Von Economo neurons are part of a larger neuronal population that are selectively vulnerable in C9orf72 frontotemporal dementia

Neuropathol Appl Neurobiol. 2019 Dec;45(7):671-680. doi: 10.1111/nan.12558. Epub 2019 Jun 10.


Aims: The behavioural variant of frontotemporal dementia with a C9orf72 expansion (C9-bvFTD) is characterised by early changes in social-emotional cognition that are linked to the loss of von Economo neurons (VENs). Together with a subset of neighbouring pyramidal neurons, VENs express the GABA receptor subunit theta (GABRQ). It is not known if the selective vulnerability of VENs in C9-bvFTD also includes this GABRQ-expressing population.

Methods: We quantified VENs and GABRQ immunopositive neurons in the anterior cingulate cortex (ACC) in C9-bvFTD (n = 16), controls (n = 12) and Alzheimer's disease (AD) (n = 7). Second, we assessed VENs and GABRQ-expressing populations in relation to the clinicopathological profiles.

Results: We found the number of VENs and GABRQ-expressing neurons and their ratio over the total layer 5 neuronal population was lower in C9-bvFTD compared to control and AD. C9-bvFTD donors with underlying TDP43 type A pathology in the ACC showed the highest loss of GABRQ-expressing neurons. C9-bvFTD donors that did not present with motor neuron disease (MND) symptoms in the first half of their disease course showed a prominent loss of GABRQ-expressing neurons compared to controls. C9-bvFTD donors with no symptoms of psychosis showed a higher loss compared to controls. Across all donors, the number of VENs correlated strongly with the number of GABRQ-expressing neurons.

Conclusion: We show that VENs, together with GABRQ-expressing neurons, are selectively vulnerable in C9-bvFTD but are both spared in AD. This suggests they are related and that this GABRQ-expressing population of VENs and pyramidal neurons, is a key modulator of social-emotional functioning.

Keywords: C9orf72; GABRQ; frontotemporal dementia; social-emotional behaviour; von Economo neuron.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • C9orf72 Protein / genetics*
  • Female
  • Frontotemporal Dementia / genetics
  • Frontotemporal Dementia / metabolism
  • Frontotemporal Dementia / pathology*
  • Gyrus Cinguli / metabolism
  • Gyrus Cinguli / pathology*
  • Humans
  • Male
  • Middle Aged
  • Neurons / metabolism
  • Neurons / pathology*
  • Receptors, GABA-A / metabolism


  • C9orf72 Protein
  • GABRQ protein, human
  • Receptors, GABA-A