Bibliographic record
Abstract
Objectives - Gaucher disease (GD) is caused by bi-allelic mutations in the glucocerebrosidase gene (GBA). GD and heterozygous carriage of GBA mutations significantly increase the risk of developing Parkinson's disease (PD). Here we studied GD patients and carriers to identify a cohort of individuals with clinical signs of prodromal PD and generated fibroblast lines from them to study why GBA mutations cause PD. Methods - 83 patients with Type I GD and 41 of their heterozygous carrier relatives were recruited from lysosomal storage disorder clinics at the Royal Free Hospital and Addenbrooke's Hospital Cambridge, along with 30 mutation negative matched controls. They were clinically screened for hyposmia (University of Pennsylvania Smell Identification Test), cognitive impairment (Montreal Cognitive Assessment), autonomic dysfunction, REM sleep behaviour disorder and motor signs of PD. Two hundred and thirty cases of sporadic PD were screened for GBA gene mutations. Fibroblasts were generated from skin biopsies taken from a selection of patients. GBA metabolism (Western blotting for protein levels, enzyme activity, immunofluorescent localisation), mitochodrial metabolism, endoplasmic reticulum and oxidative stress markers were assayed in the cell lines. Results – GD patients and heterozygous carriers had significantly lower olfactory and cognitive function scores than controls. Several GD patients and carriers had motor signs of PD (e.g. rest tremor) while controls did not. Thirteen PD patients with heterozygous GBA mutations were identified. Their clinical phenotype was similar to mutation negative PD cases. GD fibroblast lines (n=5), and lines from heterozygous GBA mutation carriers with (n=4) and without PD (n=2) had reduced GBA enzyme activity due to endoplasmic reticulum retention of GBA protein. This was associated with upregulation of endoplasmic reticulum stress markers and oxidative stress (increased rate of dihydroethidium oxidation). Conclusions – a subset of GD patients and carriers express clinical markers of prodromal PD. Study of fibroblasts from these individuals indicates that endoplasmic reticulum and oxidative stress may contribute to increased PD risk in these individuals.
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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 | 0.000 | 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) | 0.003 | 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".