Skip to main content

Advertisement

Log in

The neuroinflammatory hypothesis of delirium

  • Review
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

Delirium is a neuropsychiatric syndrome characterized by a sudden and global impairment in consciousness, attention and cognition. It is particularly frequent in elderly subjects with medical or surgical conditions and is associated with short- and long-term adverse outcomes. The pathophysiology of delirium remains poorly understood as it involves complex multi-factorial dynamic interactions between a diversity of risk factors. Several conditions associated with delirium are characterized by activation of the inflammatory cascade with acute release of inflammatory mediators into the bloodstream. There is compelling evidence that acute peripheral inflammatory stimulation induces activation of brain parenchymal cells, expression of proinflammatory cytokines and inflammatory mediators in the central nervous system. These neuroinflammatory changes induce neuronal and synaptic dysfunction and subsequent neurobehavioural and cognitive symptoms. Furthermore, ageing and neurodegenerative disorders exaggerate microglial responses following stimulation by systemic immune stimuli such as peripheral inflammation and/or infection. In this review we explore the neuroinflammatory hypothesis of delirium based on recent evidence derived from animal and human studies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Alexander JJ, Jacob A, Cunningham P, Hensley L, Quigg RJ (2008) TNF is a key mediator of septic encephalopathy acting through its receptor, TNF receptor-1. Neurochem Int 52(3):447–456

    Article  CAS  PubMed  Google Scholar 

  2. Ali MS, Harmer M, Vaughan R (2000) Serum S100 protein as a marker of cerebral damage during cardiac surgery. Br J Anaesth 85(2):287–298

    Article  CAS  PubMed  Google Scholar 

  3. Alkire MT, Hudetz AG, Tononi G (2008) Consciousness and anesthesia. Science 322(5903):876–880

    Article  CAS  PubMed  Google Scholar 

  4. Alley DE, Crimmins EM, Karlamangla A, Hu P, Seeman TE (2008) Inflammation and rate of cognitive change in high-functioning older adults. J Gerontol A Biol Sci Med Sci 63(1):50–55

    PubMed  Google Scholar 

  5. American Psychiatric Association (2000) Diagnostic and statistical manual of mental disorders, 4th edn. American Psychiatric Association, Washington, DC (text rev)

  6. Asimakopoulos G (1999) Mechanisms of the systemic inflammatory response. Perfusion 14(4):269–277

    CAS  PubMed  Google Scholar 

  7. Ballard C, Waite J (2006) The effectiveness of atypical antipsychotics for the treatment of aggression and psychosis in Alzheimer’s disease. Cochrane Database Syst Rev 25(1):CD003476

    Google Scholar 

  8. Barton GM (2008) A calculated response: control of inflammation by the innate immune system. J Clin Invest 118(2):413–420

    Article  CAS  PubMed  Google Scholar 

  9. Bell RD, Zlokovic BV (2009) Neurovascular mechanisms and blood-brain barrier disorder in Alzheimer’s disease. Acta Neuropathol 118(1):103–113

    Article  CAS  PubMed  Google Scholar 

  10. Bellelli G, Frisoni GB, Turco R, Lucchi E, Magnifico F, Trabucchi M (2007) Delirium superimposed on dementia predicts 12-month survival in elderly patients discharged from a postacute rehabilitation facility. J Gerontol A Biol Sci Med Sci 62(11):1306–1309

    PubMed  Google Scholar 

  11. Benicky J, Sánchez-Lemus E, Pavel J, Saavedra JM (2009) Anti-inflammatory effects of angiotensin receptor blockers in the brain and the periphery. Cell Mol Neurobiol 29(6–7):781–792

    Article  CAS  PubMed  Google Scholar 

  12. Bjornsson GL, Thorsteinsson L, Gudmundsson KO, Jonsson H Jr, Gudmundsson S, Gudbjornsson B (2007) Inflammatory cytokines in relation to adrenal response following total hip replacement. Scand J Immunol 65(1):99–105

    Article  CAS  PubMed  Google Scholar 

  13. Blasko I, Stampfer-Kountchev M, Robatscher P, Veerhuis R, Eikelenboom P, Grubeck-Loebenstein B (2004) How chronic inflammation can affect the brain and support the development of Alzheimer’s disease in old age: the role of microglia and astrocytes. Aging Cell 3(4):169–176

    Article  CAS  PubMed  Google Scholar 

  14. Block ML, Zecca L, Hong JS (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8(1):57–69

    Article  CAS  PubMed  Google Scholar 

  15. Boettger S, Passik S, Breitbart W (2009) Delirium superimposed on dementia versus delirium in the absence of dementia: phenomenological differences. Palliat Support Care 7(4):495–500

    Article  PubMed  Google Scholar 

  16. British Geriatrics Society. Guidelines for the Prevention, Diagnosis and Management of Delirium in Older People in Hospital. BGS, 2006 (http://www.bgs.org.uk/Publications/Clinical%20Guidelinesclinical_1-2_delirium.htm)

