Fig. 2

NFs and phases of the disease in ALS. Increased levels of NFs reflect axonal degeneration and can be detected in the prodromal phase of the disease, with the highest levels in the early symptomatic phase and seemingly stable levels as disease progresses. As the picture displays, during prodromal phase the neurodegenerative process has already begun but the patients generally complain of little disturbances (in the case of motor symptoms, for example, cramps or twitching) that do not compromise the overall function. Therefore, NFs analysis could have applications in the diagnosis, prognosis and early patient enrolment in clinical trials. However, we still need mechanism-based biomarkers that can be detected even earlier during the pre-manifest stage of the disease, when degeneration is not ongoing, and can inform us on targetable molecular and cellular alterations to be addressed in future clinical trials. An ideal disease-progression or pharmaco-dynamic biomarker (see text for explanation) would change with the progression of the disease. Doubts on the possible use of NFs as disease-progression biomarkers have been raised, but only few studies have thoroughly investigated their longitudinal behaviour