Locus coeruleus integrity as a proxy of initial tau burden: in vivo versus ex vivo observations
Bibliographic record
Abstract
Abstract Background Autopsy studies reported the locus coeruleus (LC) as one of the initial regions in the brain harboring hyperphosphorylated tau pathology. MR signal intensity in the LC has been proposed as a measure of LC integrity, but the contribution of tau pathology, commonly found in LC, to this signal intensity is not currently measurable in vivo. We related in‐vivo LC MR signal intensity to Alzheimer’s disease (AD) phenotype and PET measures and used ROSMAP autopsy data to guide interpretation of the MR LC measure as tau‐related or cellular integrity‐related. Method One‐hundred seventy‐two participants from the Harvard Aging Brain Study (HABS) underwent 3T LC‐MRI imaging, FTP and PiB‐PET imaging (median age: 75 years, 58% female, n=22 with CDR=0.5/1). In 160 individuals from ROSMAP, LC tangle density and neuronal density were quantified at autopsy (median age at death: 89 years, 67% female, 66 control, 53 mild cognitively impaired, 41 AD patients; Figure 1). Groups were compared using ANCOVA. LC measures were related to Mini‐Mental State Examination (MMSE) scores using Spearman correlations (age‐adjusted). In HABS, LC integrity was vertex‐wise regressed on tau‐PET. In ROSMAP, Spearman correlations related LC tangle or neuronal density to cortical tangle density or Braak staging. Result LC measures correlated with measures of disease progression: in HABS, LC integrity was lower in impaired individuals compared to controls, and correlated positively with MMSE score. In ROSMAP, LC tangle density was higher in MCI/AD patients compared to controls; and correlated negatively with MMSE scores. No associations were found for LC neuronal density (Figure 2). Furthermore, lower LC integrity correlated with higher tau in medial‐lateral temporal regions in HABS, mirroring the consecutive Braak‐staging. Similarly, In ROSMAP, higher LC tangle density, but not LC neuronal density, correlated positively with cortical tangle burden and Braak staging (Figure 3). Conclusion The comparable associations of MRI‐LC integrity or LC tangle density with disease progression and tau suggest that MRI‐measures of LC integrity may be a proxy for tau pathology, rather than neuronal density. Future verification using head‐to‐head comparison is warranted, but our results indicate that LC integrity holds promise as marker for detection of initial AD‐related processes.
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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".