  17. Brooks TA, Hawkins BT, Huber JD, Egleton RD, Davis TP (2005) Chronic inflammatory pain leads to increased blood-brain barrier permeability and tight junction protein alterations. Am J Physiol Heart Circ Physiol 289(2):H738–H743

    Article  CAS  PubMed  Google Scholar 

  18. Brooks TA, Ocheltree SM, Seelbach MJ et al (2006) Biphasic cytoarchitecture and functional changes in the BBB induced by chronic inflammatory pain. Brain Res 1120(1):172–182

    Article  CAS  PubMed  Google Scholar 

  19. Bruce AJ, Ritchie CW, Blizard R, Lai R, Raven P (2007) The incidence of delirium associated with orthopedic surgery: a meta-analytic review. Int Psychogeriatr 19(2):197–214

    Article  PubMed  Google Scholar 

  20. Bruunsgaard H, Pedersen AN, Schroll M, Skinhoj P, Pedersen BK (1999) Impaired production of proinflammatory cytokines in response to lipopolysaccharide (LPS) stimulation in elderly humans. Clin Exp Immunol 118(2):235–241

    Article  CAS  PubMed  Google Scholar 

  21. Brydon L, Harrison NA, Walker C, Steptoe A, Critchley HD (2008) Peripheral inflammation is associated with altered substantia nigra activity and psychomotor slowing in humans. Biol Psychiatry 63(11):1022–1029

    Article  CAS  PubMed  Google Scholar 

  22. Bucerius J, Gummert JF, Borger MA et al (2004) Predictors of delirium after cardiac surgery delirium: effect of beating-heart (off-pump) surgery. J Thorac Cardiovasc Surg 127(1):57–64

    Article  PubMed  Google Scholar 

  23. Cardona AE, Li M, Liu L, Savarin C, Ransohoff RM (2008) Chemokines in and out of the central nervous system: much more than chemotaxis and inflammation. J Leukoc Biol 84(3):587–594

    Article  CAS  PubMed  Google Scholar 

  24. Chakravarty S, Herkenham M (2005) Toll-like receptor 4 on nonhematopoietic cells sustains CNS inflammation during endotoxemia, independent of systemic cytokines. J Neurosci 25(7):1788–1796

    Article  CAS  PubMed  Google Scholar 

  25. Chen J, Buchanan JB, Sparkman NL, Godbout JP, Freund GG, Johnson RW (2008) Neuroinflammation and disruption in working memory in aged mice after acute stimulation of the peripheral innate immune system. Brain Behav Immun 22(3):301–311

    Article  CAS  PubMed  Google Scholar 

  26. Choi YK, Kim KW (2008) Blood-neural barrier: its diversity and coordinated cell-to-cell communication. BMB Rep 41(5):345–352

    CAS  PubMed  Google Scholar 

  27. Cole M, McCusker J, Dendukuri N, Han L (2003) The prognostic significance of subsyndromal delirium in elderly medical inpatients. J Am Geriatr Soc 51(6):754–760

    Article  PubMed  Google Scholar 

  28. Cunningham C, Sanderson DJ (2008) Malaise in the water maze: untangling the effects of LPS and IL-1b on learning. Brain Behav Immun 22(8):1117–1127

    Article  CAS  PubMed  Google Scholar 

  29. Cunningham C, Wilcockson DC, Campion S, Lunnon K, Perry VH (2005) Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. J Neurosci 25(40):9275–9284

    Article  CAS  PubMed  Google Scholar 

  30. D’Andrea MR, Cole GM, Ard MD (2004) The microglial phagocytic role with specific plaque types in the Alzheimer disease brain. Neurobiol Aging 25(5):675–683

    Article  PubMed  CAS  Google Scholar 

  31. Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW (2008) From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9(1):46–56

    Article  CAS  PubMed  Google Scholar 

  32. Dasgupta M, Dumbrell AC (2006) Preoperative risk assessment for delirium after noncardiac surgery: a systematic review. J Am Geriatr Soc 54(10):1578–1589

    Article  PubMed  Google Scholar 

  33. de Rooij SE, Schuurmans MJ, van der Mast RC, Levi M (2005) Clinical subtypes of delirium and their relevance for daily clinical practice: a systematic review. Int J Geriatr Psychiatry 20(7):609–615

    Article  PubMed  Google Scholar 

  34. DiCarlo G, Wilcock D, Henderson D, Gordon M, Morgan D (2001) Intrahippocampal LPS injections reduce Abeta load in APP + PS1 transgenic mice. Neurobiol Aging 22(6):1007–1012

    Article  CAS  PubMed  Google Scholar 

  35. Diegeler A, Hirsch R, Schneider F et al (2000) Neuromonitoring and neurocognitive outcome in off-pump versus conventional coronary bypass operation. Ann Thorac Surg 69(4):1162–1166

