Advertisement

Hormones

pp 1–12 | Cite as

Neurocognitive impairment in type 2 diabetes mellitus

  • Marianna KarvaniEmail author
  • P. Simos
  • S. Stavrakaki
  • D. Kapoukranidou
Historical Note

Abstract

There is emerging evidence that cognitive impairment could be a diabetes mellitus-related complication. It has been suggested that diabetic people are at increased risk of cognitive decline, since the metabolic and vascular disturbances of the disease affect brain function. Additionally, prolonged exposure to olther potential detrimental factors leads to irreversible cognitive decrements over time due to the aging process. Neurocognitive impairment signifies decreased performance in cognitive domains such as verbal and nonverbal memory, both immediate and delayed memory, executive function, attention, visuospatial and psychomotor performance, information processing speed, semantic knowledge, and language abilities. The aim of the present article is to review the existing literature on the issue of the neurocognitive decline in type 2 diabetes. A literature search of databases was performed, using as keywords “diabetes” and “cognitive impairment,” and the reference list of papers so identified were examined, with only English language papers being used. Understanding and preventing diabetes-associated cognitive deficits remains a key priority for future research. It is important to ascertain whether interventions to delay diabetes onset or better control of established disease could prevent some of its adverse effects on cognitive skills.

Keywords

Type 2 diabetes Cognitive impairment 

Notes

References

  1. 1.
    Harris MI, Klein R, Welborn TA, Knulman MW (1992) Onset of NIDDM occurs at least 4-7 yr before clinical diagnosis. Diabetes Care 15(7):815–819CrossRefGoogle Scholar
  2. 2.
    Dye L, Boyle NB, Champ C, Lawton C (2017) The relationship between obesity and cognitive health and decline. Proc Nutr Soc 74(4):443–444.  https://doi.org/10.1017/S0029665117002014 CrossRefGoogle Scholar
  3. 3.
    Miles WR, Root HF (1922) Psychologic tests applied to diabetic patients. Arch Int Med 30(6):767–777CrossRefGoogle Scholar
  4. 4.
    Yates KF, Sweat V, Yau PL, Turchiano MM (2012) Impact of metabolic syndrome on cognition and brain: a selected review of the literature. Arterioscler Tromb Vasc Biol 32(9):2060–2067.  https://doi.org/10.1161/ATVBAHA.112.252759 CrossRefGoogle Scholar
  5. 5.
    Moheet A, Mangia S, Seaquist ER (2015) Impact of diabetes on cognitive function and brain structure. Ann N Y Acad Sci 1353:60–71.  https://doi.org/10.1111/nyas.12807 CrossRefGoogle Scholar
  6. 6.
    Pal K, Mukadam N, Petersen I, Cooper C (2018) Mild cognitive impairment and progression to dementia in people with diabetes, prediabetes and metabolic syndrome: a systematic review and meta-analysis. Soc Psychiatry Psychiatr Epidemiol 53:1149–1160.  https://doi.org/10.1007/s00127-018-1581-3 CrossRefGoogle Scholar
  7. 7.
    Moon JH (2016) Endocrine risk factors for cognitive impairment. Endocrinol Metab 31:185–192.  https://doi.org/10.3803/EnM.2016.31.2.185 CrossRefGoogle Scholar
  8. 8.
    de la Monte SM, Wands JR (2008) Alzheimer’s disease is type 3 diabetes-evidence reviewed. J Diabetes Sci Technol 2:1101–1113.  https://doi.org/10.1177/193229680800200619
  9. 9.
    van den Berg E, de Craen AJM, Biessels GJ, Gussekloo J, Westendorp RGJ (2006) The impact of diabetes mellitus to cognitive decline in the oldest of the old: a prospective population-based study. Diabetologia 49:2015–2023CrossRefGoogle Scholar
  10. 10.
