Boston University Schools of Medicine and Public Health, MA, USA.
Circulation. 2012 May 1;125(17):2100-7. doi: 10.1161/CIRCULATIONAHA.110.989145. Epub 2012 Mar 28.
Several biomarkers have been individually associated with vascular brain injury, but no prior study has explored the simultaneous association of a biologically plausible panel of biomarkers with the incidence of stroke/transient ischemic attack and the prevalence of subclinical brain injury.
In 3127 stroke-free Framingham offspring (age, 59±10 years; 54% female), we related a panel of 8 biomarkers assessing inflammation (C-reactive protein), hemostasis (D-dimer and plasminogen activator inhibitor-1), neurohormonal activity (aldosterone-to-renin ratio, B-type natriuretic peptide, and N-terminal proatrial natriuretic peptides), and endothelial function (homocysteine and urinary albumin/creatinine ratio) measured at the sixth examination (1995-1998) to risk of incident stroke/transient ischemic attack. In a subset of 1901 participants with available brain magnetic resonance imaging (1999-2005), we further related these biomarkers to total cerebral brain volume, covert brain infarcts, and large white-matter hyperintensity volume. During a median follow-up of 9.2 years, 130 participants experienced incident stroke/transient ischemic attack. In multivariable analyses adjusted for stroke risk factors, the biomarker panel was associated with incident stroke/transient ischemic attack and with total cerebral brain volume (P<0.05 for both) but not with covert brain infarcts or white-matter hyperintensity volume (P>0.05). In backward elimination analyses, higher log-B-type natriuretic peptide (hazard ratio, 1.39 per 1-SD increment; P=0.002) and log-urinary albumin/creatinine ratio (hazard ratio, 1.31 per 1-SD increment; P=0.004) were associated with increased risk of stroke/transient ischemic attack and improved risk prediction compared with the Framingham Stroke Risk Profile alone; when the <5%, 5% to 15%, or >15% 10-year risk category was used, the net reclassification index was 0.109 (P=0.037). Higher C-reactive protein (β=-0.21 per 1-SD increment; P=0.008), D-dimer (β=-0.18 per 1-SD increment; P=0.041), total homocysteine (β=-0.21 per 1-SD increment; P=0.005), and urinary albumin/creatinine ratio (β=-0.15 per 1-SD increment; P=0.042) were associated with lower total cerebral brain volume.
In a middle-aged community sample, we identified multiple biomarkers that were associated with clinical and subclinical vascular brain injury and could improve risk stratification.
已有多项生物标志物被单独证实与血管性脑损伤相关，但目前尚无研究探索具有生物学意义的一组生物标志物联合用于预测中风/短暂性脑缺血发作的发生率及亚临床脑损伤的患病率。
在 3127 例无中风的弗雷明汉后代（年龄 59±10 岁；54%为女性）中，我们将在第六次检查（1995-1998 年）时测量的一组 8 种生物标志物与炎症（C 反应蛋白）、止血（D-二聚体和纤溶酶原激活物抑制剂-1）、神经激素活性（醛固酮与肾素比值、B 型利钠肽和 N 末端脑钠肽）和内皮功能（同型半胱氨酸和尿白蛋白/肌酐比值）相关联，以评估其与中风/短暂性脑缺血发作的发病风险。在 1901 名有可用脑磁共振成像（1999-2005 年）的亚组参与者中，我们进一步将这些生物标志物与总脑容量、隐匿性脑梗死和大的白质高信号体积相关联。在中位随访 9.2 年期间，130 名参与者发生中风/短暂性脑缺血发作。在调整中风危险因素的多变量分析中，生物标志物组合与中风/短暂性脑缺血发作的发生和总脑容量（均 P<0.05）相关，但与隐匿性脑梗死或白质高信号体积无关（均 P>0.05）。在向后淘汰分析中，较高的 B 型利钠肽对数（每增加 1-SD 风险比为 1.39；P=0.002）和尿白蛋白/肌酐比值对数（每增加 1-SD 风险比为 1.31；P=0.004）与中风/短暂性脑缺血发作的风险增加相关，且与单独使用弗雷明汉中风风险评分相比，改善了风险预测；当使用<5%、5%至 15%或>15%的 10 年风险类别时，净重新分类指数为 0.109（P=0.037）。较高的 C 反应蛋白（每增加 1-SD 水平降低 0.21；P=0.008）、D-二聚体（每增加 1-SD 水平降低 0.18；P=0.041）、总同型半胱氨酸（每增加 1-SD 水平降低 0.21；P=0.005）和尿白蛋白/肌酐比值（每增加 1-SD 水平降低 0.15；P=0.042）与总脑容量降低相关。
在中年人群样本中，我们确定了多个与临床和亚临床血管性脑损伤相关的生物标志物，这些标志物可以改善风险分层。
