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Diabetes and Cognitive Impairment

  • Microvascular Complications—Neuropathy (R Pop-Busui, Section Editor)
  • Published:
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Abstract

Both type 1 (T1DM) and type 2 diabetes mellitus (T2DM) have been associated with reduced performance on multiple domains of cognitive function and with evidence of abnormal structural and functional brain magnetic resonance imaging (MRI). Cognitive deficits may occur at the very earliest stages of diabetes and are further exacerbated by the metabolic syndrome. The duration of diabetes and glycemic control may have an impact on the type and severity of cognitive impairment, but as yet we cannot predict who is at greatest risk of developing cognitive impairment. The pathophysiology of cognitive impairment is multifactorial, although dysfunction in each interconnecting pathway ultimately leads to discordance in metabolic signaling. The pathophysiology includes defects in insulin signaling, autonomic function, neuroinflammatory pathways, mitochondrial (Mt) metabolism, the sirtuin-peroxisome proliferator-activated receptor-gamma co-activator 1α (SIRT-PGC-1α) axis, and Tau signaling. Several promising therapies have been identified in pre-clinical studies, but remain to be validated in clinical trials.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Wong RH, Scholey A, Howe PR. Assessing premorbid cognitive ability in adults with type 2 diabetes mellitus—a review with implications for future intervention studies. Curr Diab Rep. 2014;14(11):547–0547.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  3. Grunblatt E, Bartl J, Riederer P. The link between iron, metabolic syndrome, and Alzheimer's disease. J Neural Transm. 2010;118(3):371-79.

  4. Monette MC, Baird A, Jackson DL. A meta-analysis of cognitive functioning in nondemented adults with type 2 diabetes mellitus. Can J Diabetes. 2014;38(6):401–8. This study examines the pattern and magnitude of cognitive functioning deficits in persons withT2DM without dementia using meta-analysis.

    Article  PubMed  Google Scholar 

  5. Palta P, Schneider AL, Biessels GJ, Touradji P, Hill-Briggs F. Magnitude of cognitive dysfunction in adults with type 2 diabetes: a meta-analysis of six cognitive domains and the most frequently reported neuropsychological tests within domains. J Int Neuropsychol Soc. 2014;20(3):278–91.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Dik MG, Jonker C, Comijs HC, Deeg DJ, Kok A, Yaffe K, et al. Contribution of metabolic syndrome components to cognition in older individuals. Diabetes Care. 2007;30(10):2655–60.

    Article  PubMed  Google Scholar 

  7. Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement. 2013;9(1):63–75.

    Article  PubMed  Google Scholar 

  8. Rizzi L, Rosset I, Roriz-Cruz M. Global epidemiology of dementia: Alzheimer’s and vascular types. Biomed Res Int. 2014;2014:908915. doi:10.1155/2014/908915.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Rawlings AM, Sharrett AR, Schneider AL, Coresh J, Albert M, Couper D, et al. Diabetes in midlife and cognitive change over 20 years: a cohort study. Ann Intern Med. 2014;161(11):785–93.

    Article  PubMed  PubMed Central  Google Scholar 

  10. International Diabetes Federation. IDF diabetes atlas. 7th edn. Brussels: International Diabetes Federation; 2015. http://www.diabetesatlas.org.

  11. Chatterjee S, Peters SA, Woodward M, Mejia AS, Batty GD, Beckett N, et al. Type 2 diabetes as a risk factor for dementia in women compared with men: a pooled analysis of 2.3 million people comprising more than 100,000 cases of dementia. Diabetes Care. 2016;39(2):300–7.

    PubMed  Google Scholar 

  12. de la Monte SM. Brain insulin resistance and deficiency as therapeutic targets in Alzheimer’s disease. Curr Alzheimer Res. 2012;9(1):35–66.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Akter K, Lanza EA, Martin SA, Myronyuk N, Rua M, Raffa RB. Diabetes mellitus and Alzheimer’s disease: shared pathology and treatment? Br J Clin Pharmacol. 2011;71(3):365–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ott A, Stolk RP, van Harskamp F, Pols HA, Hofman A, Breteler MM. Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology. 1999;53(9):1937–42.

    Article  CAS  PubMed  Google Scholar 

  15. Luchsinger JA. Adiposity, hyperinsulinemia, diabetes and Alzheimer’s disease: an epidemiological perspective. Eur J Pharmacol. 2008;585(1):119–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Karan NS. Assessment of the cognitive status in diabetes mellitus. J Clin Diagn Res. 2012;6(10):1658–62.

