Tài liệu Amyotrophic lateral sclerosis - Edited by Martin H. Maurer

Contents
Preface XI
Part 1 Pathophysiology and Methodology 1
Chapter 1 Amyotrophic Lateral Sclerosis:
An Introduction to Treatment and Trials 3
Martin H. Maurer
Chapter 2 Insights Arising from Gene
Expression Profiling in Amyotrophic Lateral Sclerosis 41
Johnathan Cooper-Knock, Joanna J. Bury,
Laura Ferraiuolo, Emily F. Goodall,
Pamela J. Shaw and Janine Kirby
Chapter 3 Dynamic Meta-Analysis as a Therapeutic
Prediction Tool for Amyotrophic Lateral Sclerosis 59
Cassie S. Mitchell and Robert H. Lee
Chapter 4 In Vivo and In Vitro Models to
Study Amyotrophic Lateral Sclerosis 81
François Berthod and François Gros-Louis
Chapter 5 Advantages and Pitfalls in Experimental Models Of ALS 125
Marina Boido, Elisa Buschini, Antonio Piras,
Giada Spigolon, Valeria Valsecchi, Letizia Mazzini and
Alessandro Vercelli
Chapter 6 Electrophysiological Abnormalities in
SOD1 Transgenic Models in Amyotrophic
Lateral Sclerosis: The Commonalities and Differences 157
Sherif M. Elbasiouny, Katharina A. Quinlan,
Tahra L. Eissa and Charles J. Heckman
Chapter 7 Molecular and Electrical Abnormalities
in the Mouse Model of Amyotrophic Lateral Sclerosis 175
Katharina A. Quinlan,
Sherif M. Elbasiouny and C.J. Heckman


Part 2 Signalling Pathways and Molecular Pathophysiology 195
Chapter 8 Role of Mitochondrial Dysfunction
in Motor Neuron Degeneration in ALS 197
Luz Diana Santa-Cruz,
Uri Nimrod Ramírez-Jarquín and Ricardo Tapia
Chapter 9 Role of Neuronal Mitochondrial
Metabolic Phenotype in Pathogenesis of ALS 225
Alexander Panov, Nury Steuerwald, Valentin Vavilin,
Svetlana Dambinova and Herbert L. Bonkovsky
Chapter 10 Mutant Cu/Zn-Superoxide Dismutase Induced Mitochondrial
Dysfunction in Amyotrophic Lateral Sclerosis 249
Jari Koistinaho and Gundars Goldsteins
Chapter 11 Folding and Aggregation of
Cu, Zn-Superoxide Dismutase 265
Helen R. Broom, Heather A. Primmer,
Jessica A.O. Rumfeldt, Peter B. Stathopulos,
Kenrick A. Vassall, Young-Mi Hwang and
Elizabeth M. Meiering
Chapter 12 Oxidative Modifications of Cu,
Zn-Superoxide Dismutase (SOD1) –
The Relevance to Amyotrophic Lateral Sclerosis (ALS) 301
Seiichi Nagano
Chapter 13 Reactive Nitrogen Species in Motor Neuron Apoptosis 313
María Clara Franco and Alvaro G. Estévez
Chapter 14 Protein Aggregates in
Pathological Inclusions of Amyotrophic Lateral Sclerosis 335
Yoshiaki Furukawa
Chapter 15 The Kynurenine Pathway 357
Yiquan Chen and Gilles Guillemin


Part 3 Cellular Pathophysiology,
the Immune System and Stem Cell Strategies 375
Chapter 16 The Astrocytic Contribution in ALS:
Inflammation and Excitotoxicity 377
Kim Staats and Ludo Van Den Bosch
Chapter 17 Innate Immunity in ALS 393
John D. Lee, Jia Y. Lee,
Stephen M. Taylor, Peter G. Noakes and
Trent M. Woodruff
Chapter 18 The Role of TNF-Alpha in ALS:
New Hypotheses for Future Therapeutic Approaches 413
Cristina Cereda, Stella Gagliardi,
Emanuela Cova, Luca Diamanti and Mauro Ceroni
Chapter 19 Stem Cell Application for Amyotrophic Lateral
Sclerosis: Growth Factor Delivery and Cell Therapy 437
Masatoshi Suzuki,
Chak Foon Tso and Michael G. Meyer
Chapter 20 Glial Cells as Therapeutic Targets for ALS 455
Amanda M. Haidet-Phillips and Nicholas J. Maragakis


Part 4 Human Genetics in ALS 477
Chapter 21 Genetics of Amyotrophic Lateral Sclerosis 479
Max Koppers, Michael van Es, Leonard H. van den Berg,
Jan H. Veldink and R. Jeroen Pasterkamp
Chapter 22 Genetics of Familial
Amyotrophic Lateral Sclerosis 517
Emily F. Goodall, Joanna J. Bury,
Johnathan Cooper-Knock, Pamela J. Shaw and
Janine Kirby
Chapter 23 A Major Genetic Factor at Chromosome
9p Implicated in Amyotrophic Lateral Sclerosis (ALS)
and Frontotemporal Lobar Degeneration (FTLD) 537
Ilse Gijselinck, Kristel Sleegers,
Christine Van Broeckhoven and Marc Cruts


Part 5 Clinical Research in ALS 555
Chapter 24 Multidisciplinary Rehabilitation in
Amyotrophic Lateral Sclerosis 557
Louisa Ng and Fary Khan
Chapter 25 Assessment and Management of Respiratory Dysfunction in
Patients with Amyotrophic Lateral Sclerosis 579
Daniele Lo Coco, Paolo Volanti,
Domenico De Cicco, Antonio Spanevello,
Gianluca Battaglia, Santino Marchese,
Alfonsa Claudia Taiello, Rossella Spataro and
Vincenzo La Bella
Chapter 26 Nutritional Care in Amyotrophic
Lateral Sclerosis: An Alternative for
the Maximization of the Nutritional State 595
Luciano Bruno de Carvalho-Silva
Chapter 27 How to Assess Disease’s Severity and
Monitor Patients with Amyotrophic Lateral Sclerosis:
Lessons from Neurophysiology 613
Ferdinando Sartucci, Tommaso Bocci,
Lucia Briscese, Chiara Pecori, Chiara Rossi and Fabio Giannini
Chapter 28 Protection of Motor Neurons in
Pre-Symptomatic Individuals Carrying
SOD 1 Mutations: Results of Motor Unit
Number Estimation (MUNE) Electrophysiology 627
Arun Aggarwal
Chapter 29 Communication Impairment in
ALS Patients Assessment and Treatment 665
Paolo Bongioanni
Chapter 30 Human Computer Interactions for
Amyotrophic Lateral Sclerosis Patients 683
Ali Bülent Uşaklı
Chapter 31 Overview of Cognitive Function in ALS, with
Special Attention to the Temporal Lobe: Semantic
Fluency and Rating the Approachability of Faces 703
Heike Schmolck, Paul Schulz and Michele York

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.
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.
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.
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.
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
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.
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.
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.
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 Uşaklı 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