Abstract
ObjectiveTo characterize disease evolution in amyotrophic lateral sclerosis using an event‐based model designed to extract temporal information from cross‐sectional data. Conventional methods for understanding mechanisms of rapidly progressive neurodegenerative disorders are limited by the subjectivity inherent in the selection of a limited range of measurements, and the need to acquire longitudinal data.MethodsThe event‐based model characterizes a disease as a series of events, each comprising a significant change in subject state. The model was applied to data from 154 patients and 128 healthy controls selected from five independent diffusion MRI datasets acquired in four different imaging laboratories between 1999 and 2016. The biomarkers modeled were mean fractional anisotropy values of white matter tracts implicated in amyotrophic lateral sclerosis. The cerebral portion of the corticospinal tract was divided into three segments.ResultsApplication of the model to the pooled datasets revealed that the corticospinal tracts were involved before other white matter tracts. Distal corticospinal tract segments were involved earlier than more proximal (i.e., cephalad) segments. In addition, the model revealed early ordering of fractional anisotropy change in the corpus callosum and subsequently in long association fibers.InterpretationThese findings represent data‐driven evidence for early involvement of the corticospinal tracts and body of the corpus callosum in keeping with conventional approaches to image analysis, while providing new evidence to inform directional degeneration of the corticospinal tracts. This data‐driven model provides new insight into the dynamics of neuronal damage in amyotrophic lateral sclerosis.
Highlights
Amyotrophic Lateral Sclerosis (ALS) is recognized as both a clinically and pathogenically heterogeneous disorder.[1]
Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association
The event sequence shows with high confidence that the earliest changes detected are in the corticospinal tracts (CST) and corpus callosum (CC) body; the distal CST is more susceptible to MRI degenerative change than the proximal segment as reflected by changes in fractional anisotropy (FA) in the three segments of the CSTs
Summary
Amyotrophic Lateral Sclerosis (ALS) is recognized as both a clinically and pathogenically heterogeneous disorder.[1]. Schemes for studying the evolution and staging of these diseases have depended on the selection of phenotypic and biomarker criteria (broadly defined to include a wide range of clinical, molecular, and neuroimaging measures). The Braak postmortem histopathological staging schemes[4,5] applied to Alzheimer’s disease and ALS, depend on a priori assumptions on the pattern of pathological change, which are by definition end-stage. In this latter context, the notion of stage is necessarily an inference from the observed patterns of pathological change. Missing data[7,8] is likely to introduce bias into longitudinal analyses since missingness is unlikely to be random in ALS.[9]
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