Vulnerability of anterior cingulate Von Economo neurons to FTLD-tauopathies in behavioral variant frontotemporal dementia

Von Economo neurons (VENs) are unique spindle-shaped neurons that primarily reside in the anterior cingulate (ACC) and fronto-insular (FI) cortices. They are more numerous in species with affiliative behaviors and may support social-emotional functions. VENs are reduced in the ACC and FI of individuals with behavioral variant frontotemporal dementia (bvFTD), marked by personality changes and socially inappropriate behavior. Neuropathologies underlying bvFTD include frontotemporal lobar degenerations (FTLD) with tauopathy (FTLD-tau) or TDP-43 (FTLD-TDP). This study examined VEN density across three FTLD-tau subtypes: the 4R tauopathies of corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), and the 3R tauopathy known as Pick's disease (PiD). Twenty-six right-handed bvFTD-FTLD-tau cases were identified from the Northwestern University Alzheimer's Disease Research Center brain bank (PiD n = 9; CBD n = 11; PSP n = 6). Paraffin sections were cresyl violet-stained to visualize VENs in the ACC and analyzed using unbiased stereology. Wilcoxon rank-sum tests showed significantly lower VEN density in PiD than CBD (P < 0.05). No significant differences were found between PiD and PSP or CBD and PSP. Across isoforms, VEN density was over fourfold higher in 4R than 3R cases (P < 0.01). Overall, stereology indicates VENs are more vulnerable to 3R PiD than 4R CBD, both causes of bvFTD. The clinical implications of this differential vulnerability warrant further study.