View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by SZTE Publicatio Repozitórium - SZTE - Repository of Publications J Neural Transm DOI 10.1007/s00702-017-1763-2 NEUROLOGY AND PRECLINICAL NEUROLOGICAL STUDIES - REVIEW ARTICLE The diabetic brain and cognition 1 16 2 3 Peter Riederer • Amos D. Korczyn • Sameh S. Ali • Ovidiu Bajenaru • 4 5 7 Mun Seong Choi • Michael Chopp • Vesna Dermanovic-Dobrota • 8,9,10 11 13,14,15 Edna Gru¨nblatt • Kurt A. Jellinger • Mohammad Amjad Kamal • 12 17 19 Warda Kamal • Jerzy Leszek • Tanja Maria Sheldrick-Michel • 20 18 6 21 Gohar Mushtaq • Bernard Meglic • Rachel Natovich • Zvezdan Pirtosek • 22 23 24 Martin Rakusa • Melita Salkovic-Petrisic • Reinhold Schmidt • 25 26 27 Angelika Schmitt • G. Ramachandra Sridhar • La´szlo´ Ve´csei • 28 29 5,29 6 Zyta Beata Wojszel • Hakan Yaman • Zheng G. Zhang • Tali Cukierman-Yaffe Received: 1 June 2017 / Accepted: 13 July 2017 Ó Springer-Verlag GmbH Austria 2017 Abstract The prevalence of both Alzheimer’s disease (AD) Congress on Vascular Disorders and on literature search and vascular dementia (VaD) is increasing with the aging of using PUBMED, it can be concluded that T2DM is a risk the population. Studies from the last several years have factor for both, AD and VaD, based on a pathology of glu- shown that people with diabetes have an increased risk for cose utilization. This pathology is the consequence of a dementia and cognitive impairment. Therefore, the authors disturbance of insulin-related mechanisms leading to brain of this consensus review tried to elaborate on the role of insulin resistance. Although the underlying pathological diabetes, especially diabetes type 2 (T2DM) in both AD and mechanisms for AD and VaD are different in many aspects, VaD. Based on the clinical and experimental work of sci- the contribution of T2DM and insulin resistant brain state entists from 18 countries participating in the International (IRBS) to cerebrovascular disturbances in both disorders & Peter Riederer Tanja Maria Sheldrick-Michel [email protected] [email protected] Amos D. Korczyn Gohar Mushtaq [email protected] [email protected] Sameh S. Ali Bernard Meglic [email protected]; [email protected] [email protected] Ovidiu Bajenaru Rachel Natovich [email protected] [email protected] Mun Seong Choi Zvezdan Pirtosek [email protected]; [email protected] [email protected] Michael Chopp Martin Rakusa [email protected] [email protected] Vesna Dermanovic-Dobrota Melita Salkovic-Petrisic [email protected] [email protected] Edna Gru¨nblatt Reinhold Schmidt [email protected] [email protected] Kurt A. Jellinger Angelika Schmitt [email protected] [email protected] Mohammad Amjad Kamal G. Ramachandra Sridhar [email protected] [email protected] Warda Kamal La´szlo´ Ve´csei [email protected] [email protected] Jerzy Leszek Zyta Beata Wojszel [email protected] [email protected] 123 P. Riederer et al. cannot be neglected. Therefore, early diagnosis of metabolic BChE Butyrylcholinesterase parameters including those relevant for T2DM is required. BHB Beta-hydroxybutyrate Moreover, it is possible that therapeutic options utilized BIR Brain insulin resistance today for diabetes treatment may also have an effect on the CBF Cerebral blood flow risk for dementia. T2DM/IRBS contribute to pathological CBH Chronic brain hypoperfusion processes in AD and VaD. CSF Cerebrospinal fluid Ct Control Keywords Vascular dementia Á Alzheimer’s disease Á CVR Cerebrovascular reactivity Diabetes mellitus Á Insulin resistance Á Cognition Á DM Diabetes mellitus Neurotransmitters in dementia Á Diabetic brain Á Pathology DNA Desoxyribonucleic acid of dementia Á Experimental model of dementia Á FDG Fluorodeoxyglucose Neurogenesis in dementia Á Epidemiology of dementive FTO Fat-mass and obesity-associated gene disorders Á Imaging in dementia Gd-DTPA Gadolinium-based MRI contrast agent GLP-1 Glucagon-like peptide 1 Abbreviations GLUT3 Glucose transporter 3 Ab Beta-amyloid-protein GM Grey matter AChE Acetylcholinesterase GSK3b Glycogen synthase kinase 3 b AD Alzheimer’s disease HOMA-IR Homeostatic model assessment of insulin AGEs Advanced glycation end products resistance AKT1s1 Proline-rich AKT1 substrate 1 HNE 4-Hydroxynonenal AKT-1 RAC-alpha serine/threonine-protein kinase IDE Insulin degrading enzyme AKT-2 RAC-beta serine/threonine-protein kinase ICV Intracerebroventricular APP Beta-amyloid precursor protein IGF-1R Insulin-like growth factor 1 receptor APOE e4 Apolipoprotein E e4 IR Insulin receptor AQP4 Aquaporin-4 IRBS Insulin resistant brain state ATP Adenosine triphospate IRb Insulin receptor subunit b BBB Blood brain barrier IRS1 Insulin receptor substrate-1 IRS-1pS616 