The journal of nutrition, health & aging

, Volume 16, Issue 1, pp 40–54

The hormonal pathway to cognitive impairment in older men

  • Marcello Maggio
  • E. Dall’Aglio
  • F. Lauretani
  • C. Cattabiani
  • G. Ceresini
  • P. Caffarra
  • G. Valenti
  • R. Volpi
  • A. Vignali
  • G. Schiavi
  • G. P. Ceda
Hormonal Dysregulation and Cognition in the Elderly


In older men there is a multiple hormonal dysregulation with a relative prevalence of catabolic hormones such as thyroid hormones and cortisol and a decline in anabolic hormones such as dehydroepiandrosterone sulphate, testosterone and insulin like growth factor 1 levels. Many studies suggest that this catabolic milieu is an important predictor of frailty and mortality in older persons. There is a close relationship between frailty and cognitive impairment with studies suggesting that development of frailty is consequence of cognitive impairment and others pointing out that physical frailty is a determinant of cognitive decline. Decline in cognitive function, typically memory, is a major symptom of dementia. The “preclinical phase” of cognitive impairment occurs many years before the onset of dementia. The identification of relevant modifiable factors, including the hormonal dysregulation, may lead to therapeutic strategies for preventing the cognitive dysfunction. There are several mechanisms by which anabolic hormones play a role in neuroprotection and neuromodulation. These hormones facilitate recovery after brain injury and attenuate the neuronal loss. In contrast, elevated thyroid hormones may increase oxidative stress and apoptosis, leading to neuronal damage or death. In this mini review we will address the relationship between low levels of anabolic hormones, changes in thyroid hormones and cognitive function in older men. Then, giving the contradictory data of the literature and the multi-factorial origin of dementia, we will introduce the hypothesis of multiple hormonal derangement as a better determinant of cognitive decline in older men.

Key words

Hormonal dysregulation cognitive impairment older men 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Petersen RC, Doody R, Kurz A, Mohs RC, Morris JC, Rabins PV, Ritchie K, Rossor M, Thal L, Winblad B. (2001) Current concepts in mild cognitive impairment. Arch Neurol 58:1985–1992PubMedCrossRefGoogle Scholar
  2. 2.
    Elias MF, Beiser A, Wolf PA, Au R, White RF, D’Agostino RB. (2000) The preclinical phase of Alzheimer disease: a 22-year prospective study of the Framingham Cohort. Arch Neurol 57:808–813PubMedCrossRefGoogle Scholar
  3. 3.
    La Rue A. (2001) Aging and neuropsychological assessment. 15th ed. New York: Plenum PressGoogle Scholar
  4. 4.
    Salthouse TA. (1996) The processing-speed theory of adult age differences in cognition. Psychol Rev 103:403–428PubMedCrossRefGoogle Scholar
  5. 5.
    Bennett DA, Wilson RS, Schneider JA, Evans DA, Beckett LA, Aggarwal NT, Barnes LL, Fox JH, Bach J. (2002) Natural history of mild cognitive impairment in older persons. Neurology 59:198–205PubMedGoogle Scholar
  6. 6.
    Salthouse TA. (2004) What and when of cognitive aging. Curr Dir Psychol Sci 13:140–144CrossRefGoogle Scholar
  7. 7.
    Ferrucci L, Guralnick JM, Studenski S, Fried L, Cutler GB, Waltson JD, for the Intervention on Frailty Working Group. (2004) Designing randomized, controlled trials aimed at preventing or delaying functional decline and disability in frail, older person: A consensus report. J Am Geriatr Soc 52:625–634PubMedCrossRefGoogle Scholar
  8. 8.
    Samper-Ternent R, Al Snih S, Raji MA, Markides KS, and Ottenbacher KJ. (2008) Relationship between frailty and cognitive decline in older mexican americans. Am J Geriatr Soc Oct;56(10):1845–1852CrossRefGoogle Scholar
  9. 9.
    Maggio M, Cappola AR, Ceda GP, Basarla S, Chia CW, Valenti G, Ferrucci L. (2005) The hormonal pathway of frailty in older men. J Endocrinol Invest 28(11 Suppl Preceedings):15–19. Review.PubMedGoogle Scholar
  10. 10.
    Wolf OT. (2009) Stress and memory in hmans:twelve years of progress? Brain Research 1293:142–154PubMedCrossRefGoogle Scholar
  11. 11.
    Comijs HC, Gerritsen L, Penninx BW, Bremmer MA, Deeg DJ, Geerlings MI. (2010) The association between serum cortisol and cognitive decline in older persons. Am J Geriatr Psychiatry 18(1):42–50PubMedCrossRefGoogle Scholar
  12. 12.
    Reynolds RM, Strachan MWJ, Labad J, Lee AJ, Frier BM, Fowkes FG, Mitchell R, Seckl JR, Deary IJ, Walker BR, Price JF. (2010) Morning cortisol levels and cogntive abilities in people with type 2 diabetes. Diabetes care 33:714–720PubMedCrossRefGoogle Scholar
  13. 13.
    Labrie F, Belanger A, Cusan L, Gomez JL, Candas B. (1997) Marked decline in serum concentration of adrenal C 19 sex steroid precursor and conjugated androgen metabolites durin aging. J Clin Endocrinol Metab 82:2396–2402PubMedCrossRefGoogle Scholar
  14. 14.
    Bjørnerem A, Straume B, Midtby M, Fønnebø V, Sundsfjord, Svartberg J, Acharya G, Oian P, Berntsen GK. (2004) Endogenous sex hormones in relation to age, sex, lifestyle factors, and chronic disease in a general population: the Tromsø Study. J Clin Endocrinol Metab 89:6039–6047PubMedCrossRefGoogle Scholar
  15. 15.
    GISEG (Italian Study Group on Geriatric Endocrinology), Valenti G, Denti L, Saccò M, Ceresini G, Bossoni S, Giustina A, Maugeri D, Vigna GB, Fellin R, Paolisso G, Barbagallo M, Maggio M, Strollo F, Bollanti L, Romanelli F, Latini M. (2006) Consensus document substitution therapy with DHEA in the elderly. Aging Clin Exp Res 18:277–300PubMedGoogle Scholar
  16. 16.
    Maninger N, Wolkowitz OM, Reus VI. (2009) Neurobiological and neuropsychiatrc affects of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). Front Neuroendocrinol 2009 Jan;30(1):65–91CrossRefGoogle Scholar
  17. 17.
