O4‐11‐06: NSAIDS FOR AD PREVENTION? NAPROXEN ENTERS THE CNS WITHOUT APPARENT EFFECT ON CSF IMMUNE MARKERS
Bibliographic record
Abstract
Epidemiological studies from the 1990’s and early 2000’s indicated an inverse association between non-steroidal inflammatory drug (NSAID) use and incidence of Alzheimer's disease (AD).[1] Subsequent clinical trials failed to confirm the benefits of NSAIDs and instead suggested harm.[2-4] The purported benefits of NSAIDs had been attributed to their anti-inflammatory activity, presumed to reduce AD-associated immune activation. However, there has never been any demonstration of NSAIDs’ ability to enter the human brain and affect immune mechanisms. Therefore, we conducted longitudinal investigations of cerebrospinal fluid (CSF) concentrations of the NSAID naproxen as well as several immune markers in INTREPAD, a randomized placebo-controlled trial of naproxen for prevention of AD biomarker progression among healthy elderly at increased risk for AD. Some 160 older adults with a parental or multiple-sibling family history of AD completed the two-year INTREPAD protocol. Of these 124 completed the trial on its prescribed dosage of naproxen 220 mg b.i.d. or placebo. Among these 78 had two or more lumbar punctures, permitting multiplex assay of cerebrospinal fluid (CSF) for 12 immune proteins and apolipoprotein E (apoE). Most of the CSF samples and concurrently collected plasma were also assayed for naproxen concentration using liquid chromatography with repeated mass spectroscopy. Naproxen was detected in plasma and CSF of naproxen-treated individuals only. However, CSF naproxen concentrations were ∼100 times lower than plasma concentrations (protein-bound fractions unknown). When present, CSF naproxen was associated with negligible change in CSF immune markers, but appeared to increase CSF apolipoprotein-E in proportion to drug concentration. Oral naproxen enters the CNS but induces negligible change in CSF immune markers. The disappointing efficacy results of AD prevention trials using naproxen and related drugs may therefore reflect limited blood-brain barrier transfer, or lack of the drugs’ effect on CNS immune processes. However, CSF apoE concentrations increased substantially over a two-year observation interval. This latter phenomenon appeared to be augmented in proportion to CSF concentration of naproxen. Overall, these findings suggest reconsideration of mechanistic assumptions regarding purported benefits of NSAIDs against AD risk. References: [1]int'Veld et al. N Engl J Med.2001;345:1515-21. [2]Aisen, et al. JAMA.2003;289:2819-26. [3]Thal, et al. Neuropsychopharmacology.2005;30:1204-15. [4]AdaptResearchGroup, et al. Neurology.2007;68:1800-8.
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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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.008 | 0.002 |
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".