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The diabetic brain and cognition

  • Neurology and Preclinical Neurological Studies - Review Article
  • Published:
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Abstract

The prevalence of both Alzheimer’s disease (AD) and vascular dementia (VaD) is increasing with the aging of the population. Studies from the last several years have shown that people with diabetes have an increased risk for dementia and cognitive impairment. Therefore, the authors of this consensus review tried to elaborate on the role of diabetes, especially diabetes type 2 (T2DM) in both AD and VaD. Based on the clinical and experimental work of scientists from 18 countries participating in the International Congress on Vascular Disorders and on literature search using PUBMED, it can be concluded that T2DM is a risk factor for both, AD and VaD, based on a pathology of glucose utilization. This pathology is the consequence of a disturbance of insulin-related mechanisms leading to brain insulin resistance. Although the underlying pathological mechanisms for AD and VaD are different in many aspects, the contribution of T2DM and insulin resistant brain state (IRBS) to cerebrovascular disturbances in both disorders cannot be neglected. Therefore, early diagnosis of metabolic parameters including those relevant for T2DM is required. Moreover, it is possible that therapeutic options utilized today for diabetes treatment may also have an effect on the risk for dementia. T2DM/IRBS contribute to pathological processes in AD and VaD.

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Fig. 1

Modified from Sagare et al. (2012) (This copyright agreement is admitted by describing Cold Spring Herb Perspect Med 2012;2:a011452)

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Abbreviations

Aβ:

Beta-amyloid-protein

AChE:

Acetylcholinesterase

AD:

Alzheimer’s disease

AGEs:

Advanced glycation end products

AKT1s1:

Proline-rich AKT1 substrate 1

AKT-1:

RAC-alpha serine/threonine-protein kinase

AKT-2:

RAC-beta serine/threonine-protein kinase

APP:

Beta-amyloid precursor protein

APOE ϵ4:

Apolipoprotein E ϵ4

AQP4:

Aquaporin-4

ATP:

Adenosine triphospate

BBB:

Blood brain barrier

BChE:

Butyrylcholinesterase

BHB:

Beta-hydroxybutyrate

BIR:

Brain insulin resistance

CBF:

Cerebral blood flow

CBH:

Chronic brain hypoperfusion

CSF:

Cerebrospinal fluid

Ct:

Control

CVR:

Cerebrovascular reactivity

DM:

Diabetes mellitus

DNA:

Desoxyribonucleic acid

FDG:

Fluorodeoxyglucose

FTO:

Fat-mass and obesity-associated gene

Gd-DTPA:

Gadolinium-based MRI contrast agent

GLP-1:

Glucagon-like peptide 1

GLUT3:

Glucose transporter 3

GM:

Grey matter

GSK3β:

Glycogen synthase kinase 3 β

HOMA-IR:

Homeostatic model assessment of insulin resistance

HNE:

4-Hydroxynonenal

IDE:

Insulin degrading enzyme

ICV:

Intracerebroventricular

IGF-1R:

Insulin-like growth factor 1 receptor

IR:

Insulin receptor

IRBS:

Insulin resistant brain state

IRβ:

Insulin receptor subunit β

IRS1:

Insulin receptor substrate-1

IRS-1pS616:

Serin-phosphorylated insulin receptor substrate-1

IRS2:

Insulin receptor substrate-2

ISF:

Interstitial fluid

KAT:

Kynurenine aminotransferase

KYNAC:

Kynurenic acid

MCI:

Mild cognitive impairment

MRI:

Magnet resonance imaging

mTOR:

Mechanistic target of rapamycin

OS:

Oxidative stress

PCAD:

Pre-clinical AD

PET:

Positron emission tomography

PG:

Postprandial glycemia

PIK3CB:

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta isoform

PIK3CD:

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta

PI3:

Phosphatidylinositol-3-kinase

PI3K:

Phosphoinositid-3-kinase

PIP3:

Phosphatidylinositol (3,4,5)-triphosphate

PPARγ:

Peroxisome proliferator-activated receptor gamma

P-Tau:

Phospho-Tau-Protein

PYY:

Peptide YY

P53:

Phosphoprotein p53

QA:

Quinolinic acid

RAGE:

Receptor for AGEs

RNA:

Ribonucleic acid

ROS:

Reactive oxygen species

sAD:

Sporadic Alzheimer’s disease

SGLT2:

Sodium/glucose cotransporter 2

STZ:

Streptozotocin

T2DM:

Type 2 diabetes mellitus

T1DM:

Type 1 diabetes mellitus

VaD:

Vascular dementia

WM:

White matter

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Acknowledgements

Hakan Yaman will be supported by the Akdeniz University Research Management Unit.

