Advertisement

Journal of Molecular Neuroscience

, Volume 58, Issue 1, pp 102–108 | Cite as

Serum Phenylalanine, Tyrosine, and their Ratio in Acute Ischemic Stroke: on the Trail of a Biomarker?

  • Heidi OrmstadEmail author
  • Robert Verkerk
  • Leiv Sandvik
Article

Abstract

Fast diagnosis and appropriate treatment are of utmost importance to improving the outcome in patients with acute ischemic stroke (AIS). A rapid and sensitive blood test for ischemic stroke is required. The aim of this study was to examine the usefulness of phenylalanine (PHE) and tyrosine (TYR) as diagnostic biomarkers in AIS. Serum levels of PHE and TYR, measured using HPLC, and their ratio (PHE/TYR) were compared between 45 patients with AIS and 40 healthy control subjects. The relationship between PHE/TYR and the serum levels of several cytokines were also examined. PHE/TYR was significantly higher in AIS patients than in healthy controls (1.75 vs 1.24, p < 0.001). A receiver operating characteristic (ROC) curve analysis of PHE/TYR in AIS patients relative to healthy controls revealed promising sensitivity and specificity, which at an optimal cutoff of 1.45 were 76 and 85 %, respectively. PHE/TYR was positively correlated with interleukin (IL)-1β (r = 0.37, p = 0.011) and IL-6 (r = 0.33, p = 0.025). This study shows that PHE/TYR is highly elevated in the acute phase of AIS, and that this elevation is coupled to the inflammatory response. The ROC analysis documents the possible value of PHE/TYR as a biomarker for AIS and demonstrates its clinical potential as a blood-based test for AIS.

Keywords

Acute ischemic stroke Diagnostic biomarker Phenylalanine Tyrosine Inflammation 

Notes

Acknowledgments

The authors are indebted to the various staff members of Vestre Viken Hospital Trust, Buskerud, Drammen, and Oslo University Hospital, Ullevål, Oslo, for important contributions to the study. The presented work stems from the research project “Poststroke Fatigue,” for which Dr. Hesook Suzie Kim is the project director and Drs. Grethe Eilertsen, Anners Lerdal, and Heidi Ormstad are the principal researchers. The project is funded by the Research Council of Norway for the period from 2007 to 2010 (project no. 176503/V10), and Vestre Viken Hospital Trust.

Ethics

The study was approved by The Regional Committee for Medical Research Ethics in Norway and has therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. Informed consent was obtained from all patients prior to their inclusion in the study.

Conflict of Interest

The authors declare that they have no competing interests.

