Neurons selectively targeted in frontotemporal dementia reveal early stage TDP-43 pathobiology

Alissa L. Nana, Manu Sidhu, Stephanie E. Gaus, Ji Hye L. Hwang, Libo Li, Youngsoon Park, Eun Joo Kim, Lorenzo Pasquini, Isabel E. Allen, Katherine P. Rankin, Gianina Toller, Joel H. Kramer, Daniel H. Geschwind, Giovanni Coppola, Eric J. Huang, Lea T. Grinberg, Bruce L. Miller, William W. Seeley

Research output: Contribution to journalArticlepeer-review

46 Scopus citations


TAR DNA-binding protein 43 (TDP-43) aggregation is the most common pathological hallmark in frontotemporal dementia (FTD) and characterizes nearly all patients with motor neuron disease (MND). The earliest stages of TDP-43 pathobiology are not well-characterized, and whether neurodegeneration results from TDP-43 loss-of-function or aggregation remains unclear. In the behavioral variant of FTD (bvFTD), patients undergo selective dropout of von Economo neurons (VENs) and fork cells within the frontoinsular (FI) and anterior cingulate cortices. Here, we examined TDP-43 pathobiology within these vulnerable neurons in the FI across a clinical spectrum including 17 patients with sporadic bvFTD, MND, or both. In an exploratory analysis based on our initial observations, we further assessed ten patients with C9orf72-associated bvFTD/MND. VENs and fork cells showed early, disproportionate TDP-43 aggregation that correlated with anatomical and clinical severity, including loss of emotional empathy. The presence of a TDP-43 inclusion was associated with striking nuclear and somatodendritic atrophy. An intriguing minority of neurons lacked detectable nuclear TDP-43 despite the apparent absence of a cytoplasmic TDP-43 inclusion. These cells showed neuronal atrophy comparable to inclusion-bearing neurons, suggesting that the loss of nuclear TDP-43 function promotes neurodegeneration, even when TDP-43 aggregation is inconspicuous or absent.

Original languageEnglish
Pages (from-to)27-46
Number of pages20
JournalActa Neuropathologica
Issue number1
StatePublished - 21 Jan 2019
Externally publishedYes


  • Amyotrophic lateral sclerosis (ALS)
  • C9orf72
  • Empathy
  • Frontotemporal dementia (FTD)
  • TAR DNA-binding protein 43 (TDP-43)
  • Von Economo neuron (VEN)


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