Preface

"It is right it should be so; Man was made for joy and woe; And when this we rightly know, Thro' the world we safely go." *(William Blake, Auguries of Innocence, c. 1803)* 

When Amyotrophic Lateral Sclerosis first was described and defined as a disease entity in the middle of the 19th century, very little was know about its pathophysiology, nor any form of treatment. The early reports collected signs and symptoms and noted the disease progression. Subsequently, interest arose in the cause of the disease, and with the emergence of molecular techniques, a broad field of pathophysiological hypotheses emerged.

In this book, the reader will find a compilation of state-of-the-art reviews about the etiology, epidemiology, and pathophysiology of ALS, the molecular basis of disease progression and clinical manifestations, the genetics familial of ALS, as well as novel diagnostic criteria in the field of electrophysiology. An overview over all relevant pharmacological trials in ALS patients is included. Moreover, current advances and future trends in ALS research are presented.

The chapters assembled in Part 1, Pathophysiology and Methodology in ALS Research, introduce the current concept of disease pathophysiology and present the techniques currently used ALS research, including data mining, gene expression profiling, and animal models.

In Chapter 1, "Amyotrophic Lateral Sclerosis: An Introduction to Treatment and Trials" by Martin H. Maurer, the author introduces the spectrum of disorders and diseases subsumed by "motor neuron disease". By defining the diagnostic criteria of the disease, the author summarizes the pathophysiological basis of ALS, which has become the foundation for translational research, known as the "from bench to bedside" principle. But for ALS, this approach did not work, and the author describes the reasons and the current recommendations for ALS trials. He then provides an inventory of nearly all clinical trials conducted in ALS patients with pharmacological intervention, including compounds currently under investigation.

#### XIV Preface

Johnathan Cooper-Knock, Joanna J. Bury, Laura Ferraiuolo, Emily F. Goodall, Pamela J. Shaw, and Janine Kirby contribute to chapter 2, "Gene Expression Profiling and it's Application in Amyotrophic Lateral Sclerosis", in which they introduce principles and methods of gene expression profiling. Then the authors review sources and results from in vitro and in vivo models of ALS, as well as from human samples.

Preface XIII

the influence factors tissue preparation and extracellular calcium concentration, (2) action potential and afterhyperpolarization, (3) persistent inward currents, (4)

In chapter 7, "Molecular and electrical abnormalities in the mouse model of Amyotrophic Lateral Sclerosis", Katharina A. Quinlan, Sherif M. Elbasiouny and C.J. Heckman review altered electrophysiological properties of ALS motor neurons and the underlying molecular events. The authors first introduce ALS animal models, then provide a timeline of deficits and emphasize the role of calcium in disease pathology. Subsequent parts of the chapter discuss transport processes, mitochondrial deficiency and energy balance, as well as protein degradation and endoplasmic reticulum stress for disease progression. Then the authors point out non-cell autonomous deficits based

Part 2, "Signalling Pathways and Molecular Pathophysiology" summarizes the main findings and hypotheses with regard to mitochondrial dysfunction and the role of Cu/Zn-superoxide dismutase, as well as the influence of reactive nitrogen species, protein aggregates, and the kynurenine pathway as paradigmatic examples of disease

Chapter 8, "Role of mitochondrial dysfunction in motor neuron degeneration in ALS" by Luz Diana Santa-Cruz, Uri Nimrod Ramírez-Jarquín and Ricardo Tapia contains the role of mitochondrial dysfunction in ALS. In the first part, the authors summarize the mechanisms of motor neuron death in ALS with regard to its pathophysiology involved, including excitotoxicity, axonal transport deficits, oxidative stress, and inflammation. In the second part, the authors concentrate on mitochondrial deficits in

In Chapter 9, Alexander Panov, Nury Steuerwald, Valentin Vavilin, and Svetlana Dambinova introduce the "Role of Neuronal Mitochondrial Metabolic Phenotype in Pathogenesis of ALS" as a general overview on the characteristics of mitochondria in the central nervous system with regard to their role in energy metabolism of the brain. Then, the authors discuss the formation of reactive oxygen species and the failure of their detoxification by mitochondria in the pathogenesis of ALS. They distinguish between functional differences between mitochondria isolated from the brain and the spinal cord.

Chapter 10, "Mutant Cu/Zn-superoxide dismutase induced mitochondrial dysfunction in amyotrophic lateral sclerosis" by Jari Koistinaho and Gundars Goldsteins reviews SOD1 biochemistry in the pathogenesis of ALS. The authors discuss the disease mechanisms of SOD1 translocation to mitochondria and SOD1 activity in the mitochondrial intermembrane space as well as mechanisms for mutant SOD1 toxicity in

Chapter 11, "Folding and Aggregation of Cu,Zn-Superoxide Dismutase" by Helen R. Broom, Heather A. Primmer, Jessica A.O. Rumfeldt, Peter Stathopulous, Kenrick. A.

motoneuron gain and firing activity, and (5) motoneuron excitability.

on the interplay of astrocytes and glutamate excitotoxicity.

