Delirium is a frequent complication in medically ill elderly patients that is associated with serious adverse outcomes including increased mortality. Delirium risk is linked to older age, dementia, and illness that involves activation of inflammatory responses. IGF-I is increasingly postulated as a key link between environmental influences on body metabolism with a range of neuronal activities and has been described as the master regulator of the connection between brain and bodily well-being. The relationships between IGF-I and ageing, cognitive impairment and inflammatory illness further support a possible role in delirium pathogenesis. Five studies of IGF-I in delirium were identified by a systematic review. These conflicting findings, with three of the five studies indicating an association between IGF-1 and delirium occurrence, may relate to the considerable methodological differences in these studies. The relevance of IGF-I and related factors to delirium pathogenesis can be clarified by future studies which account for these issues and other confounding factors. Such work can inform therapeutic trials of IGF-I and/or growth hormone administration. 1. Introduction Delirium is an etiologically diverse organic cerebral syndrome of acute onset (over hours to days) characterized by a fluctuating course that includes alterations in level of consciousness, psychomotor behavior, attention and cognition, as well as variable expression of various neuropsychiatric disturbances [1]. It is a frequent complication in elderly hospitalized patients, affecting around 30% [2]. Despite this frequency, delirium is frequently misdiagnosed or missed, and considerable uncertainty remains regarding optimal management [3–5]. Delirium is associated with a range of adverse outcomes, including, longer hospital stays, greater healthcare costs, reduced subsequent functional independence, and increased mortality [6]. The pathophysiology of delirium has been understudied [5], and, in particular, it remains uncertain how such a wide range of potential etiologies, many of which involve pathology at peripheral body locations and without clear links to CNS function, can produce such a consistent complex neuropsychiatric picture that reflects generalized brain dysfunction. Central to understanding delirium is understanding mechanisms by which body and brain well-being are linked and, in particular, how brain responses to bodily homeostatic stress is mediated. 2. Delirium and the Aging Process Advanced age is an independent risk factor for developing delirium with increasing risk
References
[1]
American Psychiatric Association, Task Force on DSM-IV, DSM-IV: Diagnostic and Statistical Manual of Mental Disorders, American Psychiatric Association, Washington, DC, USA, 4th edition, 1994.
[2]
N. Siddiqi, A. O. House, and J. D. Holmes, “Occurrence and outcome of delirium in medical in-patients: a systematic literature review,” Age and Ageing, vol. 35, no. 4, pp. 350–364, 2006.
[3]
M. Elie, F. Rousseau, M. Cole, F. Primeau, J. McCusker, and F. Bellavance, “Prevalence and detection of delirium in elderly emergency department patients,” Canadian Medical Association Journal, vol. 163, no. 8, pp. 977–981, 2000.
[4]
L. J. Young and J. George, “Do guidelines improve the process and outcomes of care in delirium?” Age and Ageing, vol. 32, no. 5, pp. 525–528, 2003.
[5]
D. Meagher, “More attention, less confusion: time to lessen the burden of delirium,” International Review of Psychiatry, vol. 21, no. 1, pp. 1–3, 2009.
[6]
P. Trzepacz, D. Meagher, and M. Leonard, “Delirium,” in Textbook of Psychosomatic Medicine, J. Levenson, Ed., American Psychiatric Press, Washington, DC, USA, 2010.
[7]
Y. Gustafson, D. Berggren, B. Brannstrom et al., “Acute confusional states in elderly patients treated for femoral neck fracture,” Journal of the American Geriatrics Society, vol. 36, no. 6, pp. 525–530, 1988.
[8]
K. Rockwood, “Acute confusion in elderly medical patients,” Journal of the American Geriatrics Society, vol. 37, no. 2, pp. 150–154, 1989.
[9]
S. E. Levkoff, D. A. Evans, B. Liptzin et al., “Delirium: the occurrence and persistence of symptoms among elderly hospitalized patients,” Archives of Internal Medicine, vol. 152, no. 2, pp. 334–340, 1992.
[10]
J. D. Schor, S. E. Levkoff, L. A. Lipsitz et al., “Risk factors for delirium in hospitalized elderly,” Journal of the American Medical Association, vol. 267, no. 6, pp. 827–831, 1992.
[11]
M. Elie, M. G. Cole, F. J. Primeau, and F. Bellavance, “Delirium risk factors in elderly hospitalized patients,” Journal of General Internal Medicine, vol. 13, no. 3, pp. 204–212, 1998.
[12]
A. Hofman, W. A. Rocca, C. Brayne et al., “The prevalence of dementia in Europe: a collaborative study of 1980–1990 findings,” International Journal of Epidemiology, vol. 20, no. 3, pp. 736–748, 1991.
