Skip to main content

Advertisement

SpringerLink
Log in

Elevated Serum Levels of Neopterin at Admission Predicts Depression After Acute Ischemic Stroke: a 6-Month Follow-Up Study

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Inflammation and cell-mediated immune activation are attributed to the pathogenesis and pathophysiology in depression. Our aim was to test the possible association between serum levels of neopterin and the development of post-stroke depression (PSD) in Chinese patients. The subjects were first-ever acute ischemic stroke patients who were hospitalized at the First Affiliated Hospital of Xinxiang Medical University during the period from December 2012 to December 2013. Clinical information and stroke severity were collected at admission. Neurological and neuropsychological evaluations were conducted at the 6-month follow-up. Serum neopterin levels were measured using fluorometry and a high performance liquid chromatography (HPLC) method. Multivariate analyses were performed using logistic regression models. During the study period, 226 patients were included and finished the 6-month follow-up. Sixty-nine patients (30.5 %) were diagnosed as having major depression at 6 months. Patients with major depression showed higher levels of serum neopterin (21.6[IQR, 18.9–25.7]nmol/L vs. 14.6[IQR, 12.2–18.4]nmol/L, P < 0.0001) at admission. In multivariate analyses, serum neopterin was an independent predictor of PSD at 6 months [odds ratio (OR): 1.952 (95 % CI, 1.358–2.805), P < 0.0001]. With an AUC of 0.850 (95 % CI, 0.797–0.902), neopterin showed a significantly greater discriminatory ability as compared with high-sensitivity C-reactive protein, age, body mass index, and National Institutes of Health and Stroke Scale score. Neopterin is a novel, independent predictor of the development of depression 6 months after stroke. This indicated that the elevated neopterin levels may play a significant role in the pathology of depression and that the pathways leading to inflammation and cell-mediated immune activation warrant further exploration.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Schweizer TA, Macdonald RL (2014) The behavioral consequences of stroke. Springer, New York

    Book  Google Scholar 

  2. Li J, Zhao YD, Zeng JW, Chen XY, Wang RD, Cheng SY (2014) Serum brain-derived Neurotrophic factor levels in post-stroke depression. J Affect Disord 168:373–379

    Article  CAS  PubMed  Google Scholar 

  3. Cheng SY, Zhao YD, Li J, Chen XY, Wang RD, Zeng JW (2014) Plasma levels of glutamate during stroke is associated with development of post-stroke depression. Psychoneuroendocrinology 47:126–135

    Article  CAS  PubMed  Google Scholar 

  4. Moylan S, Maes M, Wray NR, Berk M (2012) The neuroprogressive nature of major depressive disorder: pathways to disease evolution and resistance, and therapeutic implications. Mol Psychiatry 18(5):595–606

    Article  PubMed  Google Scholar 

  5. Leonard B, Maes M (2012) Mechanistic explanations how cell-mediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathophysiology of unipolar depression. Neurosci Biobehav Rev 36(2):764–785

    Article  CAS  PubMed  Google Scholar 

  6. Maes M, Mihaylova I, Kubera M, Ringel K (2012) Activation of cell-mediated immunity in depression: association with inflammation, melancholia, clinical staging and the fatigue and somatic symptom cluster of depression. Prog Neuro-Psychopharmacol Biol Psychiatry 36(1):169–175

    Article  Google Scholar 

  7. Celik C, Erdem M, Caycı T, Ozdemir B, Ozgur Akgul E, Kurt YG, Ozsahin A (2010) The association between serum levels of neopterin and number of depressive episodes of major depression. Prog Neuro-Psychopharmacol Biol Psychiatry 34(2):372–375

    Article  CAS  Google Scholar 

  8. Maes M (2011) Depression is an inflammatory disease, but cell-mediated immune activation is the key component of depression. Prog Neuro-Psychopharmacol Biol Psychiatry 35(3):664–675

    Article  CAS  Google Scholar 

  9. Parker DC, Mielke MM, Yu Q, Rosenberg PB, Jain A, Lyketsos CG, Oh ES (2013) Plasma neopterin level as a marker of peripheral immune activation in amnestic mild cognitive impairment and Alzheimer’s disease. Int J Geriatr Psychiatry 28(2):149–154

    Article  PubMed  Google Scholar 

  10. Hautala T, Partanen T, Sironen T, Rajaniemi SM, Hautala N, Vainio O, Vaheri A (2013) Elevated cerebrospinal fluid neopterin concentration is associated with disease severity in acute Puumala hantavirus infection. J Immunol Res 2013:634632