    PubMed  PubMed Central  Google Scholar 

  17. Crane PK, Walker R, Hubbard RA, Li G, Nathan DM, Zheng H, et al. Glucose levels and risk of dementia. N Engl J Med. 2013;369(6):540–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ohara T, Doi Y, Ninomiya T, Hirakawa Y, Hata J, Iwaki T, et al. Glucose tolerance status and risk of dementia in the community: the Hisayama study. Neurology. 2011;77(12):1126–34.

    Article  CAS  PubMed  Google Scholar 

  19. Whitmer RA. Type 2 diabetes and risk of cognitive impairment and dementia. Curr Neurol Neurosci Rep. 2007;7(5):373–80.

    Article  CAS  PubMed  Google Scholar 

  20. Whitmer RA. The epidemiology of adiposity and dementia. Curr Alzheimer Res. 2007;4(2):117–22.

    Article  CAS  PubMed  Google Scholar 

  21. Gustafson D, Rothenberg E, Blennow K, Steen B, Skoog I. An 18-year follow-up of overweight and risk of Alzheimer disease. Arch Intern Med. 2003;163(13):1524–8.

    Article  PubMed  Google Scholar 

  22. Schnaider BM, Goldbourt U, Silverman JM, Noy S, Schmeidler J, Ravona-Springer R, et al. Diabetes mellitus in midlife and the risk of dementia three decades later. Neurology. 2004;63(10):1902–7.

    Article  Google Scholar 

  23. Xu W, Caracciolo B, Wang HX, Winblad B, Backman L, Qiu C, et al. Accelerated progression from mild cognitive impairment to dementia in people with diabetes. Diabetes. 2010;59(11):2928–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kanaya AM, Barrett-Connor E, Gildengorin G, Yaffe K. Change in cognitive function by glucose tolerance status in older adults: a 4-year prospective study of the Rancho Bernardo study cohort. Arch Intern Med. 2004;164(12):1327–33.

    Article  PubMed  Google Scholar 

  25. Gregg EW, Yaffe K, Cauley JA, Rolka DB, Blackwell TL, Narayan KM, et al. Is diabetes associated with cognitive impairment and cognitive decline among older women? Study of Osteoporotic Fractures Research Group. Arch Intern Med. 2000;160(2):174–80.

    Article  CAS  PubMed  Google Scholar 

  26. van den Berg E, Reijmer YD, de Bresser J, Kessels RP, Kappelle LJ, Biessels GJ. A 4 year follow-up study of cognitive functioning in patients with type 2 diabetes mellitus. Diabetologia. 2010;53(1):58–65.

    Article  PubMed  CAS  Google Scholar 

  27. Garcia-Casares N, Jorge RE, Garcia-Arnes JA, Acion L, Berthier ML, Gonzalez-Alegre P, et al. Cognitive dysfunctions in middle-aged type 2 diabetic patients and neuroimaging correlations: a cross-sectional study. J Alzheimers Dis. 2014;42(4):1337–46.

    CAS  PubMed  Google Scholar 

  28. Moheet A, Mangia S, Seaquist ER. Impact of diabetes on cognitive function and brain structure. Ann N Y Acad Sci. 2015;1353:60–71. doi:10.1111/nyas.12807.

    Article  PubMed  Google Scholar 

  29. Brands AM, Biessels GJ, de Haan EH, Kappelle LJ, Kessels RP. The effects of type 1 diabetes on cognitive performance: a meta-analysis. Diabetes Care. 2005;28(3):726–35.

    Article  PubMed  Google Scholar 

  30. Yaffe K, Blackwell T, Kanaya AM, Davidowitz N, Barrett-Connor E, Krueger K. Diabetes, impaired fasting glucose, and development of cognitive impairment in older women. Neurology. 2004;63(4):658–63.

    Article  CAS  PubMed  Google Scholar 

  31. Hassing LB, Grant MD, Hofer SM, Pedersen NL, Nilsson SE, Berg S, et al. Type 2 diabetes mellitus contributes to cognitive decline in old age: a longitudinal population-based study. J Int Neuropsychol Soc. 2004;10(4):599–607.