    Laurine E, Lafitte D, Grégoire C, Sérée E, Loret E, Douillard S, Michel B, Briand C, Verdier JM. (2003) Specific binding of dehydroepiandrosterone to the N terminus of the microtubule-associated protein MAP2. J Biol Chem. Aug 8;278(32): 29979–29986. Epub 2003 May 29.Google Scholar
  18. 18.
    Bologa L, Sharma J, Dahl D, Roberts E. (1987) Buffers and H2O2 reduce neuronal death and/or enhance differentiation of neurons and astrocytes in dissociated mouse brain cultures. Brain Res. May 19;411(2):282–290.Google Scholar
  19. 19.
    Compagnone NA, Mellon SH. (1998) Dehydroepiandrosterone: a potential signalling molecule for neocortical organization during development. Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4678–4683.PubMedCrossRefGoogle Scholar
  20. 20.
    Flood JF, Morley JE, Roberts E. (1992) Memory-enhancing effects in male mice of pregnenolone and steroids metabolically derived from it. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1567–1571.PubMedCrossRefGoogle Scholar
  21. 21.
    Majewska MD, Demirgören S, London ED. (1990) Binding of pregnenolone sulfate to rat brain membranes suggests multiple sites of steroid action at the GABAA receptor. Eur J Pharmacol. Oct 30;189(4–5):307–315.CrossRefGoogle Scholar
  22. 22.
    Steffensen SC, Jones MD, Hales K, Allison DW. (2006) Dehydroepiandrosterone sulphate and estrone sulphate reduce GABA-recurrent inhibition in hippocampus via muscarinic acetylcholine receptors. Hippocampus. 16(12):1080–1090.PubMedCrossRefGoogle Scholar
  23. 23.
    Porter JR, Abadie JM, Wright BE, Browne ES, Svec F. (1995) The effect of discontinuing dehydroepiandrosterone supplementation on Zucker rat food intake and hypothalamic neurotransmitters.Int J Obes Relat Metab Disord. Jul;19(7):480–488.Google Scholar
  24. 24.
    Bastianetto S, Ramassamy C, Poirier J, Quirion R. (1999) Dehydroepiandrosterone (DHEA) protects hippocampal cells from oxidative stress-induced damage. Brain Res Mol Brain Res. Mar 20;66(1–2):35–41.PubMedCrossRefGoogle Scholar
  25. 25.
    Kimonides VG, Khatibi NH, Svendsen CN, Sofroniew MV, Herbert J. (1998) Dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS) protect hippocampal neurons against excitatory amino acid-induced neurotoxicity. Proc Natl Acad Sci U S A. Feb 17; 95(4):1852–1857.CrossRefGoogle Scholar
  26. 26.
    Luppi C, Fioravanti M, Bertolini B, Inguscio M, Grugnetti A, Guerriero F, Rovelli C, Cantoni F, Guagnano P, Marazzi E, Rolfo E, Ghianda D, Levante D, Guerrini C, Bonacasa R, Solerte SB. (2009) Growth factors decrease in subjects with mild to moderate Alzheimer’s disease (AD): potential correction with dehydroepiandrosterone-sulphate (DHEAS). Arch Gerontol Geriatr. 49 Suppl 1:173–184.CrossRefGoogle Scholar
  27. 27.
    Kimonides VG, Spillantini MG, Sofroniew MV, Fawcett JW, Herbert J. (1999) Dehydroepiandrosterone antagonizes the neurotoxic effects of corticosterone and translocation of stress-activated protein kinase 3 in hippocampal primary cultures. Neuroscience. Mar;89(2):429–436.PubMedCrossRefGoogle Scholar
  28. 28.
    Morley JE, Kaiser F, Raum WJ, Perry M, Flood JF, Jensen J, Silver AJ, Roberts J. (1997) Potentially predictive and manipulable blood serum correlates of aging in the healthy human male: progressive decline in bioavailable testosterone, dehydroepiandrosterone sulfate, and the ratio of insulin-like growth factor 1 to growth hormone. Proc Natl Acad Sci USA Jul;94:7537–7542PubMedCrossRefGoogle Scholar
  29. 29.
    Flood JF, Farr SA, Johnson DA, Li PK, Morley JE. (1999) Pheripheral steroids sulfatase inhibition potentiate improvement of memory retention for hippocampally administred dehydroepiandrosterone sulfate but not pregnenolone sulfate. Psychoneuroendocrinology 24:799–811PubMedCrossRefGoogle Scholar
  30. 30.
    Kalmijn S, Launer LJ, Stolk RP, de Jong FH, Pols HA, Hofman A, Breteler MM, Lamberts SW. (1998) A prospective study on cortisol, dehydroepiandrosterone sulphate, and cognitive function in the elderly. J Clin Endocrinol Metab 83:3487–3492PubMedCrossRefGoogle Scholar
  31. 31.
    Moffat SD, Zonderman AB, Harman SM, Blackman MR, Kawas C, Resnick SM. (2000) The relationship between longitudinal declines in dehydroepiandrosterone sulphate concentrations and cognitive performance in older men. Arch Inter Med 160:2193–2198CrossRefGoogle Scholar
  32. 32.
    Fonda SJ, Bertrand R, O’Donnell A, Longcope C, McKinlay JB. (2005) Age, hormones, and cognitive functioning among middle-aged and elderly men: crosssectional evidence from the Massachusetts Male Aging Study. J Gerontol A Biol Sci Med Sci Mar 60(3):385–390PubMedCrossRefGoogle Scholar
  33. 33.
    Davis SR, Shah MS, McKenzie DP, Kulkarni J, Davidson SL, Bell RJ. (2008) Dehydroepiandrosterone sulfate levels are associated with more favourable cognitive function in women. J Clin Endocrinol Metab 93:801–808PubMedCrossRefGoogle Scholar
  34. 34.
    Berr C, Lafont S, Debuire B, Dartigues JF, Baulieu EE. (1996) Relationships of dehydroepiandrosterone sulfate in the elderly with functional, psychological, and mental status, and short-term mortality: a French community-based study. Proc Natl Acad Sci U S A. Nov 12;93(23):13410–13415.PubMedCrossRefGoogle Scholar
  35. 35.
