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Hyperactivation of working memory-related brain circuits in newly diagnosed middle-aged type 2 diabetics

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Abstract

Type 2 diabetes mellitus (T2DM) is well known for its adverse impacts on brain and cognition, which leads to multidimensional cognitive deficits and wildly spread cerebral structure abnormalities. However, existing literatures are mainly focused on patients with advanced age or extended T2DM duration. Therefore, it remains unclear whether and how brain function would be affected at the initial onset stage of T2DM in relatively younger population. In current study, twelve newly diagnosed middle-aged T2DM patients with no previous diabetic treatment history and twelve matched controls were recruited. Brain activations during a working memory task, the digit n-back paradigm (0-, 1- and 2-back), were obtained with functional magnetic resonance imaging and tested by repeated measures ANOVA. Whereas patients performed the n-back task comparably well as controls, significant load-by-group interactions of brain activation were found in the right dorsolateral prefrontal cortex (DLPFC), left middle/inferior frontal gyrus, and left parietal cortex, where patients exhibited hyperactivation in the 2-back, but not the 0-back or 1-back condition compared to controls. Furthermore, the severity of chronic hyperglycemia, estimated by glycosylated hemoglobin (HbA1c) level, was entered into partial correlational analyses with task-related brain activations, while controlling for the real-time influence of glucose, estimated by instant plasma glucose level measured before scanning. Significant positive correlations were found between HbA1c and brain activations in the anterior cingulate cortex and bilateral DLPFC only in patients. Taken together, these findings suggest there might be a compensatory mechanism due to brain inefficiency related to chronic hyperglycemia at the initial onset stage of T2DM.

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Notes

  1. In order to better understand how the brain is affected by daily hyperglycemic events, we intentionally scanned our patients about 1 h after their regular lunches, to mimic the “worst scenario” of their circadian glycemic fluctuations. All controls were also scanned with the same arrangement.

References

  1. McCrimmon RJ, Ryan CM, Frier BM (2012) Diabetes and cognitive dysfunction. Lancet 379:2291–2299

    Article  PubMed  Google Scholar 

  2. Biessels GJ, Deary IJ, Ryan CM (2008) Cognition and diabetes: a lifespan perspective. Lancet Neurol 7:184–190

    Article  PubMed  Google Scholar 

  3. Heni M, Schopfer P, Peter A, Sartorius T, Fritsche A, Synofzik M, Haring HU, Maetzler W, Hennige AM (2013) Evidence for altered transport of insulin across the blood–brain barrier in insulin-resistant humans. Acta Diabetol. doi:10.1007/s00592-013-0546-y

  4. Biessels G (2007) Diabetic encephalopathy. In: Veves A, Malik R (eds) Diabetic neuropathy. Humana Press, New York, pp 187–205

    Chapter  Google Scholar 

  5. Sima AA (2010) Encephalopathies: the emerging diabetic complications. Acta Diabetol 47:279–293

    Article  CAS  PubMed  Google Scholar 

  6. Ryan CM, Geckle MO (2000) Circumscribed cognitive dysfunction in middle-aged adults with type 2 diabetes. Diabetes Care 23:1486–1493

    Article  CAS  PubMed  Google Scholar 

  7. Mogi N, Umegaki H, Hattori A, Maeda N, Miura H, Kuzuya M, Shimokata H, Ando F, Ito H, Iguchi A (2004) Cognitive function in Japanese elderly with type 2 diabetes mellitus. J Diabetes Complicat 18:42–46

    Article  PubMed  Google Scholar 

  8. Sommerfield AJ, Deary IJ, Frier BM (2004) Acute hyperglycemia alters mood state and impairs cognitive performance in people with type 2 diabetes. Diabetes Care 27:2335–2340

    Article  PubMed  Google Scholar 

  9. Manschot SM, Brands AM, van der Grond J, Kessels RP, Algra A, Kappelle LJ, Biessels GJ, Utrecht Diabetic Encephalopathy Study G (2006) Brain magnetic resonance imaging correlates of impaired cognition in patients with type 2 diabetes. Diabetes 55:1106–1113

