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Vol. 28, No. 4, 2009
Issue release date: November 2009
Free Access
Dement Geriatr Cogn Disord 2009;28:281–287
(DOI:10.1159/000245156)

Peripheral Cytokines and Chemokines in Alzheimer’s Disease

Lee K.S.a, b · Chung J.H.c, d · Choi T.K.a · Suh S.Y.a · Oh B.H.b · Hong C.H.e, f
aDepartment of Psychiatry, CHA University, Bundang Cha Medical Center, Seongnam, bDepartment of Medicine, Graduate School, Yonsei University, cYonsei Integrative Research Institute for Cerebral and Cardiovascular Diseases, and dYonsei University Health System, Seoul, eDepartment of Psychiatry, Ajou University School of Medicine, and fMemory Impairment Center, Ajou University Hospital, Suwon, Korea
email Corresponding Author

Abstract

A chronic inflammatory process has been implicated in the neuropathology of Alzheimer’s disease (AD). The present review focuses on the current knowledge of circulating serum and plasma biomarkers of AD that are linked to inflammatory reactions. There is abundant evidence that inflammatory mechanisms within the central nervous system contribute to cognitive impairment via cytokine-mediated interactions between neurons and glial cells. Interleukins 1, 4, 6, 10, 12, 16, and 18, tumour necrosis factor, and several chemokines have been suggested as biomarkers of AD. Nonetheless, data on circulating cytokine levels are somewhat inconsistent with regard to peripheral cytokine dysregulation in AD. In summary, definite statements concerning differences in inflammatory biomarkers between controls and AD patients will require the use of sensitive multiplex assays in large patient groups in conjunction with measures of disease severity.


 goto top of outline Key Words

  • Alzheimer’s disease
  • Inflammation
  • Cytokines
  • Chemokines
  • Biomarkers

 goto top of outline Abstract

A chronic inflammatory process has been implicated in the neuropathology of Alzheimer’s disease (AD). The present review focuses on the current knowledge of circulating serum and plasma biomarkers of AD that are linked to inflammatory reactions. There is abundant evidence that inflammatory mechanisms within the central nervous system contribute to cognitive impairment via cytokine-mediated interactions between neurons and glial cells. Interleukins 1, 4, 6, 10, 12, 16, and 18, tumour necrosis factor, and several chemokines have been suggested as biomarkers of AD. Nonetheless, data on circulating cytokine levels are somewhat inconsistent with regard to peripheral cytokine dysregulation in AD. In summary, definite statements concerning differences in inflammatory biomarkers between controls and AD patients will require the use of sensitive multiplex assays in large patient groups in conjunction with measures of disease severity.

