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Neuro-Immune Aspects of Schizophrenia with Severe Negative Symptoms: New Diagnostic Markers of Disease Phenotype

Neuro-Immune Aspects of Schizophrenia with Severe Negative Symptoms: New Diagnostic Markers of Disease Phenotype

Malashenkova I.K., Ushakov V.L., Zakharova N.V., Krynskiy S.A., Ogurtsov D.P., Hailov N.A., Chekulaeva E.I., Ratushnyy A.Y., Kartashov S.I., Kostyuk G.P., Didkovsky N.A.
Key words: schizophrenia with negative symptoms; paranoid schizophrenia; neurocognitive markers; neurobiological markers; interleukins.
2021, volume 13, issue 6, page 24.

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The aim of the study was to analyze the immune-inflammatory profile of patients with paranoid schizophrenia and relate it to the severity of negative symptoms and the MRI data in order to identify biomarkers of schizophrenia severity, search for new approaches to therapy, and control its effectiveness.

Materials and Methods. The main group included 51 patients with paranoid schizophrenia, the control group — 30 healthy subjects. Patients underwent MRI scans and immunological studies, which included an assessment of natural and adaptive immunity, the systemic level of key pro-inflammatory and anti-inflammatory cytokines, and other markers of inflammation.

Results. Disorders of immunity and immunoinflammatory profile in patients with paranoid schizophrenia with severe negative symptoms were revealed for the first time: in the presence of severe negative symptoms (>15 points according to the NSA-4 scale), the levels of humoral immunity factors, cytokines IL-10 and IL-12p40 and neurotrophin NGF were increased as well as the markers of systemic inflammation. Morphometric changes in the brain, typical for patients with schizophrenia, and also specific for patients with severe negative symptoms, were determined. The data analysis revealed correlations between the immune changes with structural changes in some of the brain areas, including the frontal cortex and hippocampus. Associations were found between the levels of anti-inflammatory IL-10, IL-12p40 cytokines and morphometric parameters of the brain, specific only for schizophrenic patients with severe negative symptoms.

Conclusion. The interdisciplinary approach, combining brain morphometry with in-depth immunological and clinical studies, made it possible to determine neurobiological, immune, and neurocognitive markers of paranoid schizophrenia with severe negative symptoms. The results are important for further deciphering the pathogenesis of schizophrenia and its subtypes, as well as for the search for new approaches to the treatment of severe forms of the disease.