[13]
D. M. Fick, J. V. Agostini, and S. K. Inouye, “Delirium superimposed on dementia: a systematic review,” Journal of the American Geriatrics Society, vol. 50, no. 10, pp. 1723–1732, 2002.
[14]
L. Ansaloni, F. Catena, R. Chattat et al., “Risk factors and incidence of postoperative delirium in elderly patients after elective and emergency surgery,” British Journal of Surgery, vol. 97, no. 2, pp. 273–280, 2010.
[15]
A. Chrispal, K. Prasad Mathews, and V. Surekha, “The clinical profile and association of delirium in geriatric patients with hip fractures in a tertiary care hospital in India,” Journal of Association of Physicians of India, vol. 58, no. 1, pp. 15–19, 2010.
[16]
J. G. Franco, C. Valencia, C. Bernal et al., “Relationship between cognitive status at admission and incident delirium in older medical inpatients,” Journal of Neuropsychiatry and Clinical Neurosciences, vol. 22, no. 3, pp. 329–337, 2010.
[17]
D. B. Rolfson, J. E. McElhaney, G. S. Jhangri, and K. Rockwood, “Delirium: validity of the confusion assessment method in detecting postoperative delirium in the elderly,” International Psychogeriatrics, vol. 11, no. 4, pp. 431–438, 1999.
[18]
M. W. A. van Rijsbergen, A. W. Oldenbeuving, R. E. Nieuwenhuis-Mark et al., “Delirium in acute stroke: a predictor 7 of subsequent cognitive impairment? A two-year follow-up study,” Journal of the Neurological Sciences, vol. 306, no. 1-2, pp. 138–142, 2011.
[19]
K. Alagiakrishnan and C. A. Wiens, “An approach to drug induced delirium in the elderly,” Postgraduate Medical Journal, vol. 80, no. 945, pp. 388–393, 2004.
[20]
A. Clegg and J. B. Young, “Which medications to avoid in people at risk of delirium: a systematic review,” Age and Ageing, vol. 40, no. 1, pp. 23–29, 2011.
[21]
A. M. J. MacLullich, A. Beaglehole, R. J. Hall, and D. J. Meagher, “Delirium and long-term cognitive impairment,” International Review of Psychiatry, vol. 21, no. 1, pp. 30–42, 2009.
[22]
K. Rockwood, “The occurrence and duration of symptoms in elderly patients with delirium,” Journals of Gerontology, vol. 48, no. 4, pp. M162–M166, 1993.
[23]
J. McCusker, M. Cole, N. Dendukuri, L. Han, and E. Belzile, “The course of delirium in older medical inpatients: a prospective study,” Journal of General Internal Medicine, vol. 18, no. 9, pp. 696–704, 2003.
[24]
D. Adamis, A. Treloar, F. C. Martin, and A. J. D. Macdonald, “Recovery and outcome of delirium in elderly medical inpatients,” Archives of Gerontology and Geriatrics, vol. 43, no. 2, pp. 289–298, 2006.
[25]
J. C. Jackson, S. M. Gordon, R. P. Hart, R. O. Hopkins, and E. W. Ely, “The association between delirium and cognitive decline: a review of the empirical literature,” Neuropsychology Review, vol. 14, no. 2, pp. 87–98, 2004.
[26]
M. A. Rudberg, P. Pompei, M. D. Foreman, R. E. Ross, and C. K. Cassel, “The natural history of delirium in older hospitalized patients: a syndrome of heterogeneity,” Age and Ageing, vol. 26, no. 3, pp. 169–174, 1997.
[27]
A. J. D. Macdonald and A. Treloar, “Delirium and dementia; are they distinct?” Journal of the American Geriatrics Society, vol. 44, no. 8, pp. 1001–1002, 1996.
[28]
T. G. Fong, R. N. Jones, P. Shi et al., “Delirium accelerates cognitive decline in alzheimer disease,” Neurology, vol. 72, no. 18, pp. 1570–1575, 2009.
[29]
D. J. Meagher, A. M. J. MacLullich, and J. V. Laurila, “Defining delirium for the International Classification of Diseases, 11th Revision,” Journal of Psychosomatic Research, vol. 65, no. 3, pp. 207–214, 2008.
[30]
D. Adamis, A. Treloar, F. C. Martin, N. Gregson, G. Hamilton, and A. J. D. Macdonald, “APOE and cytokines as biological markers for recovery of prevalent delirium in elderly medical inpatients,” International Journal of Geriatric Psychiatry, vol. 22, no. 7, pp. 688–694, 2007.
