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Amygdalar and hippocampal volume loss in limbic-predominant age-related TDP-43 encephalopathy
Alex Wesseling, Ismael L Calandri, Maud M A Bouwman, Niels Reijner, Natasja A C Deshayes, Frederik Barkhof, Rik Ossenkoppele, Wilma D J van de Berg et al.. Brain : a journal of neurology, 2025-11-04
Topic: Plasma and spinal-fluid biomarkers
Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) refers to the aberrant accumulation of TDP-43 in the brains of ageing individuals either in isolation or in combination with neurodegenerative disease. LATE-NC is most commonly found in the amygdala and hippocampus and is associated with progressive amnestic decline in individuals with a neurodegenerative disease. Since LATE-NC can only be diagnosed post-mortem, there is a need for pathology-validated neuroimaging biomarkers for LATE-NC. In the current study we assessed MRI-measured amygdalar and hippocampal volume in brain donors with Alzheimer's disease or Lewy body diseases with and without co-occurring LATE-NC pathology. Post-mortem in situ 3D-T1 3T-MRI data were collected for 51 cases (27 Alzheimer's disease and 24 Lewy body disease) of whom 17 had post-mortem confirmed LATE-NC and 34 were non-LATE-NC (matched on age, sex and neurodegenerative disease). Amygdalar and hippocampal volumes were calculated using FreeSurfer. Within-subject amygdalar and hippocampal tissue sections were immunostained for TDP-43 (pTDP-43), phosphorylated tau (AT8), amyloid-β (4G8) and α-synuclein (pSer129). Positive cell density (TDP-43 and α-synuclein) and area percentage immunoreactivity (p-tau and amyloid-β) outcome measures were quantified using QuPath. Group differences between LATE-NC and non-LATE-NC donors were assessed with univariate analyses and correlations were assessed with linear regression models, all adjusting for intracranial volume and post-mortem delay and if applicable for primary pathology. Brain donors with LATE-NC showed significantly lower amygdalar (-26%, P = 0.014) and hippocampal (-19%, P = 0.003) volumes than non-LATE-NC brain donors, even when correcting for regional phosphorylated tau, amyloid-β and α-synuclein burden. These group differences remained significant in the Alzheimer's disease group (amygdala -24%, P = 0.028; hippocampus -21%, P = 0.002), but in the Lewy body diseases group only the amygdala was smaller in LATE-NC donors compared with non-LATE-NC donors (18%, P = 0.030). These results suggest that severity of TDP-43 burden plays a role in amygdala and hippocampus atrophy on MRI, even when correcting for effects of primary pathology. This study proposes that exceptionally low amygdalar and hippocampal volumes could indicate LATE-NC and that this may serve as a potential biomarker for in vivo studies.
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APA 7th
Wesseling, A., Calandri, I. L., Bouwman, M. M. A., Reijner, N., Deshayes, N. A. C., Barkhof, F., et al. (2025). Amygdalar and hippocampal volume loss in limbic-predominant age-related TDP-43 encephalopathy. Brain : a journal of neurology. https://doi.org/10.1093/brain/awaf201
Vancouver
Wesseling A, Calandri IL, Bouwman MMA, Reijner N, Deshayes NAC, Barkhof F, et al. Amygdalar and hippocampal volume loss in limbic-predominant age-related TDP-43 encephalopathy. Brain : a journal of neurology. 2025. doi:10.1093/brain/awaf201. PMID: 40512809.
BibTeX
@article{wesseling2025-40512809,
author = {Wesseling, Alex and Calandri, Ismael L and Bouwman, Maud M A and Reijner, Niels and Deshayes, Natasja A C and Barkhof, Frederik and Ossenkoppele, Rik and van de Berg, Wilma D J and others},
title = {{Amygdalar and hippocampal volume loss in limbic-predominant age-related TDP-43 encephalopathy}},
journal = {Brain : a journal of neurology},
year = {2025},
doi = {10.1093/brain/awaf201},
pmid = {40512809},
url = {https://doi.org/10.1093/brain/awaf201}
}
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Key findings
- LATE-NC is most commonly found in the amygdala and hippocampus and is associated with progressive amnestic decline in individuals with a neurodegenerative disease.
- Brain donors with LATE-NC showed significantly lower amygdalar (-26%, P = 0.014) and hippocampal (-19%, P = 0.003) volumes than non-LATE-NC brain donors, even when correcting for regional phosphorylated tau, amyloid-β and α-synuclein burden.
- These group differences remained significant in the Alzheimer's disease group (amygdala -24%, P = 0.028; hippocampus -21%, P = 0.002), but in the Lewy body diseases group only the amygdala was smaller in LATE-NC donors compared with non-LATE-NC donors (18%, P = 0.030).
- These results suggest that severity of TDP-43 burden plays a role in amygdala and hippocampus atrophy on MRI, even when correcting for effects of primary pathology.
Study details
- Evidence strengthLow
How this study scored 46/100
Published in a leading specialty journal. Scored zero for study design, sample size, effect reported, studied in people and randomized / 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, multicenter collaboration and free to read, so those were left out: it earned 26 of the 56 points we could judge it on, which is 46 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Brain : a journal of neurology) |
| 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 | 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) |
| Randomized / blinded | 0 / 2 | No randomization 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 |
| Multicenter collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40512809) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 26 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 26 of the 56 points we could judge it on is 46 out of 100. |
| Total | 46 / 100 | — |
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