Frontotemporal dementia (FTD) is a neurodegenerative disease that is characterized by progressive decline in social behavior, emotion, and language. In behavioral variant FTD (bvFTD), the most common FTD subtype, impairment in emotion and empathy are hallmark features that arise due to degeneration of emotion circuits. Although bvFTD begins in frontoinsula and anterior cingulate cortex, brain regions with known roles in visceromotor emotion generation and autonomic integration, the earliest signs of emotion system dysfunction are unknown. Approximately 40% of FTD cases are genetic and due to mutations in C9ORF72, GRN, and MAPT. Gene-positive mutation carriers offer a novel inroad into early emotion alterations in FTD because these individuals can be identified, studied, and followed during the asymptomatic, preclinical phase of disease and in the early symptomatic clinical phase. Changes in emotion physiology and behavior may occur early in the disease, reflect decline in emotion-relevant brain networks, and relate to affective symptoms. The proposed studies will help to characterize preclinical emotion deficits and their underlying circuitry and to determine whether these deficits are early indicators of decline in FTD. Anatomically-specific markers could be used to monitor symptom progression or to track disease-related dysfunction in clinical trials of asymptomatic or mildly symptomatic individuals. This proposal integrates laboratory measures of autonomic nervous system reactivity and facial expression with multi-modal neuroimaging techniques to identify how emotion systems change in the earliest stages of FTD. We will study 100 asymptomatic gene-positive subjects (50 C9ORF72+, 30 GRN+, and 20 MAPT+), 50 healthy controls (age-matched, gene-negative family members), 40 patients with bvFTD, and 40 older age-matched healthy controls at two annual research visits. Subjects will undergo laboratory testing of emotion in addition to a clinical work-up and structural and functional connectivity magnetic resonance imaging. The central hypothesis of this proposal is that objective measures of emotion physiology and behavior are direct readouts of vulnerable brain systems that can be measured noninvasively and track progression in the in preclinical and early symptomatic phase of FTD. We will address three key aims.
In Aim 1, we will isolate the domains of emotional dysfunction in early FTD and determine how specific emotional deficits relate to behavioral and affective symptoms.
In Aim 2, we will delineate the neural circuitry underlying identified emotional deficits in bvFTD and preclinical FTD.
In Aim 3, we will identify laboratory measures that track emotion network decline over time in early FTD. This project has the potential to advance current models of the biological basis of emotion dysfunction in FTD and other clinical disorders that have similar emotional symptoms but lack obvious brain lesions.

Public Health Relevance

Changes in emotion physiology and behavior may occur early in the course of frontotemporal dementia and be sensitive indicators of emotion system dysfunction in the preclinical and clinical phases of disease. A better understanding of the neuroanatomical system that underlies emotional decline will be critical for improving animal models and enhancing drug development efforts in humans by identifying the most relevant brain structures. This information may also improve disease models of other disorders in which emotional deficits are a central feature.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Adult Psychopathology and Disorders of Aging Study Section (APDA)
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Silverberg, Nina B
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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