The Molecular and Clinical Pathology of Neurodegenerative Disease

Patrick A. Lewis, Jennifer E. Spillane

• Publisher: Academic Press
• Year: 2018
• Print ISBN: 9780128110690
• eBook ISBN: 9780128110706
• Topic: Biological Sciences
• Subtopic: Neuroscience
• Index: Biological Sciences

The Molecular and Clinical Pathology of Neurodegenerative Disease brings together in one volume our current understanding of the molecular basis of neurodegeneration in humans, targeted at neuroscientists and graduate students in neuroscience, and the biomedical and biological sciences. Bringing together up-to-date molecular biology data with clinical evidence, this book sheds a light on common molecular mechanisms that underlie many different neurodegenerative diseases and addresses the molecular pathologies in each. The combined research and clinical background of the authors provides a unique perspective in relating clinical experiences with the molecular understanding needed to examine these diseases and is a must-read for anyone who wants to learn more about neurodegeneration.- Provides an up-to-date summary of neurodegeneration at a molecular, cellular, and tissue level for the most common human disorders- Describes the clinical background and underlying molecular processes for Alzheimer's disease, Parkinson's, Prion, Motor Neuron, Huntington's, and Multiple Sclerosis- Highlights the state-of-the-art treatment options for each disorder- Details examples of relevant cutting edge experimental systems, including genome editing and human pluripotent stem cell-derived neuronal models

Chapter 1

An Introduction to Neurodegeneration

Abstract

Neurodegenerative disease represents one of the greatest challenges to human health in the 21st century, striking the most complex organ in the human body and causing huge damage to some of the most fundamental human traits, including memory and personality. Our current understanding of these disorders builds upon decades, and sometimes centuries, of progress in neuroscience and clinical medicine. The aim of this chapter is to provide a brief introduction to neurodegeneration and to offer an overview of some of the key concepts and areas of biology that underpin efforts to develop treatments for these disorders.

Keywords

Clinical trials; Neuroanatomy; Neurodegeneration; Neurogenetics; Neurology

Chapter Outline

1. 1.1 What is Neurodegeneration?
2. 1.2 How to Use This Textbook
3. 1.3 The Fundamentals of Neuroanatomy
4. 1.4 A Beginner’s Guide to Brain Cells
5. 1.5 Clinical Tools
6. 1.6 Methods and Models for Investigating Neurodegeneration
7. 1.7 Drugs, Drug Development, and Clinical Trials
8. 1.8 Summary
9. Further Reading
10. References

1.1. What is Neurodegeneration?

The brain is the most complex organ in the body, the seat of cognition, and the control center for bodily function. It is made up of over 80 billion neurons and a supporting cast of tens of billions of other cells; it encapsulates much of what makes us human and is home to the knowledge, skills, and memories that define us as individuals. Small wonder then that diseases affecting this organ, and the consequences of these disorders upon human health, cognition, and function, are of great concern to society and health services across the world. Among the neurological disorders, neurodegenerative diseases, i.e., diseases that result in the death of neuronal cells in the central nervous system, have proved to be a particular challenge. Neurodegenerative diseases include a number of clinical entities, such as Alzheimer disease, Parkinson disease, Huntington chorea, and motor neuron disease. These disorders are characterized by the loss of cells in the central nervous system, coupled with the loss of specific brain function linked to the spatial distribution of cell death and the neuronal circuits impacted by degeneration. The impact that this has on health can be (and in the majority of cases, is) devastating, with a loss of both physical and mental ability resulting in decreased independence and incapacitation. This, in turn, leads to greatly increased mortality and huge costs on a personal level, for immediate family and friends, and more broadly at a societal level. This is most easily quantified in terms of healthcare costs, where some of the most common neurodegenerative disorders (Parkinson and Alzheimer diseases) have been estimated to afflict more than 7.5 million people in Europe alone, costing in excess of €110 billion [1,2] (Fig. 1.1). Worldwide, this represents a huge societal burden, excluding much of the unquantifiable damage and pain that these diseases bring to individuals and to families.

Figure 1.1 The estimated costs of brain diseases in Europe. The number of patients, costs per patient, and total costs are shown for a sample of the most common brain disorders. Highlighted in purple are the most common neurodegenerative disorders, indicating the high costs and disease burden inflicted by these disorders. PPP, purchasing power party.
Adapted from DiLuca M, Olesen J. The cost of brain diseases: a burden or a challenge? Neuron 2014;82:1205–8. Epub 2014/06/20.