    Google Scholar 

  11. Sucher R, Schroecksnadel K, Weiss G, Margreiter R, Fuchs D, Brandacher G (2010) Neopterin, a prognostic marker in human malignancies. Cancer Lett 287(1):13–22

    Article  CAS  PubMed  Google Scholar 

  12. Widner B, Laich A, Sperner-Unterweger B, Ledochowski M, Fuchs D (2002) Neopterin production, tryptophan degradation, and mental depression—what is the link? Brain Behav Immun 16(5):590–595

    Article  CAS  PubMed  Google Scholar 

  13. Wachter H, Fuchs D, Hausen A, Reibnegger G, Weiss G, Werner ER, Werner-Felmayer G (1992) Neopterin: biochemistry-methods-clinical application. Walter de Gruyter, New York

    Book  Google Scholar 

  14. Fuchs D, Weiss G, Reibnegger G, Wachter H (1992) The role of neopterin as a monitor of cellular immune activation in transplantation, inflammatory, infectious, and malignant diseases. Crit Rev Clin Lab Sci 29(3–4):307–344

    Article  CAS  PubMed  Google Scholar 

  15. De Rosa S, Cirillo P, Pacileo M, Petrillo G, D’Ascoli GL, Maresca F, Chiariello M (2011) Neopterin: from forgotten biomarker to leading actor in cardiovascular pathophysiology. Curr Vasc Pharmacol 9(2):188–199

    Article  PubMed  Google Scholar 

  16. Arshadi D, Nikbin B, Shakiba Y, Kiani A, Jamshidi AR, Boroushaki MT (2013) Plasma level of neopterin as a marker of disease activity in treated rheumatoid arthritis patients: association with gender, disease activity and anti-CCP antibody. Int Immunopharmacol 17(3):763–767

    Article  CAS  PubMed  Google Scholar 

  17. Zhou SJ, Sun ZX, Liu J (2013) Neopterin concentrations in synovial fluid may reflect disease severity in patients with osteoarthritis. Scand J Clin Lab Investig 73(4):344–348

    Article  CAS  Google Scholar 

  18. Sulo G, Vollset SE, Nygård O, Midttun Ø, Ueland PM, Eussen SJ, Tell GS (2013) Neopterin and kynurenine–tryptophan ratio as predictors of coronary events in older adults, the Hordaland Health Study. Int J Cardiol 168(2):1435–1440

    Article  PubMed  Google Scholar 

  19. Norton SA, Sher-Glass R, Mann S, Moccio M, Zimmerman AM, Menza M, Kusnecov AW (2014) Inflammation and post-stroke depression: preliminary progress. Brain Behav Immun 40, e47

    Article  Google Scholar 

  20. Bolu A, Erdem M, Balıkcı A, Bilgen AE, Akgül EÖ, Uzun Ö, Öztosun M (2013) The relationship between serum levels of haptoglobin and neopterin and the number of episodes in patients with major depression. J Mood Disord 3(1):1–7

    Article  Google Scholar 

  21. Hoekstra R, van den Broek WW, Fekkes D, Bruijn JA, Mulder PG, Pepplinkhuizen L (2001) Effect of electroconvulsive therapy on biopterin and large neutral amino acids in severe, medication-resistant depression. Psychiatry Res 103(2):115–123

    Article  CAS  PubMed  Google Scholar 

  22. Tiemeier H, Fekkes D, Hofman A, van Tuijl HR, Kiliaan AJ, Breteler M (2006) Plasma pterins and folate in late life depression: the Rotterdam Study. Psychiatry Res 145(2):199–206

    Article  CAS  PubMed  Google Scholar 

  23. Lin HS, Tsai TH, Liu CF, Lu CH, Chang WN, Chen SF, Yip HK (2012) Serum level and prognostic value of neopterin in patients after ischemic stroke. Clin Biochem 45(18):1596–1601

    Article  CAS  PubMed  Google Scholar 

  24. Hamilton M (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56–62

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zheng YP, Zhao JP, Phillips M, Liu JB, Cai MF, Sun SQ, Huang MF (1988) Validity and reliability of the Chinese Hamilton Depression Rating Scale. Br J Psychiatry 152:660–664

    Article  CAS  PubMed  Google Scholar 

  26. Brott T, Adams HP, Olinger CP, Marler JR, Barsan WG, Biller J, Hertzberg V (1989) Measurements of acute cerebral infarction: a clinical examination scale. Stroke 20:864–870