    Valenti G, Ferrucci L, Lauretani F, Ceresini G, Bandinelli S, Luci M, Ceda GP, Maggio M, Schwartz RS. (2009) Dehydroepiandrosterone sulfate and cognitive function in the elderly: The InCHIANTI Study. J Endocrinol Invest 32:766–772PubMedGoogle Scholar
  36. 36.
    Marx CE, Trost WT, Shampine LJ, Stevens RD, Hulette CM, Steffens DC, Ervin JF, Butterfield MI, Blazer DG, Massing MW, Lieberman JA. (2006) The neurosteroid allopregnanolone is reduced in prefrontal cortex in Alzheimer’s disease. Biol Psychiatry 60:1287–1294PubMedCrossRefGoogle Scholar
  37. 37.
    Marx CE, Steffens DC, Blazer DG, Ervin JF, Hulette CM, Massing MW, Butterfield MI, Lieberman JA, Shampine LJ. (2005) Deficits in the GABAergic neuroactive steroid allopregnanolone in Alzheimer’s disease and relevance to neuropathological disease stage: investigations in temporal cortex. Proc 44th Annual Meeting of the American College of Neuropsychopharmacology, Wailkoloa, Hawaii, p S79 (Abstract 7)Google Scholar
  38. 38.
    Naylor JC, Hulette CM, Steffens DC, Shampine LJ, Ervin JF, Payne VM, Massing MW, Kilts JD, Strauss JL, Calhoun PS, Calnaido RP, Blazer DG, Lieberman JA, Madison RD, Marx CE. (2008) Cerebrospinal fluid dehydroepiandrosterone levels are correlated with brain dehydroepiandrosterone levels, elevated in Alzheimer’s disease, and related with neuropathological disease stage. J Clin Endocrinol Metab; 93:3178–3178CrossRefGoogle Scholar
  39. 39.
    Wolf OT, Neumann O, Hellhammer DH, Geiben AC, Strasburger CJ, Dressendörfer RA, Pirke KM, Kirschbaum C. (1997) Effects of a two week physiological dehydroepiandrosterone substitution on cognitive performance and well-being in healthy elderly women and men. J Clin Endocrinol Metab 82:2363–2367PubMedCrossRefGoogle Scholar
  40. 40.
    Wolf OT, Neumann O, Hellhammer DH, Kirschbaum C. (1998) Effects of dehydroepiandrosterone replacement in elderly men on event-related potentials, memory and well-being. J Gerontol A Biol Sci Med Sci 53:M385–M390PubMedCrossRefGoogle Scholar
  41. 41.
    Wolf OT, Kudielka BM, Hellhammer DH, Hellhammer J, Kirschbaum C. (1998) Opposing effects of DHEA replacement in elderly subjects on declarative memory and attention after exposure to a laboratory stressor. Psychoneuroendocrinology 23:617–629PubMedCrossRefGoogle Scholar
  42. 42.
    Van Niekerk JK, Huppert FA, Herbert J. (2001) Salivary cortisol and DHEA: association with measures of cognition and well-being in normal older men, and effect of three months of DHEA supplementation. Psychoneuroendocrinology 26:591–612PubMedCrossRefGoogle Scholar
  43. 43.
    Barnhart KT, Freeman E, Grisso JA, Rader DJ, Sammel M, Kapoor S, Nestler JE. (1999) The effect of deydroepiandrosterone supplementation to symptomatic perimenopausal women on serum endocrine profiles, lipid parameters, and healthrelated quality of life. J Clin Endocrinol Metab 84(11): 3896–3902PubMedCrossRefGoogle Scholar
  44. 44.
    Wolkowitz OM, Kramer JH, Reus VI, Costa MM, Yaffe K, Walton P, Raskind M, Peskind E, Newhouse P, Sack D, De Souza E, Sadowsky C, Roberts E; DHEAAlzheimer’s Disease Collaborative Research. (2003) DHEA treatment of Alzheimer’s disease: a randomized, double-blind, placebo-controlled study. Neurology Apr 8;60(7):1071–1076.PubMedGoogle Scholar
  45. 45.
    Huppert FA, Van Niekerk JK. (2007) WITHDRAWN: deydroepiandrosterone (DHEA) supplementation for cognitive function. Cochrane Database Syst Rev 18(2):CD000304Google Scholar
  46. 46.
    Markowski M, Ungeheuer M, Bitran D, Locurto C. (2001) Memory-enhancing effects of DHEAS in aged mice on a win-shift water escape task. Physiol Behav 72:521–525PubMedCrossRefGoogle Scholar
  47. 47.
    Fedotova J, Sapronov N. (2004) Behavioural effects of dehydroepiandrosterone in adult male rats. Prog Neuropsychopharmacol Biol Psychiatry 28:1023–1027PubMedCrossRefGoogle Scholar
  48. 48.
    Farr SA, Banks WA, Uezu K, Gaskin FS, Morley JE. (2004) DHEAS improves learning and memory in aged SAMP8 mice but not in diabetic mice. Life Sci 75:2775–2785PubMedCrossRefGoogle Scholar
  49. 49.
    Sujkovic E, Mileusnic R, Fry JP, Rose SP. (2007) Temporal effects of dehydroepiandrosterone sulphate on memory formation in day-old chicks. Neuroscience 148:375–384PubMedCrossRefGoogle Scholar
  50. 50.
    Lamberts SWJ, van den Beld AW, van der Lely AJ. (1997) The endocrinology of aging. Science 278:419–424.PubMedCrossRefGoogle Scholar
  51. 51.
    Gouras GK, Xu H, Gross RS, Greenfield JP, Hai B, Wang R, Greengard P. (2000) Testosterone reduces neuronal secretion of Alzheimer’s beta-amyloid peptides. Proc Natl Acad Sci USA 97:1202–1205.PubMedCrossRefGoogle Scholar
  52. 52.
    Kerr JE, Allore RJ, Beck SG, Handa RJ. (1995) Distribution and hormonal regulation of androgen receptor (AR) and AR messenger ribonucleic acid in the rat hippocampus. Endocrinology 136:3213–3221PubMedCrossRefGoogle Scholar
  53. 53.
    Leranth C, Petnehazy O, MacLusky NJ. (2003) Gonadal hormones affect spine synaptic density in the CA1 hippocampal subfield of male rats. J Neurosci 23:1588–1592.PubMedGoogle Scholar
  54. 54.
