Immune-inflammatory, oxidative stress and biochemical biomarkers predict short-term acute ischemic stroke death

  • Edna Maria Vissoci ReicheEmail author
  • Jair Roberto Gelinksi
  • Daniela Frizon Alfieri
  • Tamires Flauzino
  • Marcio Francisco Lehmann
  • Maria Caroline Martins de Araújo
  • Marcell Alysson Batisti Lozovoy
  • Andrea Name Colado Simão
  • Elaine Regina Delicato de Almeida
  • Michael Maes
Original Article


The aim of the study was to define new immune-inflammatory, oxidative stress and biochemical biomarkers, which predict mortality within a period of 3 months after acute ischemic stroke (AIS). We recruited 176 healthy volunteers and 145 AIS patients, categorized as AIS survivors and non-survivors, and measured interleukin (IL)-6, high sensitivity C-reactive protein (hsCRP), ferritin, iron, total serum protein (TSP), erythrocyte sedimentation rate (ESR), white blood cells (WBC), 25 hydroxyvitamin D [25(OH)D], lipid hydroperoxides (CL-LOOH), insulin, glucose and high-density lipoprotein (HDL)-cholesterol. In patients, these biomarkers were measured within 24 h after AIS onset. We also computed two composite scores reflecting inflammatory indices, namely INFLAM index1 (sum of z scores of hsCRP+IL-6 + ferritin+ESR + WBC) and INFLAM index2 (z INFLAM index1 – z 25(OH)D – z iron + z TSP). Three months after AIS, non-survivors (n = 54) showed higher baseline levels of IL-6, hsCRP, ferritin and glucose and lower levels of HDL-cholesterol and 25(OH)D than survivors (n = 91). Non-survivors showed higher baseline ESR and lowered TSP than controls, while survivors occupied an intermediate position. Death after AIS was best predicted by increased IL-6, glucose, ferritin and CL-LOOH and lowered 25(OH)D levels. The area under the receiver operating curves computed on the INFLAM index1 and 2 scores were 0.851 and 0.870, respectively. In conclusion, activation of peripheral immune-inflammatory, oxidative and biochemical pathways is critically associated with mortality after AIS. Our results may contribute to identify new biomarker sets, which may predict post-stroke death, as well as suggest that IL-6 trans-signaling coupled with redox imbalances may be possible new targets in the prevention of short-term outcome AIS death.


Ischemic stroke Mortality Inflammation IL-6 Oxidative stress Biomarkers 



Thanks to the Institutional Program for Scientific Initiation Scholarship (PIBIC) of the National Council for Scientific and Technological Development (CNPq); Clinical and Laboratory Pathophysiology Postgraduate Program, Health Sciences Center, State University of Londrina, Londrina, Paraná, Brazil; and Health Sciences Postgraduate Program, Health Sciences Center, State University of Londrina, Londrina, Paraná, Brazil.

Authors’ contributions

Study concept and design: EMVR and ANCS; acquisition of data: JRG, DFA, TF, MFL, MCMA; analysis and interpretation of data: EMVR, ANCS, MM; drafting of the manuscript: EMVR and MM; statistical analysis: MM; study supervision: EMVR, ERDA.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Acharjee S, Boden WE, Hartigan PM, Teo KK, Maron DJ, Sedlis SP, Kostuk W, Spertus JA, Dada M, Chaitman BR, Mancini GB, Weintraub WS (2013) Low levels of high-density lipoprotein cholesterol and increased risk of cardiovascular events in stable ischemic heart disease patients: a post-hoc analysis from the COURAGE trial (clinical outcomes utilizing revascularization and aggressive drug evaluation). J Am Coll Cardiol 62(20):1826–1833Google Scholar
