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LATE-NC Stage 3: a diagnostic rubric to differentiate severe LATE-NC from FTLD-TDP
Ryan K Shahidehpour, Yuriko Katsumata, Dennis W Dickson, Nikhil B Ghayal, Khine Zin Aung, Xian Wu, Panhavuth Phe, Gregory A Jicha et al.. Acta neuropathologica, 2025-04-28
Topic: Plasma and spinal-fluid biomarkers
A diagnostic rubric is required to distinguish between limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). In LATE-NC Stage 3, TDP-43 proteinopathy is present in the middle frontal gyrus (MFG), thus posing a potential diagnostic challenge in differentiating these severe LATE-NC cases from FTLD-TDP. LATE-NC Stage 3 cases and other TDP-43 proteinopathies were analyzed from the University of Kentucky (total n = 514 with TDP-43 pathology assessed), The 90+ Study at the University of California Irvine (n = 458), and the Mayo Clinic (n = 5067) brain banks. Digital pathology was used to quantify pathology burden in a select subset of cases (n = 51), complemented by a previously-described manual counting method and expert neuropathologic examinations to evaluate qualitative features such as FTLD-TDP types and subtypes of neuronal cytoplasmic inclusions (NCIs). To evaluate clinical and genetic characteristics of LATE-NC Stage 3, data were analyzed from the National Alzheimer's Coordinating Center (NACC) Neuropathology Data set and correlated with findings from the Alzheimer's Disease Genetics Consortium (ADGC). When using TDP-43 proteinopathy quantification in the MFG as a diagnostic criterion, more than 90% of cases could be classified as either LATE-NC Stage 3 or FTLD-TDP. Diagnostically challenging scenarios included a subset of FTLD-TDP Type B cases with relatively mild MFG TDP-43 pathology and a novel non-LATE-NC, non-FTLD-TDP pathologic subtype with severe MFG TDP-43 pathology. Taking these potential pitfalls into account, a classification schema was developed that could correctly diagnose all included cases. There was no difference in the Alzheimer's disease pathological load in LATE-NC Stages 2 versus 3. In genetic analyses, the GRN (rs5848) risk allele was preferentially associated with LATE-NC Stage 3, whereas TMEM106B and APOE risk-associated variants were not. In conclusion, LATE-NC Stage 3 could be differentiated reliably from FTLD-TDP and other TDP-43-opathies, based on a data-driven diagnostic rubric.
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APA 7th
Shahidehpour, R. K., Katsumata, Y., Dickson, D. W., Ghayal, N. B., Aung, K. Z., Wu, X., et al. (2025). LATE-NC Stage 3: a diagnostic rubric to differentiate severe LATE-NC from FTLD-TDP. Acta neuropathologica. https://doi.org/10.1007/s00401-025-02876-5
Vancouver
Shahidehpour RK, Katsumata Y, Dickson DW, Ghayal NB, Aung KZ, Wu X, et al. LATE-NC Stage 3: a diagnostic rubric to differentiate severe LATE-NC from FTLD-TDP. Acta neuropathologica. 2025. doi:10.1007/s00401-025-02876-5. PMID: 40293530.
BibTeX
@article{shahidehpour2025-40293530,
author = {Shahidehpour, Ryan K and Katsumata, Yuriko and Dickson, Dennis W and Ghayal, Nikhil B and Aung, Khine Zin and Wu, Xian and Phe, Panhavuth and Jicha, Gregory A and others},
title = {{LATE-NC Stage 3: a diagnostic rubric to differentiate severe LATE-NC from FTLD-TDP}},
journal = {Acta neuropathologica},
year = {2025},
doi = {10.1007/s00401-025-02876-5},
pmid = {40293530},
url = {https://doi.org/10.1007/s00401-025-02876-5}
}
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Key findings
- There was no difference in the Alzheimer's disease pathological load in LATE-NC Stages 2 versus 3.
- In genetic analyses, the GRN (rs5848) risk allele was preferentially associated with LATE-NC Stage 3, whereas TMEM106B and APOE risk-associated variants were not.
- In conclusion, LATE-NC Stage 3 could be differentiated reliably from FTLD-TDP and other TDP-43-opathies, based on a data-driven diagnostic rubric.
Study details
- Participants514
- 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. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record, multi-centre collaboration and free to read, so those were left out: it earned 31 of the 56 points we could judge it on, which is 55 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Acta neuropathologica) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| 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 | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 2 / 4 | 514 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 | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40293530) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 31 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 31 of the 56 points we could judge it on is 55 out of 100. |
| Total | 55 / 100 | — |
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