Copyright © 2009 S. Karger AG, Basel


 goto top of outline References
  1. Eikelenboom P, van Gool WA: Neuroinflammatory perspectives on the two faces of Alzheimer’s disease. J Neural Transm 2004;111:281–294.
  2. Maccioni RB, Rojo LE, Fernandez JA, Kuljis RO: The role of neuroimmunomodulation in Alzheimer’s disease. Ann NY Acad Sci 2009;1153:240–246.
  3. Shaftel SS, Griffin WS, O’Banion MK: The role of interleukin-1 in neuroinflammation and Alzheimer disease: an evolving perspective. J Neuroinflammation 2008;5:7.
  4. Rojo LE, Fernandez JA, Maccioni AA, Jimenez JM, Maccioni RB: Neuroinflammation: implications for the pathogenesis and molecular diagnosis of Alzheimer’s disease. Arch Med Res 2008;39:1–16.
  5. Blasko I, Veerhuis R, Stampfer-Kountchev M, Saurwein-Teissl M, Eikelenboom P, Grubeck-Loebenstein B: Costimulatory effects of interferon-gamma and interleukin-1beta or tumor necrosis factor alpha on the synthesis of Abeta1–40 and Abeta1–42 by human astrocytes. Neurobiol Dis 2000;7:682–689.
  6. Gitter BD, Cox LM, Rydel RE, May PC: Amyloid beta peptide potentiates cytokine secretion by interleukin-1 beta-activated human astrocytoma cells. Proc Natl Acad Sci USA 1995;92:10738–10741.
  7. Blennow K: Cerebrospinal fluid protein biomarkers for Alzheimer’s disease. NeuroRx 2004;1:213–225.
  8. Blum-Degen D, Muller T, Kuhn W, Gerlach M, Przuntek H, Riederer P: Interleukin-1 beta and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer’s and de novo Parkinson’s disease patients. Neurosci Lett 1995;202:17–20.
  9. Cacabelos R, Barquero M, Garcia P, Alvarez XA, Varela de Seijas E: Cerebrospinal fluid interleukin-1 beta (IL-1 beta) in Alzheimer’s disease and neurological disorders. Methods Find Exp Clin Pharmacol 1991;13:455–458.
  10. Lanzrein AS, Johnston CM, Perry VH, Jobst KA, King EM, Smith AD: Longitudinal study of inflammatory factors in serum, cerebrospinal fluid, and brain tissue in Alzheimer disease: interleukin-1beta, interleukin-6, interleukin-1 receptor antagonist, tumor necrosis factor-alpha, the soluble tumor necrosis factor receptors I and II, and alpha1-antichymotrypsin. Alzheimer Dis Assoc Disord 1998;12:215–227.
  11. Pirttila T, Mehta PD, Frey H, Wisniewski HM: Alpha 1-antichymotrypsin and IL-1 beta are not increased in CSF or serum in Alzheimer’s disease. Neurobiol Aging 1994;15:313–317.
  12. Tarkowski E, Blennow K, Wallin A, Tarkowski A: Intracerebral production of tumor necrosis factor-alpha, a local neuroprotective agent, in Alzheimer disease and vascular dementia. J Clin Immunol 1999;19:223–230.
  13. Licastro F, Pedrini S, Caputo L, Annoni G, Davis LJ, Ferri C, Casadei V, Grimaldi LM: Increased plasma levels of interleukin-1, interleukin-6 and alpha-1-antichymotrypsin in patients with Alzheimer’s disease: peripheral inflammation or signals from the brain? J Neuroimmunol 2000;103:97–102.
  14. Teunissen CE, de Vente J, Steinbusch HW, De Bruijn C: Biochemical markers related to Alzheimer’s dementia in serum and cerebrospinal fluid. Neurobiol Aging 2002;23:485–508.
  15. Weisman D, Hakimian E, Ho GJ: Interleukin, inflammation, and mechanisms of Alzheimer’s disease. Vitam Horn 2006;74:505–530.
  16. Szczepanik AM, Funes S, Petko W, Ringheim GE: IL-4, IL-10 and IL-13 modulate a beta(1–42)-induced cytokine and chemokine production in primary murine microglia and a human monocyte cell line. J Neuroimmunol 2001;113:49–62.
  17. Ambi F, Reale M, Iarlori C, Salone A, Toma L, Paladini C, De Luca G, Feliciani C, Salvatore M, Salerno RM, Theoharides TC, Conti P, Exton M, Gambi D: Alzheimer patients treated with an ache inhibitor show higher IL-4 and lower IL-1 beta levels and expression in peripheral blood mononuclear cells. J Clin Psychopharmacol 2004;24:314–321.