[31]
S. E. de Rooij, B. C. van Munster, J. C. Korevaar, and M. Levi, “Cytokines and acute phase response in delirium,” Journal of Psychosomatic Research, vol. 62, no. 5, pp. 521–525, 2007.
[32]
A. M. J. MacLullich, K. J. Ferguson, T. Miller, S. E. J. A. de Rooij, and C. Cunningham, “Unravelling the pathophysiology of delirium: a focus on the role of aberrant stress responses,” Journal of Psychosomatic Research, vol. 65, no. 3, pp. 229–238, 2008.
[33]
C. Alexia, G. Fallot, M. Lasfer, G. Schweizer-Groyer, and A. Groyer, “An evaluation of the role of insulin-like growth factors (IGF) and of type-I IGF receptor signalling in hepatocarcinogenesis and in the resistance of hepatocarcinoma cells against drug-induced apoptosis,” Biochemical Pharmacology, vol. 68, no. 6, pp. 1003–1015, 2004.
[34]
B. R. Lackey, S. L. Gray, and D. M. Henricks, “Actions and interactions of the IGF system in Alzheimer's disease: review and hypotheses,” Growth Hormone and IGF Research, vol. 10, no. 1, pp. 1–13, 2000.
[35]
I. Torres-Aleman, “Toward a comprehensive neurobiology of IGF-I,” Developmental Neurobiology, vol. 70, no. 5, pp. 384–396, 2010.
[36]
C. P. Velloso, “Regulation of muscle mass by growth hormone and IGF-I,” British Journal of Pharmacology, vol. 154, no. 3, pp. 557–568, 2008.
[37]
F. M. Yang, S. K. Inouye, M. A. Fearing, D. K. Kiely, E. R. Marcantonio, and R. N. Jones, “Participation in activity and risk for incident delirium,” Journal of the American Geriatrics Society, vol. 56, no. 8, pp. 1479–1484, 2008.
[38]
H. D. Venters, S. R. Broussard, J. H. Zhou et al., “Tumor necrosis factorα and insulin-like growth factor-I in the brain: is the whole greater than the sum of its parts?” Journal of Neuroimmunology, vol. 119, no. 2, pp. 151–165, 2001.
[39]
J. A. D'Ercole, P. Ye, and J. R. O'Kusky, “Mutant mouse models of insulin-like growth factor actions in the central nervous system,” Neuropeptides, vol. 36, no. 2-3, pp. 209–220, 2002.
[40]
S. T. O'Keeffe and J. N. Lavan, “Predicting delirium in elderly patients: development and validation of a risk-stratification model,” Age and Ageing, vol. 25, no. 4, pp. 317–321, 1996.
[41]
S. K. Inouye and P. A. Charpentier, “Precipitating factors for delirium in hospitalized elderly persons: predictive model and interrelationship with baseline vulnerability,” Journal of the American Medical Association, vol. 275, no. 11, pp. 852–857, 1996.
[42]
S. Doré, S. Kar, and R. Quirion, “Insulin-like growth factor I protects and rescues hippocampal neurons against β-amyloid- and human amylin-induced toxicity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 9, pp. 4772–4777, 1997.
[43]
P. J. Jenkens and S. A. Bustin, “Evidence for a link between IGF-I and cancer,” European Journal of Endocrinology, vol. 151, supplement 1, pp. S17–S22, 2004.
[44]
A. Meager, The Molecular Biology of Cytokines, John Wiley & Sons, Chichester, UK, 1998.
[45]
F. De Benedetti, T. Alonzi, A. Moretta et al., “Interleukin 6 causes growth impairment in transgenic mice through a decrease in insulin-like growth factor-I: a model for stunted growth in children with chronic inflammation,” Journal of Clinical Investigation, vol. 99, no. 4, pp. 643–650, 1997.
[46]
B. R. Lackey, S. L. Gray, and D. M. Henricks, “Does the insulin-like growth factor system interact with prostaglandins and proinflammatory cytokines during neurodegeneration?” Experimental Biology and Medicine, vol. 224, no. 1, pp. 20–27, 2000.
[47]
C. H. Lang, L. Hong-Brown, and R. A. Frost, “Cytokine inhibition of JAK-STAT signaling: a new mechanism of growth hormone resistance,” Pediatric Nephrology, vol. 20, no. 3, pp. 306–312, 2005.
[48]
L. J. Niedernhofer, G. A. Garinis, A. Raams et al., “A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis,” Nature, vol. 444, no. 7122, pp. 1038–1043, 2006.
