title: Multiple biomarkers and risk of clinical and subclinical vascular brain injury: the Framingham Offspring Study.
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.
  
  
  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.
  
  
  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.
authors.affiliation: Boston University Schools of Medicine and Public Health, MA, USA.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Pikula
authors.forename: Alexa S
authors.initials: AS
authors.lastname: Beiser
authors.forename: Charles
authors.initials: C
authors.lastname: DeCarli
authors.forename: Jayandra J
authors.initials: JJ
authors.lastname: Himali
authors.forename: Stephanie
authors.initials: S
authors.lastname: Debette
authors.forename: Rhoda
authors.initials: R
authors.lastname: Au
authors.forename: Jacob
authors.initials: J
authors.lastname: Selhub
authors.forename: Geoffrey H
authors.initials: GH
authors.lastname: Toffler
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Wang
authors.forename: James B
authors.initials: JB
authors.lastname: Meigs
authors.forename: Margaret
authors.initials: M
authors.lastname: Kelly-Hayes
authors.forename: Carlos S
authors.initials: CS
authors.lastname: Kase
authors.forename: Philip A
authors.initials: PA
authors.lastname: Wolf
authors.forename: Ramachandran S
authors.initials: RS
authors.lastname: Vasan
authors.forename: Sudha
authors.initials: S
authors.lastname: Seshadri
mesh_terms: D000368:Aged; D000419:Albuminuria / Q000652:urine; D015415:Biomarkers / Q000097:blood* / Q000652:urine; D001798:Blood Proteins / Q000032:analysis; D001921:Brain / Q000473:pathology*; D001930:Brain Injuries / Q000097:blood* / Q000453:epidemiology / Q000652:urine; D015331:Cohort Studies; D003404:Creatinine / Q000652:urine; D004730:Endothelium, Vascular / Q000503:physiopathology; D005260:Female; D006487:Hemostasis; D006710:Homocysteine / Q000097:blood; D006728:Hormones / Q000097:blood; D006801:Humans; D015994:Incidence; D007249:Inflammation / Q000097:blood; D002546:Ischemic Attack, Transient / Q000097:blood* / Q000453:epidemiology / Q000652:urine; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009929:Organ Size; D011446:Prospective Studies; D012306:Risk; D020521:Stroke / Q000097:blood* / Q000453:epidemiology / Q000652:urine; D014481:United States / Q000453:epidemiology
chemical_list: D015415:Biomarkers; D001798:Blood Proteins; D006728:Hormones; D006710:Homocysteine; D003404:Creatinine