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Cognitive impairment and dementia: a new emerging complication of type 2 diabetes—The diabetologist’s perspective

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Abstract

Type 2 diabetes mellitus (T2D) and Alzheimer’s disease (AD) are two of the most common diseases of aging around the world. Given the frequency with which T2D and AD occur, the notion that people with T2D may be at increased risk for AD has large societal consequences, and understanding the mechanistic links between these diseases is imperative for the development of effective AD prevention and treatment strategies. Apart from being an accelerator of AD, T2D is associated with a progressive cognitive decline. Impaired insulin signaling, inflammation, the accumulation of advanced glycation end-products and oxidative stress all play an essential role in the pathogenesis of both AD and diabetic complications. Therefore, it is reasonable to postulate that these pathways are involved in the increased risk of dementia that occurs in the T2D population. The early diagnosis of cognitive impairment and the identification of the subset of patients at a higher risk of developing AD is a challenge for healthcare providers, and meeting it will permit us to implement a personalized medicine, which is an essential issue in diabetes care with significant therapeutic implications. The main gaps that should be filled to achieve this objective are examined.

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References

  1. Biessels GJ, Staekenborg S, Brunner E, Brayne C, Scheltens P (2006) Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol 5:64–74

    Article  PubMed  Google Scholar 

  2. Kopf D, Frölich L (2009) Risk of incident alzheimer’s disease in diabetic patients: a systematic review of prospective trials. J Alzheimer Dis 16:677–685

    Article  Google Scholar 

  3. Guariguata L, Nolan T, Beagley J, Linnenkamp U, Jacqmain O (2014) International Diabetes Federation diabetes atlas. International Diabetes Federation, Brussels

    Google Scholar 

  4. Thies W, Bleiler L, Alzheimer’s Association (2013) Alzheimer’s disease facts and figures. Alzheimer Dement 9:208–245

    Article  Google Scholar 

  5. Koekkoek P, Kappelle LJ, van den Berg E, Rutten GEH, Biessels GJ (2015) Cognitive function in patients with diabetes mellitus: guidance for daily care. Lancet Neurol 14:329–340

    Article  PubMed  Google Scholar 

  6. Wang KC, Woung LC, Tsai MT, Liu CC, Su YH, Li CY (2012) Risk of alzheimer’s disease in relation to diabetes: a population-based cohort study. Neuroepidemiology 38:237–244

    Article  PubMed  Google Scholar 

  7. Huang CC, Chung CM, Leu HB et al (2014) Diabetes mellitus and the risk of alzheimer’s disease: a nationwide population-based study. PLoS One 9:e87095

    Article  PubMed  PubMed Central  Google Scholar 

  8. Xu WL, von Strauss E, Qiu CX, Winblad B, Fratiglioni L (2009) Uncontrolled diabetes increases the risk of alzheimer’s disease: a population-based cohort study. Diabetologia 52:1031–1039

    Article  CAS  PubMed  Google Scholar 

  9. Tuligenga RH, Dugravot A, Tabák AG et al (2014) Midlife type 2 diabetes and poor glycemic control as risk factors for cognitive decline in early old age: a post hoc analysis of the Whitehall cohort study. Lancet Diabetes Endocrinol 2:228–235

    Article  PubMed  PubMed Central  Google Scholar 

  10. Xu W, Qiu C, Gatz M, Pedersen NL, Johansson B, Fratiglioni L (2009) Mid- and late-life diabetes in relation to the risk of dementia: a population-based twin study. Diabetes 58:71–77

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Tolppanen AM, Lavikainen P, Solomon A et al (2013) History of medically treated diabetes and risk of alzheimer disease in a nationwide case-control study. Diabetes Care 36:2015–2019

    Article  PubMed  PubMed Central  Google Scholar 

  12. De Felice FG, Ferreira ST (2014) Inflammation, defective insulin signaling, and mitochondrial dysfunction as common molecular denominators connecting type 2 diabetes to alzheimer disease. Diabetes 63:2262–2272

    Article  PubMed  Google Scholar 

  13. Baglietto-Vargas D, Shi J, Yaeger DM, Ager R, LaFerla FM (2016) Diabetes and alzheimer’s disease crosstalk. Neurosci Biobehav Rev 64:272–287

    Article  CAS  PubMed  Google Scholar 

  14. Whitmer RA, Kater AJ, Yaffe K, Quesenberry CP, Selby JV (2009) Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus. JAMA 301:1565–1572

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Feinkohl I, Aung PP, Keller M et al (2014) Severe hypoglycemia and cognitive decline in older people with type 2 diabetes: the Edinburgh type 2 diabetes study. Diabetes Care 37:507–515

