Howe Matthew D, Zhu Liang, Sansing Lauren H, Gonzales Nicole R, McCullough Louise D, Edwards Nancy J
Department of Neurology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, United States.
Department of Neurology, Yale University School of Medicine, New Haven, CT, United States.
Front Neurol. 2018 Sep 7;9:746. doi: 10.3389/fneur.2018.00746. eCollection 2018.
Intracerebral hemorrhage (ICH) is a stroke subtype associated with high disability and mortality. There is a clinical need for blood-based biomarkers that can aid in diagnosis, risk stratification, and prognostication. Given their role in the pathophysiology of ICH, we hypothesized markers of blood-brain barrier disruption and fibrosis would associate with neurologic deterioration and/or long-term functional outcomes. We also hypothesized these markers may be unique in patients with ICH due to cerebral amyloid angiopathy (CAA) vs. other etiologies. Seventy-nine patients enrolled in prospective ICH registries at two separate hospitals (the University of Texas Health Science Center at Houston and Hartford Hospital) were included in this study. We assessed initial injury severity and admission variables along with measures of inpatient deterioration (hematoma expansion, perihematomal edema (PHE), and early and delayed neurologic deterioration) and functional outcome [modified Rankin Scale (mRS) score at discharge and 90 days]. Serial biospecimens were obtained at 5 pre-specified timepoints (within 24 h, 1-2, 3-5, 6-8, and 10 days); serum samples were analyzed for fibronectin, all three TGF-β isoforms, and 7 matrix metalloproteinases (MMPs). In our initial correlation analysis, MMP 10 and 3 were associated with hematoma expansion and early neurologic deterioration, whereas MMP 8 and MMP 1 were associated with PHE and delayed neurologic deterioration (respectively). Subacute levels of MMP 8 (sampled from day 6-10) positively correlated with PHE even after adjusting for multiple comparisons ( = 0.02). Acute levels of MMP 1, TGF-β1, and TGF-β3 were predictive of functional outcome, with TGF-β1 and TGF-β3 associating with 90 day mRS independent of age, hematoma volume, hemorrhage location, GCS, and IVH [ = 0.02; OR 1.03 (95% CI 1.0-1.05); = 0.03; OR 3.1 (95% CI 1.1-8.8)]. When evaluated together as a panel, the cytokines distinguished patients with ICH due to CAA vs. ICH due to hypertension (AUC 0.81). Serum levels of fibronectin, TGF-β, and MMPs may be useful in refining ICH etiology and prognosis. Further large-scale studies are needed to confirm these findings, particularly regarding patients with CAA.
脑出血（ICH）是一种与高致残率和高死亡率相关的中风亚型。临床上需要基于血液的生物标志物来辅助诊断、风险分层和预后评估。鉴于它们在脑出血病理生理学中的作用，我们推测血脑屏障破坏和纤维化的标志物与神经功能恶化和/或长期功能结局相关。我们还推测，这些标志物在因脑淀粉样血管病（CAA）导致脑出血的患者中可能与其他病因导致的脑出血患者有所不同。本研究纳入了在两家不同医院（休斯顿德克萨斯大学健康科学中心和哈特福德医院）前瞻性脑出血登记处登记的79例患者。我们评估了初始损伤严重程度和入院变量，以及住院期间病情恶化的指标（血肿扩大、血肿周围水肿（PHE）以及早期和延迟神经功能恶化）和功能结局（出院时和90天时的改良Rankin量表（mRS）评分）。在5个预先指定的时间点（24小时内、1 - 2天、3 - 5天、6 - 8天和10天）采集系列生物样本；分析血清样本中的纤连蛋白、三种转化生长因子-β（TGF-β）亚型和7种基质金属蛋白酶（MMPs）。在我们最初的相关性分析中，MMP 10和3与血肿扩大和早期神经功能恶化相关，而MMP 8和MMP 1分别与PHE和延迟神经功能恶化相关。即使在进行多重比较校正后，MMP 8的亚急性期水平（第6 - 10天采集）与PHE仍呈正相关（P = 0.02）。MMP 1、TGF-β1和TGF-β3的急性期水平可预测功能结局，TGF-β1和TGF-β3与90天mRS相关，独立于年龄、血肿体积、出血部位、格拉斯哥昏迷量表（GCS）和脑室内出血（IVH）[P = 食 0.02；OR 1.03（95% CI 1.0 - 1.05）；P = 0.03；OR 3.1（95% CI 1.1 - 8.8）]。当作为一个组合进行评估时，这些细胞因子可区分CAA导致的脑出血患者和高血压导致的脑出血患者（曲线下面积为0.81）。纤连蛋白、TGF-β和MMPs的血清水平可能有助于明确脑出血的病因和预后。需要进一步的大规模研究来证实这些发现，特别是关于CAA患者的研究。
