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Frontotemporal dementias (FTD) constitute the second most common types of dementia before the age of 65, characterized by frontotemporal lobar degeneration. Progressive behavioural, cognitive changes and prominent language problems compromise social functioning and lead rapidly to severe loss of autonomy and dementia. Amyotrophic lateral sclerosis (ALS) leading to progressive motor deficits and disability, is associated to FTD in 20% of the patients. Selective frontal and/or temporal atrophy on MRI characteristic for FTD has proven to be preceded by structural and functional connectivity changes in white matter tracts and between specific cortical regions on functional MRI. Genetic factors play an important role, with mutations in three different genes (MAPT, GRN, and C9ORF72) associated with FTD segregating in an autosomal dominant mode of inheritance within families. Hexanucleotide, GGGGCC, expansions in the first intron of C9ORF72 gene are the most frequent mutations responsible for both FTD and ALS. This deficiency has been recently discovered by two research groups and disease processes still have to be elucidated. Therapeutic interventions in dementia are currently focusing to the earliest stages of the disease. The group of presymptomatic mutation carriers from families with hereditary FTD are an ideal study population to investigate the earliest alterations in FTD, and are also important for interventional studies. Sensitive neuroimaging and neurochemical biomarker changes as surrogate endpoints are essential in the design of such interventions. Longitudinal studies of a large international cohort of European presymptomatic FTD C9ORF72 repeat expansion carriers will enable us to define the temporal dynamics of these changes, and to determine their sensitivity over time for evaluating the effect of disease-specific modifying agents in future clinical trials. Potential protein and microRNA/RNA biomarkers are reported in recent studies on neurodegenerative diseases; these biomarkers may play an important role in the presymptomatic stage. Our aim is to carry out a longitudinal study of presymptomatic mutation carriers in order to track the disease process in the presymptomatic stage and evaluate the sensitivity of these biomarkers for disease-modifying treatments and as outcome measure. We will furthermore aim to develop embryonic fibroblasts of a transgenic mouse model expressing RNA containing expanded repeats in the C9ORF72 gene, as an innovative approach for drug screening.

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