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The Neuroimmune and Neurotoxic Fingerprint of Major Neurocognitive Psychosis or Deficit Schizophrenia: a Supervised Machine Learning Study

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Abstract

No studies have examined the immune fingerprint of major neurocognitive psychosis (MNP) or deficit schizophrenia using M1 macrophage cytokines in combination with chemokines such as CCL2 and CCL11. The present study delineated the neuroimmune fingerprint of MNP by analyzing plasma levels of IL-1β, sIL-1RA, TNFα, sTNFR1, sTNFR2, CCL2, and CCL11 in 120 MNP versus 54 healthy controls in association with neurocognitive scores (as assessed with the Brief Assessment of Cognition in Schizophrenia) and PHEMN (psychotic, hostility, excitation, mannerism and negative) symptoms. MNP was best predicted by a combination of CCL11, TNFα, IL-1β, and sIL-1RA which yielded a bootstrapped (n = 2000) area under the receiver operating curve of 0.985. Composite scores reflecting M1 macrophage activity and neurotoxic potential including effects of CCL11 and CCL2 were significantly increased in MNP. A large part of the variance in PHEM (38.4–52.6%) and negative (65.8–74.4%) symptoms were explained by combinations of immune markers whereby CCL11 was the most important. The same markers explained a large part of the variance in the Mini-Mental State examination, list learning, digit sequencing task, category instances, controlled word association, symbol coding, and Tower of London. Partial least squares analysis showed that 72.7% of the variance in overall severity of schizophrenia was explained by the regression on IL-1β, sIL-1RA, CCL11, TNFα, and education. It is concluded that the combination of the abovementioned markers defines MNP as a distinct neuroimmune disorder and that increased immune neurotoxicity determines memory and executive impairments and PHEMN symptoms as well.

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References

  • Al-Hakeim HK, Al-Rammahi DA, Al-Dujaili AH (2015) IL-6, IL-18, sIL-2R, and TNFα proinflammatory markers in depression and schizophrenia patients who are free of overt inflammation. J Affect Disord 182:106–114

    CAS  PubMed  Google Scholar 

  • Al-Hakeim HK, Al-Fadhel SZ, Al-Dujaili AH, Carvalho A, Sriswasdi S, Maes M (2019) Development of a novel neuro-immune and opioid-associated fingerprint with a cross-validated ability to identify and authenticate unknown patients with major depression: far beyond differentiation, discrimination, and classification. Mol Neurobiol. https://doi.org/10.1007/s12035-019-01647-0

    CAS  PubMed  Google Scholar 

  • Anderson G, Maes M (2013) Schizophrenia: linking prenatal infection to cytokines, the tryptophan catabolite (TRYCAT) pathway, NMDA receptor hypofunction, neurodevelopment and neuroprogression. Prog Neuro-Psychopharmacol Biol Psychiatry 42:5–19

    CAS  Google Scholar 

  • Andreasen NC (1989) The scale for the assessment of negative symptoms (SANS): conceptual and theoretical foundations. Brit J Psychiatry Suppl 7:49–58

    Google Scholar 

  • Arend WP, Guthridge CJ (2000) Biological role of interleukin 1 receptor antagonist isoforms. Ann Rheum Dis 59(Suppl 1):i60–i64

    CAS  PubMed  PubMed Central  Google Scholar 

  • Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B Methodol 57:289–300

    Google Scholar 

  • Bettcher BM, Fitch R, Wynn MJ, Lalli MA, Elofson J, Jastrzab L, Mitic L, Miller ZA et al (2016) MCP-1 and eotaxin-1 selectively and negatively associate with memory in MCI and Alzheimer’s disease dementia phenotypes. Alzheimer’s Dement Diagnosis. Assess Dis Monit 3:91–97

    Google Scholar 

  • Boerrigter D, Weickert TW, Lenroot R, O’Donnell M, Galletly C, Liu D, Burgess M, Cadiz R et al (2017) Using blood cytokine measures to define high inflammatory biotype of schizophrenia and schizoaffective disorder. J Neuroinflammation 14(1):188