  18. Ugaresi A, Di Iorio A, Iarlori C, Reale M, De Luca G, Sparvieri E, Michetti A, Conti P, Gambi D, Abate G, Paganelli R: IL-4 in vitro production is upregulated in Alzheimer’s disease patients treated with acetylcholinesterase inhibitors. Exp Gerontol 2004;39:653–657.
  19. Sun YX, Minthon L, Wallmark A, Warkentin S, Blennow K, Janciauskiene S: Inflammatory markers in matched plasma and cerebrospinal fluid from patients with Alzheimer’s disease. Dement Geriatr Cogn Disord 2003;16:136–144.
  20. Hampel H, Sunderland T, Kotter HU, Schneider C, Teipel SJ, Padberg F, Dukoff R, Levy J, Moller HJ: Decreased soluble interleukin-6 receptor in cerebrospinal fluid of patients with Alzheimer’s disease. Brain Res 1998;780:356–359.
  21. Bonaccorso S, Lin A, Song C, Verkerk R, Kenis G, Bosmans E, Scharpe S, Vandewoude M, Dossche A, Maes M: Serotonin-immune interactions in elderly volunteers and in patients with Alzheimer’s disease (DAT): lower plasma tryptophan availability to the brain in the elderly and increased serum interleukin-6 in DAT. Aging (Milano) 1998;10:316–323.
  22. Kalman J, Juhasz A, Laird G, Dickens P, Jardanhazy T, Rimanoczy A, Boncz I, Parry-Jones WL, Janka Z: Serum interleukin-6 levels correlate with the severity of dementia in down syndrome and in Alzheimer’s disease. Acta Neurol Scand 1997;96:236–240.
  23. Maes M, DeVos N, Wauters A, Demedts P, Maurits VW, Neels H, Bosmans E, Altamura C, Lin A, Song C, Vandenbroucke M, Scharpe S: Inflammatory markers in younger vs elderly normal volunteers and in patients with Alzheimer’s disease. J Psychiatr Res 1999;33:397–405.
  24. Angelis P, Scharf S, Mander A, Vajda F, Christophidis N: Serum interleukin-6 and interleukin-6 soluble receptor in Alzheimer’s disease. Neurosci Lett 1998;244:106–108.
  25. Chao CC, Ala TA, Hu S, Crossley KB, Sherman RE, Peterson PK, Frey WH 2nd: Serum cytokine levels in patients with Alzheimer’s disease. Clin Diagn Lab Immunol 1994;1:433–436.
  26. De Luigi A, Pizzimenti S, Quadri P, Lucca U, Tettamanti M, Fragiacomo C, De Simoni MG: Peripheral inflammatory response in Alzheimer’s disease and multiinfarct dementia. Neurobiol Dis 2002;11:308–314.
  27. Bonotis K, Krikki E, Holeva V, Aggouridaki C, Costa V, Baloyannis S: Systemic immune aberrations in Alzheimer’s disease patients. J Neuroimmunol 2008;193:183–187.
  28. Singh VK, Guthikonda P: Circulating cytokines in Alzheimer’s disease. J Psychiatr Res 1997;31:657–660.
  29. Tarkowski E, Wallin A, Regland B, Blennow K, Tarkowski A: Local and systemic GM-CSF increase in Alzheimer’s disease and vascular dementia. Acta Neurol Scand 2001;103:166–174.
  30. Rota E, Bellone G, Rocca P, Bergamasco B, Emanuelli G, Ferrero P: Increased intrathecal TGF-beta1, but not IL-12, IFN-gamma and IL-10 levels in Alzheimer’s disease patients. Neurol Sci 2006;27:33–39.
  31. Angelopoulos P, Agouridaki H, Vaiopoulos H, Siskou E, Doutsou K, Costa V, Baloyiannis SI: Cytokines in Alzheimer’s disease and vascular dementia. Int J Neurosci 2008;118:1659–1672.
  32. Baranowska-Bik A, Bik W, Wolinska-Witort E, Martynska L, Chmielowska M, Barcikowska M, Baranowska B: Plasma beta amyloid and cytokine profile in women with Alzheimer’s disease. Neuro Endocrinol Lett 2008;29:75–79.
  33. Strle K, Zhou JH, Shen WH, Broussard SR, Johnson RW, Freund GG, Dantzer R, Kelley KW: Interleukin-10 in the brain. Crit Rev Immunol 2001;21:427–449.
  34. Speciale L, Calabrese E, Saresella M, Tinelli C, Mariani C, Sanvito L, Longhi R, Ferrante P: Lymphocyte subset patterns and cytokine production in Alzheimer’s disease patients. Neurobiol Aging 2007;28:1163–1169.
