TDP‐43 in the ubiquitin pathology of frontotemporal dementia with VCP gene mutations
Bibliographic record
Abstract
Frontotemporal dementia with inclusion body myopathy and Paget's disease of bone (IBMPFD) is a rare, autosomal‐dominant disorder caused by mutations in the gene valosin‐containing protein (VCP). The CNS pathology is characterized by a novel pattern of ubiquitin pathology distinct from sporadic and familial frontotemporal lobar degeneration with ubiquitin‐positive inclusions (FTLD‐U) without VCP mutations. TAR DNA binding protein (TDP‐43) was recently identified as a major disease protein in the ubiquitin‐positive inclusions of sporadic and familial FTLD‐U. To determine if the ubiquitin pathology associated with mutations in VCP is characterized by the accumulation of TDP‐43, we analyzed TDP‐43 in the CNS pathology of five patients with VCP gene mutations. Accumulations of TDP‐43 co‐localized with ubiquitin pathology in IBMPFD including both the intranuclear inclusions and dystrophic neurites. Similar to FTLD‐U, phosphorylated TDP‐43 was detected only in insoluble brain extracts from affected brain regions. Identification of TDP‐43, but not VCP, within ubiquitin‐positive inclusions supports the hypothesis that VCP gene mutations lead to a dominant negative loss or alteration of VCP function culminating in impaired degradation of TDP‐43. TDP‐43 is a common pathologic substrate linking a variety of distinct patterns of FTLD‐U pathology caused by different genetic alterations.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.002 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| 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".