    Article  CAS  PubMed  Google Scholar 

  36. Dilger RN, Johnson RW (2008) Aging, microglial cell priming, and the discordant central inflammatory response to signals from the peripheral immune system. J Leukoc Biol 84(4):932–939

    Article  CAS  PubMed  Google Scholar 

  37. Ebersoldt M, Sharshar T, Annane D (2007) Sepsis-associated delirium. Intensive Care Med 33(6):941–950

    Article  PubMed  Google Scholar 

  38. Edlund A, Lundström M, Sandberg O, Bucht G, Brännström B, Gustafson Y (2007) Symptom profile of delirium in older people with and without dementia. J Geriatr Psychiatry Neurol 20(3):166–171

    Article  PubMed  Google Scholar 

  39. Eikelenboom P, Veerhuis R, Scheper W, Rozemuller AJ, van Gool WA, Hoozemans JJ (2006) The significance of neuroinflammation in understanding Alzheimer’s disease. J Neural Transm 113(11):1685–1695

    Article  CAS  PubMed  Google Scholar 

  40. Elie M, Cole MG, Primeau FJ, Bellavance F (1998) Delirium risk factors in elderly hospitalized patients. J Gen Intern Med 13(3):204–212

    Article  CAS  PubMed  Google Scholar 

  41. El Yousfi M, Mercier S, Breuillé D et al (2005) The inflammatory response to vaccination is altered in the elderly. Mech Ageing Dev 126(8):874–881

    Article  CAS  PubMed  Google Scholar 

  42. Engel GL, Romano J (1959) Delirium, a syndrome of cerebral insufficiency. J Neuropsychiatry Clin Neurosci 16(4):526–538

    Google Scholar 

  43. Farfara D, Lifshitz V, Frenkel D (2008) Neuroprotective and neurotoxic properties of glial cells in the pathogenesis of Alzheimer’s disease. J Cell Mol Med 12(3):762–780

    Article  CAS  PubMed  Google Scholar 

  44. Fick DM, Agostini JV, Inouye SK (2002) Delirium superimposed on dementia: a systematic review. J Am Geriatr Soc 50(10):1723–1732

    Article  PubMed  Google Scholar 

  45. Flierl MA, Stahel PF, Rittirsch D et al (2009) Inhibition of complement C5a prevents breakdown of the blood-brain barrier and pituitary dysfunction in experimental sepsis. Crit Care 13(1):R12

    Article  PubMed  Google Scholar 

  46. Fong TG, Jones RN, Shi P et al (2009) Delirium accelerates cognitive decline in Alzheimer disease. Neurology 72(18):1570–1575

    Article  CAS  PubMed  Google Scholar 

  47. Frank MG, Barrientos RM, Biedenkapp JC, Rudy JW, Watkins LR, Maier SF (2006) mRNA up-regulation of MHC II and pivotal pro-inflammatory genes in normal brain aging. Neurobiol Aging 27(5):717–722

    Article  CAS  PubMed  Google Scholar 

  48. Gao F, Harris DN, Sapsed-Byrne S (1999) Time course of neurone-specific enolase and S-100 protein release during and after coronary artery bypass grafting. Br J Anaesth 82(2):266–267

    CAS  PubMed  Google Scholar 

  49. Gautron L, Lafon P, Chaigniau M, Tramu G, Layé S (2002) Spatiotemporal analysis of signal transducer and activator of transcription 3 activation in rat brain astrocytes and pituitary following peripheral immune challenge. Neuroscience 112(3):717–729

    Article  CAS  PubMed  Google Scholar 

  50. Girard TD, Pandharipande PP, Ely EW (2008) Delirium in the intensive care unit. Crit Care 12(3):S3

    PubMed  Google Scholar 

  51. Godbout JP, Chen J, Abraham J et al (2005) Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system. FASEB J 19(10):1329–1331

    CAS  PubMed  Google Scholar 

  52. Gomez CR, Nomellini V, Faunce DE, Kovacs EJ (2008) Innate immunity and aging. Exp Gerontol 43(8):718–728

    Article  CAS  PubMed  Google Scholar 

  53. Groeneveld AB, Raijmakers PG, Rauwerda JA, Hack CE (1997) The inflammatory response to vascular surgery-associated ischaemia and reperfusion in man: effect on postoperative pulmonary function. Eur J Vasc Endovasc Surg 14(5):351–359

    Article  CAS  PubMed  Google Scholar 

  54. Head E, Starr A, Kim RC et al (2006) Relapsing polychondritis with features of dementia with Lewy bodies. Acta Neuropathol 112(2):217–225