    van den Berg E, Kloppenborg RP, Kessels RPC, Kappelle LJ, Biessels GJ (2009) Type 2 diabetes mellitus, hypertension, dyslipidemia and obesity: a systematic comparison of their impact on cognition. Biochim Biophys Acta 1792(5):470–481.  https://doi.org/10.1016/j.bbadis.2008.09.004 CrossRefGoogle Scholar
  11. 11.
    Pasquier F (2010) Diabetes and cognitive impairment: how to evaluate the cognitive status? Diabetes Metab 36(Suppl 3):S100–S105.  https://doi.org/10.1016/S1262-3636(10)70475-4 CrossRefGoogle Scholar
  12. 12.
    Dobi A, Bravo SB, Veeren B et al (2019) Advanced glycation end-products disrupt human endothelial cells redox homeostasis: new insights into reactive oxygen species production. Free Radic Res 1:1–20.  https://doi.org/10.1080/10715762.2018.1529866 Google Scholar
  13. 13.
    Ito F, Sono Y, Ito T (2019) Measurement and clinical significance of lipid peroxidation as a biomarker of oxidative stress: oxidative stress in diabetes, atherosclerosis, and chronic inflammation. Antioxidants (Basel) 25(3):8.  https://doi.org/10.3390/antiox8030072 Google Scholar
  14. 14.
    Solanki I, Parihar P, Shetty R, Parihar MS (2017) Synaptosomal and mitochondrial oxidative damage followed by behavioral impairments in streptozocin induced diabetes mellitus: restoration by Malvastrum tricuspidatum. Cell Mol Biol 63(7):94–101.  https://doi.org/10.14715/cmb/2017.63.7.16 CrossRefGoogle Scholar
  15. 15.
    Cho HJ, Xie C, Cai H (2018) AGE- induced neuronal cell death is enhanced in G2019S LRRK2 mutation with increased RAGE expression. Transl Neurodegener 7:1.  https://doi.org/10.1186/s40035-018-0106-z CrossRefGoogle Scholar
  16. 16.
    Cooray G, Nilsson E, Wahlin A et al (2011) Effects of intensified metabolic control on CNS function in type 2 diabetes. Psychoneuroendocrinology 36(1):77–86.  https://doi.org/10.1016/j.psyneuen.2010.06.009 CrossRefGoogle Scholar
  17. 17.
    Pappas C, Andel R, Infurna FJ, Setharaman S (2017) Glycated haemoglobin (HbA1c), diabetes and trajectories of change in episodic memory performance. J Epidemiol Community Health 71(2):115–120.  https://doi.org/10.1136/jech-2016-207588 CrossRefGoogle Scholar
  18. 18.
    Breitling LP, Olsen H, Müller H et al (2014) Self- or physician-reported diabetes, glycemia markers, and cognitive functioning in older adults in Germany. Am J Geriatr Psychiatry 22(11):1105–1115.  https://doi.org/10.1016/j.jagp.2013.06.004 CrossRefGoogle Scholar
  19. 19.
    Schneider ALC, Selvin E, Sharrett AR et al (2017) Diabetes, prediabetes, and brain volumes and subclinical cerebrovascular disease on MRI: the atherosclerosis risk in communities neurocognitive study (ARIC- NCS). Diabetes Care 40(11):1514–1521.  https://doi.org/10.2337/dc17-1185 CrossRefGoogle Scholar
  20. 20.
    Bitra VR, Rapaka D, Akula A (2015) Prediabetes and Alzheimer’s disease. Indian J Pharm Sci 77(5):511–514CrossRefGoogle Scholar
  21. 21.
    Ganmore I, Beeri MS (2018) The chicken or the egg? Does glycaemic control predict cognitive function or the other way around? Diabetologia 61(9):1913–1917.  https://doi.org/10.1007/s00125-018-4689-9 CrossRefGoogle Scholar
  22. 22.
    Anstey KJ, Sargent-Cox K, Eramudugolla R, Magliano DJ, Shaw JE (2015) Association of cognitive function with glucose tolerance and trajectories of glucose tolerance over 12 years in the AusDiab study. Alzheimers Res Ther 7(1):48.  https://doi.org/10.1186/s13195-015-0131-4 CrossRefGoogle Scholar
  23. 23.
    Lamport DJ, Chadwick HK, Dye L, Mansfield MW, Lawton CL (2014) A low glycaemic load breakfast can attenuate cognitive impairments observed in middle aged obese females with impaired glucose tolerance. Nutr Metab Cardiovasc Dis 24(10):1128–1136.  https://doi.org/10.1016/j.numecd.2014.04.015 CrossRefGoogle Scholar
