Presymptomatic studies in ALS Rationale, challenges, and approach

It is now well-established that the disease process in many neurodegenerative disorders, including Alzheimer disease, Parkinson disease, and Huntington disease, begins many years before the appearance of typical symptoms. Whether amyotrophic lateral sclerosis (ALS) is also characterized by a presymptomatic period, and if so how long this period lasts, is unclear. Answers to these questions will not only inform our understanding of disease biology and potential environmental risk factors for ALS, but also the design and implementation of early therapeutic and even preventative clinical trials. Moreover, the potential impact of studying people at genetic risk for ALS, the only population in which it is currently possible to study presymptomatic disease, is underscored by recent progress in our understanding of the shared genetic basis of familial and apparently sporadic ALS. Studying presymptomatic ALS, however, has proven difficult due to the challenge in identifying an at-risk population and various logistical and ethical considerations. In this article we present the rationale for studying presymptomatic ALS, summarize the early evidence supporting the existence of a presymptomatic phase of the disease, and discuss the challenges of studying presymptomatic ALS. We also use Pre-fALS a systematic and longitudinal investigation of a cohort of individuals at genetic risk for ALS, as an example to illustrate how one might approach these challenges. Neurology (R) 2012; 79: 1732-1739