About this item:

61 Views | 38 Downloads

Author Notes:

Michael Benatar, MD, PhD Department of Neurology, Miller School of Medicine, University of Miami 1120 NW 14 Street, CRB1318, Miami, FL 33136, USA E-mail: mbenatar@med.miami.edu

We are grateful for the very thoughtful and helpful comments received from reviewers of this paper. In addition, we are indebted to the participants in the Pre-fALS study—it is through their longstanding and ongoing commitment in this research endeavour that we have been able to gain insight into the earliest manifestations of ALS and to forge a path towards ALS prevention.

See publication for disclosures

Subjects:

Research Funding:

The First International Pre-Symptomatic ALS Workshop was supported through unrestricted grants from The ALS Association, The Muscular Dystrophy Association, The Motor Neurone Disease Association, The Association for Frontotemporal Degeneration, Biogen and AveXis. M.B. and J.W. also receive partial support for the Workshop from the National Institutes of Health (NIH) through R01 NS105479. C.M. is supported as a CReATe Scholar through funding from the National Institutes of Health (U54 NS092091).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Clinical Neurology
  • Neurosciences
  • Neurosciences & Neurology
  • neurodegeneration
  • amyotrophic lateral sclerosis (ALS)
  • pre-symptomatic
  • disease prevention
  • SPINAL MUSCULAR-ATROPHY
  • GENETIC FRONTOTEMPORAL DEMENTIA
  • MILD COGNITIVE IMPAIRMENT
  • HUNTINGTONS-DISEASE
  • NATURAL-HISTORY
  • DIAGNOSTIC-CRITERIA
  • ALZHEIMERS-DISEASE
  • POTENTIAL BIOMARKER
  • CEREBROSPINAL-FLUID
  • BEHAVIORAL VARIANT

Preventing amyotrophic lateral sclerosis: insights from pre-symptomatic neurodegenerative diseases

Show all authors Show less authors

Tools:

Journal Title:

BRAIN

Volume:

Volume 145, Number 1

Publisher:

, Pages 27-44

Type of Work:

Article | Final Publisher PDF

Abstract:

Significant progress has been made in understanding the pre-symptomatic phase of amyotrophic lateral sclerosis. While much is still unknown, advances in other neurodegenerative diseases offer valuable insights. Indeed, it is increasingly clear that the well-recognized clinical syndromes of Alzheimer's disease, Parkinson's disease, Huntington's disease, spinal muscular atrophy and frontotemporal dementia are also each preceded by a pre-symptomatic or prodromal period of varying duration, during which the underlying disease process unfolds, with associated compensatory changes and loss of inherent system redundancy. Key insights from these diseases highlight opportunities for discovery in amyotrophic lateral sclerosis. The development of biomarkers reflecting amyloid and tau has led to a shift in defining Alzheimer's disease based on inferred underlying histopathology. Parkinson's disease is unique among neurodegenerative diseases in the number and diversity of non-genetic biomarkers of pre-symptomatic disease, most notably REM sleep behaviour disorder. Huntington's disease benefits from an ability to predict the likely timing of clinically manifest disease based on age and CAG-repeat length alongside reliable neuroimaging markers of atrophy. Spinal muscular atrophy clinical trials have highlighted the transformational value of early therapeutic intervention, and studies in frontotemporal dementia illustrate the differential role of biomarkers based on genotype. Similar advances in amyotrophic lateral sclerosis would transform our understanding of key events in pathogenesis, thereby dramatically accelerating progress towards disease prevention. Deciphering the biology of pre-symptomatic amyotrophic lateral sclerosis relies on a clear conceptual framework for defining the earliest stages of disease. Clinically manifest amyotrophic lateral sclerosis may emerge abruptly, especially among those who harbour genetic mutations associated with rapidly progressive amyotrophic lateral sclerosis. However, the disease may also evolve more gradually, revealing a prodromal period of mild motor impairment preceding phenoconversion to clinically manifest disease. Similarly, cognitive and behavioural impairment, when present, may emerge gradually, evolving through a prodromal period of mild cognitive impairment or mild behavioural impairment before progression to amyotrophic lateral sclerosis. Biomarkers are critically important to studying pre-symptomatic amyotrophic lateral sclerosis and essential to efforts to intervene therapeutically before clinically manifest disease emerges. The use of non-genetic biomarkers, however, presents challenges related to counselling, informed consent, communication of results and limited protections afforded by existing legislation. Experiences from pre-symptomatic genetic testing and counselling, and the legal protections against discrimination based on genetic data, may serve as a guide. Building on what we have learned - more broadly from other pre-symptomatic neurodegenerative diseases and specifically from amyotrophic lateral sclerosis gene mutation carriers - we present a road map to early intervention, and perhaps even disease prevention, for all forms of amyotrophic lateral sclerosis.

Copyright information:

© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/rdf).
Export to EndNote