Comorbid Metabolic Syndrome and Prodromal Alzheimer's Disease in a Rat Model
Bibliographic record
Abstract
Metabolic syndrome (MetS), the development of which is associated with high-caloric Western diet intake, represents a risk factor for mild cognitive impairment (MCI) and Alzheimer’s disease (AD) and appears to contribute to AD progression when MetS and AD are comorbid. The interaction between AD and MetS might be through white matter inflammation, since white matter abnormalities and inflammation are important early events in the etiopathogenesis of both diseases. In these investigations, the effect of a high-caloric diet (HCD), to induce metabolic disturbances, on white matter neuroinflammation and cognitive function was investigated in a transgenic (TG) rat model of prodromal AD and MCI (APP21 TG). Rats maintained on the HCD developed obesity, dyslipidemia, hyperinsulinemia and glucose intolerance, but not hypertension. HCD-driven metabolic perturbations significantly exacerbated white matter microglia, but not astrocyte, activation in the TG rats. There were significant deficits in spatial reference memory in the comorbid TG HCD group compared to wildtype control rats. There were no changes in hippocampal neuronal or synaptic density in the comorbid group. In addition, single-regimen chronic prophylactic treatment with a novel brain-targeted NSAID prodrug Ketoprofen-lysine was not able to decrease the activation of white matter microglia and alleviate cognitive deficits in the comorbid model. In fact, the prodrug treatment alone was associated with two deaths and widespread neuroinflammation and neurodegeneration in a subset of rats further associated with a spatial working memory decline and cognitive inflexibility. Finally, white matter microglia activation was positively associated with visceral fat deposition and with transgene presence. Dyslipidemia was related to the greater white matter inflammation in the entire rat sample, however, showed an unexpected inverse association in the comorbid model. Thus, the APP21 TG rat combined with the HCD represents a good model for future studies on prodromal AD pathology and MetS. It can be used to study related cognitive dysfunction including effects of various comorbidities on the disease presentation, as well as provide a platform for testing treatment strategies and biomarker identification. The results support an important role of white matter inflammation in the interaction between prodromal AD and MetS and as a contributor to cognitive impairment.
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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) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".