    Simerly RB, Chang C, Muramatsu M, Swanson LW. (1990) Distribution of androgen and estrogen receptor mRNA-containing cells in the rat brain: and in situ hybridization study. J Comp Neurol 294:76–95PubMedCrossRefGoogle Scholar
  55. 55.
    Brown TJ, Sharma M, Karsan N, Walters MJ, MacLusky NJ. (1995) In vitro autoradiographic measurement of gonadal steroid receptors in brain tissue sections. Steroids 60:726–737.PubMedCrossRefGoogle Scholar
  56. 56.
    Pomerantz SM, Sholl SA. (1987) Analysis of sex and regional differences in androgen receptors in fetal rhesus monkey brain. Brain Res 433:151–154.PubMedGoogle Scholar
  57. 57.
    Choate JV, Slayden OD, Resko JA. (1998) Immunocytochemical localization of androgen receptors in brains of developing and adult male rhesus monkeys. Endocrine 8:51–60.PubMedCrossRefGoogle Scholar
  58. 58.
    Roselli CE, Klosterman S, Resko JA. (2001) Anatomic relationships between aromatase and androgen receptor mRNA expression in the hypothalamus and amygdala of adult male cynomolgus monkeys. J Comp Neurol 439:208–223PubMedCrossRefGoogle Scholar
  59. 59.
    Clancy AN, Bonsall RW, Michael RP. (1992) Immunohistochemical labelling of androgen receptors in the brain of rat and monkey. Life Sci 50:409–417.PubMedCrossRefGoogle Scholar
  60. 60.
    Bachevalier J, Hagger C (1991) Sex differences in the development of learning abilities in primates. Psychoneuroendocrinology 16:177–188.PubMedCrossRefGoogle Scholar
  61. 61.
    Clark AS, Goldman-Rakic PS. (1989) Gonadal hormones influence the emergence of cortical function in nonhuman primates. Behav Neurosci 103:1287–1295PubMedCrossRefGoogle Scholar
  62. 62.
    Rosario ER, Carroll J, Pike CJ. (2010) Testosterone regulation of Alzheimer-like neuropathology in male 3xTg-AD mice involves both estrogens andandrogens pathways. Brain Research;1359:281–290CrossRefGoogle Scholar
  63. 63.
    Pouliot WA, Handa RJ, Beck SG. (1996) Androgen modulates N-methyl-daspartate-mediated depolarization in CA1 hippocampal pyramidal cells. Synapse 23:10–19PubMedCrossRefGoogle Scholar
  64. 64.
    Morse JK, DeKosky ST, Scheff SW. (1992) Neurotrophic effects of steroids on lesion-induced growth in the hippocampus. II. Hormone replacement. Exp Neurol 118:47–52PubMedCrossRefGoogle Scholar
  65. 65.
    Tirassa P, Thiblin I, Agren G, Vigneti E, Aloe L, Stenfors C. (1997) High-dose anabolic androgenic steroids modulate concentrations of nerve growth factor and expression of its low affinity receptor (p75-NGFr) in male rat brain. J Neurosci Res 47:198–207PubMedCrossRefGoogle Scholar
  66. 66.
    Pike CJ, Carroll JC, Rosario ER, Barron AM. (2009) Protective actions of sex steroid hormones in Alzheimer disease. Frontiers in Neuroendocrinology 30 239–258. ReviewPubMedCrossRefGoogle Scholar
  67. 67.
    Gandy S, Almeida OV, Fonte J, Lim D, Waterrus A, Spray N, Flicker N, Martins RN. (2001) Chemical andropause and -amyloid peptide. JAMA May 2;285(17):2195–2196CrossRefGoogle Scholar
  68. 68.
    Raber J, Bongers G, LeFevour A, Buttini M, Mucke L. (2002) Androgens protect against apolipoprotein E4-induced cognitive deficits. J Neurosci 22:5204–5209PubMedGoogle Scholar
  69. 69.
    Raber J. (2004) Androgens, apoE, and Alzheimer’s disease. Science Aging Knowl Environ 2004:1–11Google Scholar
  70. 70.
    Hogervorst E, Lehmann DJ, Warden DR, McBroom J, Smith AD. (2002) Apolipoprotein E epsilon4 and testosterone interact in the risk of Alzheimer’s disease in men. Int J Geriatr Psychiatry 17:938–940PubMedCrossRefGoogle Scholar
  71. 71.
    Panizzon MS, Hauger R, Dale AM, Eyler LJ, Fischl B, Fennema-Notestine C, Franz CE, Grant MD, Jak AJ, Jacobson KJ et al. (2010) Testosterone modifies the effect of APO E genotype on hippocampal volume in middle-aged men. Neurology 75:874–880PubMedCrossRefGoogle Scholar
  72. 72.
    Lehmann DJ, Hogervorst E, Warden DR, Smith AD, Butler HD, Ragoussis J. (2004) The androgen receptor CAGrepeat and serum testosterone in the risk of Alzheimer’s disease in men. J Neurol Neurosurg Psychiatry 75;163–171Google Scholar
  73. 73.
    Kovacs D, Vassos E, Liu X, Sun X, Hu J, Breen G, Tompa P, Collier DA, Li T. (2009) The androgen receptor gene polyglycine repeat polymorphism is associated with memory performance in Chinese individuals. Psyconeuroendocrinology 34;947–952Google Scholar
  74. 74.
    Lee DM, Ulubaev A, Tajar A, Pye SR, Pendleton N, Purandare N, O’Neill TW, O’Connor DB, Labrie F, Platt D, Payne D, Bartfai G, Boonen F, Casanueva SS, Finn JD, Forti G, Giwercman A, Han TS, Huhtaniemi IT, Kula K, Lean ME, Punab B, Silman AJ, Vandershueren D, Wu FC; EMAS Study Group. (2010) Endogenous hormones, androgen receptor CAG repeat length and fluid cognition in middle-aged and older men: results from the European Male Ageing Study. Eur J Endocrinol Jun;162(6):1155–1164. Epub 2010 Mar 15PubMedCrossRefGoogle Scholar
  75. 75.
    Moffat SD, Hampson E. (1996) A curvilinear relationship between testosterone and spatial cognition in humans: possible influence of hand preference. Psychoneuroendocrinology 21:323–337PubMedCrossRefGoogle Scholar
  76. 76.