The challenge presented to human health by neurodegenerative disorders is magnified by the fact that the majority of these disorders increase in incidence with age [3]. In a world where the global human population is aging, neurodegenerative disease is set to become an even bigger challenge to healthcare systems. Unfortunately, to date, this is a challenge that biomedical research has struggled to address. For symptomatic relief, there are drugs available for a subset of neurodegenerative diseases with variable clinical outcomes; for example, there are excellent drugs that combat the movement symptoms associated with Parkinson disease during the early stages of the disease (see Chapter 3 for further detail). For disease-modifying treatments, that is, a treatment that either delays or halts the progress of the disease, there are very few examples to hold up as evidence that we can change the clinical trajectory of these disorders. As such, the development of a detailed understanding of the molecular basis of these disorders—to know why cells are dying in the central nervous system—is of critical importance for drug development, as well as providing insight into the fundamental biology of the human brain. This molecular basis of neurodegenerative disease is the subject of this textbook.

1.2. How to Use This Textbook

The goal of this textbook is to provide a detailed grounding in the molecular cause of neurodegenerative diseases. To achieve this, each chapter is divided into a number of relevant areas, including a brief historical introduction to the disorder/disorders, a description of the clinical presentation of the disease entity in question, an overview of the pathological condition observed in the brains of people with these disorders, a detailed description of our present understanding of the molecular basis of the disease, and finally an overview of the current state of therapies and drug development. It is important to emphasize at this point that this book is not intended to be a textbook of neurology or neuropathology, and for in-depth coverage of these areas the reader is directed to a number of excellent reference texts [4–6]. In order to understand the molecular basis of neurodegeneration, however, it is absolutely essential to have an overview of both the underlying changes in the brain (with regard to cellular pathology and spatial distribution) and the clinical consequences of these changes.

Although there is considerable variation in the presentation and the underlying pathological condition of neurodegenerative diseases, as well as in the molecular basis of these disorders, there are a number of key concepts and approaches that readers should be familiar with to gain most from the disease-specific chapters. This introduction aims to provide a brief overview of these concepts, and for a more detailed description of each of these topics there are excellent reviews and books available, some of which are indicated at the end of the chapter.

1.3. The Fundamentals of Neuroanatomy

Central to our ability to explore how the brain goes wrong in neurodegeneration is a detailed understanding of how the brain functions as an organ and at a cellular level. This, in turn, is underpinned by insights into the organization of the brain—the study of neuroanatomy [7]. Our understanding of the structure and function of the human brain has undergone significant changes over the past several centuries (Box 1.1). Moving from early modern concepts of the brain being divided into discrete structures, we now have a very detailed understanding of the organization of the brain and how this connects outside the central nervous system to the rest of the body.

The macroscopic organization of the human central nervous system can be described in several different ways. It can be divided up into functionally and anatomically distinct macrostructures that are commonly noted as the cerebrum or cerebral hemispheres (the outer convoluted layers of the brain that are visible to the eye when a brain is removed from the skull combined with deeper structures), the diencephalon (made up of the thalamus and hypothalamus), the brain stem (consisting of the midbrain, pons, and medulla oblongata), the cerebellum at the base of the skull, and finally the spinal cord descending out of the brain and out to the rest of the body (Fig. 1.2A). Each of these structures can be further divided in several ways. The cerebral hemispheres, for example, can be functionally divided into several distinct structures: the amygdala, the hippocampus, the basal ganglia, and the cerebral cortex, which in turn can be subdivided into four lobes, the frontal, temporal, parietal, and occipital (Fig. 1.2B). These anatomical divisions relate to important functional distinctions. The hippocampus (the name of which derives from the Greek for seahorse, based on its distinctive shape), for example, plays a key role in spatial memory, which in turn allows us to navigate through our environment.

Box 1.1 Neuroanatomy through the ages

Our understanding of the brain has progressed from simple division of the brain into ventricles through more complex projections of the brain by Leonardo da Vinci and detailed anatomical descriptions to sophisticated computer-based imaging of the connections formed within the brain. Images from the top show a depiction of the brain dating from the 14th century, Leonardo da Vinci’s diagram of the brain from the 16th century, a drawing of the brain by Jean-Baptiste Bourgery from the 19th century, a diagrammatic representation of some of the anatomical subdivisions of the brain from the early 20th century by Johannes Sobotta, and a connectomics map of the brain using advanced imaging techniques by Flavia Dell’Acqua. Images re-used by permission of Creative Commons licence from the Wellcome Image library or in the public domain.

Figure 1.2 The neuroanatomy of the human brain. An overview of the macroscopic organization of the human brain, showing (A) the functionally and anatomically distinct major areas of the brain and (B) the division of the cerebrum into the frontal, parietal, temporal, and occipital lobes.
Images adapted from the Blau...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Preface
• Acknowledgments
• Chapter 1. An Introduction to Neurodegeneration
• Chapter 2. Alzheimer’s Disease and Dementia
• Chapter 3. Parkinson’s Disease
• Chapter 4. The Prion Diseases
• Chapter 5. The Motor Neuron Diseases and Amyotrophic Lateral Sclerosis
• Chapter 6. Huntington’s Chorea
• Chapter 7. Multiple Sclerosis
• Index