Biomarkers of agitation in moderate‐to‐severe Alzheimer's disease patients enrolled in an RCT with nabilone
Bibliographic record
Abstract
Abstract Background Brain cholesterol metabolism, neuroinflammation, and oxidative stress are processes altered during Alzheimer’s disease (AD), which may impede endocannabinoid signaling, and thus worsen agitation. We assessed whether the brain cholesterol metabolite, cerebrocholesterol (Cchol), proinflammatory cytokine, tumor necrosis factor (TNF), and oxidative stress marker, 4‐hydroxynonenal (4‐HNE) were associated with agitation severity and response to nabilone. Method Serum Cchol, TNF and 4‐HNE, were collected from AD patients enrolled in a 14‐week, double‐blind cross‐over trial comparing 6 weeks of nabilone to placebo, at the start and end of each phase. We assessed the relationship between agitation (Cohen Mansfield Agitation Inventory (CMAI)) and baseline (BL) biomarker levels; the relationship between change in agitation and BL biomarker levels within each phase; and the relationship between change in agitation and change in biomarker levels within each phase. Exploratory analyses included adjustments for BL cognition (Mini‐Mental Status Exam (MMSE)), and analyses with CMAI subtotals consistent with the International Psychogeriatric Association (IPA) definition for agitation. Result Serum was collected from thirty‐eight participants (mean±SD age=87±10, 77% male, CMAI=68±18, MMSE=6.3±6.3). Cchol was not associated with CMAI cross‐sectionally or longitudinally, before and after adjusting for MMSE. However, BL Cchol was negatively correlated with BL CMAI IPA (F(1,36)=4.95, p=.03). In placebo only, lower BL Cchol was associated with increases in CMAI IPA (b=‐35.2, p=.02), and decreases in Cchol were associated with increases in CMAI IPA (b=‐20.94, p=.03). After adjusting for MMSE, BL TNF was positively correlated with BL CMAI (F(2,25)=3.69, p=.04), and predicted improvements in CMAI during nabilone only (b=‐1.14, p=.045). Decreases in TNF were associated with improvements in CMAI during nabilone only (b=1.12, p=.006). BL 4‐HNE was positively correlated with BL CMAI (F(1,35)=6.41, p=.02), and predicted worsening in CMAI during placebo only (b=0.01, p=.01). Changes in 4‐HNE were not associated with changes in CMAI in either phase. Conclusion Cchol, TNF, and 4‐HNE may be markers of agitation severity in AD. Though neither Cchol nor 4‐HNE predicted response to nabilone and did not change over time with nabilone, these markers may be associated with changes in agitation severity. Findings with TNF suggest that this marker predicts treatment response, and decreases with nabilone treatment.
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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 | 0.004 | 0.005 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.002 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| 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".