  24. 24.
    Welters A, Klüppel C, Mrugala J et al (2017) NMDAR antagonists for the treatment of diabetes mellitus- current status and future directions. Diabetes Obes Metab 19(Suppl 1):95–106.  https://doi.org/10.1111/dom.13017 CrossRefGoogle Scholar
  25. 25.
    Bie-Olsen LG, Kjaer TW, Pedersen-Bjergaard U et al (2009) Changes of cognition and regional cerebral activity during acute hypoglycemia in normal subjects: a H2 150 positron emission tomographic study. J Neurosci Res 87(8):1922–1928.  https://doi.org/10.1002/jnr.22002 CrossRefGoogle Scholar
  26. 26.
    McMillan JM, Mele BS, Hogan DB, Leung AA (2018) Impact of pharmacological treatment of diabetes mellitus on dementia risk: systematic review and meta-analysis. BMJ Open Diab Res Care 16(1):6.  https://doi.org/10.1135/bmjdrc-2018-000563 Google Scholar
  27. 27.
    Ojo O, Brooke J (2015) Evaluating the association between diabetes, cognitive decline and dementia. Int J Environ Res Public Health 12(7):8281–8294.  https://doi.org/10.3390/ijerph120708281 CrossRefGoogle Scholar
  28. 28.
    Lin CH, Sheu WH (2013) Hypoglycaemic episodes and risk of dementia in diabetes mellitus: 7 year follow up study. J Intern Med 273(1):102–110.  https://doi.org/10.1111/joim.12000 CrossRefGoogle Scholar
  29. 29.
    Tuligenga RH (2015) Intensive glycemic control and cognitive decline in patients with type 2 diabetes: a meta-analysis. Endocr Connect 4(2):R16–R24.  https://doi.org/10.1530/EC-15-0004 CrossRefGoogle Scholar
  30. 30.
    Murray AM, Hsu FC, Williamson JD et al (2017) ACCORDION MIND: results of the observational extension of the ACCORD MIND randomized trial. Diabetologia 60(1):69–80CrossRefGoogle Scholar
  31. 31.
    Kawamura T, Umemura T, Hotta N (2012) Cognitive impairment in diabetic patients: can diabetic control prevent cognitive decline? Journal of Diabetes Investigation 3(5):413–423.  https://doi.org/10.1111/j.2040-1124.2012.00234.x CrossRefGoogle Scholar
  32. 32.
    Umegaki H (2014) Type 2 diabetes as a risk factor for cognitive impairment: current insights. Clin Interv Aging 9:1011–1019.  https://doi.org/10.2147/CIA.548926 CrossRefGoogle Scholar
  33. 33.
    Molnár G, Faragó N, Kocsis ÁK et al (2014) GABAergic neurogliaform cells represent local sources of insulin in the cerebral cortex. J Neurosci 34(4):1133–1137.  https://doi.org/10.1523/JNEUROSCI.4082-13.2014 CrossRefGoogle Scholar
  34. 34.
    Kern W, Peters A, Fruehwald-Schultes B et al (2001) Improving influence of insulin on cognitive functions in humans. Neuroendocrinology 74(4):270–280CrossRefGoogle Scholar
  35. 35.
    Kullmann S, Heni M, Hallschmid M et al (2016) Brain insulin resistance at the crossroads of metabolic and cognitive disorders in humans. Physiol Rev 96(4):1169–1209.  https://doi.org/10.1152/physrev.00032.2015 CrossRefGoogle Scholar
  36. 36.
    Hu DH, Li YL, Liang ZJ et al (2018) Long-term high-fat diet inhibits hippocampal expression of insulin receptor substrates and accelerates cognitive deterioration in obese rats. Nan Fang Yi Ke Da Xue Xue Bao 38(4):460–465Google Scholar
  37. 37.
    de Nazareth AM (2017) Type 2 diabetes mellitus in the pathophysiology of Alzheimer’s disease. Dement Neuropsychol 11(2):105–113.  https://doi.org/10.1590/1980-57642016dn11-020002 CrossRefGoogle Scholar
  38. 38.
    Tumminia A, Vinciquerra F, Parisi M, Frittitta L (2018) Type 2 diabetes mellitus and Alzheimer’s disease: role of insulin signalling and therapeutic implications. Int J Mol Sci 24:19 (11).  https://doi.org/10.3390/ijms19113306 Google Scholar