  10. Moran C, Phan TG, Chen J, Blizzard L, Beare R, Venn A, Munch G, Wood AG, Forbes J, Greenaway TM, Pearson S, Srikanth V (2013) Brain atrophy in type 2 diabetes: regional distribution and influence on cognition. Diabetes Care 36:4036–4042

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. van Elderen SG, de Roos A, de Craen AJ, Westendorp RG, Blauw GJ, Jukema JW, Bollen EL, Middelkoop HA, van Buchem MA, van der Grond J (2010) Progression of brain atrophy and cognitive decline in diabetes mellitus: a 3-year follow-up. Neurology 75:997–1002

    Article  PubMed  Google Scholar 

  12. Dey J, Misra A, Desai NG, Mahapatra AK, Padma MV (1997) Cognitive function in younger type 2 diabetes. Diabetes Care 20:32–35

    Article  CAS  PubMed  Google Scholar 

  13. Cox DJ, Kovatchev BP, Gonder-Frederick LA, Summers KH, McCall A, Grimm KJ, Clarke WL (2005) Relationships between hyperglycemia and cognitive performance among adults with type 1 and type 2 diabetes. Diabetes Care 28:71–77

    Article  PubMed  Google Scholar 

  14. Arvanitakis Z, Wilson RS, Li Y, Aggarwal NT, Bennett DA (2006) Diabetes and function in different cognitive systems in older individuals without dementia. Diabetes Care 29:560–565

    Article  PubMed  Google Scholar 

  15. Bruehl H, Rueger M, Dziobek I, Sweat V, Tirsi A, Javier E, Arentoft A, Wolf OT, Convit A (2007) Hypothalamic-pituitary-adrenal axis dysregulation and memory impairments in type 2 diabetes. J Clin Endocrinol Metab 92:2439–2445

    Article  CAS  PubMed  Google Scholar 

  16. Bruehl H, Wolf OT, Sweat V, Tirsi A, Richardson S, Convit A (2009) Modifiers of cognitive function and brain structure in middle-aged and elderly individuals with type 2 diabetes mellitus. Brain Res 1280:186–194

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Arvanitakis Z, Bennett DA, Wilson RS, Barnes LL (2010) Diabetes and cognitive systems in older black and white persons. Alzheimer Dis Assoc Disord 24:37–42

    Article  PubMed Central  PubMed  Google Scholar 

  18. Chen Z, Li L, Sun J, Ma L (2012) Mapping the brain in type 2 diabetes: voxel-based morphometry using DARTEL. Eur J Radiol 81:1870–1876

    Article  PubMed  Google Scholar 

  19. Hoogenboom WS, Marder TJ, Flores VL, Huisman S, Eaton HP, Schneiderman JS, Bolo NR, Simonson DC, Jacobson AM, Kubicki M, Shenton ME, Musen G (2014) Cerebral white matter integrity and resting-state functional connectivity in middle-aged patients with type 2 diabetes. Diabetes 63:728–738

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Musen G, Jacobson AM, Bolo NR, Simonson DC, Shenton ME, McCartney RL, Flores VL, Hoogenboom WS (2012) Resting-state brain functional connectivity is altered in type 2 diabetes. Diabetes 61:2375–2379

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Xia W, Wang S, Sun Z, Bai F, Zhou Y, Yang Y, Wang P, Huang Y, Yuan Y (2013) Altered baseline brain activity in type 2 diabetes: a resting-state fMRI study. Psychoneuroendocrinology 38:2493–2501

    Article  PubMed  Google Scholar 

  22. Naor M, Steingruber HJ, Westhoff K, Schottenfeld-Naor Y, Gries AF (1997) Cognitive function in elderly non-insulin-dependent diabetic patients before and after inpatient treatment for metabolic control. J Diabetes Complicat 11:40–46

    Article  CAS  PubMed  Google Scholar 

  23. Owen AM, McMillan KM, Laird AR, Bullmore E (2005) N-back working memory paradigm: a meta-analysis of normative functional neuroimaging studies. Hum Brain Mapp 25:46–59

    Article  PubMed  Google Scholar 

  24. Zhu DF, Wang ZX, Zhang DR, Pan ZL, He S, Hu XP, Chen XC, Zhou JN (2006) fMRI revealed neural substrate for reversible working memory dysfunction in subclinical hypothyroidism. Brain 129:2923–2930

