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

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.

Keywords: amyotrophic lateral sclerosis (ALS); disease prevention; neurodegeneration; pre-symptomatic.

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.

Figure 2

Conceptual framework for studying pre-symptomatic ALS. The natural history of ALS, as a biological entity, includes a pre-manifest (i.e. clinically silent) stage that is typically not observable except when disease-related biomarker abnormalities are detected. These biomarker abnormalities, if present, serve as the first (and only) indication that the disease process has begun. The pre-manifest stage may be followed by a prodromal stage that is characterized by mild motor, cognitive or behavioural impairment (MMI, MCI or MBI, respectively); the prodromal stage is most likely to be observed in individuals with more slowly progressing disease. In turn, this prodromal clinical stage gives way to clinically manifest ALS. The term phenotransition describes the transition from the pre-manifest to the prodromal stage, and the term phenoconversion describes the transition to clinically manifest ALS. The shaded gradient reflects the fact that these periods exist along a continuum. Note that the figure is not drawn to scale, as the relative duration of each period is largely unknown and may vary between individuals.

Figure 3

Decision-tree for the classification of MCI and MBI in pre-symptomatic ALS. An approach to determining the presence of MCI and MBI, based on the results of formal neuropsychological testing and an interview with a reliable informant. This decision-tree emphasizes the need to document changes in cognition and behaviour, and incorporates a hierarchical approach to weighing data from different sources. These guidelines also distinguish mild impairment from instances in which there is uncertainty about cognitive or behavioural impairment.