  39. 39.
    Wang H, Chen F, Du YF et al (2018) Targeted inhibition of RAGE reduces amyloid-β influx across the blood-brain barrier and improves cognitive deficits in db/db mice. Neuropharmacology 131:143–153.  https://doi.org/10.1016/j.neuropharm.2017.12.026 CrossRefGoogle Scholar
  40. 40.
    Butterfield DA, Domenico FD, Barone E (2014) Elevated risk of type 2 diabetes for development of Alzheimer disease: a key role for oxidative stress in brain. Biochim Biophys Acta 1482(9):1693–1706.  https://doi.org/10.1016/j.bbadis.2014.06.010 CrossRefGoogle Scholar
  41. 41.
    Leino M, Popova SN, Alafuzoff I (2017) Transactive DNA binding protein 43 rather than other misfolded proteins in the brain is associated with islet amyloid polypeptide in pancreas in aged subjects with diabetes mellitus. J Alzheimer Dis 59(1):43–56.  https://doi.org/10.3233/JAD-170192 CrossRefGoogle Scholar
  42. 42.
    Rivera EJ, Goldin A, Fulmer N et al (2005) Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer’s disease: link to brain reductions in acetylcholine. J Alzheimers Dis 8(3):247–268CrossRefGoogle Scholar
  43. 43.
    Zhou X, Zhu Q, Han X et al (2015) Quantitative-profiling of neurotransmitter abnormalities in the disease progression of experimental diabetic encephalopathy rat. Can J Physiol Pharmacol 93(11):1007–1013.  https://doi.org/10.1139/cjpp-2015-0118 CrossRefGoogle Scholar
  44. 44.
    Moganti K, Li F, Schmuttermaier C et al (2017) Hyperglycemia induces mixed M1/M2 cytokine profile in primary human monocyte-derived macrophages. Immunobiology 222(10):952–959.  https://doi.org/10.1016/j.imbio.2016.07.006 CrossRefGoogle Scholar
  45. 45.
    Zhang Y, Bai J, Wu H, Ying JY (2015) Trapping cells in paper for white blood cell count. Biosens Bioelectron 69:121–127.  https://doi.org/10.1016/j.bios.2015.02.019 CrossRefGoogle Scholar
  46. 46.
    Zhen J, Lin T, Huang X et al (2018) Association of ApoE genetic polymorphism and type 2 diabetes with cognition in non-demented aging Chinese adults: a community based cross-sectional study. Aging Dis 9(3):346–357.  https://doi.org/10.14336/AD.2017.0715 CrossRefGoogle Scholar
  47. 47.
    van Eersel MAE, Joosen H, Gansevoort RT et al (2013) The interaction of age and type 2 diabetes on executive function and memory in persons aged 35 years or older. PLoS One 8(12).  https://doi.org/10.1371/journal.pone.0082991
  48. 48.
    Kino T, Chrousos GP (2005) Glucocorticoid effects on gene expression. In: Steckler T, Kalin NH, Reul JMHM (eds) Handbook of stress and the brain. Elsevier B.V, Amsterdam, pp 295–311Google Scholar
  49. 49.
    Bruehl H, Wolf OT, Sweat V et al (2009) Modifiers of cognitive function and brain structure in middle-aged and elderly individuals with type 2 diabetes mellitus. Brain Res 14(1280):186–194.  https://doi.org/10.1016/j.brainres.2009.05.032 CrossRefGoogle Scholar
  50. 50.
    Dey A, Hao S, Erion JR et al (2014) Glucocorticoid sensitization of microglia in a genetic mouse model of obesity and diabetes. J Neuroimmuno 269(1–2):20–27.  https://doi.org/10.1016/j.jneuroim.2014.01.013 CrossRefGoogle Scholar
  51. 51.
    Nader N, Chrousos GP, Kino T (2010) Interactions of the circadian CLOCK system and the HPA axis. Trends Endocrinol Metab 21(5):277–286.  https://doi.org/10.1016/j.tem.2009.12.011 CrossRefGoogle Scholar
  52. 52.
    Lee JH, Choi Y, Jun C et al (2014) Neurocognitive changes and their neural correlates in patients with type 2 diabetes mellitus. Endocrinol Metab (Seoul) 29(2):112–121.  https://doi.org/10.3803/EnM.2014.29.2.112
  53. 53.