    Article  PubMed  Google Scholar 

  32. Cukierman-Yaffe T, Gerstein HC, Williamson JD, Lazar RM, Lovato L, Miller ME, et al. Relationship between baseline glycemic control and cognitive function in individuals with type 2 diabetes and other cardiovascular risk factors: the action to control cardiovascular risk in diabetes-memory in diabetes (ACCORD-MIND) trial. Diabetes Care. 2009;32(2):221–6.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Launer LJ, Miller ME, Williamson JD, Lazar RM, Gerstein HC, Murray AM, et al. Effects of intensive glucose lowering on brain structure and function in people with type 2 diabetes (ACCORD MIND): a randomised open-label substudy. Lancet Neurol. 2011;10(11):969–77.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Erus G, Battapady H, Zhang T, Lovato J, Miller ME, Williamson JD, et al. Spatial patterns of structural brain changes in type 2 diabetic patients and their longitudinal progression with intensive control of blood glucose. Diabetes Care. 2015;38(1):97–104.

    Article  CAS  PubMed  Google Scholar 

  35. Jacobson AM, Musen G, Ryan CM, Silvers N, Cleary P, Waberski B, et al. Long-term effect of diabetes and its treatment on cognitive function. N Engl J Med. 2007;356(18):1842–52.

    Article  PubMed  Google Scholar 

  36. Gaudieri PA, Chen R, Greer TF, Holmes CS. Cognitive function in children with type 1 diabetes: a meta-analysis. Diabetes Care. 2008;31(9):1892–7.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Choi J, Chandrasekaran K, Demarest TG, Kristian T, Xu S, Vijaykumar K, et al. Brain diabetic neurodegeneration segregates with low intrinsic aerobic capacity. Ann Clin Transl Neurol. 2014;1(8):589–604. This paper links mitochondrial p-tau hyperphosphorylation, a marker of AD, with mitochondrial dysfunction in the hippocampus in a rat model of T2DM.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Chen Y, Liu Z, Zhang J, Xu K, Zhang S, Wei D, et al. Altered brain activation patterns under different working memory loads in patients with type 2 diabetes. Diabetes Care. 2014;37(12):3157–63.

    Article  PubMed  Google Scholar 

  39. Cherbuin N, Sachdev P, Anstey KJ. Higher normal fasting plasma glucose is associated with hippocampal atrophy: The PATH Study. Neurology. 2012;79(10):1019–26.

    Article  PubMed  Google Scholar 

  40. Biessels GJ, Reijmer YD. Brain changes underlying cognitive dysfunction in diabetes: what can we learn from MRI? Diabetes. 2014;63(7):2244–52.

    Article  PubMed  Google Scholar 

  41. Marjanska M, Curran GL, Wengenack TM, Henry PG, Bliss RL, Poduslo JF, et al. Monitoring disease progression in transgenic mouse models of Alzheimer’s disease with proton magnetic resonance spectroscopy. Proc Natl Acad Sci U S A. 2005;102(33):11906–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Xu S, Zhuo J, Racz J, Shi D, Roys S, Fiskum G, et al. Early microstructural and metabolic changes following controlled cortical impact injury in rat: a magnetic resonance imaging and spectroscopy study. J Neurotrauma. 2011;28(10):2091–102.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Santhakumari R, Reddy IY, Archana R. Effect of type 2 diabetes mellitus on brain metabolites by using proton magnetic resonance spectroscopy a systematic review. Int J Pharma Bio Sci. 2014;5(4):1118–23.

    PubMed  PubMed Central  Google Scholar 

  44. Abbott MA, Wells DG, Fallon JR. The insulin receptor tyrosine kinase substrate p58/53 and the insulin receptor are components of CNS synapses. J Neurosci. 1999;19(17):7300–8.

    CAS  PubMed  Google Scholar 

  45. Werther GA, Hogg A, Oldfield BJ, McKinley MJ, Figdor R, Mendelsohn FA. Localization and characterization of Insulin-Like Growth Factor-I Receptors in rat brain and pituitary gland using in vitro autoradiography and computerized densitometry* a distinct distribution from insulin receptors. J Neuroendocrinol. 1989;1(5):369–77.

    Article  CAS  PubMed  Google Scholar 

  46. Zhao W, Chen H, Xu H, Moore E, Meiri N, Quon MJ, et al. Brain insulin receptors and spatial memory. Correlated changes in gene expression, tyrosine phosphorylation, and signaling molecules in the hippocampus of water maze trained rats. J Biol Chem. 1999;274(49):34893–902.