ALS with regard to the basic mechanisms.

biochemistry.

mitochondria.

Chapter 3, "Dynamic meta-analysis as a therapeutic prediction tool for Amyotrophic Lateral Sclerosis" by Cassie S. Mitchell and Robert H. Lee introduces a novel method for literature data mining which is called dynamic meta-analysis. The authors provide a step-by-step flow chart and demonstrate the method in a feasibility study in the G93A SOD1 mouse model. Their findings indicate that dynamic meta-analysis can be used to predict treatment outcomes in a high-throughput manner.

In Chapter 4, François Berthod and François Gros-Louis describe in their chapter "In vivo and in vitro models to study Amyotrophic Lateral Sclerosis" experimental models for ALS research, including invertebrate models such as C. elegans and drosophila, as well as vertebrate models such as mouse, rat, zebrafish, dog, and pig. Additionally, they provide information about in vitro models including organotypic slice cultures, spinal cord cell cultures, motor neuron cultures, stem cell cultures and oocyte cultures.

Chapter 5, "Advantages and pitfalls in experimental models of ALS" by Marina Boido, Elisa Buschini, Antonio Piras, Giada Spigolon, Valeria Valsecchi, Letizia Mazzini and Alessandro Vercelli provides an in-depth review of the animals models for ALS which are currently available. The authors describe the animal model and the underlying genetic mutation for superoxide dismutase 1 (SOD1), TAR DNA-binding protein-43 (TDP-43), and rare mutations, such as alsin, vescicle-associated membrane protein B (VAPB), vascular endothelial growth factor (VEGF), and cytoskeletal protein mutations such as dynactin, neurofilaments, peripherin, and tau. Moreover, spontaneous mutation models, i.e. the Wobbler (Wbl), neuromuscular degeneration (NMD), progressive motor neuronopathy (PMN), Wasted (Wst), Legs at odd angles (LOA), Cramping 1 (CRA) mice are included. Additionally, a section on in vitro models is added. The authors reflect paradigmatically also on the problems of animal models with regard to translational research: Does the animal model "mimic" the motor disabilities in ALS patients? Or, is the underlying gene mutation similar to the human disease? The provocative chapter makes the reader thinking about our research models.

In chapter 6, "Electrophysiological abnormalities in SOD1 transgenic models in Amyotrophic Lateral Sclerosis: the commons and differences" by Sherif M. Elbasiouny, Katharina A. Quinlan, Tahra M. Eissa, and Charles J. Heckman, the authors provide a review chapter on the electrophysiological abnormalities in the most common mouse model for ALS, the SOD1-G93A transgenic mouse, and compare the results of the in vivo studies to other animal models of ALS.

The authors discuss both changes in the motor neuron anatomical properties and changes in the motor neuron electrical properties, including (1) input resistance, with the influence factors tissue preparation and extracellular calcium concentration, (2) action potential and afterhyperpolarization, (3) persistent inward currents, (4) motoneuron gain and firing activity, and (5) motoneuron excitability.

XII Preface

Johnathan Cooper-Knock, Joanna J. Bury, Laura Ferraiuolo, Emily F. Goodall, Pamela J. Shaw, and Janine Kirby contribute to chapter 2, "Gene Expression Profiling and it's Application in Amyotrophic Lateral Sclerosis", in which they introduce principles and methods of gene expression profiling. Then the authors review sources and results

Chapter 3, "Dynamic meta-analysis as a therapeutic prediction tool for Amyotrophic Lateral Sclerosis" by Cassie S. Mitchell and Robert H. Lee introduces a novel method for literature data mining which is called dynamic meta-analysis. The authors provide a step-by-step flow chart and demonstrate the method in a feasibility study in the G93A SOD1 mouse model. Their findings indicate that dynamic meta-analysis can be

In Chapter 4, François Berthod and François Gros-Louis describe in their chapter "In vivo and in vitro models to study Amyotrophic Lateral Sclerosis" experimental models for ALS research, including invertebrate models such as C. elegans and drosophila, as well as vertebrate models such as mouse, rat, zebrafish, dog, and pig. Additionally, they provide information about in vitro models including organotypic slice cultures, spinal cord cell cultures, motor neuron cultures, stem cell cultures and oocyte cultures.

