NEW YORK – Nonprofit research organization Brain Chemistry Labs has identified a set of eight microRNAs that may speed up the diagnosis of amyotrophic lateral sclerosis (ALS) and help to differentiate it from other neurodegenerative disorders.

纽约——非营利研究组织脑化学实验室（Brain Chemistry Labs）已鉴定出一组八种microRNA，它们可能加速肌萎缩侧索硬化症（ALS）的诊断，并有助于将其与其他神经退行性疾病区分开。

The Jackson Hole, Wyoming-based institution published a confirmatory study of their earlier work identifying this biomarker on Thursday in the journal Brain Communications and is now in discussions with potential commercialization partners to bring the test to market in the next 18 to 24 months.

总部位于怀俄明州杰克逊霍尔的研究所周四在《大脑通讯》杂志上发表了一项关于他们早期鉴定这种生物标志物的工作的验证性研究，目前正在与潜在的商业化合作伙伴进行讨论，以在未来18至24个月内将该测试推向市场。

ALS, also known as Lou Gehrig's disease, is a rare and fatal neurodegenerative illness. Over the course of the disease, motor neurons deteriorate, resulting in the progressive loss of muscle control. Respiratory failure caused by the loss of control over the muscles responsible for breathing is the leading cause of death in ALS, and few treatments specific to the disorder exist..

ALS，也称为Lou Gehrig病，是一种罕见且致命的神经退行性疾病。在疾病过程中，运动神经元恶化，导致肌肉控制逐渐丧失。由于失去对负责呼吸的肌肉的控制而导致的呼吸衰竭是ALS死亡的主要原因，并且很少有针对该疾病的治疗方法。。

The highly variable clinical presentation of ALS complicates diagnosis and drives the need for more accurate biomarkers, particularly fluid-based ones, as symptoms can make neuroimaging uncomfortable for patients and sometimes cannot distinguish between ALS and other neuropathies, such as primary lateral sclerosis and Parkinson's disease..

ALS的高度可变的临床表现使诊断复杂化，并促使人们需要更准确的生物标志物，特别是基于液体的标志物，因为症状会使患者神经影像学不舒服，有时无法区分ALS和其他神经病变，如原发性侧索硬化症和帕金森氏病。。

To search for such biomarkers, a team of scientists with Brain Chemistry Labs turned their attention to exosomes, small lipid-bound particles released into circulation by cells.

为了寻找这样的生物标志物，大脑化学实验室的一组科学家将注意力转向外泌体，即细胞释放到循环中的脂质结合的小颗粒。

Sandra Banack, senior scientist at Brain Chemistry Labs and the first author of the study, explained that exosomes carry protein markers on their surface that are specific to their cells of origin, in this case, brain tissue. 'Material that comes from neurological tissue has a biomarker,' she said, 'and we use those markers to see which of these exosomes are coming from the brain.'.

脑化学实验室的资深科学家、该研究的第一作者桑德拉·巴纳克解释说，外泌体表面带有特定于其起源细胞（本例中为脑组织）的蛋白质标记“来自神经组织的物质有一个生物标志物，”她说，“我们使用这些标志物来观察哪些外来体来自大脑。”。

Rachael Dunlop, a senior research fellow at the institute and a coauthor of the study, added that the phospholipid bilayer surrounding exosomes plays a critical function in making them attractive targets for liquid biopsies.

该研究所高级研究员、该研究的合著者雷切尔·邓洛普补充说，外泌体周围的磷脂双层在使其成为液体活检的有吸引力的靶标方面起着至关重要的作用。

'MicroRNA is highly susceptible to degradation from [circulating] nucleases,' she said. 'The fact that it's contained in this phospholipid bilayer protects it, not just in situ but once it comes out of the patient. It doesn't break down in transit, or because someone left the plasma on the bench and went for a cup of tea or something.' .

她说：“MicroRNA极易被[循环]核酸酶降解。”它包含在磷脂双层中的事实不仅可以在原位保护它，而且可以在它从患者体内出来后保护它。它不会在运输过程中发生故障，也不会因为有人把血浆留在了板凳上，去喝杯茶什么的。”。

In their retrospective study, Banack, Dunlop, and their colleagues used immunoaffinity purification to extract exosomes found in blood samples from 119 individuals diagnosed with amyotrophic lateral sclerosis, 42 with primary lateral sclerosis, and 20 with Parkinson's disease, along with 150 healthy controls.

在他们的回顾性研究中，Banack，Dunlop及其同事使用免疫亲和纯化从119名被诊断患有肌萎缩侧索硬化症的个体，42名患有原发性侧索硬化症的个体和20名患有帕金森氏病的个体以及150名健康对照者的血液样本中提取外泌体。

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The eight ALS-specific miRNAs that the Brain Chemistry Labs team identified came from two prior publications. In the first, published in Open Biology, two 20-person cohorts of 10 ALS patients and 10 healthy controls each led to the discovery of 101 neural-associated miRNAs that differed significantly between cases and controls..

大脑化学实验室小组确定的八种ALS特异性miRNA来自之前的两篇出版物。。。

'Critically, they were all patients who had been diagnosed by the same neurologist and collected under a very specific protocol,' Dunlop said.

邓洛普说：“至关重要的是，这些患者都是由同一位神经科医生诊断出来的，并按照非常具体的方案收集的。”。

In the second study, published in the Journal of the Neurological Sciences, the researchers obtained 100 samples from the US National ALS Biorepository, comprising 50 samples from people diagnosed with ALS and 50 healthy controls.

