Background: Rheumatoid arthritis (RA) has been associated with premature immunosenescence and an increased prevalence of age-related morbidities including poor cognitive function. Objective: We explored the relationships among lymphocyte subsets and memory in RA. Methods: Thirty patients with RA and 19 age-matched healthy controls took part in this study. Cognitive function stress and depression scores were evaluated by structured clinical questionnaires. Lymphocytes were isolated and immunophenotyped by flow cytometry to investigate the following subsets: B cells, activated and naïve/memory T cells, regulatory FoxP3+ T (Treg) cells, Th17+ cells, NK cells and senescence-associated CD28- T cells. Results: RA patients were more depressed than controls, but stress levels were similar in the 2 groups. Patients had impaired memory performance compared to controls, demonstrated by lower Mini-Mental State Examination scores and logical and working memories (all p < 0.0001). These group effects remained significant after correcting for depression and age. Patients had expansion of regulatory T cells, naïve CD4+ T cells and CD8+CD28- cells but reduced percentages of B cells and memory CD8+CD45RO+ T cells compared to controls. CD8+CD28- and CD8+CD45RO+ T cells were found to be negatively associated with memory. Conclusion: RA patients had reduced memory performance compared to healthy controls. Expansion of activated and senescence-associated T cells was correlated with poor memory performance.

1.
de Melo LF, Da-Silva SL: Neuropsychological assessment of cognitive disorders in patients with fibromyalgia, rheumatoid arthritis, and systemic lupus erythematosus. Rev Bras Reumatol 2012;52:175-188.
2.
Shin SY, Katz P, Wallhagen M, Julian L: Cognitive impairment in persons with rheumatoid arthritis. Arthritis Care Res (Hoboken) 2012;64:1144-1150.
3.
Boyd TD, Bennett SP, Mori T, Governatori N, Runfeldt M, Norden M, Padmanabhan J, Neame P, Wefes I, Sanchez-Ramos J, Arendash GW, Potter H: GM-CSF upregulated in rheumatoid arthritis reverses cognitive impairment and amyloidosis in Alzheimer mice. J Alzheimers Dis 2010;21:507-518.
4.
Shin SY, Julian L, Katz P: The relationship between cognitive function and physical function in rheumatoid arthritis. J Rheumatol 2013;40:236-243.
5.
Bartolini M, Candela M, Brugni M, Catena L, Mari F, Pomponio G, Provinciali L, Danieli G: Are behaviour and motor performances of rheumatoid arthritis patients influenced by subclinical cognitive impairments? A clinical and neuroimaging study. Clin Exp Rheumatol 2002;20:491-497.
6.
Appenzeller S, Bertolo MB, Costallat LT: Cognitive impairment in rheumatoid arthritis. Methods Find Exp Clin Pharmacol 2004;26:339-343.
7.
Komulainen P, Lakka TA, Kivipelto M, Hassinen M, Penttila IM, Helkala EL, Gylling H, Nissinen A, Rauramaa R: Serum high sensitivity C-reactive protein and cognitive function in elderly women. Age Ageing 2007;36:443-448.
8.
Bi BT, Lin HB, Cheng YF, Zhou H, Lin T, Zhang MZ, Li TJ, Xu JP: Promotion of beta-amyloid production by C-reactive protein and its implications in the early pathogenesis of Alzheimer's disease. Neurochem Int 2012;60:257-266.
9.
Grassi-Oliveira R, Bauer ME, Pezzi JC, Teixeira AL, Brietzke E: Interleukin-6 and verbal memory in recurrent major depressive disorder. Neuro Endocrinol Lett 2011;32:540-544.
10.
Cohen H, Ziv Y, Cardon M, Kaplan Z, Matar MA, Gidron Y, Schwartz M, Kipnis J: Maladaptation to mental stress mitigated by the adaptive immune system via depletion of naturally occurring regulatory CD4+CD25+ cells. J Neurobiol 2006;66:552-563.
11.
Kipnis J, Cohen H, Cardon M, Ziv Y, Schwartz M: T cell deficiency leads to cognitive dysfunction: implications for therapeutic vaccination for schizophrenia and other psychiatric conditions. Proc Natl Acad Sci USA 2004;101:8180-8185.
12.
Brynskikh A, Warren T, Zhu J, Kipnis J: Adaptive immunity affects learning behavior in mice. Brain Behav Immun 2008;22:861-869.
13.
Ziv Y, Ron N, Butovsky O, Landa G, Sudai E, Greenberg N, Cohen H, Kipnis J, Schwartz M: Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat Neurosci 2006;9:268-275.