[49]
Y. Li, W. Xu, M. W. McBurney, and V. D. Longo, “SirT1 inhibition reduces IGF-I/IRS-2/Ras/ERK1/2 signaling and protects neurons,” Cell Metabolism, vol. 8, no. 1, pp. 38–48, 2008.
[50]
D. Rudman, M. H. Kutner, and C. M. Rogers, “Impaired growth hormone secretion in the adult population: relation to age and adiposity,” Journal of Clinical Investigation, vol. 67, no. 5, pp. 1361–1369, 1981.
[51]
D. R. Clemmons and J. J. Van Wyk, “Factors controlling blood concentration of somatomedin C,” Clinics in Endocrinology and Metabolism, vol. 13, no. 1, pp. 113–143, 1984.
[52]
K. Landin-Wilhelmsen, L. Wilhelmsen, G. Lappas et al., “Serum insulin-like growth factor I in a random population sample of men and women: relation to age, sex, smoking habits, coffee consumption and physical activity, blood pressure and concentrations of plasma lipids, fibrinogen, parathyroid hormone and osteocalcin,” Clinical Endocrinology, vol. 41, no. 3, pp. 351–357, 1994.
[53]
S. Boonen, E. Lesaffre, J. Dequeker et al., “Relationship between baseline insulin-like growth factor-I (IGF-I) and femoral bone density in women aged over 70 years: potential implications for the prevention of age-related bone loss,” Journal of the American Geriatrics Society, vol. 44, no. 11, pp. 1301–1306, 1996.
[54]
J. A. M. J. L. Janssen, R. P. Stolk, H. A. P. Pols, D. E. Grobbee, F. H. De Jong, and S. W. J. Lamberts, “Serum free IGF-I, total IGF-I, IGFBP-1 and IGFBP-3 levels in an elderly population: relation to age and sex steroid levels,” Clinical Endocrinology, vol. 48, no. 4, pp. 471–478, 1998.
[55]
A. Juul, K. Main, W. F. Blum, J. Lindholm, M. B. Ranke, and N. E. Skakkebaek, “The ratio between serum levels of insulin-like growth factor (IGF)-I and the IGF binding proteins (IGFBP-1, 2 and 3) decreases with age in healthy adults and is increased in acromegalic patients,” Clinical Endocrinology, vol. 41, no. 1, pp. 85–93, 1994.
[56]
G. Paolisso, S. Ammendola, A. Del Buono et al., “Serum levels of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 in healthy centenarians: relationship with plasma leptin and lipid concentrations, insulin action, and cognitive function,” Journal of Clinical Endocrinology and Metabolism, vol. 82, no. 7, pp. 2204–2209, 1997.
[57]
Y. Arai, N. Hirose, K. Yamamura et al., “Serum insulin-like growth factor-1 in centenarians: implications of IGF-1 as a rapid turnover protein,” Journals of Gerontology A, vol. 56, no. 2, pp. M79–M82, 2001.
[58]
F. C. Martin, “Growth hormone, aging and frailty,” Reviews in Clinical Gerontology, vol. 9, no. 3, pp. 207–214, 1999.
[59]
J. L. Thompson, G. E. Butterfield, R. Marcus et al., “The effects of recombinant human insulin-like growth factor-I and growth hormone on body composition in elderly women,” Journal of Clinical Endocrinology and Metabolism, vol. 80, no. 6, pp. 1845–1852, 1995.
[60]
K. C. Copeland, R. B. Colletti, J. T. Devlin, and T. L. McAuliffe, “The relationship between insulin-like growth factor-I, adiposity, and aging,” Metabolism, vol. 39, no. 6, pp. 584–587, 1990.
[61]
T. B. Harris, D. Kiel, R. Roubenoff et al., “Association of insulin-like growth factor-I with body composition, weight history, and past health behaviors in the very old: the Framingham Heart Study,” Journal of the American Geriatrics Society, vol. 45, no. 2, pp. 133–139, 1997.
[62]
A. R. Cappola, K. Bandeen-Roche, G. S. Wand, S. Volpato, and L. P. Fried, “Association of IGF-I levels with muscle strength and mobility in older women,” Journal of Clinical Endocrinology and Metabolism, vol. 86, no. 9, pp. 4139–4146, 2001.
[63]
A. R. Cappola, Q. L. Xue, L. Ferrucci, J. M. Guralnik, S. Volpato, and L. P. Fried, “Insulin-like growth factor I and interleukin-6 contribute synergistically to disability and mortality in older women,” Journal of Clinical Endocrinology and Metabolism, vol. 88, no. 5, pp. 2019–2025, 2003.
