Defining pre-symptomatic amyotrophic lateral sclerosis

Abstract

Successful treatment of neurodegenerative disease may hinge on early therapeutic intervention. This requires an understanding of early/pre-symptomatic disease, a need that is underscored by advances in antisense oligonucleotide, and viral-vector-based gene therapies. In amyotrophic lateral sclerosis (ALS), the study of pre-symptomatic disease requires a cohesive conceptual framework for describing this phase of disease. Informed by the literature in other neurodegenerative diseases and extensive personal experience, a model is proposed that distinguishes ALS as a clinical syndrome from ALS as a disease, and characterizes pre-symptomatic ALS as having two identifiable stages: pre-manifest and prodromal. The unique and critical importance of biomarker development is articulated and an operational definition of phenoconversion is provided. It is hoped that this framework will accelerate collective efforts to study pre-symptomatic ALS, and aid in the design and implementation of an early intervention- or disease-prevention trial.

Phases and Stages of ALS: A Conceptual Model.

(A) The natural history of ALS: From (heightened) susceptibility to disease onset; from the pre-symptomatic to the symptomatic phase of disease; and from the pre-manifest to the prodromal stage within the pre-symptomatic phase. Color gradient reflects the likelihood that these phases and stages exist along a continuum. (Note that the figure is not drawn to scale, as the relative duration of each phase and stage is largely unknown and may vary between individuals.) The vertical dotted line demarcates the earliest biomarker evidence of disease (e.g., neurofilament light concentration based on currently published data), but development of more sensitive biomarkers might permit even earlier detection of pre-symptomatic disease. (B) The increase in serum and cerebrospinal fluid levels of neurofilament proteins (red), as has been observed during the pre-symptomatic and early symptomatic phases of disease, indicating underlying axonal degeneration. The red arrow marks the earliest evidence of disease as evidenced by an increase in neurofilament. (C) Hypothesized biomarker(s) (blue) indicative of a molecular, cellular, or network phenotype that begins prior to axonal loss. The blue arrow marks the earliest detectable increase in the novel biomarker(s). The period of this novel biomarker increase without evidence of axonal loss (and prior to clinical manifestations) may be regarded as a “compensated” state; the emergence of axonal degeneration in the pre-symptomatic phase indicates a “decompensating” state; and the emergence of clinical manifestations along with axonal degeneration reflect a “decompensated” state.