肌萎缩性脊髓侧索硬化症的 microRNA 诊断生物标志物。

IF 4.1 Q1 CLINICAL NEUROLOGY Brain communications Pub Date : 2024-09-13 eCollection Date: 2024-01-01 DOI:10.1093/braincomms/fcae268
Sandra Anne Banack, Rachael A Dunlop, Paul Mehta, Hiroshi Mitsumoto, Stewart P Wood, Moon Han, Paul Alan Cox
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引用次数: 0

摘要

肌萎缩侧索硬化症的血液诊断生物标志物将改善患者的预后,并对新药开发产生积极影响。开发此类生物标记物的关键在于利用足够的样本量和神经系统疾病比较血液样本进行稳健的方法验证、优化和复制。我们试图测试从不同样本中提取的肌萎缩侧索硬化症生物标记物,以确定它是否具有疾病特异性。我们从确诊为肌萎缩侧索硬化症、原发性侧索硬化症、帕金森病患者和健康对照组的血浆中提取了细胞外囊泡。采用免疫亲和纯化技术产生了富含神经的细胞外囊泡部分。使用实时聚合酶链反应测量了不同样本组群的微RNA。采用 Kruskal-Wallis 检验评估血浆 microRNAs 的差异,然后采用事后 Mann-Whitney 检验比较疾病组别。使用机器学习算法和逻辑回归模型确定诊断准确性。我们确定了肌萎缩侧索硬化症患者血液样本的八种 microRNA 诊断特征,其灵敏度和特异性都很高,曲线下面积计算值为 98%,与神经系统对照组有明显的统计学区分。鉴定出的 8 个 microRNA 代表了与肌萎缩侧索硬化症一致的疾病相关生物过程。基因折叠调节的方向和幅度在四个独立的患者队列中是一致的,在两个实验室对不同的样本和样本收集程序进行了实时聚合酶链反应分析。我们认为,这种诊断特征可以帮助神经科医生补充目前用于诊断肌萎缩性脊髓侧索硬化症的临床指标。
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A microRNA diagnostic biomarker for amyotrophic lateral sclerosis.

Blood-based diagnostic biomarkers for amyotrophic lateral sclerosis will improve patient outcomes and positively impact novel drug development. Critical to the development of such biomarkers is robust method validation, optimization and replication with adequate sample sizes and neurological disease comparative blood samples. We sought to test an amyotrophic lateral sclerosis biomarker derived from diverse samples to determine if it is disease specific. Extracellular vesicles were extracted from blood plasma obtained from individuals diagnosed with amyotrophic lateral sclerosis, primary lateral sclerosis, Parkinson's disease and healthy controls. Immunoaffinity purification was used to create a neural-enriched extracellular vesicle fraction. MicroRNAs were measured across sample cohorts using real-time polymerase chain reaction. A Kruskal-Wallis test was used to assess differences in plasma microRNAs followed by post hoc Mann-Whitney tests to compare disease groups. Diagnostic accuracy was determined using a machine learning algorithm and a logistic regression model. We identified an eight-microRNA diagnostic signature for blood samples from amyotrophic lateral sclerosis patients with high sensitivity and specificity and an area under the curve calculation of 98% with clear statistical separation from neurological controls. The eight identified microRNAs represent disease-related biological processes consistent with amyotrophic lateral sclerosis. The direction and magnitude of gene fold regulation are consistent across four separate patient cohorts with real-time polymerase chain reaction analyses conducted in two laboratories from diverse samples and sample collection procedures. We propose that this diagnostic signature could be an aid to neurologists to supplement current clinical metrics used to diagnose amyotrophic lateral sclerosis.

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