P2‐255: Ketone bodies, sodium oxybate and Alzheimer's disease: Oxidative stress and neuroprotection
Bibliographic record
Abstract
A decrease in the cerebral metabolic rate for glucose (CMRglu) is one of the earliest manifestations of Alzheimer's disease (AD) and has been detected in cognitively normal individuals at risk for AD years before the onset of widespread neuronal damage. The cause of this decrease is unknown but it is paralleled by decreased pyruvate dehydrogenase (PDH) activity, impaired oxidative phosphorylation, increased formation of reactive oxygen species (ROS) and oxidative damage. The Alzheimer brain compensates for the reduction in CMRglu by using ketone bodies (KB) as an alternative fuel. KB have been shown to be neuroprotective in cellular models of AD and to improve cognition in patients with AD who are APOE4 (-). KB bypasse the PDH block and provide NADH to the mitochondrial electron transport chain, thus maintaining ATP production, cellular redox potentials and antioxidant levels. We suggest that sodium oxybate (SO) will be more effective than KB for the treatment of AD. SO has been shown to be neuroprotective and uniquely combines 3 properties: it bypasses the PDH block and provides energy by forming succinate; it generates two antioxidants, NADH and NADPH; it activates the pentose phosphate pathway to promote reductive biosynthesis and cell repair. Hepatocytes were isolated by collagenase liver perfusion from male Sprague-Dawley rats weighing 275-300g. Isolated heptatocytes were suspended in Krebs-Henseleit buffer containing 12.5 mM HEPES in continuously rotating 50 ml round-bottom flasks in a 37 °C water bath. Cytotoxicity was tested using the trypan blue (0.1% w/v) exclusion test to determine plasma membrane integrity. Oxidative stress cytotoxicity induced by H2O2 formed by glucose/glucose oxidase was best prevented by the antioxidant catechin > SO > acetoacetate. Reductive stress cytotoxicity, induced by 95% N2 and 5% O2, was best prevented by catechin > SO > acetoacetate. In both cases, cytotoxicity was markedly increased by beta-hydroxybutyrate or lactate. These studies are being repeated in astrocytes. SO was more powerful at maintaining the cellular redox potential and antioxidant capacity than KB. SO, a short chain fatty acid, may also decrease ROS production and prevent the onset of oxidative stress by activating mitochondrial-uncoupling proteins.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".