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Serum Levels of High-sensitivity C-Reactive Protein at Admission Are More Strongly Associated with Poststroke Depression in Acute Ischemic Stroke than Homocysteine Levels

Molecular Neurobiology volume 53, pages 2152–2160 (2016)Cite this article

Abstract

Inflammatory processes have fundamental roles in depression. The primary purpose of this study was to assess the serum levels of high-sensitivity C-reactive protein (Hs-CRP) and homocysteine (HCY) at admission to the presence of poststroke depression (PSD). From December 2012 to December 2013, first-ever acute ischemic stroke patients who were admitted to the hospital within the first 24 h after stroke onset were consecutively recruited and followed up for 6 months. Serum levels of Hs-CRP and HCY were tested at admission. Based on the symptoms, diagnoses of depression were made in accordance with DSM-IV criteria for depression at 6 months after stroke. Ninety-five patients (42.0 %) showed depression (major + minor) at 6 months after admission, and in 69 patients (30.5 %), this depression was classified as major. In the 69 patients with major depression, our results showed significantly higher Hs-CRP and HCY levels at admission than patients without major depression. After adjusting all other possible covariates, Hs-CRP and HCY still were independent predicators of PSD with adjusted OR of 1.332 (95 % CI, 1.230–1.452; P < 0.001) and 1.138 (95 % CI, 1.072–1.274; P < 0.001), respectively. The area under the receiver operating characteristic curve values of Hs-CRP and HCY were 0.765 (95 % CI, 0.701–0.9825) and 0.684 (95 % CI, 0.610–0.757) for PSD, respectively. The prognostic accuracy of combined model (HCY and Hs-CRP) was higher compared to those biomarkers alone and other markers. Elevated serum levels of Hs-CRP and HCY at admission were found to be associated with depression 6 months after stroke, suggesting that these alterations might participate in the pathophysiology of depression symptoms in stroke patients.

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References

  1. Linden T, Blomstrand C, Skoog I (2007) Depressive disorders after 20 months in elderly stroke patients: a case–control study. Stroke 38:1860–1863

    Article  PubMed  Google Scholar 

  2. Cheng SY, Zhao YD, Li J et al (2014) Plasma levels of glutamate during stroke is associated with development of post-stroke depression. Psychoneuroendocrinology 47:126–135

    CAS  Article  PubMed  Google Scholar 

  3. Yue W, Xiang L, Zhang YJ et al (2014) Association of serum 25-hydroxyvitamin D with symptoms of depression after 6 months in stroke patients. Neurochem Res 39(11):2218–2224

    CAS  Article  PubMed  Google Scholar 

  4. 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

    CAS  Article  Google Scholar 

  5. Rawdin BJ, Mellon SH, Dhabhar FS et al (2013) Dysregulated relationship of inflammation and oxidative stress in major depression. Brain Behav Immun 31:143–152

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. Baune BT, Smith E, Reppermund S et al (2012) Inflammatory biomarkers predict depressive, but not anxiety symptoms during aging: the prospective Sydney memory and aging study. Psychoneuroendocrinology 37(9):1521–1530

    CAS  Article  PubMed  Google Scholar 

  7. Becking K, Boschloo L, Vogelzangs N et al (2013) The association between immune activation and manic symptoms in patients with a depressive disorder. Transl Psychiatry 3(10):e314

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. Maes M, Berk M, Goehler L et al (2012) Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways. BMC Med 10(1):66

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. Maes M, Meltzer HY, Scharpé S et al (1993) Psychomotor retardation, anorexia, weight loss, sleep disturbances, and loss of energy: psychopathological correlates of hyperhaptoglobinemia during major depression. Psychiatry Res 47(3):229–241

    CAS  Article  PubMed  Google Scholar 

  10. Tu WJ, Zhao SJ, Liu TG et al (2013) Combination of high-sensitivity C-reactive protein and homocysteine predicts the short-term outcomes of Chinese patients with acute ischemic stroke[J]. Neurol Res 35(9):912–921

