Which TDP-43 biomarkers can reliably distinguish between reversible phase separation and irreversible pathological aggregation in living patients?

Multiple biomarkers were mentioned (stathmin-2, extracellular vesicle TDP-43, neurofilament) but the debate did not resolve which can differentiate early reversible dysfunction from late-stage irreversible pathology. This distinction is crucial for therapeutic timing and patient stratification.

Source: Debate session sess_sda-2026-04-01-gap-006 (Analysis: sda-2026-04-01-gap-006)

Gap closes when: (1) A biomarker validation study using CSF and/or plasma from confirmed ALS/FTLD-TDP patients (n >= 80, staged disease) demonstrates that at least one biomarker (stathmin-2, neurofilament, EV-TDP-43, or novel candidate) achieves AUC >= 0.80 for distinguishing early-stage reversible dysfunction (TDP-43 nuclear clearance without cytoplasmic aggregation) from late-stage irreversible aggregation by neuropathological or imaging confirmation; and (2) the biomarker correlates with functional decline rate (r >= 0.5, p < 0.01). Deliverable: validated biomarker with ROC curve data and longitudinal correlation analysis deposited in a public repository.

Resolved by hypothesis h-var-e2b5a7e7db: GluN2B-Mediated Thalamocortical Control of Glymphatic Tau Clearance. Score: 0.964. Supporting PMIDs: 19449329, 23431156, 26282667, 40994429, 40796363.