14.
Lindstrom TM, Robinson WH: Rheumatoid arthritis: a role for immunosenescence? J Am Geriatr Soc 2010;58:1565-1575.
15.
Thewissen M, Linsen L, Somers V, Geusens P, Raus J, Stinissen P: Premature immunosenescence in rheumatoid arthritis and multiple sclerosis patients. Ann NY Acad Sci 2005;1051:255-262.
16.
Koetz K, Bryl E, Spickschen K, O'Fallon WM, Goronzy JJ, Weyand CM: T cell homeostasis in patients with rheumatoid arthritis. Proc Natl Acad Sci USA 2000;97:9203-9208.
17.
Goronzy JJ, Weyand CM: Immune aging and autoimmunity. Cell Mol Life Sci 2012;69:1615-1623.
18.
Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham C, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MC, Combe B, Costenbader KH, Dougados M, Emery P, Ferraccioli G, Hazes JMW, Hobbs K, Huizinga TW, Kavanaugh A, Kay J, Kvien TK, Laing T, Mease P, Ménard HA, Moreland LW, Naden RL, Pincus T, Smolen JF, Stanislawska-Biernat E, Symmons D, Tak PP, Upchurch KS, Vencovsky J, Wolfe F, Hawker G: 2010 Rheumatoid Arthritis Classification Criteria. Arthritis Rheum 2010;62:2569-2581.
19.
Prevoo MLL, Van't Hof MA, Kuper HH, van Leeuwen MA, van de Putte LBA, van Riel PLCM: Modified disease activity scores that include twenty-eight-joint counts. Arthritis Rheum 1995;38:44-48.
20.
Folstein MF, Folstein SE, McHugh PR: ‘Mini-mental state'. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189-198.
21.
Bertolucci PHF, BruckiI S, Campacci SR, Juliano Y: O mini-exame do estado mental em uma população geral. Arq. Neuropsiquiatr 1994;52:1-7.
22.
Owen AM, McMillan KM, Laird AR, Bullmore E: N-back working memory paradigm: a meta-analysis of normative functional neuroimaging studies. Hum Brain Mapp 2005;25:46-59.
23.
Wechsler D: Wechsler Memory Scale - revised manual. San Antonio, Psychological Corporation, 1987.
24.
Grassi-Oliveira R, Stein LM, Lopes RP, Teixeira AL, Bauer ME: Low plasma brain-derived neurotrophic factor and childhood physical neglect are associated with verbal memory impairment in major depression - a preliminary report. Biol Psychiatry 2008;64:281-285.
25.
Beck AT, Steer RA, Ball R, Ranieri W: Comparison of Beck Depression Inventories -IA and -II in psychiatric outpatients. J Pers Assess 1996;67:588-597.
26.
Luft CD, Sanches Sde O, Mazo GZ, Andrade A: Brazilian version of the Perceived Stress Scale: translation and validation for the elderly. Rev Saude Publica 2007;41:606-615.
27.
Pinheiro GR: Pooled indices to measure rheumatoid arthrits activity - why and how to use them. Rev Bras Reumatol 2007;47:362-365.
28.
Richartz-Salzburger E, Batra A, Stransky E, Laske C, Kohler N, Bartels M, Buchkremer G, Schott K: Altered lymphocyte distribution in Alzheimer's disease. J Psychiatr Res 2007;41:174-178.
29.
Wolf OT, Convit A, McHugh PF, Kandil E, Thorn EL, De Santi S, McEwen BS, de Leon MJ: Cortisol differentially affects memory in young and elderly men. Behav Neurosci 2001;115:1002-1011.
30.
Coluccia D, Wolf OT, Kollias S, Roozendaal B, Forster A, de Quervain DJ: Glucocorticoid therapy-induced memory deficits: acute versus chronic effects. J Neurosci 2008;28:3474-3478.
31.
Almela M, van der Meij L, Hidalgo V, Villada C, Salvador A: The cortisol awakening response and memory performance in older men and women. Psychoneuroendocrinology 2012;37:1929-1940.
32.
Jameison K, Dinan TG: Glucocorticoids and cognitive function: from physiology to pathophysiology. Hum Psychopharmacol 2001;16:293-302.
33.
Trollor JN, Smith E, Agars E, Kuan SA, Baune BT, Campbell L, Samaras K, Crawford J, Lux O, Kochan NA, Brodaty H, Sachdev P: The association between systemic inflammation and cognitive performance in the elderly: the Sydney Memory and Ageing Study. Age (Dordr) 2012;34:1295-1308.
