IC‐P‐004: Cerebral hypoperfusion in young transgenic APP mice predicts spatial distribution of amyloid deposition
Bibliographic record
Abstract
Regional cerebral hypoperfusion has been identified in Alzheimer's disease (AD) patients by arterial spin labeling (ASL) MRI. The association between hypoperfusion and β-amyloid deposition, however, remains poorly understood. In order to elucidate this relationship, we have performed in vivo 3D ASL MRI in young and old mutant human amyloid precursor protein (APP) transgenic (TG) mice and correlated regional perfusion data with gold-standard, post-mortem quantitative immunohistochemistry (qIHC) measures of β-amyloid burden. Anatomical and perfusion MRI data were acquired from 3-4 month-old (young) and 18-19 month-old (aged) APP TG and wild-type (WT) mice (n = 20 per group). Images were acquired using 3D b-SSFP sequence (anatomical) and pseudo-continuous 3D ASL sequence (perfusion) covering the entire brain on a 7T animal MRI system. MR images were processed using a fully-automated pipeline. The animals were sacrificed following completion of MRI scans and the brains were fixed. The formalin-fixed, paraffin-embedded brains were serially-sectioned from olfactory bulb through brainstem. The sections underwent IHC staining with 4G8 anti-amyloid monoclonal antibody and were counterstained with Acid Blue 129. The IHC sections were digitized using a MIRAX Scan automated, ultra-high-resolution slide scanner. The digitized tissue sections were then reconstructed into 3D β-amyloid parametric volumes. The anatomical/perfusion MRI volumes and 3D IHC parametric volumes were then spatially normalized to a customized anatomical MRI template/atlas. Voxel-wise and ROI-based statistical analyses were performed on these parametric volumes. Young APP TG mice demonstrated significantly reduced cerebral perfusion in several neuroanatomical regions relative to age-matched WT mice. At this age, the mice did not demonstrate IHC-visible β-amyloid deposits. However, the spatial distribution of hypoperfusion in the young TG mice and high β-amyloid burden in the aged APP TG mice were strongly correlated. We have demonstrated significant regional differences in blood flow between young, pre-plaque stage APP and WT mice using ASL MRI. Our unique approach of co-registering quantitative MRI and IHC volumes revealed that this pattern of hypoperfusion appears to predict the distribution of β-amyloid deposition in later life. As such, ASL perfusion MRI may serve as a powerful imaging biomarker for the assessment of disease evolution and therapeutic intervention in clinical AD studies.
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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) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 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) | 0.009 | 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".