  1. Millan M.J., Fone K., Steckler T., Horan W.P. Negative symptoms of schizophrenia: clinical characteristics, pathophysiological substrates, experimental models and prospects for improved treatment. Eur Neuropsychopharmacol 2014; 24(5): 645–836, https://doi.org/10.1016/j.euroneuro.2014.03.008.
  2. Iasevoli F., Avagliano C., Altavilla B., Barone A., D’Ambrosio L., Matrone M., Notar Francesco D., Razzino E., de Bartolomeis A. Disease severity in treatment resistant schizophrenia patients is mainly affected by negative symptoms, which mediate the effects of cognitive dysfunctions and neurological soft signs. Front Psychiatry 2018; 9: 553, https://doi.org/10.3389/fpsyt.2018.00553.
  3. Laursen T.M., Nordentoft M., Mortensen P.B. Excess early mortality in schizophrenia. Annu Rev Clin Psychol 2014; 10: 425–448, https://doi.org/10.1146/annurev-clinpsy-032813-153657.
  4. Corsi-Zuelli F.M.D.G., Brognara F., Quirino G.F.D.S., Hiroki C.H., Fais R.S., Del-Ben C.M., Ulloa L., Salgado H.C., Kanashiro A., Loureiro C.M. Neuroimmune interactions in schizophrenia: focus on vagus nerve stimulation and activation of the alpha-7 nicotinic acetylcholine receptor. Front Immunol 2017; 8: 618, https://doi.org/10.3389/fimmu.2017.00618.
  5. Kennedy J.L., Altar C.A., Taylor D.L., Degtiar I., Hornberger J.C. The social and economic burden of treatment-resistant schizophrenia: a systematic literature review. Int Clin Psychopharmacol 2014; 29(2): 63–76, https://doi.org/10.1097/yic.0b013e32836508e6.
  6. Miller B.J., Goldsmith D.R. Towards an immunophenotype of schizophrenia: progress, potential mechanisms, and future directions. Neuropsychopharmacology 2017; 42(1): 299–317, https://doi.org/10.1038/npp.2016.211.
  7. Malashenkova I.K., Krynskiy S.A., Ogurtsov D.P., Mamoshina M.V., Zakharova N.V., Ushakov V.L., Velichkovsky B.M., Didkovsky N.A. A role of the immune system in the pathogenesis of schizophrenia. Zhurnal nevrologii i psihiatrii imeni S.S. Korsakova 2018; 118(12): 72–80, https://doi.org/10.17116/jnevro201811812172.
  8. Noto C., Maes M., Ota V.K., Teixeira A.L., Bressan R.A., Gadelha A., Brietzke E. High predictive value of immune-inflammatory biomarkers for schizophrenia diagnosis and association with treatment resistance. World J Biol Psychiatry 2015; 16(6): 422–429, https://doi.org/10.3109/15622975.2015.1062552.
  9. Kroken R.A., Sommer I.E., Steen V.M., Dieset I., Johnsen E. Constructing the immune signature of schizophrenia for clinical use and research; an integrative review translating descriptives into diagnostics. Front Psychiatry 2019; 9: 753, https://doi.org/10.3389/fpsyt.2018.00753.
  10. Dantzer R. Neuroimmune interactions: from the brain to the immune system and vice versa. Physiol Rev 2018; 98(1): 477–504, https://doi.org/10.1152/physrev.00039.2016.
  11. Malashenkova I.K., Krynskiy S.A., Khailov N.A., Kazanova G.V., Velichkovsky B.B., Didkovsky N.A. The role of cytokines in memory consolidation. Biol Bull Rev 2016; 6(2): 126–140, https://doi.org/10.1134/s2079086416020055.
  12. Bennett F.C., Molofsky A.V. The immune system and psychiatric disease: a basic science perspective. Clin Exp Immunol 2019; 197(3): 294–307, https://doi.org/10.1111/cei.13334.
  13. Ushakov V.L., Sharaev M.G., Malashenkova I.K., Krynskiy S.A., Kartashov S.I., Orlov V.A., Malakhov D.G., Hailov N.A., Ogurtsov D.P., Zakharova N.V., Didkovsky N.A., Maslennikova A.V., Arkhipov A.Yu., Strelets V.B., Arsalidou M., Velichkovsky B.M., Kostyuk G.P. Basic cognitive architectures and neuroimmune serum biomarkers in schizophrenia. Procedia Comput Sci 2018; 145: 596–603, https://doi.org/10.1016/j.procs.2018.11.097.
  14. Neugebauer K., Hammans C., Wensing T., Kumar V., Grodd W., Mevissen L., Sternkopf M.A., Novakovic A., Abel T., Habel U., Nickl-Jockschat T. Nerve growth factor serum levels are associated with regional gray matter volume differences in schizophrenia patients. Front Psychiatry 2019; 10: 275, https://doi.org/10.3389/fpsyt.2019.00275.
