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Cerebrospinal fluid biomarker candidates of schizophrenia: where do we stand?

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European Archives of Psychiatry and Clinical Neuroscience Aims and scope Submit manuscript

Abstract

Here, we review the cerebrospinal fluid (CSF) candidate markers with regard to their clinical relevance as potential surrogates for disease activity, prognosis assessment, and predictors of treatment response. We searched different online databases such as MEDLINE and EMBASE for studies on schizophrenia and CSF. Initial studies on cerebrospinal fluid in patients with schizophrenia revealed increased brain–blood barrier permeability with elevated total protein content, increased CSF-to-serum ratio for albumin, and intrathecal production of immunoglobulins in subgroups of patients. Analyses of metabolites in CSF suggest alterations within glutamatergic neurotransmission as well as monoamine and cannabinoid metabolism. Decreased levels of brain-derived neurotrophic factor and nerve growth factor in CSF of first-episode patients with schizophrenia reported in recent studies point to a dysregulation of neuroprotective and neurodevelopmental processes. Still, these findings must be considered as non-specific. A more profound characterization of the particular psychopathological profiles, the investigation of patients in the prodromal phase or within the first episode of schizophrenia promoting longitudinal investigations, implementation of different approaches of proteomics, and rigorous adherence to standard procedures based on international CSF guidelines are necessary to improve the quality of CSF studies in schizophrenia, paving the way for identification of syndrome-specific biomarker candidates.

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References

  1. Albrecht P, Torrey EF, Boone E, Hicks JT, Daniel N (1980) Raised cytomegalovirus-antibody level in cerebrospinal fluid of schizophrenic patients. Lancet 2:769–772

    Article  PubMed  CAS  Google Scholar 

  2. Alder J, Thakker-Varia S, Bangasser DA, Kuroiwa M, Plummer MR, Shors TJ, Black IB (2003) Brain-derived neurotrophic factor-induced gene expression reveals novel actions of VGF in hippocampal synaptic plasticity. J Neurosci 23:10800–10808

    PubMed  CAS  Google Scholar 

  3. Amminger GP, McGorry PD, Berger GE, Wade D, Yung AR, Phillips LJ, Harrigan SM, Francey SM, Yolken RH (2007) Antibodies to infectious agents in individuals at ultra-high risk for psychosis. Biol Psychiatry 61:1215–1217

    Article  PubMed  CAS  Google Scholar 

  4. Amminger GP, Schafer MR, Papageorgiou K, Klier CM, Cotton SM, Harrigan SM, Mackinnon A, McGorry PD, Berger GE (2010) Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebo-controlled trial. Arch Gen Psychiatry 67:146–154

    Article  PubMed  CAS  Google Scholar 

  5. Araque A, Parpura V, Sanzgiri RP, Haydon PG (1999) Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci 22:208–215

    Article  PubMed  CAS  Google Scholar 

  6. Aurell A, Rosengren LE, Karlsson B, Olsson JE, Zbornikova V, Haglid KG (1991) Determination of S-100 and glial fibrillary acidic protein concentrations in cerebrospinal fluid after brain infarction. Stroke 22:1254–1258

    Article  PubMed  CAS  Google Scholar 

  7. Axelsson R, Martensson E, Alling C (1982) Impairment of the blood-brain barrier as an aetiological factor in paranoid psychosis. Br J Psychiatry 141:273–281

    Article  PubMed  CAS  Google Scholar 

  8. Barak V, Barak Y, Levine J, Nisman B, Roisman I (1995) Changes in interleukin-1 beta and soluble interleukin-2 receptor levels in CSF and serum of schizophrenic patients. J Basic Clin Physiol Pharmacol 6:61–69

    Article  PubMed  CAS  Google Scholar 

  9. Bauer K, Kornhuber J (1987) Blood-cerebrospinal fluid barrier in schizophrenic patients. Eur Arch Psychiatry Neurol Sci 236:257–259

    Article  PubMed  CAS  Google Scholar 

  10. Beaudry P, Cohen P, Brandel JP, Delasnerie-Laupretre N, Richard S, Launay JM, Laplanche JL (1999) 14–3-3 protein, neuron-specific enolase, and S-100 protein in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. Dement Geriatr Cogn Disord 10:40–46

    Article  PubMed  CAS  Google Scholar 

  11. Bechter K, Reiber H, Herzog S, Fuchs D, Tumani H, Maxeiner HG (2010) Cerebrospinal fluid analysis in affective and schizophrenic spectrum disorders: identification of subgroups with immune responses and blood-CSF barrier dysfunction. J Psychiatr Res 44:321–330

    Article  CAS  Google Scholar 

  12. Ben-Shachar D, Livne E, Spanier I, Leenders KL, Youdim MB (1994) Typical and atypical neuroleptics induce alteration in blood-brain barrier and brain 59FeCl3 uptake. J Neurochem 62:1112–1118

    Article  PubMed  CAS  Google Scholar 

  13. Bendikov I, Nadri C, Amar S, Panizzutti R, De Miranda J, Wolosker H, Agam G (2007) A CSF and postmortem brain study of d-serine metabolic parameters in schizophrenia. Schizophr Res 90:41–51

    Article  PubMed  Google Scholar 

  14. Bianchi R, Giambanco I, Donato R (1993) S-100 protein, but not calmodulin, binds to the glial fibrillary acidic protein and inhibits its polymerization in a Ca(2 +)-dependent manner. J Biol Chem 268:12669–12674

    PubMed  CAS  Google Scholar 

  15. Blennow K, Fredman P, Wallin A, Gottfries CG, Karlsson I, Langstrom G, Skoog I, Svennerholm L, Wikkelso C (1993) Protein analysis in cerebrospinal fluid. II. Reference values derived from healthy individuals 18–88 years of age. Eur Neurol 33:129–133

    Article  PubMed  CAS  Google Scholar 

  16. Blennow K, Fredman P, Wallin A, Gottfries CG, Langstrom G, Svennerholm L (1993) Protein analyses in cerebrospinal fluid. I. Influence of concentration gradients for proteins on cerebrospinal fluid/serum albumin ratio. Eur Neurol 33:126–128