[64]
R. Roubenoff, H. Parise, H. A. Payette et al., “Cytokines, insulin-like growth factor 1, sarcopenia, and mortality in very old community-dwelling men and women: the Framingham Heart Study,” American Journal of Medicine, vol. 115, no. 6, pp. 429–435, 2003.
[65]
M. Andreassen, I. Raymond, C. Kistorp, P. Hildebrandt, J. Eaber, and L. ？. Kristensen, “IGF1 as predictor of all cause mortality and cardiovascular disease in an elderly population,” European Journal of Endocrinology, vol. 160, no. 1, pp. 25–31, 2009.
[66]
G. A. Laughlin, E. Barrett-Connor, M. H. Criqui, and D. Kritz-Silverstein, “The prospective association of serum insulin-like growth factor I (IGF-I) and IGF-binding protein-1 levels with all cause and cardiovascular disease mortality in older adults: the Rancho Bernardo study,” Journal of Clinical Endocrinology and Metabolism, vol. 89, no. 1, pp. 114–120, 2004.
[67]
S. Saydah, B. Graubard, R. Ballard-Barbash, and D. Berrigan, “Insulin-like growth factors and subsequent risk of mortality in the United States,” American Journal of Epidemiology, vol. 166, no. 5, pp. 518–526, 2007.
[68]
K. A. Woods, C. Camacho-Hübner, M. O. Savage, and A. J. L. Clark, “Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene,” New England Journal of Medicine, vol. 335, no. 18, pp. 1363–1367, 1996.
[69]
C. M. Cheng, R. R. Reinhardt, W. H. Lee, G. Joncas, S. C. Patel, and C. A. Bondy, “Insulin-like growth factor 1 regulates developing brain glucose metabolism,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 18, pp. 10236–10241, 2000.
[70]
K. D. Beck, L. Powell-Braxton, H. R. Widmer, J. Valverde, and F. Hefti, “Igf1 gene disruption results in reduced brain size, CNS hypomyelination, and loss of hippocampal granule and striatal parvalbumin-containing neurons,” Neuron, vol. 14, no. 4, pp. 717–730, 1995.
[71]
J. B. Deijen, H. De Boer, and E. A. Van Der Veen, “Cognitive changes during growth hormone replacement in adult men,” Psychoneuroendocrinology, vol. 23, no. 1, pp. 45–55, 1998.
[72]
M. A. Papadakis, D. Grady, D. Black et al., “Growth hormone replacement in healthy older men improves body composition but not functional ability,” Annals of Internal Medicine, vol. 124, no. 8, pp. 708–716, 1996.
[73]
A. Aleman, W. R. De Vries, E. H. F. De Haan, H. J. J. Verhaar, M. M. Samson, and H. P. F. Koppeschaar, “Age-sensitive cognitive function, growth hormone and insulin-like growth factor 1 plasma levels in healthy older men,” Neuropsychobiology, vol. 41, no. 2, pp. 73–78, 2000.
[74]
A. Aleman, H. J. J. Verhaar, E. H. F. De Haan et al., “Insulin-like growth factor-I and cognitive function in healthy older men,” Journal of Clinical Endocrinology and Metabolism, vol. 84, no. 2, pp. 471–475, 1999.
[75]
A. Mustafa, L. Lannfelt, L. Lilius, A. Islam, B. Winblad, and A. Adem, “Decreased plasma insulin-like growth factor-I level in familial Alzheimer's disease patients carrying the Swedish APP 670/671 mutation,” Dementia and Geriatric Cognitive Disorders, vol. 10, no. 6, pp. 446–451, 1999.
[76]
G. Murialdo, A. Barreca, F. Nobili et al., “Relationships between cortisol, dehydroepiandrosterone sulphate and insulin-like growth factor-I system in dementia,” Journal of Endocrinological Investigation, vol. 24, no. 3, pp. 139–146, 2001.
[77]
V. R. Sara, K. Hall, and K. Enzell, “Somatomedins in aging and dementia disorders of the Alzheimer type,” Neurobiology of Aging, vol. 3, no. 2, pp. 117–120, 1982.
[78]
A. Tham, A. Nordberg, F. E. Grissom, C. Carlsson-Skwirut, M. Viitanen, and V. R. Sara, “Insulin-like growth factors and insulin-like growth factor binding proteins in cerebrospinal fluid and serum of patients with dementia of the Alzheimer type,” Journal of Neural Transmission Parkinson's Disease and Dementia Section, vol. 5, no. 3, pp. 165–176, 1993.
[79]
B. Nasmanl, T. Olsson, J. R. Seckl, et al., “Abnormalities in adrenal androgens, but not of glucocorticoids, in early Alzheimer's disease,” Psychoneuroendocrinology, vol. 20, no. 1, pp. 83–94, 1995.