  15. Szkultecka-Dębek M., Walczak J., Augustyńska J., Miernik K., Stelmachowski J., Pieniążek I., Obrzut G., Pogroszewska A., Paulić G., Damir M., Antolić S., Tavčar R., Indrikson A., Aadamsoo K., Jankovic S., Pulay A.J., Rimay J., Varga M., Sulkova I., Veržun P. Epidemiology and treatment guidelines of negative symptoms in schizo-phrenia in Central and Eastern Europe: a literature review. Clin Pract Epidemiol Ment Health 2015; 11: 158–165, https://doi.org/10.2174/1745017901511010158.
  16. Correll C.U., Schooler N.R. Negative symptoms in schizophrenia: a review and clinical guide for recognition, assessment, and treatment. Neuropsychiatr Dis Treat 2020; 16: 519–534, https://doi.org/10.2147/ndt.s225643.
  17. Goldsmith D.R., Rapaport M.H. Inflammation and negative symptoms of schizophrenia: implications for reward processing and motivational deficits. Front Psychiatry 2020; 11: 46, https://doi.org/10.3389/fpsyt.2020.00046.
  18. Kraguljac N.V., Lahti A.C. Neuroimaging as a window into the pathophysiological mechanisms of schizophrenia. Front Psychiatry 2021; 12: 613764, https://doi.org/10.3389/fpsyt.2021.613764.
  19. Mubarik A., Tohid H. Frontal lobe alterations in schizophrenia: a review. Trends Psychiatry Psychother 2016; 38(4): 198–206, https://doi.org/10.1590/2237-6089-2015-0088.
  20. Birur B., Kraguljac N.V., Shelton R.C., Lahti A.C. Brain structure, function, and neurochemistry in schizophrenia and bipolar disorder — a systematic review of the magnetic resonance neuroimaging literature. NPJ Schizophr 2017; 3: 15, https://doi.org/10.1038/s41537-017-0013-9.
  21. Ewald D.R., Sumner S.C.J. Human microbiota, blood group antigens, and disease. Wiley Interdiscip Rev Syst Biol Med 2018; 10(3): e1413, https://doi.org/10.1002/wsbm.1413.
  22. Just D., Månberg A., Mitsios N., Stockmeier C.A., Rajkowska G., Uhlén M., Mulder J., Feuk L., Cunningham J.L., Nilsson P., Carlström E.L. Exploring autoantibody signatures in brain tissue from patients with severe mental illness. Transl Psychiatry 2020; 10(1): 401, https://doi.org/10.1038/s41398-020-01079-8.
  23. Almeida P.G.C., Nani J.V., Oses J.P., Brietzke E., Hayashi M.A.F. Neuroinflammation and glial cell activation in mental disorders. Brain Behav Immun Health 2020; 2: 100034, https://doi.org/10.1016/j.bbih.2019.100034.
  24. Laskaris L.E., Di Biase M.A., Everall I., Chana G., Christopoulos A., Skafidas E., Cropley V.L., Pantelis C. Microglial activation and progressive brain changes in schizophrenia. Br J Pharmacol 2016; 173(4): 666–680, https://doi.org/10.1111/bph.13364.
  25. Duarte L.F., Farías M.A., Álvarez D.M., Bueno S.M., Riedel C.A., González P.A. Herpes simplex virus type 1 infection of the central nervous system: insights into proposed interrelationships with neurodegenerative disorders. Front Cell Neurosci 2019; 13: 46, https://doi.org/10.3389/fncel.2019.00046.
  26. Fu G., Zhang W., Dai J., Liu J., Li F., Wu D., Xiao Y., Shah C., Sweeney J.A., Wu M., Lui S. Increased peripheral interleukin 10 relate to white matter integrity in schizophrenia. Front Neurosci 2019; 13: 52, https://doi.org/10.3389/fnins.2019.00052.
  27. Bedrossian N., Haidar M., Fares J., Kobeissy F.H., Fares Y. Inflammation and elevation of interleukin-12p40 in patients with schizophrenia. Front Mol Neurosci 2016; 9: 16, https://doi.org/10.3389/fnmol.2016.00016.
  28. Mondal S., Kundu M., Jana M., Roy A., Rangasamy S.B., Modi K.K., Wallace J., Albalawi Y.A., Balabanov R., Pahan K. IL-12 p40 monomer is different from other IL-12 family members to selectively inhibit IL-12Rβ1 internalization and suppress EAE. Proc Natl Acad Sci U S A 2020; 117(35): 21557–21567, https://doi.org/10.1073/pnas.2000653117.