    Article  PubMed  CAS  Google Scholar 

  17. Blennow K, Fredman P, Wallin A, Gottfries CG, Skoog I, Wikkelso C, Svennerholm L (1993) Protein analysis in cerebrospinal fluid. III. Relation to blood-cerebrospinal fluid barrier function for formulas for quantitative determination of intrathecal IgG production. Eur Neurol 33:134–142

    Article  PubMed  CAS  Google Scholar 

  18. Blennow K, Vanmechelen E, Hampel H (2001) CSF total tau, Abeta42 and phosphorylated tau protein as biomarkers for Alzheimer’s disease. Mol Neurobiol 24:87–97

    Article  PubMed  CAS  Google Scholar 

  19. Bock E (1978) Immunoglobulins, prealbumin, transferrin, albumin, and alpha2-macroglobulin in cerebrospinal fluid and serum in schizophrenic patients. Birth Defects Orig Artic Ser 14:283–295

    PubMed  CAS  Google Scholar 

  20. Brettschneider J, Claus A, Kassubek J, Tumani H (2005) Isolated blood-cerebrospinal fluid barrier dysfunction: prevalence and associated diseases. J Neurol 252:1067–1073

    Article  PubMed  CAS  Google Scholar 

  21. Brown KW, Kynoch PA, Thompson RJ (1980) Immunoreactive nervous system of specific enolase (14–3-2 protein) in human serum and cerebrospinal fluid. Clin Chim Acta 101:257–264

    Article  PubMed  CAS  Google Scholar 

  22. Bruetsch WL, Bahr MA, Skobba JS, Dieter WJ (1942) The group of dementia praecox patients with an increase of the protein content of the cerebrospinal fluid. J Nerv Ment Dis 95:669–679

    Google Scholar 

  23. Buckley PF, Pillai A, Evans D, Stirewalt E, Mahadik S (2007) Brain derived neurotropic factor in first-episode psychosis. Schizophr Res 91:1–5

    Article  PubMed  Google Scholar 

  24. Buttner T, Weyers S, Postert T, Sprengelmeyer R, Kuhn W (1997) S-100 protein: serum marker of focal brain damage after ischemic territorial MCA infarction. Stroke 28:1961–1965

    Article  PubMed  CAS  Google Scholar 

  25. Chapman ER (2002) Synaptotagmin: a Ca(2 +) sensor that triggers exocytosis? Natl Rev Mol Cell Biol 3:498–508

    Article  CAS  Google Scholar 

  26. Chen da C, Wang J, Wang B, Yang SC, Zhang CX, Zheng YL, Li YL, Wang N, Yang KB, Xiu MH, Kosten TR, Zhang XY (2009) Decreased levels of serum brain-derived neurotrophic factor in drug-naive first-episode schizophrenia: relationship to clinical phenotypes. Psychopharmacology (Berl) 207:375–380

    Article  CAS  Google Scholar 

  27. Corradini I, Verderio C, Sala M, Wilson MC, Matteoli M (2009) SNAP-25 in neuropsychiatric disorders. Ann N Y Acad Sci 1152:93–99

    Article  PubMed  CAS  Google Scholar 

  28. Crols R, Saerens J, Noppe M, Lowenthal A (1986) Increased GFAp levels in CSF as a marker of organicity in patients with Alzheimer’s disease and other types of irreversible chronic organic brain syndrome. J Neurol 233:157–160

    Article  PubMed  CAS  Google Scholar 

  29. Delisi LE, Weinberger DR, Potkin S, Neckers LM, Shiling DJ, Wyatt RJ (1981) Quantitative determination of immunoglobulins in CSF and plasma of chronic schizophrenic patients. Br J Psychiatry 139:513–518

    Google Scholar 

  30. Dencker SJ, Zethraeus S (1961) Sex differences in total protein content of cerebrospinal fluid. Acta Psychiatr Scand 36:76–82

    Google Scholar 

  31. Do KQ, Lauer CJ, Schreiber W, Zollinger M, Gutteck-Amsler U, Cuenod M, Holsboer F (1995) gamma-Glutamylglutamine and taurine concentrations are decreased in the cerebrospinal fluid of drug-naive patients with schizophrenic disorders. J Neurochem 65:2652–2662

    Article  PubMed  CAS  Google Scholar 

  32. Durany N, Michel T, Zochling R, Boissl KW, Cruz-Sanchez FF, Riederer P, Thome J (2001) Brain-derived neurotrophic factor and neurotrophin 3 in schizophrenic psychoses. Schizophr Res 52:79–86

    Article  PubMed  CAS  Google Scholar 

  33. Egan MF, el-Mallakh RS, Suddath RL, Lohr JB, Bracha HS, Wyatt RJ (1992) Cerebrospinal fluid and serum levels of neuron-specific enolase in patients with schizophrenia. Psychiatry Res 43:187–195

    Article  PubMed  CAS  Google Scholar 

  34. el-Mallakh RS, Suddath RL, Wyatt RJ (1993) Interleukin-1 alpha and interleukin-2 in cerebrospinal fluid of schizophrenic subjects. Prog Neuropsychopharmacol Biol Psychiatry 17:383–391

    Article  PubMed  CAS  Google Scholar 

  35. Fassbender K, Schmidt R, Schreiner A, Fatar M, Muhlhauser F, Daffertshofer M, Hennerici M (1997) Leakage of brain-originated proteins in peripheral blood: temporal profile and diagnostic value in early ischemic stroke. J Neurol Sci 148:101–105

    Article  PubMed  CAS  Google Scholar 

  36. Fernandez-Espejo E, Viveros MP, Nunez L, Ellenbroek BA, Rodriguez de Fonseca F (2009) Role of cannabis and endocannabinoids in the genesis of schizophrenia. Psychopharmacology (Berl) 206:531–549

    Article  CAS  Google Scholar 

  37. Fuchs SA, De Barse MM, Scheepers FE, Cahn W, Dorland L, der Velden MG, Klomp LW, Berger R, Kahn RS, de Koning TJ (2008) Cerebrospinal fluid d-serine and glycine concentrations are unaltered and unaffected by olanzapine therapy in male schizophrenic patients. Eur Neuropsychopharmacol 18:333–338