Chapter 5, "Advantages and pitfalls in experimental models of ALS" by Marina Boido, Elisa Buschini, Antonio Piras, Giada Spigolon, Valeria Valsecchi, Letizia Mazzini and Alessandro Vercelli provides an in-depth review of the animals models for ALS which are currently available. The authors describe the animal model and the underlying genetic mutation for superoxide dismutase 1 (SOD1), TAR DNA-binding protein-43 (TDP-43), and rare mutations, such as alsin, vescicle-associated membrane protein B (VAPB), vascular endothelial growth factor (VEGF), and cytoskeletal protein mutations such as dynactin, neurofilaments, peripherin, and tau. Moreover, spontaneous mutation models, i.e. the Wobbler (Wbl), neuromuscular degeneration (NMD), progressive motor neuronopathy (PMN), Wasted (Wst), Legs at odd angles (LOA), Cramping 1 (CRA) mice are included. Additionally, a section on in vitro models is added. The authors reflect paradigmatically also on the problems of animal models with regard to translational research: Does the animal model "mimic" the motor disabilities in ALS patients? Or, is the underlying gene mutation similar to the human disease? The provocative chapter

In chapter 6, "Electrophysiological abnormalities in SOD1 transgenic models in Amyotrophic Lateral Sclerosis: the commons and differences" by Sherif M. Elbasiouny, Katharina A. Quinlan, Tahra M. Eissa, and Charles J. Heckman, the authors provide a review chapter on the electrophysiological abnormalities in the most common mouse model for ALS, the SOD1-G93A transgenic mouse, and compare the

The authors discuss both changes in the motor neuron anatomical properties and changes in the motor neuron electrical properties, including (1) input resistance, with

from in vitro and in vivo models of ALS, as well as from human samples.

used to predict treatment outcomes in a high-throughput manner.

makes the reader thinking about our research models.

results of the in vivo studies to other animal models of ALS.

In chapter 7, "Molecular and electrical abnormalities in the mouse model of Amyotrophic Lateral Sclerosis", Katharina A. Quinlan, Sherif M. Elbasiouny and C.J. Heckman review altered electrophysiological properties of ALS motor neurons and the underlying molecular events. The authors first introduce ALS animal models, then provide a timeline of deficits and emphasize the role of calcium in disease pathology. Subsequent parts of the chapter discuss transport processes, mitochondrial deficiency and energy balance, as well as protein degradation and endoplasmic reticulum stress for disease progression. Then the authors point out non-cell autonomous deficits based on the interplay of astrocytes and glutamate excitotoxicity.

Part 2, "Signalling Pathways and Molecular Pathophysiology" summarizes the main findings and hypotheses with regard to mitochondrial dysfunction and the role of Cu/Zn-superoxide dismutase, as well as the influence of reactive nitrogen species, protein aggregates, and the kynurenine pathway as paradigmatic examples of disease biochemistry.

Chapter 8, "Role of mitochondrial dysfunction in motor neuron degeneration in ALS" by Luz Diana Santa-Cruz, Uri Nimrod Ramírez-Jarquín and Ricardo Tapia contains the role of mitochondrial dysfunction in ALS. In the first part, the authors summarize the mechanisms of motor neuron death in ALS with regard to its pathophysiology involved, including excitotoxicity, axonal transport deficits, oxidative stress, and inflammation. In the second part, the authors concentrate on mitochondrial deficits in ALS with regard to the basic mechanisms.

In Chapter 9, Alexander Panov, Nury Steuerwald, Valentin Vavilin, and Svetlana Dambinova introduce the "Role of Neuronal Mitochondrial Metabolic Phenotype in Pathogenesis of ALS" as a general overview on the characteristics of mitochondria in the central nervous system with regard to their role in energy metabolism of the brain. Then, the authors discuss the formation of reactive oxygen species and the failure of their detoxification by mitochondria in the pathogenesis of ALS. They distinguish between functional differences between mitochondria isolated from the brain and the spinal cord.

Chapter 10, "Mutant Cu/Zn-superoxide dismutase induced mitochondrial dysfunction in amyotrophic lateral sclerosis" by Jari Koistinaho and Gundars Goldsteins reviews SOD1 biochemistry in the pathogenesis of ALS. The authors discuss the disease mechanisms of SOD1 translocation to mitochondria and SOD1 activity in the mitochondrial intermembrane space as well as mechanisms for mutant SOD1 toxicity in mitochondria.

Chapter 11, "Folding and Aggregation of Cu,Zn-Superoxide Dismutase" by Helen R. Broom, Heather A. Primmer, Jessica A.O. Rumfeldt, Peter Stathopulous, Kenrick. A.