Serin-phosphorylated insulin receptor substrate-1 Hakan Yaman 7 Clinical Hospital Merkur-University, Clinic Vuk Vrhovac, [email protected] Zajcˇeva (Zajceva) 19, 10000 Zagreb, Croatia Zheng G. Zhang 8 Department of Child and Adolescent Psychiatry and [email protected]; [email protected] Psychotherapy, Psychiatric Hospital, University Zurich, Zurich, Switzerland Tali Cukierman-Yaffe [email protected] 9 Neuroscience Center Zurich, University of Zurich and the ETH Zurich, Zurich, Switzerland 1 Center of Mental Health, Department Psychiatry, 10 Zurich Center for Integrative Human Physiology, University Psychosomatics and Psychotherapy, University Hospital of Zurich, 5th Floor Room K118, Wagistrasse 12, Wu¨rzburg, 97080 Wu¨rzburg, Germany 8952 Zurich, Switzerland 2 Center for Aging and Associated Diseases, Helmy Institute of 11 Institute of Clinical Neurobiology, Alberichgasse 5/13, Medical Science, Zewail City of Science and Technology, 1150 Vienna, Austria Giza, Egypt 12 Biomediotronics, Enzymoic, 7 Peterlee Pl, Hebersham, 3 Department of Neurology, Neurosurgery and Psychiatry, NSW 2770, Australia University of Medicine and Pharmacy Carol Davila Bucharest, S Plaiul Independentei 169, Sector 5, 13 King Fahd Medical Research Center, King Abdulaziz 050098 Bucharest, Romania University, P. O. Box 80216, Jeddah 21589, Saudi Arabia 4 Department of Neurology, Hallym Hospital, 900-4 14 Enzymoics, 7 Peterlee Place, Hebersham, NSW 2770, Jakjeon-dong, Gyeyang-gu, Incheon-si 407-060, Korea Australia 5 Department of Neurology, Henry Ford Hospital, Detroit, 15 Novel Global Community Educational Foundation, Sydney, MI, USA Australia 6 The Center for Successful Aging with Diabetes, 16 Department of Neurology, Tel Aviv University, Endocrinology Institute, Gertner Institute, Sheba Medical 69978 Ramat Aviv, Israel Center, Epidemiology D., Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel 123 The diabetic brain and cognition IRS2 Insulin receptor substrate-2 Introduction ISF Interstitial fluid KAT Kynurenine aminotransferase A causative association between diabetes mellitus (DM) KYNAC Kynurenic acid and cognitive impairment has been suggested based on MCI Mild cognitive impairment clinical, epidemiological, and experimental studies (Ala- MRI Magnet resonance imaging fuzoff et al. 2009; Bitel et al. 2012; Vagelatos and Eslick mTOR Mechanistic target of rapamycin 2013; Carvalho et al. 2015; Feinkohl et al. 2015; Jellinger OS Oxidative stress 2015a). PCAD Pre-clinical AD In fact, recent studies demonstrate a pathophysiological PET Positron emission tomography link between diabetes mellitus type II (T2DM) and cog- PG Postprandial glycemia nitive decline (Jellinger 2015b). This is demonstrated in PIK3CB Phosphatidylinositol-4,5-bisphosphate persons with DM showing that a higher risk of developing 3-kinase catalytic subunit beta isoform Alzheimer’s disease (AD), vascular dementia (VaD) and PIK3CD Phosphatidylinositol-4,5-bisphosphate mixed-type dementia (AD plus cerebrovascular disease), 3-kinase catalytic subunit delta and comorbidity, in particular cerebrovascular disease, PI3 Phosphatidylinositol-3-kinase hypertension, hypercholesterolemia, etc. increases this risk PI3K Phosphoinositid-3-kinase (Jellinger 2015b; Haroon et al. 2015; Kuo et al. 2015). PIP3 Phosphatidylinositol (3,4,5)-triphosphate Insulin resistance predicts medial temporal hyperme- PPARc Peroxisome proliferator-activated receptor tabolism in Mild Cognitive Impairment (MCI) conversion gamma to AD (Willette et al. 2015b). In addition, changes in P-Tau Phospho-Tau-Protein glucose uptake in medial temporal regions in AD predict PYY Peptide YY worse memory performance (Willette et al. 2015a). P53 Phosphoprotein p53 Moreover, DM facilitates cognitive decline in patients with QA Quinolinic acid mild AD compared to those without comorbid DM (Jel- RAGE Receptor for AGEs linger 2015a; Ascher-Svanum et al. 2015). However, the RNA Ribonucleic acid precise mechanisms involved in the development of AD in ROS Reactive oxygen species diabetics are not yet fully understood, and several patho- sAD Sporadic Alzheimer’s disease genic pathways have been discussed (Feinkohl et al. 2015; SGLT2 Sodium/glucose cotransporter 2 Abner et al. 2016; Hao et al. 2015; Chiu et al. 2015; STZ Streptozotocin Verdile et al. 2015; Bedse et al. 2015; De Felice et al. T2DM Type 2 diabetes mellitus 2014), including vascular brain disease, insulin resistance, T1DM Type 1 diabetes mellitus and other metabolic effects on the brain. VaD Vascular dementia In a meta-analysis, Chatterjee et al. (2016) estimated the WM White matter sex-specific relationship between women and men with DM with incident dementia. Fourteen