    Article  PubMed  Google Scholar 

  55. Henry CJ, Huang Y, Wynne AM, Godbout JP (2009) Peripheral lipopolysaccharide (LPS) challenge promotes microglial hyperactivity in aged mice that is associated with exaggerated induction of both pro-inflammatory IL-1beta and anti-inflammatory IL-10 cytokines. Brain Behav Immun 23(3):309–317

    Article  CAS  PubMed  Google Scholar 

  56. Henry CJ, Huang Y, Wynne A et al (2008) Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia. J Neuroinflamm 5:15

    Article  CAS  Google Scholar 

  57. Herber DL, Roth LM, Wilson D et al (2004) Time-dependent reduction in Abeta levels after intracranial LPS administration in APP transgenic mice. Exp Neurol 190(1):245–253

    Article  CAS  PubMed  Google Scholar 

  58. Herber DL, Mercer M, Roth LM et al (2007) Microglial activation is required for Abeta clearance after intracranial injection of lipopolysaccharide in APP transgenic mice. J Neuroimmune Pharmacol 2(2):222–231

    Article  PubMed  Google Scholar 

  59. Hickman SE, Allison EK, El Khoury J (2008) Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer’s disease mice. J Neurosci 28(33):8354–8360

    Article  CAS  PubMed  Google Scholar 

  60. Higuchi M, Hatta K, Honma T et al. (2009) Association between altered systemic inflammatory interleukin-1beta and natural killer cell activity and subsequently agitation in patients with alzheimer disease. Int J Geriatr Psychiatry. doi:10.1002/gps.2381

  61. Hofer S, Bopp C, Hoerner C et al (2008) Injury of the blood brain barrier and up-regulation of ICAM-1 in polymicrobial sepsis. J Surg Res 146:276–281

    CAS  PubMed  Google Scholar 

  62. Holmes C, Cunningham C, Zotova E et al (2009) Systemic inflammation and disease progression in Alzheimer disease. Neurology 73(10):768–774

    Article  CAS  PubMed  Google Scholar 

  63. Hopkins SJ (2007) Central nervous system recognition of peripheral inflammation: a neural, hormonal collaboration. Acta Biomed 78(Suppl 1):231–247

    PubMed  Google Scholar 

  64. Hshieh TT, Fong TG, Marcantonio ER, Inouye SK (2008) Cholinergic deficiency hypothesis in delirium: a synthesis of current evidence. J Gerontol A Biol Sci Med Sci 63(7):764–772

    PubMed  Google Scholar 

  65. Huang Y, Henry CJ, Dantzer R, Johnson RW, Godbout JP (2008) Exaggerated sickness behavior and brain proinflammatory cytokine expression in aged mice in response to intracerebroventricular lipopolysaccharide. Neurobiol Aging 29(11):1744–1753

    Article  CAS  PubMed  Google Scholar 

  66. Huber JD, Campos CR, Mark KS, Davis TP (2006) Alterations in blood-brain barrier ICAM-1 expression and brain microglial activation after lambda-carrageenan-induced inflammatory pain. Am J Physiol Heart Circ Physiol 290(2):H732–H740

    Article  CAS  PubMed  Google Scholar 

  67. Huber JD, Hau VS, Borg L, Campos CR, Egleton RD, Davis TP (2002) Blood-brain barrier tight junctions are altered during a 72-h exposure to lambda-carrageenan-induced inflammatory pain. Am J Physiol Heart Circ Physiol 283(4):H1531–H1537

    CAS  PubMed  Google Scholar 

  68. Huber JD, Witt KA, Hom S, Egleton RD, Mark KS, Davis TP (2001) Inflammatory pain alters blood-brain barrier permeability and tight junctional protein expression. Am J Physiol Heart Circ Physiol 280(3):H1241–H1248

    CAS  PubMed  Google Scholar 

  69. Inouye SK, Viscoli CM, Horwitz RI et al (1993) A predictive model for delirium in hospitalized elderly medical patients based on admission characteristics. Ann Intern Med 119:474–481

    CAS  PubMed  Google Scholar 

  70. Kalisvaart KJ, Vreeswijk R, de Jonghe JF, van der Ploeg T, van Gool WA, Eikelenboom P (2006) Risk factors and prediction of postoperative delirium in elderly hip-surgery patients: implementation and validation of a medical risk factor model. J Am Geriatr Soc 54(5):817–822

    Article  PubMed  Google Scholar 

  71. Keck M, Herndon DH, Kamolz LP, Frey M, Jeschke MG (2009) Pathophysiology of burns. Wien Med Wochenschr 159(13–14):327–336

    Article  PubMed  Google Scholar 

  72. Keller JN (2006) Age-related neuropathology, cognitive decline, and Alzheimer’s disease. Ageing Res Rev 5(1):1–13

    Article  CAS  PubMed  Google Scholar 

  73. Kitazawa M, Yamasaki TR, LaFerla FM (2004) Microglia as a potential bridge between the amyloid beta-peptide and tau. Ann N Y Acad Sci 1035:85–103