#### XVI Preface

Vassall, Young-Mi Hwang, and Elizabeth M. Meiering reviews the biochemical mechanisms of SOD1 toxicity. The authors introduce factors which influence protein folding, stability and aggregation. Then they review structure and function of Cu, Zn-Superoxide Dismutase (SOD1), and reveal biochemical mechanisms of folding, unfolding and misfolding, as well as aggregation of SOD1 with regard to the pathogenesis of ALS

Preface XV

processes - inflammation and excitotoxicity - which have great implications in disease

In Chapter 17, John D. Lee, Jia Y. Lee, Stephen M. Taylor, Peter G. Noakes, and Trent M. Woodruff review in their chapter "Innate immunity in ALS" the contribution of the innate immune system to disease progression in ALS. The authors define the role of the complement system and review the role of toll-like receptors (TLRs) and the receptor for advanced glycosylation end products (RAGEs) in the pathophysiology of ALS. In the last part of their chapter, the authors provide a clinical outlook by modulating neuroinflammation. The inhibition of the complement 5a receptor, or

In Chapter 18, "TNF-alpha role in ALS: new hypotheses for future therapeutic approaches", Cristina Cereda, Stella Gagliardi, Emanuela Cova, L. Diamanti, and Mauro Ceroni describe the role of TNF-alpha in signal transduction processes which are related to ALS pathophysiology. They discuss the somewhat controversial role of

In Chapter 19, "Stem Cell Application for Amyotrophic Lateral Sclerosis: Growth Factor Delivery and Cell Therapy" by Masatoshi Suzuki, Chak Foon Tso, and Michael G. Meyer, the authors introduce an overview over growth factors and gene therapy in ALS. They review strategies and sites of growth factor delivery in the disease and discuss the rationale for cell replacement strategies, such as motor neuron replacement, or astrocyte replacement, as well as the rationale for the neuroprotection strategy by growth factor delivery, including a immunomodulatory effect. They review data on translational research, where genetically engineered stem cells have

Chapter 20, "Glial Cells as Therapeutic Targets for ALS" by Amanda M. Haidet-Phillips and Nicholas J. Maragakis, the authors introduce the role of glial cells in disease formation and progression in ALS. They review the contributions of the different types of non-neural cells in the central nervous system, mainly those of astrocytes and microglia to the pathogenesis of ALS and discuss the still undefined role of oligodendrocytes. In the second part of their chapter, the authors review disease models of ALS involving glial cells. In the third part, they discuss therapeutic strategies for targeting glial cells, either by cell therapy, genetic reprogramming, or gene targeting.

Part 4 id dedicated to "Human Genetics in ALS". In this part of the book, the reader will find an overview of the results of recent genetic studies in ALS research,

In Chapter 21, "Genetics of amyotrophic lateral sclerosis" by Max Koppers, Michael van Es, Leonard H. van den Berg, Jan H. Veldink, and R. Jeroen Pasterkamp, the authors review the genetics of both sporadic and familial ALS. In the first part of their chapter, the authors provide an insight into the current knowledge of gene mutations involved in

compiling all information of genes which are involved in ALS pathophysiology.

other factors in the cascade, may be a future topic for discussion.

the cytokine with regard to its interaction with the SOD1 gene.

been used for growth factor delivery, for example, using GDNF.

pathophysiology and progression in ALS.

In Chapter 12, "Oxidative modifications of Cu, Zn-superoxide dismutase (SOD1)-the relevance to amyotrophic lateral sclerosis (ALS)" by Seiichi Nagano, the author reviews the biochemistry of SOD1 toxicity with regard to the copper-mediated oxidative toxicity. Moreover, conformational changes of the SOD1 molecule and oxidative stress by cysteine oxidation are explained for both familial and sporadic forms of ALS.

In Chapter 13, "Reactive Nitrogen Species in Motor Neuron Apoptosis", Maria Clara Franco and Alvaro G. Estévez review the role of reactive nitrogen species in the pathogenesis of ALS. They describe the reaction pathways leading to toxic by- and endproducts, such as peroxynitrite, and nitrotyrosine, and the biochemical pathways involving reactive nitrogen species, which lead to motor neuron disease. In ALS, namely apoptosis and SOD1 toxicity contribute to the fatal events in disease development.

In Chapter 14, Yoshiaki Furukawa contributes a review chapter on "Protein aggregates in pathological inclusions of amyotrophic lateral sclerosis" where he summarizes the current knowledge about the pathological inclusions of superoxide dismutase 1 (SOD1), TAR DNA-binding protein-43 (TDP-43), and the Fused in Sarcoma (FUS) protein. He discusses the relevant inclusion bodies for ALS patients, animal models, and in vitro models, respectively. Moreover, biochemical mechanisms of SOD1 aggregation, such as post-translational modifications such as disulfide reduction, are reviewed.

In Chapter 15, "Involvement of the kynurenine pathway in amyotrophic lateral sclerosis", Guillemin Gilles introduces the kynurenine pathway as a major route for the catabolism of the amino acid tryptophan, which is also involved in the synthesis of the neurotransmitter serotonin (5-hydroxy tryptamin), or melatonin. The author proposes that the kynurenine pathway is involved in the pathogenesis of ALS by linking several pathophysiological models, such as glutamate excitotoxicity, oxidative stress, non-cell-autonomous mechanism and apoptosis. Moreover, the role of quinolinic acid (QUIN) as neurotoxic substance discussed. The second part of the chapter contains a discussion on the neuropharmacology in ALS research with regard to compounds influencing the kynurenine pathway.

