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/TIA, and the prevalence of subclinical brain injury.
Methods and Results—In 3127 stroke-free Framingham Offspring (59±10 yrs, 54%F), we related a panel of 8 biomarkers assessing inflammation (C-reactive protein[CRP]), hemostasis (D-dimer and plasminogen activator inhibitor-1), neurohormonal activity (aldosterone-to renin ratio, B-type natriuretic peptide[BNP] and N-terminal pro-atrial natriuretic peptides) and endothelial function (homocysteine and urinary albumin/creatinine ratio[UACR]) measured at the 6th examination (1995-98) to risk of incident stroke/TIA. In a subset of 1901 participants with available brain MRI (1999-2005), we further related these biomarkers to total cerebral brain volume (TCBV), covert brain infarcts (CBI), and large white matter hyperintensity volume (LWMHV). During a median follow-up of 9.2 years, 130 participants experienced incident stroke/TIA. In multivariable analyses adjusted for stroke risk factors, the biomarker panel was associated with incident stroke/TIA and with TCBV (p<0.05 for both), but not with CBI or LWMHV (p >0.05). In backwards elimination analyses higher log-BNP (hazards ratio [HR] 1.39/SD, p=0.002) and log-UACR (HR1.31/SD, p=0.004) were associated with increased risk of stroke/TIA and improved risk prediction over using the Framingham stroke risk profile alone; using <5%, 5-15% or >15% 10-year risk categories the net reclassification index was 0.109;p=0.037). Higher CRP (β=-0.21/SD,p=0.008), D-dimer(β==-0.18/SD,p=0.041), tHcy(β=-0.21/SD,p=0.005), and UACR(β=-0.15/SD,p=0.042) were associated with lower TCBV.
Conclusions—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.