    Article  CAS  PubMed  Google Scholar 

  74. Krabbe KS, Pedersen M, Bruunsgaard H (2004) Inflammatory mediators in the elderly. Exp Gerontol 39(5):687–699

    Article  CAS  PubMed  Google Scholar 

  75. Krabbe KS, Reichenberg A, Yirmiya R, Smed A, Pedersen BK, Bruunsgaard H (2005) Low-dose endotoxemia and human neuropsychological functions. Brain Behav Immun 19(5):453–460

    Article  CAS  PubMed  Google Scholar 

  76. Kragsbjerg P, Holmberg H, Vikerfors T (1995) Serum concentrations of interleukin-6, tumour necrosis factor-alpha, and C-reactive protein in patients undergoing major operations. Eur J Surg 161(1):17–22

    CAS  PubMed  Google Scholar 

  77. Krzyszton CP, Sparkman NL, Grant RW et al (2008) Exacerbated fatigue and motor deficits in interleukin-10-deficient mice after peripheral immune stimulation. Am J Physiol Regul Integr Comp Physiol 295(4):R1109–R1114

    CAS  PubMed  Google Scholar 

  78. Kurosawa S, Kato M (2008) Anesthetics, immune cells, and immune responses. J Anesth 22(3):263–277

    Article  PubMed  Google Scholar 

  79. Ladeby R, Wirenfeldt M, Garcia-Ovejero D et al (2005) Microglial cell population dynamics in the injured adult central nervous system. Brain Res Brain Res Rev 48(2):196–206

    Article  CAS  PubMed  Google Scholar 

  80. Le Bitoux MA, Stamenkovic I (2008) Tumor–host interactions: the role of inflammation. Histochem Cell Biol 130(6):1079–1090

    Article  PubMed  CAS  Google Scholar 

  81. Lee JW, Lee YK, Yuk DY et al (2008) Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation. J Neuroinflamm 29;5:37

    Article  CAS  Google Scholar 

  82. Lee YB, Nagai A, Kim SU (2002) Cytokines, chemokines, and cytokine receptors in human microglia. J Neurosci Res 69(1):94–103

    Article  CAS  PubMed  Google Scholar 

  83. Lenz A, Franklin GA, Cheadle WG (2007) Systemic inflammation after trauma. Injury 38(12):1336–1345

    Article  PubMed  Google Scholar 

  84. Lin ST, Wang Y, Xue Y, Feng DC, Xu Y, Xu LY (2008) Tetrandrine suppresses LPS-induced astrocyte activation via modulating IKKs-IkappaBalpha-NF-kappaB signaling pathway. Mol Cell Biochem 315(1–2):41–49

    Article  CAS  PubMed  Google Scholar 

  85. Liu Y, Walter S, Stagi M et al (2005) LPS receptor (CD14): a receptor for phagocytosis of Alzheimer’s amyloid peptide. Brain 102(Pt 8):1778–1789

    Article  Google Scholar 

  86. MacLullich AM, Beaglehole A, Hall RJ, Meagher DJ (2009) Delirium and long-term cognitive impairment. Int Rev Psychiatry 21(1):30–42

    Article  PubMed  Google Scholar 

  87. Maldonado JR (2008) Pathoetiological model of delirium: a comprehensive understanding of the neurobiology of delirium and an evidence-based approach to prevention and treatment. Crit Care Clin 24(4):789–856 ix

    Article  CAS  PubMed  Google Scholar 

  88. Malek-Ahmadi P, Hilsabeck RC (2007) Neuropsychiatric complications of interferons: classification, neurochemical bases, and management. Ann Clin Psychiatry 19(2):113–123

    Article  PubMed  Google Scholar 

  89. Marchi N, Cavaglia M, Fazio V, Bhudia S, Hallene K, Janigro D (2004) Peripheral markers of blood-brain barrier damage. Clin Chim Acta 342(1–2):1

    Article  CAS  PubMed  Google Scholar 

  90. Marx N, Neumann FJ, Ott I et al (1997) Induction of cytokine expression in leukocytes in acute myocardial infarction. J Am Coll Cardiol 30(1):165–170

    Article  CAS  PubMed  Google Scholar 

  91. McAfoose J, Baune BT (2009) Evidence for a cytokine model of cognitive function. Neurosci Biobehav Rev 33(3):355–366

    Article  CAS  PubMed  Google Scholar 

  92. McCaffrey G, Seelbach MJ, Staatz WD et al (2008) Occludin oligomeric assembly at tight junctions of the blood-brain barrier is disrupted by peripheral inflammatory hyperalgesia. J Neurochem 106(6):2395–2409

    Article  CAS  PubMed  Google Scholar 

  93. McCaffrey G, Willis CL, Staatz WD et al (2009) Occludin oligomeric assemblies at tight junctions of the blood-brain barrier are altered by hypoxia and reoxygenation stress. J Neurochem 110(1):58–71