[80]
E. Carro, J. L. Trejo, T. Gomez-Isla, D. LeRoith, and I. Torres-Aleman, “Serum insulin-like growth factor I regulates brain amyloid-β levels,” Nature Medicine, vol. 8, no. 12, pp. 1390–1397, 2002.
[81]
W. Q. Zhao, P. N. Lacor, H. Chen et al., “Insulin receptor dysfunction impairs cellular clearance of neurotoxic oligomeric Aβ,” Journal of Biological Chemistry, vol. 284, no. 28, pp. 18742–18753, 2009.
[82]
S. Sharma, J. Prasanthi, E. Schommer, G. Feist, and O. Ghribi, “Hypercholesterolemia-induced Aβ accumulation in rabbit brain is associated with alteration in IGF-1 signaling,” Neurobiology of Disease, vol. 32, no. 3, pp. 426–432, 2008.
[83]
S. Kar, D. Seto, S. Doré, U. K. Hanisch, and R. Quirion, “Insulin-like growth factors-I and -II differentially regulate endogenous acetylcholine release from the rat hippocampal formation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 25, pp. 14054–14059, 1997.
[84]
M. A. I. ？berg, N. D. ？berg, H. Hedb？cker, J. Oscarsson, and P. S. Eriksson, “Peripheral infusion of IGF-I selectively induces neurogenesis in the adult rat hippocampus,” Journal of Neuroscience, vol. 20, no. 8, pp. 2896–2903, 2000.
[85]
M. A. I. ？berg, N. D. ？berg, T. D. Palmer et al., “IGF-I has a direct proliferative effect in adult hippocampal progenitor cells,” Molecular and Cellular Neuroscience, vol. 24, no. 1, pp. 23–40, 2003.
[86]
S. Doré, S. Bastianetto, S. Kar, and R. Quirion, “Protective and rescuing abilities of IGF-I and some putative free radical scavengers against β-amyloid-inducing toxicity in neurons,” Annals of the New York Academy of Sciences, vol. 890, pp. 356–364, 1999.
[87]
L. Gasparini and H. Xu, “Potential roles of insulin and IGF-1 in Alzheimer's disease,” Trends in Neurosciences, vol. 26, no. 8, pp. 404–406, 2003.
[88]
E. Giovannucci, “Nutrition, insulin, insulin-like growth factors and cancer,” Hormone and Metabolic Research, vol. 35, no. 11-12, pp. 694–704, 2003.
[89]
W. M. Zawada, D. L. Kirschman, J. J. Cohen, K. A. Heidenreich, and C. R. Freed, “Growth factors rescue embryonic dopamine neurons from programmed cell death,” Experimental Neurology, vol. 140, no. 1, pp. 60–67, 1996.
[90]
W. M. Zawada, D. J. Zastrow, E. D. Clarkson, F. S. Adams, K. P. Bell, and C. R. Freed, “Growth factors improve immediate survival of embryonic dopamine neurons after transplantation into rats,” Brain Research, vol. 786, no. 1-2, pp. 96–103, 1998.
[91]
J. Guan, R. Krishnamurthi, H. J. Waldvogel, R. L. M. Faull, R. Clark, and P. Gluckman, “N-terminal tripeptide of IGF-1 (GPE) prevents the loss of TH positive neurons after 6-OHDA induced nigral lesion in rats,” Brain Research, vol. 859, no. 2, pp. 286–292, 2000.
[92]
R. Krishnamurthi, S. Stott, M. Maingay et al., “N-terminal tripeptide of IGF-I improves functional deficits after 6-OHDA lesion in rats,” NeuroReport, vol. 15, no. 10, pp. 1601–1604, 2004.
[93]
P. T. Trzepacz, “The neuropathogenesis of delirium: a need to focus our research,” Psychosomatics, vol. 35, no. 4, pp. 374–391, 1994.
[94]
P. T. Trzepacz, “Update on the neuropathogenesis of delirium,” Dementia and Geriatric Cognitive Disorders, vol. 10, no. 5, pp. 330–334, 1999.
[95]
C. Murray, D. J. Sanderson, C. Barkus et al., “Systemic inflammation induces acute working memory deficits in the primed brain: relevance for delirium,” Neurobiology of Aging. In press.
[96]
K. Wilson, C. Broadhurst, M. Diver, M. Jackson, and P. Mottram, “Plasma insulin growth factor-1 and incident delirium in older people,” International Journal of Geriatric Psychiatry, vol. 20, no. 2, pp. 154–159, 2005.