    Article  CAS  PubMed  Google Scholar 

  27. Adams HP, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh E (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 24:35–41

    Article  PubMed  Google Scholar 

  28. Sims JR, Gharai LR, Schaefer PW, Vangel M, Rosenthal ES, Lev MH, Schwamm LH (2009) ABC/2 for rapid clinical estimate of infarct, perfusion, and mismatch volumes. Neurology 72:2104–2110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. First MB, Spitzer RL, Gibbon M (1995) Structured clinical interview for DSM-IV axis I disorders—patient edition (SCID-I/P, version 2.0). Biometrics Research Department, New York State Psychiatric Institute, New York

    Google Scholar 

  30. Bonita RBR (1988) Modification of Rankin Scale: recovery of motor function after stroke. Stroke 19:1497–1500

    Article  CAS  PubMed  Google Scholar 

  31. Alrashed M, Abougoush M, Akgul EO, Erbil MK (2002) Detection method of serum and urine neopterin levels by high performance liquid chromatography. Gulhane MJ 44:273–277

    Google Scholar 

  32. Berk M, Williams LJ, Jacka FN, O’Neil A, Pasco JA, Moylan S, Maes M (2013) So depression is an inflammatory disease, but where does the inflammation come from? BMC Med 11:200

    Article  PubMed  PubMed Central  Google Scholar 

  33. Modabbernia A, Taslimi S, Brietzke E, Ashrafi M (2013) Cytokine alterations in bipolar disorder: a meta-analysis of 30 studies. Biol Psychiatry 74(1):15–25

    Article  CAS  PubMed  Google Scholar 

  34. Fenn AM, Gensel JC, Huang Y, Popovich PG, Lifshitz J, Godbout JP (2014) Immune activation promotes depression 1 month after diffuse brain injury: a role for primed microglia. Biol Psychiatry 76(7):575–584

    Article  CAS  PubMed  Google Scholar 

  35. Rybka J, Kędziora-Kornatowska K, Banaś-Leżańska P, Majsterek I, Carvalho LA, Cattaneo A, Kędziora J (2013) Interplay between the pro-oxidant and antioxidant systems and proinflammatory cytokine levels, in relation to iron metabolism and the erythron in depression. Free Radic Biol Med 63:187–194

    Article  CAS  PubMed  Google Scholar 

  36. Maes M, Twisk FN, Ringel K (2012) Inflammatory and cell-mediated immune biomarkers in myalgic encephalomyelitis/chronic fatigue syndrome and depression: inflammatory markers are higher in myalgic encephalomyelitis/chronic fatigue syndrome than in depression. Psychother Psychosom 81(5):286–295

    Article  PubMed  Google Scholar 

  37. Maes M, Scharpé S, Meltzer HY, Okayli G, Bosmans E, D’Hondt P, Cosyns P (1994) Increased neopterin and interferon-gamma secretion and lower availability of L-tryptophan in major depression: further evidence for an immune response. Psychiatry Res 54(2):143–160

    Article  CAS  PubMed  Google Scholar 

  38. Valkanova V, Ebmeier KP, Allan CL (2013) CRP, IL-6 and depression: a systematic review and meta-analysis of longitudinal studies. J Affect Disord 150(3):736–744

    Article  CAS  PubMed  Google Scholar 

  39. Luukinen H, Jokelainen J, Hedberg P (2010) The relationships between high-sensitivity C-reactive protein and incident depressed mood among older adults. Scand J Clin Lab Investig 70(2):75–79

    Article  CAS  Google Scholar 

  40. Pasco JA, Nicholson GC, Williams LJ, Jacka FN, Henry MJ, Kotowicz MA, Berk M (2010) Association of high-sensitivity C-reactive protein with de novo major depression. Br J Psychiatry 197(5):372–377

    Article  PubMed  Google Scholar 

  41. Liukkonen T, Silvennoinen-Kassinen S, Jokelainen J, Räsänen P, Leinonen M, Meyer-Rochow VB, Timonen M (2006) The association between C-reactive protein levels and depression: results from the northern Finland 1966 birth cohort study. Biol Psychiatry 60(8):825–830

    Article  CAS  PubMed  Google Scholar 

  42. Maes M, Bosmans E, Scharpé S, D’Hondt P, Desnyder R (1995) Plasma soluble interleukin-2-receptor in depression: relationships to plasma neopterin and serum IL-2 concentrations and HPA-axis activity. Eur Psychiatry 10(8):397–403

    Article  CAS  PubMed  Google Scholar 

  43. D’Mello C, Le T, Swain MG (2009) Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factoralpha signaling during peripheral organ inflammation. J Neurosci 29:2089–2102

