Molecular Mechanisms of Dementia

Biomarkers, Neurochemistry, and Therapy

Akhlaq A. Farooqui

• Publisher: Academic Press
• Year: 2019
• ISBN:
  9780128167311
• Topic: Biological Sciences
• Subtopic: Neuroscience
• Index: Biological Sciences

Considerable progress has been made in neurochemical and therapeutic aspects of dementia research in recent years. Molecular and Therapeutic Aspects of Dementia presents readers with comprehensive and cutting-edge information on the neurochemical mechanisms of various types of dementias. It provides a clearly written and logically organized and comprehensive overview of molecular aspects of risk factors, symptoms, pathogenesis, biomarkers, and therapeutic strategies for various types of dementia. This book is written for the international audience of neurochemists, neuroscientists, neurologists, neuropharmacologists, and clinicians. The hope is that this discussion will not only integrate and consolidate knowledge in this field, but will jumpstart more studies on molecular mechanisms and therapeutic aspects of dementia.

The comprehensive information in this monograph may not only help in early detection of various types of dementia and dementia linked neurological disorders, but also promote discovery of new drugs, which may block or delay the onset of dementia in elderly patients. Understanding the course of dementia is important not only for patients, caregivers, and health professionals, but also for health policy-makers, who have to plan for national resources needed in the management of an increasing number of dementia cases.

• Provides a comprehensive overview of molecular aspects of risk factors, symptoms, pathogenesis, biomarkers, and therapeutic strategies for various types of dementia
• Summarizes cutting edge research information on signal transduction processes associated with neurochemistry of dementia
• Discusses the synthesis, metabolism, and role of lipid mediators in dementia

Chapter 1

Neurochemical Aspects of Dementia

Abstract

Dementia is becoming increasingly prevalent among the elderly population. In 2001, ~24 million people worldwide were afflicted with dementia, and that number is estimated to double to an estimated prevalence of 42 million by 2020 and 81 million by 2040. Dementia is challenging from a medical care perspective since it is both progressive and irreversible. Additionally, dementia is a leading cause of admission to long-term care facilities and a major risk factor for hospitalization. AD is the most common form of dementia, and it constitutes approximately two-thirds of all cases. It is currently hypothesized that the pathophysiology of AD involves the accumulation of amyloid beta proteins and the hyperphosphorylation of tau proteins, which leads to neurofibrillary tangles and neuronal loss in the brain. However, AD pathogenesis is multifactorial, whereby both genetic susceptibility and environmental factors contribute to neurodegeneration.

Keywords

Aging; cognition; risk factors; dementia; behavioral changes; psychological symptoms

Introduction

Due to the increase in life expectancy, the number of elderly across the globe is increasing at a constant rate and it is estimated that the number of seniors will increase to approximate 2.1 billion by the year 2050 worldwide (United Nations, 2015; WHO, 2016). In the United States, the number of seniors is predicted to increase from approximately 45 million currently to 70 million by the year 2030 (Ortman et al., 2014); similarly, in the European Union the number of seniors over the age of 80 is expected to grow from 5% to 12% of the population (The 2015 Ageing Report, 2015). In 2016, Canada had more persons over the age of 65 (16.9%) than under the age of 15 (16.6%) (Government of Canada, Statistics Canada, 2016). This global trend is driven largely by the baby boom generation, born between 1946 and 1964, which began entering their senior years in 2011. Increase in life expectancy is a major risk factor for cognitive deterioration. Dementia is a Latin word which means madness or mindlessness (De means without and ment means mind). In a medical context, dementia is not a name for a particular disease, but a progressive neurodegenerative syndrome, which is characterized by impairment in memory and activities of daily living, altered behavior, personality, and other cognitive dysfunctions (Sosa-Ortiz et al., 2012). Dementia mainly affects older people: only 2% of cases start before the age of 65 years. After this, the prevalence doubles with every 5-year increment in age. Dementia is one of the major causes of disability in later life. In 2010, there were 35.6 million people suffering from dementia worldwide and this number is projected to double over the subsequent 20 years (Prince et al., 2013a). Dementia not only results in deterioration in cognitive function (i.e., the ability to process thought) beyond what might be expected from normal aging, but also affects memory, thinking, orientation, comprehension, calculation, learning capacity, language, and judgment. The prevalence rate for dementia increases with advancing age (Sosa-Ortiz et al., 2012). Thus, persons above 60 years of age show 0.43% prevalence whereas persons aged above 65 years show 2.44% prevalence. The prevalence rate rises to 54.8% in individuals above 95 years of age (Vas et al., 2001). The impairment in cognitive function is commonly accompanied, and occasionally preceded, by deterioration in emotional control, social behavior, or motivation. Importantly, 75% of people with dementia manifest some, but not all, symptoms of dementia at a given time (Lyketsos et al., 2002). According to World Health Organization estimates 35.6 million people live with dementia, a number that is anticipated to triple by 2050 (World Health Organization, 2012).