    Article  PubMed  Google Scholar 

  25. Lee JH, Yoon S, Renshaw PF, Kim TS, Jung JJ, Choi Y, Kim BN, Jacobson AM, Lyoo IK (2013) Morphometric changes in lateral ventricles of patients with recent-onset type 2 diabetes mellitus. PLoS ONE 8:e60515

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Last D, Alsop DC, Abduljalil AM, Marquis RP, de Bazelaire C, Hu K, Cavallerano J, Novak V (2007) Global and regional effects of type 2 diabetes on brain tissue volumes and cerebral vasoreactivity. Diabetes Care 30:1193–1199

    Article  PubMed Central  PubMed  Google Scholar 

  27. Smith EE, Jonides J, Marshuetz C, Koeppe RA (1998) Components of verbal working memory: evidence from neuroimaging. Proc Natl Acad Sci USA 95:876–882

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. D’Esposito M, Postle BR, Rypma B (2000) Prefrontal cortical contributions to working memory: evidence from event-related fMRI studies. Exp Brain Res 133:3–11

    Article  PubMed  Google Scholar 

  29. Cabeza R, Daselaar SM, Dolcos F, Prince SE, Budde M, Nyberg L (2004) Task-independent and task-specific age effects on brain activity during working memory, visual attention and episodic retrieval. Cereb Cortex 14:364–375

    Article  PubMed  Google Scholar 

  30. Emery L, Heaven TJ, Paxton JL, Braver TS (2008) Age-related changes in neural activity during performance matched working memory manipulation. Neuroimage 42:1577–1586

    Article  PubMed Central  PubMed  Google Scholar 

  31. He XS, Ma N, Pan ZL, Wang ZX, Li N, Zhang XC, Zhou JN, Zhu DF, Zhang DR (2011) Functional magnetic resource imaging assessment of altered brain function in hypothyroidism during working memory processing. Eur J Endocrinol 164:951–959

    Article  CAS  PubMed  Google Scholar 

  32. Koenig RJ, Peterson CM, Jones RL, Saudek C, Lehrman M, Cerami A (1976) Correlation of glucose regulation and hemoglobin AIc in diabetes mellitus. N Engl J Med 295:417–420

    Article  CAS  PubMed  Google Scholar 

  33. Alberti KG, Zimmet PZ (1998) Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 15:539–553

    Article  CAS  PubMed  Google Scholar 

  34. Ashburner J, Friston KJ (2000) Voxel-based morphometry—the methods. Neuroimage 11:805–821

    Article  CAS  PubMed  Google Scholar 

  35. Levy JC, Matthews DR, Hermans MP (1998) Correct homeostasis model assessment (HOMA) evaluation uses the computer program. Diabetes Care 21:2191–2192

    Article  CAS  PubMed  Google Scholar 

  36. Wallace TM, Levy JC, Matthews DR (2004) Use and abuse of HOMA modeling. Diabetes Care 27:1487–1495

    Article  PubMed  Google Scholar 

  37. Cox RW (1996) AFNI: software for analysis and visualization of functional magnetic resonance neuroimages. Comput Biomed Res 29:162–173

    Article  CAS  PubMed  Google Scholar 

  38. Wang ZX, Zhang JX, Wu QL, Liu N, Hu XP, Chan RC, Xiao ZW (2010) Alterations in the processing of non-drug-related affective stimuli in abstinent heroin addicts. Neuroimage 49:971–976

    Article  PubMed  Google Scholar 

  39. Wessels AM, Rombouts SA, Simsek S, Kuijer JP, Kostense PJ, Barkhof F, Scheltens P, Snoek FJ, Heine RJ (2006) Microvascular disease in type 1 diabetes alters brain activation: a functional magnetic resonance imaging study. Diabetes 55:334–340

    Article  CAS  PubMed  Google Scholar 

  40. Dickerson BC, Salat DH, Greve DN, Chua EF, Rand-Giovannetti E, Rentz DM, Bertram L, Mullin K, Tanzi RE, Blacker D, Albert MS, Sperling RA (2005) Increased hippocampal activation in mild cognitive impairment compared to normal aging and AD. Neurology 65:404–411

