Preprint Article Version 1 This version is not peer-reviewed

Increased Levels of Plasma Tumor Necrosis Factor-α Mediate Schizophrenia Symptom Dimensions and Neurocognitive Impairments and Are Inversely Associated with Natural IgM and Paraoxonase 1 Activity

Version 1 : Received: 12 November 2019 / Approved: 12 November 2019 / Online: 12 November 2019 (17:02:22 CET)

How to cite: Maes, M.; Sirivichayakul, S.; Matsumoto, A.K.; Maes, A.; Michelin, A.P.; de Oliveira Semeão, L.; de Lima Pedrão, J.V.; Moreira, E.G.; Barbosa, D.S.; Geffard, M.; Carvalho, A.F.; Kanchanatawan, B. Increased Levels of Plasma Tumor Necrosis Factor-α Mediate Schizophrenia Symptom Dimensions and Neurocognitive Impairments and Are Inversely Associated with Natural IgM and Paraoxonase 1 Activity . Preprints 2019, 2019110135 (doi: 10.20944/preprints201911.0135.v1). Maes, M.; Sirivichayakul, S.; Matsumoto, A.K.; Maes, A.; Michelin, A.P.; de Oliveira Semeão, L.; de Lima Pedrão, J.V.; Moreira, E.G.; Barbosa, D.S.; Geffard, M.; Carvalho, A.F.; Kanchanatawan, B. Increased Levels of Plasma Tumor Necrosis Factor-α Mediate Schizophrenia Symptom Dimensions and Neurocognitive Impairments and Are Inversely Associated with Natural IgM and Paraoxonase 1 Activity . Preprints 2019, 2019110135 (doi: 10.20944/preprints201911.0135.v1).

Abstract

Accumulating evidence suggests that TNF-α-mediated immune-neurotoxicity contributes to cognitive impairments and the overall severity of schizophrenia (OSOS). There are no data whether peripheral IL-6 and IL-4 may affect the phenome of schizophrenia above and beyond the effects of TNF-α and whether those cytokines are regulated by lowered natural IgM to malondialdehyde (MDA) and paraoxonase 1 enzyme activity. We assessed the aforementioned biomarkers in schizophrenia patients with (n=40) and without (n=40) deficit schizophrenia and 40 healthy controls. Deficit schizophrenia was best predicted by a combination of increased IL-6 and PON1 status (QQ genotype and lowered CMPAase activity) and lowered IgM to MDA. Partial Least Squares bootstrapping shows that 41.0% of the variance in negative symptoms, psychosis, hostility, excitation, mannerism, psychomotor retardation, and formal thought disorders was explained by increased TNF-α and PON1 status (QQ genotype and lowered CMPAase activity), lowered IL-4 and IgM to MDA as well as male sex and lowered education. We found that 47.9% of the variance in verbal fluency, word list memory, true recall, Mini-Mental State Examination, and executive functions was predicted by increased TNF-α and lowered IL-4, IgM to MDA and education. In addition, both TNF-α and IL-4 levels were significantly associated with lowered IgM to MDA, while TNF-α was correlated with PON1 status. These data provide evidence that the symptomatic (both the deficit subtype and OSOS) and cognitive impairments in schizophrenia are to a large extent mediated by the effects of immune-mediated neurotoxicity as well as lowered regulation by the innate immune system.

Subject Areas

cytokines, neuro-immune, inflammation, antioxidants, oxidative stress, paraoxonase 1

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