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Updated TDP-43 in Alzheimer's disease staging scheme
Josephs KA, Murray ME, Whitwell JL, Tosakulwong N, Weigand SD, Petrucelli L, Liesinger AM, Petersen RC et al.. Acta neuropathologica, 2016-01-25
Topic: Amyloid, tau and blood-test diagnosis
In this study, we update the TDP-43 in Alzheimer's disease staging scheme by assessing the topography of TDP-43 in 193 cases of Alzheimer's disease, in 14 different brain regions (eight previously described plus six newly reported) and use conditional probability to model the spread of TDP-43 across the 14 brain regions. We show that in addition to the eight original regions we previously reported [amygdala, entorhinal cortex, subiculum, dentate gyrus of the hippocampus, occipitotemporal cortex, inferior temporal cortex, middle frontal cortex and basal ganglia (putamen/globus pallidum)] that TDP-43 is also deposited in the insular cortex, ventral striatum, basal forebrain, substantia nigra, midbrain tectum, and the inferior olive of the medulla oblongata, in Alzheimer's disease. The conditional probability analysis produced six significantly different stages (P < 0.01), and suggests that TDP-43 deposition begins in the amygdala (stage 1), then moves to entorhinal cortex and subiculum (stage 2); to the dentate gyrus of the hippocampus and occipitotemporal cortex (stage 3); insular cortex, ventral striatum, basal forebrain and inferior temporal cortex (stage 4); substantia nigra, inferior olive and midbrain tectum (stage 5); and finally to basal ganglia and middle frontal cortex (stage 6). This updated staging scheme is superior to our previous staging scheme, classifying 100% of the cases (versus 94% in the old scheme), based on criteria provided, and shows clinical significance with some regions and with increasing stage. We discuss the relevance of the updated staging scheme, as well as its impact on the prion-like hypothesis of protein spread in neurodegenerative disease. We also address the issue of whether frontotemporal lobar degeneration with TDP-43 could be the primary pathology in stage 6.
Key findings
- The conditional probability analysis produced six significantly different stages (P < 0.01), and suggests that TDP-43 deposition begins in the amygdala (stage 1), then moves to entorhinal cortex and subiculum (stage 2); to the dentate gyrus of the hippocampus and occipitotemporal cortex (stage 3); insular cortex, ventral striatum, basal forebrain and inferior temporal cortex (stage 4); substantia nigra, inferior olive and midbrain tectum (stage 5); and finally to basal ganglia and middle frontal cortex (stage 6).
- This updated staging scheme is superior to our previous staging scheme, classifying 100% of the cases (versus 94% in the old scheme), based on criteria provided, and shows clinical significance with some regions and with increasing stage.
Why it matters
In 193 Alzheimer's disease cases, TDP-43 was found in 14 brain regions and a conditional probability analysis produced six stages of spread beginning in the amygdala. This updated staging scheme classifies cases and shows clinical significance but reports no treatment, cure, or prevention.
Study details
- Evidence strengthLow
How this study scored 54/100
Published in a leading specialty journal. Scored zero for study design, sample size, effect reported, studied in people 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 | 1 / 5 | 2016 — within 20 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 6 / 7 | Cited 376 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 31.3 citations a year over 12 year(s) since 2016 |
| Impact for its field and year | 4 / 6 | Cited 19.2× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 4 / 6 | Cited by 30 other studies in this library |
| Still being cited | 3 / 4 | Cited 118 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Dennis W. Dickson: h-index 218 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Mayo Clinic: institution h-index 1,606 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 2 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 26810071) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 54 / 100 | — |
What each of these 20 components measures, and what this score is not →
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APA 7th
Josephs, K. A., Murray, M. E., Whitwell, J. L., Tosakulwong, N., Weigand, S. D., Petrucelli, L., et al. (2016). Updated TDP-43 in Alzheimer's disease staging scheme. Acta neuropathologica. https://doi.org/10.1007/s00401-016-1537-1
Vancouver
Josephs KA, Murray ME, Whitwell JL, Tosakulwong N, Weigand SD, Petrucelli L, et al. Updated TDP-43 in Alzheimer's disease staging scheme. Acta neuropathologica. 2016. doi:10.1007/s00401-016-1537-1. PMID: 26810071.
BibTeX
@article{josephs2016-26810071,
author = {Josephs, K. A. and Murray, M. E. and Whitwell, J. L. and Tosakulwong, N. and Weigand, S. D. and Petrucelli, L. and Liesinger, A. M. and Petersen, R. C. and others},
title = {{Updated TDP-43 in Alzheimer's disease staging scheme}},
journal = {Acta neuropathologica},
year = {2016},
doi = {10.1007/s00401-016-1537-1},
pmid = {26810071},
url = {https://doi.org/10.1007/s00401-016-1537-1}
}
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