Multiple Biomarkers and Risk of Clinical and Subclinical Vascular Brain InjuryClinical Perspective
The Framingham Offspring Study
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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 (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.
- Received September 11, 2010.
- Accepted March 15, 2012.
- © 2012 American Heart Association, Inc.