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Authors and Affiliations

  1. Center of Mental Health, Department Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg, 97080, Würzburg, Germany

    Peter Riederer

  2. Center for Aging and Associated Diseases, Helmy Institute of Medical Science, Zewail City of Science and Technology, Giza, Egypt

    Sameh S. Ali

  3. Department of Neurology, Neurosurgery and Psychiatry, University of Medicine and Pharmacy Carol Davila Bucharest, S Plaiul Independentei 169, Sector 5, 050098, Bucharest, Romania

    Ovidiu Bajenaru

  4. Department of Neurology, Hallym Hospital, 900-4 Jakjeon-dong, Gyeyang-gu, Incheon-si, 407-060, Korea

    Mun Seong Choi

  5. Department of Neurology, Henry Ford Hospital, Detroit, MI, USA

    Michael Chopp & Zheng G. Zhang

  6. The Center for Successful Aging with Diabetes, Endocrinology Institute, Gertner Institute, Sheba Medical Center, Epidemiology D., Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    Rachel Natovich & Tali Cukierman-Yaffe

  7. Clinical Hospital Merkur-University, Clinic Vuk Vrhovac, Zajčeva (Zajceva) 19, 10000, Zagreb, Croatia

    Vesna Dermanovic-Dobrota

  8. Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric Hospital, University Zurich, Zurich, Switzerland

    Edna Grünblatt

  9. Neuroscience Center Zurich, University of Zurich and the ETH Zurich, Zurich, Switzerland

    Edna Grünblatt

  10. Zurich Center for Integrative Human Physiology, University of Zurich, 5th Floor Room K118, Wagistrasse 12, 8952, Zurich, Switzerland

    Edna Grünblatt

  11. Institute of Clinical Neurobiology, Alberichgasse 5/13, 1150, Vienna, Austria

    Kurt A. Jellinger

  12. Biomediotronics, Enzymoic, 7 Peterlee Pl, Hebersham, NSW, 2770, Australia

    Warda Kamal

  13. King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah, 21589, Saudi Arabia

    Mohammad Amjad Kamal

  14. Enzymoics, 7 Peterlee Place, Hebersham, NSW, 2770, Australia

    Mohammad Amjad Kamal

  15. Novel Global Community Educational Foundation, Sydney, Australia

    Mohammad Amjad Kamal

  16. Department of Neurology, Tel Aviv University, 69978, Ramat Aviv, Israel

    Amos D. Korczyn

  17. Department of Psychiatry, Wroclaw Medical University, Pasteura 10, Str., 50-367, Wroclaw, Poland

    Jerzy Leszek

  18. Department of Neurology, University Medical Center Ljubljana, Zaloska 7, 1525, Ljubljana, Slovenia

    Bernard Meglic

  19. Chair of Psychiatry and Head of the Odense Brain, Research Center, Department of Psychiatry Odense, University of Southern Denmark, Winslowsvej 20, 5000, Odense C, Denmark

    Tanja Maria Sheldrick-Michel

  20. Department of Biochemistry, College of Science, King Abdulaziz University, Jeddah, 21589, Saudi Arabia

    Gohar Mushtaq

  21. Department of Neurology, University Ljubljana, Ljubljana, Slovenia

    Zvezdan Pirtosek

  22. Department of Neurology, University Medical Centre Maribor, Maribor, Slovenia

    Martin Rakusa

  23. Department of Pharmacology, University of Zagreb School of Medicine, Salata 11, 10 000, Zagreb, Croatia

    Melita Salkovic-Petrisic

  24. Department of Neurology, Med. Univ. Graz, Auenbruggerplatz 22, 8036, Graz, Austria

    Reinhold Schmidt

  25. Labor für translationale Neurowissenschaften, der Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie, Universitätsklinikum Würzburg, Margarete Höppel-Platz 1, 97080, Würzburg, Germany

    Angelika Schmitt

  26. Endocrine and Diabetes Centre, 15-12-15 Krishnanagar, Visakhapatnam, 530 002, India

    G. Ramachandra Sridhar

  27. Department of Neurology and MTA-SZTE Neuroscience Research Group, Faculty of Medicine, Albert Szent-Györgyi Clinical Center, University of Szeged, Semmelweis u. 6., 6725, Szeged, Hungary

    László Vécsei

  28. Department of Geriatrics, Medical University of Bialystok, Fabryczna Str.27, 15-741, Bialystok, Poland

    Zyta Beata Wojszel

  29. Department of Family Medicine, Faculty of Medicine, Akdeniz University, 07059, Antalya, Turkey

    Hakan Yaman & Zheng G. Zhang

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Correspondence to Peter Riederer.

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Riederer, P., Korczyn, A.D., Ali, S.S. et al. The diabetic brain and cognition. J Neural Transm 124, 1431–1454 (2017). https://doi.org/10.1007/s00702-017-1763-2

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