    Muller M, Aleman A, Grobbee DE, De Haan EH, van der Schouw YT. (2005) Endogenous sex hormone levels and cognitive function in aging men: is there an optimal level? Neurology 64:866–871PubMedCrossRefGoogle Scholar
  77. 77.
    Yaffe K, Lui LY, Zmuda J, Cauley J. (2002) Sex hormones and cognitive function in older men. J Am Geriatr Soc 50:707–712.PubMedCrossRefGoogle Scholar
  78. 78.
    Moffat SD, Zonderman AB, Metter EJ, Blackman MR, Harman SM, Resnick SM. (2002) Longitudinal assessment of serum free testosterone concentration predicts memory performance and cognitive status in elderly men. J Clin Endocrinol Metab 87:5001–5007PubMedCrossRefGoogle Scholar
  79. 79.
    Martin DM, Wittert G, Burns NR, Haren MT, Sugarman R. (2007) Testosterone and cognitive function in ageing men: data from the Florey Adelaide Male Aging Study (FAMAS). Maturitas 57:182–194PubMedCrossRefGoogle Scholar
  80. 80.
    Chu LW, Tam S, Wong RL, Yik PY, Song Y, Cheung BM, Morley JE, Lam KS. (2010) Bioavailable testosterone predicts a lower risk of Alzheimer’s Disease in older men. J Alzheimers Dis Aug 6. Epub ahead of print.Google Scholar
  81. 81.
    Chu LW, Tam S, Lee PWH, Wong RLC, Yik PY, Tsui W, Song Y, Cheung BMY, Morley JE, Lam KSL. (2008) Bioavailable testosterone is associated with a reduced risk of amnestic mild cognitive impairment in older men. Clin Endocrinol 68:589–598.CrossRefGoogle Scholar
  82. 82.
    Yeap BB, Almeida OP, Hyde Z, Chubb SAP, Hankey GJ, Jamrozik K, Flicker R. (2008) Higher serum free testosterone is associated with better cognitive function in older men, while total testosterone is not. The Health In Men Study. Clin Endocrinol 68; 404–412Google Scholar
  83. 83.
    Maggio M, Ceda GP, Lauretani F, Bandinelli S, Metter EJ, Guralnik JK, Basaria S, Cattabiani C, Luci M, Dall’Aglio E, Vignali A, Volpi R, Valenti G, Ferrucci L. (2010) Gonadal Status and physical performance in older men. 92th Endo Society Annual Meeting Abstract Book 2010.Google Scholar
  84. 84.
    Beer TM, Bland LB, Bussiere JR, Neiss MB, Wersinger EM, Garzotto M, Ryan CW, Janowsky JS. (2006) Testosterone loss and estradiol administration modify memory in men. J Urol Jan 175;130–135CrossRefGoogle Scholar
  85. 85.
    Nelson CJ, Lee JS, Gamboa MC, Roth AJ. (2008) Cognitive effects of hormone therapy in men with prostate cancer. Cancer;113:1097–11PubMedCrossRefGoogle Scholar
  86. 86.
    Alibhai SMH, Mahmoud S, Hussain F, Naglie G, Tannock I, Tomlinson G, Fleshner N, Krahn M, Warde P, Klots L, Breunis H, Leach M, Canning SD. (2010) Leveles of sex hormones have limited effect on cognition in older men with or without prostate cancer. Critical Reviews in Oncology and Hematology 73:167–175CrossRefGoogle Scholar
  87. 87.
    Wolf OT, Kirschbaum C. (2002) Endogenous estradiol and testosterone levels are associated with cognitive performance in older women and men. Horm and Behavior 41:259–266CrossRefGoogle Scholar
  88. 88.
    Lessov-Schlaggar CN, Reed T, Swan GE, krasnow RE, DeCarli C, Marcus R, Holloway L, Wolf PA, Carmelli D. (2005) Association of sex steroid hormones with brain morphology and cognition in healthy elderly men. Neurology 65:1591–1596PubMedCrossRefGoogle Scholar
  89. 89.
    Yonker JE; Eriksson E, Nilsson LG, Herlitz A. (2006) Negative association of testosterone on spatial visualization in 35 to 50 years old men. Cortex Apr;42(3):376–386PubMedCrossRefGoogle Scholar
  90. 90.
    Janowsky JS, Oviatt SK, Orwoll ES. (1994) Testosterone influences spatial cognition in older men. Behav. Neurosci 108:325–332.PubMedCrossRefGoogle Scholar
  91. 91.
    Postma A, Meyer G, Tuiten A, van Honk J, Kessels RP, Thijssen J. (2000) Effects of testosterone administration on selective aspects of object-location memory in healthy young women. Psychoneuroendocrinology 25:563–575.PubMedCrossRefGoogle Scholar
  92. 92.
    Wolf OT, Preut R, Hellhammer DH, Kudielka BM, Schurmeyer TH, Kirschbaum C. (2000) Testosterone and cognition in elderly men: a single testosterone injection blocks the practice effect in verbal fluency, but has no effect on spatial or verbal memory. Biol. Psychiatry 47:650–654.PubMedCrossRefGoogle Scholar
  93. 93.
    Cherrier MM, Asthana S, Plymate S, Baker L, Matsumoto AM, Peskind E, Raskind MA, Brodkin K, Bremner W, Petrova A, LaTendresse S, Craft S. (2001) Testosterone supplementation improves spatial and verbal memory in healthy older men. Neurology 57:80–88.PubMedGoogle Scholar
  94. 94.
    Cherrier MM, Anawalt BD, Herbst KL, Amory JK, Craft S, Matsumoto AM, Bremner WJ. (2002) Cognitive effects of short-term manipulation of serum sex steroids in healthy young men. J. Clin. Endocrinol. Metab 87:3090–3096.PubMedCrossRefGoogle Scholar
  95. 95.
    Cherrier MM, Matsumoto AM, Amory JK, Asthana S, Bremner W, Peskind ER, Raskind MA, Craft S. (2005) Testosterone improves spatial memory in men with Alzheimer disease and mild cognitive impairment. Neurology 64;2063–2068PubMedCrossRefGoogle Scholar
  96. 96.
    Fukai S, Akishita M, Yamada S, Toba K, Ouchi Y. (2010) Effects of testosterone in older men with mild-to-moderate cognitive impairment. J Am Geriatr Soc 58:1419–1421.PubMedCrossRefGoogle Scholar
  97. 97.