Part 3 of the book, "Cellular Pathophysiology, the Immune System and Stem Cell Strategies" collects novel findings based on cellular approaches.

Chapter 16, "The astrocytic contribution in ALS: inflammation and excitotoxicity" by Kim Staats and Ludo van den Bosch provides a deeper insight into the role of astrocytes in ALS. The author's review the role of astrocytes in the two pathogenetic processes - inflammation and excitotoxicity - which have great implications in disease pathophysiology and progression in ALS.

XIV Preface

pathogenesis of ALS

Vassall, Young-Mi Hwang, and Elizabeth M. Meiering reviews the biochemical mechanisms of SOD1 toxicity. The authors introduce factors which influence protein folding, stability and aggregation. Then they review structure and function of Cu, Zn-Superoxide Dismutase (SOD1), and reveal biochemical mechanisms of folding, unfolding and misfolding, as well as aggregation of SOD1 with regard to the

In Chapter 12, "Oxidative modifications of Cu, Zn-superoxide dismutase (SOD1)-the relevance to amyotrophic lateral sclerosis (ALS)" by Seiichi Nagano, the author reviews the biochemistry of SOD1 toxicity with regard to the copper-mediated oxidative toxicity. Moreover, conformational changes of the SOD1 molecule and oxidative stress by

In Chapter 13, "Reactive Nitrogen Species in Motor Neuron Apoptosis", Maria Clara Franco and Alvaro G. Estévez review the role of reactive nitrogen species in the pathogenesis of ALS. They describe the reaction pathways leading to toxic by- and endproducts, such as peroxynitrite, and nitrotyrosine, and the biochemical pathways involving reactive nitrogen species, which lead to motor neuron disease. In ALS, namely apoptosis and SOD1 toxicity contribute to the fatal events in disease development.

In Chapter 14, Yoshiaki Furukawa contributes a review chapter on "Protein aggregates in pathological inclusions of amyotrophic lateral sclerosis" where he summarizes the current knowledge about the pathological inclusions of superoxide dismutase 1 (SOD1), TAR DNA-binding protein-43 (TDP-43), and the Fused in Sarcoma (FUS) protein. He discusses the relevant inclusion bodies for ALS patients, animal models, and in vitro models, respectively. Moreover, biochemical mechanisms of SOD1 aggregation, such as

In Chapter 15, "Involvement of the kynurenine pathway in amyotrophic lateral sclerosis", Guillemin Gilles introduces the kynurenine pathway as a major route for the catabolism of the amino acid tryptophan, which is also involved in the synthesis of the neurotransmitter serotonin (5-hydroxy tryptamin), or melatonin. The author proposes that the kynurenine pathway is involved in the pathogenesis of ALS by linking several pathophysiological models, such as glutamate excitotoxicity, oxidative stress, non-cell-autonomous mechanism and apoptosis. Moreover, the role of quinolinic acid (QUIN) as neurotoxic substance discussed. The second part of the chapter contains a discussion on the neuropharmacology in ALS research with regard

Part 3 of the book, "Cellular Pathophysiology, the Immune System and Stem Cell

Chapter 16, "The astrocytic contribution in ALS: inflammation and excitotoxicity" by Kim Staats and Ludo van den Bosch provides a deeper insight into the role of astrocytes in ALS. The author's review the role of astrocytes in the two pathogenetic

cysteine oxidation are explained for both familial and sporadic forms of ALS.

post-translational modifications such as disulfide reduction, are reviewed.

to compounds influencing the kynurenine pathway.

Strategies" collects novel findings based on cellular approaches.

In Chapter 17, John D. Lee, Jia Y. Lee, Stephen M. Taylor, Peter G. Noakes, and Trent M. Woodruff review in their chapter "Innate immunity in ALS" the contribution of the innate immune system to disease progression in ALS. The authors define the role of the complement system and review the role of toll-like receptors (TLRs) and the receptor for advanced glycosylation end products (RAGEs) in the pathophysiology of ALS. In the last part of their chapter, the authors provide a clinical outlook by modulating neuroinflammation. The inhibition of the complement 5a receptor, or other factors in the cascade, may be a future topic for discussion.

In Chapter 18, "TNF-alpha role in ALS: new hypotheses for future therapeutic approaches", Cristina Cereda, Stella Gagliardi, Emanuela Cova, L. Diamanti, and Mauro Ceroni describe the role of TNF-alpha in signal transduction processes which are related to ALS pathophysiology. They discuss the somewhat controversial role of the cytokine with regard to its interaction with the SOD1 gene.

