ABSTRACT Frontotemporal dementia (FTD) is a family of neurodegenerative syndromes characterized by progressive decline in emotion, social behavior, and language. The behavioral variant of FTD is the most common clinical subtype and is characterized by deficits in emotion, empathy, and social behavior. FTD is often sporadic but can be caused by genetic mutations in C9orf72, GRN, and MAPT. Genetic forms of FTD offer a critical window into the disease's early stages because individuals with genetic mutations can be identified, studied, and followed when they are asymptomatic and as they enter the symptomatic stage of the disease. Our previous laboratory-based studies have found alterations in autonomic nervous system activity, facial expression, and experience occur early in FTD and reflect dysfunction in specific brain networks. Anatomically specific emotion biomarkers could be used to monitor symptom progression or treatment response in clinical trials of asymptomatic or mildly symptomatic individuals, but more scalable approaches are needed. The proposed project will build on our prior laboratory-based studies of emotion in asymptomatic and symptomatic individuals with FTD and will include longitudinal, multi-day assessments of emotion and behavior in the real world. These data will allow us to test whether novel emotion biomarkers we have discovered in the laboratory can be tracked with remote tools and will enable us to determine whether there are additional areas of change in early FTD that have previously gone undetected. The central hypothesis of this proposal is that emotions are direct readouts of vulnerable brain systems that can be used to monitor progression in the asymptomatic and early symptomatic phase of FTD. We will conduct laboratory-based assessments of emotion in 100 mutation carriers across the clinical spectrum, 50 mutation non-carrier family member controls, 50 people with sporadic behavioral variant FTD, and 50 older healthy controls at three annual research visits that include a clinical work-up and neuroimaging. We will also conduct five biannual remote assessments of emotion during which we will measure real-world autonomic physiology (with wearable devices), behavior (with participants' photographs and self-reported activities), and subjective feelings (with experience sampling methods). We will address three key aims. In Aim 1, we will map the real-world landscape of emotion in asymptomatic mutation carriers and early FTD and its associations with laboratory measures of emotion and affective symptoms. In Aim 2, we will isolate the neural systems underlying FTD-relevant aberrations in emotion as measured in the real world and laboratory. In Aim 3, we will quantify longitudinal emotion system decline in early FTD. By integrating neuroimaging techniques with measures of emotion from the laboratory and the real world, this project has the potential to advance current models of the biological basis of emotion dysfunction and...