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Cognitive impairment in rheumatoid arthritis: role of lymphocyte subsets, cytokines and neurotrophic factors

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Abstract

To what extent the cognitive impairment of rheumatoid arthritis (RA) is modulated by autoimmune and/or inflammatory activity is largely unknown. The aim of this study was to investigate the role of peripheral inflammation on cognitive functions of patients with active (Ac-), controlled (Co-) RA and healthy controls. In a cross-sectional study, 102 RA patients and 30 matched healthy controls were recruited. B and T cell subsets were immunophenotyped by flow cytometry. Plasma cytokines and neurotrophins were measured by flow cytometry and ELISA, respectively. Cognitive performance, depression and stress were evaluated by structured clinical interviews. Generalized linear modeling (GzLM) was used to compare differences between groups and multiple linear regression models were used to explore the predictive value of immune variables on cognitive performance. RA patients had overall cognitive impairment. Of note, the Ac-RA had the poorest performance on digit span (DST) and N-back when compared to Co-RA and control group (DST 9.9 ± 2.1, 12.9 ± 4.2, 15.5 ± 4.7, respectively; N-back 49.2 ± 8.3, 55.5 ± 11.1, 60.8 ± 9.1, respectively, all p < 0.0001). RA patients had expansions of immature B cells (Ac-RA 11.2 ± 7.1, Co-RA: 9 ± 5.7, control 5.9 ± 2.1) and plasma cells (Ac-RA 5.2 ± 2.5, Co-RA 6.9 ± 3.7, control 2.8 ± 1.7) as compared to controls, all p < 0.05. RA patients (controlled and active disease) had higher plasma levels of TNF, IL-2, IL-4, IL-6 and IL-10 than controls (all p < 0.002). RA patients had higher BDNF levels (Ac-RA 17,354.4 ± 5357.3, Co-RA 13,841.2 ± 5953.7, control 11,543.3 ± 3772), but lower GDNF levels [median (interquartile range) Ac-RA 0 pg/ml (0.0), Co-RA 0 pg/ml (4.6) and control 4.7 pg/ml (18.1)] than controls (all p < 0.05). RA patients had global cognitive impairment, which was associated with disease activity and immune changes.

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References

  1. Petersen LE, Grassi-Oliveira R, Siara T, dos Santos SG, Ilha M, de Nardi T, Keisermann M, Bauer ME (2015) Premature immunosenescence is associated with memory dysfunction in rheumatoid arthritis. Neuroimmunomodulation 22(3):130–137. https://doi.org/10.1159/000358437

    Article  CAS  PubMed  Google Scholar 

  2. Prete M, Racanelli V, Digiglio L, Vacca A, Dammacco F, Perosa F (2011) Extra-articular manifestations of rheumatoid arthritis: an update. Autoimmun Rev 11(2):123–131. https://doi.org/10.1016/j.autrev.2011.09.001

    Article  PubMed  Google Scholar 

  3. Niitsu T, Shirayama Y, Matsuzawa D, Shimizu E, Hashimoto K, Iyo M (2014) Association between serum levels of glial cell-line derived neurotrophic factor and attention deficits in schizophrenia. Neurosci Lett 575:37–41. https://doi.org/10.1016/j.neulet.2014.05.034

    Article  CAS  PubMed  Google Scholar 

  4. Joaquim AF, Appenzeller S (2015) Neuropsychiatric manifestations in rheumatoid arthritis. Autoimmun Rev 14(12):1116–1122. https://doi.org/10.1016/j.autrev.2015.07.015

    Article  PubMed  Google Scholar 

  5. Bartolini M, Candela M, Brugni M, Catena L, Mari F, Pomponio G, Provinciali L, Danieli G (2002) Are behaviour and motor performances of rheumatoid arthritis patients influenced by subclinical cognitive impairments? A clinical and neuroimaging study. Clin Exp Rheumatol 20(4):491–497

    CAS  PubMed  Google Scholar 

  6. Dantzer R, Kelley KW (2007) Twenty years of research on cytokine-induced sickness behavior. Brain Behav Immun 21(2):153–160. https://doi.org/10.1016/j.bbi.2006.09.006

    Article  CAS  PubMed  Google Scholar 

  7. Trollor JN, Smith E, Agars E, Kuan SA, Baune BT, Campbell L, Samaras K, Crawford J, Lux O, Kochan NA, Brodaty H, Sachdev P (2012) The association between systemic inflammation and cognitive performance in the elderly: the Sydney memory and ageing study. Age (Dordr) 34(5):1295–1308. https://doi.org/10.1007/s11357-011-9301-x