    Article  PubMed  CAS  Google Scholar 

  38. Giuffrida A, Leweke FM, Gerth CW, Schreiber D, Koethe D, Faulhaber J, Klosterkotter J, Piomelli D (2004) Cerebrospinal anandamide levels are elevated in acute schizophrenia and are inversely correlated with psychotic symptoms. Neuropsychopharmacology 29:2108–2114

    Article  PubMed  CAS  Google Scholar 

  39. Hashimoto K, Engberg G, Shimizu E, Nordin C, Lindstrom LH, Iyo M (2005) Reduced d-serine to total serine ratio in the cerebrospinal fluid of drug naive schizophrenic patients. Prog Neuropsychopharmacol Biol Psychiatry 29:767–769

    Article  PubMed  CAS  Google Scholar 

  40. Hashimoto K, Fukushima T, Shimizu E, Komatsu N, Watanabe H, Shinoda N, Nakazato M, Kumakiri C, Okada S, Hasegawa H, Imai K, Iyo M (2003) Decreased serum levels of d-serine in patients with schizophrenia: evidence in support of the N-methyl-D-aspartate receptor hypofunction hypothesis of schizophrenia. Arch Gen Psychiatry 60:572–576

    Article  PubMed  CAS  Google Scholar 

  41. Hayakawa T, Ushio Y, Mori T, Arita N, Yoshimine T, Maeda Y, Shimizu K, Myoga A (1979) Levels in stroke patients of CSF astroprotein, an astrocyte-specific cerebroprotein. Stroke 10:685–689

    Article  PubMed  CAS  Google Scholar 

  42. Hodel A (1998) Snap-25. Int J Biochem Cell Biol 30:1069–1073

    Article  PubMed  CAS  Google Scholar 

  43. Hoerster SA Jr, Hillman FA, Bohls SW, Lara FY, Thurman N (1963) Cerebrospinal fluid in mental diseases (a study using paper electrophoresis). Dis Nerv Syst 24:357–360

  44. Holmes E, Tsang TM, Huang JT, Leweke FM, Koethe D, Gerth CW, Nolden BM, Gross S, Schreiber D, Nicholson JK, Bahn S (2006) Metabolic profiling of CSF: evidence that early intervention may impact on disease progression and outcome in schizophrenia. PLoS Med 3:e327

    Article  PubMed  CAS  Google Scholar 

  45. Huang JT, Leweke FM, Oxley D, Wang L, Harris N, Koethe D, Gerth CW, Nolden BM, Gross S, Schreiber D, Reed B, Bahn S (2006) Disease biomarkers in cerebrospinal fluid of patients with first-onset psychosis. PLoS Med 3:e428

    Article  PubMed  CAS  Google Scholar 

  46. Huang JT, Leweke FM, Tsang TM, Koethe D, Kranaster L, Gerth CW, Gross S, Schreiber D, Ruhrmann S, Schultze-Lutter F, Klosterkotter J, Holmes E, Bahn S (2007) CSF metabolic and proteomic profiles in patients prodromal for psychosis. PLoS One 2:e756

    Article  PubMed  CAS  Google Scholar 

  47. Hunnerkopf R, Grassl J, Thome J (2007) Proteomics: biomarker research in psychiatry. Fortschr Neurol Psychiatry 75:579–586

    Article  CAS  Google Scholar 

  48. Hunter R, Jones M, Malleson A (1969) Abnormal cerebrospinal fluid protein and gammaglobulin levels in 256 patients admitted to a psychiatric unit. J Neurol Sci 9:11–38

    Google Scholar 

  49. Hur EM, Zhou FQ (2010) GSK3 signalling in neural development. Nat Rev Neurosci 11:539–551

    Article  PubMed  CAS  Google Scholar 

  50. Issa G, Wilson C, Terry AV Jr, Pillai A (2010) An inverse relationship between cortisol and BDNF levels in schizophrenia: data from human postmortem and animal studies. Neurobiol Dis 39:327–333

    Article  PubMed  CAS  Google Scholar 

  51. Jablensky A (1997) The 100-year epidemiology of schizophrenia. Schizophr Res 28:111–125

    Article  PubMed  CAS  Google Scholar 

  52. Jacobsen LK, Frazier JA, Malhotra AK, Karoum F, McKenna K, Gordon CT, Hamburger SD, Lenane MC, Pickar D, Potter WZ, Rapoport JL (1997) Cerebrospinal fluid monoamine metabolites in childhood-onset schizophrenia. Am J Psychiatry 154:69–74

    PubMed  CAS  Google Scholar 

  53. Jesse S, Steinacker P, Cepek L, von Arnim CA, Tumani H, Lehnert S, Kretzschmar HA, Baier M, Otto M (2009) Glial fibrillary acidic protein and protein S-100B: different concentration pattern of glial proteins in cerebrospinal fluid of patients with Alzheimer’s disease and Creutzfeldt-Jakob disease. J Alzheimers Dis 17:541–551

    PubMed  CAS  Google Scholar 

  54. Jessen KR, Mirsky R (1980) Glial cells in the enteric nervous system contain glial fibrillary acidic protein. Nature 286:736–737

    Article  PubMed  CAS  Google Scholar 

  55. Jethwa PH, Ebling FJ (2008) Role of VGF-derived peptides in the control of food intake, body weight and reproduction. Neuroendocrinology 88:80–87

    Article  PubMed  CAS  Google Scholar 

  56. Jiang L, Lindpaintner K, Li HF, Gu NF, Langen H, He L, Fountoulakis M (2003) Proteomic analysis of the cerebrospinal fluid of patients with schizophrenia. Amino Acids 25:49–57

    PubMed  CAS  Google Scholar 

  57. Jindal RD, Pillai AK, Mahadik SP, Eklund K, Montrose DM, Keshavan MS (2010) Decreased BDNF in patients with antipsychotic naive first episode schizophrenia. Schizophr Res 119:47–51

    Article  PubMed  Google Scholar 

  58. Joy CB, Mumby-Croft R, Joy LA (2006) Polyunsaturated fatty acid supplementation for schizophrenia. Cochrane Database Syst Rev 3:CD001257

