Motor Neurone Disease

1st Edition, Volume 176 - May 29, 2024
Editors: Pamela J. Shaw, Janine Kirby
Language: English
Hardback ISBN:
9 7 8 - 0 - 4 4 3 - 1 4 1 1 6 - 4
eBook ISBN:
9 7 8 - 0 - 4 4 3 - 1 4 1 1 7 - 1

Motor Neurone Disease, Volume 176 in the International Review in Neurobiology serial highlights new advances, with this new volume presenting interesting chapters written by an in… Read more

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Motor Neurone Disease, Volume 176 in the International Review in Neurobiology serial highlights new advances, with this new volume presenting interesting chapters written by an international board of authors. Updates include chapters on Clinical features, differential diagnosis and pathology, Recent advances in genetics of familial and sporadic ALS, Non-coding genome contribution to ALS, Contribution of neurophysiology to the diagnosis and monitoring ALS, Advances in symptom management and monitoring disease progression, Use of biomarkers in clinical trials and future developments that will help identify new biomarkers, Application of systems biology to identify therapeutic targets, and much more.

Additional sections cover Evidence of mitochondrial dysfunction (in ALS) and how to measure it in model systems, Current neuroprotective therapies and future prospects, The role of glial cells in ALS, Dysregulation of RNA biology in ALS, New developments in pre-clinical models of ALS to guide translation.

Cover image
Title page
Table of Contents
Series Page
Copyright
Contributors
Preface
Chapter One: Amyotrophic lateral sclerosis; clinical features, differential diagnosis and pathology
Abstract
1 Introduction
2 Epidemiology
3 Clinical presentations
4 Diagnostic approach & criteria
5 Bulbar onset amyotrophic lateral sclerosis
6 Upper motor neurons predominant amyotrophic lateral sclerosis
7 Lower motor neurons predominant amyotrophic lateral sclerosis
8 Lower motor neurons & upper motor neurons involvement
9 Respiratory onset
10 Rapidly progressive weight loss
11 Increasing clinical relevance of genetic test results
12 Pathology in amyotrophic lateral sclerosis
13 Conclusions
References
Chapter Two: Recent advances in the genetics of familial and sporadic ALS
Abstract
1 ALS genetics
2 Clinical impact of ALS genetics
Glossary of terms
References
Chapter Three: Non-coding genome contribution to ALS
Abstract
1 Introduction
2 Genetic architecture of sporadic ALS
3 Genome-wide search for regulatory variants within MN
4 Regulatory variants linked to expression of known monogenic ALS genes
5 Conclusion
Acknowledgements
References
Chapter Four: Contribution of neurophysiology to the diagnosis and monitoring of ALS
Abstract
1 Part I: Neurophysiology and the diagnosis of MND
2 Neurophysiological measures with diagnostic potential
3 Part II: Neurophysiology and monitoring ALS
4 Concluding remarks
References
Chapter Five: Advances in symptom management and in monitoring disease progression in motor neuron disease
Abstract
1 Introduction
2 Aims of supportive care
3 Organisation of care
4 Monitoring progression and predicting future needs
5 Management of physical symptoms
6 Management of dysphagia and nutrition
7 Management of dysarthria and communication
8 Management of respiratory dysfunction
9 Management of oropharyngeal secretions and cough
10 Emotional, behavioural and cognitive symptoms
11 Social, carer and family support
12 Supportive care near the end of life
13 Concluding remarks
References
Chapter Six: Use of biomarkers in clinical trials and future developments that will help identify novel biomarkers
Abstract
1 Clinical trials and biomarkers in amyotrophic lateral sclerosis: Challenges and opportunities
2 A biomarkers-based optimization of amyotrophic lateral sclerosis clinical trials for accelerated drug discovery
3 Are there clinical trial-ready biomarkers in amyotrophic lateral sclerosis
4 New therapeutic strategies for amyotrophic lateral sclerosis enabled by biomarkers
5 Barriers and opportunities in the developments of novel biomarkers for amyotrophic lateral sclerosis
6 Technical advances for biomarker measurement
References
Chapter Seven: From use of omics to systems biology: Identifying therapeutic targets for amyotrophic lateral sclerosis
Abstract
1 Introduction to systems biology and ALS
2 Use of genomics to identify therapeutic targets
3 Use of transcriptomics to identify therapeutic targets
4 Use of other methods to identify therapeutic targets
5 Environment
6 Neuroimaging
7 Value of integration of omics methods to identify and validate therapeutic targets
8 Use of multiomic data in clinical trials
9 Future perspectives
References
Chapter Eight: Evidence of mitochondrial dysfunction in ALS and methods for measuring in model systems
Abstract
1 Introduction
2 Measuring mitochondrial functions
3 Mitochondrial abnormalities in ALS
References
Chapter Nine: Current neuroprotective therapies and future prospects for motor neuron disease
Abstract
1 Introduction to MND, its genetic subtypes and the complexity of its pathophysiological mechanisms
2 Current neuroprotective therapies and their limitations
3 Future prospects: pipeline of therapeutic agents in clinical trials and pre-clinical development
4 Future prospects: advances in clinical trial design
5 Biomarkers of target engagement and therapeutic efficacy
6 Polypharmacy and personalized medicine approaches
References
Chapter Ten: The role of glial cells in amyotrophic lateral sclerosis
Abstract
1 Introduction
2 Central Nervous System Glia
3 Peripheral Nervous System Glia
4 Discussion
5 Concluding remarks
References
Chapter Eleven: RNP granules in ALS and neurodegeneration: From multifunctional membraneless organelles to therapeutic opportunities
Abstract
1 Introduction
2 RNP granules: Properties, regulation and the central role of RBPs
3 RNP granules as a double-edged sword in neurodegeneration
4 RNP granule network in stress and ALS
5 Therapeutic targeting of RNP granules and their (protein and RNA) components in neurodegeneration
6 Conclusions and outlook
Acknowledgements
References
Chapter Twelve: New developments in pre-clinical models of ALS to guide translation
Abstract
1 Introduction
2 Challenges in modelling ALS
3 Rodent models: the gold standard
4 Zebrafish models: an emerging in vivo alternative
5 Human stem cell-based models: a promising newcomer
6 Patient-derived xenografts: the best of both worlds
7 Conclusion and future perspective
Acknowledgements
References

