Acta Neuropathologica

, Volume 137, Issue 1, pp 27–46 | Cite as

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. SeeleyEmail author
Original Paper


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.


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



This study was supported by NIH grants R01AG033017 (WWS), P01AG019724 and P50AG023501 (BLM), and the John Douglas French Alzheimer’s Foundation (GC). LL was supported by the Reserve Talents of Universities Overseas Research Program of Heilongjiang in China (Document Number: Heijiaogao [2012]381). We thank the patients and their families for their invaluable contributions to FTD/MND research.

Author contributions

ALN, MS, JLH, SEG, LL, EJK, and YP performed the experiments and cell counting. MS performed morphometric analysis. ALN, LP, and IEA analyzed the data. WWS, LTG, and EJH performed neuropathological diagnoses. DHG and GHC performed genetic analysis. JHK, BLM, and WWS obtained behavioral and clinical data. WWS, SEG, and ALN conceived and designed the project. WWS, and ALN wrote the paper. All authors reviewed the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

401_2018_1942_MOESM1_ESM.pdf (10.8 mb)
Supplementary material 1 (PDF 11103 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Alissa L. Nana
    • 1
  • Manu Sidhu
    • 1
  • Stephanie E. Gaus
    • 1
  • Ji-Hye L. Hwang
    • 1
  • Libo Li
    • 1
    • 2
  • Youngsoon Park
    • 1
  • Eun-Joo Kim
    • 1
  • Lorenzo Pasquini
    • 1
  • Isabel E. Allen
    • 3
  • Katherine P. Rankin
    • 1
  • Gianina Toller
    • 1
  • Joel H. Kramer
    • 1
  • Daniel H. Geschwind
    • 4
  • Giovanni Coppola
    • 4
  • Eric J. Huang
    • 5
  • Lea T. Grinberg
    • 1
    • 5
    • 6
  • Bruce L. Miller
    • 1
  • William W. Seeley
    • 1
    • 5
    Email author
  1. 1.Department of Neurology, UCSF Weill Institute for NeurosciencesUniversity of California, San FranciscoSan FranciscoUSA
  2. 2.Department of PsychopharmacologyQiqihar Medical UniversityQiqiharChina
  3. 3.Department of Epidemiology and BiostatisticsUniversity of California, San FranciscoSan FranciscoUSA
  4. 4.Neurogenetics Program, Department of Neurology and Semel Institute for Neuroscience and Human Behavior, David Geffen School of MedicineUniversity of California Los AngelesLos AngelesUSA
  5. 5.Department of Pathology and Laboratory MedicineUniversity of California, San FranciscoSan FranciscoUSA
  6. 6.Global Brain Health InstituteUniversity of California, San FranciscoSan FranciscoUSA

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