    Article  CAS  PubMed  Google Scholar 

  94. McCusker J, Cole M, Dendukuri N, Belzile E, Primeau F (2001) Delirium in older medical inpatients and subsequent cognitive and functional status: a prospective study. CMAJ 165(5):575–583

    CAS  PubMed  Google Scholar 

  95. Mukaetova-Ladinska EB, Harrington CR, Roth M, Wischik CM (1996) Alterations in tau protein metabolism during normal aging. Dementia 7(2):95–103

    CAS  PubMed  Google Scholar 

  96. Mullington J, Korth C, Hermann DM et al (2000) Dose-dependent effects of endotoxin on human sleep. Am J Physiol Regul Integr Comp Physiol 278(4):R947–R955

    CAS  PubMed  Google Scholar 

  97. Nagele RG, Wegiel J, Venkataraman V, Imaki H, Wang KC, Wegiel J (2004) Contribution of glial cells to the development of amyloid plaques in Alzheimer’s disease. Neurobiol Aging 25(5):663–674

    Article  CAS  PubMed  Google Scholar 

  98. Neumann H (2001) Control of glial immune function by neurons. Glia 36(2):191–199

    Article  CAS  PubMed  Google Scholar 

  99. Nguyen DN, Spapen H, Su F et al (2006) Elevated serum levels of S-100beta protein and neuron-specific enolase are associated with brain injury in patients with severe sepsis and septic shock. Crit Care Med 34(7):1967–1974

    Article  CAS  PubMed  Google Scholar 

  100. Nishioku T, Dohgu S, Takata F et al (2009) Detachment of brain pericytes from the basal lamina is involved in disruption of the blood-brain barrier caused by lipopolysaccharide-induced sepsis in mice. Cell Mol Neurobiol 29(3):309–316

    Article  CAS  PubMed  Google Scholar 

  101. Noble F, Rubira E, Boulanouar M et al (2007) Acute systemic inflammation induces central mitochondrial damage and mnesic deficit in adult Swiss mice. Neurosci Lett 7;424(2):106–110

    Article  CAS  Google Scholar 

  102. O’Keeffe ST, Ní Chonchubhair A (1994) Postoperative delirium in the elderly. Br J Anaesth 73(5):673–687

    Article  PubMed  Google Scholar 

  103. Olson JK, Miller SD (2004) Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J Immunol 173(6):3916–3924

    CAS  PubMed  Google Scholar 

  104. Oztaş B, Akgül S, Arslan FB (2004) Influence of surgical pain stress on the blood-brain barrier permeability in rats. Life Sci 74(16):1973–1979

    Article  PubMed  CAS  Google Scholar 

  105. Pugh CR, Kumagawa K, Fleshner M, Watkins LR, Maier SF, Rudy JW (1998) Selective effects of peripheral lipopolysaccharide administration on contextual and auditory-cue fear conditioning. Brain Behav Immun 12(3):212–229

    Article  CAS  PubMed  Google Scholar 

  106. Qiao X, Cummins DJ, Paul SM (2001) Neuroinflammation-induced acceleration of amyloid deposition in the APPV717F transgenic mouse. Eur J Neurosci 14(3):474–482

    Article  CAS  PubMed  Google Scholar 

  107. Qin L, Wu X, Block ML et al (2007) Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 55(5):453–462

    Article  PubMed  Google Scholar 

  108. Qu T, Uz T, Manev H (2000) Inflammatory 5-LOX mRNA and protein are increased in brain of aging rats. Neurobiol Aging 21(5):647–652

    Article  CAS  PubMed  Google Scholar 

  109. Rachal Pugh C, Fleshner M, Watkins LR, Maier SF, Rudy JW (2001) The immune system and memory consolidation: a role for the cytokine IL-1beta. Neurosci Biobehav Rev 25(1):29–41

    Article  CAS  PubMed  Google Scholar 

  110. Reichenberg A, Yirmiya R, Schuld A et al (2001) Cytokine-associated emotional and cognitive disturbances in humans. Arch Gen Psychiatry 58(5):445–452

    Article  CAS  PubMed  Google Scholar 

  111. Richwine AF, Parkin AO, Buchanan JB et al (2008) Architectural changes to CA1 pyramidal neurons in adult and aged mice after peripheral immune stimulation. Psychoneuroendocrinology 33(10):1369–1377

    Article  CAS  PubMed  Google Scholar 

  112. Richwine AF, Sparkman NL, Dilger RN, Buchanan JB, Johnson RW (2009) Cognitive deficits in interleukin-10-deficient mice after peripheral injection of lipopolysaccharide. Brain Behav Immun 23(6):794–802

    Article  CAS  PubMed  Google Scholar 

  113. Rosczyk HA, Sparkman NL, Johnson RW (2008) Neuroinflammation and cognitive function in aged mice following minor surgery. Exp Gerontol 43(9):840–846

