Front Cover

Type 2 Diabetes and Dementia

Type 2 Diabetes and Dementia

Copyright

Contents

List of Contributors

Foreword

1 - Introduction

REFERENCES

2 - Epidemiology of Type 2 Diabetes and Dementia

INTRODUCTION

CONSIDERATIONS WHEN EVALUATING THE OBSERVATIONAL EPIDEMIOLOGIC LITERATURE

EPIDEMIOLOGIC STUDIES EVALUATING THE ASSOCIATION OF TYPE 2 DIABETES AND LATE-ONSET DEMENTIAS

Diabetes and Dementia Are Syndromes

Type 2 Diabetes and Mild Cognitive Impairment or Cognition and Cognitive Decline

Vascular and Metabolic Risk Factors and Comorbidities

Genetic Influences on the Type 2 Diabetes–Dementia Association

Ethnoracial Considerations

Brain Outcomes and Biological Markers

Intervention and Prevention Studies

Insulin Therapies

Oral Hypoglycemic Agents

Prevention Studies

CONCLUSION

ACKNOWLEDGMENTS

REFERENCES

3 - Magnitude and Trajectories of Cognitive Dysfunction in Type 2 Diabetes Mellitus

INTRODUCTION

TYPE 2 DIABETES AND COGNITIVE DYSFUNCTION

Type 2 Diabetes and Cognitive Performance (Cross-sectional Evidence)

Memory

Attention and Processing Speed

Executive Function and Working Memory

Verbal Fluency and Language

Perceptual–Motor Function

Global Cognitive Function

Type 2 Diabetes and Cognitive Decline (Longitudinal Evidence)

Memory

Attention and Processing Speed

Executive Function and Working Memory

Language and Verbal Fluency

Perceptual–Motor Function

Global Cognitive Function

SUMMARY

ABBREVIATIONS

REFERENCES

4 - Brain Imaging in Type 2 Diabetes

INTRODUCTION

BRAIN MAGNETIC RESONANCE IMAGING STUDIES OF TYPE 2 DIABETES

Diabetes and Magnetic Resonance Imaging Markers of Cerebrovascular Disease

Type 2 Diabetes, Cerebral Infarcts, and Cognitive Function

Type 2 Diabetes, White Matter Hyperintensities, and Cognitive Function

Type 2 Diabetes, Cerebral Microbleed, and Cognitive Function

Type 2 Diabetes, Cerebral Perfusion, and Blood–Brain Barrier

Type 2 Diabetes, Magnetic Resonance Imaging Markers of Neurodegeneration, and Connectivity

Type 2 Diabetes and Brain Volumes

Type 2 Diabetes, White Matter Microstructure, and Structural Networks

Type 2 Diabetes and Functional Connectivity

POSITRON EMISSION TOMOGRAPHY STUDIES IN TYPE 2 DIABETES

Fluorodeoxyglucose Positron Emission Tomography Studies in Type 2 Diabetes

Positron Emission Tomography Studies of Amyloid, Tau, and Neuroinflammation in Type 2 Diabetes

CONCLUSION

REFERENCES

5 - Cerebrospinal Fluid and Blood-Based Biomarkers in Alzheimer’s Disease and Type 2 Diabetes Spectrum Disorders

INTRODUCTION

ALZHEIMER’S DISEASE FLUID BIOMARKERS

ALZHEIMER’S DISEASE BIOMARKERS IN INSULIN RESISTANCE AND TYPE 2 DIABETES

MARKERS OF INFLAMMATION AND NEURAL INJURY

MARKERS OF BLOOD–BRAIN BARRIER AND ENDOTHELIAL/VASCULAR FUNCTION

MARKERS OF RECEPTOR-MEDIATED Β-AMYLOID TRANSPORT

MARKERS OF MICRORNA EXPRESSION

MARKERS OF PROTEIN GLYCATION AND OXIDATION

MARKERS OF EXOSOMAL COMPOSITION

SUMMARY AND FUTURE DIRECTIONS

ACKNOWLEDGMENT

REFERENCES

6 - Neuropathological Insights Into the Link Between Type 2 Diabetes and Dementia

INTRODUCTION

VASCULAR NEUROPATHOLOGY

Brain Infarcts

Atherosclerosis

Arteriolosclerosis

Cerebral Amyloid Angiopathy

Other Pathophysiologies: Blood–Brain Barrier, Lymphatics, and Indirect Vascular Effects

ALZHEIMER’S DISEASE NEUROPATHOLOGY

Neuritic Amyloid Plaques

Neurofibrillary Tangles

Alzheimer’s Disease Neuropathology by Brain Region

Alzheimer’s Disease Neuropathology and Apolipoprotein E ε4

Other Neurodegenerative Pathologies: Parkinson’s Disease, Lewy Body Dementia, and Tauopathies

SUMMARY AND FUTURE DIRECTIONS

REFERENCES

7 - Diet, Obesity, and Physical Inactivity: Linking Diabetes and Dementia

INTRODUCTION

DELETERIOUS EFFECTS OF OBESITY ON NEUROCOGNITION AND THE RELATIONSHIP TO TYPE 2 DIABETES

Executive and Appetitive Function

Hippocampal-Dependent Functions

Dopamine Adaptations

Hippocampal Dysfunction

Mood and Emotion

Effects of Diet and Macronutrients

Effects of Sedentary Behavior

BENEFICIAL EFFECTS OF DIET AND PHYSICAL ACTIVITY ON NEUROCOGNITION, AND THE RELATIONSHIP TO NEUROCOGNITIVE DYSFUNCTION IN OBESIT...