  59. Kahn RS, Davidson M, Knott P, Stern RG, Apter S, Davis KL (1993) Effect of neuroleptic medication on cerebrospinal fluid monoamine metabolite concentrations in schizophrenia. Serotonin-dopamine interactions as a target for treatment. Arch Gen Psychiatry 50:599–605

    Article  PubMed  CAS  Google Scholar 

  60. Kale A, Joshi S, Pillai A, Naphade N, Raju M, Nasrallah H, Mahadik SP (2009) Reduced cerebrospinal fluid and plasma nerve growth factor in drug-naive psychotic patients. Schizophr Res 115:209–214

    Article  PubMed  Google Scholar 

  61. Katila H, Hurme M, Wahlbeck K, Appelberg B, Rimon R (1994) Plasma and cerebrospinal fluid interleukin-1 beta and interleukin-6 in hospitalized schizophrenic patients. Neuropsychobiology 30:20–23

    Article  PubMed  CAS  Google Scholar 

  62. Kirch DG, Kaufmann CA, Papadopoulos NM, Martin B, Weinberger DR (1985) Abnormal cerebrospinal fluid protein indices in schizophrenia. Biol Psychiatry 20:1039–1046

    Google Scholar 

  63. Kirch DG, Alexander RC, Suddath RL, Papadopoulos NM, Kaufmann CA, Daniel DG, Wyatt RJ (1992) Blood-CSF barrier permeability and central nervous system immunoglobulin G in schizophrenia. J Neural Transm Gen Sect 89:219–232

    Article  PubMed  CAS  Google Scholar 

  64. Koethe D, Giuffrida A, Schreiber D, Hellmich M, Schultze-Lutter F, Ruhrmann S, Klosterkotter J, Piomelli D, Leweke FM (2009) Anandamide elevation in cerebrospinal fluid in initial prodromal states of psychosis. Br J Psychiatry 194:371–372

    Article  PubMed  Google Scholar 

  65. Koros E, Dorner-Ciossek C (2007) The role of glycogen synthase kinase-3beta in schizophrenia. Drug News Perspect 20:437–445

    Article  PubMed  CAS  Google Scholar 

  66. Kozlovsky N, Belmaker RH, Agam G (2001) Low GSK-3 activity in frontal cortex of schizophrenic patients. Schizophr Res 52:101–105

    Article  PubMed  CAS  Google Scholar 

  67. Kozlovsky N, Belmaker RH, Agam G (2000) Low GSK-3beta immunoreactivity in postmortem frontal cortex of schizophrenic patients. Am J Psychiatry 157:831–833

    Article  PubMed  CAS  Google Scholar 

  68. Kozlovsky N, Nadri C, Agam G (2005) Low GSK-3beta in schizophrenia as a consequence of neurodevelopmental insult. Eur Neuropsychopharmacol 15:1–11

    Article  PubMed  CAS  Google Scholar 

  69. Kozlovsky N, Regenold WT, Levine J, Rapoport A, Belmaker RH, Agam G (2004) GSK-3beta in cerebrospinal fluid of schizophrenia patients. J Neural Transm 111:1093–1098

    PubMed  CAS  Google Scholar 

  70. Kranaster L, Koethe D, Hoyer C, Meyer-Lindenberg A, Leweke FM (2011) Cerebrospinal fluid diagnostics in first-episode schizophrenia. Eur Arch Psychiatry Clin Neurosci 261:529–530

    Article  PubMed  Google Scholar 

  71. Kronfol Z, Remick DG (2000) Cytokines and the brain: implications for clinical psychiatry. Am J Psychiatr 157:683–694

    Article  PubMed  CAS  Google Scholar 

  72. Lara DR, Gama CS, Belmonte-de-Abreu P, Portela LV, Goncalves CA, Fonseca M, Hauck S, Souza DO (2001) Increased serum S100B protein in schizophrenia: a study in medication-free patients. J Psychiatry Res 35:11–14

    Article  CAS  Google Scholar 

  73. Leweke FM, Gerth CW, Koethe D, Klosterkotter J, Ruslanova I, Krivogorsky B, Torrey EF, Yolken RH (2004) Antibodies to infectious agents in individuals with recent onset schizophrenia. Eur Arch Psychiatry Clin Neurosci 254:4–8

    Article  PubMed  Google Scholar 

  74. Leweke FM, Giuffrida A, Koethe D, Schreiber D, Nolden BM, Kranaster L, Neatby MA, Schneider M, Gerth CW, Hellmich M, Klosterkotter J, Piomelli D (2007) Anandamide levels in cerebrospinal fluid of first-episode schizophrenic patients: impact of cannabis use. Schizophr Res 94:29–36

    Article  PubMed  Google Scholar 

  75. Leweke FM, Giuffrida A, Wurster U, Emrich HM, Piomelli D (1999) Elevated endogenous cannabinoids in schizophrenia. Neuroreport 10:1665–1669

    Article  PubMed  CAS  Google Scholar 

  76. Li S, Wu H, Guo H, Zhao Z (2006) Neuron-specific Enolase and myelin basic protein in cerebrospinal fluid of patients with first episode schizophrenia. J Huazhong Univ Sci Technolog Med Sci 26:228–230

    Article  PubMed  CAS  Google Scholar 

  77. Licinio J, Seibyl JP, Altemus M, Charney DS, Krystal JH (1993) Elevated CSF levels of interleukin-2 in neuroleptic-free schizophrenic patients. Am J Psychiatry 150:1408–1410

    PubMed  CAS  Google Scholar 

  78. Ling SH, Tang YL, Jiang F, Wiste A, Guo SS, Weng YZ, Yang TS (2007) Plasma S-100B protein in Chinese patients with schizophrenia: comparison with healthy controls and effect of antipsychotics treatment. J Psychiatry Res 41:36–42

    Article  Google Scholar 

  79. Liu J, Shi Y, Tang J, Guo T, Li X, Yang Y, Chen Q, Zhao X, He G, Feng G, Gu N, Zhu S, Liu H, He L (2005) SNPs and haplotypes in the S100B gene reveal association with schizophrenia. Biochem Biophys Res Commun 328:335–341