[97]
A. W. Lemstra, K. J. Kalisvaart, R. Vreeswijk, W. A. van Gool, and P. Eikelenboom, “Pre-operative inflammatory markers and the risk of postoperative delirium in elderly patients,” International Journal of Geriatric Psychiatry, vol. 23, no. 9, pp. 943–948, 2008.
[98]
D. Adamis, M. Lunn, F. C. Martin et al., “Cytokines and IGF-I in delirious and non-delirious acutely ill older medical inpatients,” Age and Ageing, vol. 38, no. 3, pp. 326–332, 2009.
[99]
A. Morandi, M. L. Gunther, P. P. Pandharipande et al., “Insulin-like growth factor-1 and delirium in critically ill mechanically ventilated patients: a preliminary investigation,” International Psychogeriatrics. In press.
[100]
C. Charriaut-Marlangue and Y. Ben-Ari, “A cautionary note on the use of the TUNEL stain to determine apoptosis,” NeuroReport, vol. 7, no. 1, pp. 61–64, 1995.
[101]
P. D. Gluckman, J. Guan, C. Williams et al., “Asphyxial brain injury—the role of the IGF system,” Molecular and Cellular Endocrinology, vol. 140, no. 1-2, pp. 95–99, 1998.
[102]
C. D. M. Filho and M. Holzenberger, “IGF receptors in the adult brain,” in IGFs: Local Repair and Survival Factors Throughout Life Span, D. Clemmons, I. C. A. F. Robinson, and Y. Christen, Eds., pp. 125–142, Springer, London, UK, 2010.
[103]
F. Peruzzi, M. Prisco, M. Dews et al., “Multiple signaling pathways of the insulin-like growth factor 1 receptor in protection from apoptosis,” Molecular and Cellular Biology, vol. 19, no. 10, pp. 7203–7215, 1999.
[104]
M. Párrizas and D. LeRoith, “Insulin-like growth factor-1 inhibition of apoptosis is associated with increased expression of the bcl-xL gene product,” Endocrinology, vol. 138, no. 3, pp. 1355–1358, 1997.
[105]
R. W. Matheny and M. L. Adamo, “PI3K p110 alpha and p110 beta have differential effects on Akt activation and protection against oxidative stress-induced apoptosis in myoblasts,” Cell Death and Differentiation, vol. 17, no. 4, pp. 677–688, 2010.
[106]
E. Carro, J. L. Trejo, S. Fernandez, A. M. Fernandez, and I. Torres-Aleman, “Insulin-like growth factor-I and neuroprotection,” in The Somatotrophic Axis in Brain Function, F. Nyberg, Ed., Elsevier Academic Press, London, UK, 2006.
[107]
R. Yirmiya and I. Goshen, “Immune modulation of learning, memory, neural plasticity and neurogenesis,” Brain, Behavior, and Immunity, vol. 25, no. 2, pp. 181–213, 2011.
[108]
K. E. Saatman, P. C. Contreras, D. H. Smith et al., “Insulin-like growth factor-1 (IGF-1) improves both neurological motor and cognitive outcome following experimental brain injury,” Experimental Neurology, vol. 147, no. 2, pp. 418–427, 1997.
[109]
L. S. Mathews, G. Norstedt, and R. D. Palmiter, “Regulation of insulin-like growth factor I gene expression by growth hormone,” Proceedings of the National Academy of Sciences of the United States of America, vol. 83, no. 24, pp. 9343–9347, 1986.
[110]
M. A. Hynes, J. J. Van Wijk, P. J. Brooks, A. J. D'Ercole, M. Jansen, and P. K. Lund, “Growth hormone dependence of somatomedin-C/insulin-like growth factor-I and insulin-like growth factor-II messenger ribonucleic acids,” Molecular Endocrinology, vol. 1, no. 3, pp. 233–242, 1987.
[111]
F. Lupu, J. D. Terwilliger, K. Lee, G. V. Segre, and A. Efstratiadis, “Roles of growth hormone and insulin-like growth factor 1 in mouse postnatal growth,” Developmental Biology, vol. 229, no. 1, pp. 141–162, 2001.
[112]
O. Khorram, “Use of growth hormone and growth hormone secretagogues in aging: help or harm,” Clinical Obstetrics and Gynecology, vol. 44, no. 4, pp. 893–901, 2001.
[113]
A. L. Yeo, D. Levy, F. C. Martin et al., “Frailty and the biochemical effects of recombinant human growth hormone in women after surgery for hip fracture,” Growth Hormone and IGF Research, vol. 13, no. 6, pp. 361–370, 2003.
