Prodromal FTD ‐ what do we know about it and what do we still have to learn?

Abstract

AbstractBackgroundFrontotemporal dementia (FTD) is a complex disease that can initially present with subtle symptoms across several domains including behavior, cognitive/language, psychiatric and motor. This heterogenous prodromal phase is preceded by a slowly progressive presymptomatic accumulation of biological changes. With the emergence of new potential therapeutic agents for genetic forms, there is a need for robust clinical characterization and diagnostic definitions of these disease phases.MethodWe performed a systematic literature review on the current state of the science on prodromal FTD and provide expert consensus recommendations on diagnostic definitions.ResultThe preclinical phase should extend from the first signs of protein misfolding to the first FTD symptoms, however we lack molecular biomarkers to characterize this stage, with maybe the exception of C9orf72 expansion cases. In genetic mutation carriers it is uncertain if a ‘no disease’ phase exists, or if there is a neurodevelopmental component. To account for all possible clinical presentations, the definition of the prodromal stage of FTD needs to include the possibility of symptoms emerging with behavioral/psychiatric, cognitive and/or motor features. We subsume these features under the term mild cognitive and/or behavioral and/or motor impairment due to FTD (MCBMI‐FTD). MCBMI‐FTD needs to include psychiatric symptoms outside of typical bvFTD criteria as potential initial prodromal manifestations of FTD in genetic mutation carriers, however this would not be applicable in sporadic cases given the lack of specificity of such symptoms.ConclusionCharacterizing the preclinical and prodromal stages of FTD is crucial for disease detection and patient stratification for future clinical trials. However, several issues remain including the need to develop molecular biomarkers to better characterize the preclinical phase and more accurate models to predict symptom onset.