  35. Engelborghs S, De Brabander M, De Cree J, D’Hooge R, Geerts H, Verhaegen H, De Deyn PP: Unchanged levels of interleukins, neopterin, interferon-gamma and tumor necrosis factor-alpha in cerebrospinal fluid of patients with dementia of the Alzheimer type. Neurochem Int 1999;34:523–530.
  36. Motta M, Imbesi R, Di Rosa M, Stivala F, Malaguarnera L: Altered plasma cytokine levels in Alzheimer’s disease: correlation with the disease progression. Immunol Lett 2007;114:46–51.
  37. Bruunsgaard H, Andersen-Ranberg K, Jeune B, Pedersen AN, Skinhoj P, Pedersen BK: A high plasma concentration of TNF-alpha is associated with dementia in centenarians. J Gerontol A Biol Sci Med Sci 1999;54:M357–M364.
  38. Hasegawa Y, Sawada M, Ozaki N, Inagaki T, Suzumura A: Increased soluble tumor necrosis factor receptor levels in the serum of elderly people. Gerontology 2000;46:185–188.
  39. Cacabelos R, Alvarez XA, Franco-Maside A, Fernandez-Novoa L, Caamano J: Serum tumor necrosis factor (TNF) in Alzheimer’s disease and multi-infarct dementia. Methods Find Exp Clin Pharmacol 1994;16:29–35.
  40. Paganelli R, Di Iorio A, Patricelli L, Ripani F, Sparvieri E, Faricelli R, Iarlori C, Porreca E, Di Gioacchino M, Abate G: Proinflammatory cytokines in sera of elderly patients with dementia: levels in vascular injury are higher than those of mild-moderate Alzheimer’s disease patients. Exp Gerontol 2002;37:257–263.
  41. Alvarez XA, Franco A, Fernandez-Novoa L, Cacabelos R: Blood levels of histamine, IL-1 beta, and TNF-alpha in patients with mild to moderate Alzheimer disease. Mol Chem Neuropathol 1996;29:237–252.
  42. Fillit H, Ding WH, Buee L, Kalman J, Altstiel L, Lawlor B, Wolf-Klein G: Elevated circulating tumor necrosis factor levels in Alzheimer’s disease. Neurosci Lett 1991;129:318–320.
  43. Bermejo P, Martin-Aragon S, Benedi J, Susin C, Felici E, Gil P, Ribera JM, Villar AM: Differences of peripheral inflammatory markers between mild cognitive impairment and Alzheimer’s disease. Immunol Lett 2008;117:198–202.
  44. Ray S, Britschgi M, Herbert C, Takeda-Uchimura Y, Boxer A, Blennow K, Friedman LF, Galasko DR, Jutel M, Karydas A, Kaye JA, Leszek J, Miller BL, Minthon L, Quinn JF, Rabinovici GD, Robinson WH, Sabbagh MN, So YT, Sparks DL, Tabaton M, Tinklenberg J, Yesavage JA, Tibshirani R, Wyss-Coray T: Classification and prediction of clinical Alzheimer’s diagnosis based on plasma signaling proteins. Nat Med 2007;13:1359–1362.
  45. Galimberti D, Schoonenboom N, Scarpini E, Scheltens P: Chemokines in serum and cerebrospinal fluid of Alzheimer’s disease patients. Ann Neurol 2003;53:547–548.
  46. Blasko I, Lederer W, Oberbauer H, Walch T, Kemmler G, Hinterhuber H, Marksteiner J, Humpel C: Measurement of thirteen biological markers in CSF of patients with Alzheimer’s disease and other dementias. Dement Geriatr Cogn Disord 2006;21:9–15.
  47. Lee KS, Chung JH, Lee KH, Shin MJ, Oh BH, Hong CH: Bioplex analysis of plasma cytokines in Alzheimer’s disease and mild cognitive impairment. Immunol Lett 2008;121:105–109.
  48. Kim TS, Lim HK, Lee JY, Kim DJ, Park S, Lee C, Lee CU: Changes in the levels of plasma soluble fractalkine in patients with mild cognitive impairment and Alzheimer’s disease. Neurosci Lett 2008;436:196–200.
  49. Quan N, Herkenham M: Connecting cytokines and brain: a review of current issues. Histol Histopathol 2002;17:273–288.
  50. Fulton RJ, McDade RL, Smith PL, Kienker LJ, Kettman JR Jr: Advanced multiplexed analysis with the FlowMetrix system. Clin Chem 1997;43:1749–1756.