    Article  CAS  PubMed  Google Scholar 

  47. Baskin DG, Figlewicz DP, Woods SC, Porte Jr D, Dorsa DM. Insulin in the brain. Annu Rev Physiol. 1987;49:335–47.

    Article  CAS  PubMed  Google Scholar 

  48. Banks WA, Owen JB, Erickson MA. Insulin in the brain: there and back again. Pharmacol Ther. 2012;136(1):82–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Woods SC, Seeley RJ, Baskin DG, Schwartz MW. Insulin and the blood-brain barrier. Curr Pharm Des. 2003;9(10):795–800.

    Article  CAS  PubMed  Google Scholar 

  50. Devaskar SU, Giddings SJ, Rajakumar PA, Carnaghi LR, Menon RK, Zahm DS. Insulin gene expression and insulin synthesis in mammalian neuronal cells. J Biol Chem. 1994;269(11):8445–54.

    CAS  PubMed  Google Scholar 

  51. Devaskar SU, Singh BS, Carnaghi LR, Rajakumar PA, Giddings SJ. Insulin II gene expression in rat central nervous system. Regul Pept. 1993;48:55–63.

    Article  CAS  PubMed  Google Scholar 

  52. Kuwabara T, Kagalwala MN, Onuma Y, Ito Y, Warashina M, Terashima K, et al. Insulin biosynthesis in neuronal progenitors derived from adult hippocampus and the olfactory bulb. EMBO Mol Med. 2011;3(12):742–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Skeberdis VA, Lan J, Zheng X, Zukin RS, Bennett MV. Insulin promotes rapid delivery of N-methyl-D- aspartate receptors to the cell surface by exocytosis. Proc Natl Acad Sci U S A. 2001;98(6):3561–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Boyd Jr FT, Clarke DW, Muther TF, Raizada MK. Insulin receptors and insulin modulation of norepinephrine uptake in neuronal cultures from rat brain. J Biol Chem. 1985;260(29):15880–4.

    CAS  PubMed  Google Scholar 

  55. Wan Q, Xiong ZG, Man HY, Ackerley CA, Braunton J, Lu WY, et al. Recruitment of functional GABA(A) receptors to postsynaptic domains by insulin. Nature. 1997;388(6643):686–90.

    Article  CAS  PubMed  Google Scholar 

  56. Marks DR, Tucker K, Cavallin MA, Mast TG, Fadool DA. Awake intranasal insulin delivery modifies protein complexes and alters memory, anxiety, and olfactory behaviors. J Neurosci. 2009;29(20):6734–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Shemesh E, Rudich A, Harman-Boehm I, Cukierman-Yaffe T. Effect of intranasal insulin on cognitive function: a systematic review. J Clin Endocrinol Metab. 2012;97(2):366–76.

    Article  CAS  PubMed  Google Scholar 

  58. Morris JK, Vidoni ED, Mahnken JD, Montgomery RN, Johnson DK, Thyfault JP, et al. Cognitively impaired elderly exhibit insulin resistance and no memory improvement with infused insulin. Neurobiol Aging. 2016;39:19–24. doi:10.1016/j.neurobiolaging.2015.11.005.

    Article  CAS  PubMed  Google Scholar 

  59. Calvo-Ochoa E, Arias C. Cellular and metabolic alterations in the hippocampus caused by insulin signalling dysfunction and its association with cognitive impairment during aging and Alzheimer’s disease: studies in animal models. Diabetes Metab Res Rev. 2015;31(1):1–13.

    Article  CAS  PubMed  Google Scholar 

  60. Heras-Sandoval D, Ferrera P, Arias C. Amyloid-beta protein modulates insulin signaling in presynaptic terminals. Neurochem Res. 2012;37(9):1879–85.

    Article  CAS  PubMed  Google Scholar 

  61. Choi J, Malakowsky CA, Talent JM, Conrad CC, Gracy RW. Identification of oxidized plasma proteins in Alzheimer’s disease. Biochem Biophys Res Commun. 2002;293(5):1566–70.

    Article  CAS  PubMed  Google Scholar 

  62. Lu T, Pan Y, Kao SY, Li C, Kohane I, Chan J, et al. Gene regulation and DNA damage in the ageing human brain. Nature. 2004;429(6994):883–91.

