Advertisement

Current Diabetes Reports

, 16:87 | Cite as

Diabetes and Cognitive Impairment

  • Lindsay A. Zilliox
  • Krish Chadrasekaran
  • Justin Y. Kwan
  • James W. RussellEmail author
Microvascular Complications—Neuropathy (R Pop-Busui, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Microvascular Complications—Neuropathy

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.

Keywords

Diabetes Brain Dementia Encephalopathy Neuropathy Mitochondria MRI Treatment 

Notes

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.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no competing interests.

Human and Animal Rights and Informed Consent

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

References

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

  1. 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.PubMedCrossRefGoogle Scholar
  2. 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.PubMedCrossRefGoogle Scholar
  3. 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.Google Scholar
  4. 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.PubMedCrossRefGoogle Scholar
  5. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 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.PubMedCrossRefGoogle Scholar
  7. 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.PubMedCrossRefGoogle Scholar
  8. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    International Diabetes Federation. IDF diabetes atlas. 7th edn. Brussels: International Diabetes Federation; 2015. http://www.diabetesatlas.org.
  11. 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.PubMedGoogle Scholar
  12. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 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.PubMedCrossRefGoogle Scholar
  15. 15.
    Luchsinger JA. Adiposity, hyperinsulinemia, diabetes and Alzheimer’s disease: an epidemiological perspective. Eur J Pharmacol. 2008;585(1):119–29.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Karan NS. Assessment of the cognitive status in diabetes mellitus. J Clin Diagn Res. 2012;6(10):1658–62.PubMedPubMedCentralGoogle Scholar
  17. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 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.PubMedCrossRefGoogle Scholar
  19. 19.
    Whitmer RA. Type 2 diabetes and risk of cognitive impairment and dementia. Curr Neurol Neurosci Rep. 2007;7(5):373–80.PubMedCrossRefGoogle Scholar
  20. 20.
    Whitmer RA. The epidemiology of adiposity and dementia. Curr Alzheimer Res. 2007;4(2):117–22.PubMedCrossRefGoogle Scholar
  21. 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.PubMedCrossRefGoogle Scholar
  22. 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.CrossRefGoogle Scholar
  23. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 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.PubMedCrossRefGoogle Scholar
  25. 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.PubMedCrossRefGoogle Scholar
  26. 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.PubMedCrossRefGoogle Scholar
  27. 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.PubMedGoogle Scholar
  28. 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.PubMedCrossRefGoogle Scholar
  29. 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.PubMedCrossRefGoogle Scholar
  30. 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.PubMedCrossRefGoogle Scholar
  31. 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.PubMedCrossRefGoogle Scholar
  32. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 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.PubMedCrossRefGoogle Scholar
  35. 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.PubMedCrossRefGoogle Scholar
  36. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 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.PubMedCrossRefGoogle Scholar
  39. 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.PubMedCrossRefGoogle Scholar
  40. 40.
    Biessels GJ, Reijmer YD. Brain changes underlying cognitive dysfunction in diabetes: what can we learn from MRI? Diabetes. 2014;63(7):2244–52.PubMedCrossRefGoogle Scholar
  41. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 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.PubMedPubMedCentralGoogle Scholar
  44. 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.PubMedGoogle Scholar
  45. 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.PubMedCrossRefGoogle Scholar
  46. 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.PubMedCrossRefGoogle Scholar
  47. 47.
    Baskin DG, Figlewicz DP, Woods SC, Porte Jr D, Dorsa DM. Insulin in the brain. Annu Rev Physiol. 1987;49:335–47.PubMedCrossRefGoogle Scholar
  48. 48.
    Banks WA, Owen JB, Erickson MA. Insulin in the brain: there and back again. Pharmacol Ther. 2012;136(1):82–93.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Woods SC, Seeley RJ, Baskin DG, Schwartz MW. Insulin and the blood-brain barrier. Curr Pharm Des. 2003;9(10):795–800.PubMedCrossRefGoogle Scholar
  50. 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.PubMedGoogle Scholar
