Neurodegenerative Disease & Movement Disorders A clinical perspective into early stages of neurodegenerative disease

Advances in therapeutical strategies for neurodegenerative diseases would reduce the burden related to these diseases. To test effectively compounds for diseases such as Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia (FTD), or Alzheimer’s disease (AD) bring therapy to individuals as early as possible, there is an urgent need for the establishment of standards and networks for identification and qualification of biological marker candidates in early stages of neurodegeneration. Biomarkers are needed not just for pre-clinical diagnosis but also to monitor drug safety, to identify individuals who are most likely to respond to specific treatments after stratification of presymptomatic conditions and to quantify the benefits of treatments. In this prospective, genetic markers appear more useful in ALS/FTD: 19 disease genes have been reported to be associated with typical ALS or atypical motor neuron diseases with or without associated frontotemporal dementia (ALS-FTD). Mutations in four genes, namely SOD1, TARDBP, FUS, and C9orf72, account for ~50% of all FALS cases and ~10% of SALS. Given the relatively high mutational frequency, a robust genotype-phenotype correlation can be drawn for these genes. Conversely, pathogenic mutations in the other 15 ALS-associated genes (ALS2, SETX, SPG11, VAPB, ANG, FIG4, OPTN, ATXN2, VCP, UBQLN2, SIGMAR1, CHMP2B, PFN1, ERBB4, and HNRNPA1) are collectively responsible for less than 5% of cases. Usually those variants are found in isolated pedigrees, often with atypical ALS phenotypes and are private mutations, thus making a clear genotype-phenotype correlation extremely difficult (Renton et al., 2014). The recent discovery of C9orf72 gene as the main cause of ALS and FTD definitively consolidated the hypothesis that the two diseases belong to the same phenotypical, neuropathological, and genetic spectrum, opening new prospective in pre-clinical diagnosis. Even before this momentous discovery, however, similar neuropathological features and common mutations in several other genes have been described in both diseases. TDP-43 immunoreactive ubiquitinated inclusions are in fact present in >50% of all FTD cases, while a FUS pathology similar to ALS6 is also observed in atypical FTD, basophilic inclusion body dementia, and neuronal intermediate filament inclusion disease. Not