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Dement Geriatr Cogn Disord 2009;28:187–195

The Role of Genetics in Delirium in the Elderly Patient

van Munster B.C.a, b · de Rooij S.E.b · Korevaar J.C.a
aDepartment of Clinical Epidemiology, Biostatistics and Bioinformatics, and bDepartment of Internal Medicine, Academic Medical Centre, Amsterdam, The Netherlands
email Corresponding Author

 goto top of outline Key Words

  • Delirium, diagnosis
  • Genetics
  • Risk factors, delirium
  • Pathophysiology
  • Review

 goto top of outline Abstract

Delirium is an important neuropsychiatric syndrome in the elderly that is associated with an increase in mortality, impaired physical and cognitive recovery, and increased healthcare costs. Two important gaps in daily practice with delirium are the pathophysiological obscurity and the low recognition rates. Genetics offers the possibility to contribute knowledge to both of these gaps with its unique and diverse techniques. However, genetic studies in delirium have been scarce until recently, due to the nature of the diagnosis, the etiology of the syndrome, and the pitfalls inherent in the design of genetic studies. This review describes the barriers of this field of research and the implications for our current knowledge of delirium.

Copyright © 2009 S. Karger AG, Basel

 goto top of outline References
  1. Michaud L, Bula C, Berney A, Camus V, Voellinger R, Stiefel F, Burnand B: Delirium: guidelines for general hospitals. J Psychosom Res 2007;62:371–383.
  2. Inouye SK: Delirium in older persons. N Engl J Med 2006;354:1157–1165.
  3. Maclullich AM, Ferguson KJ, Miller T, de Rooij SE, Cunningham C: Unravelling the pathophysiology of delirium: a focus on the role of aberrant stress responses. J Psychosom Res 2008;65:229–238.
  4. Gunther ML, Morandi A, Ely EW: Pathophysiology of delirium in the intensive care unit. Crit Care Clin 2008;24:45–65.
  5. Marcantonio ER, Rudolph JL, Culley D, Crosby G, Alsop D, Inouye SK: Serum biomarkers for delirium. J Gerontol A Biol Sci Med Sci 2006;61:1281–1286.
  6. Blacker D, Lovestone S: Genetics and dementia nosology. J Geriatr Psychiatry Neurol 2006;19:186–191.
  7. Beck AT: The evolution of the cognitive model of depression and its neurobiological correlates. Am J Psychiatry 2008;165:969–977.
  8. Maier W: Common risk genes for affective and schizophrenic psychoses. Eur Arch Psychiatry Clin Neurosci 2008;258(suppl 2):37–40.
  9. Zuchner S, Roberts ST, Speer MC, Beckham JC: Update on psychiatric genetics. Genet Med 2007;9:332–340.
  10. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders: DSM IV-TR. Washington, American Psychiatric Association, 2000.
  11. Meagher DJ, Maclullich AM, Laurila JV: Defining delirium for the International Classification of Diseases, 11th Revision. J Psychosom Res 2008;65:207–214.
  12. Korevaar JC, van Munster BC, de Rooij SE: Risk factors for delirium in acutely admitted elderly patients: a prospective cohort study. BMC Geriatr 2005;5:6.
  13. Rockwood K, Cosway S, Carver D, Jarrett P, Stadnyk K, Fisk J: The risk of dementia and death after delirium. Age Ageing 1999;28:551–556.
  14. Van der Mast RC, Huyse FJ, Rosier PF: Guideline ‘Delirium’. Ned Tijdschr Geneeskd 2005;149:1027–1032.
  15. Inouye SK, Foreman MD, Mion LC, Katz KH, Cooney LM, Jr: Nurses’ recognition of delirium and its symptoms: comparison of nurse and researcher ratings. Arch Intern Med 2001;161:2467–2473.
  16. Meagher DJ, Trzepacz PT: Motoric subtypes of delirium. Semin Clin Neuropsychiatry 2000;5:75–85.
  17. Trzepacz PT: Is there a final common neural pathway in delirium? Focus on acetylcholine and dopamine. Semin Clin Neuropsychiatry 2000;5:132–148.
