Early detection of neuropsychiatric, language and motor symptoms in genetic frontotemporal dementia (FTD): Defining prodromal FTD

Abstract

AbstractBackgroundThe prodromal stage of genetic frontotemporal dementia (FTD) is currently poorly defined. Whilst the majority of people with genetic FTD develop behavioural symptoms, a number of people present with primary progressive aphasia (PPA), neuropsychiatric symptoms, parkinsonism, including corticobasal syndrome (CBS) or progressive supranuclear palsy (PSP), or amyotrophic lateral sclerosis (ALS). Such variable phenotypes pose a barrier to clearer definitions of prodromal FTD.Methods1139 people have been recruited to the Genetic FTD Initiative (GENFI), a deep phenotyping international multicentre cohort study of FTD. Clinical data on symptoms within the language, neuropsychiatric and motor domains have been collected on presymptomatic and symptomatic mutation carriers, as well as mutation‐negative controls using the GENFI Symptom Scales.Results Language: In the symptomatic phase, 19 participants met Gorno‐Tempini diagnostic criteria for primary progressive aphasia (PPA), the majority (17) of whom had a progranulin (GRN) mutation. The phenotype in these cases was either nonfluent variant (8) or did not meet criteria for a specific variant (9). Additionally, 42 presymptomatic participants had subtle early language problems. Neuropsychiatric: Symptoms were reported most frequently in symptomatic C9orf72 mutation carriers (91.7% of all symptomatic C9orf72 carriers) and to a lesser extent in GRN and MAPT mutation carriers. Depression and anxiety were common in mutation‐negative controls (14%) as well as mutation carriers. Motor: ALS and FTD‐ALS were most frequent in C9orf72‐associated FTD (12.5% of all symptomatic C9orf72 carriers). Parkinsonism (including PSP and CBS) was present to a lesser extent in C9orf72, GRN, and MAPT mutation carriers.ConclusionsLanguage, neuropsychiatric and motor features are common in genetic FTD and will need to be included in any prodromal staging system. Improved, operationalised measurement of such symptoms will allow improved stratification of individuals, and aid clinical trials. Future work should unravel the temporal trajectory of such symptoms within each form of genetic FTD.