    Article  PubMed  CAS  Google Scholar 

  80. Manabe T (2002) Does BDNF have pre- or postsynaptic targets? Science 295:1651–1653

    Article  PubMed  CAS  Google Scholar 

  81. Martins-de-Souza D (2010) Is the word ‘biomarker’ being properly used by proteomics research in neuroscience? Eur Arch Psychiatry Clin Neurosci 260:561–562

    Article  PubMed  Google Scholar 

  82. Martins-de-Souza D, Maccarrone G, Wobrock T, Zerr I, Gormanns P, Reckow S, Falkai P, Schmitt A, Turck CW (2010) Proteome analysis of the thalamus and cerebrospinal fluid reveals glycolysis dysfunction and potential biomarkers candidates for schizophrenia. J Psychiatry Res 44:1176–1189

    Article  Google Scholar 

  83. Martins-De-Souza D, Wobrock T, Zerr I, Schmitt A, Gawinecka J, Schneider-Axmann T, Falkai P, Turck CW (2010) Different apolipoprotein E, apolipoprotein A1 and prostaglandin-H2 D-isomerase levels in cerebrospinal fluid of schizophrenia patients and healthy controls. World J Biol Psychiatry 11:719–728

    Article  PubMed  Google Scholar 

  84. McAllister CG, van Kammen DP, Rehn TJ, Miller AL, Gurklis J, Kelley ME, Yao J, Peters JL (1995) Increases in CSF levels of interleukin-2 in schizophrenia: effects of recurrence of psychosis and medication status. Am J Psychiatry 152:1291–1297

    PubMed  CAS  Google Scholar 

  85. McGrath J, Saha S, Welham J, El Saadi O, MacCauley C, Chant D (2004) A systematic review of the incidence of schizophrenia: the distribution of rates and the influence of sex, urbanicity, migrant status and methodology. BMC Med 2:13

    Article  PubMed  Google Scholar 

  86. Miller C, Kirchmair R, Troger J, Saria A, Fleischhacker WW, Fischer-Colbrie R, Benzer A, Winkler H (1996) CSF of neuroleptic-naive first-episode schizophrenic patients: levels of biogenic amines, substance P, and peptides derived from chromogranin A (GE-25) and secretogranin II (secretoneurin). Biol Psychiatry 39:911–918

    Article  PubMed  CAS  Google Scholar 

  87. Mischak H, Apweiler R, Banks RE, Conaway M, Coon J, Dominiczak A, Ehrich JH, Fliser D, Girolami M, Hermjakob H, Hochstrasser D, Jankowski J, Julian BA, Kolch W, Massy ZA, Neusuess C, Novak J, Peter K, Rossing K, Schanstra J, Semmes OJ, Theodorescu D, Thongboonkerd V, Weissinger EM, Van Eyk JE, Yamamoto T (2007) Clinical proteomics: a need to define the field and to begin to set adequate standards. Proteomics Clin Appl 1:148–156

    Article  PubMed  CAS  Google Scholar 

  88. Misu T, Takano R, Fujihara K, Takahashi T, Sato S, Itoyama Y (2009) Marked increase in cerebrospinal fluid glial fibrillar acidic protein in neuromyelitis optica: an astrocytic damage marker. J Neurol Neurosurg Psychiatry 80:575–577

    Article  PubMed  CAS  Google Scholar 

  89. Mollenhauer B, Cepek L, Bibl M, Wiltfang J, Schulz-Schaeffer WJ, Ciesielczyk B, Neumann M, Steinacker P, Kretzschmar HA, Poser S, Trenkwalder C, Otto M (2005) Tau protein, Abeta42 and S-100B protein in cerebrospinal fluid of patients with dementia with Lewy bodies. Dement Geriatr Cogn Disord 19:164–170

    Article  PubMed  CAS  Google Scholar 

  90. Müller N, Ackenheil M (1995) Immunoglobulin and albumin content of cerebrospinal fluid in schizophrenic patients: relationship to negative symptomatology. Schizophr Res 14:223–228

    Google Scholar 

  91. Muller DJ, Klempan TA, De Luca V, Sicard T, Volavka J, Czobor P, Sheitman BB, Lindenmayer JP, Citrome L, McEvoy JP, Lieberman JA, Honer WG, Kennedy JL (2005) The SNAP-25 gene may be associated with clinical response and weight gain in antipsychotic treatment of schizophrenia. Neurosci Lett 379:81–89

    Article  PubMed  CAS  Google Scholar 

  92. Musil R, Spellmann I, Riedel M, Dehning S, Douhet A, Maino K, Zill P, Muller N, Moller HJ, Bondy B (2008) SNAP-25 gene polymorphisms and weight gain in schizophrenic patients. J Psychiatry Res 42:963–970

    Article  Google Scholar 

  93. Mustafa AK, Kumar M, Selvakumar B, Ho GP, Ehmsen JT, Barrow RK, Amzel LM, Snyder SH (2007) Nitric oxide S-nitrosylates serine racemase, mediating feedback inhibition of d-serine formation. Proc Natl Acad Sci USA 104:2950–2955

    Article  PubMed  CAS  Google Scholar 

  94. Nadri C, Dean B, Scarr E, Agam G (2004) GSK-3 parameters in postmortem frontal cortex and hippocampus of schizophrenic patients. Schizophr Res 71:377–382

    Article  PubMed  Google Scholar 

  95. Nadri C, Kozlovsky N, Agam G, Bersudsky Y (2002) GSK-3 parameters in lymphocytes of schizophrenic patients. Psychiatry Res 112:51–57

    Article  PubMed  CAS  Google Scholar 

  96. Niebuhr DW, Millikan AM, Cowan DN, Yolken R, Li Y, Weber NS (2008) Selected infectious agents and risk of schizophrenia among U.S. military personnel. Am J Psychiatry 165:99–106

    Article  PubMed  Google Scholar 

  97. Niebuhr DW, Millikan AM, Yolken R, Li Y, Weber NS (2008) Results from a hypothesis generating case-control study: herpes family viruses and schizophrenia among military personnel. Schizophr Bull 34:1182–1188

    Article  PubMed  Google Scholar 

  98. Nikkila HV, Muller K, Ahokas A, Miettinen K, Rimon R, Andersson LC (1999) Accumulation of macrophages in the CSF of schizophrenic patients during acute psychotic episodes. Am J Psychiatry 156:1725–1729

