Type 2 Diabetes and Dementia

Velandai Srikanth, Zoe Arvanitakis

• Publisher: Academic Press
• Year: 2018
• Print ISBN: 9780128094549
• eBook ISBN: 9780128096949
• Topic: Medicine
• Subtopic: Neurology

Type 2 Diabetes and Dementia details the relationship between diabetes, dementia and the future of medicine and therapeutics. Chapters range from epidemiology, clinical features, neuroimaging biomarkers, neuropathology, macrostructural and molecular mechanisms, risk assessment and prevention strategies, and the application of therapeutics. The book reflects the translational aspects of the current science in the field, with an emphasis on the display of neuroimaging and neuropathology. It contains contributions from world experts, and is ideal for clinicians and researchers in the fields of neurology, neuroscience, geriatric medicine and endocrinology.- Presents a comprehensive overview that details the relationship between diabetes, dementia and the future of medicine and therapeutics- Written for researchers and clinicians in neurology, neuroscience, geriatric medicine and endocrinology- Includes topics ranging from epidemiology, clinical features, neuroimaging biomarkers, neuropathology, macrostructural and molecular mechanisms, risk assessment, prevention strategies and therapeutic applications

Chapter 1

Introduction

Velandai Srikanth¹, and Zoe Arvanitakis^2     1Peninsula Health and Monash University, Melbourne, VIC, Australia     ²Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, United States

We warmly congratulate the authors who have so graciously given their time and intellect to assist us in compiling this book. We believe that is the first book to synthesize state-of-the-art knowledge comprehensively about the complex relationship between two of the most prevalent and pressing health conditions in the world: type 2 diabetes mellitus (T2D) and dementia. This work comes from increasing recognition that the two disorders are strongly linked and at a time when we are on the cusp of a surge of research to clarify whether T2D and poor metabolic health are causal factors for dementia, and whether this understanding will advance knowledge about biological mechanisms underlying dementia and assist in devising interventions to prevent or delay the expression of dementia. The book draws from the significant expertise of internationally acclaimed researchers who have led the field in an understanding of this area. It presents a wide range of knowledge, spanning evidence from epidemiological, imaging, and neuropathological studies, through basic mechanisms linking the two disorders, and finally to potential ways to translate such findings, to modify the risk of dementia. We believe that this book will stimulate new and exciting research in dementia that will lead to discovery, translation, and ultimately, to therapeutic benefit.

Dementia is a major health condition predominantly affecting older people, a significant public health problem, and a global health priority. Dementia was highlighted as a major societal issue by the Group of Eight nations owing to the absence of effective disease-modifying medications (The Lancet, 2014). Interventions addressing risk factors and disease mechanisms in middle age or early older adult life are considered likely to be most effective in delaying the onset of dementia. Delaying symptoms by as little as 1 year could potentially lower dementia prevalence by >9 million cases worldwide over the next 30–40 years (Brookmeyer, Johnson, Ziegler-Graham, & Arrighi, 2007). Crucial to the development of interventions is an understanding of biological mechanisms underlying dementia. Study of the link between T2D and dementia provides a fertile ground for understanding new such mechanisms and a potential avenue toward developing therapeutic interventions relevant to a high-risk group.

T2D is a fast-growing chronic disease worldwide. The number of people with T2D rose from 108 million in 1980 to 422 million in 2014, resulting in an increase in adult T2D prevalence globally, particularly in the developing world (World Health Organization, 2016). It is composed of a cluster of features including adiposity, insulin resistance, insulin deficiency, hyperglycemia, high blood pressure, and hyperlipidemia that combine in various ways to cause disease in several organs including the heart, vascular tree, kidneys, eyes, and nerves. Only in the past decade or so has the potential contribution of T2D to brain health has become more obvious, leading to a surge in research efforts in the field. T2D is associated with a nearly twofold increase in the risk for incident dementia (Sutherland, Lim, Srikanth, & Bruce, 2017) irrespective of the subtype of dementia, and it is thought that 1 in 10 cases of dementia in the world are potentially attributable to T2D. Thus, study of the relationship between the two conditions provides an exciting opportunity to explore the contributions of several potential pathways and mechanisms leading to dementia. The chapters in this book take us on a journey of understanding in this field by presenting current knowledge while emphasizing gaps in knowledge and thus opportunities for future research.

The first two content-related chapters present readers with epidemiological evidence linking T2D and dementia. Gustafson et al. provide a concise introduction to this issue while bringing insights into the influence of certain important factors such as race/ethnicity and genes. Ganmore and Beeri then provide a comprehensive review of cross-sectional and longitudinal associations between T2D and cognitive function, drawing from an extensive search of the published literature to highlight particular cognitive functions that may be at risk for being affected in T2D. After this excellent introduction, the subsequent three chapters expand on evidence linking T2D to in vivo markers of dementia and to the neuropathology of dementia, to examine whether the impact of T2D on the brain may be explained by cerebrovascular disease, neurodegeneration, or both. Srikanth et al. elaborate on the impact of T2D on neuroimaging markers of dementia, drawing from studies using magnetic resonance imaging and positron emission tomography. Craft et al. provide a succinct review of the relationship of T2D with known cerebrospinal fluid biomarkers of Alzheimer’s disease and neurodegeneration. Pruzin et al. then complete this picture with a comprehensive update on the association of T2D with neuropathological markers of dementia, including evidence related to both cerebrovascular disease and neurodegeneration. The next series of chapters deal with potential causal mechanisms, modifiers or mediators that may underlie the link between T2D and dementia. Stoeckel et al. give some novel insights into the effects of diet, physical activity, and adiposity on the brain, while emphasizing the importance of disentangling their effects from those of T2D. Koening et al. then take on the complex task of reviewing the role of insulin in the brain, and whether insulin resistance and its related downstream molecular pathways may explain the pathophysiology of dementia. The subsequent two chapters deal with the potential roles of advanced glycation (Dhananjayan et al.), neuroinflammation (Bruce et al.), and blood–brain barrier integrity (Gray and Barrett) as mediators of the effect of T2D on the brain, and suggest future work to clarify their roles based on the potential for future therapies. The final chapter summarizes current clinical trial evidence regarding interventions in people with T2D designed to reduce the risk for dementia, highlighting this area as one of significant research opportunity.

