Multiple Biomarkers and Risk of Clinical and Subclinical Vascular Brain InjuryClinical Perspective: 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 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 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. 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.