Pamela J. Shaw

Professor Dame Pam Shaw is Professor of Neurology at the University of Sheffield and Director of: the Sheffield Institute for Translational Neuroscience (SITraN); the NIHR Sheffield Biomedical Research Centre for Translational Neuroscience; the Sheffield Care and Research Centre for Motor Neuron Disorders and the cross-faculty Sheffield Neuroscience Institute. She is a Clinician Scientist in Neurology, formerly a Wellcome Trust Senior Fellow and an NIHR Senior Investigator. Her team investigates genetic, molecular and neurochemical mechanisms underlying ALS/MND; investigates new therapeutic targets and translates new neuroprotective and symptomatic treatment approaches into the clinic, including genetic therapy approaches. She has active programmes in systematic biosample collection and biomarker identification in ALS/MND. She has authored more than 550 publications (H-index 116). Her research is funded by NIHR, the MRC, Wellcome Trust, MND Association, MyName’5 Doddie Foundation, EU and biotech/pharmaceutical industry partners. From 2009-2016 she initiated and led the national UK Clinical Studies Group for ALS/MND, a clinical research and trials network which links 20 ALS/MND Care and Research Centres. Prof. Shaw has taken part in more than 25 ALS/MND clinical trials, including roles as Chief Investigator and Steering Committee member and also including several academic-led studies. She is an active member of the European Network for the Cure of ALS (ENCALS) and the TRICALS clinical trials platform.

Affiliations and expertise

Professor of Neurology, Academic Neurology Unit, Division of Genomic Medicine, University of Sheffield, Sheffield, UK

Janine Kirby

My research interests encompass the genetics of neurodegenerative diseases and how gene expression profiling can be used to investigate the pathogenic mechanisms of neurodegeneration and to identify diagnostic and prognostic biomarkers. I have used both Sanger and next generation sequencing (exome and targeted) to screen known and establish novel causative genes in ALS and other neurodegenerative diseases (NDD). Most recently, I demonstrated the value of genetic screening in all patients with ALS, identifying actionable clinical results in patients who would normally not be offered it. I have performed genotype/phenotype correlations to link genetic, clinical, and neuropathological findings with multiple ALS genes including SOD1, TARDBP, FUS, C9ORF72, ANG, OPTN and most recently TBK1. Sampling of CNS and peripheral tissues, as well as animal and cellular models, has been used to establish pathogenic mechanisms involved in both genetic and sporadic ALS. One of these studies established the dysregulation of NRF2, an important cell survival transcription factor, and this is now a therapeutic target for ALS. Expression profiling of CNS, blood, and fibroblast samples from genetic variants of MND and sporadic cases has also identified distinct gene signatures associated with the different genetic subtypes. Variation in miRNAs and other non-coding RNAs are also emerging as potential disease biomarkers. MiRNA profiling in serum and CSF by quantitative PCR, microarrays and small RNA sequencing has determined multiple miRNAs dysregulated in ALS. Finally, gene expression profiling of longitudinal blood samples from patient’s blood samples have established the effect of low-dose interleukin-2 and demonstrated the effect of the drug on the blood transcriptome as well as the patient’s personalized response, demonstrating the importance of a personalized medicine approach for the future.

Affiliations and expertise

Professor in Neurogenetics Department of Neuroscience University of Sheffield

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