In Chapter 19, "Stem Cell Application for Amyotrophic Lateral Sclerosis: Growth Factor Delivery and Cell Therapy" by Masatoshi Suzuki, Chak Foon Tso, and Michael G. Meyer, the authors introduce an overview over growth factors and gene therapy in ALS. They review strategies and sites of growth factor delivery in the disease and discuss the rationale for cell replacement strategies, such as motor neuron replacement, or astrocyte replacement, as well as the rationale for the neuroprotection strategy by growth factor delivery, including a immunomodulatory effect. They review data on translational research, where genetically engineered stem cells have been used for growth factor delivery, for example, using GDNF.

Chapter 20, "Glial Cells as Therapeutic Targets for ALS" by Amanda M. Haidet-Phillips and Nicholas J. Maragakis, the authors introduce the role of glial cells in disease formation and progression in ALS. They review the contributions of the different types of non-neural cells in the central nervous system, mainly those of astrocytes and microglia to the pathogenesis of ALS and discuss the still undefined role of oligodendrocytes. In the second part of their chapter, the authors review disease models of ALS involving glial cells. In the third part, they discuss therapeutic strategies for targeting glial cells, either by cell therapy, genetic reprogramming, or gene targeting.

Part 4 id dedicated to "Human Genetics in ALS". In this part of the book, the reader will find an overview of the results of recent genetic studies in ALS research, compiling all information of genes which are involved in ALS pathophysiology.

In Chapter 21, "Genetics of amyotrophic lateral sclerosis" by Max Koppers, Michael van Es, Leonard H. van den Berg, Jan H. Veldink, and R. Jeroen Pasterkamp, the authors review the genetics of both sporadic and familial ALS. In the first part of their chapter, the authors provide an insight into the current knowledge of gene mutations involved in the pathogenesis of familial ALS. Then, they provide an overview over mutation involved in sporadic ALS. In the second part of their chapter, the authors focus paradigmatically on two genomic regions associated with sporadic ALS, namely, chromosomal regions 9p21.2 and 19p13.11. They discuss the evidence for the association within these regions as well as the function of the genes found in these regions.

Preface XVII

nutrition, exercise, mobility and activities of daily living, incontinence and sexuality, pain, fatigue and sleep disorders, cognition and behavioural impairment, pseudobulbar affect, and psychosocial issues. Of note, they provide a subsection on

In Chapter 25, "Assessment and management of respiratory dysfunction in patients with Amyotrophic Lateral Sclerosis" by Daniele Lo Coco, Paolo Volanti, Domenico De Cicco, Antonio Spanevello, Gianluca Battaglia, Santino Marchese, Alfonsa Claudia Taiello, Rossella Spataro and Vincenzo La Bella, the authors provide a review on one of the most threatening problems in the disease progression of ALS, respiratory dysfunction. Respiratory dysfunction is not only part of the disabling course of the disease, but also contributes to the cause of death. The authors discuss the evaluation of pulmonary function. In the following sections, non-invasive mechanical ventilation, invasive mechanical mentilation, and physiotherapy are reviewed in the light of

Chapter 26, "Nutritional care in Amyotrophic lateral sclerosis: an alternative for the maximization of the nutritional state" by Luciano Bruno de Carvalho-Silva discusses the current management of nutritional care in ALS patients based on physiological parameters such as body composition and functional measurements. He also provides practical clinical recommendations for the preparation of suitable food both in clinical

In Chapter 27, "The electrodiagnostic methods macro-EMG and MUNE to assess disease severity and monitor patients with Amyotrophic Lateral Sclerosis: overview and own experience", Ferdinando Sartucci, Tommaso Bocci, Lucia Briscese, Chiara Pecori, Chiara Rossi, and Fabio Giannini present own original data from electrophysiological studies in ALS patients. The report that Motor Unit Number Estimation (MUNE) techniques can be a useful tool to assess and evaluate

The first part of Chapter 28, "Protection of motor neurons in pre-symptomatic individuals carrying SOD1 mutations: Results of motor unit number estimation (MUNE) electrophysiology" by Arun Aggarwal, provides a review of mechanisms and patterns of motor neuron loss involved in ALS disease progression with regard to the genetic components of familial ALS. In the second part, the author contributes own original data of an electrophysiological study in unsymptomatic individuals who carry

The chapter shows nicely which heavy burden genetic testing can impose on carriers of genetic mutations, and it should also make us think about our narrow definition of

Chapter 29, "Communication Impairment in ALS patients -- Assessment and Treatment" by Paolo Bongioanni reviews the impaired communication of ALS patients

end-of-life issues, where ethical issues come to an immediate focus.

prevention of deterioration and symptomatic therapy.

pharmacological interventions, such as treatment with riluzole.

specific SOD1 mutations. The chapter ends with a number of case studies.

and everyday aspects.

a "healthy" person and a patient.