    Article  CAS  PubMed  Google Scholar 

  114. Sakamoto K, Arakawa H, Mita S et al (1994) Elevation of circulating interleukin 6 after surgery: factors influencing the serum level. Cytokine 6(2):181–186

    Article  CAS  PubMed  Google Scholar 

  115. Sampson EL, Blanchard MR, Jones L, Tookman A, King M (2009) Dementia in the acute hospital: prospective cohort study of prevalence and mortality. Br J Psychiatry 195(1):61–66

    Article  PubMed  Google Scholar 

  116. Sastre M, Walter J, Gentleman SM (2008) Interactions between APP secretases and inflammatory mediators. J Neuroinflamm 5:25

    Article  CAS  Google Scholar 

  117. Schram MT, Euser SM, de Craen AJ et al (2007) Systemic markers of inflammation and cognitive decline in old age. J Am Geriatr Soc 55(5):708–716

    Article  PubMed  Google Scholar 

  118. Semmler A, Okulla T, Sastre M, Dumitrescu-Ozimek L, Heneka M (2005) Systemic inflammation induces apoptosis with variable vulnerability of different brain regions. J Chem Neuroanat 30:144–157

    Article  CAS  PubMed  Google Scholar 

  119. Sharshar T, Carlier R, Bernard F et al (2007) Brain lesions in septic shock: a magnetic resonance imaging study. Intensive Care Med 33(5):798–806

    Article  PubMed  Google Scholar 

  120. Sharshar T, Gray F, Lorin de la Grandmaison G et al (2003) Apoptosis of neurons in cardiovascular autonomic centres triggered by inducible nitric oxide synthase after death from septic shock. Lancet 362(9398):1799–1805

    Article  CAS  PubMed  Google Scholar 

  121. Shawcross DL, Shabbir SS, Taylor NJ, Hughes RD (2009) Ammonia and the neutrophil in the pathogenesis of hepatic encephalopathy in cirrhosis. Hepatology. doi:10.1002/hep.23367

  122. Sheng JG, Bora SH, Xu G, Borchelt DR, Price DL, Koliatsos VE (2003) Lipopolysaccharide-induced-neuroinflammation increases intracellular accumulation of amyloid precursor protein and amyloid beta peptide in APPswe transgenic mice. Neurobiol Dis 14(1):133–145

    Article  CAS  PubMed  Google Scholar 

  123. Shimaoka M, Park EJ (2008) Advances in understanding sepsis. Eur J Anaesthesiol Suppl 42:146–153

    Article  CAS  PubMed  Google Scholar 

  124. Siami S, Annane D, Sharshar T (2008) The encephalopathy in sepsis. Crit Care Clin 24(1):67–82, viii

    Article  PubMed  Google Scholar 

  125. Siddiqi N, House AO, Holmes JD (2006) Occurrence and outcome of delirium in medical in-patients: a systematic literature review. Age Ageing 35(4):350–364

    Article  PubMed  Google Scholar 

  126. Sparkman NL, Buchanan JB, Heyen JR, Chen J, Beverly JL, Johnson RW (2006) Interleukin-6 facilitates lipopolysaccharide-induced disruption in working memory and expression of other proinflammatory cytokines in hippocampal neuronal cell layers. J Neurosci 26(42):10709–10716

    Article  CAS  PubMed  Google Scholar 

  127. Stagno D, Gibson C, Breitbart W (2004) The delirium subtypes: a review of prevalence, phenomenology, pathophysiology, and treatment response. Palliat Support Care 2(2):171–179

    Article  PubMed  Google Scholar 

  128. Stinghen AE, Gonçalves SM, Martines EG et al (2009) Increased plasma and endothelial cell expression of chemokines and adhesion molecules in chronic kidney disease. Nephron Clin Pract 111(2):c117–c126

    Article  CAS  PubMed  Google Scholar 

  129. Sun Y, Tawara I, Toubai T, Reddy P (2007) Pathophysiology of acute graft-versus-host disease: recent advances. Transl Res 150(4):197–214

    Article  CAS  PubMed  Google Scholar 

  130. Tanaka S, Ide M, Shibutani T et al (2006) Lipopolysaccharide-induced microglial activation induces learning and memory deficits without neuronal cell death in rats. J Neurosci Res 83(4):557–566

    Article  CAS  PubMed  Google Scholar 

  131. Thompson WL, Karpus WJ, Van Eldik LJ (2008) MCP-1-deficient mice show reduced neuroinflammatory responses and increased peripheral inflammatory responses to peripheral endotoxin insult. J Neuroinflamm 5:35

    Article  CAS  Google Scholar 

  132. Tizard I (2008) Sickness behavior, its mechanisms, significance. Anim Health Res Rev 9(1):87–99

    Article  PubMed  Google Scholar 

  133. Trzepacz PT (2000) Is there a final common neural pathway in delirium? Focus on acetylcholine and dopamine. Semin Clin Neuropsychiatry 5(2):132–148

