Department of Psychiatry and Psychotherapy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.
PLoS One. 2018 May 10;13(5):e0197329. doi: 10.1371/journal.pone.0197329. eCollection 2018.
Information on circulating miRNAs in frontotemporal lobar degeneration is very limited and conflicting results have complicated an interpretation in Alzheimer's disease thus far. In the present study we I) collected samples from multiple clinical centers across Germany, II) defined 3 homogenous patient groups with high sample sizes (bvFTD n = 48, AD n = 48 and cognitively healthy controls n = 44), III) compared expression levels in both CSF and serum samples and IV) detected a limited set of miRNAs by using a MIQE compliant protocol based on SYBR-green miRCURY assays that have proven reliable to generate reproducible results. We included several quality controls that identified and reduced technical variation to increase the reliability of our data. We showed that the expression levels of circulating miRNAs measured in CSF did not correlate with levels in serum. Using cluster analysis we found expression pattern in serum that, in part, reflects the genomic organization and affiliation to a specific miRNA family and that were specifically altered in bvFTD, AD, and control groups. Applying factor analysis we identified a 3-factor model characterized by a miRNA signature that explained 80% of the variance classifying healthy controls with 97%, bvFTD with 77% and AD with 72% accuracy. MANOVA confirmed signals like miR-320a and miR-26b-5p at BH corrected significance that contributed most to discriminate bvFTD cases with 96% sensitivity and 90% specificity and AD cases with 89% sensitivity and specificity compared to healthy controls, respectively. Correlation analysis revealed that miRNAs from the 3-factor model also correlated with levels of protein biomarker amyloid-beta1-42 and phosphorylated neurofilament heavy chain, indicating their potential role in the monitoring of progressive neuronal degeneration. Our data show that miRNAs can be reproducibly measured in serum and CSF without pre-amplification and that serum includes higher expressed signals that demonstrate an overall better ability to classify bvFTD, AD and healthy controls compared to signals detected in CSF.
关于额颞叶变性中循环 miRNA 的信息非常有限，到目前为止，阿尔茨海默病的结果相互矛盾，使得解释变得复杂。在本研究中，我们：I）从德国多个临床中心收集样本；II）定义了 3 个具有大样本量的同质患者组（额颞叶痴呆 n = 48，AD n = 48 和认知健康对照 n = 44）；III）比较了 CSF 和血清样本中的表达水平；IV）使用基于 SYBR 绿色 miRCURY 测定的符合 MIQE 协议的有限 miRNA 检测，该协议已被证明可靠，可产生可重复的结果。我们纳入了多个质量控制措施，这些措施可以识别和减少技术变异，以提高数据的可靠性。我们表明，CSF 中测量的循环 miRNA 的表达水平与血清中的水平不相关。通过聚类分析，我们发现血清中的表达模式在一定程度上反映了基因组组织和与特定 miRNA 家族的隶属关系，并且在 bvFTD、AD 和对照组中特异性改变。应用因子分析，我们确定了一个由 miRNA 特征解释 80%方差的 3 因子模型，该模型以 97%的准确率将健康对照者分类，以 77%的准确率将 bvFTD 患者分类，以 72%的准确率将 AD 患者分类。MANOVA 证实了像 miR-320a 和 miR-26b-5p 这样的信号在 BH 校正的显著水平上，它们对区分 bvFTD 病例具有 96%的敏感性和 90%的特异性，对 AD 病例具有 89%的敏感性和特异性，与健康对照者相比，分别。相关性分析表明，3 因子模型中的 miRNA 也与蛋白生物标志物淀粉样蛋白-β 1-42 和磷酸化神经丝重链的水平相关，表明它们在监测进行性神经元变性方面具有潜在作用。我们的数据表明，miRNA 可以在未经预扩增的情况下在血清和 CSF 中重复测量，并且血清中包含更高表达的信号，与 CSF 中检测到的信号相比，其总体分类 bvFTD、AD 和健康对照者的能力更好。
