Cholinergic innervation topography in GBA-associated <i>de novo</i> Parkinson’s disease patients
Bibliographic record
Abstract
Abstract The most common genetic risk factors for Parkinson’s disease are GBA1 mutations, encoding the lysosomal enzyme glucocerebrosidase. Patients with GBA1 mutations (GBA-PD) exhibit earlier age of onset and faster disease progression with more severe cognitive impairments, postural instability, and gait problems. The GBA-PD features suggests more severe cholinergic system pathologies. PET imaging with the vesicular acetylcholine transporter ligand [ 18 F]-F-fluoroethoxybenzovesamicol ([ 18 F]FEOBV PET) provides the opportunity to investigate cholinergic systems changes and their relationship to clinical features of GBA-PD. One hundred and twenty three newly diagnosed, treatment-naive Parkinson’s disease subjects – with confirmed presynaptic dopaminergic deficits on PET imaging – were included, all part of the Dutch Parkinson Cohort (DUPARC) study. Full GBA1 sequencing of saliva samples was performed to evaluate GBA1 variants. Patients underwent extensive neuropsychological assessment assessing all cognitive domains, motor evaluation with the Unified Parkinson’s disease Rating Scale, brain MRI, dopaminergic PET to measure striatal-to-occipital ratios of the putamen and [ 18 F]FEOBV PET. We investigated differences in regional cholinergic innervation between GBA-PD carriers and non- GBA1 mutation carriers (non-GBA-PD), using voxel-wise and volume-of-interest (VOI)-based approaches. The degree of overlap between t-maps from two-sample t-test models was quantified using the Dice similarity coefficient. Seventeen (13.8%) subjects had a GBA1 mutation. No significant differences were found in the clinical features and dopaminergic ratios between GBA-PD and non-GBA-PD at diagnosis. Lower [ 18 F]FEOBV binding was found in both the GBA-PD and non-GBA-PD group compared to controls. Dice ( P < 0.05, cluster size 100) showed a good overlap (0.6233) between the GBA-PD and non-GBA-PD maps. GBA-PD patients showed more widespread reduction in [ 18 F]FEOBV binding than non-GBA-PD when compared to controls in occipital, parietal, temporal, and frontal cortices ( P < 0.05, FDR-corrected). In VOI analyses (Bonferroni corrected), the left cuneus, entorhinal cortex, fusiform gyrus and supramarginal gyrus were more affected in GBA-PD. De novo GBA-PD show a distinct topography of regional cholinergic terminal ligand binding, including both higher and lower binding regions. Although the Parkinson’s disease groups were not distinguishable clinically, in comparison to healthy controls, GBA-PD showed more extensive cholinergic denervation compared to non-GBA-PD. Our results suggest that de novo GBA-PD and non-GBA-PD show differential patterns of cholinergic system changes before clinical differences are observable.
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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 | 0.001 |
| 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) | 0.002 | 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".