Identification of a presymptomatic and early disease signature for amyotrophic lateral sclerosis (ALS): protocol of the premodiALS study

Abstract

Introduction: The median time to diagnosis of amyotrophic lateral sclerosis (ALS) is approximately 12 months after the onset of first symptoms. This diagnostic delay is primarily due to the nonspecific nature of early symptoms and the clinical challenges in differentiating ALS from its mimics. Therefore, the discovery of reliable biomarkers for the early and accurate diagnosis of ALS represents a critical medical need.

Methods: A total of 330 participants will be recruited across six international study sites. The cohort will include (1) pre-symptomatic gene mutation carriers, (2) symptomatic individuals up to 12 months after symptom onset with either ALS, ALS mimics, or a pure motor syndrome with yet unclear assignment, and (3) healthy controls. Participants will engage in a one-year longitudinal study, consisting of an initial evaluation at baseline visit and a follow-up visit 12 months later. Assessments will include an environmental and medical history questionnaire, neurological examinations, olfactory testing, cognitive/behavioral evaluations, and the collection of biological samples (serum, plasma, urine, tear fluid, and cerebrospinal fluid). Proteomic, metabolomic, and lipidomic analyses will be performed using mass spectrometry and targeted immunoassays, with all samples processed under standardized protocols. The resulting multimodal dataset will be systematically integrated in an effort to uncover a presymptomatic and early ALS signature. Perspective The premodiALS study aim to identify a clinico-molecular signature characteristic of presymptomatic and early ALS. These findings may have relevance to early diagnosis and future clinical practice for ALS disease.

Keywords: Biomarkers; Early diagnosis; Motoneuron disease; Multi-omic; Observational study; Pre-symptomatic.

Fig. 1

Overview of the premodiALS study procedures, analyses and outcomes. (a) Clinical and biomaterial collection from the PGMC, control and symptomatic patients’ groups. The symptomatic patients group includes subjects within 12 months of symptom onset with either early ALS or an ALS mimic, or a pure motor syndrome that does not permit to establish a certain diagnosis at the baseline visit (V0). The categorization into early ALS and ALS mimic groups will be determined a posteriori at the follow up visit (V1). (b) Analysis and integration of the clinical data and molecular data obtained from the biomaterial collection. (c) Identification of a clinico-molecular fingerprint of PGMC and early ALS. V: visit; PGMC: pre-symptomatic gene mutation carrier. Created in BioRender. Tzeplaeff, L. (2025)

Fig. 2

premodiALS recruitment status (as of 06/2025). (a) Number of participants recruited per country in the V0 and V1 for all groups. (b) Number of participants recruited per country in the control, PGMC and the symptomatic patient groups. V: visit; PGMC: pre-symptomatic gene mutation carrier; SYMP: symptomatic patients’ group (early ALS or ALS mimics or pure motor syndrome). Created in Graphpad Prism. Tzeplaeff, L.