在发表在《神经科学杂志》上的第二项研究中，研究人员从美国国家ALS生物储存库获得了100个样本，其中包括50个来自被诊断患有ALS的人和50个健康对照的样本。

'[That] biorepository has a wide range of samples,' Dunlop said, including ones that were collected via different protocols, were stored differently, and were from patients diagnosed by different neurologists.

邓洛普说：“生物储存库的样本范围很广，包括通过不同方案收集的样本，它们的存储方式不同，来自不同神经科医生诊断的患者。”。

Dunlop and her colleagues used this dataset to narrow down the set of candidate biomarkers from the earlier set of 101 miRNAs to 34 that were the most differentially expressed between individuals diagnosed with ALS and healthy controls. The Brain Chemistry Labs team further whittled these down to eight miRNAs that most consistently separated ALS samples from control samples with the strongest statistical significance, which they then used in the latest study.

Dunlop和她的同事使用这个数据集将候选生物标志物的范围从早期的101个miRNA缩小到34个，这些miRNA在诊断为ALS的个体和健康对照之间差异最大。大脑化学实验室的研究小组进一步将其缩减为8个miRNA，这些miRNA最一致地将ALS样本与具有最强统计学意义的对照样本分开，然后将其用于最新研究。

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Dunlop said that in the current Brain Communications study, 'we've now been able to incorporate neurological diseases that are similar [to ALS] in their symptoms, in the early stages of disease.'

邓洛普说，在目前的大脑交流研究中，“我们现在能够在疾病的早期阶段将类似于ALS的神经系统疾病纳入其症状中。”

The comparison to other neurological disorders is vital for ALS biomarker development, she explained, because diagnosis currently relies heavily on observing how symptoms progress.

她解释说，与其他神经系统疾病的比较对于ALS生物标志物的发展至关重要，因为目前的诊断在很大程度上依赖于观察症状的进展。

'This is not ideal for people with ALS,' Dunlop said, 'considering the median life expectancy [post-diagnosis] is about three years. They don't really have time to wait for progression.'

邓洛普说：“考虑到（诊断后）平均预期寿命约为三年，这对ALS患者来说并不理想。他们真的没有时间等待进展。”

Banack and Dunlop tested three different computational approaches –– random forest split, random forest separate cohorts, and logistic regression –– to estimate the accuracy of their miRNA biomarker.

Banack和Dunlop测试了三种不同的计算方法-随机森林分裂，随机森林分离队列和逻辑回归-以估计其miRNA生物标志物的准确性。

'They have very different approaches as to how they use the data to classify whether a patient has or does not have ALS,' Banack said.

巴纳克说：“对于如何使用数据对患者是否患有ALS进行分类，他们有非常不同的方法。”。

Across all methods, sensitivity ranged between 96 percent and 100 percent, and specificity was consistently 97 percent. While Banack said that these numbers are likely to change as the biomarker set is further developed into a diagnostic assay, she said the data presented in their current study should give a sense of the range that can be expected.

在所有方法中，敏感性在96%至100%之间，特异性始终为97%。虽然巴纳克说，随着生物标志物集进一步发展成为诊断分析，这些数字可能会发生变化，但她说，他们目前研究中提供的数据应该给出可以预期的范围。

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'And as sample size increases, we're hoping that we can nail that down even further,' she said.

她说：“随着样本量的增加，我们希望能够进一步确定这一点。”。

Sulev Koks, head of epidemiology research at Australia's Murdoch University who specializes in neurodegenerative disorders, praised the study for its methodology and clarity, adding that its focus on miRNA is one of its key strengths, as total RNA analysis can be much more challenging.

澳大利亚默多克大学专门研究神经退行性疾病的流行病学研究负责人Sulev Koks赞扬了这项研究的方法和清晰度，并补充说，它对miRNA的关注是其关键优势之一，因为总RNA分析可能更具挑战性。

He also applauded the use of exosomes as a means of isolating brain-derived miRNA.

他还赞扬使用外泌体作为分离脑源性miRNA的手段。

'The problem with the pathologies affecting the brain is that the brain is non-accessible tissue,' he said. 'We cannot take a biopsy from the brain.'

“影响大脑的病理问题是大脑是不可接近的组织，”他说我们不能进行大脑活检。”

This has created a 'massive gap' in obtaining biosamples from individuals with diseases of the brain, Koks explained, with numerous research efforts underway to figure out how to extract relevant biomarkers from peripheral tissues and blood.

科克斯解释说，这在从患有大脑疾病的个体获得生物样本方面产生了“巨大差距”，目前正在进行大量研究工作，以找出如何从外周组织和血液中提取相关生物标志物。

'Using exosomes makes the analysis more specific and increases accuracy,' he said. 'I think that this is really where the field is moving.'

他说：“使用外泌体可以使分析更加具体，提高准确性。”我认为这才是真正的领域。”

Koks noted that some technological challenges remain to be solved to translate the study's results into the clinical setting, such as developing simpler methods to purify exosomes, which would facilitate its implementation into everyday practice.

Koks指出，将研究结果转化为临床环境仍有待解决一些技术挑战，例如开发更简单的纯化外泌体的方法，这将有助于其在日常实践中的实施。

'But this can be useful for clinical trials and [as] an additional tool for practitioners,' he said.

他说：“但这对临床试验很有用，也可以作为从业者的额外工具。”。

Brain Chemistry Labs intends to develop its miRNA ALS signature into a diagnostic test, with the help of an industry partner.

脑化学实验室打算在行业合作伙伴的帮助下，将其miRNA-ALS特征开发成诊断测试。

'We are speaking with diagnostic companies but have not yet selected one to become our partner,' Banack said.

巴纳克说，我们正在与诊断公司进行谈判，但尚未选择一家成为我们的合作伙伴。