    PubMed  PubMed Central  Google Scholar 

  • Boll KM, Noto C, Bonifácio KL, Bortolasci CC, Gadelha A, Bressan RA, Barbosa DS, Maes M, Moreira EG (2017) Oxidative and nitrosative stress biomarkers in chronic schizophrenia. Psychiatry Res 253:43–48

    CAS  PubMed  Google Scholar 

  • Bouma MG, Buurman WA (1999) Assay of soluble tumor necrosis factor receptors. In: Evans TJ (ed) Methods in molecular medicine, vol. 36: septic shock. Humana Press, Totowa, NJ, pp 91–100

    Google Scholar 

  • Butcher L, Peres K, Andre P, Walter S, Dartigues J, Rodriguez-Manas L, Feart C, Erusalimsky JD (2017) Cognitive status is associated with CCL11 in older rural dwellers: findings from the FRAILOMIC study. Innov Aging 1(suppl-1):595

    PubMed Central  Google Scholar 

  • CAMO (2019) The Unscrambler appendices: method references. 2019. Accessed 19 March 2019. www.camo.com/helpdocs/The_Unscrambler_Method_References.pdf

  • Cepeda-Carrion GA, Nitzl C, Roldan JL (2018) Mediation analyses in partial least squares structural equation modeling: guidelines and empirical examples. In: Latan H, Noonan R (eds) Chapter 9. Partial least squares structural equation modeling: basic concepts, methodological issues and applications. Springer, Heidelberg, pp 173–195

    Google Scholar 

  • Dasgupta S, Jana M, Liu X, Pahan K (2002) Myelin basic protein-primed T cells induced nitric oxide synthase in microglial cells. Implications for multiple sclerosis. J Biol Chem 277:39327–39333

    CAS  PubMed  Google Scholar 

  • Davis J, Moylan S, Harvey BH, Maes M, Berk M (2014) Neuroprogression in schizophrenia: pathways underpinning clinical staging and therapeutic corollaries. Aust NZ J Psychiatry 48:512–529

    Google Scholar 

  • Davis J, Eyre H, Jacka FN, Dodd S, Dean O, McEwen S, Debnath M, McGrath J, Maes M, Amminger P, McGorry PD, Pantelis C, Berk M (2016) A review of vulnerability and risks for schizophrenia: beyond the two hit hypothesis. Neurosci Biobehav Rev 65:185–194

    PubMed  PubMed Central  Google Scholar 

  • Erickson MA, Morofuji Y, Owen JB, Banks WA (2014) Rapid transport of CCL11 across the blood-brain barrier: regional variation and importance of blood cells. J Pharmacol Exp Ther 349(3):497–507

    PubMed  PubMed Central  Google Scholar 

  • Franklin RJ, Ffrench-Constant C (2008) Remyelination in the CNS: from biology to therapy. Nat Rev Neurosci 9:839–855

    CAS  PubMed  Google Scholar 

  • Frydecka D, Krzystek-Korpacka M, Lubeiro A, Stramecki F, Stańczykiewicz B, Beszłej JA, Piotrowski P, Kotowicz K, Szewczuk-Bogusławska M, Pawlak-Adamska E, Misiak B (2018) Profiling inflammatory signatures of schizophrenia: a cross-sectional and meta-analysis study. Brain Behav Immun 71:28–36

    PubMed  Google Scholar 

  • Gądek-Michalska A, Tadeusz J, Rachwalska P, Spyrka J, Bugajski J (2012) Brain nitric oxide synthases in the interleukin-1β-induced activation of hypothalamic-pituitary-adrenal axis. Pharmacol Rep 64(6):1455–1465

    PubMed  Google Scholar 

  • Gilbert RO, Kinnison RR (1981) Statistical methods for estimating the mean and variance from radionuclide data sets containing negative, unreported or less-than values. Health Phys 40(3):377–390

    CAS  PubMed  Google Scholar 

  • Goldsmith DR, Rapaport MH, Miller BJ (2016) A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression. Mol Psychiatry 21(12):1696–1709

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gutierrez EG, Banks WA, Kastin AJ (1994) Blood-borne interleukin-1 receptor antagonist crosses the blood-brain barrier. J Neuroimmunol 55:135–160

    Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hennessy E, Gormley S, Lopez-Rodriguez AB, Murray C, Murray C, Cunningham C (2017) Systemic TNF-α produces acute cognitive dysfunction and exaggerated sickness behavior when superimposed upon progressive neurodegeneration. Brain Behav Immun 59:233–244

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hong S, Lee EE, Martin AS, Soontornniyomkij B, Soontornniyomkij V, Achim CL, Reuter C, Irwin MR, Eyler LT, Jeste DV (2017) Abnormalities in chemokine levels in schizophrenia and their clinical correlates. Schizophr Res 181:63–69

    PubMed  Google Scholar 

  • Hope S, Melle I, Aukrust P, Steen NE, Birkenaes AB, Lorentzen S, Agartz I, Ueland T, Andreassen OA (2009) Similar immune profile in bipolar disorder and schizophrenia: selective increase in soluble tumor necrosis factor receptor I and von Willebrand factor. Bipolar Disord 11(7):726–734

    CAS  PubMed  Google Scholar 

  • Hope S, Ueland T, Steen NE, Dieset I, Lorentzen S, Berg AO, Agartz I, Aukrust P, Andreassen OA (2013) Interleukin 1 receptor antagonist and soluble tumor necrosis factor receptor 1 are associated with general severity and psychotic symptoms in schizophrenia and bipolar disorder. Schizophr Res 145(1–3):36–42

    PubMed  Google Scholar 

  • Hope S, Hoseth E, Dieset I, Morch RH, Aas M, Aukrus P, Djurovic S, Melle I et al (2015) Inflammatory markers are associated with general cognitive abilities in schizophrenia and bipolar disorder patients and healthy controls. Schizophr Res 165(2–3):188–194

    PubMed  Google Scholar 

  • Hoseth EZ, Westlye LT, Hope S, Dieset I, Aukrust P, Melle I, Haukvik UK, Agartz I, Ueland T, Ueland T, Andreassen OA (2016) Association between cytokine levels, verbal memory and hippocampus volume in psychotic disorders and healthy controls. Acta Psychiatr Scand 133(1):53–62

    CAS  PubMed  Google Scholar 

  • Idriss HT, Naismith JH (2000) TNF alpha and the TNF receptor superfamily: structure-function relationship(s). Microsc Res Tech 50(3):184–195

    CAS  PubMed  Google Scholar 

  • Kanchanatawan B, Hemrungrojn S, Thika S, Sirivichayakul S, Ruxrungtham K, Carvalho AF, Geffard M, Anderson G, Maes M (2018a) Changes in tryptophan catabolite (TRYCAT) pathway patterning are associated with mild impairments in declarative memory in schizophrenia and deficits in semantic and episodic memory coupled with increased false-memory creation in deficit schizophrenia. Mol Neurobiol 55(6):5184–5201

    CAS  PubMed  Google Scholar 

  • Kanchanatawan B, Sirivichayakul S, Ruxrungtham K, Carvalho AF, Geffard M, Anderson G, Maes M (2018b) Deficit schizophrenia is characterized by defects in IgM-mediated responses to tryptophan catabolites (TRYCATs): a paradigm shift towards defects in natural self-regulatory immune responses coupled with mucosa-derived TRYCAT pathway activation. Mol Neurobiol 55(3):2214–2226

    CAS  PubMed  Google Scholar 

  • Kanchanatawan B, Sriswasdi S, Thika S, Sirivichayakul S, Carvalho AF, Geffard M, Kubera M, Maes M (2018c) Deficit schizophrenia is a discrete diagnostic category defined by neuroimmune and neurocognitive features: results of supervised machine learning. Metab Brain Dis 33(4):1053–1067

    PubMed  Google Scholar 

  • Kanchanatawan B, Sriswasdi S, Thika S, Stoyanov D, Sirivichayakul S, Carvalho AF, Geffard M, Maes M (2018d) Towards a new classification of stable phase schizophrenia into major and simple neuro-cognitive psychosis: results of unsupervised machine learning analysis. J Eval Clin Pract 24(4):879–891