34.
Bauer ME: Chronic stress and immunosenescence: a review. Neuroimmunomodulation 2008;15:241-250.
35.
van den Kommer TN, Dik MG, Comijs HC, Jonker C, Deeg DJ: Homocysteine and inflammation: predictors of cognitive decline in older persons? Neurobiol Aging 2010;31:1700-1709.
36.
Phillips AC, Batty GD, van Zanten JJ, Mortensen LH, Deary IJ, Calvin CM, Carroll D: Cognitive ability in early adulthood is associated with systemic inflammation in middle age: the Vietnam experience study. Brain Behav Immun 2011;25:298-301.
37.
do Prado CH, Rizzo LB, Wieck A, Lopes RP, Teixeira AL, Grassi-Oliveira R, Bauer ME: Reduced regulatory T cells are associated with higher levels of Th1/Th17 cytokines and activated MAPK in type 1 bipolar disorder. Psychoneuroendocrinology 2013;38:667-676.
38.
Goronzy JJ, Shao L, Weyand CM: Immune aging and rheumatoid arthritis. Rheum Dis Clin North Am 2010;36:297-310.
39.
Weyand CM, Fulbright JW, Goronzy JJ: Immunosenescence, autoimmunity, and rheumatoid arthritis. Exp Gerontol 2003;38:833-841.
40.
Goronzy JJ, Weyand CM: Aging, autoimmunity and arthritis: T-cell senescence and contraction of T-cell repertoire diversity - catalysts of autoimmunity and chronic inflammation. Arthritis Res Ther 2003;5:225-234.
41.
Haque R, Lei F, Xiong X, Bian Y, Zhao B, Wu Y, Song J: Programming of regulatory T cells from pluripotent stem cells and prevention of autoimmunity. J Immunol 2012;189:1228-1236.
42.
Cao D, Malmstrom V, Baecher-Allan C, Hafler D, Klareskog L, Trollmo C: Isolation and functional characterization of regulatory CD25brightCD4+ T cells from the target organ of patients with rheumatoid arthritis. Eur J Immunol 2003;33:215-223.
43.
Valencia X, Stephens G, Goldbach-Mansky R, Wilson M, Shevach EM, Lipsky PE: TNF downmodulates the function of human CD4+CD25hi T-regulatory cells. Blood 2006;108:253-261.
44.
Yoles E, Hauben E, Palgi O, Agranov E, Gothilf A, Cohen A, Kuchroo V, Cohen IR, Weiner H, Schwartz M: Protective autoimmunity is a physiological response to CNS trauma. J Neurosci 2001;21:3740-3748.
45.
Kipnis J, Gadani S, Derecki NC: Pro-cognitive properties of T cells. Nat Rev Immunol 2012;12:663-669.
46.
Engelhardt B, Ransohoff RM: The ins and outs of T-lymphocyte trafficking to the CNS: anatomical sites and molecular mechanisms. Trends Immunol 2005;26:485-495.
47.
Magaki S, Yellon SM, Mueller C, Kirsch WM: Immunophenotypes in the circulation of patients with mild cognitive impairment. J Psychiatr Res 2008;42:240-246.
48.
Larbi A, Pawelec G, Witkowski JM, Schipper HM, Derhovanessian E, Goldeck D, Fulop T: Dramatic shifts in circulating CD4 but not CD8 T cell subsets in mild Alzheimer's disease. J Alzheimers Dis 2009;17:91-103.
49.
Pellicano M, Larbi A, Goldeck D, Colonna-Romano G, Buffa S, Bulati M, Rubino G, Iemolo F, Candore G, Caruso C, Derhovanessian E, Pawelec G: Immune profiling of Alzheimer patients. J Neuroimmunol 2012;242:52-59.
50.
Saresella M, Calabrese E, Marventano I, Piancone F, Gatti A, Alberoni M, Nemni R, Clerici M: Increased activity of Th-17 and Th-9 lymphocytes and a skewing of the post-thymic differentiation pathway are seen in Alzheimer's disease. Brain Behav Immun 2011;25:539-547.
51.
Baruch K, Ron-Harel N, Gal H, Deczkowska A, Shifrut E, Ndifon W, Mirlas-Neisberg N, Cardon M, Vaknin I, Cahalon L, Berkutzki T, Mattson MP, Gomez-Pinilla F, Friedman N, Schwartz M: CNS-specific immunity at the choroid plexus shifts toward destructive Th2 inflammation in brain aging. Proc Natl Acad Sci USA 2013;110:2264-2269.
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