    PubMed  CAS  Google Scholar 

  99. Nikkila HV, Muller K, Ahokas A, Rimon R, Andersson LC (2001) Increased frequency of activated lymphocytes in the cerebrospinal fluid of patients with acute schizophrenia. Schizophr Res 49:99–105

    Article  PubMed  CAS  Google Scholar 

  100. Ohnuma T, Sakai Y, Maeshima H, Hatano T, Hanzawa R, Abe S, Kida S, Shibata N, Suzuki T, Arai H (2008) Changes in plasma glycine, l-serine, and d-serine levels in patients with schizophrenia as their clinical symptoms improve: results from the Juntendo University Schizophrenia Projects (JUSP). Prog Neuropsychopharmacol Biol Psychiatry 32:1905–1912

    Article  PubMed  CAS  Google Scholar 

  101. Otto M, Wiltfang J, Tumani H, Zerr I, Lantsch M, Kornhuber J, Weber T, Kretzschmar HA, Poser S (1997) Elevated levels of tau-protein in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. Neurosci Lett 225:210–212

    Article  PubMed  CAS  Google Scholar 

  102. Oxenstierna G, Bergstrand G, Bjerkenstedt L, Sedvall G, Wik G (1984) Evidence of disturbed CSF circulation and brain atrophy in cases of schizophrenic psychosis. Br J Psychiatry 144:654–661

    Article  PubMed  CAS  Google Scholar 

  103. Oxenstierna G, Bergstrand G, Edman G, Flyckt L, Nyback H, Sedvall G (1996) Increased frequency of aberrant CSF circulation in schizophrenic patients compared to healthy volunteers. Eur Psychiatry 11:16–20

    Article  PubMed  CAS  Google Scholar 

  104. Pennington K, Cotter D, Dunn MJ (2005) The role of proteomics in investigating psychiatric disorders. Br J Psychiatry 187:4–6

    Article  PubMed  CAS  Google Scholar 

  105. Petzold A, Keir G, Green AJ, Giovannoni G, Thompson EJ (2004) An ELISA for glial fibrillary acidic protein. J Immunol Methods 287:169–177

    Article  PubMed  CAS  Google Scholar 

  106. Pillai A, Kale A, Joshi S, Naphade N, Raju MS, Nasrallah H, Mahadik SP (2010) Decreased BDNF levels in CSF of drug-naive first-episode psychotic subjects: correlation with plasma BDNF and psychopathology. Int J Neuropsychopharmacol 13:535–539

    Article  PubMed  CAS  Google Scholar 

  107. Puri BK (2010) Progressive structural brain changes in schizophrenia. Expert Rev Neurother 10:33–42

    Article  PubMed  Google Scholar 

  108. Raedler TJ, Wiedemann K (2006) CSF-studies in neuropsychiatric disorders. Neuro Endocrinol Lett 27:297–305

    PubMed  CAS  Google Scholar 

  109. Rais M, van Haren NE, Cahn W, Schnack HG, Lepage C, Collins L, Evans AC, Hulshoff Pol HE, Kahn RS (2010) Cannabis use and progressive cortical thickness loss in areas rich in CB1 receptors during the first five years of schizophrenia. Eur Neuropsychopharmacol 20:855–865

    Article  PubMed  CAS  Google Scholar 

  110. Rapaport MH, McAllister CG, Pickar D, Tamarkin L, Kirch DG, Paul SM (1997) CSF IL-1 and IL-2 in medicated schizophrenic patients and normal volunteers. Schizophr Res 25:123–129

    Article  PubMed  CAS  Google Scholar 

  111. Reiber H (2001) Dynamics of brain-derived proteins in cerebrospinal fluid. Clin Chim Acta 310:173–186

    Article  PubMed  CAS  Google Scholar 

  112. Reiber H, Felgenhauer K (1987) Protein transfer at the blood cerebrospinal fluid barrier and the quantitation of the humoral immune response within the central nervous system. Clin Chim Acta 163:319–328

    Article  PubMed  CAS  Google Scholar 

  113. Reichardt LF (2003) Neurobiology: signals that make waves. Nature 426:25–26

    Article  PubMed  CAS  Google Scholar 

  114. Rizos EN, Rontos I, Laskos E, Arsenis G, Michalopoulou PG, Vasilopoulos D, Gournellis R, Lykouras L (2008) Investigation of serum BDNF levels in drug-naive patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 32:1308–1311

    Article  PubMed  CAS  Google Scholar 

  115. Roos KL (2003) Lumbar puncture. Semin Neurol 23:105–114

    Article  PubMed  Google Scholar 

  116. Rose CR, Blum R, Pichler B, Lepier A, Kafitz KW, Konnerth A (2003) Truncated TrkB-T1 mediates neurotrophin-evoked calcium signalling in glia cells. Nature 426:74–78

    Article  PubMed  CAS  Google Scholar 

  117. Rosengren LE, Ahlsen G, Belfrage M, Gillberg C, Haglid KG, Hamberger A (1992) A sensitive ELISA for glial fibrillary acidic protein: application in CSF of children. J Neurosci Methods 44:113–119

    Article  PubMed  CAS  Google Scholar 

  118. Rosenling T, Slim CL, Christin C, Coulier L, Shi S, Stoop MP, Bosman J, Suits F, Horvatovich PL, Stockhofe-Zurwieden N, Vreeken R, Hankemeier T, van Gool AJ, Luider TM, Bischoff R (2009) The effect of preanalytical factors on stability of the proteome and selected metabolites in cerebrospinal fluid (CSF). J Proteome Res 8:5511–5522

    Article  PubMed  CAS  Google Scholar 

  119. Rothermundt M, Ahn JN, Jorgens S (2009) S100B in schizophrenia: an update. Gen Physiol Biophys 28 Spec No Focus:F76–F81

  120. Rothermundt M, Falkai P, Ponath G, Abel S, Burkle H, Diedrich M, Hetzel G, Peters M, Siegmund A, Pedersen A, Maier W, Schramm J, Suslow T, Ohrmann P, Arolt V (2004) Glial cell dysfunction in schizophrenia indicated by increased S100B in the CSF. Mol Psychiatry 9:897–899