References

  1. Adams HP Jr et al (1993) Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 24:35–41CrossRefPubMedGoogle Scholar
  2. Anderson DN et al (1994) Recovery from depression after electroconvulsive therapy is accompanied by evidence of increased tetrahydrobiopterin-dependent hydroxylation. Acta Psychiatr Scand 90:10–13CrossRefPubMedGoogle Scholar
  3. Askanazi J et al (1980) Muscle and plasma amino acids following injury. Influence of intercurrent infection. Ann Surg 192:78–85PubMedCentralCrossRefPubMedGoogle Scholar
  4. Brouns R, De Deyn PP (2009) The complexity of neurobiological processes in acute ischemic stroke. Clin Neurol Neurosurg 111:483–495CrossRefPubMedGoogle Scholar
  5. Chiarla C, Giovannini I, Siegel JH (2004) The relationship between plasma cholesterol, amino acids and acute phase proteins in sepsis. Amino Acids 27:97–100CrossRefPubMedGoogle Scholar
  6. Collin C et al (1988) The Barthel ADL Index: a reliability study. Int Disabil Stud 10:61–63CrossRefPubMedGoogle Scholar
  7. Crabtree MJ, Channon KM (2011) Synthesis and recycling of tetrahydrobiopterin in endothelial function and vascular disease. Nitric Oxide 25:81–88CrossRefPubMedGoogle Scholar
  8. Crabtree MJ, Hale AB, Channon KM (2011) Dihydrofolate reductase protects endothelial nitric oxide synthase from uncoupling in tetrahydrobiopterin deficiency. Free Radic Biol Med 50:1639–1646PubMedCentralCrossRefPubMedGoogle Scholar
  9. Foerch C et al (2009) Invited article: searching for oracles? Blood biomarkers in acute stroke. Neurology 73:393–399PubMedCentralCrossRefPubMedGoogle Scholar
  10. Forstermann U, Sessa WC (2012) Nitric oxide synthases: regulation and function. Eur Heart J 33:829–837, 837a-837d PubMedCentralCrossRefPubMedGoogle Scholar
  11. Freund H et al (1979) Plasma amino acids as predictors of the severity and outcome of sepsis. Ann Surg 190:571–576PubMedCentralCrossRefPubMedGoogle Scholar
  12. Fuchs JE et al (2012) Dynamic regulation of phenylalanine hydroxylase by simulated redox manipulation. PLoS One 7:e53005PubMedCentralCrossRefPubMedGoogle Scholar
  13. Hasan N et al (2012) Towards the identification of blood biomarkers for acute stroke in humans: a comprehensive systematic review. Br J Clin Pharmacol 74:230–240PubMedCentralCrossRefPubMedGoogle Scholar
  14. Hoekstra R et al (2001) Effect of electroconvulsive therapy on biopterin and large neutral amino acids in severe, medication-resistant depression. Psychiatry Res 103:115–123CrossRefPubMedGoogle Scholar
  15. Jin R, Yang G, Li G (2010) Inflammatory mechanisms in ischemic stroke: role of inflammatory cells. J Leukoc Biol 87:779–789PubMedCentralCrossRefPubMedGoogle Scholar
  16. Kim SJ, Moon GJ, Bang OY (2013) Biomarkers for stroke. J Stroke 15:27–37PubMedCentralCrossRefPubMedGoogle Scholar
  17. Kwon NS, Nathan CF, Stuehr DJ (1989) Reduced biopterin as a cofactor in the generation of nitrogen oxides by murine macrophages. J Biol Chem 264:20496–20501PubMedGoogle Scholar
  18. Lerdal A, et al. 2012. The course of fatigue during the first 18 months after first-ever stroke: a longitudinal study. Stroke research and treatment. 2012, 126275Google Scholar
  19. Lopansri BK et al (2006) Elevated plasma phenylalanine in severe malaria and implications for pathophysiology of neurological complications. Infect Immun 74:3355–3359PubMedCentralCrossRefPubMedGoogle Scholar
  20. Love S (1999) Oxidative stress in brain ischemia. Brain Pathol 9:119–131CrossRefPubMedGoogle Scholar
  21. Manzanero S, Santro T, Arumugam TV (2013) Neuronal oxidative stress in acute ischemic stroke: sources and contribution to cell injury. Neurochem Int 62:712–718CrossRefPubMedGoogle Scholar
  22. McColl BW, Allan SM, Rothwell NJ (2009) Systemic infection, inflammation and acute ischemic stroke. Neuroscience 158:1049–1061CrossRefPubMedGoogle Scholar
  23. Nanetti L et al (2007) Reactive oxygen species plasmatic levels in ischemic stroke. Mol Cell Biochem 303:19–25CrossRefPubMedGoogle Scholar
