Skip to main content

Advertisement

SpringerLink
Log in

Investigations of possible links between Alzheimer’s disease and type 2 diabetes mellitus by positron emission tomography: a systematic review

  • Systematic Review
  • Published:
Clinical and Translational Imaging Aims and scope Submit manuscript

Abstract

Purpose

To review published evidence of possible links between Alzheimer’s disease (AD) and type-2 diabetes mellitus revealed by positron emission tomography (PET).

Methods

We searched online databases with keywords diabetes mellitus (DM), AD, and PET. We assessed the studies in terms of purpose, methodology, materials, and relationships between AD and DM suggested by PET imaging.

Results

After removal of 142 duplicates, 227 hits yielded no more than 15 full-length publications, from which we excluded six for specific reasons. The remaining nine studies were not directly comparable because of differences of purpose, study design, material, and methods. Individual subject materials consisted of 4–154 patients in case–control (4), observational (4), and longitudinal (1) studies, the last including only four DM patients. Mean patient age was 76.4 years (range 45–90). In five studies, researchers examined regional cerebral glucose metabolism with 18F-fluorodeoxyglucose (FDG), in three studies, researchers imaged amyloid with PET, and in one study, they measured both glucose metabolism and amyloid deposition. All four studies of amyloid tracers led to the conclusion that amyloid deposition was unaffected by DM status. Evidence of insulin resistance and increased blood glucose was associated with decreased FDG accumulation in AD signature regions in DM patients.

Conclusion

The relationships between DM and AD identified by PET appear to be independent of amyloid deposition and predominantly highlighted by reduced glucose metabolism, as suggested by four of the five glucose metabolism studies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. de la Monte SM, Wands JR (2004) Alzheimer-associated neuronal thread protein mediated cell death is linked to impaired insulin signaling. J Alzheimers Dis 6(3):231–242

    Article  PubMed  Google Scholar 

  2. de la Monte SM, Wands JR (2005) Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: relevance to Alzheimer’s disease. J Alzheimers Dis 7(1):45–61

    Article  PubMed  Google Scholar 

  3. Luchsinger J, Reitz C, Honig LS, Tang M-X, Shea S, Mayeux R (2005) Aggregation of vascular risk factors and risk of incident Alzheimer disease. Neurology 65(4):545–551

    Article  CAS  PubMed  Google Scholar 

  4. Xu W, von Strauss E, Qiu C, Winblad B, Fratiglioni L (2009) Uncontrolled diabetes increases the risk of Alzheimer’s disease: a population-based cohort study. Diabetologia 52(6):1031

    Article  CAS  PubMed  Google Scholar 

  5. Arvanitakis Z, Wilson RS, Bienias JL, Evans DA, Bennett DA (2004) Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. Arch Neurol 61(5):661–666

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  7. Iadecola C (2015) Sugar and Alzheimer’s disease: a bittersweet. Nat Neurosci 18(4):477–478. https://doi.org/10.1038/nn.3986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gaenslen A, Wurster I, Brockmann K, Huber H, Godau J, Faust B, Lerche S, Eschweiler G, Maetzler W, Berg D (2014) Prodromal features for Parkinson’s disease–baseline data from the TREND study. Eur J Neurol 21(5):766–772

    Article  CAS  PubMed  Google Scholar 

  9. Schilling MA (2016) Unraveling Alzheimer’s: making sense of the relationship between diabetes and Alzheimer’s disease 1. J Alzheimers Dis 51(4):961–977

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Steinberg H, Baron A (2002) Vascular function, insulin resistance and fatty acids. Diabetologia 45(5):623–634

    Article  CAS  PubMed  Google Scholar 

  11. Cheng CM, Reinhardt RR, Lee W-H, Joncas G, Patel SC, Bondy CA (2000) Insulin-like growth factor 1 regulates developing brain glucose metabolism. Proc Natl Acad Sci 97(18):10236–10241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP, Eckman CB, Tanzi RE, Selkoe DJ, Guénette S (2003) Insulin-degrading enzyme regulates the levels of insulin, amyloid β-protein, and the β-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci 100(7):4162–4167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Plum L, Schubert M, Brüning JC (2005) The role of insulin receptor signaling in the brain. Trends Endocrinol Metab 16(2):59–65

    Article  CAS  PubMed  Google Scholar 

  14. Watson GS, Craft S (2004) Modulation of memory by insulin and glucose: neuropsychological observations in Alzheimer’s disease. Eur J Pharmacol 490(1):97–113

    Article  CAS  PubMed  Google Scholar 

  15. Fernando RN, Albiston AL, Chai SY (2008) The insulin-regulated aminopeptidase IRAP is colocalised with GLUT4 in the mouse hippocampus–potential role in modulation of glucose uptake in neurones? Eur J Neurosci 28(3):588–598