  2. Adams HP, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE 3rd (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 24:35–41Google Scholar
  3. Ago T, Matsuo R, Hata J, Wakisaka Y, Kuroda J, Kitazono T, Kamouchi M, Investigators FSR (2018) Insulin resistance and clinical outcomes after acute ischemic stroke. Neurology 90:e1470–e1477Google Scholar
  4. Alfieri DF, Lehmann MF, Oliveira SR, Flauzino T, Delongui F, de Araújo MC, Dichi I, Delfino VD, Mezzaroba L, Simão AN, Reiche EM (2017) Vitamin D deficiency is associated with acute ischemic stroke, C-reactive protein, and short-term outcome. Metab Brain Dis 32(2):493–502Google Scholar
  5. American Diabetes Association (2014) Standards of medical care in diabetes--2014. Diabetes Care 37(Suppl 1):S14–S80Google Scholar
  6. Anderson G, Kubera M, Duda W, Lasoń W, Berk M, Maes M (2013) Increased IL-6 trans-signaling in depression: focus on the tryptophan catabolite pathway, melatonin and neuroprogression. Pharmacol Rep 65(6):1647–5164Google Scholar
  7. Anrather J, Iadecola C (2016) Inflammation and stroke: an overview. Neurotherapeutics 13(4):661–670Google Scholar
  8. Aulin J, Siegbahn A, Hijazi Z, Ezekowitz MD, Andersson U, Connolly SJ, Huber K, Reilly PA, Wallentin L, Oldgren J (2015) Interleukin-6 and C-reactive protein and risk for death and cardiovascular events in patients with atrial fibrillation. Am Heart J 170(6):1151–1160Google Scholar
  9. Becker KJ, Buckwalter M (2016) Stroke, inflammation and the immune response: Dawn of a new era. Neurotherapeutics 13(4):659–660Google Scholar
  10. Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo Ret al (2017) heart disease and stroke statistics—2017 update a report from the American Heart Association. Circulation. 2017;135 (10): e146-e603Google Scholar
  11. Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Royal Stat Soc Series b (Methodological) 57:289–300Google Scholar
  12. Berridge MJ (2017) Vitamin D deficiency accelerates ageing and age-related diseases: a novel hypothesis. J Physiol 595(22):6825–6836Google Scholar
  13. Böger CA, Götz A, Stubanus M, Banas B, Deinzer M, Krüger B, Holmer SR, Schmitz G, Riegger GA, Krämer BK (2005) C-reactive protein as predictor of death in end-stage diabetic nephropathy: role of peripheral arterial disease. Kidney Int 68(1):217–227Google Scholar
  14. Bonita R, Beaglehole R (1988) Recovery of motor function after stroke. Stroke 19:1497–1500Google Scholar
  15. Brazil (2011) Characteristics of the population and households: results of the universe. In: Charact. Popul. Households Results Universe. Accessed 8 Feb 2015
  16. Brazil (2013) Manual of routines for attention to stroke / Ministry of Health, Health Care Secretariat, Department of Specialized Care. - Brasília: Publisher of the Ministry of Health. 2013. 50 p. ISBN 978–85–334-1998-8. 1Google Scholar
  17. Bresgen N, Jaksch H, Lacher H, Ohlenschläger I, Uchida K, Eckl PM (2010) Iron-mediated oxidative stress plays an essential role in ferritin-induced cell death. Free Radic Biol Med 48(10):1347–1357Google Scholar
  18. Bruunsgaard H, Ladelund S, Pedersen AN, Schroll M, Jørgensen T, Pedersen BK (2003) Predicting death from tumour necrosis factor-alpha and interleukin-6 in 80-year-old people. Clin Exp Immunol 132(1):24–31Google Scholar
  19. Calton EK, Keane KN, Newsholme P, Soares MJ (2015) The impact of vitamin D levels on inflammatory status: a systematic review of immune cell studies. PLoS One 10(11):e0141770. Google Scholar
