Salience Network Atrophy Links Neuron Type-Specific Pathobiology to Loss of Empathy in Frontotemporal Dementia. (5th June 2020)

• Record Type: Journal Article
• Authors: Pasquini, Lorenzo; Nana, Alissa L; Toller, Gianina; Brown, Jesse A; Deng, Jersey; Staffaroni, Adam; Kim, Eun-Joo; Hwang, Ji-Hye L; Li, Libo; Park, Youngsoon; Gaus, Stephanie E; Allen, Isabel; Sturm, Virginia E; Spina, Salvatore; Grinberg, Lea T; Rankin, Katherine P; Kramer, Joel H; Rosen, Howard J; Miller, Bruce L; Seeley, William W
• Is Part Of: Cerebral cortex. Volume 30:Number 10(2020)
• Page Start: 5387
• Page End: 5399
• Publication Date: 2020-06-05
• Subjects: empathy -- frontoinsular cortex -- frontotemporal dementia -- salience network -- von Economo neurons; Cerebral cortex -- Periodicals; Brain -- Periodicals; 612.825
• DOI: 10.1093/cercor/bhaa119
• Languages: English
• ISSNs: 1047-3211

Abstract

Abstract: Each neurodegenerative syndrome reflects a stereotyped pattern of cellular, regional, and large-scale brain network degeneration. In behavioral variant of frontotemporal dementia (bvFTD), a disorder of social-emotional function, von Economo neurons (VENs), and fork cells are among the initial neuronal 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. Here, we studied patients with bvFTD, amyotrophic lateral sclerosis (ALS), or both, given that these syndromes share common pathobiological and genetic factors. Our goal was to determine how neuron type-specific TAR DNA-binding protein of 43 kDa (TDP-43) pathobiology relates to atrophy in specific brain structures and to loss of emotional empathy, a cardinal feature of bvFTD. We combined questionnaire-based empathy assessments, in vivo structural MR imaging, and quantitative histopathological data from 16 patients across the bvFTD/ALS spectrum. We show that TDP-43 pathobiology within right FI VENs and fork cells is associated with salience network atrophy spanning insular, medial frontal, and thalamic regions. Gray matter degeneration within these structures mediated loss of emotional empathy, suggesting a chain of influence linking the cellular, regional/network, and behavioral levels in producing signature bvFTD clinical features.