    Haren MT, Wittert GA, Chapman IM, Coates P, Morley JE. (2005) Effects of oral testosterone undecanoate on visuospatial cognition, mood and quality of life in elderly men with low-normal gonadal status. Maturitas 50:124–133PubMedCrossRefGoogle Scholar
  98. 98.
    Vaughan C, Goldstein FC, Tenover JL. (2007) Exogenous testosterone alone or with finasteride does not improve measurements of cognition in healthy older men with low serum testosterone. J Androl 28:875–882.PubMedCrossRefGoogle Scholar
  99. 99.
    Emmelot-Vonk MH, Verhaar HJ, Nakhai Pour HR, Aleman A, Lock TM, Bosch JL, Grobbee DE, van der Schouw YT. (2008) Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial. JAMA Jan 2;299(1):39–52.CrossRefGoogle Scholar
  100. 100.
    Maki PM, Ernst M, London ED, Merdecai KL, Perschler P, Durso SC, Brandt J, Dobs A, Resnick SM. (2007) Intramuscular testosterone treatment in elderly men: evidence of memory decline and altered brain function. J Clin Endocrinol Metab Nov;92(11):4107–4114. Epub 2007 Aug 28.PubMedCrossRefGoogle Scholar
  101. 101.
    Lu Ph, Masterman DA, Mulnard R, Cotman C, Miller, Yaffe K, Reback E, Porter V, Swerdloff R, Cummings JL. (2006) Effects of testosterone on cognition and mood in male patients with mild Alzheimer disease and healthy elderly men. Arch Neurol Feb;63(2):177–185. Epub 2005 Dec 12.PubMedCrossRefGoogle Scholar
  102. 102.
    Asthana S, Craft S, Baker LD, Raskind MA, Birnbaum RS, Lofgreen CP, Veith RC, Plymate SR. (1999) Cognitive and neuroendocrine response to transdermal estrogen in postmenopausal women with Alzheimer’s disease: results of a placebo-controlled, double-blind, pilot study. Psychoneuroendocrinology 24:657–677.PubMedCrossRefGoogle Scholar
  103. 103.
    Hogervorst E, Boshuisen M, Riedel W, Willeken C, Jolles J. (1999) Richter Award. The effect of hormone replacement therapy on cognitive function in elderly women. Psychoneuroendocrinology 24:43–68.PubMedCrossRefGoogle Scholar
  104. 104.
    Miles C, Green R, Sanders G, Hines M. (1998) Estrogen and memory in a transsexual population. Horm Behav 34:199–208PubMedCrossRefGoogle Scholar
  105. 105.
    Barrett-Connor E, Goodman-Gruen D, Patay B. (1999) Endogenous sex hormones and cognitive function in older men. J Clin Endocrinol Metab 84: 3681–3685.PubMedCrossRefGoogle Scholar
  106. 106.
    Yaffe K, Lui LY, Grady D, Cauley J, Kramer J, Cummings SR. (2000) Cognitive decline in women in relation to non-protein-bound oestradiol concentration. Lancet 356:708–712.PubMedCrossRefGoogle Scholar
  107. 107.
    Geerlings MI, Lauren LJ, de Jong FH, Ruitenberg A, Stijnen T, van Swieten JC, Hofman A, Witteman JC, Pols HA, Breteler MM; Rotterdam Study. (2003) Endogenous estradiol and risk of dementia in women and men: The Rotterdam Study. Ann Neurol 53:607–615.PubMedCrossRefGoogle Scholar
  108. 108.
    Shumaker SA, Legault C, Rapp SR, Thal L, Wallace RB, Ockene JK, Hendrix SL, Jones BN 3rd, Assaf AR, Jackson RD, Kotchen JM, Wassertheil-Smoller S, Wactawski-Wende J; WHIMS Investigators. (2003) Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. JAMA 289:2651–2662PubMedCrossRefGoogle Scholar
  109. 109.
    Muller M, van den Beld AW, Grobbee DE, de Jong FH, Lamberts SW. (2009) Sex hormones and cognitive decline in elderly men. Psychoneuroendocrinology 34:27–31PubMedCrossRefGoogle Scholar
  110. 110.
    Laughlin GA, Kritz-Silverstein D, Barrett-Connor E. (2010) Endogenous oestrogens predict 4-year decline in verbal fluency in postmenopausal women: the Rancho Bernardo Study. Clin Endocrinol 72:99–106CrossRefGoogle Scholar
  111. 111.
    Le Blanc ES, Wang PY, Janowsky JS, Neiss MB, Fink HA, Yaffe K, Marshall LM, Lapidus JA, Stefanick ML, Orwoll ES; Osteoporotic Fractures in Men (MrOS) Research Group. (2010) Association between sex steroids and cognition in elderly men. Clin Endocrinol 72(3); 393–403CrossRefGoogle Scholar
  112. 112.
    Rosario ER, Chang L, Stanczyk FZ, Pike CJ. (2004) Age-related testosterone depletion and the development of Alzheimer disease. JAMA 292(12): 1431–1432PubMedCrossRefGoogle Scholar
  113. 113.
    Corpas E, Harman SM, Blackman MR. (1993) Human growth hormone and human aging. Endocr Rev 14:20–39PubMedGoogle Scholar
  114. 114.
    Hoffman AR, Pyka G, Lieberman SA, et al. (1993) The somatopause. In: Muller EE, Cocchi D, Locatelli V, eds. Growth hormone and somatomedins during lifespan. Berlin: Springer VerlagGoogle Scholar
  115. 115.
    Jörgensen JOL, Pedersen SA, Thuesen L, Jørgensen J, Ingemann-Hansen T, Skakkebaek NE, Christiansen JS. (1989) Beneficial effects of GH treatment in GHD adults. Lancet 1:1221–1225.PubMedCrossRefGoogle Scholar
  116. 116.
    Rudman D, Feller AG, Nagraj HS, Gergans GA, Lalitha PY, Goldberg AF, Schlenker RA, Cohn L, Rudman IW, Mattson DE. (1990) Effects of human growth hormone in men over 60 years old. N Engl J Med 323:1–6.PubMedCrossRefGoogle Scholar
  117. 117.