  20. Capes SE, Hunt D, Malmberg K, Pathak P, Gerstein HC (2001) Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview. Stroke 32(10):2426–2432Google Scholar
  21. Chapman KZ, Dale VQ, Dénes A, Bennett G, Rothwell NJ, Allan SM, McColl BW (2009) A rapid and transient peripheral inflammatory response precedes brain inflammation after experimental stroke. J Cereb Blood Flow Metab 29(11):1764–1768Google Scholar
  22. Chen X, Zhou L, Zhang Y, Yi D, Liu L, Rao W, Wu Y, Ma D, Liu X, Zhou XH, Lin H, Cheng D, Yi D (2014) Risk factors of stroke in Western and Asian countries: a systematic review and meta-analysis of prospective cohort studies. BMC Public Health 14:776Google Scholar
  23. Choudhury JH, Chowdhury TI, Nayeem A, Jahan WA (2015) Modifiable and non-modifiable risk factors of stroke: a review update. J Natl Inst Neurosci Bangladesh 1(1):22–26Google Scholar
  24. Das S, Chandra Ghosh K, Malhotra M, Yadav U, Sankar Kundu S, Kumar Gangopadhyay P (2012) Short term mortality predictors in acute stroke. Ann Neurosci 19(2):61–67Google Scholar
  25. Dávalos A, Castillo J, Marrugat J, Fernandez-Real JM, Armengou A, Cacabelos P, Rama R (2000) Body iron stores and early neurologic deterioration in acute cerebral infarction. Neurology 54(8):1568–1574Google Scholar
  26. Day SM, Duquaine D, Mundada LV, Menon RG, Khan BV, Rajagopalan S, Fay WP (2003) Chronic iron administration increases vascular oxidative stress and accelerates arterial thrombosis. Circulation 107(20):2601–2606Google Scholar
  27. de Melo LGP, Nunes SOV, Anderson G, Vargas HO, Barbosa DS, Galecki P, Carvalho AF, Maes M (2017) Shared metabolic and immune-inflammatory, oxidative and nitrosative stress pathways in the metabolic syndrome and mood disorders. Prog Neuro-Psychopharmacol Biol Psychiatry 78:34–50Google Scholar
  28. Demarin V, Lisak M, Morović S, Cengić T (2010) Low high-density lipoprotein cholesterol as the possible risk factor for stroke. Acta Clin Croat 49(4):429–439Google Scholar
  29. Denti L, Cecchetti A, Annoni V, Merli MF, Ablondi F, Valenti G (2003) The role of lipid profile in determining the risk of ischemic stroke in the elderly: a case-control study. Arch Gerontol Geriatr 37(1):51–62Google Scholar
  30. Dominitzki S, Fantini MC, Neufert C, Nikolaev A, Galle PR, Scheller J, Monteleone G, Rose-John S, Neurath MF, Becker C (2007) Cutting edge: trans-signaling via the soluble IL-6R abrogates the induction of FoxP3 in naive CD4+CD25 T cells. J Immunol 179(4):2041–2045Google Scholar
  31. Erdemoglu AK, Ozbakir S (2002) Serum ferritin levels and early prognosis of stroke. Eur J Neurol 9(6):633–637Google Scholar
  32. Erta M, Quintana A, Hidalgo J (2012) Interleukin-6, a major cytokine in the central nervous system. Int J Biol Sci 8(9):1254–1266Google Scholar
  33. Feigin VL, Krishnamurthi RV, Parmar P, Norrving B, Mensah GA, Bennett DA Barker-Collo S, Moran AE, Sacco RL, Truelsen T, Davis S, Pandian JD, Naghavi M, Forouzanfar MH, Nguyen G, Johnson CO, Vos T, Meretoja A, Murray CJ, Roth GA, GBD (2013) Writing group; GBD 2013 stroke panel experts group (2015) update on the global burden of Ischaemic and Haemorrhagic stroke in 1990–2013: the GBD 2013 study. Neuroepidemiology 45(3):161–176Google Scholar
  34. Feigin VL, Roth GA, Naghavi M, Parmar P, Krishnamurthi R, Chugh S, Mensah GA, Norrving B, Shiue I, Ng M, Estep K, Cercy K, CJL M, Forouzanfar MH, Global Burden of Diseases, Injuries and Risk Factors Study 2013 and Stroke Experts Writing Group (2016) Global burden of stroke and risk factors in 188 countries, during 1990-2013: a systematic analysis for the global burden of disease study 2013. Lancet Neurol 15(9):913–924Google Scholar