    Article  CAS  PubMed  Google Scholar 

  63. Wang X, Su B, Lee HG, Li X, Perry G, Smith MA, et al. Impaired balance of mitochondrial fission and fusion in Alzheimer’s disease. J Neurosci. 2009;29(28):9090–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Su B, Wang X, Zheng L, Perry G, Smith MA, Zhu X. Abnormal mitochondrial dynamics and neurodegenerative diseases. Biochim Biophys Acta. 2010;1802(1):135–42.

    Article  CAS  PubMed  Google Scholar 

  65. Chandrasekaran K, Hatanpaa K, Rapoport SI, Brady DR. Decreased expression of nuclear and mitochondrial DNA-encoded genes of oxidative phosphorylation in association neocortex in Alzheimer disease. Brain Res Mol Brain Res. 1997;44(1):99–104.

    Article  CAS  PubMed  Google Scholar 

  66. Kim B, Backus C, Oh S, Hayes JM, Feldman EL. Increased tau phosphorylation and cleavage in mouse models of type 1 and type 2 diabetes. Endocrinology. 2009;150(12):5294–301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Eckert A, Schulz KL, Rhein V, Gotz J. Convergence of amyloid-beta and tau pathologies on mitochondria in vivo. Mol Neurobiol. 2010;41(2–3):107–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Choi J, Batchu VV, Schubert M, Castellani RJ, Russell JW. A novel PGC-1alpha isoform in brain localizes to mitochondria and associates with PINK1 and VDAC. Biochem Biophys Res Commun. 2013;435(4):671–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Choi J, Ravipati A, Nimmagadda V, Schubert M, Castellani RJ, Russell JW. Potential roles of PINK1 for increased PGC-1alpha-mediated mitochondrial fatty acid oxidation and their associations with Alzheimer disease and diabetes. Mitochondrion. 2014;18:41–8. doi:10.1016/j.mito.2014.09.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Wilhelmus MM, van der Pol SM, Jansen Q, Witte ME, van der Valk P, Rozemuller AJ et al. Association of Parkinson disease-related protein PINK1 with Alzheimer disease and multiple sclerosis brain lesions. Free Radic Biol Med. 2011;50(3):469–76.

  71. Choi J, Chandrasekaran K, Inoue T, Muragundla A, Russell JW. PGC-1alpha regulation of mitochondrial degeneration in experimental diabetic neuropathy. Neurobiol Dis. 2014;64:118–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Lin J, Wu PH, Tarr PT, Lindenberg KS, St Pierre J, Zhang CY, et al. Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1alpha null mice.[see comment]. Cell. 2004;119(1):125–35.

    Article  Google Scholar 

  73. Scuderi C, Stecca C, Bronzuoli MR, Rotili D, Valente S, Mai A, et al. Sirtuin modulators control reactive gliosis in an in vitro model of Alzheimer’s disease. Front Pharmacol. 2014;5:89. doi:10.3389/fphar.2014.00089. eCollection: 2014.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Zaslavsky LM, Gross JL, Chaves ML, Machado R. Memory dysfunction and autonomic neuropathy in non-insulin-dependent (type 2) diabetic patients. Diabetes Res Clin Pract. 1995;30(2):101–10.

    Article  CAS  PubMed  Google Scholar 

  75. Nicolini P, Ciulla MM, Malfatto G, Abbate C, Mari D, Rossi PD, et al. Autonomic dysfunction in mild cognitive impairment: evidence from power spectral analysis of heart rate variability in a cross-sectional case-control study. PLoS One. 2014;9(5):e96656. The study links autonomic dysfunction with presence of MCI.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Seeley WW. Anterior insula degeneration in frontotemporal dementia. Brain Struct Funct. 2010;214(5–6):465–75.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Frewen J, Finucane C, Savva GM, Boyle G, Coen RF, Kenny RA. Cognitive function is associated with impaired heart rate variability in ageing adults: the Irish longitudinal study on ageing wave one results. Clin Auton Res. 2013;23(6):313–23.

    Article  PubMed  Google Scholar 

  78. Guaraldi P, Poda R, Calandra-Buonaura G, Solieri L, Sambati L, Gallassi R, et al. Cognitive function in peripheral autonomic disorders. PLoS One. 2014;9(1):e85020.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Gibbons CH, Centi J, Vernino S, Freeman R. Autoimmune autonomic ganglionopathy with reversible cognitive impairment. Arch Neurol. 2012;69(4):461–6.

    Article  PubMed  Google Scholar 

  80. Gaspar JM, Baptista FI, Macedo MP, Ambrosio AF. Inside the diabetic brain: role of different players involved in cognitive decline. ACS Chem Neurosci. 2016;7(2):131–42. This manuscript provides an in depth review of the current known pathways that can lead to impairment in cognition in the diabetic brain.

