4R-tau seeding activity reveals molecular subtypes in progressive supranuclear palsy
Bibliographic record
Abstract
Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterized by abnormal accumulation of the protein tau in the brain, leading to motor and cognitive symptoms that vary between individuals. The reasons for this clinical heterogeneity are unknown. Here we show that distinct molecular forms of tau, particularly high molecular weight (HMW) assemblies, differ in abundance and biological activity across PSP brains. By combining biochemical examination, seed amplification assays, proteomic profiling, and spatial transcriptomics, we identify that HMW tau species drive the strongest aggregation activity in the primary motor cortex. Cases with high tau seeding activity display molecular signatures of altered immune and metabolic pathways. These findings reveal that tau seeding activity reflects underlying molecular heterogeneity in PSP and suggest that measuring 4R-tau seeding capacity could help stratify patients and guide the development of targeted therapeutic approaches. This study shows that high-molecular weight tau has enhanced seeding capacity, and seeding differences can define molecular subtypes of progressive supranuclear palsy, underpinning the disease’s heterogeneity.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".