    Article  PubMed  CAS  Google Scholar 

  121. Rothermundt M, Missler U, Arolt V, Peters M, Leadbeater J, Wiesmann M, Rudolf S, Wandinger KP, Kirchner H (2001) Increased S100B blood levels in unmedicated and treated schizophrenic patients are correlated with negative symptomatology. Mol Psychiatry 6:445–449

    Article  PubMed  CAS  Google Scholar 

  122. Rothermundt M, Ponath G, Glaser T, Hetzel G, Arolt V (2004) S100B serum levels and long-term improvement of negative symptoms in patients with schizophrenia. Neuropsychopharmacology 29:1004–1011

    Article  PubMed  CAS  Google Scholar 

  123. Sarandol A, Kirli S, Akkaya C, Altin A, Demirci M, Sarandol E (2007) Oxidative-antioxidative systems and their relation with serum S100 B levels in patients with schizophrenia: effects of short term antipsychotic treatment. Prog Neuropsychopharmacol Biol Psychiatrty 31:1164–1169

    Article  CAS  Google Scholar 

  124. Scheepers FE, Gispen-de Wied CC, Westenberg HG, Kahn RS (2001) The effect of olanzapine treatment on monoamine metabolite concentrations in the cerebrospinal fluid of schizophrenic patients. Neuropsychopharmacology 25:468–475

    Article  PubMed  CAS  Google Scholar 

  125. Schmitt A, Bertsch T, Henning U, Tost H, Klimke A, Henn FA, Falkai P (2005) Increased serum S100B in elderly, chronic schizophrenic patients: negative correlation with deficit symptoms. Schizophr Res 80:305–313

    Article  PubMed  Google Scholar 

  126. Schönknecht P, Hempel A, Hunt A, Seidl U, Volkmann M, Pantel J, Schröder J (2003) Cerebrospinal fluid tau protein levels in schizophrenia. Eur Arch Psychiatry Clin Neurosci 253:100–102

    Google Scholar 

  127. Schroeter ML, Abdul-Khaliq H, Krebs M, Diefenbacher A, Blasig IE (2009) Neuron-specific enolase is unaltered whereas S100B is elevated in serum of patients with schizophrenia–original research and meta-analysis. Psychiatry Res 167:66–72

    Article  PubMed  CAS  Google Scholar 

  128. Schuller EA, Benabdallah S, Sagar HJ, Reboul JA, Tompe LC (1987) IgG synthesis within the central nervous system. Comparison of three formulas. Arch Neurol 44:600–604

    Article  PubMed  CAS  Google Scholar 

  129. Schwarz E, Bahn S (2008) Biomarker discovery in psychiatric disorders. Electrophoresis 29:2884–2890

    PubMed  CAS  Google Scholar 

  130. Schwarz E, Bahn S (2008) Cerebrospinal fluid: identification of diagnostic markers for schizophrenia. Expert Rev Mol Diagn 8:209–216

    Article  PubMed  Google Scholar 

  131. Schwarz E, Bahn S (2008) The utility of biomarker discovery approaches for the detection of disease mechanisms in psychiatric disorders. Br J Pharmacol 153(Suppl 1):S133–S136

    PubMed  CAS  Google Scholar 

  132. Schwarz MJ, Ackenheil M, Riedel M, Muller N (1998) Blood-cerebrospinal fluid barrier impairment as indicator for an immune process in schizophrenia. Neurosci Lett 253:201–203

    Article  PubMed  CAS  Google Scholar 

  133. Seehusen DA, Reeves MM, Fomin DA (2003) Cerebrospinal fluid analysis. Am Fam Physician 68:1103–1108

    PubMed  Google Scholar 

  134. Selemon LD, Goldman-Rakic PS (1999) The reduced neuropil hypothesis: a circuit based model of schizophrenia. Biol Psychiatry 45:17–25

    Article  PubMed  CAS  Google Scholar 

  135. Selemon LD, Mrzljak J, Kleinman JE, Herman MM, Goldman-Rakic PS (2003) Regional specificity in the neuropathologic substrates of schizophrenia: a morphometric analysis of Broca’s area 44 and area 9. Arch Gen Psychiatry 60:69–77

    Article  PubMed  Google Scholar 

  136. Sokol DK, O’Brien RS, Wagenknecht DR, Rao T, McIntyre JA (2007) Antiphospholipid antibodies in blood and cerebrospinal fluids of patients with psychosis. J Neuroimmunol 190:151–156

    Article  PubMed  CAS  Google Scholar 

  137. Southwell BR, Duan W, Alcorn D, Brack C, Richardson SJ, Kohrle J, Schreiber G (1993) Thyroxine transport to the brain: role of protein synthesis by the choroid plexus. Endocrinology 133:2116–2126

    Article  PubMed  CAS  Google Scholar 

  138. Spellmann I, Muller N, Musil R, Zill P, Douhet A, Dehning S, Cerovecki A, Bondy B, Moller HJ, Riedel M (2008) Associations of SNAP-25 polymorphisms with cognitive dysfunctions in Caucasian patients with schizophrenia during a brief trail of treatment with atypical antipsychotics. Eur Arch Psychiatry Clin Neurosci 258:335–344

    Article  PubMed  Google Scholar 

  139. Steiner J, Bielau H, Bernstein HG, Bogerts B, Wunderlich MT (2006) Increased cerebrospinal fluid and serum levels of S100B in first-onset schizophrenia are not related to a degenerative release of glial fibrillar acidic protein, myelin basic protein and neurone-specific enolase from glia or neurones. J Neurol Neurosurg Psychiatry 77:1284–1287

    Article  PubMed  CAS  Google Scholar 

  140. Sugerman HJ, DeMaria EJ, Felton WL 3rd, Nakatsuka M, Sismanis A (1997) Increased intra-abdominal pressure and cardiac filling pressures in obesity-associated pseudotumor cerebri. Neurology 49:507–511