    Article  CAS  PubMed  Google Scholar 

  81. Datusalia AK, Sharma SS. NF-kappaB inhibition resolves cognitive deficits in experimental type 2 diabetes mellitus through CREB and Glutamate/GABA neurotransmitters pathway. Curr Neurovasc Res. 2016;13(1):22–32.

    Article  CAS  PubMed  Google Scholar 

  82. Valente T, Gella A, Fernandez-Busquets X, Unzeta M, Durany N. Immunohistochemical analysis of human brain suggests pathological synergism of Alzheimer’s disease and diabetes mellitus. Neurobiol Dis. 2010;37(1):67–76.

    Article  CAS  PubMed  Google Scholar 

  83. Puig KL, Floden AM, Adhikari R, Golovko MY, Combs CK. Amyloid precursor protein and proinflammatory changes are regulated in brain and adipose tissue in a murine model of high fat diet-induced obesity. PLoS One. 2012;7(1):e30378.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Dinel AL, Andre C, Aubert A, Ferreira G, Laye S, Castanon N. Cognitive and emotional alterations are related to hippocampal inflammation in a mouse model of metabolic syndrome. PLoS One. 2011;6(9):e24325.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Tomlinson DR, Gardiner NJ. Glucose neurotoxicity. Nat Rev Neurosci. 2008;9(1):36–45.

    Article  CAS  PubMed  Google Scholar 

  86. Kuhad A, Bishnoi M, Tiwari V, Chopra K. Suppression of NF-kappabeta signaling pathway by tocotrienol can prevent diabetes associated cognitive deficits. Pharmacol Biochem Behav. 2009;92(2):251–9.

    Article  CAS  PubMed  Google Scholar 

  87. Wang J, Li G, Wang Z, Zhang X, Yao L, Wang F, et al. High glucose-induced expression of inflammatory cytokines and reactive oxygen species in cultured astrocytes. Neuroscience. 2012;202:58–68. doi:10.1016/j.neuroscience.2011.11.062.

    Article  CAS  PubMed  Google Scholar 

  88. Sima AA. Encephalopathies: the emerging diabetic complications. Acta Diabetol. 2010;47(4):279–93.

    Article  CAS  PubMed  Google Scholar 

  89. Fiatarone Singh MA, Gates N, Saigal N, Wilson GC, Meiklejohn J, Brodaty H, et al. The Study of Mental and Resistance Training (SMART) study-resistance training and/or cognitive training in mild cognitive impairment: a randomized, double-blind, double-sham controlled trial. J Am Med Dir Assoc. 2014;15(12):873–80.

    Article  PubMed  Google Scholar 

  90. Guimaraes FC, Amorim PR, Dos Reis FF, Bonoto RT, de Oliveira WC, Moura TA, et al. Physical activity and better medication compliance improve mini-mental state examination scores in the elderly. Dement Geriatr Cogn Disord. 2015;39(1–2):25–31.

    Article  CAS  PubMed  Google Scholar 

  91. Gates N, Fiatarone Singh MA, Sachdev PS, Valenzuela M. The effect of exercise training on cognitive function in older adults with mild cognitive impairment: a meta-analysis of randomized controlled trials. Am J Geriatr Psychiatry. 2013;21(11):1086–97.

    Article  PubMed  Google Scholar 

  92. Fiocco AJ, Scarcello S, Marzolini S, Chan A, Oh P, Proulx G, et al. The effects of an exercise and lifestyle intervention program on cardiovascular, metabolic factors and cognitive performance in middle-aged adults with type II diabetes: a pilot study. Can J Diabetes. 2013;37(4):214–9.

    Article  PubMed  Google Scholar 

  93. Baker LD, Frank LL, Foster-Schubert K, Green PS, Wilkinson CW, McTiernan A, et al. Aerobic exercise improves cognition for older adults with glucose intolerance, a risk factor for Alzheimer’s disease. J Alzheimers Dis. 2010;22(2):569–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Watson GS, Reger MA, Baker LD, McNeely MJ, Fujimoto WY, Kahn SE, et al. Effects of exercise and nutrition on memory in Japanese Americans with impaired glucose tolerance. Diabetes Care. 2006;29(1):135–6.