Mild cognitive impairment (MCI) is form of predementia, which is characterized by objective impairment in cognition that is not severe enough to require help with usual activities of daily living. MCI leads to general forgetfulness in many people as they age. However, only a few MCI patients develop dementia. The mild dementia involves memory loss, confusion, personality changes, getting lost, and difficulty in planning and carrying out tasks. In moderate dementia daily life becomes more challenging, and the patient may require help in performing daily life activities. Symptoms are similar to mild dementia along with significant changes in personality (Sosa-Ortiz et al., 2012; Rizzi et al., 2014). Severe dementia involves all the symptoms of moderate dementia and the loss of the ability to communicate. The patient may need full-time care. Simple tasks, such as sitting and holding one’s head up become impossible along with the loss of bladder control. According to the World Health Organization (2012) most of the increase in dementia patients will occur in low- and middle-income countries. Thus, currently 62% of all people with dementia live in such regions. This proportion may increase to 66% in 2030 and 71% in 2050. The fastest growth in the elderly population is taking place in China, India, and their south Asian and western Pacific neighbors (Dong et al., 2007; Llibre Rodriguez et al., 2008; Plassman et al., 2007). Although recent studies suggest a decline in prevalence (Matthews et al., 2013), dementia remains a devastating and costly disease. In the United States the cost of dementia has already surpassed that of cancer and heart diseases (Hurd et al., 2013). The realization of its paramount public health impact has led nations, including the United States, to develop national plans to cope with dementia and attempt to reduce its devastating effects (National Alzheimer’s Project Act; Public Law 111-375).

As stated above, dementia syndrome not only results in deterioration in cognitive function (i.e., the ability to process thought) beyond what may be expected from normal aging, but also affects memory, thinking, orientation, comprehension, calculation, learning capacity, language, and judgment. A gradual age-related cognitive dysfunction, particularly in executive function and mental speed, is evident even in nondemented oldest-old. Hearing and vision losses, which are also prevalent in the oldest-old and found in some cases to precede/predict cognitive decline, may mechanically interfere in neuropsychological evaluations. As stated above, the prevalence rate for dementia increases essentially with advancing age (Savva et al., 2009). Thus, persons above 60 years of age show 0.43% prevalence, whereas persons aged above 65 years show 2.44% prevalence. The prevalence rate rises to 54.8% in individuals above 95 years of age (Vas et al., 2001; Cerejeira et al., 2012). It is stated that impairment in cognitive function in dementia is commonly accompanied, and occasionally preceded, by deterioration in emotional control, social behavior, or motivation. These processes may result in memory loss, and cognitive impairment. Among humans, the impact of dementia can be felt at three interrelated levels: the individual (patients with dementia), their family and friends, and wider society. While dementia does shorten the lives of those affected, its greatest impact is upon quality of life, both for individuals living with dementia, and for their family and carers. The total estimated worldwide costs of managing dementia were US$ 604 billion in 2010, equivalent to 1% of the world’s gross domestic product (Prince et al., 2013a,b). Low-income countries accounted for just less than 1% of total worldwide costs (but 14% of the prevalence of dementia), middle-income countries for 10% of the costs (but 40% of the prevalence of dementia) and high-income countries for 89% of the costs (but 46% of the prevalence of dementia). About 70% of the global costs occurred in just two regions: Western Europe and North America. These discrepancies are accounted for by the much lower costs per person in lower income countries – US$ 868 in low-income countries, US$ 3109 in lower-middle-income, US$ 6827 in upper-middle-income, and US$ 32,865 in high-income countries (Wimo et al., 2017).

Classification of Dementias

Several types of dementia have been reported to occur in the human population including Alzheimer’s type of dementia (30%), vascular dementia (VaD; 26%), mixed dementia (21%), Lewy body dementia (LBD; 11%), frontotemporal dementia (FTD)/degeneration (7%), and infective dementia (5%) (Fig. 1.1). Secondary causes of dementia include vascular, CNS infections, trauma, metabolic derangements, and other reversible/treatable causes such as type 2 diabetes, stroke, AIDS, or multiple sclerosis (Kabasakalian and Finney, 2009; Ironside and Bell, 2007). Sometimes dementia-mediated changes become reversible. This is called pseudodementia. Pseudodementia is caused by depression, malnourishment (vitamin deficiency), dehydration, medications, sleep deprivation, metabolic problems, excessive drinking, smoking, and infections. Symptoms of dementia are underrecognized. The understanding of behavioral and psychological symptoms of dementia (BPSD) would be helpful for an early diagnosis and better management so as to improve the patients’ quality of life (Levy and Chelune, 2007; Cerejeira et al., 2012; Kales et al., 2015).

Figure 1.1 Proportions of various types of dementia found in the human population. AD, Alzheimer’s type of dementia; FTD, frontotemporal dementia; ID, infective dementia; LBD, Lewy body dementia; MD, mixed dementia; VD, vascular dementia.

Alzheimer’s disease (AD) type of dementia is the most common cause of dementia (30%) and is rare before 60 years of age. AD type of dementia is characterized clinically by progressive memory and orientation loss and other cognitive deficits, including impaired judgment and decision-making, apraxia, and language disturbances. AD type of dementia is accompanied by the accumulation of Aβ peptide in the form of senile plaques (Farooqui, 2017). These Aβ plaques are tho...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Dedication
• About the Author
• Preface
• Acknowledgments
• List of Abbreviations
• Chapter 1. Neurochemical Aspects of Dementia
• Chapter 2. Neurochemical Aspects of Poststroke Dementia
• Chapter 3. Neurochemical Aspects of Alzheimer’s Type of Dementia
• Chapter 4. Neurochemical Aspects of Lewy Body Dementia
• Chapter 5. Neurochemical Aspects of Vascular Dementia
• Chapter 6. Neurochemical Aspects of Frontotemporal Dementia
• Chapter 7. Potential Treatment Strategies for Dementia With Pharmacological and Nonpharmacological Interventions
• Chapter 8. Potential Treatment Strategies for the Treatment of Dementia With Chinese Medicinal Plants
• Chapter 9. Potential Treatment Strategies of Dementia With Ayurvedic Medicines
• Chapter 10. Summary and Perspective for Future Research on Dementia
• Index