Salience network atrophy links neuron type-specific degeneration to loss of empathy in frontotemporal dementia

Each neurodegenerative syndrome presents with characteristic symptoms that reflect the specific pattern of cellular, regional, and large-scale network vulnerability. In behavioral variant frontotemporal dementia (bvFTD), a disorder of social-emotional function, von Economo neurons (VENs) and fork cells are among the initial cellular targets. These large layer 5 projection neurons are concentrated in the anterior cingulate and frontoinsular (FI) cortices, regions that anchor the salience network, a large-scale system linked to social-emotional function via roles in autonomic processing and homeostatic behavioral guidance. Here, we combined questionnaire-based empathy assessments, in vivo structural neuroimaging, and quantitative histopathological data from 16 patients across the FTD-amyotrophic lateral sclerosis clinicopathological spectrum linked to TAR DNA-binding protein 43 pathobiology. We sought to examine how neuron type-specific degeneration is linked to regional gray and white matter atrophy and, in turn, to loss of emotional empathy. We show that disease protein aggregation within right FI VENs and fork cells is associated with atrophy in insular, medial frontal, and subcortical regions including the dorsomedial thalamus that represent key nodes within the salience network. Gray and white matter degeneration within these structures, in turn, mediated loss of emotional empathy, suggesting a chain of influence linking the cellular, regional/network, and behavioral levels in producing the signature bvFTD clinical features. Overall, the findings suggest that VENs and fork cells facilitate specialized human social-emotional capacities by contributing to salience network function.