In all, the book is designed not only to provide upto date knowledge but also to point to avenues for future research. We hope that it achieves its purpose and thus contribute to the betterment of health in people with T2D and those at risk for or experiencing dementia.

References

Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi H.M. Forecasting the global burden of Alzheimer’s disease. Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association. 2007;3(3):186–191. doi: 10.1016/j.jalz.2007.04.381.

Sutherland G.T, Lim J, Srikanth V, Bruce D.G. Epidemiological approaches to understanding the link between type 2 diabetes and dementia. Journal of Alzheimers Disease. 2017;59(2):393–403. doi: 10.3233/JAD-161194.

The Lancet. G8 dementia summit: A chance for united action. Lancet Neurology. 2014;13(1):1. doi: 10.1016/S1474-4422(13)70275-8.

World Health Organization. Global report on diabetes. 2016.

Chapter 2

Epidemiology of Type 2 Diabetes and Dementia

Deborah R. Gustafson^1,2,3, and Samy I. McFarlane^{1 1}State University of New York, Downstate Medical Center, Brooklyn, NY, United States ²University of Gothenburg, Gothenburg, Sweden ³University of Skövde, Skövde, Sweden

Abstract

Type 2 diabetes (T2D) has been associated with dementia in countless observational epidemiology studies. The expansion of epidemiologic research on T2D and dementia is due to scientific recognition of the roles of metabolic and vascular factors as etiologic players in dementia, as well as ominous global demographic shifts in aging, obesity, and dementia. This chapter addresses epidemiologic studies evaluating the association between T2D and late-onset dementias with foci on (1) T2D and dementia as syndromes; (2) T2D and mild cognitive impairment or cognition and cognitive decline; (3) vascular and metabolic risk factors and comorbidities; (4) genetic influences on the T2D–dementia association; (5) ethnoracial considerations; (6) T2D and brain outcomes and biological markers; and (7) clinical trials of T2D medications and cognition and dementia.

Keywords

Alzheimer; Biomarkers; Cognitive impairment; Dementia; Diabetes; Genetics; Metabolic; Vascular

Introduction

Epidemiological evidence of the association of type 2 diabetes (T2D) and brain health has been evolving for over 50 years. The occurrence of cognitive changes with T2D has been noted since the early 20th century, but a PubMed search indicates the first description of mental aberrations in T2D in 1963 (Ives, 1963). Ten years later, a description of brain damage in T2D was published in the British Journal of Psychiatry (Bale, 1973). An investigation of the potential association between T2D (and other metabolic and vascular risk factors) and “dementia of the Alzheimer type” (DAT) was based on a clinical sample of persons with and without T2D, and suggested that T2D was not associated with DAT. In 1989 the term “brittle diabetes” was introduced to describe elderly individuals whose lives were disrupted by large variations in metabolic control. This was particularly observed among those termed as having “prodromal or senile dementia,” who mismanaged the T2D, as well as those experiencing large variations in metabolic control reflecting early mental deterioration. A first prospective study of T2D and dementia was also published in 1989 and included volunteers aged 75–85 years who were observed for 5 years (Katzman et al., 1989). Although the number of participants was not large, T2D was associated with higher risk of vascular dementia (VaD) but not Alzheimer’s disease (AD) (Katzman et al., 1989).

Since the late 1980s, case–control and prospective epidemiologic studies around the world have reported an association between T2D and dementia (Akomolafe et al., 2006; Arvanitakis, Wilson, Bienias, Evans, & Bennett, 2004; Bellou et al., 2016; Chatterjee et al., 2016; Cheng, Huang, Deng, & Wang, 2012; Cheng, Sy, Wu, Wang, & Chen, 2012; Chiu et al., 2015; Ganguli, Fu, Snitz, Hughes, & Chang, 2013; Gould, Beaudreau, & Salman, 2013; Goveas et al., 2016; Haring ...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• List of Contributors
• Foreword
• Chapter 1. Introduction
• Chapter 2. Epidemiology of Type 2 Diabetes and Dementia
• Chapter 3. Magnitude and Trajectories of Cognitive Dysfunction in Type 2 Diabetes Mellitus
• Chapter 4. Brain Imaging in Type 2 Diabetes
• Chapter 5. Cerebrospinal Fluid and Blood-Based Biomarkers in Alzheimer’s Disease and Type 2 Diabetes Spectrum Disorders
• Chapter 6. Neuropathological Insights Into the Link Between Type 2 Diabetes and Dementia
• Chapter 7. Diet, Obesity, and Physical Inactivity: Linking Diabetes and Dementia
• Chapter 8. The Role of Insulin Resistance and Signaling in Dementia
• Chapter 9. Advanced Glycation, Diabetes, and Dementia
• Chapter 10. Neuroinflammation, Type 2 Diabetes, and Dementia
• Chapter 11. The Blood–Brain Barrier in Diabetes Mellitus
• Chapter 12. Pharmacological and Nonpharmacological Interventions for Cognitive Impairment and Dementia Related to Type 2 Diabetes and Metabolic Disturbances in Aging
• Author Index
• Subject Index