    Article  CAS  PubMed  Google Scholar 

  16. Koekkoek PS, Janssen J, Kooistra M et al (2016) Case-finding for cognitive impairment among people with type 2 diabetes in primary care using test your memory and self-administered gerocognitive examination questionnaires: the Cog-ID study. Diabet Med 33:812–819

    Article  CAS  PubMed  Google Scholar 

  17. Exalto LG, Biessels GJ, Karter AJ et al (2013) Risk score for prediction of 10 year dementia risk in individuals with type 2 diabetes: a cohort study. Lancet Diabetes Endocrinol 1:183–190

    Article  PubMed  PubMed Central  Google Scholar 

  18. Sullivan MD, Katon WJ, Lovato LC et al (2013) Association of depression with accelerated cognitive decline among patients with type 2 diabetes in the ACCORD-MIND trial. JAMA Psychiatry 70:1041–1047

    Article  PubMed  PubMed Central  Google Scholar 

  19. Biessels GJ, Reijmer YD (2014) Brain changes underlying cognitive dysfunction in diabetes: what can we learn from MRI? Diabetes 63:2244–2252

    Article  PubMed  Google Scholar 

  20. Wisse LE, de Bresser J, Geerlings MI et al (2014) Global brain atrophy but not hippocampal atrophy is related to type 2 diabetes. J Neurol Sci 344:32–36

    Article  PubMed  Google Scholar 

  21. De Flores R, La Joie R, Chételat G (2015) Structural imaging of hippocampal subfields in healthy aging and alzheimer’s disease. Neuroscience 309:29–50

    Article  PubMed  Google Scholar 

  22. Biessels GJ, Reagan LP (2015) Hippocampal insulin resistance and cognitive dysfunction. Nat Rev Neurosci 16:660–671

    Article  CAS  PubMed  Google Scholar 

  23. Willette AA, Xu G, Johnson SC et al (2013) Insulin resistance, brain atrophy, and cognitive performance in late middle-aged adults. Diabetes Care 36:443–449

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Raffield LM, Cox AJ, Freedman BI et al (2016) Analysis of the relationships between type 2 diabetes status, glycemic control, and neuroimaging measures in the diabetes heart study mind. Acta Diabetol 53:439–447

    Article  CAS  PubMed  Google Scholar 

  25. 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

    Article  PubMed  PubMed Central  Google Scholar 

  26. Exalto LG, Biessels GJ, Karter AJ, Huang ES, Quesenberry CP, Whitmer RA (2014) Severe diabetic retinal disease and dementia risk in type 2 diabetes. J Alzheimer Dis 42(Suppl 3):S109–S117

    Google Scholar 

  27. de Bresser J, Reijmer YD, van der Exalto E et al (2010) Microvascular determinants of cognitive decline and brain volume change in elderly patients with type 2 diabetes. Dement Geriatr Cogn Disord 30:381–386

    Article  PubMed  Google Scholar 

  28. Barzilay JI, Lovato JF, Murray AM et al (2013) Albuminuria and cognitive decline in people with diabetes and normal renal function. Clin J Am Soc Nephrol 8:1907–1914

    Article  PubMed  PubMed Central  Google Scholar 

  29. Lin CH, Sheu WHH (2013) Hypoglycaemic episodes and risk of dementia in diabetes mellitus: 7-year follow-up study. J Intern Med 273:102–110

    Article  PubMed  Google Scholar 

  30. Mattishent K, Loke YK (2016) Bi-directional interaction between hypoglycaemia and cognitive impairment in elderly patients treated with glucose-lowering agents: a systematic review and meta-analysis. Diabetes Obes Metab 18(2):135–141

    Article  CAS  PubMed  Google Scholar 

  31. Zhang Z, Lovato J, Battapady H et al (2014) Effect of hypoglycemia on brain structure in people with type 2 diabetes: epidemiological analysis of the ACCORD-MIND MRI trial. Diabetes Care 37(12):3279–3285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Rizzo MR, Marfella R, Barbieri M et al (2010) Relationship between daily acute glucose fluctuations and cognitive performance among type 2 diabetic patients. Diabetes Care 33:2169–2174

    Article  PubMed  PubMed Central  Google Scholar 

  33. Rizzo MR, Barbieri M, Boccardi V, Angellotti E, Marfella R, Paolisso G (2014) Dipeptidyl peptidase-4 inhibitors have protective effect on cognitive impairment in aged diabetic patients with mild cognitive impairment. J Gerontol A Biol Sci Med Sci 69:1122–1131

