Spectrums of Amyotrophic Lateral Sclerosis

Heterogeneity, Pathogenesis and Therapeutic Directions

Christopher A. Shaw, Jessica R. Morrice, Christopher A. Shaw, Jessia R. Morrice

• Publisher: Wiley-Blackwell
• Year: 2021
• ISBN:
  9781119745518
• Edition: 1
• Topic: Biological Sciences
• Subtopic: Neuroscience
• Index: Biological Sciences

SPECTRUMS OF AMYOTROPHIC LATERAL SCLEROSIS

Discover state-of-the-art research findings on ALS from leading authors and editors in the field

In Spectrums of Amyotrophic Lateral Sclerosis: Heterogeneity, Pathogenesis & Therapeutic Directions, distinguished researchers and editors Dr. Christopher A. Shaw and Jessica R. Morrice deliver a practical and powerful perspective on Amyotrophic Lateral Sclerosis (ALS) as a heterogeneous spectrum of disorders. This increasingly accepted point-of-view allows researchers and medical professionals to develop better targeted interventions and more precise therapies.

In the book, readers will find chapters on a wide variety of critical issues facing ALS researchers and healthcare practitioners treating ALS sufferers, including animal models of ALS, neuronal support cells known to have a pivotal role in ALS, and current challenges in ALS clinical trials, among others. The authors describe pathologic features common to all cases of ALS and why animal models, though crucial, should be interpreted with caution. Finally, multiple genetic and environmental etiologies of the disease are discussed.

Readers will also benefit from the inclusion of:

• A thorough introduction to ALS as a spectrum disease and the implications for models, therapeutic development and clinical trial design
• Explorations of the genetic basis of ALS, prospective sALS etiologies, and the involvement of microbiome in ALS
• Discussions of ALS-PDC and environmental risk factors, protein aggregation in ALS, defects in RNA metabolism in ALS, and the non-cell autonomous nature of ALS and the involvement of glial cells
• Examinations of animal models of ALS and perspectives on previously failed ALS therapeutics and current therapeutic strategies

Perfect for clinical neurologists, healthcare providers and caretakers, clinicians, and researchers studying motor neuron disease, Spectrums of Amyotrophic Lateral Sclerosis: Heterogeneity, Pathogenesis & Therapeutic Directions is also an indispensable resource for the neurodegenerative research community, neurology residents, and graduate-level neuroscience students.

CHAPTER 1
Clinical Heterogeneity of ALS – Implications for Models and Therapeutic Development

Serena Lattante^1,2 and Mario Sabatelli^3,4

¹ Unità Operativa Complessa di Genetica Medica, Dipartimento di Scienze di Laboratorio e Infettivologico, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy

² Sezione di Medicina Genomica, Dipartimento Scienze della Vita e Sanità Pubblica, Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore, Rome, Italy

³ Centro Clinico NEMO adulti, U.O.C. Neurologia, Dipartimento di Scienze dell’Invecchiamento, Neurologiche, Ortopediche e della Testa‐Collo Fondazione

⁴ Sezione di Neurologia, Dipartimento di Neuroscienze, Facoltà di Medicina e Chirurgia, Università Cattolica Sacro Cuore, Rome, Italy

INTRODUCTION

Amyotrophic lateral sclerosis (ALS) was first described in 1874 as a specific neurological disease by the French neurologist Jean‐Martin Charcot, who chose this term to reflect both clinical observations and post‐mortem pathological findings. Amyotrophic refers to clinical evidence of muscle atrophy as a consequence of the loss of lower motor neurons (LMNs). Lateral sclerosis refers to the pathological observation of hardness of the lateral columns of the spinal cord, following upper motor neuron (UMN) degeneration [1]. UMN degeneration is followed by the formation of a sort of scar. The disease leads to progressive paralysis, with death occurring due to respiratory failure within three to five years after symptom onset.

The classical form is characterized by the concomitant involvement of UMNs in the cerebral cortex and LMNs located in the brainstem and the spinal cord. Clinical manifestations of UMN damage are loss of dexterity of the hands and spastic gait associated with overactive tendon reflexes. These signs are frequently associated with pathological reflexes, including Chaddock and Babinski signs (extension of the big toe after rubbing the lateral malleolus and the sole of the foot, respectively) and Hoffmann sign (flexion and adduction of index finger and thumb when flicking the nail of the middle finger downward). Corticobulbar involvement leads to slurred speech and difficulty swallowing, often with pathological crying and laughing. The consequence of LMN degeneration is weakness, which may involve any muscle of the body including those of the tongue, pharynx, or larynx (innervated by bulbar motor neurons); those of upper and lower limbs; and the respiratory muscles. Oculomotor and Onuf's motor neurons are usually spared. Muscular atrophy, reduced reflexes, and signs of hyperexcitability in motor neurons, such as fasciculation and cramps, are additional features of LMN degeneration.

The combination of the these symptoms and signs of UMN and LMN dysfunction results in a peculiar and stereotypical picture, which in most cases is easy for expert clinicians to identify. However, there is an evident clinical heterogeneity among ALS patients, which is determined by several independent elements. The age of onset and survival, two major phenotype features, show a marked variability among patients. Furthermore, the relative number of UMN and LMN signs may show substantial differences. An additional contributor to this heterogeneity is the evidence that the types of cells impaired in ALS may extend beyond UMNs and LMNs to include the frontal and temporal cortex, extrapyramidal system, peripheral nerves, and skeletal muscles, giving rise to variable and sometimes overlapping phenotypes.

Finally, genetic research has revealed that ALS is linked with several causative genes – a list that will probably increase in the coming years due to the rapid improvement of next‐generation sequencing technologies. ALS‐related genes are implicated in various cellular functions, including RNA metabolism, autophagy, and axonal transport, suggesting significant heterogeneity in disease mechanisms as well.

Thus, it appears that ALS is used as an umbrella term referring to a spectrum of disorders with diverse clinical manifestations, heterogeneous disease mechanisms, and (probably) different responses to therapies. On the other hand, all ALS patients, except carriers of superoxide dismutase 1 (SOD1) and fused in sarcoma (FUS) variants, appear to be unified by a single pathological signature: the presence of abnormal accumulation of the transactivation response DNA binding protein (TDP‐43) in the cytoplasm of neuronal and glial cel...

Table of contents

• Cover
• Table of Contents
• Title Page
• Copyright Page
• Dedication Page
• Contributors
• Foreword
• Preface
• Acknowledgments
• CHAPTER 1: Clinical Heterogeneity of ALS – Implications for Models and Therapeutic Development
• CHAPTER 2: Genetic Basis of ALS
• CHAPTER 3: Susceptibility Genes and Epigenetics in Sporadic ALS
• CHAPTER 4: The Lessons of ALS‐PDC – Environmental Factors in ALS Etiology
• CHAPTER 5: The Microbiome of ALS – Does It Start from the Gut?
• CHAPTER 6: Protein Aggregation in Amyotrophic Lateral Sclerosis
• CHAPTER 7: Evidence for a Growing Involvement of Glia in Amyotrophic Lateral Sclerosis
• CHAPTER 8: Animal Models of ALS – Current and Future Perspectives
• CHAPTER 9: Clinical Trials in ALS – Current Challenges and Strategies for Future Directions
• CHAPTER 10: Future Priorities and Directions in ALS Research and Treatment
• Index
• End User License Agreement