Preventing Amyotrophic Lateral Sclerosis: Insights From Pre-symptomatic Neurodegenerative Diseases

Michael Benatar; Joanne Wuu; Caroline McHutchison; Ronald B. Postuma; Bradley F. Boeve; Ronald Petersen; Christopher A. Ross; Howard Rosen; Jalayne J. Arias; Stephanie Fradette; Michael P. McDermott; Jeremy Shefner; Christine Stanislaw; Sharon Abrahams; Stephanie Cosentino; Peter M. Andersen; Richard S. Finkel; Volkan Granit; Anne-Laure Grignon; Jonathan D. Rohrer; Corey T. McMillan; Murray Grossman; Ammar Al-Chalabi; Martin R. Turner


Brain. 2022;145(1):27-44. 

In This Article

Abstract and Introduction


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.


Emerging evidence from the study of a host of neurodegenerative diseases has made it abundantly clear that the well-recognized clinical syndromes of Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are preceded by periods of variable duration during which the underlying disease process is active despite the absence of even mild, prodromal symptoms. The same may also be true of all but the most severe type of spinal muscular atrophy (SMA). The impact of this understanding has been profound, revealing a disjunction between the presence of disease at the molecular, cellular and network levels versus its clinical manifestations, the latter being influenced by a variety of adaptive processes permitting functional tolerance despite underlying pathology. Increasing opportunity and ability to study the pre-symptomatic phases of these diseases (Figure 1) has heightened interest in the possibility that early therapeutic intervention—or even prevention—may offer the best hope for the millions predisposed to these devastating neurodegenerative diseases.

Figure 1.

Terminologies most commonly used in different neurodegenerative diseases. Different fields have used different terms to describe the prodromal phase of disease that precedes clinically overt disease. For Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and FTD, this period is designated as MCI, prodromal Parkinson's disease, prodromal Huntington's disease and prodromal FTD, respectively. In some parlance, prodromal FTD encompasses both MCI-cognition and MCI-behaviour. Similarly, each of these disorders is also characterized by an even earlier stage of asymptomatic disease (pre-MCI, preclinical Parkinson's disease, pre-symptomatic Huntington's disease and preclinical FTD, respectively), during which clinical symptoms and signs are absent, but biomarker evidence may be present. Terminology for SMA is less well-defined.

This background served as the impetus for the First International Pre-Symptomatic ALS Workshop (27 January 2020, in Miami, FL; Supplementary material) and on which this paper is based. First, we review the state-of-the-field as well as experiences and lessons shared by attendees who study the pre-symptomatic phases of various neurodegenerative diseases and their relevance for the study of pre-symptomatic ALS. We then summarize our recommendations for the study of motor, cognitive and behavioural manifestations of early ALS; the critical importance of biomarkers to this endeavour; the challenges of genetic and biomarker counselling; the pertinent ethical, legal and social implications; and considerations for the design of early intervention or disease prevention clinical trials.