Multiple Biomarkers and Risk of Clinical and Subclinical Vascular Brain Injury The Framingham Offspring Study

Background-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. Methods and Results-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 (beta = -0.21 per 1-SD increment; P = 0.008), D-dimer (beta = -0.18 per 1-SD increment; P = 0.041), total homocysteine (beta = -0.21 per 1-SD increment; P = 0.005), and urinary albumin/creatinine ratio (beta = -0.15 per 1-SD increment; P = 0.042) were associated with lower total cerebral brain volume. Conclusion-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. (Circulation. 2012;125:2100-2107.)