Unraveling the Heterogeneity of ALS-A Call to Redefine Patient Stratification for Better Outcomes in Clinical Trials

Abstract

Despite tremendous efforts in basic research and a growing number of clinical trials aiming to find effective treatments, amyotrophic lateral sclerosis (ALS) remains an incurable disease. One possible reason for the lack of effective causative treatment options is that ALS may not be a single disease entity but rather may represent a clinical syndrome, with diverse genetic and molecular causes, histopathological alterations, and subsequent clinical presentations contributing to its complexity and variability among individuals. Defining a way to subcluster ALS patients is becoming a central endeavor in the field. Identifying specific clusters and applying them in clinical trials could enable the development of more effective treatments. This review aims to summarize the available data on heterogeneity in ALS with regard to various aspects, e.g., clinical, genetic, and molecular.

Keywords: amyotrophic lateral sclerosis; clinical trials; heterogeneity; subcluster.

Figure 1

Overview of the different aspects of heterogeneity in ALS. (a) Genetic heterogeneity; (b) pathological heterogeneity; (c) clinical heterogeneity regarding; (i) disease onset; (ii) disease progression; (iii) motor and behavioral/cognitive phenotype; (iv) apparative diagnostics and (v) metabolic profiles; and (d) molecular heterogeneity. ALS, amyotrophic lateral sclerosis; SOD1 and SOD1, superoxide dismutase 1; TARDBP, TAR-DNA-binding protein; FUS and FUS, fused in sarcoma; C9orf72, chromosome open reading frame 72; TDP-43, TAR DNA-binding protein 43; PLS, primary lateral sclerosis; PMA, progressive muscular atrophy; UMN, upper motor neuron; LMN, lower motor neuron; FTD, frontotemporal dementia; MND, motor neuron disease; ci, cognitive impairment; bi, behavioral impairment; bci, behavioral and cognitive impairment; CNS, central nervous system; PNS, peripheral nervous system. Created by Laura Tzeplaeff and Camilla Wohnrade with “BioRender.com”.

Figure 2

Current state of ALS treatment and proposed subclustering for personalized medicine.