Chapter 22, "Genetics of Familial Amyotrophic Lateral Sclerosis" by Emily F. Goodall, Joanna J. Bury, Johnathan Cooper-Knock, Pamela J. Shaw and Janine Kirby contains all important information on genes involved in the disease. Although only 5 percent of all ALS cases are caused by inheritable mutations in the ALS genes and with the majority of familial cases being clinically and pathologically indistinguishable from the sporadic cases, the genetics of familial ALS is necessary to approach the disease. Its results can be used to generate genetic models of ALS, to investigate the mechanisms of motor neuron degeneration, to identify therapeutic targets, and to screen for candidate therapeutic agents. In the second part of their chapter, the authors provide insight into advances in the sequencing technology, which allow sequencing large genomes and finding novel genetic mutations. These techniques may help finding novel genes involved in familial ALS.

Chapter 23, "A major genetic factor at chromosome 9p implicated in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD)" by Ilse Gijselinck, Kristel Sleegers, Christine van Broeckhoven, and Marc Cruts reviews the latest findings on genetic studies focussing on chromosome 9p21. On this chromosome, common genetic features of ALS and fronto-temporal lobar degeneration (FTLD) have been localized.

In Part 5, "Clinical Research in ALS", contains reviews and collections of original data obtained from ALS patients. It summarizes clinical recommendations such as for rehabilitation and palliative care, nutrition, and respiratory function. Moreover, results of electrophysiological studies are presented which aimed at finding parameters for disease progression and prognosis. In the final section of this part, the main issues in patient communication, ortheses and human-computer interactions, as well as insights in neuropsychology and neuropsychiatry of ALS patients are discussed.

The Latin word "pallium" describes a special cloak. Thus, palliative care means that the patient is sheltered by the means provided by the caregivers. In Chapter 24, "Multidisciplinary rehabilitation in Amyotrophic Lateral Sclerosis", Louisa Ng and Fary Khan review aspects of clinical rehabilitation in ALS, where rehabilitation means, that the patient is enabled to take part in daily life activities at the best of remaining competences. In the first part of their chapter, they define the setting for a prosperous rehabilitation and describe the needs of a care-giving surrounding of the patients, including family, specialized health care professionals, and the social environment, including friends and spiritual guidance. In the second part of their review, the authors address all questions of practical issues during the day and the night. They discuss the points of respiratory dysfunction, communication, swallowing and nutrition, exercise, mobility and activities of daily living, incontinence and sexuality, pain, fatigue and sleep disorders, cognition and behavioural impairment, pseudobulbar affect, and psychosocial issues. Of note, they provide a subsection on end-of-life issues, where ethical issues come to an immediate focus.

XVI Preface

the pathogenesis of familial ALS. Then, they provide an overview over mutation involved in sporadic ALS. In the second part of their chapter, the authors focus paradigmatically on two genomic regions associated with sporadic ALS, namely, chromosomal regions 9p21.2 and 19p13.11. They discuss the evidence for the association

Chapter 22, "Genetics of Familial Amyotrophic Lateral Sclerosis" by Emily F. Goodall, Joanna J. Bury, Johnathan Cooper-Knock, Pamela J. Shaw and Janine Kirby contains all important information on genes involved in the disease. Although only 5 percent of all ALS cases are caused by inheritable mutations in the ALS genes and with the majority of familial cases being clinically and pathologically indistinguishable from the sporadic cases, the genetics of familial ALS is necessary to approach the disease. Its results can be used to generate genetic models of ALS, to investigate the mechanisms of motor neuron degeneration, to identify therapeutic targets, and to screen for candidate therapeutic agents. In the second part of their chapter, the authors provide insight into advances in the sequencing technology, which allow sequencing large genomes and finding novel genetic mutations. These techniques may help finding

Chapter 23, "A major genetic factor at chromosome 9p implicated in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD)" by Ilse Gijselinck, Kristel Sleegers, Christine van Broeckhoven, and Marc Cruts reviews the latest findings on genetic studies focussing on chromosome 9p21. On this chromosome, common genetic features of ALS and fronto-temporal lobar

In Part 5, "Clinical Research in ALS", contains reviews and collections of original data obtained from ALS patients. It summarizes clinical recommendations such as for rehabilitation and palliative care, nutrition, and respiratory function. Moreover, results of electrophysiological studies are presented which aimed at finding parameters for disease progression and prognosis. In the final section of this part, the main issues in patient communication, ortheses and human-computer interactions, as well as insights

The Latin word "pallium" describes a special cloak. Thus, palliative care means that the patient is sheltered by the means provided by the caregivers. In Chapter 24, "Multidisciplinary rehabilitation in Amyotrophic Lateral Sclerosis", Louisa Ng and Fary Khan review aspects of clinical rehabilitation in ALS, where rehabilitation means, that the patient is enabled to take part in daily life activities at the best of remaining competences. In the first part of their chapter, they define the setting for a prosperous rehabilitation and describe the needs of a care-giving surrounding of the patients, including family, specialized health care professionals, and the social environment, including friends and spiritual guidance. In the second part of their review, the authors address all questions of practical issues during the day and the night. They discuss the points of respiratory dysfunction, communication, swallowing and

in neuropsychology and neuropsychiatry of ALS patients are discussed.

within these regions as well as the function of the genes found in these regions.

novel genes involved in familial ALS.

degeneration (FTLD) have been localized.

