Molecular Biomarker Core, Case Western Reserve University, Cleveland, OH, USA; School of Nursing, Case Western Reserve University, Cleveland, OH, USA.
School of Nursing, Case Western Reserve University, Cleveland, OH, USA.
Neuroscience. 2024 Jul 23;551:79-93. doi: 10.1016/j.neuroscience.2024.05.017. Epub 2024 May 16.
It is increasingly evident that blood biomarkers have potential to improve the diagnosis and management of both acute and chronic neurological conditions. The most well-studied candidates, and arguably those with the broadest utility, are proteins that are highly enriched in neural tissues and released into circulation upon cellular damage. It is currently unknown how the brain expression levels of these proteins is influenced by demographic factors such as sex, race, and age. Given that source tissue abundance is likely a key determinant of the levels observed in the blood during neurological pathology, understanding such influences is important in terms of identifying potential clinical scenarios that could produce diagnostic bias. In this study, we leveraged existing mRNA sequencing data originating from 2,642 normal brain specimens harvested from 382 human donors to examine potential demographic variability in the expression levels of genes which code for 28 candidate blood biomarkers of neurological damage. Existing mass spectrometry data originating from 26 additional normal brain specimens harvested from 26 separate human donors was subsequently used to tentatively assess whether observed transcriptional variance was likely to produce corresponding variance in terms of protein abundance. Genes associated with several well-studied or emerging candidate biomarkers including neurofilament light chain (NfL), ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCH-L1), neuron-specific enolase (NSE), and synaptosomal-associated protein 25 (SNAP-25) exhibited significant differences in expression with respect to sex, race, and age. In many instances, these differences in brain expression align well with and provide a mechanistic explanation for previously reported differences in blood levels.
越来越明显的是，血液生物标志物有可能改善急性和慢性神经状况的诊断和管理。研究最多的候选标志物，也是具有最广泛用途的标志物，是那些在神经组织中高度富集并在细胞损伤时释放到循环中的蛋白质。目前尚不清楚这些蛋白质在大脑中的表达水平如何受到性别、种族和年龄等人口因素的影响。鉴于来源组织的丰度很可能是神经病理学期间血液中观察到的水平的关键决定因素，了解这种影响对于确定可能产生诊断偏差的潜在临床情况很重要。在这项研究中，我们利用了源自 382 名供体的 2642 个正常脑组织的现有 mRNA 测序数据，检查了编码 28 种神经损伤血液生物标志物候选物的基因在表达水平上的潜在人口统计学变异性。随后，使用源自 26 名不同供体的另外 26 个正常脑组织的现有质谱数据，初步评估观察到的转录变异性是否可能在蛋白质丰度方面产生相应的变异性。与几种研究较多或新兴的候选生物标志物相关的基因，包括神经丝轻链 (NfL)、泛素羧基末端水解酶同工酶 L1 (UCH-L1)、神经元特异性烯醇化酶 (NSE) 和突触体相关蛋白 25 (SNAP-25)，在表达方面表现出显著的性别、种族和年龄差异。在许多情况下，这些大脑表达上的差异与之前报道的血液水平差异很好地一致，并提供了一种机制解释。