    Article  PubMed  Google Scholar 

  95. Ang L, Jaiswal M, Martin C, Pop-Busui R. Glucose control and diabetic neuropathy: lessons from recent large clinical trials. Curr Diab Rep. 2014;14(9):528–0528.

    Article  PubMed  CAS  Google Scholar 

  96. Rdzak GM, Abdelghany O. Does insulin therapy for type 1 diabetes mellitus protect against Alzheimer’s disease? Pharmacotherapy. 2014;34(12):1317–23.

    Article  CAS  PubMed  Google Scholar 

  97. Liu W, Li G, Holscher C, Li L. Neuroprotective effects of geniposide on Alzheimer’s disease pathology. Rev Neurosci. 2015;26(4):371–83.

    PubMed  Google Scholar 

  98. Kosaraju J, Murthy V, Khatwal RB, Dubala A, Chinni S, Muthureddy Nataraj SK, et al. Vildagliptin: an anti-diabetes agent ameliorates cognitive deficits and pathology observed in streptozotocin-induced Alzheimer’s disease. J Pharm Pharmacol. 2013;65(12):1773–84.

    Article  CAS  PubMed  Google Scholar 

  99. McClean PL, Holscher C. Lixisenatide, a drug developed to treat type 2 diabetes, shows neuroprotective effects in a mouse model of Alzheimer’s disease. Neuropharmacology. 2014;86:241–58. doi:10.1016/j.neuropharm.2014.07.015.

    Article  CAS  PubMed  Google Scholar 

  100. McClean PL, Parthsarathy V, Faivre E, Holscher C. The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer’s disease. J Neurosci. 2011;31(17):6587–94.

    Article  CAS  PubMed  Google Scholar 

  101. Pipatpiboon N, Pintana H, Pratchayasakul W, Chattipakorn N, Chattipakorn SC. DPP4-inhibitor improves neuronal insulin receptor function, brain mitochondrial function and cognitive function in rats with insulin resistance induced by high-fat diet consumption. Eur J Neurosci. 2013;37(5):839–49.

    Article  PubMed  Google Scholar 

  102. Pintana H, Apaijai N, Chattipakorn N, Chattipakorn SC. DPP-4 inhibitors improve cognition and brain mitochondrial function of insulin-resistant rats. J Endocrinol. 2013;218(1):1–11.

    Article  CAS  PubMed  Google Scholar 

  103. Kuhad A, Chopra K. Effect of sesamol on diabetes-associated cognitive decline in rats. Exp Brain Res. 2008;185(3):411–20.

    Article  PubMed  Google Scholar 

  104. Tuzcu M, Baydas G. Effect of melatonin and vitamin E on diabetes-induced learning and memory impairment in rats. Eur J Pharmacol. 2006;537(1–3):106–10.

    Article  CAS  PubMed  Google Scholar 

  105. Kuhad A, Chopra K. Curcumin attenuates diabetic encephalopathy in rats: behavioral and biochemical evidences. Eur J Pharmacol. 2007;576(1–3):34–42.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Supported in part by the Office of Research Development (R&D), Department of Veterans Affairs (LZ); Office of Research Development, Department of Veterans Affairs (Biomemedical and Laboratory Research Service and Rehabilitation Research and Development, 101RX001030), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health 1R01DK107007-01A1, Diabetes Action Research and Education Foundation (JWR), and grant P30DK072488 from the National Institute of Diabetes and Digestive and Kidney Diseases.

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Authors and Affiliations

  1. Department of Neurology, Maryland VA Healthcare System and University of Maryland, 110 South Paca Street, Baltimore, MD, 21201, USA

    Lindsay A. Zilliox, Krish Chadrasekaran, Justin Y. Kwan & James W. Russell

  2. School of Medicine, Department of Neurology, University of Maryland, 3S-129, 110 South Paca Street, Baltimore, MD, 21201-1595, USA

    James W. Russell

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  1. Lindsay A. Zilliox
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  2. Krish Chadrasekaran
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  3. Justin Y. Kwan
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  4. James W. Russell
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Correspondence to James W. Russell.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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This article is part of the Topical Collection on Microvascular Complications—Neuropathy

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Zilliox, L.A., Chadrasekaran, K., Kwan, J.Y. et al. Diabetes and Cognitive Impairment. Curr Diab Rep 16, 87 (2016). https://doi.org/10.1007/s11892-016-0775-x

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  • DOI: https://doi.org/10.1007/s11892-016-0775-x

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