    Article  CAS  Google Scholar 

  8. Lindqvist D, Hall S, Surova Y, Nielsen HM, Janelidze S, Brundin L, Hansson O (2013) Cerebrospinal fluid inflammatory markers in Parkinson’s disease—associations with depression, fatigue, and cognitive impairment. Brain Behav Immun 33:183–189. https://doi.org/10.1016/j.bbi.2013.07.007

    Article  CAS  PubMed  Google Scholar 

  9. Kipnis J, Gadani S, Derecki NC (2012) Pro-cognitive properties of T cells. Nat Rev Immunol 12(9):663–669. https://doi.org/10.1038/nri3280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Baruch K, Deczkowska A, David E, Castellano JM, Miller O, Kertser A, Berkutzki T, Barnett-Itzhaki Z, Bezalel D, Wyss-Coray T, Amit I, Schwartz M (2014) Aging. Aging-induced type I interferon response at the choroid plexus negatively affects brain function. Science 346(6205):89–93. https://doi.org/10.1126/science.1252945

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Derecki NC, Cardani AN, Yang CH, Quinnies KM, Crihfield A, Lynch KR, Kipnis J (2010) Regulation of learning and memory by meningeal immunity: a key role for IL-4. J Exp Med 207(5):1067–1080. https://doi.org/10.1084/jem.20091419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Grassi-Oliveira R, Stein LM, Lopes RP, Teixeira AL, Bauer ME (2008) Low plasma brain-derived neurotrophic factor and childhood physical neglect are associated with verbal memory impairment in major depression—a preliminary report. Biol Psychiatry 64(4):281–285. https://doi.org/10.1016/j.biopsych.2008.02.023

    Article  CAS  PubMed  Google Scholar 

  13. Lee SJ, Baek JH, Kim YH (2015) Brain-derived neurotrophic factor is associated with cognitive impairment in elderly Korean individuals. Clin Psychopharmacol Neurosci 13(3):283–287. https://doi.org/10.9758/cpn.2015.13.3.283

    Article  PubMed  PubMed Central  Google Scholar 

  14. Diniz BS, Teixeira AL (2011) Brain-derived neurotrophic factor and Alzheimer’s disease: physiopathology and beyond. NeuroMolecular Med 13(4):217–222. https://doi.org/10.1007/s12017-011-8154-x

    Article  CAS  PubMed  Google Scholar 

  15. Grimsholm O, Rantapaa-Dahlqvist S, Dalen T, Forsgren S (2008) BDNF in RA: downregulated in plasma following anti-TNF treatment but no correlation with inflammatory parameters. Clin Rheumatol 27(10):1289–1297. https://doi.org/10.1007/s10067-008-0910-4

    Article  PubMed  Google Scholar 

  16. del Porto F, Aloe L, Lagana B, Triaca V, Nofroni I, D'Amelio R (2006) Nerve growth factor and brain-derived neurotrophic factor levels in patients with rheumatoid arthritis treated with TNF-alpha blockers. Ann N Y Acad Sci 1069(1):438–443. https://doi.org/10.1196/annals.1351.042

    Article  PubMed  Google Scholar 

  17. Kipnis J, Cohen H, Cardon M, Ziv Y, Schwartz M (2004) T cell deficiency leads to cognitive dysfunction: implications for therapeutic vaccination for schizophrenia and other psychiatric conditions. Proc Natl Acad Sci U S A 101(21):8180–8185. https://doi.org/10.1073/pnas.0402268101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ziv Y, Ron N, Butovsky O, Landa G, Sudai E, Greenberg N, Cohen H, Kipnis J, Schwartz M (2006) Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat Neurosci 9(2):268–275. https://doi.org/10.1038/nn1629

    Article  CAS  PubMed  Google Scholar 

  19. Filiano AJ, Xu Y, Tustison NJ, Marsh RL, Baker W, Smirnov I, Overall CC, Gadani SP, Turner SD, Weng Z, Peerzade SN, Chen H, Lee KS, Scott MM, Beenhakker MP, Litvak V, Kipnis J (2016) Unexpected role of interferon-gamma in regulating neuronal connectivity and social behaviour. Nature 535(7612):425–429. https://doi.org/10.1038/nature18626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Underwood J, Cole JH, Caan M, De Francesco D, Leech R, van Zoest RA, Su T, Geurtsen GJ, Schmand BA, Portegies P, Prins M, Wit F, Sabin CA, Majoie C, Reiss P, Winston A, Sharp DJ (2017) Gray and white matter abnormalities in treated human immunodeficiency virus disease and their relationship to cognitive function. Clin Infect Dis 65(3):422–432. https://doi.org/10.1093/cid/cix301