  24. Neurauter G et al (2008a) Serum phenylalanine concentrations in patients with ovarian carcinoma correlate with concentrations of immune activation markers and of isoprostane-8. Cancer Lett 272:141–147CrossRefPubMedGoogle Scholar
  25. Neurauter G et al (2008b) Chronic immune stimulation correlates with reduced phenylalanine turnover. Curr Drug Metab 9:622–627CrossRefPubMedGoogle Scholar
  26. Ormstad H et al (2011a) Serum cytokine and glucose levels as predictors of poststroke fatigue in acute ischemic stroke patients. J Neurol 258:670–676PubMedCentralCrossRefPubMedGoogle Scholar
  27. Ormstad H et al (2011b) Serum levels of cytokines and C-reactive protein in acute ischemic stroke patients, and their relationship to stroke lateralization, type, and infarct volume. J Neurol 258:677–685PubMedCentralCrossRefPubMedGoogle Scholar
  28. Ploder M et al (2008) Serum phenylalanine in patients post trauma and with sepsis correlate to neopterin concentrations. Amino Acids 35:303–307CrossRefPubMedGoogle Scholar
  29. Powanda MC et al (1974) Distribution and metabolism of phenylalanine and tyrosine during tualraemia in the rat. Biochem J 144:173–176PubMedCentralCrossRefPubMedGoogle Scholar
  30. Ribas GS et al (2011) Oxidative stress in phenylketonuria: what is the evidence? Cell Mol Neurobiol 31:653–662CrossRefPubMedGoogle Scholar
  31. Rosenblatt D, Scriver CR (1968) Heterogeneity in genetic control of phenylalanine metabolism in man. Nature 218:677–678CrossRefPubMedGoogle Scholar
  32. Rothstein L, Jickling GC (2013) Ischemic stroke biomarkers in blood. Biomark Med 7:37–47CrossRefPubMedGoogle Scholar
  33. Schmidt TS, Alp NJ (2007) Mechanisms for the role of tetrahydrobiopterin in endothelial function and vascular disease. Clin Sci (Lond) 113:47–63CrossRefGoogle Scholar
  34. Sprung CL et al (1991) Amino acid alterations and encephalopathy in the sepsis syndrome. Crit Care Med 19:753–757CrossRefPubMedGoogle Scholar
  35. Taffi R et al (2008) Plasma levels of nitric oxide and stroke outcome. J Neurol 255:94–98CrossRefPubMedGoogle Scholar
  36. Turnell DC, Cooper JD (1982) Rapid assay for amino acids in serum or urine by pre-column derivatization and reversed-phase liquid chromatography. Clin Chem 28:527–531PubMedGoogle Scholar
  37. Vente JP et al (1989) Plasma-amino acid profiles in sepsis and stress. Ann Surg 209:57–62PubMedCentralCrossRefPubMedGoogle Scholar
  38. Vogelgesang A, Becker KJ, Dressel A (2014) Immunological consequences of ischemic stroke. Acta Neurol Scand 129:1–12CrossRefPubMedGoogle Scholar
  39. Wannemacher RW Jr et al (1976) The significance and mechanism of an increased serum phenylalanine-tyrosine ratio during infection. Am J Clin Nutr 29:997–1006PubMedGoogle Scholar
  40. Werner ER, Blau N, Thony B (2011) Tetrahydrobiopterin: biochemistry and pathophysiology. Biochem J 438:397–414CrossRefPubMedGoogle Scholar
  41. Whiteley W, Tseng MC, Sandercock P (2008) Blood biomarkers in the diagnosis of ischemic stroke: a systematic review. Stroke 39:2902–2909CrossRefPubMedGoogle Scholar
  42. Whiteley W, Tian Y, Jickling GC (2012) Blood biomarkers in stroke: research and clinical practice. Int J Stroke 7:435–439CrossRefPubMedGoogle Scholar
  43. Whitsett J et al (2013) Human endothelial dihydrofolate reductase low activity limits vascular tetrahydrobiopterin recycling. Free Radic Biol Med 63:143–150PubMedCentralCrossRefPubMedGoogle Scholar
  44. Wolfe CD et al (1991) Assessment of scales of disability and handicap for stroke patients. Stroke 22:1242–1244CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Faculty of Health SciencesBuskerud and Vestfold University CollegeDrammenNorway
  2. 2.Laboratory of Medical BiochemistryUniversity of AntwerpAntwerpBelgium
  3. 3.Section of BiostatisticsOslo University Hospital, UllevålOsloNorway

Personalised recommendations