Evaluating the pharmacodynamic effects of padsevonil in healthy volunteers using simultaneous [11C]-UCB-J PET and MR Arterial Spin Labeling measurements
Bibliographic record
Abstract
Integrated PET-MR scanners can measure simultaneously tracer binding, downstream cerebral blood flow (CBF) and neuronal activation. An integrated GE Signa PET-MR system was used to combine [11C]-UCB-J PET scanning with MR Arterial Spin Labeling (ASL) measurements to evaluate the effects of padsevonil (PSL) on SV2A occupancy and CBF simultaneously. PET-MR scanning was performed in 10 healthy controls (8M/2F; 27.6 ± 10.0 yrs) at baseline, and at two timepoints (post1: 2−24h and post2: 6−30h) after administration of a single PSL dose (6.2−100 mg). Dynamic [11C]-UCB-J PET scanning with arterial blood sampling was performed to estimate distribution volumes and corresponding SV2A occupancies. Simultaneously, MR ASL data were acquired and spatially normalized to Montreal Neurological Institute (MNI) space for voxel wise analysis while brain Volume-Of-Interest (VOI) were defined using a simplified Hammers atlas. PET measurements showed a SV2A occupancy range of 57–98% and 16−63% and a corresponding PSL plasma concentration range of 3.6–189.23 ng/mL and 1.3–9.8 ng/mL for post1 and post2, respectively. When comparing post1 to baseline ASL measurements, a VOI-based analysis detected a significant CBF decrease in thalamus, insula, cerebellum, posterior cingulate cortex, and brain stem, which was confirmed by a voxel-wise analysis comparing baseline and post1 ASL measurements and identifying significantly different clusters covering the same brain regions. In addition, we demonstrated CBF recovery in these brain regions for the post2 ASL measurements compared to baseline measurements. For the thalamus, a VOI-based correlation analysis detected a significant correlation between PSL plasma concentration and CBF decrease relative to baseline conditions. A pattern of local and dose dependent CBF decrease was demonstrated following PSL administration. More generally, these findings present the potential of simultaneous PET and ASL measurements to follow the time course of drug effects and to differentiate between the efficacy of different drugs in patient groups.
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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) | 0.001 | 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".