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Selective vulnerability and resilience of thalamic neuronal populations in Frontotemporal Dementia
Trujillo A, Sohn M, Macias M, Grochowska M, Joyce J, Ber IL, Huh D, Schulmann A et al.. Research Square, 2026-09-11
Topic: Genetics and APOE
Frontotemporal dementia (FTD) caused by progranulin (GRN) mutations is associated with pronounced thalamic degeneration, yet the cellular basis of selective thalamic vulnerability remains poorly understood. Here, we generated an integrated single-nucleus RNA-sequencing atlas of the human antero-median thalamus comprising 331,065 nuclei from 92 individuals across three independent cohorts spanning GRN-associated FTD, sporadic FTD with TDP-43 proteinopathy, Alzheimer’s disease (AD), and neurologically normal aging. While AD samples exhibited minimal thalamic cellular remodeling, FTD cases were characterized by highly selective and reproducible degeneration of discrete neuronal populations across independent cohorts. In particular, two inhibitory neuronal populations were markedly depleted in FTD, which was accompanied by impaired GABAergic communication. Among excitatory neurons, RNF220+ neurons exhibited extensive transcriptional dysregulation, altered sterol metabolic pathways, together with robust TDP-43-associated STMN2 cryptic splicing pathology and reduced glutamatergic signaling. By contrast, RNF220- excitatory neurons were comparatively resilient, displaying preserved neuronal communication, and resistance to STMN2 cryptic exon accumulation. In control individuals, RNF220- excitatory neurons exhibited elevated GRN expression and an intrinsic enrichment of cytoskeletal maintenance programs. Spatial transcriptomics confirmed the anatomical distribution of vulnerable neuronal populations in the adult human thalamus. In parallel, FTD samples demonstrated expansion of vascular-associated and lymphocyte populations as well as reactive glial signatures. Together, these findings define a cellular framework for selective vulnerability and resilience in the human FTD thalamus and identify intrinsic molecular programs associated with resistance to neurodegeneration.
Key findings
- Frontotemporal dementia (FTD) caused by progranulin (GRN) mutations is associated with pronounced thalamic degeneration, yet the cellular basis of selective thalamic vulnerability remains poorly understood.
- In parallel, FTD samples demonstrated expansion of vascular-associated and lymphocyte populations as well as reactive glial signatures.
- Together, these findings define a cellular framework for selective vulnerability and resilience in the human FTD thalamus and identify intrinsic molecular programs associated with resistance to neurodegeneration.
Study details
- Participants92
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 27 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, effect reported and randomised / blinded because the record does not state it. We have no data on 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 and multi-centre collaboration, so those were left out: it earned 17 of the 62 points we could judge it on, which is 27 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (Research Square) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| 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 | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 1 / 4 | 92 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 | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 17 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 17 of the 62 points we could judge it on is 27 out of 100. |
| Total | 27 / 100 | Capped to 16 because this is not a peer-reviewed article. |
What each of these 20 components measures, and what this score is not →
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APA 7th
Trujillo, A., Sohn, M., Macias, M., Grochowska, M., Joyce, J., Ber, I. L., et al. (2026). Selective vulnerability and resilience of thalamic neuronal populations in Frontotemporal Dementia. Research Square. https://doi.org/10.21203/rs.3.rs-10670822/v1
Vancouver
Trujillo A, Sohn M, Macias M, Grochowska M, Joyce J, Ber IL, et al. Selective vulnerability and resilience of thalamic neuronal populations in Frontotemporal Dementia. Research Square. 2026. doi:10.21203/rs.3.rs-10670822/v1.
BibTeX
@article{trujillo2026-8f94bb08,
author = {Trujillo, A. and Sohn, M. and Macias, M. and Grochowska, M. and Joyce, J. and Ber, I. L. and Huh, D. and Schulmann, A. and others},
title = {{Selective vulnerability and resilience of thalamic neuronal populations in Frontotemporal Dementia}},
journal = {Research Square},
year = {2026},
doi = {10.21203/rs.3.rs-10670822/v1},
url = {https://doi.org/10.21203/rs.3.rs-10670822/v1}
}