 goto top of outline Author Contacts

Chang Hyung Hong
Ajou University School of Medicine
San 5, Wonchun-dong, Youngtong-gu
Suwon-si 443-749 (Korea)
Tel. +82 31 219 5180, Fax +82 31 219 5179, E-Mail antiaging@ajou.ac.kr


 goto top of outline Article Information

Accepted: August 11, 2009
Published online: October 10, 2009
Number of Print Pages : 7
Number of Figures : 0, Number of Tables : 1, Number of References : 50


 goto top of outline Publication Details

Dementia and Geriatric Cognitive Disorders

Vol. 28, No. 4, Year 2009 (Cover Date: November 2009)

Journal Editor: Chan-Palay V. (New York, N.Y.)
ISSN: 1420-8008 (Print), eISSN: 1421-9824 (Online)

For additional information: http://www.karger.com/DEM


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

A chronic inflammatory process has been implicated in the neuropathology of Alzheimer’s disease (AD). The present review focuses on the current knowledge of circulating serum and plasma biomarkers of AD that are linked to inflammatory reactions. There is abundant evidence that inflammatory mechanisms within the central nervous system contribute to cognitive impairment via cytokine-mediated interactions between neurons and glial cells. Interleukins 1, 4, 6, 10, 12, 16, and 18, tumour necrosis factor, and several chemokines have been suggested as biomarkers of AD. Nonetheless, data on circulating cytokine levels are somewhat inconsistent with regard to peripheral cytokine dysregulation in AD. In summary, definite statements concerning differences in inflammatory biomarkers between controls and AD patients will require the use of sensitive multiplex assays in large patient groups in conjunction with measures of disease severity.



 goto top of outline Author Contacts

Chang Hyung Hong
Ajou University School of Medicine
San 5, Wonchun-dong, Youngtong-gu
Suwon-si 443-749 (Korea)
Tel. +82 31 219 5180, Fax +82 31 219 5179, E-Mail antiaging@ajou.ac.kr


 goto top of outline Article Information

Accepted: August 11, 2009
Published online: October 10, 2009
Number of Print Pages : 7
Number of Figures : 0, Number of Tables : 1, Number of References : 50


 goto top of outline Publication Details

Dementia and Geriatric Cognitive Disorders

Vol. 28, No. 4, Year 2009 (Cover Date: November 2009)

Journal Editor: Chan-Palay V. (New York, N.Y.)
ISSN: 1420-8008 (Print), eISSN: 1421-9824 (Online)