  29. Oliveira S.L., Pillat M.M., Cheffer A., Lameu C., Schwindt T.T., Ulrich H. Functions of neurotrophins and growth factors in neurogenesis and brain repair. Cytometry A 2013; 83(1): 76–89, https://doi.org/10.1002/cyto.a.22161.
  30. Skaper S.D. Nerve growth factor: a neuroimmune crosstalk mediator for all seasons. Immunology 2017; 151(1): 1–15, https://doi.org/10.1111/imm.12717.
  31. Eu W.Z., Chen Y.J., Chen W.T., Wu K.Y., Tsai C.Y., Cheng S.J., Carter R.N., Huang G.J. The effect of nerve growth factor on supporting spatial memory depends upon hippocampal cholinergic innervation. Transl Psychiatry 2021; 11(1): 162, https://doi.org/10.1038/s41398-021-01280-3.
  32. Kale A., Joshi S., Pillai A., Naphade N., Raju M., Nasrallah H., Mahadik S.P. Reduced cerebrospinal fluid and plasma nerve growth factor in drug-naïve psychotic patients. Schizophr Res 2009; 115(2–3): 209–214, https://doi.org/10.1016/j.schres.2009.07.022.
  33. Zhuo C., Ma X., Qu H., Wang L., Jia F., Wang C. Schizophrenia patients demonstrate both inter-voxel level and intra-voxel level white matter alterations. PLoS One 2016; 11(9): e0162656, https://doi.org/10.1371/journal.pone.0162656.
  34. Xiong P., Zeng Y., Zhu Z., Tan D., Xu F., Lu J., Wan J., Ma M. Reduced NGF serum levels and abnormal P300 event-related potential in first episode schizophrenia. Schizophr Res 2010; 119(1–3): 34–39, https://doi.org/10.1016/j.schres.2010.02.1063.
  35. Ajami A., Hosseini S.H., Taghipour M., Khalilian A. Changes in serum levels of brain derived neurotrophic factor and nerve growth factor-beta in schizophrenic patients before and after treatment. Scand J Immunol 2014; 80(1): 36–42, https://doi.org/10.1111/sji.12158.
  36. Qin X.Y., Wu H.T., Cao C., Loh Y.P., Cheng Y. A meta-analysis of peripheral blood nerve growth factor levels in patients with schizophrenia. Mol Psychiatry 2017; 22(9): 1306–1312, https://doi.org/10.1038/mp.2016.235.
  37. Berry A., Bindocci E., Alleva E. NGF, brain and behavioral plasticity. Neural Plast 2012; 2012: 784040, https://doi.org/10.1155/2012/784040.
  38. Mubarik A., Tohid H. Frontal lobe alterations in schizophrenia: a review. Trends Psychiatry Psychother 2016; 38(4): 198–206, https://doi.org/10.1590/2237-6089-2015-0088.
  39. Li M., Li X., Das T.K., Deng W., Li Y., Zhao L., Ma X., Wang Y., Yu H., Meng Y., Wang Q., Palaniyappan L., Li T. Prognostic utility of multivariate morphometry in schizophrenia. Front Psychiatry 2019; 10: 245, https://doi.org/10.3389/fpsyt.2019.00245.
  40. Zhang T., Koutsouleris N., Meisenzahl E., Davatzikos C. Heterogeneity of structural brain changes in subtypes of schizophrenia revealed using magnetic resonance imaging pattern analysis. Schizophr Bull 2015; 41(1): 74–84, https://doi.org/10.1093/schbul/sbu136.
  41. Chee T.T., Chua L., Morrin H., Lim M.F., Fam J., Ho R. Neuroanatomy of patients with deficit schizophrenia: an exploratory quantitative meta-analysis of structural neuroimaging studies. Int J Environ Res Public Health 2020; 17(17): 6227, https://doi.org/10.3390/ijerph17176227.
  42. Kaladjian A., Belzeaux R., Adida M., Azorin J.M. Negative symptoms and cerebral imaging. Encephale 2015; 41(6 Suppl 1): 6S22–6S26, https://doi.org/10.1016/s0013-7006(16)30006-9.
  43. Khandaker G.M., Dantzer R. Is there a role for immune-to-brain communication in schizophrenia? Psychopharmacology (Berl) 2016; 233(9): 1559–1573, https://doi.org/10.1007/s00213-015-3975-1.
Malashenkova I.K., Ushakov V.L., Zakharova N.V., Krynskiy S.A., Ogurtsov D.P., Hailov N.A., Chekulaeva E.I., Ratushnyy A.Y., Kartashov S.I., Kostyuk G.P., Didkovsky N.A. Neuro-Immune Aspects of Schizophrenia with Severe Negative Symptoms: New Diagnostic Markers of Disease Phenotype. Sovremennye tehnologii v medicine 2021; 13(6): 24, https://doi.org/10.17691/stm2021.13.6.03


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