    Cui D, Liu X, Liu M et al (2019) Subcortical gray matter structural alterations in prediabetes and type 2 diabetes. Neuroreport 30(6):441–445.  https://doi.org/10.1097/WNR.0000000000001224 CrossRefGoogle Scholar
  54. 54.
    Rawlings AM, Sharrett AR, Schneider AL et al (2014) Diabetes in midlife and cognitive change over 20 years: a cohort study. Ann Intern Med 161(11):785–793.  https://doi.org/10.7326/M14-0737 CrossRefGoogle Scholar
  55. 55.
    Xiong Y, Sui Y, Zhang S et al (2018) Brain microstructural alterations in type 2 diabetes: diffusion kurtosis imaging provides added value to diffusion tensor imaging. Eur Radiol 24(9):1997–2008.  https://doi.org/10.1007/s00330-018-5746-y Google Scholar
  56. 56.
    Zhang Y, Cao Y, Xie Y et al (2019) Altered brain structural topological properties in type 2 diabetes mellitus patients without complications. J Diabetes 11(2):129–138.  https://doi.org/10.1111/1753-0407.12826 CrossRefGoogle Scholar
  57. 57.
    Tan X, Liang Y, Zeng H et al (2019) Altered functional connectivity of the posterior cingulate cortex in type 2 diabetes with cognitive impairment. Brain Imaging Behav 5.  https://doi.org/10.1007/s11682-018-0017-8
  58. 58.
    Liu D, Duan S, Zhou C et al (2018) Altered brain functional hubs and connectivity in type 2 diabetes mellitus patients: a resting-state fMRI study. Front Aging Neurosci 6(10):55.  https://doi.org/10.3389/fnagi.2018.00055 CrossRefGoogle Scholar
  59. 59.
    Chen Y, Liu Z, Zhang J et al (2014) Altered brain activation patterns under different working memory loads in patients with type 2 diabetes. Diabetes Care 37(12):3157–3163.  https://doi.org/10.2337/dc14-1683 CrossRefGoogle Scholar
  60. 60.
    Arnold SE, Arvanitakis Z, Macauley-Rambach SL et al (2018) Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums. Nat Rev Neurol 14(3):168–181.  https://doi.org/10.1038/nrneurol.2017.185 CrossRefGoogle Scholar
  61. 61.
    Stehouwer CDA (2018) Microvascular dysfunction and hyperglycemia: a vicious cycle with widespread consequences. Diabetes 67(9):1729–1741.  https://doi.org/10.2337/dbi17-0044 ReviewCrossRefGoogle Scholar
  62. 62.
    Hugenschmidt CE, Lovato JF, Ambrosius WT et al (2014) The cross-sectional and longitudinal associations of diabetic retinopathy with cognitive function and brain MRI findings: the action to control cardiovascular risk in diabetes (ACCORD) trial. Diabetes Care 37:3244–3252.  https://doi.org/10.2337/dc14-0502 CrossRefGoogle Scholar
  63. 63.
    de la Monte SM, Wands JR (2005) Review of insulin, insulin-like growth factor expression, signaling, and malfunction in the central nervous system: relevance to Alzheimer’s disease. Journal of Alzheimer’s disease: JAD 7:45–61CrossRefGoogle Scholar
  64. 64.
    Balakumar P, Maung-U K, Jagadeesh G (2016) Prevalence and prevention of cardiovascular disease and diabetes mellitus. Pharmacol Res 113(Pt A):600–609.  https://doi.org/10.1016/j.phrs.2016.09.040 CrossRefGoogle Scholar
  65. 65.
    Emerging Risk Factors Collaboration, Sarwar N, Gao P, Seshasai SR et al (2010) Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet 375(9733):2215–2222.  https://doi.org/10.1016/S0140-6736(10)60484-9 CrossRefGoogle Scholar
  66. 66.
    Van Dyken P, Lacoste B (2018) Impact of metabolic syndrome on neuroinflammation and the blood-brain barrier. Front Neurosci 12:930.  https://doi.org/10.3389/fnins.2018.00930 CrossRefGoogle Scholar
  67. 67.
    Jin L, Li YP, Feng Q et al (2018) Cognitive deficits and Alzheimer-like neuropathological impairments during adolescence in a rat model of type 2 diabetes mellitus. Neural Regen Res 13(11):1995–2004.  https://doi.org/10.4103/1673-5374.239448 CrossRefGoogle Scholar
