title: Metabolite profiling identifies a branched chain amino acid signature in acute cardioembolic stroke.
abstract: OBJECTIVE
  There is limited information about changes in metabolism during acute ischemic stroke. The identification of changes in circulating plasma metabolites during cerebral infarction may provide insight into disease pathogenesis and identify novel biomarkers.
  
  
  METHODS
  We performed filament occlusion of the middle cerebral artery of Wistar rats and collected plasma and cerebrospinal fluid 2 hours after the onset of ischemia. Plasma samples from control and patients with acute stroke were also analyzed. All samples were examined using liquid chromatography followed by tandem mass spectrometry. Positively charged metabolites, including amino acids, nucleotides, and neurotransmitters, were quantified using electrospray ionization followed by scheduled multiple reaction monitoring.
  
  
  RESULTS
  The concentrations of several metabolites were altered in the setting of cerebral ischemia. We detected a reduction in the branched chain amino acids (valine, leucine, isoleucine) in rat plasma, rat cerebrospinal fluid, and human plasma compared with respective controls (16%, 23%, and 17%, respectively; P<0.01 for each). In patients, lower branched chain amino acids levels also correlated with poor neurological outcome (modified Rankin Scale, 0-2 versus 3-6; P=0.002).
  
  
  CONCLUSIONS
  Branched chain amino acids are reduced in ischemic stroke, and the degree of reduction correlates with worse neurological outcome. Whether branched chain amino acids are in a causal pathway or are an epiphenomenon of ischemic stroke remains to be determined.
authors.affiliation: Center for Human Genetic Research and Division of Neurocritical Care and Emergency Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. wtkimberly@partners.org
authors.forename: W Taylor
authors.initials: WT
authors.lastname: Kimberly
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Ly
authors.initials: L
authors.lastname: Pham
authors.forename: Karen L
authors.initials: KL
authors.lastname: Furie
authors.forename: Robert E
authors.initials: RE
authors.lastname: Gerszten
mesh_terms: D000328:Adult; D000597:Amino Acids, Branched-Chain / Q000097:blood* / Q000134:cerebrospinal fluid; D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000134:cerebrospinal fluid; D002545:Brain Ischemia / Q000097:blood* / Q000134:cerebrospinal fluid; D005260:Female; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D051381:Rats; D017208:Rats, Wistar; D020521:Stroke / Q000097:blood* / Q000134:cerebrospinal fluid
chemical_list: D000597:Amino Acids, Branched-Chain; D015415:Biomarkers