    CAS  PubMed  Google Scholar 

  134. Trzepacz PT, Mulsant BH, Dew MA, Pasternak R, Sweet RA, Zubenko GS (1998) Is delirium different when it occurs in dementia? A study using the delirium rating scale. J Neuropsychiatry Clin Neurosci 10(2):199–204

    CAS  PubMed  Google Scholar 

  135. Uchikado H, Akiyama H, Kondo H et al (2004) Activation of vascular endothelial cells and perivascular cells by systemic inflammation-an immunohistochemical study of postmortem human brain tissues. Acta Neuropathol 107(4):341–351

    Article  CAS  PubMed  Google Scholar 

  136. Uylings HB, de Brabander JM (2002) Neuronal changes in normal human aging and Alzheimer’s disease. Brain Cogn 49(3):268–276

    Article  PubMed  Google Scholar 

  137. van der Cammen TJ, Tiemeier H, Engelhart MJ, Fekkes D (2006) Abnormal neurotransmitter metabolite levels in Alzheimer patients with a delirium. Int J Geriatr Psychiatry 21(9):838–843

    Article  PubMed  Google Scholar 

  138. van der Mast RC, Roest FH (1996) Delirium after cardiac surgery: a critical review. J Psychosom Res 41(1):13–30

    Article  PubMed  Google Scholar 

  139. van Munster BC, Korevaar JC, Korse CM, Bonfrer JM, Zwinderman AH, de Rooij SE (2010) Serum S100B in elderly patients with and without delirium. Int J Geriatr Psychiatry 25(3):234–239

    Article  PubMed  Google Scholar 

  140. van Munster BC, Korevaar JC, Zwinderman AH, Levi M, Wiersinga WJ, De Rooij SE (2008) Time-course of cytokines during delirium in elderly patients with hip fractures. J Am Geriatr Soc 56(9):1704–1709

    Article  PubMed  Google Scholar 

  141. Volterra A, Meldolesi J (2005) Astrocytes, from brain glue to communication elements: the revolution continues. Nat Rev Neurosci 6(8):626–640

    Article  CAS  PubMed  Google Scholar 

  142. von Bernhardi R, Ramírez G, Toro R, Eugenín J (2007) Pro-inflammatory conditions promote neuronal damage mediated by amyloid precursor protein and decrease its phagocytosis and degradation by microglial cells in culture. Neurobiol Dis 26(1):153–164

    Article  CAS  Google Scholar 

  143. Wan Y, Xu J, Ma D, Zeng Y, Cibelli M, Maze M (2007) Postoperative impairment of cognitive function in rats: a possible role for cytokine-mediated inflammation in the hippocampus. Anesthesiology 106(3):436–443

    Article  PubMed  Google Scholar 

  144. Weichhart T, Haidinger M, Hörl WH, Säemann MD (2008) Current concepts of molecular defence mechanisms operative during urinary tract infection. Eur J Clin Invest 38(Suppl 2):29–38

    Article  CAS  PubMed  Google Scholar 

  145. Williams-Russo P, Urquhart BL, Sharrock NE, Charlson ME (1992) Post-operative delirium: predictors and prognosis in elderly orthopedic patients. J Am Geriatr Soc 40(8):759–767

    CAS  PubMed  Google Scholar 

  146. World Health Organization (1992) The ICD-10 classification of mental and behavioural disorders: clinical descriptions and diagnostic guidelines. World Health Organization, Geneva

  147. Yang FM, Marcantonio ER, Inouye SK et al (2009) Phenomenological subtypes of delirium in older persons: patterns, prevalence, and prognosis. Psychosomatics 50(3):248–254

    Article  PubMed  Google Scholar 

  148. Yankner BA, Lu T, Loerch P (2008) The aging brain. Annu Rev Pathol 3:41–66

    Article  CAS  PubMed  Google Scholar 

  149. Young GB, Pigott SE (1999) Neurobiological basis of consciousness. Arch Neurol 56(2):153–157

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We are grateful to Pedro Batista and Vasco Nogueira for critical reading of this manuscript and helpful comments. We would like to thank the anonymous reviewers for their useful and constructive comments, as well as Mrs. Alyson Goldwater and Mrs. Isabel Amoedo for secretarial support and editing the text. This work was supported by a BIAL (Porto, Portugal) grant to JC and Alzheimer Society (London, UK) award to EBM-L.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Joaquim Cerejeira.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cerejeira, J., Firmino, H., Vaz-Serra, A. et al. The neuroinflammatory hypothesis of delirium. Acta Neuropathol 119, 737–754 (2010). https://doi.org/10.1007/s00401-010-0674-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-010-0674-1

Keywords

Navigation