  68. 68.
    Mahmood SS, Levy D, Vasan RS, Wang TJ (2014) The Framingham Heart Study and the epidemiology of cardiovascular disease: a historical perspective. Lancet 383(9921):999–1008.  https://doi.org/10.1016/S0140-6736(13)61752-3 CrossRefGoogle Scholar
  69. 69.
    Palta P, Huang ES, Kalyani RR et al (2017) Hemoglobin A1c and mortality in older adults with and without diabetes: results from the National Health and Nutrition Examination Surveys (1988-2011). Diabetes Care 40(4):453–460.  https://doi.org/10.2337/dci16-0042 CrossRefGoogle Scholar
  70. 70.
    Zilliox LA, Chadrasekaran K, Kwan JY, Russell JW (2016) Diabetes and cognitive impairment. Curr Diab Rep 16(9):87.  https://doi.org/10.1007/s11892-016-0775-x CrossRefGoogle Scholar
  71. 71.
    van Gemert T, Wölwer W, Weber KS et al (2018) Cognitive function is impaired in patients with recently diagnosed type 2 diabetes, but not type 1 diabetes. J Diabetes Res 9:1470476.  https://doi.org/10.1155/1470476 Google Scholar
  72. 72.
    Rojas-Carranza CA, Bustos-Cruz RH, Pino-Pinzon CJ et al (2018) Diabetes-related neurological implications and pharmacogenomics. Curr Pharm Des 24(15):1695–1710.  https://doi.org/10.2174/1381612823666170317165350 CrossRefGoogle Scholar
  73. 73.
    Goh DA, Dong Y, Lee WY et al (2014) A pilot study to examine the correlation between cognition and blood biomarkers in a Singapore Chinese male cohort with type 2 diabetes mellitus. PLoS One 9(5):e96874.  https://doi.org/10.1371/journal.pone.0096874.eCollection CrossRefGoogle Scholar
  74. 74.
    Zhao WQ, Alkon DL (2001) Role of insulin and insulin receptor in learning and memory. Mol Cell Endocrinol 177(1–2):125–134CrossRefGoogle Scholar
  75. 75.
    Laakso M, Kuusisto J (2017) Diabetes secondary to treatment with statins. Curr Diab Rep 17(2):10.  https://doi.org/10.1007/s11892-017-0837-8 CrossRefGoogle Scholar
  76. 76.
    Martinac M, Pehar D, Karlović D et al (2014) Metabolic syndrome, activity of the hypothalamic-pituitary-adrenal axis and inflammatory mediators in depressive disorder. Acta Clin Croat 53(1):55–71Google Scholar
  77. 77.
    Wardlaw JM, Smith EE, Biessels GJ et al (2013b) Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol 12(8):822–838.  https://doi.org/10.1016/S1474-4422(13)70124-8 CrossRefGoogle Scholar
  78. 78.
    Rensma SP, van Sloten TT, Launer LJ, Stehouwer CDA (2018) Cerebral small vessel disease and risk of incident stroke, dementia and depression, and all-cause mortality: a systematic review and, meta-analysis. Neurosci Biobehav Rev 90:164–173.  https://doi.org/10.1016/j.neubiorev.2018.04.003 CrossRefGoogle Scholar
  79. 79.
    Gradman TJ, Laws A, Thompson LW, Reaven GM (1993) Verbal learning and/or memory improves with glycaemic control in older subjects with non-insulin-dependent diabetes mellitus. J Am Geriatr Soc 41(12):1305–1312CrossRefGoogle Scholar

Copyright information

© Hellenic Endocrine Society 2019

Authors and Affiliations

  • Marianna Karvani
    • 1
    Email author
  • P. Simos
    • 2
  • S. Stavrakaki
    • 3
  • D. Kapoukranidou
    • 4
  1. 1.Department of Physiology, School of MedicineAristotle University of ThessalonikiThessalonikiGreece
  2. 2.Department of Psychiatry and Behavioral Sciences, School of MedicineUniversity of CreteHerakleion, CreteGreece
  3. 3.Department of Italian Language and Literature, School of PhilosophyAristotle University of ThessalonikiThessalonikiGreece
  4. 4.Department of Physiology, School of MedicineAristotle University of ThessalonikiThessalonikiGreece

Personalised recommendations