Characterization of Platelet Molecular Profiles in ALS for the Identification of Specific Diagnostic Biomarkers - A Pilot Study

Overview

The search for diagnostic biomarkers that can be used routinely is a major challenge to manage Amyotrophic lateral sclerosis (ALS) in order to characterize the pathophysiology and accelerate the management of the disease. Some non-specific biomarkers have been proposed (Neurofilaments, TDP-43) but their diagnostic value remains controversial. This study aims to identify ALS-specific platelet biomarkers using targeted and untargeted multi-omic approaches, in order to enable differential diagnosis between ALS and other motor neuron diseases.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of motor neurons, leading to increasing muscle paralysis. The pathophysiology of ALS remains poorly understood, and the absence of a diagnostic test makes this disease a real challenge, requiring an average of 12 months before a reliable ALS diagnosis can be established. Yet, this disease progresses rapidly, leading to death on average 36 months after the onset of symptoms. The search for diagnostic biomarkers that can be used routinely is therefore a major challenge in order to characterize the pathophysiology and accelerate the management of the disease. To date, a few avenues have been explored, including the concentration in the blood or cerebrospinal fluid of neurofilaments, a protein that can be used to assess the progression of neuronal loss. This biomarker has shown some potential but is not specific to ALS and its diagnostic value remains controversial. In addition, the TDP-43 protein, involved in RNA metabolism, has been widely described as pathogenic in ALS. Indeed, its aggregation and modification of its localization are thought to be associated with motor neuron degeneration. Several studies have demonstrated the presence of this protein in platelets, suggesting their potential as a source of peripheral biomarkers. This project aims to identify platelet molecular biomarkers in ALS patients within three months of diagnosis, using targeted (TDP-43 and neurofilaments) and non-targeted (metabo-lipidomic, transcriptomic, and proteomic profiles) approaches. This multi-omic approach could reveal a complex, comprehensive, and specific signature of ALS. The results will allow us to evaluate the diagnostic and prognostic performance of platelet biomarkers, either on their own or in combination.