Quantifying disease progression in amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) exhibits characteristic variability of onset and rate of disease progression, with inherent clinical heterogeneity making disease quantitation difficult. Recent advances in understanding pathogenic mechanisms linked to the development of ALS impose an increasing need to develop strategies to predict and more objectively measure disease progression. This review explores phenotypic and genetic determinants of disease progression in ALS, and examines established and evolving biomarkers that may contribute to robust measurement in longitudinal clinical studies. With targeted neuroprotective strategies on the horizon, developing efficiencies in clinical trial design may facilitate timely entry of novel treatments into the clinic.

Figure 1

Markers of lower motor neuron loss. Illustration of the motor unit, comprising the anterior horn cell in the spinal cord projecting to innervate a group of muscle fibers. Methods used to measure loss of anterior horn cells are depicted. (A) Muscle ultrasound may show increased muscle echogenicity and reduced muscle thickness. A grayscale histogram derived from the depicted ultrasound image shows the distribution of grayscale values (red curve), superimposed onto average (± standard deviation) grayscale histograms of 44 normal control subjects (black curves). (B) Ultrasound changes reflect histopathological abnormalities with fiber-type grouping, suggesting reinnervation, and grouped atrophy (red box), suggesting motor neuron loss, typical of motor neuron diseases. (C) These muscle denervation and reinnervation changes may be identified on electromyography, with prolongation of individual motor units, as a result of dyssynchrony of muscle fiber firing secondary to poorly myelinated regenerating branches. Jitter and block of muscle fiber action potentials may be seen as a result (arrowhead). (D) Anterior horn cell loss, independent of muscle reinnervation changes, may be quantified using motor unit number estimation techniques, in this instance using an incremental stimulation technique. ALS = amyotrophic lateral sclerosis; CMAP = compound muscle action potential.

Figure 2

Brain imaging markers of disease. (A) The corticospinal tracts (CST) can be reconstructed using diffusion tensor tractography. (B) A scatterplot of the extracted mean CST fractional anisotropy (FA) against the rate of decline of Amyotrophic Lateral Sclerosis (ALS) Functional Rating Scale (ALSFRS) score (points per month) shows a negative correlation, with potential to prognostically stratify patients (adapted from Fig 3 in Turner et al64). (C) Longitudinal gray matter changes are extensive in ALS, detected using voxel-based morphometry. They include extramotor frontal lobe regions and basal ganglia (regions of significantly reduced gray matter density common to a large group of ALS patients over time, shown in yellow–red scale overlaid on standard brain image in 3 planes, with anterior [A], posterior [P], right [R], and left [L] marked).