IMPORTANCE Behavioral disturbances are core features of frontotemporal dementia (FTD); however, symptom progression across the course of disease is not well characterized in genetic FTD.OBJECTIVE To investigate behavioral symptom frequency and severity and their evolution and progression in different forms of genetic FTD.

Frontotemporal dementia (FTD), marked by impairments in behavior, language and sometimes motor function, is a common form of early-onset dementia 1 . Approximately 20-30% of FTD is caused by autosomal dominant mutations (familial, or f-FTD), usually in one of three genes: chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN) or microtubule-associated protein tau (MAPT) 2 . FTD is uniformly fatal, and there are no approved therapies; however, a growing number of new treatments targeting C9orf72, GRN and MAPT are moving into clinical trials 3,4 . Experience from Alzheimer's disease (AD), spinal muscular Temporal order of clinical and biomarker changes in familial frontotemporal dementia

Objective To investigate the optimal method of adding motor features to a clinical rating scale for frontotemporal dementia (FTD). Methods Eight hundred and thirty-two participants from the international multicentre Genetic FTD Initiative (GENFI) study were recruited: 522 mutation carriers (with C9orf72, GRN and MAPT mutations) and 310 mutation-negative controls. A standardised clinical questionnaire was used to assess eight motor symptoms (dysarthria, dysphagia, tremor, slowness, weakness, gait disorder, falls and functional difficulties using hands). Frequency and severity of each motor symptom was assessed, and a principal component analysis (PCA) was performed to identify how the different motor symptoms loaded together. Finally, addition of a motor component to the CDR® plus NACC FTLD was investigated (CDR® plus NACC FTLD-M). Results 24.3% of mutation carriers had motor symptoms (31.7% C9orf72, 18.8% GRN, 19.3% MAPT) compared to 6.8% of controls. Slowness and gait disorder were the commonest in all genetic groups while tremor and falls were the least frequent. Symptom severity scores were similar to equivalent physical motor examination scores. PCA revealed that all motor symptoms loaded together so a single additional motor component was added to the CDR® plus NACC FTLD to form the CDR® plus NACC FTLD-M. Individual global scores were more severe with the CDR® plus NACC FTLD-M, and no patients with a clinically diagnosed motor disorder (ALS/FTD-ALS or parkinsonism) were classified anymore as asymptomatic (unlike the CDR® plus NACC FTLD alone). Conclusions Motor features are present in mutation carriers at all disease stages across all three genetic groups. Inclusion of motor symptoms in a rating scale that can be used in future clinical trials will not only ensure a more accurate severity measure is recorded but that a wider spectrum of FTD phenotypes can be included in the same trial.

While frontotemporal dementia (frontotemporal dementia) has been considered a neurodegenerative disease that starts in mid-life or later, it is now clearly established that cortical and subcortical volume loss is observed more than a decade prior to symptom onset and progresses with aging. To test the hypothesis that genetic mutations causing frontotemporal dementia have neurodevelopmental consequences, we have examined the youngest adults in the GENFI cohort of pre-symptomatic frontotemporal dementia mutation carriers who are between the ages of 19 and 30y. Structural brain differences and improved performance on some cognitive tests was found for MAPT and GRN mutation carriers relative to familial non-carriers, while smaller volumes were observed in C9orf72 repeat expansion carriers at a mean age of 26y. The detection of such early differences supports potential advantageous neurodevelopmental consequences of some frontotemporal dementia causing genetic mutations. These results have implications for design of therapeutic interventions for frontotemporal dementia. Future studies at younger ages are needed to identify specific early pathophysiologic or compensatory processes in the neurodevelopmental period.

L'objectif de cette recherche est d'étudier l'évolution avec le vieillissement du processus taxonomique impliqué dans une version adaptée du test des Similitudes de Wechsler, qui distingue la catégorisation des mots concrets versus abstraits. Deux groupes ont été constitués : 20 adultes jeunes (M =20ans, SD=1.36) et 20 adultes âgés (M =70ans, SD=4.66). Les résultats montrent un déclin de la catégorisation taxonomique avec l'âge, notamment pour les mots abstraits. L'effet de concrétude est donc observé mais seulement chez les âgés du fait d'un effet « plafond » des performances chez les jeunes adultes. De plus, il s'avère que la moyenne des réponses taxonomiques des âgés est à peu près équivalente à celle d'enfants de 9 ans d'une étude antérieure. La courbe curvilinéaire du développement de la catégorisation taxonomique observée par de nombreux auteurs est donc retrouvée. Néanmoins, une analyse plus précise des items et des réponses montre que les âgés ont davantage de difficultés avec des mots faciles qu'avec des mots difficiles. Ce résultat suggère que le processus de catégorisation serait préservé mais que des variables affectives viendraient moduler l'activation du processus taxonomique.