    PubMed  Google Scholar 

  • Kanchanatawan B, Thika S, Sirivichayakul S, Carvalho AF, Geffard M, Maes M (2018e) In schizophrenia, depression, anxiety, and physiosomatic symptoms are strongly related to psychotic symptoms and excitation, impairments in episodic memory, and increased production of neurotoxic tryptophan catabolites: a multivariate and machine learning study. Neurotox Res 33(3):621–633

    CAS  PubMed  Google Scholar 

  • Kay SR, Fiszbein A, Opler LA (1987) The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 13:261–276

    CAS  PubMed  Google Scholar 

  • Keefe RSE, Goldberg TE, Harvey PD, Gold JM, Poe MP, Coughenour L (2004) The brief assessment of cognition in schizophrenia: reliability, sensitivity, and comparison with a standard neurocognitive battery. Schizophr Res 68:283–297

    PubMed  Google Scholar 

  • Kirkpatrick B, Buchanan RW, McKenney PD, Alphs LD, Carpenter WT (1989) The schedule for the deficit syndrome: an instrument for research in schizophrenia. Psychiatry Res 30:119–123

    CAS  PubMed  Google Scholar 

  • Kudo N, Yamamori H, Ishima T, Nemoto K, Yasuda Y, Fujimoto M, Azechi H, Niitsu T, Numata S, Ikeda M, Iyo M, Ohmori T, Fukunaga M, Watanabe Y, Hashimoto K, Hashimoto R (2018) Plasma levels of soluble tumor necrosis factor receptor 2 (sTNFR2) are associated with hippocampal volume and cognitive performance in patients with schizophrenia. Int J Neuropsychopharmacol 21(7):631–639

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lee EE, Hong S, Martin AS, Eyler LT, Jeste DV (2017) Inflammation in schizophrenia: cytokine levels and their relationships to demographic and clinical variables. Am J Geriatr Psychiatry 25:50–61

    PubMed  Google Scholar 

  • Levkovitz Y, Mendlovich S, Riwkes S, Braw Y, Levkovitch-Verbin H, Gal G, Fennig S, Treves I, Kron S (2010) A double-blind, randomized study of minocycline for the treatment of negative and cognitive symptoms in early-phase schizophrenia. J Clin Psychiatry 71:138–149

    CAS  PubMed  Google Scholar 

  • Maes M, Carvalho AF (2018) The compensatory immune-regulatory reflex system (CIRS) in depression and bipolar disorder. Mol Neurobiol 55(12):8885–8903

    CAS  PubMed  Google Scholar 

  • Maes M, Rief W (2012) Diagnostic classifications in depression and somatization should include biomarkers, such as disorders in the tryptophan catabolite (TRYCAT) pathway. Psychiatry Res 196(2–3):243–249

    CAS  PubMed  Google Scholar 

  • Maes M, Schotte C, Maes L, Cosyns P (1990) Clinical subtypes of unipolar depression: part II. Quantitative and qualitative clinical differences between the vital and nonvital depression groups. Psychiatry Res 34(1):43–57

    CAS  PubMed  Google Scholar 

  • Maes M, Lambrechts J, Bosmans E, Jacobs J, Suy E, Vandervorst C, de Jonckheere C, Minner B, Raus J (1992) Evidence for a systemic immune activation during depression: results of leukocyte enumeration by flow cytometry in conjunction with monoclonal antibody staining. Psychol Med 22(1):45–53

    CAS  PubMed  Google Scholar 

  • Maes M, Meltzer HY, Bosmans E (1994) Immune-inflammatory markers in schizophrenia: comparison to normal controls and effects of clozapine. Acta Psychiatr Scand 89(5):346–351

    CAS  PubMed  Google Scholar 

  • Maes M, Bosmans E, Ranjan R, Vandoolaeghe E, Meltzer HY, De Ley M, Berghmans R, Stans G, Desnyder R (1996) Lower plasma CC16, a natural anti-inflammatory protein, and increased plasma interleukin-1 receptor antagonist in schizophrenia: effects of antipsychotic drugs. Schizophr Res 21(1):39–50

