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Pathophysiology and Treatment of Non-motor Dysfunction in Amyotrophic Lateral Sclerosis

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Abstract

Amyotrophic lateral sclerosis is a progressive and fatal neurodegenerative disease typically presenting with bulbar or limb weakness. There is increasing evidence that amyotrophic lateral sclerosis is a multisystem disease with early and frequent impacts on cognition, behaviour, sleep, pain and fatigue. Dysfunction of normal physiological and metabolic processes also appears common. Evidence from pre-symptomatic studies and large epidemiological cohorts examining risk factors for the future development of amyotrophic lateral sclerosis have reported a high prevalence of changes in behaviour and mental health before the emergence of motor weakness. This suggests that changes beyond the motor system are underway at an early stage with dysfunction across brain networks regulating a variety of cognitive, behavioural and other homeostatic processes. The full impact of non-motor dysfunction continues to be established but there is now sufficient evidence that the presence of non-motor symptoms impacts overall survival in amyotrophic lateral sclerosis, and with up to 80% reporting non-motor symptoms, there is an urgent need to develop more robust therapeutic approaches. This review provides a contemporary overview of the pathobiology of non-motor dysfunction, offering readers a practical approach with regard to assessment and management. We review the current evidence for pharmacological and non-pharmacological treatment of non-motor dysfunction in amyotrophic lateral sclerosis and highlight the need to further integrate non-motor dysfunction as an important outcome measure for future clinical trial design.

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Authors and Affiliations

  1. Brain and Mind Centre, The University of Sydney, 94 Mallett Street, Camperdown, NSW, Australia

    Colin J. Mahoney, Rebekah M. Ahmed, William Huynh, Sicong Tu & Matthew C. Kiernan

  2. Department of Neurology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia

    Rebekah M. Ahmed & Matthew C. Kiernan

  3. Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK

    Jonathan D. Rohrer

  4. Department of Neurology, Duke University Hospital, Durham, North Carolina, USA

    Richard S. Bedlack

  5. Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College, Dublin, Ireland

    Orla Hardiman

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  1. Colin J. Mahoney
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Correspondence to Colin J. Mahoney.

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Funding

Colin J. Mahoney is funded by a post-doctoral University of Sydney Fellowship. This study was conducted by ForeFront, a large collaborative research group dedicated to the study of neurodegenerative diseases and funded by the National Health and Medical Research Council of Australia Program Grant (1132524), Dementia Research Team Grant (#1095127) and Partnership Project (1153439). Matthew C. Kiernan was supported by a NHMRC Practitioner Fellowship (1156093). Orla Hardiman reports receiving grants from Science Foundation Ireland. No specific funding was provided for the preparation of this article.

Conflicts of interest/Competing interests

Orla Hardiman reports personal fees from Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, Taylor & Francis, Cytokinetics and Wave Pharmaceuticals. Matthew C. Kiernan is the Editor-in-Chief of the Journal of Neurology, Neurosurgery and Psychiatry. Colin J. Mahoney, Rebekah M. Ahmed, William Huynh, Sicong Tu, Jonathan D. Rohrer and Richard S. Bedlack have no conflicts of interest that are directly relevant to the content of this article.

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Authors’ contributions

CJM and MCK conceived this article. CJM, RMA, WH and MCK determined the scope of article. CJM undertook the literature search and completed the initial draft paper. RMA, WH, ST, JDR, RSB and OH provided critical commentary and revised the final article. All authors reviewed and approved the final manuscript and agree to be accountable for the article content.

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Mahoney, C.J., Ahmed, R.M., Huynh, W. et al. Pathophysiology and Treatment of Non-motor Dysfunction in Amyotrophic Lateral Sclerosis. CNS Drugs 35, 483–505 (2021). https://doi.org/10.1007/s40263-021-00820-1

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