水平）与认知正常受试者和其他病症的分析物;和（2）在多种疾病中改变的分析物（NrCAM、PDGF、C3、IL-1 α），但在认知正常受试者中不改变。一项多方面的分析方法显示，通过传统AD生物标志物和新型多重生物标志物的组合，AD患者与非AD病例（包括认知正常受试者和患有其他神经退行性疾病的患者）的最佳区分。在38例轻度认知障碍受试者中，6种新型生物标志物（C3、CgA、IL-1 α、I-309、NrCAM和VEGF）与CSF采集时认知障碍的严重程度相关，IL-1 α和TECK水平的改变与随后的认知下降相关。总之，我们的靶向蛋白质组学筛选揭示了新的CSF生物标志物，可以通过单独建立的生物标志物改善AD和非AD病例之间的区别。
Altered levels of cerebrospinal fluid (CSF) peptides related to Alzheimer's disease (AD) are associated with pathologic AD diagnosis, although cognitively normal subjects can also have abnormal levels of these AD biomarkers. To identify novel CSF biomarkers that distinguish pathologically confirmed AD from cognitively normal subjects and patients with other neurodegenerative disorders, we collected antemortem CSF samples from 66 AD patients and 25 patients with other neurodegenerative dementias followed longitudinally to neuropathologic confirmation, plus CSF from 33 cognitively normal subjects. We measured levels of 151 novel analytes via a targeted multiplex panel enriched in cytokines, chemokines and growth factors, as well as established AD CSF biomarkers (levels of A beta 42, tau and p-tau(181)). Two categories of biomarkers were identified: (1) analytes that specifically distinguished AD (especially CSF A beta 42 levels) from cognitively normal subjects and other disorders; and (2) analytes altered in multiple diseases (NrCAM, PDGF, C3, IL-1 alpha), but not in cognitively normal subjects. A multi-prong analytical approach showed AD patients were best distinguished from non-AD cases (including cognitively normal subjects and patients with other neurodegenerative disorders) by a combination of traditional AD biomarkers and novel multiplex biomarkers. Six novel biomarkers (C3, CgA, IL-1 alpha, I-309, NrCAM and VEGF) were correlated with the severity of cognitive impairment at CSF collection, and altered levels of IL-1 alpha and TECK associated with subsequent cognitive decline in 38 longitudinally followed subjects with mild cognitive impairment. In summary, our targeted proteomic screen revealed novel CSF biomarkers that can improve the distinction between AD and non-AD cases by established biomarkers alone.