    CAS  PubMed  Google Scholar 

  • Maes M, Delange J, Ranjan R, Meltzer HY, Desnyder R, Cooremans W, Scharpé S (1997) Acute phase proteins in schizophrenia, mania and major depression: modulation by psychotropic drugs. Psychiatry Res 66(1):1–11

    CAS  PubMed  Google Scholar 

  • Maes M, Bocchio Chiavetto L, Bignotti S, Battisa Tura GJ, Pioli R, Boin F, Kenis G, Bosmans E, de Jongh R, Altamura CA (2002) Increased serum interleukin-8 and interleukin-10 in schizophrenic patients resistant to treatment with neuroleptics and the stimulatory effects of clozapine on serum leukemia inhibitory factor receptor. Schizophr Res 54(3):281–291

    PubMed  Google Scholar 

  • Maes M, Song C, Yirmiya R (2012a) Targeting IL-1 in depression. Expert Opin Ther Targets 16(11):1097–1112

    CAS  PubMed  Google Scholar 

  • Maes M, Twisk FN, Johnson C (2012b) Myalgic encephalomyelitis (ME), chronic fatigue yndrome (CFS), and chronic fatigue (CF) are distinguished accurately: results of supervised learning techniques applied on clinical and inflammatory data. Psychiatry Res 200(2–3):754–760

    PubMed  Google Scholar 

  • 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 18:495–512

    CAS  PubMed  Google Scholar 

  • Maes M, Brum MJ, Congio A, Bonifacio K, Barbosa D, Vargas H, Michelin A, Carvalho AF et al (2018) Development of a novel staging model for affective disorders using partial least squares bootstrapping: effects of lipid-associated antioxidant defenses and neuro-oxidative stress. Mol Neurobiol 56(9):6626–6644. https://doi.org/10.20944/preprints201812.0092.v1

    Article  Google Scholar 

  • Maes M, Kanchanatawan B, Sirivichayakul S, Carvalho AF (2019a) In schizophrenia, deficits in natural IgM isotype antibodies including those directed to malondialdehyde and azelaic acid strongly predict negative symptoms, neurocognitive impairments, and the deficit syndrome. Mol Neurobiol 56:5122–5135

    CAS  PubMed  Google Scholar 

  • Maes M, Kanchanatawan B, Sirivichayakul S, Carvalho AF (2019b) In schizophrenia, increased plasma IgM/IgA responses to gut commensal bacteria are associated with negative symptoms, neurocognitive impairments, and the deficit phenotype. Neurotox Res 35(3):684–698

    CAS  PubMed  Google Scholar 

  • Maes, M, Sirivichayakul, S, Kanchanatawan, B, Carvalho AF. (2019c) In schizophrenia, psychomotor retardation is associated with executive and memory impairments, negative and psychotic symptoms, neurotoxic immune products and lower natural IgM to malondialdehyde. Preprints, 2019-010108. doi: https://doi.org/10.20944/preprints201901.0108.v1

  • Maes M, Sirivichayakul S, Kanchanatawan B, Vodjani A (2019d) Breakdown of the paracellular tight and adherens junctions in the gut and blood brain barrier and damage to the vascular barrier in patients with deficit schizophrenia. Neurotox Res 36:306–322. https://doi.org/10.1007/s12640-019-00054-6

    Article  CAS  PubMed  Google Scholar 

  • Miller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick B (2011) Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry 70:663–671

    CAS  PubMed  PubMed Central  Google Scholar 

  • Morch RH, Dieset I, Faerden A, Hope S, Aas M, Nerhus M, Gardsjord ES, Haram M et al (2017) Persistent increase in TNF and IL-1 markers in severe mental disorders suggests trait-related inflammation: a one year follow-up study. Acta Psychiatr Scand 136(4):400–408

    CAS  PubMed  Google Scholar 

  • Morris G, Berk M, Galecki P, Walder K, Maes M (2016) The neuro-immune pathophysiology of central and peripheral fatigue in systemic immune-inflammatory and neuro-immune diseases. Mol Neurobiol 53:1195–1219

