ALS motor phenotype heterogeneity, focality, and spread: deconstructing motor neuron degeneration

Abstract

Heterogeneity of motor phenotypes is a clinically well-recognized fundamental aspect of amyotrophic lateral sclerosis (ALS) and is determined by variability of 3 independent primary attributes: body region of onset; relative mix of upper motor neuron (UMN) and lower motor neuron (LMN) deficits; and rate of progression. Motor phenotypes are determined by the anatomy of the underlying neuropathology and the common defining elements underlying their heterogeneity are that motor neuron degeneration is fundamentally a focal process and that it spreads contiguously through the 3-dimensional anatomy of the UMN and LMN levels, thus causing seemingly complex and varied clinical manifestations. This suggests motor neuron degeneration in ALS is in actuality a very orderly and actively propagating process and that fundamental molecular mechanisms may be uniform and their chief properties deduced. This also suggests opportunities for translational research to seek pathobiology directly in the less affected regions of the nervous system.

Figure An idealized model of the natural history of amyotrophic lateral sclerosis (ALS) based upon focality and contiguous spread (A) Onset: At clinical onset, degeneration involves upper motor neurons (UMNs) and lower motor neurons (LMNs) that innervate the same peripheral body region; the site of onset, ratio of UMN to LMN involvement, and rate of progression are each highly variable but independent of each other. (B) Early spread: As the disease process spreads neuroanatomically through UMN and LMN levels, clinical manifestations become complex due to differences (“incongruity”) between somatotopic anatomy and anatomic distances of the 2 levels. (C) Continued outward spread: For LMN, the ALS disease process continues to spread rostral-caudal (severity ipsilateral > contralateral) and must pass through the long thoracic region and thus appears to be mostly at one level. Degeneration may have preferential caudal spread (“directionality”) as discussed in the text. For UMN, however, the ALS disease process continues to spread medial-lateral and more quickly begins to appear as diffuse. (D) Advanced spread: Ultimately, degeneration appears to be diffuse and symmetric through temporal-spatial summation within and between UMN and LMN levels, the natural history of which has depended upon the features established at onset.