Diet and Macronutrients

Physical Activity and Exercise

CONCLUSIONS

FUTURE DIRECTIONS

SUMMARY

REFERENCES

8 - The Role of Insulin Resistance and Signaling in Dementia

INTRODUCTION

INSULIN AND ITS DIVERSE CELLULAR ACTIONS

INSULIN AND THE BLOOD–BRAIN BARRIER

DOES INSULIN SYNTHESIS OCCUR IN THE BRAIN?

INSULIN’S ACTIONS IN THE BRAIN

Neurons and Synapses

Astrocytes

Oligodendrocytes

Microglia

THE OVERARCHING EFFECTS OF INSULIN IN THE BRAIN: METABOLISM AND COGNITION

Effects on Systemic Metabolism

Cognitive Function

BRAIN INSULIN RESISTANCE: AN EMERGING CONSTRUCT

Type 2 Diabetes–Associated Cognitive Impairment

Brain Insulin Resistance in Aging, Alzheimer’s Disease, and Other Neurodegenerative Disorders

SUMMARY

REFERENCES

9 - Advanced Glycation, Diabetes, and Dementia

INTRODUCTION

ADVANCED GLYCATION END PRODUCTS AND THEIR PRECURSORS

ADVANCED GLYCATION END PRODUCTS AND THEIR PRECURSORS ACCUMULATE IN TISSUES OF PEOPLE WITH TYPE 2 DIABETES MELLITUS

NONRECEPTOR MEDIATED INTERACTION OF ADVANCED GLYCATION END PRODUCTS

Cross-linking of Collagen in Blood Vessels

ADVANCED GLYCATION END PRODUCT–RECEPTOR FOR ADVANCED GLYCATION END PRODUCT INTERACTION AND GLUCOSE DYSREGULATION IN TYPE 2 DIABE...

Advanced Glycation End Product–Receptor for Advanced Glycation End Product: Downstream Signaling Pathways Contributing to Reacti...

Reactive Oxygen Species Formation

Inflammation and Insulin Resistance

ADVANCED GLYCATION END PRODUCTS AND THEIR PRECURSORS AS MECHANISTIC FACTORS FOR COGNITIVE DECLINE IN DIABETES: CLINICAL STUDIES

PHARMACOTHERAPEUTIC INTERVENTION: DECREASING ADVANCED GLYCATION END PRODUCT ACCUMULATION AND SIGNALING TO PREVENT COGNITIVE DECL...

Receptor for Advanced Glycation End Product Antagonists

Advanced Glycation End Product Inhibitors/Methylglyoxal Scavengers

FUTURE PERSPECTIVE

REFERENCES

10 - Neuroinflammation, Type 2 Diabetes, and Dementia

INTRODUCTION

TYPE 2 DIABETES AND SYSTEMIC INFLAMMATION

MICROGLIAL PRIMING, NEUROINFLAMMATION, AND ALZHEIMER’S DISEASE

TYPE 2 DIABETES AND NEUROINFLAMMATION

Evidence From Human Studies

Relevant Animal Models of Type 2 Diabetes

Genetically Obese (Lepob/ob and Leprdb/db) Mice

Zucker Diabetic Fatty Rats

High-Fat Feeding

Combination Models

CONCLUSION AND PERSPECTIVES

REFERENCES

11 - The Blood–Brain Barrier in Diabetes Mellitus

INTRODUCTION

STRUCTURE AND FUNCTION OF THE BLOOD–BRAIN BARRIER IN HEALTH

The Blood–Brain Barrier and Cerebrospinal Fluid Circulation

Transiting From Blood Into the Brain—First Obstacle: The Microvascular Endothelial Cell

Microvascular Endothelial Cells Selectively Facilitate Blood–Brain Barrier Nutrient Transport

How Microvascular Endothelial Cell Transport Is Regulated by Other Cells

Astrocytes Regulate Blood–Brain Barrier (Neurovascular Couplings and Vascular Tone)

ALTERED BLOOD–BRAIN BARRIER STRUCTURE AND FUNCTION WITH DIABETES

Structural Brain Microvascular Changes With Diabetes

Functional Blood–Brain Barrier Changes in Diabetes

What Is the Effect of Diabetes on Known Transporters Within the Microvascular Endothelial Cell?

SUMMARY AND CONCLUSION

ACKNOWLEDGMENTS

REFERENCES

12 - Pharmacological and Nonpharmacological Interventions for Cognitive Impairment and Dementia Related to Type 2 Diabetes and Metabolic Disturbances in Aging

PHARMACOLOGICAL INTERVENTIONS

Glycemic Control

Glucose-Lowering Drugs

Metformin

Sulfonylureas

Thiazolidinediones

Glucagon-like Peptide-1

Dipeptidyl Peptidase IV Inhibitors

Insulin

Blood Pressure Control

NONPHARMACOLOGICAL INTERVENTIONS

Exercise

Diet and Nutrition

Combination Interventions of Diet and Exercise

Bariatric/Metabolic Surgery

CONCLUSION AND FUTURE DIRECTIONS

REFERENCES

Author Index

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Subject Index

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