[114]
A. Pearson, A. De Vries, S. D. Middleton et al., “Cerebrospinal fluid cortisol levels are higher in patients with delirium versus controls,” BMC Research Notes, vol. 3, Article ID 33, 2010.
[115]
M. Adamo, H. Werner, W. Farnsworth, C. T. Roberts, M. Raizada, and D. LeRoith, “Dexamethasone reduces steady state insulin-like growth factor I messenger ribonucleic acid levels in rat neuronal and glial cells in primary culture,” Endocrinology, vol. 123, no. 5, pp. 2565–2570, 1988.
[116]
W. L. Lowe Jr., T. Meyer, C. W. Karpen, and L. R. Lorentzen, “Regulation of insulin-like growth factor I production in rat C6 glioma cells: possible role as an autocrine/paracrine growth factor,” Endocrinology, vol. 130, no. 5, pp. 2683–2691, 1992.
[117]
C. B. Chan, M. C. Tse, and C. H. K. Cheng, “Regulation and mechanism of growth hormone and insulin-like growth factor-I biosynthesis and secretion,” in The Somatotrophic Axis in Brain Function, F. Nyberg, Ed., pp. 7–23, Elsevier Academic Press, London, UK, 2006.
[118]
C. Broadhurst and K. Wilson, “Immunology of delirium: new opportunities for treatment and research,” British Journal of Psychiatry, vol. 179, pp. 288–289, 2001.
[119]
O. Nozaki, C. Takagi, K. Takaoka, T. Takata, and M. Yoshida, “Psychiatric manifestations accompanying interferon therapy for patients with chronic hepatitis C: an overview of cases in Japan,” Psychiatry and Clinical Neurosciences, vol. 51, no. 4, pp. 175–180, 1997.
[120]
C. J. Auernhammer and C. J. Strasburger, “Effects of growth hormone and insulin-like growth factor I on the immune system,” European Journal of Endocrinology, vol. 133, no. 6, pp. 635–645, 1995.
[121]
V. Hwa, B. Little, E. M. Kofoed, and R. G. Rosenfeld, “Transcriptional regulation of insulin-like growth factor-I by interferon-gamma requires STAT-5b,” Journal of Biological Chemistry, vol. 279, no. 4, pp. 2728–2736, 2004.
[122]
D. Adamis, F. C. Martin, A. Treloar, and A. J. D. Macdonald, “Capacity, consent, and selection bias in a study of delirium,” Journal of Medical Ethics, vol. 31, no. 3, pp. 137–143, 2005.
[123]
K. B. Auerswald, P. A. Charpentier, and S. K. Inouye, “The informed consent process in older patients who developed delirium: a clinical epidemiologic study,” American Journal of Medicine, vol. 103, no. 5, pp. 410–418, 1997.
[124]
J. Francis, “A half-century of delirium research: time to close the gap,” Journal of the American Geriatrics Society, vol. 43, no. 5, pp. 585–586, 1995.
[125]
D. Adamis, A. Treloar, F. C. Martin, and A. J. D. Macdonald, “Ethical research in delirium: arguments for including decisionally incapacitated subjects,” Science and Engineering Ethics, vol. 16, no. 1, pp. 169–174, 2010.
[126]
H. P. Guler, J. Zapf, C. Schmid, and E. R. Froesch, “Insulin-like growth factors I and II in healthy man. Estimations of half-lives and production rates,” Acta Endocrinologica, vol. 121, no. 6, pp. 753–758, 1989.
[127]
A. L. Barkan, “Defining normalcy of the somatotropic axis: an attainable goal?” Pituitary, vol. 10, no. 2, pp. 135–139, 2007.
[128]
H. J. Koponen, E. Leinonen, U. Lepola, and P. J. Riekkinen, “A long-term follow-up study of cerebrospinal fluid somatostatin in delirium,” Acta Psychiatrica Scandinavica, vol. 89, no. 5, pp. 329–334, 1994.
[129]
R. Ross, J. Miell, E. Freeman et al., “Critically ill patients have high basal growth hormone levels with attenuated oscillatory activity associated with low levels of insulin-like growth factor-I,” Clinical Endocrinology, vol. 35, no. 1, pp. 47–54, 1991.
[130]
P. Cohen, “Insulin-like growth factor binding protein-3: insulin-like growth factor independence comes of age,” Endocrinology, vol. 147, no. 5, pp. 2109–2111, 2006.
[131]
R. C. Kaplan, A. P. McGinn, M. N. Pollak et al., “Total insulinlike growth factor 1 and insulinlike growth factor binding protein levels, functional status, and mortality in older adults,” Journal of the American Geriatrics Society, vol. 56, no. 4, pp. 652–660, 2008.