    Article  PubMed  CAS  Google Scholar 

  141. Teunissen CE, Petzold A, Bennett JL, Berven FS, Brundin L, Comabella M, Franciotta D, Frederiksen JL, Fleming JO, Furlan R, Hintzen RQ, Hughes SG, Johnson MH, Krasulova E, Kuhle J, Magnone MC, Rajda C, Rejdak K, Schmidt HK, van Pesch V, Waubant E, Wolf C, Giovannoni G, Hemmer B, Tumani H, Deisenhammer F (2009) A consensus protocol for the standardization of cerebrospinal fluid collection and biobanking. Neurology 73:1914–1922

    Article  PubMed  CAS  Google Scholar 

  142. Thakker-Varia S, Alder J (2009) Neuropeptides in depression: role of VGF. Behav Brain Res 197:262–278

    Article  PubMed  CAS  Google Scholar 

  143. Thompson PM, Kelley M, Yao J, Tsai G, van Kammen DP (2003) Elevated cerebrospinal fluid SNAP-25 in schizophrenia. Biol Psychiatry 53:1132–1137

    Article  PubMed  CAS  Google Scholar 

  144. Thompson PM, Rosenberger C, Qualls C (1999) CSF SNAP-25 in schizophrenia and bipolar illness. A pilot study. Neuropsychopharmacology 21:717–722

    Article  PubMed  CAS  Google Scholar 

  145. Toorey EF, Peterson MR, Brannon WL, Carpenter WT, Post RM, Van Kammen DP (1978) Immunoglobulins and viral antibodies in psychiatric patients. Br J Psychiatry 132:342–348

    Article  PubMed  CAS  Google Scholar 

  146. Torrey EF, Albrecht P, Behr DE (1985) Permeability of the blood-brain barrier in psychiatric patients. Am J Psychiatry 142:657–658

    Google Scholar 

  147. Tumani H, Teunissen C, Sussmuth S, Otto M, Ludolph AC, Brettschneider J (2008) Cerebrospinal fluid biomarkers of neurodegeneration in chronic neurological diseases. Expert Rev Mol Diagn 8:479–494

    Article  PubMed  CAS  Google Scholar 

  148. Van Eldik LJ, Wainwright MS (2003) The Janus face of glial-derived S100B: beneficial and detrimental functions in the brain. Restor Neurol Neurosci 21:97–108

    PubMed  Google Scholar 

  149. van Haren NE, Schnack HG, Cahn W, van den Heuvel MP, Lepage C, Collins L, Evans AC, Hulshoff Pol HE, Kahn RS (2011) Changes in cortical thickness during the course of illness in schizophrenia. Arch Gen Psychiatry 68:871–880

    Article  PubMed  Google Scholar 

  150. van Kammen DP, McAllister-Sistilli CG, Kelley ME, Gurklis JA, Yao JK (1999) Elevated interleukin-6 in schizophrenia. Psychiatry Res 87:129–136

    Article  PubMed  Google Scholar 

  151. Vasic N, Wolf RC (2006) How early is it possible to detect and to treat schizophrenia? Nervenheilkunde 25:351–358

    Google Scholar 

  152. Verheecke P (1975) On the tau-protein in cerebrospinal fluid. J Neurol Sci 26:277–281

    Article  PubMed  CAS  Google Scholar 

  153. Verrall L, Walker M, Rawlings N, Benzel I, Kew JN, Harrison PJ, Burnet PW (2007) d-Amino acid oxidase and serine racemase in human brain: normal distribution and altered expression in schizophrenia. Eur J Neurosci 26:1657–1669

    Article  PubMed  Google Scholar 

  154. Wiesmann M, Wandinger KP, Missler U, Eckhoff D, Rothermundt M, Arolt V, Kirchner H (1999) Elevated plasma levels of S-100b protein in schizophrenic patients. Biol Psychiatry 45:1508–1511

    Article  PubMed  CAS  Google Scholar 

  155. Wilson RI, Nicoll RA (2002) Endocannabinoid signaling in the brain. Science 296:678–682

    Article  PubMed  CAS  Google Scholar 

  156. Wunderlich MT, Lins H, Skalej M, Wallesch CW, Goertler M (2006) Neuron-specific enolase and tau protein as neurobiochemical markers of neuronal damage are related to early clinical course and long-term outcome in acute ischemic stroke. Clin Neurol Neurosurg 108:558–563

    Article  PubMed  Google Scholar 

  157. Yolken R (2004) Viruses and schizophrenia: a focus on herpes simplex virus. Herpes 11(Suppl 2):83A–88A

    PubMed  Google Scholar 

  158. Yolken RH, Torrey EF (2008) Are some cases of psychosis caused by microbial agents? A review of the evidence. Mol Psychiatry 13:470–479

    Article  PubMed  CAS  Google Scholar 

  159. Young G, Conquer J (2005) Omega-3 fatty acids and neuropsychiatric disorders. Reprod Nutr Dev 45:1–28

    Article  PubMed  CAS  Google Scholar 

  160. Yuan J, Yankner BA (2000) Apoptosis in the nervous system. Nature 407:802–809

    Article  PubMed  CAS  Google Scholar 

  161. Zimmer DB, Cornwall EH, Landar A, Song W (1995) The S100 protein family: history, function, and expression. Brain Res Bull 37:417–429

    Article  PubMed  CAS  Google Scholar 

  162. Zimmer DB, Van Eldik LJ (1986) Identification of a molecular target for the calcium-modulated protein S100. Fructose-1, 6-bisphosphate aldolase. J Biol Chem 261:11424–11428

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Psychiatry and Psychotherapy III, University of Ulm, Leimgrubenweg 12-14, 89075, Ulm, Germany

    Nenad Vasic & Bernhard J. Connemann

  2. Department of General Psychiatry, Center of Psychosocial Medicine, University of Heidelberg, Heidelberg, Germany

    Robert C. Wolf

  3. Department of Neurology, University of Ulm, Ulm, Germany

    Hayrettin Tumani & Johannes Brettschneider

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  1. Nenad Vasic
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Vasic, N., Connemann, B.J., Wolf, R.C. et al. Cerebrospinal fluid biomarker candidates of schizophrenia: where do we stand?. Eur Arch Psychiatry Clin Neurosci 262, 375–391 (2012). https://doi.org/10.1007/s00406-011-0280-9

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