Novel CSF glial‐related biomarkers reflect Alzheimer's and Parkinson's pathological changes
Bibliographic record
Abstract
Abstract Background Glial cells play important roles in the pathophysiology of neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Glial dysfunction is thought to contribute to neurodegeneration progression, but a few cerebrospinal fluid (CSF) biomarkers effectively capture these changes. Identifying novel glial‐derived CSF biomarkers may improve our understanding of AD and PD pathology and aid in disease monitoring. Method We selected astrocyte‐, oligodendrocyte‐, oligodendrocyte precursor cell (OPC)‐, and microglia‐enriched and enhanced genes from single‐cell and single‐nucleus transcriptomic datasets. These gene lists were cross‐referenced with CSF proteomic data (SomaLogic) from two AD cohorts (cohorts 1 and 2) and a PD cohort (cohort 3) (Figures 1‐3ADF). Linear regression models were used to assess differential protein expression in CSF between cognitively unimpaired (CU) and cognitively impaired (CI) individuals, as well as between amyloid‐beta (Aβ)‐positive and alpha‐synuclein (α‐syn)‐positive individuals, within each glial cell type. In cohorts 1 and 3, differentially abundant proteins were clustered based on their pseudo‐progression across CU and CI individuals, further stratified by Aβ (pTau181/Aβ42 ratio cut‐off=0.028) or α‐syn status. In a subset of cohort 1, voxelwise analyses examined associations between protein cluster averages and [ 18 F]Florbetapir‐PET amyloid imaging, adjusting for age and sex. Random field theory (RFT) was applied for multiple comparison correction in imaging analyses. Result We identified 47 astrocyte‐, 94 oligodendrocyte/OPC‐, and 94 microglia‐related proteins that were significantly altered in CI individuals compared to CU. In Aβ+ individuals, 52 astrocyte‐ (Figure 1BE), 99 oligodendrocyte/OPC‐ (Figure 2BE), and 117 microglia‐related proteins (Figure 3BE) were differentially expressed. Similarly, in α‐syn+ individuals, 143 glial proteins were altered across astrocytes, oligodendrocytes/OPCs, and microglia (Figures 1‐3G). Clustering analysis categorized proteins into four distinct groups per cell type and cohort (Figures 1‐3CH). In cohort 1, voxelwise analyses demonstrated that at least one cluster per cell type presented an association with [ 18 F]Florbetapir‐PET imaging, particularly in cortical gray matter (data not shown). Conclusion This study identified 485 glial‐related CSF proteins altered in AD or PD. We also uncovered distinct glial protein clusters across AD pseudo‐progression and their association with Aβ burden in the brain, highlighting potential glial biomarkers for neurodegenerative disease progression. These findings can help uncover the glial heterogeneity present in AD and PD.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| 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".