    CAS  PubMed  Google Scholar 

  • Noto C, Maes M, Ota VK, Teixeira AL, Bressan RA, Gadelha A, Brietzke E et al (2015) High predictive value of immune-inflammatory biomarkers for schizophrenia diagnosis and association with treatment resistance. World J Biol Psychiatry 16:422–429

    PubMed  Google Scholar 

  • Noto MN, Maes M, Nunes SOV, Ota VK, Rossaneis AC, Verri WA, Cordeiro Q, Belangero SI, Gadelha A, Bressan RA, Noto C (2019) Activation of the immune-inflammatory response system and the compensatory immune-regulatory system in antipsychotic naive first episode psychosis. Eur Neuropsychopharmacol 29(3):416–431

    CAS  PubMed  Google Scholar 

  • OLink Proteomics (2019) How is the limit of detection (LOD) estimated and how is this handled in the data analysis? Accessed 4 Sept 2019. https://www.olink.com/question/how-is-the-limit-of-detection-lod-estimated-and-handled/

  • Overall JE, Gorham DR (1962) The brief psychiatric rating scale. Psychol Rep 10:799–812

    Google Scholar 

  • Piccioli P, Rubartelli A (2013) The secretion of IL-1β and options for release. Semin Immunol 5(6):425–429

    Google Scholar 

  • Porter PS, Ward RC, Bell HF (1988) The detection limit. Environ Sci Technol 22(8):856–861

    CAS  PubMed  Google Scholar 

  • Potvin S, Stip E, Sepehry AA, Gendron A, Bah R, Kouassi E (2008) Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review. Biol Psychiatry 63(8):801–808

    CAS  PubMed  Google Scholar 

  • Relton JK, Rothwell NJ (1992) Interleukin-1 receptor antagonist inhibits ischemic and excitatory neuronal damage in the rat. Brain Res Bull 29:243–246

    CAS  PubMed  Google Scholar 

  • Ringle CM, Wende S, Becker J-M (2015) SmartPLS 3. SmartPLS, Bönningstedt Retrieved from http://www.smartpls.com. Accessed 11 May 2019

    Google Scholar 

  • Roomruangwong C, Noto C, Kanchanatawan B, Anderson G, Kubera M, Carvalho AF, Maes M. (2019) The role of aberrations in the immune-inflammatory reflex system (IRS) and the compensatory immune-regulatory reflex system (CIRS) in different phenotypes of schizophrenia: the IRS-CIRS theory of schizophrenia. Preprints 2018, 2018090289, doi: https://doi.org/10.20944/preprints201809.0289.v1. Mol Neurobiol

  • Selinsky CL, Boroughs KL, Halsey WA, Howell MD (1998) Multifaceted inhibition of anti-tumour immune mechanisms by soluble tumour necrosis factor receptor type I. Immunology 94(1):88–93

    CAS  PubMed  PubMed Central  Google Scholar 

  • Siegel A, Zalcman SS (2009) The neuroimmunological basis of behavior and mental disorders. Springer, New York

    Google Scholar 

  • Sirivichayakul S, Kanchanatawan B, Thika S, Carvalho AF, Maes M (2019a) A new schizophrenia model: immune activation is associated with induction of different neurotoxic products which together determine memory impairments and schizophrenia symptom dimensions. CNS Neurol Disord Drug Targets 18(2):124–140

    CAS  PubMed  Google Scholar 

  • Sirivichayakul S, Kanchanatawan B, Thika S, Carvalho AF, Maes M (2019b) Eotaxin, an endogenous cognitive deteriorating chemokine (ECDC), is a major contributor to cognitive decline in normal people and to executive, memory, and sustained attention deficits, formal thought disorders, and psychopathology in schizophrenia patients. Neurotox Res 35(1):122–138

    CAS  PubMed  Google Scholar 

  • Smith RS, Maes M (1995) The macrophage-T-lymphocyte theory of schizophrenia: additional evidence. Med Hypotheses 45(2):135–141

