Inflammation in the white matter relates to core Alzheimer's disease pathophysiological processes
Bibliographic record
Abstract
Abstract Background In‐vivo PET imaging studies have demonstrated neuroinflammation (microglia reactivity) in the neocortex of Alzheimer’s disease (AD) patients. However, the extent and implication of microglia reactivity in white matter regions remains unclear. Here, we explored microglia reactivity in white matter using PET imaging of the translocator protein (TSPO) in relation to core AD biomarkers (amyloid, tau, and astrogliosis), microstructural damage, and cognitive decline. Method Ninety‐one participants from the Translational Biomarkers in Aging and Dementia cohort (45% Aβ‐positive, 39% cognitively impaired) underwent diffusion‐weighted MRI, TSPO‐PET (11C‐PBR28), amyloid‐PET (18F‐NAV4694), tau‐PET (18F‐MK6240), and plasma Aβ42/40, ptau181, ptau217, and ptau231. We investigated the associations of TSPO‐PET SUVR in white matter lobes (eroded by 2mm3) with each of the AD biomarkers, diffusion metrics, and cognition, adjusted for demographics and global cortical TSPO‐PET. Longitudinally, we investigated the interaction between time (up to 2y) and baseline white matter TSPO‐PET SUVR on cognitive decline, adjusted for demographics and cortical amyloid. Result White matter TSPO‐PET was increased globally with older age and frontally with male sex (p<0.05). In impaired individuals, TSPO‐PET was elevated in temporo‐occipital white matter regions compared to controls (p=0.01‐0.02). The occipital increases were associated with reactive astrogliosis (p=0.011) and higher‐Braak tau‐PET (p=0.003‐0.034 for Braak3‐4) and plasma ptau181 (p=0.014) (Figure 1A‐B), but not with Aβ, ptau231 or ptau217. In addition, higher occipital TSPO‐PET was associated with lower fibre integrity (fractional anisotropy, p=0.025) but not free water. Finally, in relation to cognition, higher occipital and parietal TSPO‐PET was significantly associated with impaired memory and language, respectively, independent of Aβ (Figure 1C). Longitudinally, within the same patient, higher white matter TSPO‐PET at baseline was significantly associated with favorable clinical outcome over time (Figure 1D). Conclusion Increased microglia reactivity (TSPO‐PET) in posterior white matter may indicate later‐stage AD associated with astrogliosis, tau, and dysfunction of the memory and language domains. Another novel finding is that individuals with higher white matter TSPO‐PET at baseline displayed better clinical prognosis over time. As such, assessing white matter inflammation could be promising to evaluate target engagement in clinical trials of anti‐inflammatory drugs and to subtype patients for better patient‐centric treatment outcome.
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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) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 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".