    Article  PubMed  Google Scholar 

  16. Gambhir SS, Czernin J, Schwimmer J, Silverman DH, Coleman RE, Phelps ME (2001) A tabulated summary of the FDG PET literature. J Nucl Med 42(5 suppl):1S–93S

    CAS  PubMed  Google Scholar 

  17. Aizenstein HJ, Nebes RD, Saxton JA, Price JC, Mathis CA, Tsopelas ND, Ziolko SK, James JA, Snitz BE, Houck PR (2008) Frequent amyloid deposition without significant cognitive impairment among the elderly. Arch Neurol 65(11):1509–1517

    Article  PubMed  PubMed Central  Google Scholar 

  18. Rabinovici G, Furst A, O’neil J, Racine C, Mormino E, Baker S, Chetty S, Patel P, Pagliaro T, Klunk W (2007) 11C-PIB PET imaging in Alzheimer disease and frontotemporal lobar degeneration. Neurology 68(15):1205–1212

    Article  CAS  PubMed  Google Scholar 

  19. Minoshima S, Giordani B, Berent S, Frey KA, Foster NL, Kuhl DE (1997) Metabolic reduction in the posterior cingulate cortex in very early Alzheimer’s disease. Ann Neurol 42(1):85–94

    Article  CAS  PubMed  Google Scholar 

  20. Mosconi L, Tsui WH, Rusinek H, De Santi S, Li Y, Wang G-J, Pupi A, Fowler J, de Leon MJ (2007) Quantitation, regional vulnerability, and kinetic modeling of brain glucose metabolism in mild Alzheimer’s disease. Eur J Nucl Med Mol Imaging 34(9):1467–1479. https://doi.org/10.1007/s00259-007-0406-5

    Article  CAS  PubMed  Google Scholar 

  21. Aanerud J, Borghammer P, Chakravarty MM, Vang K, Rodell AB, Jónsdottir KY, Møller A, Ashkanian M, Vafaee MS, Iversen P, Johannsen P, Gjedde A (2012) Brain energy metabolism and blood flow differences in healthy aging. J Cereb Blood Flow Metab 32(7):1177–1187. https://doi.org/10.1038/jcbfm.2012.18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6(7):e1000097

    Article  PubMed  PubMed Central  Google Scholar 

  23. Fukasawa R, Hanyu H, Shimizu S, Kanetaka H, Sakurai H, Ishii K (2015) Identification of diabetes-related dementia: longitudinal perfusion SPECT and amyloid PET studies. J Neurol Sci 349(1):45–51

    Article  PubMed  Google Scholar 

  24. Ishibashi K, Onishi A, Fujiwara Y, Ishiwata K, Ishii K (2016) Plasma glucose levels affect cerebral 18F-FDG distribution in cognitively normal subjects with diabetes. Clin Nucl Med 41(6):e274–e280

    Article  PubMed  Google Scholar 

  25. Tomita N, Furukawa K, Okamura N, Tashiro M, Une K, Furumoto S, Iwata R, Yanai K, Kudo Y, Arai H (2013) Brain accumulation of amyloid β protein visualized by positron emission tomography and BF-227 in Alzheimer’s disease patients with or without diabetes mellitus. Geriatr Gerontol Int 13(1):215–221

    Article  PubMed  Google Scholar 

  26. García-Casares N, García-Arnés JA, Rioja J, Ariza MJ, Gutiérrez A, Alfaro F, Nabrozidis A, González-Alegre P, González-Santos P (2016) Alzheimer’s like brain changes correlate with low adiponectin plasma levels in type 2 diabetic patients. J Diabetes Complicat 30(2):281–286

    Article  Google Scholar 

  27. Li W, Risacher SL, Huang E, Saykin AJ, AsDN Initiative (2016) Type 2 diabetes mellitus is associated with brain atrophy and hypometabolism in the ADNI cohort. Neurology 87(6):595–600

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Willette AA, Modanlo N, Kapogiannis D (2015) Insulin resistance predicts medial temporal hypermetabolism in mild cognitive impairment conversion to Alzheimer disease. Diabetes 64(6):1933–1940. https://doi.org/10.2337/db14-1507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Baker LD, Cross DJ, Minoshima S, Belongia D, Watson GS, Craft S (2011) Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes. Arch Neurol 68(1):51–57