    CAS  PubMed  Google Scholar 

  • Stoyanov D, Machamer PK, Schaffner KF, Rivera-Hernandez R (2012) The challenge of psychiatric nosology and diagnosis. J Eval Clin Pract 18(3):704–709

    PubMed  Google Scholar 

  • Su X, Zhou T, Yang P, Edwards CK, Mountz JD (1998) Reduction of arthritis and pneumonitis in motheaten mice by soluble tumor necrosis factor receptor. Arthritis Rheum 41(1):139–149

    CAS  PubMed  Google Scholar 

  • Teixeira AL, Reis HJ, Nicolato R, Brito-Melo G, Correa H, Teixeira MM, Romano-Silva MA (2008) Increased serum levels of CCL11/eotaxin in schizophrenia. Prog Neuro-Psychopharmacol Biol Psychiatry 32(3):710–714

    CAS  Google Scholar 

  • Uranova NA, Bonartsev PD, Androsova LV, Rakhmanova VI, Kaleda VG (2017) Impaired monocyte activation in schizophrenia: ultrastructural abnormalities and increased IL-1β production. Eur Arch Psychiatry Clin Neurosci 267(5):417–426

    PubMed  Google Scholar 

  • Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, Stan TM, Fainberg N, Ding Z, Eggel A, Lucin KM, Czirr E, Park JS, Couillard-Després S, Aigner L, Li G, Peskind ER, Kaye JA, Quinn JF, Galasko DR, Xie XS, Rando TA, Wyss-Coray T (2011) The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477(7362):90–94

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wen W, Hao Z, Yang X (2010) Robust least squares support vector machine based on recursive outlier elimination. Soft Comput 14(11):1241–1251

    Google Scholar 

  • Ye L, Huang Y, Zhao L, Li Y, Sun L, Zhou Y, Qian G, Zheng JC (2013) IL-1β and TNF-α induce neurotoxicity through glutamate production: a potential role for neuronal glutaminase. J Neurochem 125(6):897–908

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zachar P, Stoyanov DS, Aragona M, Jablensky A (2014) Alternative perspectives on psychiatric validation: DSM, ICD, RDoC, and beyond. In: International perspectives in philosophy and psychiatry. Oxford University Press, Oxford

    Google Scholar 

  • Zhao J, Bi W, Xiao S, Lan X, Cheng X, Zhang J, Lu D, Wei W, Wang Y, Li H, Fu Y, Zhu L (2019) Neuroinflammation induced by lipopolysaccharide causes cognitive impairment in mice. Sci Rep 9(1):5790

    PubMed  PubMed Central  Google Scholar 

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Acknowledgments

We acknowledge the staff of Ibn-Rushd Hospital for their help in the collection of samples especially Dr. Mokhlad Swadi Abed. We also acknowledge the work of the high-skilled staff of Asia Clinical Laboratory in Najaf City for their help in the ELISA measurements and Asia Lab in the estimation of biomarkers levels.

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Authors and Affiliations

  1. Department of Chemistry, College of Science, University of Kufa, Kufa, Iraq

    Hussein Kadhem Al-Hakeim

  2. Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq

    Abbas F. Almulla

  3. Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

    Michael Maes

  4. Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria

    Michael Maes

  5. IMPACT Strategic Research Centre, Deakin University, PO Box 281, Geelong, VIC, 3220, Australia

    Michael Maes

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  1. Hussein Kadhem Al-Hakeim
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Correspondence to Michael Maes.

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The study was conducted according to international and Iraq ethics and privacy laws. Approval for the study was obtained from the Institutional Review Board of the University of Kufa (347/2019), which is in compliance with the International Guidelines for Human Research protection as required by the Declaration of Helsinki, The Belmont Report, Council for International Organizations of Medical Sciences (CIOMS) Guideline, and International Conference on Harmonization on Good Clinical Practice (ICH-GCP).

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Al-Hakeim, H.K., Almulla, A.F. & Maes, M. The Neuroimmune and Neurotoxic Fingerprint of Major Neurocognitive Psychosis or Deficit Schizophrenia: a Supervised Machine Learning Study. Neurotox Res 37, 753–771 (2020). https://doi.org/10.1007/s12640-019-00112-z

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