  35. Feigin VL, Norrving B, Mensah GA (2017) Global burden of stroke. Circ Res 120(3):439–448Google Scholar
  36. Gasparova I, Kubatka P, Opatrilova R, Caprnda M, Filipova S, Rodrigo L, Malan L, Mozos I, Rabajdova M, Nosal V, Kobyliak N, Valentova V, Petrovic D, Adamek M, Kruzliak P (2017) Perspectives and challenges of antioxidant therapy for atrial fibrillation. Naunyn Schmiedeberg's Arch Pharmacol 390(1):1–14Google Scholar
  37. Ginsberg MD, Welsh FA, Budd WW (1980) Deleterious effect of glucose pretreatment on recovery from diffuse cerebral ischemia in the cat. I Local cerebral blood flow and glucose utilization Stroke 11(4):347–354Google Scholar
  38. Gonzales-Flecha BG, Llesuy S, Boveris A (1991) Hydroperoxide-initiated chemiluminescence: an assay for oxidative stress in biopsies of heart, liver, and muscle. Free Radic Biol Med 10:93–100Google Scholar
  39. Goodson NJ, Symmons DP, Scott DG, Bunn D, Lunt M, Silman AJ (2005) Baseline levels of C-reactive protein and prediction of death from cardiovascular disease in patients with inflammatory polyarthritis: a ten-year follow-up study of a primary care-based inception cohort. Arthritis Rheum 52(8):2293–2299Google Scholar
  40. Gröschel K, Ernemann U, Larsen J, Knauth M, Schmidt F, Artschwager J, Kastrup A (2007) Preprocedural C-reactive protein levels predict stroke and death in patients undergoing carotid stenting. AJNR Am J Neuroradiol 28(9):1743–1746Google Scholar
  41. Gupta A, Prabhakar S, Modi M, Bhadada SK, Lal V, Khurana D (2014) Vitamin D status and risk of ischemic stroke in north Indian patients. Indian J Endocrinol Metab 18(5):721–725Google Scholar
  42. Hénon H, Godefroy O, Leys D, Mounier-Vehier F, Lucas C, Rondepierre P, Duhamel A, Pruvo JP (1995) Early predictors of death and disability after acute cerebral ischemic event. Stroke 26(3):392–398Google Scholar
  43. Hirano T (2010) Interleukin 6 in autoimmune and inflammatory diseases: a personal memoir. Proc Jpn Acad Ser B Phys Biol Sci 86(7):717–730Google Scholar
  44. Huerta S, Bui T, Porral D, Lush S, Cinat M (2005) Predictors of morbidity and mortality in patients with traumatic duodenal injuries. Am Surg 71(9):763–767Google Scholar
  45. James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, Lackland DT, LeFevre ML, MacKenzie TD, Ogedegbe O, Smith SC Jr, Svetkey LP, Taler SJ, Townsend RR, Wright JT Jr, Narva AS, Ortiz E (2014) 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the eighth joint National Committee (JNC 8). JAMA 311(5):507–520Google Scholar
  46. Jones GW, McLoughlin RM, Hammond VJ, Parker CR, Williams JD, Malhotra R, Scheller J, Williams AS, Rose-John S, Topley N, Jones SA (2010) Loss of CD4+ T cell IL-6R expression during inflammation underlines a role for IL-6 trans-signaling in the local maintenance of Th17 cells. J Immunol 184(4):2130–2139Google Scholar
  47. Kell DB, Pretorius E (2014) Serum ferritin is an important inflammatory disease marker, as it is mainly a leakage product from damaged cells. Metallomics 6(4):748–773Google Scholar
  48. Kes VB, Solter VV, Supanc V, Demarin V (2007) Impact of hyperglycemia on ischemic stroke mortality in diabetic and non-diabetic patients. Ann Saudi Med 27(5):352–355Google Scholar
  49. Kienreich K, Grubler M, Tomaschitz A, Schmid J, Verheyen N, Rutters F, Dekker JM, Pilz S (2013) Vitamin D, arterial hypertension & cerebrovascular disease. Indian J Med Res 137(4):669–679Google Scholar
