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Neurons selectively targeted in frontotemporal dementia reveal early stage TDP-43 pathobiology
Nana AL, Sidhu M, Gaus SE, Hwang JL, Li L, Park Y, Kim EJ, Pasquini L et al.. Acta neuropathologica, 2018-12-03
Topic: Brain proteins, microglia and lab models
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.
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APA 7th
Nana, A. L., Sidhu, M., Gaus, S. E., Hwang, J. L., Li, L., Park, Y., et al. (2019). Neurons selectively targeted in frontotemporal dementia reveal early stage TDP-43 pathobiology. Acta neuropathologica. https://doi.org/10.1007/s00401-018-1942-8
Vancouver
Nana AL, Sidhu M, Gaus SE, Hwang JL, Li L, Park Y, et al. Neurons selectively targeted in frontotemporal dementia reveal early stage TDP-43 pathobiology. Acta neuropathologica. 2019. doi:10.1007/s00401-018-1942-8. PMID: 30511086.
BibTeX
@article{nana2019-30511086,
author = {Nana, A. L. and Sidhu, M. and Gaus, S. E. and Hwang, J. L. and Li, L. and Park, Y. and Kim, E. J. and Pasquini, L. and others},
title = {{Neurons selectively targeted in frontotemporal dementia reveal early stage TDP-43 pathobiology}},
journal = {Acta neuropathologica},
year = {2019},
doi = {10.1007/s00401-018-1942-8},
pmid = {30511086},
url = {https://doi.org/10.1007/s00401-018-1942-8}
}
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Key findings
- 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.
- The presence of a TDP-43 inclusion was associated with striking nuclear and somatodendritic atrophy.
- 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.
Why it matters
This study examined TDP-43 pathology in vulnerable neurons in frontotemporal dementia and suggests that loss of nuclear TDP-43 function may promote neurodegeneration. It is early-stage research in a small number of patients and does not test any treatment, cure, or prevention for Alzheimer's disease.
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Study details
- Participants17
- Evidence strengthLow
How this study scored 55/100
Published in a leading specialty journal. Scored zero for study design, effect reported and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Acta neuropathologica) |
| Journal's citation record | 3 / 4 | Acta Neuropathologica: journal h-index 287 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 2 / 5 | 2019 — within 10 year(s) of the newest study here |
| Sample size | 1 / 4 | 17 participants |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 5 / 7 | Cited 130 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 14.4 citations a year over 9 year(s) since 2019 |
| Impact for its field and year | 3 / 6 | Cited 6.1× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 12 other studies in this library |
| Still being cited | 2 / 4 | Cited 41 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author William W. Seeley: h-index 126 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University of California, Los Angeles: institution h-index 1,923 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 4 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 30511086) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 55 / 100 | — |
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