    Papadakis MA, Grady D, Black D, Tierney MJ, Gooding GA, Schamberlan M, Grunfeld C. (1996) Growth hormone replacement in healthy older men improves body composition but not functional ability. Ann Int Med 124:708–716.PubMedGoogle Scholar
  118. 118.
    Sartorio A, Conti A, Molinari E, Riva G, Morabito F, Faglia G. (1996) Growth, growth hormone and cognitive functions. Horm Res 45:23–29.PubMedCrossRefGoogle Scholar
  119. 119.
    Kelijman M. (1991) Age related alterations of the growth hormone/insulin-like growth factor I axis. J Am Geriatr Soc 39:295–307.PubMedGoogle Scholar
  120. 120.
    Bondy CA, Cheng CM. (2004) Signalling by insulin-like growth factor 1 in brain. Eur J Pharmacol 490:25–31PubMedCrossRefGoogle Scholar
  121. 121.
    Carro E, Torrs-Aleman I. (2006) Serum Isulin-like growth factor I in brain function. Keio J Med 55 (2): 59–63PubMedCrossRefGoogle Scholar
  122. 122.
    Trejo J, Piriz J, Llorens-Martin MV, Fernandez AM, Bolós M, LeRoith D, Nuñez A, Torres-Aleman I. (2007) Central actions of liver-derived insulin-like growth factor I underlying its pro-cognitive effects. Mol. Psychiatry 12, 1118–1128PubMedCrossRefGoogle Scholar
  123. 123.
    Sonntag WE, Bennett SA, Khan AS, Thornton PL, Xu X, Ingram RL, Brunso-Bechtold JK. (2000) Age and insulin-like growth factor-1 modulate N-methyl-Daspartate receptor subtype expression in rats. Brain Res. Bull. 51, 331–338.PubMedCrossRefGoogle Scholar
  124. 124.
    Aleman A, Torres-Aleman I. (2009) Circulating insulin-like growth factor I and cognitive function: neuromodulation throughout the lifespan. Progress in Neurobiology 89 256–265Google Scholar
  125. 125.
    Paolisso G, Ammendola S, Del Buono A, Gambardella A, Riondino M, Tagliamonte MR, Rizzo MR, Carella C, Varricchio M. (1997) Serum levels of insulinlike growth factor-I (IGF-I) and IGF-I binding protein-3 in healthy centenarians: relationship with plasma leptin and lipid concentrations, insulin action and cognitive function. J Clin Endocrinol Metab 82:2204–2209PubMedCrossRefGoogle Scholar
  126. 126.
    Aleman A, Verhaar HJJ, de Haan EHF, De Vries WR, Samson MM, Drent ML, Van der Veen EA, Koppeschaar HP. (1999) Insulin-like growth factor-I and cognitive function in healthy older men. J Clin Endocrinol Metab 84:471–475.PubMedCrossRefGoogle Scholar
  127. 127.
    Rollero A, Murialdo G, Fonzi S, Garrone S, Gianelli S, Gazzerro E, Barreca A, Polleri A. (1998) Relationship between cognitive function, growth hormone and insulin-like growth factor I plasma levels in aged subjects. Neuropsychobiology 38:73–79.PubMedCrossRefGoogle Scholar
  128. 128.
    Abbott D, Rotnem D, Genel M, Cohen DJ. (1982) Cognitive and emotional functioning in hypopituitary short-statured children. Schizophr Bull 8:310–319.PubMedGoogle Scholar
  129. 129.
    Siegel PT. (1990) Intellectual and academic functioning in children with growth delay. In: Holmes CS, ed. Psychoneuroendocrinology; brain, behavior and hormonal interactions. New York: Springer-VerlagGoogle Scholar
  130. 130.
    Deijen JB, de Boer H, Blok GJ, van der Veen EA. (1996) Cognitive impairments and mood disturbances in growth hormone deficient men. Psychoneuroendocrinology 21:313–322PubMedCrossRefGoogle Scholar
  131. 131.
    Kalmijn S, Janssen JA, Pols HA, Lamberts SW, Breteler MM. (2000) A prospective study on circulating insulin-like growth factor I (IGF-I), IGF-binding proteins, and cognitive function in the elderly. J Clin Endocrinol Metab Dec;85(12):4551–4555.PubMedCrossRefGoogle Scholar
  132. 132.
    Zelissen PMJ, Heijnen VA, Koppeschaar, HPF, De Haan EHF, Hijman R. (1995) Neuropsychological profile in growth hormone deficient adults: preliminary results. In: Von Werder R, Stalla GK, Clemmons DR, Gunnarsson R, eds. Proc 20th International Symposium on Growth Hormone and Growth Factors in Endocrinology and Metabolism, Berlin, Sept., 138Google Scholar
  133. 133.
    Papadakis MA, Grady D, Tierney MJ, Black D, Wells L, Grunfeld C. (1995) Insulinlike growth factor 1 and functional status in healthy older men. J Am Geriatr Soc. 43, 1350–1355PubMedGoogle Scholar
  134. 134.
    Dik MG, Pluijmm SM, Jonker C, Deeg DJ, Lomecky MZ, Lips P. (2003) Insulinlike growth factor I (IGF-I) and cognitive decline in older persons. Neurobiol. Aging 24, 573–581.PubMedCrossRefGoogle Scholar
  135. 135.
    Roberts LM, Pattison H, Roalfe A, Franklyn J, Wilson S, Hobbs FD, Parle JV. (2006) Is subclinical thyroid dysfunction in the elderly associated with depression or cognitive dysfunction? Ann Intern Med 145:573–581PubMedGoogle Scholar
  136. 136.
    Wilson S, Parle JV, Roberts LM, Roalfe AK, Hobbs FD, Clark P, Sheppard MC, Gammage MD, Pattison HM, Franklyn JA; Birmingham Elderly Thyroid Study Team. (2006) Prevalence of subclinical thyroid dysfunction and its relation to socioeconomic deprivation in the elderly: A community-based cross-sectional survey. J Clin Endocrinol Metab 9:4809–4816CrossRefGoogle Scholar
  137. 137.
    Aghini-Lombardi F, Antonangeli L, Marino E, Vitti P, Maccherini D, Leoli F, Rago T, Grasso L, Valeriano R, Balestrieri A, Pinchera A.(1999) The spectrum of thyroid disorders in an iodine-deficient community: The Pescopagano survay. J Clin Endocrinol Metab 84:561–566.PubMedCrossRefGoogle Scholar
  138. 138.