    CAS  Article  PubMed  Google Scholar 

  11. Folstein M, Liu T, Peter I et al (2007) The homocysteine hypothesis of depression[J]. Am J Psychiatry 164(6):861–867

    Article  PubMed  Google Scholar 

  12. Madsen SK, Rajagopalan P, Joshi SH et al (2015) Higher homocysteine associated with thinner cortical gray matter in 803 participants from the Alzheimer’s Disease Neuroimaging Initiative. Neurobiol Aging 36:S203–S210

    CAS  Article  PubMed  Google Scholar 

  13. Feng L, Isaac V, Sim S et al (2013) Associations between elevated homocysteine, cognitive impairment, and reduced white matter volume in healthy old adults. Am J Geriatr Psychiatr 21(2):164–172

    Article  Google Scholar 

  14. Tu W, Yin C, Guo Y et al (2013) Serum homocysteine concentrations in Chinese children with autism. Clin Chem Lab Med 51(2):e19–e22

    CAS  Article  PubMed  Google Scholar 

  15. Eikelboom JW, Hankey GJ, Anand SS, Lofthouse E, Staples N, Baker RI (2000) Association between high homocyst(e)ine and ischemic stroke due to large- and small-artery disease but not other etiologic subtypes of ischemic stroke. Stroke 31:1069–1075

    CAS  Article  PubMed  Google Scholar 

  16. Sasaki T, Watanabe M, Nagai Y, Hoshi T, Takasawa M, Nukata M, Taguchi A, Kitagawa K, Kinoshita N, Matsumoto M (2002) Association of plasma homocysteine concentration with atherosclerotic carotid plaques and lacunar infarction. Stroke 33:1493–1496

    CAS  Article  PubMed  Google Scholar 

  17. Kim JM, Stewart R, Kim SW et al (2008) Predictive value of folate, vitamin B12 and homocysteine levels in late-life depression. Br J Psychiatry 192(4):268–274

    Article  PubMed  Google Scholar 

  18. Yoo JH, Chung CS, Kang SS (1998) Relation of plasma homocyst(e)ine to cerebral infarction and cerebral atherosclerosis. Stroke 29:2478–2483

    CAS  Article  PubMed  Google Scholar 

  19. Norton SA, Sher-Glass R, Mann S et al (2014) Inflammation and post-stroke depression: preliminary progress. Brain Behav Immun 40:e47

    Article  Google Scholar 

  20. Pascoe MC, Crewther SG, Carey LM, et al. (2012) Homocysteine as a potential biochemical marker for depression in elderly stroke survivors. Adv Food Nutr Res, 56

  21. 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 

  22. 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

    CAS  Article  PubMed  Google Scholar 

  23. Sims JR, Gharai LR, Schaefer PW et al (2009) ABC/2 for rapid clinical estimate of infarct, perfusion, and mismatch volumes. Neurology 72(24):2104–2110

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. Bonita RBR (1988) Modification of rankin scale: recovery of motor function after stroke. Stroke 19:1497–1500

    CAS  Article  PubMed  Google Scholar 

  27. 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

    CAS  Article  PubMed  Google Scholar 

  28. Nabi H, Bochud M, Glaus J et al (2013) Association of serum homocysteine with major depressive disorder: results from a large population-based study. Psychoneuroendocrinology 38(10):2309–2318

    CAS  Article  PubMed  Google Scholar 

  29. Wium-Andersen MK, Orsted DD, Nielsen SF, Nordestgaard BG (2013) Elevated C-reactive protein levels, psychological distress, and depression in 73131 individuals. JAMA Psychiatry 70(2):176–184

    CAS  Article  PubMed  Google Scholar 

  30. Nashaat M, Hamdi E, Mawella SA et al (2012) Homocysteine level and depression in patients with ischaemic heart disease. Egypt J Psychiatry 33(2):83

    Article  Google Scholar 

  31. Robinson RG (2003) Poststroke depression: prevalence, diagnosis, treatment, and disease progression. Biol Psychiatry 54:376–387

    Article  PubMed  Google Scholar 

  32. Wang X, Li YH, Li MH, Lu J, Zhao JG, Sun XJ, Ye JL (2012) Glutamate level detection by magnetic resonance spectroscopy in patients with post-stroke depression. Eur Arch Psychiatry Neurol Sci 262:33–38

