Mapping cerebellar influence in FTD: unraveling the role of the cerebellum in social cognition and clinical trajectory

About This Grant

PROJECT SUMMARY/ABSTRACT Behavioral variant frontotemporal dementia (bvFTD) is a devastating neurodegenerative disorder characterized by early and profound social cognitive deficits, including impairments in theory of mind, emotion reading, and empathy, which cause significant distress and burden for caregivers. While research has traditionally focused on cortical degeneration in bvFTD, mounting evidence highlights the cerebellum’s critical role in cognitive and social processing. Despite comprising 80% of the brain’s neurons and demonstrating early atrophy in bvFTD, the cerebellum’s contributions to social cognition and its potential as a biomarker for disease progression remain underexplored. This study aims to address this gap by investigating the cerebellum’s influence on social cognitive deficits and its value for predicting clinical trajectories in bvFTD. Leveraging cross-sectional and longitudinal neuroimaging and clinical data from the University of California San Francisco (UCSF), Memory and Aging Center and the multisite ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study, this project is structured to achieve two primary aims. Aim 1 will use cross-sectional data from UCSF to characterize the relationship between social cognition and cerebellar structure and function in bvFTD across disease stages, using neuroimaging to identify compensatory and degenerative mechanisms. Aim 2 will use longitudinal data from ALLFTD to assess the predictive value of early cerebellar atrophy for later social, cognitive, and psychiatric decline, enhancing understanding of the cerebellum’s impact on clinical outcomes. This research is poised to fill critical gaps in our understanding of bvFTD by highlighting the cerebellum’s involvement beyond traditional motor functions, thereby offering new insights into brain network dynamics and their clinical implications. Findings from this study have the potential to enhance diagnosis and inform novel intervention strategies targeting cerebellar circuits, ultimately enhancing patient management in bvFTD. This project supports Dr. Chen’s career development goals of becoming an independent researcher specializing in advanced quantitative neuroimaging and neuropsychology in individuals with neurodegenerative disease. The K99 phase will provide training in cognitive neuroscience, interpretation of social cognition testing, and multimodal neuroimaging, enhancing her ability to integrate clinical and neuroimaging data to study neurodegenerative disease mechanisms. The R00 phase will support the establishment of her research program at a leading academic institution, leveraging advanced neuroimaging techniques to address key questions in dementia diagnosis, disease monitoring, and intervention. Dr. Chen’s training will take place in a highly collaborative, resource-rich environment at UCSF, which offers cutting-edge neuroimaging facilities, access to a well- characterized dementia cohort, and mentorship from experts in neurodegeneration, social cognition, and imaging analytics. This comprehensive training will position her to lead an impactful independent research program that advances our understanding of bvFTD and related neurodegenerative disorders.