For additional information: http://www.karger.com/DEM


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Eikelenboom P, van Gool WA: Neuroinflammatory perspectives on the two faces of Alzheimer’s disease. J Neural Transm 2004;111:281–294.
  2. Maccioni RB, Rojo LE, Fernandez JA, Kuljis RO: The role of neuroimmunomodulation in Alzheimer’s disease. Ann NY Acad Sci 2009;1153:240–246.
  3. Shaftel SS, Griffin WS, O’Banion MK: The role of interleukin-1 in neuroinflammation and Alzheimer disease: an evolving perspective. J Neuroinflammation 2008;5:7.
  4. Rojo LE, Fernandez JA, Maccioni AA, Jimenez JM, Maccioni RB: Neuroinflammation: implications for the pathogenesis and molecular diagnosis of Alzheimer’s disease. Arch Med Res 2008;39:1–16.
  5. Blasko I, Veerhuis R, Stampfer-Kountchev M, Saurwein-Teissl M, Eikelenboom P, Grubeck-Loebenstein B: Costimulatory effects of interferon-gamma and interleukin-1beta or tumor necrosis factor alpha on the synthesis of Abeta1–40 and Abeta1–42 by human astrocytes. Neurobiol Dis 2000;7:682–689.
  6. Gitter BD, Cox LM, Rydel RE, May PC: Amyloid beta peptide potentiates cytokine secretion by interleukin-1 beta-activated human astrocytoma cells. Proc Natl Acad Sci USA 1995;92:10738–10741.
  7. Blennow K: Cerebrospinal fluid protein biomarkers for Alzheimer’s disease. NeuroRx 2004;1:213–225.
  8. Blum-Degen D, Muller T, Kuhn W, Gerlach M, Przuntek H, Riederer P: Interleukin-1 beta and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer’s and de novo Parkinson’s disease patients. Neurosci Lett 1995;202:17–20.
  9. Cacabelos R, Barquero M, Garcia P, Alvarez XA, Varela de Seijas E: Cerebrospinal fluid interleukin-1 beta (IL-1 beta) in Alzheimer’s disease and neurological disorders. Methods Find Exp Clin Pharmacol 1991;13:455–458.
  10. Lanzrein AS, Johnston CM, Perry VH, Jobst KA, King EM, Smith AD: Longitudinal study of inflammatory factors in serum, cerebrospinal fluid, and brain tissue in Alzheimer disease: interleukin-1beta, interleukin-6, interleukin-1 receptor antagonist, tumor necrosis factor-alpha, the soluble tumor necrosis factor receptors I and II, and alpha1-antichymotrypsin. Alzheimer Dis Assoc Disord 1998;12:215–227.
  11. Pirttila T, Mehta PD, Frey H, Wisniewski HM: Alpha 1-antichymotrypsin and IL-1 beta are not increased in CSF or serum in Alzheimer’s disease. Neurobiol Aging 1994;15:313–317.
  12. Tarkowski E, Blennow K, Wallin A, Tarkowski A: Intracerebral production of tumor necrosis factor-alpha, a local neuroprotective agent, in Alzheimer disease and vascular dementia. J Clin Immunol 1999;19:223–230.
  13. Licastro F, Pedrini S, Caputo L, Annoni G, Davis LJ, Ferri C, Casadei V, Grimaldi LM: Increased plasma levels of interleukin-1, interleukin-6 and alpha-1-antichymotrypsin in patients with Alzheimer’s disease: peripheral inflammation or signals from the brain? J Neuroimmunol 2000;103:97–102.
  14. Teunissen CE, de Vente J, Steinbusch HW, De Bruijn C: Biochemical markers related to Alzheimer’s dementia in serum and cerebrospinal fluid. Neurobiol Aging 2002;23:485–508.
  15. Weisman D, Hakimian E, Ho GJ: Interleukin, inflammation, and mechanisms of Alzheimer’s disease. Vitam Horn 2006;74:505–530.
  16. Szczepanik AM, Funes S, Petko W, Ringheim GE: IL-4, IL-10 and IL-13 modulate a beta(1–42)-induced cytokine and chemokine production in primary murine microglia and a human monocyte cell line. J Neuroimmunol 2001;113:49–62.
  17. Ambi F, Reale M, Iarlori C, Salone A, Toma L, Paladini C, De Luca G, Feliciani C, Salvatore M, Salerno RM, Theoharides TC, Conti P, Exton M, Gambi D: Alzheimer patients treated with an ache inhibitor show higher IL-4 and lower IL-1 beta levels and expression in peripheral blood mononuclear cells. J Clin Psychopharmacol 2004;24:314–321.
  18. Ugaresi A, Di Iorio A, Iarlori C, Reale M, De Luca G, Sparvieri E, Michetti A, Conti P, Gambi D, Abate G, Paganelli R: IL-4 in vitro production is upregulated in Alzheimer’s disease patients treated with acetylcholinesterase inhibitors. Exp Gerontol 2004;39:653–657.
  19. Sun YX, Minthon L, Wallmark A, Warkentin S, Blennow K, Janciauskiene S: Inflammatory markers in matched plasma and cerebrospinal fluid from patients with Alzheimer’s disease. Dement Geriatr Cogn Disord 2003;16:136–144.