  18. Maldonado JR: Pathoetiological model of delirium: a comprehensive understanding of the neurobiology of delirium and an evidence-based approach to prevention and treatment. Crit Care Clin 2008;24:789–856.
  19. Alagiakrishnan K, Wiens CA: An approach to drug-induced delirium in the elderly. Postgrad Med J 2004;80:388–393.
  20. Reichenberg A, Yirmiya R, Schuld A, Kraus T, Haack M, Morag A, Pollmacher T: Cytokine-associated emotional and cognitive disturbances in humans. Arch Gen Psychiatry 2001;58:445–452.
  21. De Rooij SE, van Munster BC, Korevaar JC, Levi M: Cytokines and acute phase response in delirium. J Psychosom Res 2007;62:521–525.
  22. Van Munster BC, Korevaar JC, Zwinderman AH, Levi M, Wiersinga WJ, de Rooij SE: Time course of cytokines during delirium in elderly patients with hip fractures. J Am Geriatr Soc 2008;56:1704–1709.
  23. Lewis MC, Barnett SR: Postoperative delirium: the tryptophan dyregulation model. Med Hypotheses 2004;63:402–406.
  24. Shigeta H, Yasui A, Nimura Y, Machida N, Kageyama M, Miura M, Menjo M, Ikeda K: Postoperative delirium and melatonin levels in elderly patients. Am J Surg 2001;182:449–454.
  25. Inouye SK, Charpentier PA: Precipitating factors for delirium in hospitalized elderly persons: predictive model and interrelationship with baseline vulnerability. JAMA 1996;275:852–857.
  26. Bacanu SA, Devlin B, Chowdari KV, DeKosky ST, Nimgaonkar VL, Sweet RA: Heritability of psychosis in Alzheimer disease. Am J Geriatr Psychiatry 2005;13:624–627.
  27. Kennedy JL, Farrer LA, Andreasen NC, Mayeux R, St George-Hyslop P: The genetics of adult-onset neuropsychiatric disease: complexities and conundra? Science 2003;302:822–826.
  28. Baudoin C, Cohen-Solal ME, Beaudreuil J, De Vernejoul MC: Genetic and environmental factors affect bone density variances of families of men and women with osteoporosis. J Clin Endocrinol Metab 2002;87:2053–2059.
  29. Van Munster BC, Korevaar JC, de Rooij SE, Levi M, Zwinderman AH: Genetic polymorphisms related to delirium tremens: a systematic review. Alcohol Clin Exp Res 2007;31:177–184.
  30. Abdolmaleky HM, Thiagalingam S, Wilcox M: Genetics and epigenetics in major psychiatric disorders: dilemmas, achievements, applications, and future scope. Am J Pharmacogenomics 2005;5:149–160.
  31. Olsson T: Activity in the hypothalamic-pituitary-adrenal axis and delirium. Dement Geriatr Cogn Disord 1999;10:345–349.
  32. Edwards BJ, Haynes C, Levenstien MA, Finch SJ, Gordon D: Power and sample size calculations in the presence of phenotype errors for case/control genetic association studies. BMC Genet 2005;6:18.
  33. Holt R, Siddiqi N, Young J: The ethics of consent in delirium studies. J Psychosom Res 2008;65:283–287.
  34. Olde Rikkert MG, van der Vorm A, Burns A, Dekkers W, Robert P, Sartorius N, Selmes J, Stoppe G, Vernooij-Dassen M, Waldemar G: Consensus statement on genetic research in dementia. Am J Alzheimers Dis Other Demen 2008;23:262–266.
  35. Jorm AF: A short form of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE): development and cross-validation. Psychol Med 1994;24:145–153.
  36. Ely EW, Girard TD, Shintani AK, Jackson JC, Gordon SM, Thomason JW, Pun BT, Canonico AE, Light RW, Pandharipande P, Laskowitz DT: Apolipoprotein E4 polymorphism as a genetic predisposition to delirium in critically ill patients. Crit Care Med 2007;35:112–117.
  37. Tagarakis GI, Tsolaki-Tagaraki F, Tsolaki M, Diegeler A, Kazis D, Rouska E, Papassotiropoulos A: The role of SOAT-1 polymorphisms in cognitive decline and delirium after bypass heart surgery. Clin Res Cardiol 2007;96:600–603.
  38. Tagarakis GI, Tsolaki-Tagaraki F, Tsolaki M, Diegeler A, Tsilimingas NB, Papassotiropoulos A: The role of apolipoprotein E in cognitive decline and delirium after bypass heart operations. Am J Alzheimers Dis Other Demen 2007;22:223–228.