  51. 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.PubMedCrossRefGoogle Scholar
  52. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 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.PubMedGoogle Scholar
  55. 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.PubMedCrossRefGoogle Scholar
  56. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 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.PubMedCrossRefGoogle Scholar
  58. 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.PubMedCrossRefGoogle Scholar
  59. 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.PubMedCrossRefGoogle Scholar
  60. 60.
    Heras-Sandoval D, Ferrera P, Arias C. Amyloid-beta protein modulates insulin signaling in presynaptic terminals. Neurochem Res. 2012;37(9):1879–85.PubMedCrossRefGoogle Scholar
  61. 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.PubMedCrossRefGoogle Scholar
  62. 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.PubMedCrossRefGoogle Scholar
  63. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 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.PubMedCrossRefGoogle Scholar
  65. 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.PubMedCrossRefGoogle Scholar
  66. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 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.Google Scholar
  71. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 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.CrossRefGoogle Scholar
  73. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 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.PubMedCrossRefGoogle Scholar
  75. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Seeley WW. Anterior insula degeneration in frontotemporal dementia. Brain Struct Funct. 2010;214(5–6):465–75.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 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.PubMedCrossRefGoogle Scholar
  78. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Gibbons CH, Centi J, Vernino S, Freeman R. Autoimmune autonomic ganglionopathy with reversible cognitive impairment. Arch Neurol. 2012;69(4):461–6.PubMedCrossRefGoogle Scholar
  80. 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.PubMedCrossRefGoogle Scholar
  81. 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.PubMedCrossRefGoogle Scholar
  82. 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.PubMedCrossRefGoogle Scholar
  83. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Tomlinson DR, Gardiner NJ. Glucose neurotoxicity. Nat Rev Neurosci. 2008;9(1):36–45.PubMedCrossRefGoogle Scholar
  86. 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.PubMedCrossRefGoogle Scholar
  87. 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.PubMedCrossRefGoogle Scholar
  88. 88.
    Sima AA. Encephalopathies: the emerging diabetic complications. Acta Diabetol. 2010;47(4):279–93.PubMedCrossRefGoogle Scholar
  89. 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.PubMedCrossRefGoogle Scholar
  90. 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.PubMedCrossRefGoogle Scholar
  91. 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.PubMedCrossRefGoogle Scholar
  92. 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.PubMedCrossRefGoogle Scholar
  93. 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.PubMedPubMedCentralGoogle Scholar
  94. 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.PubMedCrossRefGoogle Scholar
  95. 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.PubMedCrossRefGoogle Scholar
  96. 96.
    Rdzak GM, Abdelghany O. Does insulin therapy for type 1 diabetes mellitus protect against Alzheimer’s disease? Pharmacotherapy. 2014;34(12):1317–23.PubMedCrossRefGoogle Scholar
  97. 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.PubMedGoogle Scholar
  98. 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.PubMedCrossRefGoogle Scholar
  99. 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.PubMedCrossRefGoogle Scholar
  100. 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.PubMedCrossRefGoogle Scholar
  101. 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.PubMedCrossRefGoogle Scholar
  102. 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.PubMedCrossRefGoogle Scholar
  103. 103.
    Kuhad A, Chopra K. Effect of sesamol on diabetes-associated cognitive decline in rats. Exp Brain Res. 2008;185(3):411–20.PubMedCrossRefGoogle Scholar
  104. 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.PubMedCrossRefGoogle Scholar
  105. 105.
    Kuhad A, Chopra K. Curcumin attenuates diabetic encephalopathy in rats: behavioral and biochemical evidences. Eur J Pharmacol. 2007;576(1–3):34–42.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York (outside the USA) 2016

Authors and Affiliations

  • Lindsay A. Zilliox
    • 1
  • Krish Chadrasekaran
    • 1
  • Justin Y. Kwan
    • 1
  • James W. Russell
    • 1
    • 2
    Email author
  1. 1.Department of NeurologyMaryland VA Healthcare System and University of MarylandBaltimoreUSA
  2. 2.School of Medicine, Department of NeurologyUniversity of MarylandBaltimoreUSA

Personalised recommendations