  20. Hampel H, Sunderland T, Kotter HU, Schneider C, Teipel SJ, Padberg F, Dukoff R, Levy J, Moller HJ: Decreased soluble interleukin-6 receptor in cerebrospinal fluid of patients with Alzheimer’s disease. Brain Res 1998;780:356–359.
  21. Bonaccorso S, Lin A, Song C, Verkerk R, Kenis G, Bosmans E, Scharpe S, Vandewoude M, Dossche A, Maes M: Serotonin-immune interactions in elderly volunteers and in patients with Alzheimer’s disease (DAT): lower plasma tryptophan availability to the brain in the elderly and increased serum interleukin-6 in DAT. Aging (Milano) 1998;10:316–323.
  22. Kalman J, Juhasz A, Laird G, Dickens P, Jardanhazy T, Rimanoczy A, Boncz I, Parry-Jones WL, Janka Z: Serum interleukin-6 levels correlate with the severity of dementia in down syndrome and in Alzheimer’s disease. Acta Neurol Scand 1997;96:236–240.
  23. Maes M, DeVos N, Wauters A, Demedts P, Maurits VW, Neels H, Bosmans E, Altamura C, Lin A, Song C, Vandenbroucke M, Scharpe S: Inflammatory markers in younger vs elderly normal volunteers and in patients with Alzheimer’s disease. J Psychiatr Res 1999;33:397–405.
  24. Angelis P, Scharf S, Mander A, Vajda F, Christophidis N: Serum interleukin-6 and interleukin-6 soluble receptor in Alzheimer’s disease. Neurosci Lett 1998;244:106–108.
  25. Chao CC, Ala TA, Hu S, Crossley KB, Sherman RE, Peterson PK, Frey WH 2nd: Serum cytokine levels in patients with Alzheimer’s disease. Clin Diagn Lab Immunol 1994;1:433–436.
  26. De Luigi A, Pizzimenti S, Quadri P, Lucca U, Tettamanti M, Fragiacomo C, De Simoni MG: Peripheral inflammatory response in Alzheimer’s disease and multiinfarct dementia. Neurobiol Dis 2002;11:308–314.
  27. Bonotis K, Krikki E, Holeva V, Aggouridaki C, Costa V, Baloyannis S: Systemic immune aberrations in Alzheimer’s disease patients. J Neuroimmunol 2008;193:183–187.
  28. Singh VK, Guthikonda P: Circulating cytokines in Alzheimer’s disease. J Psychiatr Res 1997;31:657–660.
  29. Tarkowski E, Wallin A, Regland B, Blennow K, Tarkowski A: Local and systemic GM-CSF increase in Alzheimer’s disease and vascular dementia. Acta Neurol Scand 2001;103:166–174.
  30. Rota E, Bellone G, Rocca P, Bergamasco B, Emanuelli G, Ferrero P: Increased intrathecal TGF-beta1, but not IL-12, IFN-gamma and IL-10 levels in Alzheimer’s disease patients. Neurol Sci 2006;27:33–39.
  31. Angelopoulos P, Agouridaki H, Vaiopoulos H, Siskou E, Doutsou K, Costa V, Baloyiannis SI: Cytokines in Alzheimer’s disease and vascular dementia. Int J Neurosci 2008;118:1659–1672.
  32. Baranowska-Bik A, Bik W, Wolinska-Witort E, Martynska L, Chmielowska M, Barcikowska M, Baranowska B: Plasma beta amyloid and cytokine profile in women with Alzheimer’s disease. Neuro Endocrinol Lett 2008;29:75–79.
  33. Strle K, Zhou JH, Shen WH, Broussard SR, Johnson RW, Freund GG, Dantzer R, Kelley KW: Interleukin-10 in the brain. Crit Rev Immunol 2001;21:427–449.
  34. Speciale L, Calabrese E, Saresella M, Tinelli C, Mariani C, Sanvito L, Longhi R, Ferrante P: Lymphocyte subset patterns and cytokine production in Alzheimer’s disease patients. Neurobiol Aging 2007;28:1163–1169.
  35. Engelborghs S, De Brabander M, De Cree J, D’Hooge R, Geerts H, Verhaegen H, De Deyn PP: Unchanged levels of interleukins, neopterin, interferon-gamma and tumor necrosis factor-alpha in cerebrospinal fluid of patients with dementia of the Alzheimer type. Neurochem Int 1999;34:523–530.
  36. Motta M, Imbesi R, Di Rosa M, Stivala F, Malaguarnera L: Altered plasma cytokine levels in Alzheimer’s disease: correlation with the disease progression. Immunol Lett 2007;114:46–51.
  37. Bruunsgaard H, Andersen-Ranberg K, Jeune B, Pedersen AN, Skinhoj P, Pedersen BK: A high plasma concentration of TNF-alpha is associated with dementia in centenarians. J Gerontol A Biol Sci Med Sci 1999;54:M357–M364.
  38. Hasegawa Y, Sawada M, Ozaki N, Inagaki T, Suzumura A: Increased soluble tumor necrosis factor receptor levels in the serum of elderly people. Gerontology 2000;46:185–188.
  39. Cacabelos R, Alvarez XA, Franco-Maside A, Fernandez-Novoa L, Caamano J: Serum tumor necrosis factor (TNF) in Alzheimer’s disease and multi-infarct dementia. Methods Find Exp Clin Pharmacol 1994;16:29–35.
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