Pre-Symptomatic Familial ALS (Pre-fALS) Study: From Prodrome and Biomarkers to ALS/FTD Prevention - PROJECT SUMMARY Amyotrophic lateral sclerosis (ALS) remains a fatal neurodegenerative disorder, in part because diagnosis is delayed and treatment is initiated late in disease course. Therapeutic success is most likely when treatment is initiated early, ideally while still pre-symptomatic. Unaffected carriers of pathogenic variants associated with either ALS or both ALS and frontotemporal dementia (FTD), hereafter collectively referred to as ALS/FTD are the only population currently known to be at significantly elevated risk for these disorders, and in whom the study of pre-symptomatic disease is feasible. Pre-Symptomatic Familial ALS (Pre-fALS) is the first and most longstanding natural history and biomarker study of this population. The overarching goals of Pre-fALS are to: (a) understand pre-symptomatic ALS/FTD; (b) discover the earliest markers of disease; and (c) empower ALS/FTD prevention. Through Pre-fALS we have developed a conceptual framework and proposed a lexicon for describing the pre-symptomatic stages of these diseases; identified neurofilament light chain as the first risk/susceptibility biomarker that predicts phenoconversion to clinically manifest ALS; discovered and developed diagnostic criteria for mild motor impairment (MMI), a novel clinical syndrome and prodromal clinical marker of disease; and designed and launched, in collaboration with an industry partner, the first-ever ALS prevention trial (ATLAS) in a subset of the SOD1 population. Pre-fALS is also a unique resource for pre- symptomatic clinical marker and biomarker discovery, given the longitudinally collected deep phenotypic data (motor and cognitive/behavioral) as well as biological specimens, both before and after phenoconversion. In this renewal application, we will expand upon our pioneering work that led to ATLAS, to prepare for prevention trials in other (and larger) populations at genetic risk for ALS/FTD, which we believe will require a multimodal approach. Specifically, we will: characterize the prodromal stages of ALS and FTD among ALS/FTD- associated pathogenic variant carriers (Aim 1); characterize the longitudinal trajectory (and variability) of an array of clinical markers and biomarkers in the pre-symptomatic phase of disease, which comprises both clinically silent and prodromal stages (Aim 2); and identify the subgroup of individuals, based on their clinical and biomarker profile, who are at greatest risk for progressing to clinically manifest disease (ALS or FTD) within 5 years (Aim 3). In turn, the results of the work outlined in this proposal will fuel translation of prodromal disease and biomarker discovery into viable strategies for preventing both ALS and FTD.