    Article  PubMed  Google Scholar 

  21. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MD, Combe B, Costenbader KH, Dougados M, Emery P, Ferraccioli G, Hazes JM, Hobbs K, Huizinga TW, Kavanaugh A, Kay J, Kvien TK, Laing T, Mease P, Menard HA, Moreland LW, Naden RL, Pincus T, Smolen JS, Stanislawska-Biernat E, Symmons D, Tak PP, Upchurch KS, Vencovsky J, Wolfe F, Hawker G (2010) 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European league against rheumatism collaborative initiative. Arthritis Rheum 62(9):2569–2581. https://doi.org/10.1002/art.27584

    Article  PubMed  Google Scholar 

  22. Pinheiro GRC (2007) Pooled indices to measure rheumatoid arthrits activity: why and how to use them. Rev Bras Reumatol 47(5):362–365. https://doi.org/10.1590/S0482-50042007000500011

    Article  Google Scholar 

  23. Folstein MF, Folstein SE, McHugh PR (1975) “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12(3):189–198

    Article  CAS  PubMed  Google Scholar 

  24. Wechsler D (1987) WMS-R: Wechsler memory scale-revised : manual. Harcourt Brace Jovanovich, San Diego

    Google Scholar 

  25. Lezak MD (1995) Neuropsychological assessment. Oxford University Press, USA

    Google Scholar 

  26. Guise BJ, Thompson MD, Greve KW, Bianchini KJ, West L (2014) Assessment of performance validity in the Stroop Color and Word Test in mild traumatic brain injury patients: a criterion-groups validation design. J Neuropsychol 8(1):20–33. https://doi.org/10.1111/jnp.12002

    Article  PubMed  Google Scholar 

  27. Owen AM, McMillan KM, Laird AR, Bullmore E (2005) N-back working memory paradigm: a meta-analysis of normative functional neuroimaging studies. Hum Brain Mapp 25(1):46–59. https://doi.org/10.1002/hbm.20131

    Article  PubMed  Google Scholar 

  28. Beck AT, Steer RA, Ball R, Ranieri W (1996) Comparison of Beck Depression Inventories -IA and -II in psychiatric outpatients. J Pers Assess 67(3):588–597. https://doi.org/10.1207/s15327752jpa6703_13

    Article  CAS  PubMed  Google Scholar 

  29. Luft CB, Sanches SO, Mazo GZ, Andrade A (2007) Brazilian version of the perceived stress scale: translation and validation for the elderly. Rev Saúde Pública 41(4):606–615.

    Article  PubMed  Google Scholar 

  30. Marin IA, Kipnis J (2017) Central nervous system: (immunological) ivory tower or not? Neuropsychopharmacology 42(1):28–35. https://doi.org/10.1038/npp.2016.122

    Article  CAS  PubMed  Google Scholar 

  31. Shin SY, Katz P, Wallhagen M, Julian L (2012) Cognitive impairment in persons with rheumatoid arthritis. Arthritis Care Res (Hoboken) 64(8):1144–1150. https://doi.org/10.1002/acr.21683

    Google Scholar 

  32. Hamed SA, Selim ZI, Elattar AM, Elserogy YM, Ahmed EA, Mohamed HO (2012) Assessment of biocorrelates for brain involvement in female patients with rheumatoid arthritis. Clin Rheumatol 31(1):123–132. https://doi.org/10.1007/s10067-011-1795-1

    Article  PubMed  Google Scholar 

  33. Baptista TSA, Petersen LE, Molina JK, de Nardi T, Wieck A, do Prado A, Piovesan DM, Keisermann M, Grassi-Oliveira R, Bauer ME (2017) Autoantibodies against myelin sheath and S100beta are associated with cognitive dysfunction in patients with rheumatoid arthritis. Clin Rheumatol 36(9):1959–1968. https://doi.org/10.1007/s10067-017-3724-4

    Article  PubMed  Google Scholar 

  34. Meade T, Manolios N, Cumming SR, Conaghan PG, Katz P (2017) Cognitive impairment in rheumatoid arthritis: a systematic review. Arthritis Care Res (Hoboken) 70(1):39–52. https://doi.org/10.1002/acr.23243

    Article  Google Scholar 

  35. Wang W, Shao S, Jiao Z, Guo M, Xu H, Wang S (2012) The Th17/Treg imbalance and cytokine environment in peripheral blood of patients with rheumatoid arthritis. Rheumatol Int 32(4):887–893. https://doi.org/10.1007/s00296-010-1710-0