    Article  CAS  PubMed  Google Scholar 

  41. Sperling R (2007) Functional MRI studies of associative encoding in normal aging, mild cognitive impairment, and Alzheimer’s disease. Ann N Y Acad Sci 1097:146–155

    Article  PubMed  Google Scholar 

  42. Dickerson BC, Salat DH, Bates JF, Atiya M, Killiany RJ, Greve DN, Dale AM, Stern CE, Blacker D, Albert MS, Sperling RA (2004) Medial temporal lobe function and structure in mild cognitive impairment. Ann Neurol 56:27–35

    Article  PubMed  Google Scholar 

  43. Hamalainen A, Pihlajamaki M, Tanila H, Hanninen T, Niskanen E, Tervo S, Karjalainen PA, Vanninen RL, Soininen H (2007) Increased fMRI responses during encoding in mild cognitive impairment. Neurobiol Aging 28:1889–1903

    Article  PubMed  Google Scholar 

  44. Miller SL, Fenstermacher E, Bates J, Blacker D, Sperling RA, Dickerson BC (2008) Hippocampal activation in adults with mild cognitive impairment predicts subsequent cognitive decline. J Neurol Neurosurg Psychiatry 79:630–635

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. O’Brien JL, O’Keefe KM, LaViolette PS, DeLuca AN, Blacker D, Dickerson BC, Sperling RA (2010) Longitudinal fMRI in elderly reveals loss of hippocampal activation with clinical decline. Neurology 74:1969–1976

    Article  PubMed Central  PubMed  Google Scholar 

  46. Ryan JP, Fine DF, Rosano C (2014) Type 2 diabetes and cognitive impairment: contributions from neuroimaging. J Geriatr Psychiatry Neurol 27:47–55

    Article  PubMed  Google Scholar 

  47. Gruetter R, Ugurbil K, Seaquist ER (2000) Effect of acute hyperglycemia on visual cortical activation as measured by functional MRI. J Neurosci Res 62:279–285

    Article  CAS  PubMed  Google Scholar 

  48. Ebady SA, Arami MA, Shafigh MH (2008) Investigation on the relationship between diabetes mellitus type 2 and cognitive impairment. Diabetes Res Clin Pract 82:305–309

    Article  CAS  PubMed  Google Scholar 

  49. Cukierman-Yaffe T, Gerstein HC, Williamson JD, Lazar RM, Lovato L, Miller ME, Coker LH, Murray A, Sullivan MD, Marcovina SM, Launer LJ (2009) 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 32:221–226

    Article  PubMed Central  PubMed  Google Scholar 

  50. Ishizawa KT, Kumano H, Sato A, Sakura H, Iwamoto Y (2010) Decreased response inhibition in middle-aged male patients with type 2 diabetes. Biopsychosoc Med 4:1

    Article  PubMed Central  PubMed  Google Scholar 

  51. Miller EK, Cohen JD (2001) An integrative theory of prefrontal cortex function. Annu Rev Neurosci 24:167–202

    Article  CAS  PubMed  Google Scholar 

  52. Smith EE, Jonides J (1999) Storage and executive processes in the frontal lobes. Science 283:1657–1661

    Article  CAS  PubMed  Google Scholar 

  53. Bruehl H, Sweat V, Tirsi A, Shah B, Convit A (2011) Obese adolescents with type 2 diabetes mellitus have hippocampal and frontal lobe volume reductions. Neurosci Med 2:34–42

    Article  PubMed Central  PubMed  Google Scholar 

  54. Strachan MW, Reynolds RM, Frier BM, Mitchell RJ, Price JF (2008) The relationship between type 2 diabetes and dementia. Br Med Bull 88:131–146

    Article  CAS  PubMed  Google Scholar 

  55. Gjedde A, Crone C (1981) Blood–brain glucose transfer: repression in chronic hyperglycemia. Science 214:456–457

    Article  CAS  PubMed  Google Scholar 

  56. Duckrow RB, Beard DC, Brennan RW (1987) Regional cerebral blood flow decreases during chronic and acute hyperglycemia. Stroke 18:52–58

    Article  CAS  PubMed  Google Scholar 

  57. Jakobsen J, Nedergaard M, Aarslew-Jensen M, Diemer NH (1990) Regional brain glucose metabolism and blood flow in streptozocin-induced diabetic rats. Diabetes 39:437–440

