Because of the increasing life expectancy in our society, aging-related neurodegenerative disorders are one of the main issues in global health. Most of these diseases are characterized by the deposition of misfolded proteins and a progressive cognitive decline. Among these diseases, Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) are the most common types of degenerative dementia. Although both show specific features, an important neuropathological and clinical overlap between them hampers their correct diagnosis. In this work, we identified molecular biomarkers aiming to improve the misdiagnosis between both diseases. Plasma extracellular vesicles (EVs) -from DLB, AD and healthy controls- were isolated using size-exclusion chromatography (SEC) and characterized by flow cytometry, Nanoparticle Tracking Analysis (NTA) and cryo-electron microscopy. Next Generation Sequencing (NGS) and related bibliographic search was performed and a selected group of EV-associated microRNAs (miRNAs) was analysed by qPCR. Results uncovered two miRNAs (hsa-miR-451a and hsa-miR-21-5p) significantly down-regulated in AD samples respect to DLB patients, and a set of four miRNAs (hsa-miR-23a-3p, hsa-miR-126-3p, hsa-let-7i-5p, and hsa-miR-151a-3p) significantly decreased in AD respect to controls. The two miRNAs showing decreased expression in AD in comparison to DLB provided area under the curve (AUC) values of 0.9 in ROC curve analysis, thus suggesting their possible use as biomarkers to discriminate between both diseases. Target gene analysis of these miRNAs using prediction online tools showed accumulation of phosphorylation enzymes, presence of proteasome-related proteins and genes involved in cell death among others. Our data suggest that plasma-EV associated miRNAs may reflect a differential profile for a given dementia-related disorder which, once validated in larger cohorts of patients, could help to improve the differential diagnosis of DLB versus AD.

中文翻译：

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阿尔茨海默病和路易体痴呆中血浆来源细胞外囊泡中 microRNA 谱的探索性研究

由于我们社会的预期寿命不断增加，与衰老相关的神经退行性疾病是全球健康的主要问题之一。大多数这些疾病的特征在于错误折叠的蛋白质的沉积和进行性认知衰退。在这些疾病中，阿尔茨海默病（AD）和路易体痴呆（DLB）是最常见的退行性痴呆类型。尽管两者都显示出特定的特征，但它们之间的重要神经病理学和临床重叠阻碍了它们的正确诊断。在这项工作中，我们确定了旨在改善两种疾病之间误诊的分子生物标志物。血浆细胞外囊泡 (EV) - 来自 DLB、AD 和健康对照 - 使用尺寸排阻色谱 (SEC) 分离并通过流式细胞术进行表征，纳米粒子追踪分析 (NTA) 和低温电子显微镜。进行了下一代测序 (NGS) 和相关的书目搜索，并通过 qPCR 分析了一组选定的 EV 相关 microRNA (miRNA)。结果发现两种 miRNA（hsa-miR-451a 和 hsa-miR-21-5p）在 DLB 患者的 AD 样本中显着下调，一组四种 miRNA（hsa-miR-23a-3p、hsa-miR- 126-3p、hsa-let-7i-5p 和 hsa-miR-151a-3p) 在 AD 中相对于对照组显着降低。与 DLB 相比，两种 miRNA 在 AD 中的表达降低，在 ROC 曲线分析中提供了 0.9 的曲线下面积 (AUC) 值，因此表明它们可能用作区分两种疾病的生物标志物。使用预测在线工具对这些 miRNA 的靶基因分析显示磷酸化酶的积累，蛋白酶体相关蛋白和参与细胞死亡的基因的存在。我们的数据表明，血浆-EV 相关 miRNA 可能反映给定痴呆相关疾病的差异特征，一旦在更大的患者群体中得到验证，可能有助于改善 DLB 与 AD 的鉴别诊断。