    Article  CAS  PubMed  Google Scholar 

  36. Doyle KP, Buckwalter MS (2016) Does B lymphocyte-mediated autoimmunity contribute to post-stroke dementia? Brain Behav Immun 64:1–8. https://doi.org/10.1016/j.bbi.2016.08.009

    Article  PubMed  Google Scholar 

  37. Grassi-Oliveira R, Bauer ME, Pezzi JC, Teixeira AL, Brietzke E (2011) Interleukin-6 and verbal memory in recurrent major depressive disorder. Neuro Endocrinol Lett 32(4):540–544

    CAS  PubMed  Google Scholar 

  38. Wang JB, Li H, Wang LL, Liang HD, Zhao L, Dong J (2015) Role of IL-1beta, IL-6, IL-8 and IFN-gamma in pathogenesis of central nervous system neuropsychiatric systemic lupus erythematous. Int J Clin Exp Med 8(9):16658–16663

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Gimeno D, Marmot MG, Singh-Manoux A (2008) Inflammatory markers and cognitive function in middle-aged adults: the Whitehall II study. Psychoneuroendocrinology 33(10):1322–1334. https://doi.org/10.1016/j.psyneuen.2008.07.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Barbosa IG, Rocha NP, Huguet RB, Ferreira RA, Salgado JV, Carvalho LA, Pariante CM, Teixeira AL (2012) Executive dysfunction in euthymic bipolar disorder patients and its association with plasma biomarkers. J Affect Disord 137(1–3):151–155. https://doi.org/10.1016/j.jad.2011.12.034

    Article  CAS  PubMed  Google Scholar 

  41. Kerschensteiner M, Gallmeier E, Behrens L, Leal VV, Misgeld T, Klinkert WE, Kolbeck R, Hoppe E, Oropeza-Wekerle RL, Bartke I, Stadelmann C, Lassmann H, Wekerle H, Hohlfeld R (1999) Activated human T cells, B cells, and monocytes produce brain-derived neurotrophic factor in vitro and in inflammatory brain lesions: a neuroprotective role of inflammation? J Exp Med 189(5):865–870. https://doi.org/10.1084/jem.189.5.865

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lundborg C, Hahn-Zoric M, Biber B, Hansson E (2010) Glial cell line-derived neurotrophic factor is increased in cerebrospinal fluid but decreased in blood during long-term pain. J Neuroimmunol 220(1–2):108–113. https://doi.org/10.1016/j.jneuroim.2010.01.007

    Article  CAS  PubMed  Google Scholar 

  43. Appel E, Kolman O, Kazimirsky G, Blumberg PM, Brodie C (1997) Regulation of GDNF expression in cultured astrocytes by inflammatory stimuli. Neuroreport 8(15):3309–3312. https://doi.org/10.1097/00001756-199710200-00023

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We are very grateful to the patients and staff of São Lucas Hospital (Porto Alegre, Brazil). The authors acknowledge support by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).

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Authors and Affiliations

  1. Laboratory of Stress Immunology, School of Sciences, Pontifical Catholic University of the Rio Grande do Sul (PUCRS), Porto Alegre, Brazil

    Laura E. Petersen, Julia G. Motta, Rodrigo Grassi-Oliveira & Moisés Evandro Bauer

  2. Developmental Cognitive Neuroscience Laboratory (DCNL), Faculty of Psychology, PUCRS, Porto Alegre, Brazil

    Talita S. A. Baptista, Júlia K. Molina, Tatiana de Nardi, Thiago W. Viola & Rodrigo Grassi-Oliveira

  3. Division of Rheumatology, São Lucas Hospital, PUCRS, Porto Alegre, Brazil

    Aline do Prado & Deise M. Piovesan

  4. Interdisciplinary Laboratory of Medical Investigation, School of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, Brazil

    Érica L. M. Vieira & Antonio L. Teixeira

  5. Neuropsychiatry Program, Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA

    Antonio L. Teixeira

  6. National Institute of Science and Technology on Neuroimmunomodulation (INCT-NIM), Rio de Janeiro, Brazil

    Moisés Evandro Bauer

  7. Instituto de Pesquisas Biomédicas, Faculdade de Biociências, Hospital São Lucas da PUCRS, Av. Ipiranga 6690, 2° andar, P.O. Box 1429, Porto Alegre, RS, 90610-000, Brazil

    Moisés Evandro Bauer

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  1. Laura E. Petersen
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Petersen, L.E., Baptista, T.S.A., Molina, J.K. et al. Cognitive impairment in rheumatoid arthritis: role of lymphocyte subsets, cytokines and neurotrophic factors. Clin Rheumatol 37, 1171–1181 (2018). https://doi.org/10.1007/s10067-018-3990-9

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