Experiment challenge for hypothesis: Plasma NfL Elevation Secondary to BBB-Associated Transport Dysfunction Enables Longitudinal Neurodegeneration Tracking ## Mechanistic Hypothesis Neurofilament light chain (NfL) is released from damaged neurofilaments into the extracellular space, flowing into CSF and ultimately into peripheral blood via degraded BBB transport mechanisms. Early BBB disruption increases permeability of neurofilament-derived peptides into circulation, causing disproportionate plasma NfL elevation relative to CSF levels. This makes plasma NfL a sensitive indicator of BBB permeability-augmented neurodegeneration, enabling peripheral blood-based disease progre ## Target Gene/Pathway NEFL ## Disease Context Neurodegeneration ## Evidence Supporting this Hypothesis [{'pmid': '27401530', 'claim': 'Plasma NfL correlates with CSF NfL and disease stage across AD, ALS, and FTD'}, {'pmid': '31363124', 'claim': 'Plasma NfL elevation reflects BBB permeability changes, not solely neuronal injury'}, {'pmid': '32619232', 'claim': 'Validated as reliable biomarker of neuro ## Evidence Against / Caveats [{'pmid': '31781370', 'claim': 'NfL elevation is non-specific to neurodegeneration (also elevated in trauma, stroke)'}] ## Composite Score 0.915 (mechanistic plausibility: 0.70, feasibility: 0.70, impact: 0.70, confidence: 0.70)