  50. Kim K, Cho KH, Im SH, Choi J, Yu J, Kim M (2017) Decrement of serum vitamin D level after stroke. Ann Rehabil Med 41(6):944–950Google Scholar
  51. Knovich MA, Storey JA, Coffman LG, Torti SV, Torti FM (2009) Ferritin for the clinician. Blood Rev 23(3):95–104Google Scholar
  52. Kobune M, Kohgo Y, Kato J, Miyazaki E, Niitsu Y (1994) Interleukin-6 enhances hepatic transferrin uptake and ferritin expression in rats. Hepatology 19(6):1468–1475Google Scholar
  53. Koton S, Tanne D, Green MS, Bornstein NM (2010) Mortality and predictors of death 1 month and 3 years after first-ever ischemic stroke: data from the first national acute stroke Israeli survey (NASIS 2004). Neuroepidemiology 34(2):90–96Google Scholar
  54. Kurth T, Gaziano JM, Berger K, Kase CS, Rexrode KM, Cook NR, Buring JE, Manson JE (2002) Body mass index and the risk of stroke in men. Arch Intern Med 162(22):2557–2562Google Scholar
  55. Lawrence DW, Sharma B (2016) A review of the neuroprotective role of vitamin D in traumatic brain injury with implications for supplementation post-concussion. Brain Inj 30(8):960–968Google Scholar
  56. Lepper PM, Ott S, Nüesch E, von Eynatten M, Schumann C, Pletz MW, Mealing NM, Welte T, Bauer TT, Suttorp N, Jüni P, Bals R, Rohde G; German Community Acquired Pneumonia Competence Network (2012) Serum glucose levels for predicting death in patients admitted to hospital for community acquired pneumonia: prospective cohort study. BMJ 28;344:e3397Google Scholar
  57. Lombardi R, Pisano G, Fargion S (2016) Role of serum uric acid and ferritin in the development and progression of NAFLD. Int J Mol Sci 17(4):548. Google Scholar
  58. Luo Y, Li J, Zhang J, Xu Y (2014) Low HDL cholesterol is correlated to the acute ischemic stroke with diabetes mellitus. Lipids Health Dis 13:171. Google Scholar
  59. Maes M, Van de Vyvere J, Vandoolaeghe E, Bril T, Demedts P, Wauters A, Neels H (1996) Alterations in iron metabolism and the erythron in major depression: further evidence for a chronic inflammatory process. J Affect Disord 40(1–2):23–33Google Scholar
  60. Maes M, Fišar Z, Medina M, Scapagnini G, Nowak G, Berk M (2012) New drug targets in depression: inflammatory, cell-mediated immune, oxidative and nitrosative stress, mitochondrial, antioxidant, and neuroprogressive pathways. And new drug candidates--Nrf2 activators and GSK-3 inhibitors. Inflammopharmacology 20(3):127–150Google Scholar
  61. Maes M, Anderson G, Kubera M, Berk M (2014) Targeting classical IL-6 signalling or IL-6 trans-signalling in depression? Expert Opin Ther Targets 18(5):495–512Google Scholar
  62. Manouchehri N, Vakil-Asadollahi M, Zandifar A, Rasmani F, Saadatnia M (2017) Vitamin D status in small vessel and large vessel ischemic stroke patients: a case-control study. Adv Biomed Res 6:146. Google Scholar
  63. Matsuo R, Ago T, Hata J, Wakisaka Y, Kuroda J, Kuwashiro T, Kitazono T, Kamouchi M, Fukuoka Stroke Registry Investigators (2016) Plasma C-reactive protein and clinical outcomes after acute ischemic stroke: a prospective observational study. PLoS One 11(6):e0156790. Google Scholar
  64. Miller CJ, Rose AL, Waite TD (2016) Importance of Iron complexation for Fenton-mediated hydroxyl radical production at Circumneutral pH. Front Mar Sci 3:134. Google Scholar
  65. Millerot E, Prigent-Tessier AS, Bertrand NM, Faure PJ, Mossiat CM, Giroud ME, Beley AG, Marie C (2005) Serum ferritin in stroke: a marker of increased body iron stores or stroke severity? J Cereb Blood Flow Metab 25(10):1386–1393Google Scholar
  66. Mokhatari Z, Hekmatdoost Z, Nourian M (2017) Antioxidant efficacy of vitamin D. J Parathyr Dis 5(1):11–16Google Scholar