    Article  PubMed  Google Scholar 

  30. Gottesman RF, Schneider AL, Zhou Y, Coresh J, Green E, Gupta N, Knopman DS, Mintz A, Rahmim A, Sharrett AR (2017) Association between midlife vascular risk factors and estimated brain amyloid deposition. JAMA 317(14):1443–1450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Roberts RO, Knopman DS, Cha RH, Mielke MM, Pankratz VS, Boeve BF, Kantarci K, Geda YE, Jack CR, Petersen RC (2014) Diabetes and elevated hemoglobin A1c levels are associated with brain hypometabolism but not amyloid accumulation. J Nucl Med 55(5):759–764

    Article  CAS  PubMed  Google Scholar 

  32. Fukasawa R, Hanyu H, Namioka N, Hatanaka H, Sato T, Sakurai H (2014) Elevated inflammatory markers in diabetes-related dementia. Geriatr Gerontol Int 14(1):229–231

    Article  PubMed  Google Scholar 

  33. Jack CR, Wiste HJ, Weigand SD, Knopman DS, Lowe V, Vemuri P, Mielke MM, Jones DT, Senjem ML, Gunter JL (2013) Amyloid-first and neurodegeneration-first profiles characterize incident amyloid PET positivity. Neurology 81(20):1732–1740

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wirth M, Villeneuve S, Haase CM, Madison CM, Oh H, Landau SM, Rabinovici GD, Jagust WJ (2013) Associations between Alzheimer disease biomarkers, neurodegeneration, and cognition in cognitively normal older people. JAMA Neurol 70(12):1512–1519

    PubMed  PubMed Central  Google Scholar 

  35. Frisoni GB, Boccardi M, Barkhof F, Blennow K, Cappa S, Chiotis K, Demonet JF, Garibotto V, Giannakopoulos P, Gietl A, Hansson O, Herholz K, Jack CR Jr, Nobili F, Nordberg A, Snyder HM, Ten Kate M, Varrone A, Albanese E, Becker S, Bossuyt P, Carrillo MC, Cerami C, Dubois B, Gallo V, Giacobini E, Gold G, Hurst S, Lonneborg A, Lovblad KO, Mattsson N, Molinuevo JL, Monsch AU, Mosimann U, Padovani A, Picco A, Porteri C, Ratib O, Saint-Aubert L, Scerri C, Scheltens P, Schott JM, Sonni I, Teipel S, Vineis P, Visser PJ, Yasui Y, Winblad B (2017) Strategic roadmap for an early diagnosis of Alzheimer’s disease based on biomarkers. Lancet Neurol 16(8):661–676. https://doi.org/10.1016/s1474-4422(17)30159-x

    Article  PubMed  Google Scholar 

  36. Garibotto V, Herholz K, Boccardi M, Picco A, Varrone A, Nordberg A, Nobili F, Ratib O (2017) Clinical validity of brain fluorodeoxyglucose positron emission tomography as a biomarker for Alzheimer’s disease in the context of a structured 5-phase development framework. Neurobiol Aging 52:183–195. https://doi.org/10.1016/j.neurobiolaging.2016.03.033

    Article  CAS  PubMed  Google Scholar 

  37. Hamley IW (2012) The amyloid beta peptide: a chemist’s perspective. Role in Alzheimer’s and fibrillization. Chem Rev 112(10):5147–5192. https://doi.org/10.1021/cr3000994

    Article  CAS  PubMed  Google Scholar 

  38. Li L, Hölscher C (2007) Common pathological processes in Alzheimer disease and type 2 diabetes: a review. Brain Res Rev 56(2):384–402

    Article  CAS  PubMed  Google Scholar 

  39. Ikonomovic MD, Klunk WE, Abrahamson EE, Mathis CA, Price JC, Tsopelas ND, Lopresti BJ, Ziolko S, Bi W, Paljug WR (2008) Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer’s disease. Brain 131(6):1630–1645

    Article  PubMed  PubMed Central  Google Scholar 

  40. Sabri O, Sabbagh MN, Seibyl J, Barthel H, Akatsu H, Ouchi Y, Senda K, Murayama S, Ishii K, Takao M, Beach TG, Rowe CC, Leverenz JB, Ghetti B, Ironside JW, Catafau AM, Stephens AW, Mueller A, Koglin N, Hoffmann A, Roth K, Reininger C, Schulz-Schaeffer WJ (2015) Florbetaben PET imaging to detect amyloid beta plaques in Alzheimer’s disease: phase 3 study. Alzheimer’s Dement 11(8):964–974. https://doi.org/10.1016/j.jalz.2015.02.004

    Article  Google Scholar 

  41. Furumoto S, Okamura N, Furukawa K, Tashiro M, Ishikawa Y, Sugi K, Tomita N, Waragai M, Harada R, Tago T, Iwata R, Yanai K, Arai H, Kudo Y (2013) A 18F-labeled BF-227 derivative as a potential radioligand for imaging dense amyloid plaques by positron emission tomography. Mol Imaging Biol 15(4):497–506. https://doi.org/10.1007/s11307-012-0608-5

