Lu Alex Y, Damisah Eyiyemisi C, Winkler Ethan A, Grant Ryan A, Eid Tore, Bulsara Ketan R
a Department of Neurological Surgery , University of California San Francisco , San Francisco , CA , USA.
b Department of Neurosurgery , Yale School of Medicine , New Haven , CT , USA.
Br J Neurosurg. 2018 Dec;32(6):637-641. doi: 10.1080/02688697.2018.1519107. Epub 2018 Dec 26.
Despite advancements in medical and surgical therapies, clinical outcomes of aneurysmal subarachnoid hemorrhage (aSAH) continue to be poor. Currently, aSAH pathophysiology remains poorly understood. No aSAH biomarkers are commonly used in the clinical setting. This exploratory study used metabolomics profiling to identify global metabolic changes and metabolite predictors of long-term outcome using cerebrospinal fluid (CSF) samples of aSAH patients.
Gas chromatography time-of-flight mass spectrometry was applied to CSF samples collected from 15 consecutive high-grade aSAH patients (modified Fisher grade 3 or 4). Collected CSF samples were analyzed at two time points (admission and the anticipated vasospasm timeframe). Metabolite levels at both time points were compared and correlated with vasospasm status and Glasgow Outcome Scale (GOS) of patients at 1 year post-aSAH. Significance level was defined as p < 0.05 with false discovery rate correction for multiple comparisons.
Of 97 metabolites identified, 16 metabolites, primarily free amino acids, significantly changed between the two time points. These changes were magnified in modified Fisher grade 4 compared with grade 3. Six metabolites (2-hydroxyglutarate, tryptophan, glycine, proline, isoleucine, and alanine) correlated with GOS at 1 year post-aSAH independent of vasospasm status. When predicting patients who had low disability (GOS 5 vs. GOS ≤4), 2-hydroxyglutarate had a sensitivity and specificity of 0.89 and 0.83 respectively.
Our preliminary study suggests that specific metabolite changes occur in the brain during the course of aSAH and that quantification of specific CSF metabolites may be used to predict long-term outcome in patients with aSAH. This is the first study to implicate 2-hydroxyglutarate, a known marker of tissue hypoxia, in aSAH pathogenesis.
尽管医学和外科治疗取得了进展，但动脉瘤性蛛网膜下腔出血（aSAH）的临床结局仍然很差。目前，aSAH的病理生理学仍知之甚少。临床上尚未普遍使用aSAH生物标志物。这项探索性研究使用代谢组学分析，通过aSAH患者的脑脊液（CSF）样本识别整体代谢变化和长期预后的代谢物预测指标。
采用气相色谱飞行时间质谱法对15例连续的重度aSAH患者（改良Fisher分级3级或4级）采集的CSF样本进行分析。在两个时间点（入院时和预期的血管痉挛时间窗）对采集的CSF样本进行分析。比较两个时间点的代谢物水平，并与aSAH后1年患者的血管痉挛状态和格拉斯哥预后量表（GOS）进行相关性分析。显著性水平定义为p < 0.05，并对多重比较进行错误发现率校正。
在鉴定出的97种代谢物中，有16种代谢物（主要是游离氨基酸）在两个时间点之间有显著变化。与3级相比，这些变化在改良Fisher 4级中更为明显。六种代谢物（2-羟基戊二酸、色氨酸、甘氨酸、脯氨酸、异亮氨酸和丙氨酸）与aSAH后1年的GOS相关，且与血管痉挛状态无关。在预测低残疾患者（GOS 5级与GOS≤4级）时，2-羟基戊二酸的敏感性和特异性分别为0.89和0.83。
我们的初步研究表明，在aSAH病程中大脑会发生特定的代谢物变化，特定脑脊液代谢物的定量分析可用于预测aSAH患者的长期预后。这是第一项将已知的组织缺氧标志物2-羟基戊二酸与aSAH发病机制联系起来的研究。