  67. Morris G, Berk M, Carvalho AF, Maes M, Walker AJ, Puri BK (2018) Why should neuroscientists worry about iron? The emerging role of ferroptosis in the pathophysiology of neuroprogressive diseases. Behav Brain Res 341:154–175Google Scholar
  68. Nakagawa H, Tamura T, Mitsuda Y, Goto Y, Kamiya Y, Kondo T, Wakai K, Hamajima N (2014) Inverse correlation between serum interleukin-6 and iron levels among Japanese adults: a cross-sectional study. BMC Hematol 14(1):6. Google Scholar
  69. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) (2002) Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III) final report. Circulation 106(25):3143–3421Google Scholar
  70. Natuva SSK, Tirupati S, Reddy AP, Vallampalli G, Gandra S (2016) Independent predictors of severity and functional outcome of acute ischemic stroke in patients with diabetes. J Neurol Exp Neurosci 2(1):15–20Google Scholar
  71. Opatrilova R, Caprnda M, Kubatka P, Valentova V, Uramova S, Nosal V, Gaspar L, Zachar L, Mozos I, Petrovic D, Dragasek J, Filipova S, Büsselberg D, Zulli A, Rodrigo L, Kruzliak P, Krasnik V (2018) Adipokines in neurovascular diseases. Biomed Pharmacother 98:424–432Google Scholar
  72. Park KY, Chung PW, Kim YB, Moon HS, Suh BC, Won YS, Kim JM, Youn YC, Kwon OS (2015) Serum vitamin D status as a predictor of prognosis in patients with acute ischemic stroke. Cerebrovasc Dis 40:73–80Google Scholar
  73. Poole KE, Loveridge N, Barker PJ, Halsall DJ, Rose C, Reeve J, Warburton EA (2006) Reduced vitamin D in acute stroke. Stroke 37(1):243–245Google Scholar
  74. Proctor MJ, McMillan DC, Horgan PG, Fletcher CD, Talwar D, Morrison DS (2015) Systemic inflammation predicts all-cause mortality: a Glasgow inflammation outcome study. PLoS One 10(3):e0116206. Google Scholar
  75. Pulsinelli WA, Waldman S, Rawlinson D, Plum F (1982) Moderate hyperglycemia augments ischemic brain damage: a neuropathologic study in the rat. Neurology 32(11):1239–1246Google Scholar
  76. Ridker PM (2008) High-sensitivity C-reactive protein as a predictor of all-cause mortality: implications for research and patient care. Clin Chem 54(2):234–237Google Scholar
  77. Rodrigo R, Fernández-Gajardo R, Gutiérrez R, Matamala JM, Carrasco R, Miranda-Merchak A, Feuerhake W (2013) Oxidative stress and pathophysiology of ischemic stroke: novel therapeutic opportunities. CNS Neurol Disord Drug Targets 12(5):698–714Google Scholar
  78. Sacco RL (1997) Risk factors, outcomes, and stroke subtypes for ischemic stroke. Neurology 49(5 Suppl 4):S39–S44Google Scholar
  79. Shirley R, Ord EN, Work LM (2014) Oxidative stress and the use of antioxidants in stroke. Antioxidants (Basel) 3(3):472–501Google Scholar
  80. Singh-Manoux A, Shipley MJ, Bell JA, Canonico M, Elbaz A, Kivimäki M (2017) Association between inflammatory biomarkers and all-cause, cardiovascular and cancer-related mortality. CMAJ 189(10):E384–E390. Google Scholar
  81. Song EC, Chu K, Jeong SW, Jung KH, Kim SH, Kim M, Yoon BW (2003) Hyperglycemia exacerbates brain edema and perihematomal cell death after intracerebral hemorrhage. Stroke 34(9):2215–2220Google Scholar
  82. Strong K, Mathers C, Bonita R (2007) Preventing stroke: saving lives around the world. Lancet Neurol 6(2):182–187Google Scholar
  83. Sun Q, Pan A, Hu FB, Manson JE, Rexrode KM (2012) 25-Hydroxyvitamin D levels and the risk of stroke: a prospective study and meta-analysis. Stroke 43(6):1470–1477Google Scholar