In Chapter 25, "Assessment and management of respiratory dysfunction in patients with Amyotrophic Lateral Sclerosis" by Daniele Lo Coco, Paolo Volanti, Domenico De Cicco, Antonio Spanevello, Gianluca Battaglia, Santino Marchese, Alfonsa Claudia Taiello, Rossella Spataro and Vincenzo La Bella, the authors provide a review on one of the most threatening problems in the disease progression of ALS, respiratory dysfunction. Respiratory dysfunction is not only part of the disabling course of the disease, but also contributes to the cause of death. The authors discuss the evaluation of pulmonary function. In the following sections, non-invasive mechanical ventilation, invasive mechanical mentilation, and physiotherapy are reviewed in the light of prevention of deterioration and symptomatic therapy.

Chapter 26, "Nutritional care in Amyotrophic lateral sclerosis: an alternative for the maximization of the nutritional state" by Luciano Bruno de Carvalho-Silva discusses the current management of nutritional care in ALS patients based on physiological parameters such as body composition and functional measurements. He also provides practical clinical recommendations for the preparation of suitable food both in clinical and everyday aspects.

In Chapter 27, "The electrodiagnostic methods macro-EMG and MUNE to assess disease severity and monitor patients with Amyotrophic Lateral Sclerosis: overview and own experience", Ferdinando Sartucci, Tommaso Bocci, Lucia Briscese, Chiara Pecori, Chiara Rossi, and Fabio Giannini present own original data from electrophysiological studies in ALS patients. The report that Motor Unit Number Estimation (MUNE) techniques can be a useful tool to assess and evaluate pharmacological interventions, such as treatment with riluzole.

The first part of Chapter 28, "Protection of motor neurons in pre-symptomatic individuals carrying SOD1 mutations: Results of motor unit number estimation (MUNE) electrophysiology" by Arun Aggarwal, provides a review of mechanisms and patterns of motor neuron loss involved in ALS disease progression with regard to the genetic components of familial ALS. In the second part, the author contributes own original data of an electrophysiological study in unsymptomatic individuals who carry specific SOD1 mutations. The chapter ends with a number of case studies.

The chapter shows nicely which heavy burden genetic testing can impose on carriers of genetic mutations, and it should also make us think about our narrow definition of a "healthy" person and a patient.

Chapter 29, "Communication Impairment in ALS patients -- Assessment and Treatment" by Paolo Bongioanni reviews the impaired communication of ALS patients resulting from speech and language deficits, as well as non-verbal communication impairments by paralysis which deteriorate writing and gesture. The authors discusses the methods and techniques for assessing the severity of motor deficits with a focus on dysphonia and dysarthria.

In the second part of his chapter, the author reviews rehabilitation approaches, including gaze-controlled high-tech communication aids and brain-computer interface-based devices. He points out that, besides the improvement in assisted care, the dignity of the patients has to stand in the center of our help strategies.

Chapter 30, "Human Computer Interactions for Amyotrophic Lateral Sclerosis Patients" by Ali Bülent Uşakl describes novel applications and developments for human computer interactions (HCIs). With deteriorating muscle function, communication and autonomy is impaired. Therefore, devices have been developed for daily life activities. The author summarizes recent advances in the field of controlling these devices by electrical brain activity, eye movement and haemoglobin levels in the blood.

In Chapter 31, "Overview of cognitive function in ALS, with special attention to the temporal lobe: Semantic fluency and rating the approachability of faces" by Heike Schmolck, Paul E. Schulz, and Michele K. York, the authors introduce a field of research which came into the focus of interest only recently: cognitive function is impaired in ALS, which led to the hypothesis of a continuum of ALS and certain types of dementia.

In the first part of the chapter, the authors provide original data on a study which showed an unusual response pattern when ALS patients were asked to judge unfamiliar faces in a social context, suggesting amygdala dysfunction. In the second part of their chapter, original data on phonemic and semantic verbal fluency showed impaired temporal lobe function, contributing to the novel understanding of the disease also with lesions outside the motor system.

Although a considerable amount of research, both pre-clinical and clinical, has been conducted during recent years, Amyotrophic Lateral Sclerosis (ALS) remains one of the mysterious diseases of the 21st century. Great efforts have been made to develop pathophysiological models and to clarify the underlying pathology, and with novel instruments in genetics and transgenic techniques, the aim for finding a durable cure comes into scope. On the other hand, most pharmacological trials failed to show a benefit for ALS patients, but major improvements in clinical care could be achieved. *Amyotrophic Lateral Sclerosis* documents the relevant findings and provides the current knowledge for the research community.

> **Martin H. Maurer**  University of Heidelberg Germany
