Cognitive and Neural Mechanisms of Antisocial Behavior in Frontotemporal Dementia

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ABSTRACT: Antisocial behavior is common in patients with frontotemporal dementia (FTD). These behaviors result in significant morbidity and can lead to crimes in extreme cases. Yet despite being one of the most challenging and problematic symptoms to manage clinically, the mechanisms leading to antisocial behavior in FTD are unknown, and treatments remain limited. The goal of the current proposal is to determine the cognitive and neural mechanisms leading to antisocial behavior in FTD. Understanding these mechanisms will have a major impact on FTD patients by improving clinical evaluations to monitor the onset and progression of antisocial behaviors, helping to develop novel pharmacologic and neuromodulatory treatment strategies, and informing legal and ethical treatment of FTD patients who commit crimes. In Aim 1 I will examine the neural mechanisms and the hypothesis that FTD patients with antisocial behavior will have atrophy in a pre-defined network of brain regions I identified in patients with antisocial behaviors caused by focal brain lesions. I will test this hypothesis using a new neuroimaging method I recently developed and validated called atrophy network mapping that uses the human connectome and single-subject atrophy maps to localize neurological symptoms to brain networks rather than an isolated region. In Aim 2 I will examine the cognitive mechanisms and the hypothesis that FTD patients with antisocial behavior have specific impairments in moral decision-making. My long-term goal is to use multimodal neuroimaging and decision-making tasks to better understand the mechanisms leading to antisocial behavior and other behavioral problems in dementia patients. To achieve this goal, a training plan is proposed to learn additional research skills in functional neuroimaging methods (Training goal 1) and the neuropsychology of social decision-making (Training Goal 2). Additional training in leadership, biostatistics, and grant-writing will prepare me to achieve independence (Training goal 3). A mentorship team of experts has been assembled to help me achieve these training goals, consisting of Dr. Daniel Claassen (primary mentor), a behavioral neurologists who studies reward-based decision-making and functional neuroimaging in patients with neurodegenerative disorders; Dr. David Zald (co- primary mentor), a neuropsychologist and cognitive neuroscientist who uses functional neuroimaging to study decision-making in aging and antisocial behavior; and Dr. Bennett Landman (co-mentor), a neuroimager who develops computational methods to study neuroimaging changes in aging. The team will also include Dr. Hakmook Kang (collaborator), a biostatistician with expertise in neuroimaging, Dr. Catherine Chang, a neuroimager with expertise in functional connectivity, and Dr. Katherine Rankin (external consultant), a neuropsychologist with expertise in psychometric assessments of social and emotional processing in FTD.