    Article  PubMed  Google Scholar 

  44. Chen Z, Jalabi W, Shpargel KB, Farabaugh KT, Dutta R, Yin X, Kidd GJ, Bergmann CC, Stohlman SA, Trapp BD (2012) Lipopolysaccharide-induced microglial activation and neuroprotection against experimental brain injury is independent of hematogenous TLR4. J Neurosci 32:11706–11715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Fujigaki H, Saito K, Fujigaki S, Takemura M, Sudo K, Ishiguro H, Seishima M (2006) The signal transducer and activator of transcription 1alpha and interferon regulatory factor 1 are not essential for the induction of indoleamine 2,3-dioxygenase by lipopolysaccharide: involvement of p38 mitogen-activated protein kinase and nuclear factor-kappaB pathways, and synergistic effect of several proinflammatory cytokines. J Biochem 139:655–662

    Article  CAS  PubMed  Google Scholar 

  46. Felger JC, Lotrich FE (2013) Inflammatory cytokines in depression: neurobiological mechanisms and therapeutic implications. Neuroscience 246:199–229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Cortese GP, Barrientos RM, Maier SF, Patterson SL (2011) Aging and a peripheral immune challenge interact to reduce mature brain-derived Neurotrophic factor and activation of TrkB, PLCgamma1, and ERK in Hippocampal synaptoneurosomes. J Neurosci 31:4274–4279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Murr C, Widner B, Wirleitner B, Fuchs D (2002) Neopterin as a marker for immune system activation. Curr Drug Metab 3(2):175–187

    Article  CAS  PubMed  Google Scholar 

  49. Gawryluk JW, Wang JF, Andreazza AC, Shao L, Young LT (2011) Decreased levels of glutathione, the major brain antioxidant, in post-mortem prefrontal cortex from patients with psychiatric disorders. Int J Neuropsychopharmacol 14:123–130

    Article  CAS  PubMed  Google Scholar 

  50. Black CN, Bot M, Scheffer PG, Cuijpers P, Penninx BW (2015) Is depression associated with increased oxidative stress? A systematic review and meta-analysis. Psychoneuroendocrinology 51:164–175

    Article  CAS  PubMed  Google Scholar 

  51. Tiemeier H, van Dijck W, Hofman A, Witteman JC, Stijnen T, Breteler MM (2004) Relationship between atherosclerosis and late-life depression: the Rotterdam Study. Arch Gen Psychiatry 61(4):369–376

    Article  PubMed  Google Scholar 

  52. Thomas AJ, O’Brien JT, Davis S, Ballard C, Barber R, Kalaria RN, Perry RH (2002) Ischemic basis for deep white matter hyperintensities in major depression: a neuropathological study. Arch Gen Psychiatry 59(9):785–792

    Article  PubMed  Google Scholar 

  53. Rothenburg LS, Herrmann N, Swardfager W, Black SE, Tennen G, Kiss A, Lanctôt KL (2010) The relationship between inflammatory markers and post stroke cognitive impairment. J Geriatr Psychiatry Neurol 23(3):199–205

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation of China (No: 31170733) and the Doctoral Scientific Research Start-up Foundation of Henan Normal University. We also express our gratitude to all the patients, the nurses, and physicians who participated in this study and thereby made this work possible.

Role of Funding

The funding plays no role in the study process.

Conflict of Interest

The authors declare that there is no competing interest.

Author information

Author notes

    Authors and Affiliations

    1. Laboratory of Molecular Medicine, College of Life Science, Henan Normal University, No. 46, Jianshedong Road, Xinxiang, Henan Province, 453007, China

      Chao-Zhi Tang, Yu-Ling Zhang, Wen-Sheng Wang & Wei-Guo Li

    2. The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan Province, China

      Ji-Peng Shi

    Authors
    1. Chao-Zhi Tang
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Yu-Ling Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Wen-Sheng Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Wei-Guo Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Ji-Peng Shi
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Wen-Sheng Wang.

    Additional information

    Chao-Zhi Tang and Yu-Ling Zhang contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Tang, CZ., Zhang, YL., Wang, WS. et al. Elevated Serum Levels of Neopterin at Admission Predicts Depression After Acute Ischemic Stroke: a 6-Month Follow-Up Study. Mol Neurobiol 53, 3194–3204 (2016). https://doi.org/10.1007/s12035-015-9220-4

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s12035-015-9220-4

    Keywords

    Search

    Navigation