  39. Leung JM, Sands LP, Wang Y, Poon A, Kwok PY, Kane JP, Pullinger CR: Apolipoprotein E e4 allele increases the risk of early postoperative delirium in older patients undergoing noncardiac surgery. Anesthesiology 2007;107:406–411.
  40. Adamis D, Treloar A, Martin FC, Gregson N, Hamilton G, Macdonald AJ: APOE and cytokines as biological markers for recovery of prevalent delirium in elderly medical inpatients. Int J Geriatr Psychiatry 2007;22:688–694.
  41. Van Munster BC, Korevaar JC, de Rooij SE, Levi M, Zwinderman AH: The association between delirium and the apolipoprotein E ε4 allele in the elderly. Psychiatr Genet 2007;17:261–266.
  42. Van Munster BC, Yazdanpanah M, Tanck MW, de Rooij SE, van de Giessen E, Sijbrands EJ, Zwinderman AH, Korevaar JC: Genetic polymorphisms in the DRD2, DRD3, and SLC6A3 gene in elderly patients with delirium. Am J Med Genet B Neuropsychiatr Genet 2009;Mar 23, Epub ahead of print.
  43. Adamis D, Macdonald AJ: A review of the association of apolipoprotein E and delirium; in Penfield LR, Nelson RT (eds): Apoprotein Research. Hauppauge, Nova Science Publishers, 2009.
  44. Siest G, Pillot T, Regis-Bailly A, Leininger-Muller B, Steinmetz J, Galteau MM, Visvikis S: Apolipoprotein E: an important gene and protein to follow in laboratory medicine. Clin Chem 1995;41:1068–1086.
  45. Vasto S, Candore G, Listi F, Balistreri CR, Colonna-Romano G, Malavolta M, Lio D, Nuzzo D, Mocchegiani E, Di BD, Caruso C: Inflammation, genes and zinc in Alzheimer’s disease. Brain Res Rev 2008;58:96–105.
  46. Allen SJ, MacGowan SH, Tyler S, Wilcock GK, Robertson AG, Holden PH, Smith SK, Dawbarn D: Reduced cholinergic function in normal and Alzheimer’s disease brain is associated with apolipoprotein E4 genotype. Neurosci Lett 1997;239:33–36.
  47. Willard LB, Hauss-Wegrzyniak B, Wenk GL: Pathological and biochemical consequences of acute and chronic neuroinflammation within the basal forebrain cholinergic system of rats. Neuroscience 1999;88:193–200.
  48. Lucht M, Barnow S, Schroeder W, Grabe HJ, Rosskopf D, Brummer C, John U, Freyberger HJ, Herrmann FH: Alcohol consumption is associated with an interaction between DRD2 exon 8 A/A genotype and self-directedness in males. Neuropsychobiology 2007;56:24–31.
  49. Nikolaus S, Antke C, Kley K, Poeppel TD, Hautzel H, Schmidt D, Muller HW: Investigating the dopaminergic synapse in vivo. I. Molecular imaging studies in humans. Rev Neurosci 2007;18:439–472.
  50. Van Dyck CH, Malison RT, Jacobsen LK, Seibyl JP, Staley JK, Laruelle M, Baldwin RM, Innis RB, Gelernter J: Increased dopamine transporter availability associated with the 9-repeat allele of the SLC6A3 gene. J Nucl Med 2005;46:745–751.
  51. Stoltenberg SF, Burmeister M: Recent progress in psychiatric genetics – some hope but no hype. Hum Mol Genet 2000;9:927–935.
  52. Lango H, Weedon MN: What will whole genome searches for susceptibility genes for common complex disease offer to clinical practice? J Intern Med 2008;263:16–27.

 goto top of outline Author Contacts

B.C. van Munster
Department of Clinical Epidemiology, Biostatistics and Bioinformatics
Room J1B-207-1, Academic Medical Centre, University of Amsterdam, PO Box 22660
NL–1100 DD Amsterdam (The Netherlands)
Tel. +31 20 566 6945, Fax +31 20 691 2683, E-Mail

 goto top of outline Article Information

Accepted: May 29, 2009
Published online: August 28, 2009
Number of Print Pages : 9
Number of Figures : 1, Number of Tables : 2, Number of References : 52

 goto top of outline Publication Details

Dementia and Geriatric Cognitive Disorders

Vol. 28, No. 3, Year 2009 (Cover Date: October 2009)

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

For additional information:

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