    Article  Google Scholar 

  33. Farner L, Wagle J, Engedal K, Flekkøy KM, Wyller TB, Fure B (2010) Depressive symptoms in stroke patients: a 13 month follow-up study of patients referred to a rehabilitation unit. J Affect Disord 127:211–218

    Article  PubMed  Google Scholar 

  34. Jimenez I, Sobrino T, Rodriguez-Yanez M, Pouso M, Cristobo I, Sabucedo M, Castillo J (2009) High serum levels of leptin are associated with post-stroke depression. Psychol Med 39:1201–1209

    CAS  Article  PubMed  Google Scholar 

  35. Kim JM, Stewart R, Bae KY, Kim SW, Kang HJ, Shin IS, Yoon JS (2012) Serotonergic and BDNF genes and risk of depression after stroke. J Affect Disord 136:833–840

    CAS  Article  PubMed  Google Scholar 

  36. Hafner S, Baghai TC, Eser D, Schule C, Rupprecht R, Bondy B, Bedarida G, von Schacky C (2008) C-reactive protein is associated with polymorphisms of the angiotensin-converting enzyme gene in major depressed patients. J Psychiatr Res 42:163–165

    Article  PubMed  Google Scholar 

  37. Gimeno D, Marmot MG, Singh-Manoux A (2008) Inflammatory markers and cognitive function in middle-aged adults: the Whitehall II study. Psychoneuroendocrinology 33:1322–1334

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. Belmaker RH, Agam G (2008) Major depressive disorder. N Engl J Med 358:55–68

    CAS  Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  40. 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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 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

    CAS  Article  PubMed  Google Scholar 

  42. Huang L, Baban B, Johnson BA 3rd, Mellor AL (2010) Dendritic cells, indoleamine 2,3 dioxygenase and acquired immune privilege. Int Rev Immunol 29:133–155

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. Capuron L, Geisler S, Kurz K et al (2014) Activated immune system and inflammation in healthy ageing: relevance for tryptophan and neopterin metabolism. Curr Pharm Des 20(38):6048–6057

    CAS  Article  PubMed  Google Scholar 

  44. Jesmin J, Rashid MS, Jamil H, Hontecillas R, Bassaganya-Riera J (2010) Gene regulatory network reveals oxidative stress as the underlying molecular mechanism of type 2 diabetes and hypertension. BMC Med Genet 3(1):45

    Google Scholar 

  45. Sanchez-Villegas A, Martinez-Gonzalez MA (2013) Diet, a new target to prevent depression? BMC Med 11:3

    Article  PubMed  PubMed Central  Google Scholar 

  46. 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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. Bottiglieri T, Laundy M, Crellin R, Toone BK, Carney MW, Reynolds EH (2000) Homocysteine, folate, methylation, and monoamine metabolism in depression. J Neurol Neurosurg Psychiatry 69:228–232

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. Toole JF, Malinow MR, Chambless LE et al (2004) Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 291(5):565–575

    CAS  Article  PubMed  Google Scholar 

  49. Di Napoli M, Papa F, Bocola V (2001) C-reactive protein in ischemic stroke an independent prognostic factor. Stroke 32(4):917–924

    Article  PubMed  Google Scholar 

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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.

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The content has not been published or submitted for publication elsewhere. All authors have contributed significantly, and that all authors are in agreement with the content of the manuscript.

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

      Ji-Peng Shi

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    1. Chao-Zhi Tang
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    Correspondence to Wen-Sheng Wang.

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

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    Tang, CZ., Zhang, YL., Wang, WS. et al. Serum Levels of High-sensitivity C-Reactive Protein at Admission Are More Strongly Associated with Poststroke Depression in Acute Ischemic Stroke than Homocysteine Levels. Mol Neurobiol 53, 2152–2160 (2016). https://doi.org/10.1007/s12035-015-9186-2

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    • DOI: https://doi.org/10.1007/s12035-015-9186-2

    Keywords

    • High-sensitivity C-reactive protein
    • Homocysteine
    • Inflammation
    • Stroke
    • Depression