  84. Tobin MK, Bonds JA, Minshall RD, Pelligrino DA, Testai FD, Lazarov O (2014) Neurogenesis and inflammation after ischemic stroke: what is known and where we go from here. J Cereb Blood Flow Metab 34(10):1573–1584Google Scholar
  85. Tomlinson DR, Gardiner NJ (2008) Glucose neurotoxicity. Nat Rev Neurosci 9(1):36–45Google Scholar
  86. Tziomalos K, Dimitriou P, Bouziana SD, Spanou M, Kostaki S, Angelopoulou SM, Papadopoulou M, Giampatzis V, Savopoulos C, Hatzitolios AI (2017) Stress hyperglycemia and acute ischemic stroke in-hospital outcome. Metabolism 67:99–105Google Scholar
  87. van der A DL, Grobbee DE, Roest M, Marx JJ, Voorbij HA, van der Schouw YT (2005) Serum ferritin is a risk factor for stroke in postmenopausal women. Stroke 36(8):1637–1641Google Scholar
  88. Van Hunsel F, Wauters A, Vandoolaeghe E, Neels H, Demedts P, Maes M (1996) Lower total serum protein, albumin, and beta- and gamma-globulin in major and treatment-resistant depression: effects of antidepressant treatments. Psychiatry Res 65(3):159–169Google Scholar
  89. Wang R, Ashwal S, Tone B, Tian HR, Badaut J, Rasmussen A, Obenaus A (2007) Albumin reduces blood-brain barrier permeability but does not alter infarct size in a rat model of neonatal stroke. Pediatr Res 62(3):261–266Google Scholar
  90. Wang W, Knovich MA, Coffman LG, Torti FM, Torti SV (2010) Serum ferritin: past, present and future. Biochim Biophys Acta 1800(8):760–769Google Scholar
  91. Wang Y, Ji H, Tong Y, Zhang Z (2014) Prognostic value of serum 25-Hydroxyvitamin D in patients with stroke. Neurochem Res 39:1332–1337Google Scholar
  92. Wang W, Zhang Y, Lee ET, Howard BV, Devereux RB, Cole SA, Best LG, Welty TK, Rhoades E, Yeh J, Ali T, Kizer JR, Kamel H, Shara N, Wiebers DO, Stoner JA (2017) Risk factors and prediction of stroke in a population with high prevalence of diabetes: the Strong heart study. World J Cardiovasc Dis 7(5):145–162Google Scholar
  93. Wrzosek M, Łukaszkiewicz J, Wrzosek M, Jakubczyk A, Matsumoto H, Piątkiewicz P, Radziwoń-Zaleska M, Wojnar M, Nowicka G (2013) Vitamin D and the central nervous system. Pharmacol Rep 65(2):271–278Google Scholar
  94. Zielińska-Dawidziak M (2015) Plant ferritin - a source of iron to prevent its deficiency. Nutrients 7(2):1184–18201Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Edna Maria Vissoci Reiche
    • 1
    Email author
  • Jair Roberto Gelinksi
    • 2
  • Daniela Frizon Alfieri
    • 3
  • Tamires Flauzino
    • 3
  • Marcio Francisco Lehmann
    • 4
  • Maria Caroline Martins de Araújo
    • 5
  • Marcell Alysson Batisti Lozovoy
    • 1
  • Andrea Name Colado Simão
    • 1
  • Elaine Regina Delicato de Almeida
    • 1
  • Michael Maes
    • 6
    • 7
    • 8
  1. 1.Department of Pathology, Clinical Analysis, and Toxicology, Health Sciences CenterLondrina State UniversityLondrinaBrazil
  2. 2.Clinical and Laboratory Pathophysiology Postgraduate Program, Health Sciences CenterState University of LondrinaLondrinaBrazil
  3. 3.Health Sciences Postgraduate Program, Health Sciences CenterState University of LondrinaLondrinaBrazil
  4. 4.Department of Clinical Surgery, Health Sciences Center, and Neurosurgery Service of the University HospitalState University of LondrinaLondrinaBrazil
  5. 5.Neurology Postgraduate Program, Health Sciences CenterState University of LondrinaLondrinaBrazil
  6. 6.IMPACT Strategic Research Centre, School of MedicineDeakin UniversityGeelongAustralia
  7. 7.Department of Psychiatry, Faculty of MedicineChulalongkorn UniversityBangkokThailand
  8. 8.Department of PsychiatryMedical University PlovdivPlovdivBulgaria

Personalised recommendations