    Article  CAS  PubMed  Google Scholar 

  58. Gispen WH, Biessels GJ (2000) Cognition and synaptic plasticity in diabetes mellitus. Trends Neurosci 23:542–549

    Article  CAS  PubMed  Google Scholar 

  59. Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414:813–820

    Article  CAS  PubMed  Google Scholar 

  60. Zhao B, Pan BS, Shen SW, Sun X, Hou ZZ, Yan R, Sun FY (2013) Diabetes-induced central neuritic dystrophy and cognitive deficits are associated with the formation of oligomeric reticulon-3 via oxidative stress. J Biol Chem 288:15590–15599

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  61. Stranahan AM, Arumugam TV, Cutler RG, Lee K, Egan JM, Mattson MP (2008) Diabetes impairs hippocampal function through glucocorticoid-mediated effects on new and mature neurons. Nat Neurosci 11:309–317

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  62. 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 

  63. Brundel M, Kappelle LJ, Biessels GJ (2014) Brain imaging in type 2 diabetes. Eur Neuropsychopharmacol. doi:10.1016/j.euroneuro.2014.01.023

  64. Wardlaw JM, Smith EE, Biessels GJ, Cordonnier C, Fazekas F, Frayne R, Lindley RI, O’Brien JT, Barkhof F, Benavente OR, Black SE, Brayne C, Breteler M, Chabriat H, Decarli C, de Leeuw FE, Doubal F, Duering M, Fox NC, Greenberg S, Hachinski V, Kilimann I, Mok V, Oostenbrugge R, Pantoni L, Speck O, Stephan BC, Teipel S, Viswanathan A, Werring D, Chen C, Smith C, van Buchem M, Norrving B, Gorelick PB, Dichgans M, nEuroimaging STfRVco (2013) Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol 12:822–838

    Article  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

We thank Mr. Zhong-Lin Pan for assisting with MRI data collection. We also thank Dr. Ning Ma and Dr. Nan Li for their advices. Thanks for two anonymous reviewers for their very helpful comments on our previous manuscript. This research was supported by the Natural Science Foundation of China (Nos. 30700235, 31070986, 30870764, 91132304, and 81272152), National Institutes of Health of the United States (RO1EB002009), and China Postdoctoral Science Foundation (2012M520424).

Conflict of interest

Xiao-Song He, Zhao-Xin Wang, You-Zhi Zhu, Nan Wang, Xiaoping Hu, Da-Ren Zhang, De-Fa Zhu, Jiang-Ning Zhou declare that they have no conflict of interest.

Human and Animal Rights

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008.

Informed consent

Informed consent was obtained from all participants for being included in the study.

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Authors and Affiliations

  1. CAS Key Laboratory of Brain Function and Diseases, School of Life Science, University of Science and Technology of China, 433 Huangshan Road, Hefei, 230027, Anhui, China

    Xiao-Song He, Zhao-Xin Wang, Da-Ren Zhang & Jiang-Ning Zhou

  2. Department of Radiology, PLA 105 Hospital, Hefei, Anhui, China

    You-Zhi Zhu

  3. Department of Endocrinology, Anhui Geriatric Institute, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, 230022, Anhui, China

    Nan Wang & De-Fa Zhu

  4. Department of Biomedical Engineering, Georgia Tech and Emory University, Atlanta, GA, USA

    Xiaoping Hu

  5. Key Laboratory of Behavioral Science, Institute of Psychology, Chinese Academy of Sciences, Beijing, China

    Xiao-Song He

  6. Key Laboratory of Brain Functional Genomics (MOE and STCSM), Institute of Cognitive Neuroscience, School of Psychology and Cognitive Science, East China Normal University, Shanghai, China

    Zhao-Xin Wang

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  1. Xiao-Song He
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Xiao-Song He and Zhao-Xin Wang have contributed equally to this work.

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He, XS., Wang, ZX., Zhu, YZ. et al. Hyperactivation of working memory-related brain circuits in newly diagnosed middle-aged type 2 diabetics. Acta Diabetol 52, 133–142 (2015). https://doi.org/10.1007/s00592-014-0618-7

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