    Cooper DS. (2004) Subclinical thyroid disease: consensus or conundrum? Clin Endocrinol 60:410–412.CrossRefGoogle Scholar
  139. 139.
    Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, Franklyn JA, Hershman JM, Burman KD, Denke MA, Gorman C, Cooper RS, Weissman NJ. (2004) Subclinical thyroid disease. Scientific Review and Guidelines for Diagnosis and Management. JAMA 291:228–238.PubMedCrossRefGoogle Scholar
  140. 140.
    Trentin GA. (2006) Thyroid hormones and astrocyte morphogenesis. Journal of Endocrinology; 189:189–197.PubMedCrossRefGoogle Scholar
  141. 141.
    Nedel Mendes-de-Aguiar CB, Alchini R, Decker H, Alvarez-Silva M, Tasca CI, Trentin AG. (2008) Thyroid hormone Increases Astrocytic Glutamate Uptake and Protects Astrocytes and neurons against Glutamate Toxicity. J Neurosci Res 86;3117-3125.Google Scholar
  142. 142.
    Ceresini G, Lauretani F, Maggio M, Ceda GP, Moranti S, Usberti E, Chezzi C, Valcavi R, Bandinelli S, Guralnick JM, Cappola AR, Valenti G, Ferrucci L. (2009) Thyroid function abnormalities and cognitive impairment in the elderly. Results of the InCHIANTI study. J Am Geriatr Soc; 57(1):89–93PubMedCrossRefGoogle Scholar
  143. 143.
    Gussekloo J, vanExel E, de Craen AJ, Meinders AE, Frölich M, Westendorp RG. (2004) Thyroid status, disability and cognitive function, and survival in old age. JAMA 292:2591–2599.PubMedCrossRefGoogle Scholar
  144. 144.
    Jorde R, Waterloo K, Storhaugh H, Nyrnes A, Sundsfjord J, Jenssen TG. (2006) Neuropsychological function and symptoms in subjects with subclinical hypothyroidism and the effect of thyroxine treatment. J Clin Endocrinol Metab 91:145–153.PubMedCrossRefGoogle Scholar
  145. 145.
    Kalmijn S, Mehta KM, Pols HA, Hofman A, Drexhage HA, Breteler MM. (2000) Subclinical hyperthyroidism and the risk of dementia. The Rotterdam study. Clin Endocrinol 53:733–737.CrossRefGoogle Scholar
  146. 146.
    Etgen T, Bickel H, Förstl H. (2010) Metabolic and endocrine factors in mild cognitive impairment. Ageing Res Review 9:280–288CrossRefGoogle Scholar
  147. 147.
    Roberts LM, Pattison H, Roalfe A, Franklyn J, Wilson S, Hobbs FD, Parle JV. (2006) Is subclinical thyroid dysfunction in the elderly associated with depression or cognitive dysfunction? Ann. Intern. Med. 145, 573–581PubMedGoogle Scholar
  148. 148.
    Ceresini G, Lauretani F, Maggio M, Ceda GP, Morganti S, Usberti E, Chezzi C, Valcavi R, Bandinelli S, Guralnik JM, Cappola AR, Valenti G, Ferrucci L. (2009) Thyroid function abnormalities and cognitive impairment in the Elderly. Results of the InCHIANTI Study. J Am Geriatr Soc 57:89–93.PubMedCrossRefGoogle Scholar
  149. 149.
    Quinlan P, Nordlund A, Lind K, Gustafson D, Edman A, Wallin A. (2010) Thyroid Hormones are associated with poorer cognition in mild cognitive impairment. Dement Geriatr Cogn Disord. 26;30(3):205–211. [Epub ahead of print]PubMedCrossRefGoogle Scholar
  150. 150.
    Biondi B, Cooper DS. (2008) The clinical significance of subclinical thyroid dysfunction. Endocr Rev 29:76–131PubMedCrossRefGoogle Scholar
  151. 151.
    Parle J, Roberts L, Wilson S, Pattison H, Roalfe A, Haque MS, Heath C, Sheppard M, Franklyn J, Hobbs FD. (2010) A randomized controlled trial of the effect of thyroxine replacement on cognitive function in community-living elderly subjects with subclinical hypothyroidism: The Birmingham Elderly Thyroid Study. J Clin Endocrinol Metab 95:3623–3632PubMedCrossRefGoogle Scholar
  152. 152.
    Jaeschke R, Guyatt G, Gerstein H, Patterson C, Molloy W, Cook D, Harper S, Griffith L, Carbotte R. (1996) Does treatment with L-thyroxine influence health status in middle age and older adults with subclinical hypothyroidism? J Gen Intern Med 11:744–749.PubMedCrossRefGoogle Scholar
  153. 153.
    Maggio M, Lauretani F, Ceda GP, Bandinelli S, Ling SM, Metter EJ, Artoni A, Carassale L, Cazzato A, Ceresini G, Guralnik JM, Basaria S, Valenti G, Ferrucci L. (2007) Relationship between low levels of anabolic hormones and 6-years mortality in older men: the aging in the Chianti Area (InCHIANTI) Study. Arch Intern Med 167:2249–2254.PubMedCrossRefGoogle Scholar

Copyright information

© Serdi and Springer Verlag France 2012

Authors and Affiliations

  • Marcello Maggio
    • 1
    • 5
  • E. Dall’Aglio
    • 1
  • F. Lauretani
    • 2
  • C. Cattabiani
    • 1
  • G. Ceresini
    • 1
  • P. Caffarra
    • 3
    • 4
  • G. Valenti
    • 1
  • R. Volpi
    • 1
  • A. Vignali
    • 1
  • G. Schiavi
    • 1
  • G. P. Ceda
    • 1
    • 2
  1. 1.Department of Internal Medicine and Biomedical Sciences, Section of GeriatricsUniversity of ParmaParmaItaly
  2. 2.Geriatric Unit and Laboratory of Movement Analysis, Geriatric-Rehabilitation, DepartmentUniversity HospitalParmaItaly
  3. 3.Department of NeuroscienceUniversity of ParmaParmaItaly
  4. 4.Clinical Neuroscience CentreUniversity of HullHullUK
  5. 5.Department of Internal Medicine and Biomedical Sciences, Section of GeriatricsUniversity of ParmaParmaItaly

Personalised recommendations