    Article  PubMed  Google Scholar 

  42. Driscoll I, Troncoso JC, Rudow G, Sojkova J, Pletnikova O, Zhou Y, Kraut MA, Ferrucci L, Mathis CA, Klunk WE, O’Brien RJ, Davatzikos C, Wong DF, Resnick SM (2012) Correspondence between in vivo 11C-PiB-PET amyloid imaging and postmortem, region-matched assessment of plaques. Acta Neuropathol (Berl) 124(6):823–831. https://doi.org/10.1007/s00401-012-1025-1

    Article  Google Scholar 

  43. Cairns NJ, Ikonomovic MD, Benzinger T, Storandt M, Fagan AM, Shah AR, Reinwald LT, Carter D, Felton A, Holtzman DM, Mintun MA, Klunk WE, Morris JC (2009) Absence of Pittsburgh compound B detection of cerebral amyloid β in a patient with clinical, cognitive, and cerebrospinal fluid markers of Alzheimer disease: a case report. Arch Neurol 66(12):1557–1562. https://doi.org/10.1001/archneurol.2009.279

    Article  PubMed  PubMed Central  Google Scholar 

  44. Fodero-Tavoletti MT, Mulligan RS, Okamura N, Furumoto S, Rowe CC, Kudo Y, Masters CL, Cappai R, Yanai K, Villemagne VL (2009) In vitro characterisation of BF227 binding to alpha-synuclein/Lewy bodies. Eur J Pharmacol 617(1–3):54–58. https://doi.org/10.1016/j.ejphar.2009.06.042

    Article  CAS  PubMed  Google Scholar 

  45. Kim J, Basak JM, Holtzman DM (2009) The role of apolipoprotein E in Alzheimer’s disease. Neuron 63(3):287–303. https://doi.org/10.1016/j.neuron.2009.06.026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Santos CY, Snyder PJ, Wu WC, Zhang M, Echeverria A, Alber J (2017) Pathophysiologic relationship between Alzheimer’s disease, cerebrovascular disease, and cardiovascular risk: a review and synthesis. Alzheimers Dement (Amst) 7:69–87. https://doi.org/10.1016/j.dadm.2017.01.005

    Article  Google Scholar 

  47. Chiotis K, Saint-Aubert L, Boccardi M, Gietl A, Picco A, Varrone A, Garibotto V, Herholz K, Nobili F, Nordberg A (2017) Clinical validity of increased cortical uptake of amyloid ligands on PET as a biomarker for Alzheimer’s disease in the context of a structured 5-phase development framework. Neurobiol Aging 52:214–227. https://doi.org/10.1016/j.neurobiolaging.2016.07.012

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to Mrs. Herdis Foverskov (Library, Odense University Hospital, Odense, Denmark) for her assistance in the search process. This study was supported by the Lundbeckfonden Grant No. 124506.

Author information

Author notes

  1. Reza Piri and Mohammad Naghavi-Behzad shared first authorship.

Authors and Affiliations

  1. Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark

    Reza Piri, Mohammad Naghavi-Behzad, Oke Gerke, Poul F. Høilund-Carlsen & Manouchehr Seyedi Vafaee

  2. Students’ Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran

    Mohammad Naghavi-Behzad

  3. Department of Clinical Research, University of Southern Denmark, Odense, Denmark

    Poul F. Høilund-Carlsen

  4. Department of Psychiatry, Odense University Hospital, Odense, Denmark

    Manouchehr Seyedi Vafaee

  5. Department of Clinical Research, BRIDGE-Brain Research-Inter-Disciplinary Guided Excellence, University of Southern Denmark, Odense, Denmark

    Manouchehr Seyedi Vafaee

Authors
  1. Reza Piri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mohammad Naghavi-Behzad
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Oke Gerke
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Poul F. Høilund-Carlsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Manouchehr Seyedi Vafaee
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

RP and MNB: content planning, literature search and review, writing, and editing. OG: literature search and editing. PFHC: content planning and editing. MSV: content planning, literature review, writing, and editing.

Corresponding author

Correspondence to Manouchehr Seyedi Vafaee.

Ethics declarations

Conflict of interest

All authors declare that they have no conflict of interest.

Human and animal rights

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

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 19 kb)

Supplementary material 2 (DOC 66 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Piri, R., Naghavi-Behzad, M., Gerke, O. et al. Investigations of possible links between Alzheimer’s disease and type 2 diabetes mellitus by positron emission tomography: a systematic review. Clin Transl Imaging 7, 327–336 (2019). https://doi.org/10.1007/s40336-019-00339-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40336-019-00339-y

Keywords

Search

Navigation