    Article  PubMed  Google Scholar 

  34. Marciani E, Pomati S, Ramolfo P et al (2013) Evaluation of retinal nerve fiber layer and ganglion cell layer thickness in alzheimer’s disease using spectral-domain optical coherence tomography. Invest Ophthalmol Vis Sci 54:5953–5958

    Article  Google Scholar 

  35. Frost S, Kanagasingam Y, Macaulay L, Koronyo-Hamaoui M, Koronyo Y, Biggs D (2014) Retinal amyloid fluorescence imaging predicts cerebral amyloid burden and alzheimer’s disease. Alzheimer Dement 10:234–235

    Article  Google Scholar 

  36. Simó R, Hernández C, European consortium for the early treatment of diabetic retinopathy (EUROCONDOR) (2014) Neurodegeneration in the diabetic eye: new insights and therapeutic perspectives. Trends Endocrinol Metab 25:23–33

    Article  PubMed  Google Scholar 

  37. Trento M, Durando O, Lavecchia S et al (2016) Vision related quality of life in patients with type 2 diabetes in the EUROCONDOR trial. Endocrine. doi:10.1007/s12020-016-1097-0

    PubMed  Google Scholar 

  38. Trento M, Charrier L, Salassa M et al (2016) Cognitive function may be a predictor of retinopathy progression in patients with type 2 diabetes. Eur J Ophthalmol. doi:10.5301/ejo.5000885

    PubMed  Google Scholar 

  39. American Diabetes Association (2013) Clinical practice recommendations. Diabetes Care 36(Suppl 1):S3

    Google Scholar 

  40. Nicolucci A, Pintaudi B, Rossi MC et al (2015) The social burden of hypoglycemia in the elderly. Acta Diabetol 52:677–685

    Article  CAS  PubMed  Google Scholar 

  41. Hölscher C (2014) Insulin, incretins and other growth factors as potential novel treatments for alzheimer’s and parkinson’s diseases. Biochem Soc Trans 42:593–599

    Article  PubMed  Google Scholar 

  42. Hernández C, Bogdanov P, Corraliza L et al (2016) Topical administration of GLP-1 receptor agonists prevents retinal neurodegeneration in experimental diabetes. Diabetes 65:172–187

    PubMed  Google Scholar 

  43. Heneka MT, Fink A, Doblhammer G (2015) Effect of pioglitazone medication on the incidence of dementia. Ann Neurol 78(2):284–294

    Article  CAS  PubMed  Google Scholar 

  44. Galimberti D, Scarpini E (2017) Pioglitazone for the treatment of alzheimer’s disease. Expert Opin Investig Drugs 26(1):97–101

    Article  CAS  PubMed  Google Scholar 

  45. Risner ME, Saunders AM, Altman JF et al (2006) Rosiglitazone in alzheimer’s disease study group. Pharmacogenomics J. 6(4):246–254

    CAS  PubMed  Google Scholar 

  46. Chen Y, Zhang J, Zhang B, Gong CX (2016) Targeting insulin signaling for the treatment of alzheimer’s disease. Curr Top Med Chem 16:485–492

    Article  CAS  PubMed  Google Scholar 

  47. Claxton A, Baker LD, Hanson A et al (2015) Long-acting intranasal insulin detemir improves cognition for adults with mild cognitive impairment or early-stage alzheimer’s disease dementia. J Alzheimer Dis 44:897–906

    CAS  Google Scholar 

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Acknowledgements

The authors’ work is funded by the European Foundation for the Study of Diabetes (EFSD/Lilly-Mental Health and Diabetes Programme) and the Agència de Gestió d’Ajuts Universitaris i de Recerca (2014 SGR 270). The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript.

Author contributions

RS, AC, OS, and CH all took part in the intellectual discussions leading up to the review. RS and CH wrote the manuscript, which was approved by all authors. RS is the guarantor of this work and, as such, has full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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Authors and Affiliations

  1. Diabetes and Metabolism Research Unit, Vall d’Hebron Research Institute, Universitat Autònoma de Barcelona, Pg. Vall d’Hebron 119-129, 08035, Barcelona, Spain

    Rafael Simó, Andreea Ciudin, Olga Simó-Servat & Cristina Hernández

  2. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain

    Rafael Simó, Andreea Ciudin, Olga Simó-Servat & Cristina Hernández

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  1. Rafael Simó
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  4. Cristina Hernández
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Correspondence to Rafael Simó.

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Simó, R., Ciudin, A., Simó-Servat, O. et al. Cognitive impairment and dementia: a new emerging complication of type 2 diabetes—The diabetologist’s perspective. Acta Diabetol 54, 417–424 (2017). https://doi.org/10.1007/s00592-017-0970-5

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  • DOI: https://doi.org/10.1007/s00592-017-0970-5

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