Locus coeruleus structural integrity relates to cortical amyloid and tau pathology <i>in vivo</i>
Bibliographic record
Abstract
Abstract Background The locus coeruleus (LC) is one of the first epicentres of tau pathology in Alzheimer’s disease, displaying pathology decades before clinical symptom onset. We investigated whether LC integrity was associated with cortical deposition of amyloid and tau in vivo in asymptomatic, at‐risk older adults. Method 208 healthy older adults with first‐degree familial history of Alzheimer’s disease were included from the PREVENT‐AD cohort (mean age 68.4 ± 5.14y, 69% female). 155 subjects were also examined longitudinally over 38.8 ± 14.0 months. Subjects underwent longitudinal 3T MRI: 1mm 3 T1w MPRAGE and Neuromelanin‐sensitive brainstem imaging (0.7x0.7x1.8mm). Cortical amyloid and tau were quantified using PET imaging (single timepoint), with 18F‐NAV4694 and 18F‐flortaucipir tracers, respectively. Regional specific uptake value ratios (SUVR) were calculated for each, relative to cerebellar grey matter. LC was automatically delineated on individual neuromelanin‐sensitive brainstem scans by identifying 10 brightest connected voxels within an approximate region of interest and calculating contrast‐to‐noise relative to a pontine control region (LC CNR ). We tested associations between LC CNR and regional amyloid and tau SUVR using robust linear mixed effects models for each region with random intercepts across subjects. Longitudinal change was tested as an interaction term between the PET measure and time. We also tested the dependence of the Tau‐LC association on global amyloid pathology at baseline using linear regression. All analyses were corrected for baseline age, sex and education and p ‐values were FDR‐adjusted. Results We observed negative associations between LC integrity and amyloid SUVR across almost all cortical regions (Figure 1). Associations between LC integrity and cortical tau were restricted to temporal lobes, including parahippocampal gyrus, and inferior parietal regions (Figure 1). Associations with both amyloid and tau were particularly strong in the left hemisphere. These associations were observed only at baseline, with no longitudinal effects observed. The relationship between baseline LC integrity and cortical tau was modulated by global amyloid in lateral temporal cortices, particularly along in the left lateral temporal cortex (Figure 2). Conclusion LC degeneration was associated with greater expression of key hallmarks of AD pathology in asymptomatic older adults. We support the model that LC is central to the earliest pathophysiological changes of AD.
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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 | 0.001 |
| 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".