Fast Progression in Amyotrophic Lateral Sclerosis: Pathways and Biomarkers from Multi-Omics Analysis
Roland Huber1, Crystal Jing Jing Yeo1,2,3,4
1A*STAR, 2Department of Neurology, Feinberg School of Medicine, Northwestern University, 3School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, 4LKC School of Medicine, Imperial College London and NTU Singapore
Objective:

Utilizing multi-omics data from AnswerALS database to identify therapeutic targets and biomarkers for fast progressing amyotrophic lateral sclerosis(ALS). 

Background:

Heterogeneity in ALS disease progression poses challenges to detecting decline and assessing treatment response. Recent edaravone and AMX0035 clinical trials showed treatment response in fast progressors who declined more than 1.5/month on the ALS Functional Rating Scale–revised (ALSFRS-R) scale over 6 months. Cognitive and/or behavioral disturbances are assessed using ALS-Cognitive Behavioral Score(CBS) and associated with worse prognosis.

Design/Methods:

Epigenomics, transcriptomics and proteomics data from 122 patients (105 ALS, 17 control) were analyzed. The population was split according to ALSFRS-R slope (fast, <-1.5/month, n=8; slow, >-0.5/month, n=34) and ALS-CBS slope (fast, <-0.5, n=2; slow, >+0.5, n=2) and omics data contrasts were calculated to identify significant differences between fast and slow progressors at the extremes of clinical phenotype. Candidate drugs targeting dysregulated pathways were predicted by CMAP and STITCH. Cluster analysis of the entire study population was performed based on identified gene and protein sets and clades identified.

Results:

Contrasting along the ALSFRS-R identified extensive epigenetic (less accessible: n=834, more accessible: n=106) and proteomic changes (downregulated: n=37, upregulated: n=1) in fast progressors compared to slow progressors, with significant dysregulation of innate/adaptive immunity, chromatin remodeling, electron transport and olfactory receptor pathways. Contrasting along the ALS-CBS scale yielded similar numbers of epigenetic (less accessible: n=73, more accessible: n=22) and proteomic changes (downregulated: n=37, upregulated: n=65), with significant dysregulation of synaptic function and RNA processing pathways. Transcriptomic changes were not significant. Candidate drugs included amantadine, cephalexin, ampalex and mycretin. Fast progressors were split amongst clades but slow progressors made up entire clades.

Conclusions:
Multiple clades associated with fast progressors suggested heterogeneity among this patient population, with identified gene and protein sets providing potentially useful prognostic biomarkers for stratification and individualized treatment.