Multiple biomarkers and risk of clinical and subclinical vascular brain injury: The framingham offspring study

Aleksandra Pikula, Alexa S. Beiser, Charles DeCarli, Jayandra J. Himali, Stephanie Debette, Rhoda Au, Jacob Selhub, Geoffrey H. Toffler, Thomas J. Wang, James B. Meigs, Margaret Kelly-Hayes, Carlos S. Kase, Philip A. Wolf, Ramachandran S. Vasan, Sudha Seshadri

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2100-2107
Number of pages8
JournalCirculation
Volume125
Issue number17
DOIs
StatePublished - May 1 2012

Keywords

  • Biological markers
  • Epidemiology
  • Magnetic resonance imaging
  • Primary prevention
  • Risk assessment
  • Stroke

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

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    Pikula, A., Beiser, A. S., DeCarli, C., Himali, J. J., Debette, S., Au, R., Selhub, J., Toffler, G. H., Wang, T. J., Meigs, J. B., Kelly-Hayes, M., Kase, C. S., Wolf, P. A., Vasan, R. S., & Seshadri, S. (2012). Multiple biomarkers and risk of clinical and subclinical vascular brain injury: The framingham offspring study. Circulation, 125(17), 2100-2107. https://doi.org/10.1161/CIRCULATIONAHA.110.989145