The gap can be tested by treating tight-junction remodeling as an upstream driver rather than a passive correlate. If true, perturbing dynamic contrast MRI should shift CSF/serum albumin ratio before downstream neurodegeneration markers change.
Curated pathway from expert analysis
flowchart TD
A["Tight Junction Complex<br/>CLDN5 and OCLN Assembly"]
B["Paracellular Barrier Integrity<br/>Selective Permeability"]
C["Inflammatory Mediators<br/>VEGF TNF and IL-1beta"]
D["ZO-1 Scaffold Dissociation<br/>TJ Protein Phosphorylation"]
E["Claudin-5 Internalization<br/>Lysosomal Degradation Route"]
F["BBB Leakage<br/>Albumin and Fibrinogen Entry"]
G["Neuroinflammation<br/>Peripheral Immune Cell Infiltration"]
A --> B
C -.->|"disrupts"| A
C --> D
D --> E
E --> F
F --> G
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style C fill:#7b1fa2,stroke:#ce93d8,color:#ce93d8
style F fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style G fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo curated PDB or AlphaFold mapping for TIGHT-JUNCTION yet. Search RCSB →
No clinical trials data linked to this hypothesis yet.
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for tight-junction remodeling.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
No resource usage or linked notebooks recorded for this hypothesis yet.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF tight-junction remodeling is an upstream BBB driver, THEN reducing claudin-5/occludin integrity in brain endothelial cultures will increase albumin permeability by >=50% before neuronal injury-cond | Endothelial barrier model shows >=50% albumin permeability increase before neuronal injury markers exceed baseline by 10%. | — no observation — | pending | 0.63 |
| IF dynamic contrast MRI captures tight-junction-driven BBB change, THEN DCE-MRI permeability will rise >=10% at least 12 months before CSF/serum albumin ratio or NfL rises in at-risk older adults. | Regional DCE-MRI Ktrans increases >=10% before albumin ratio or NfL threshold crossing. | — no observation — | pending | 0.55 |