{
  "cutoff": "2026-10-09",
  "note": "Selected publication milestones, not an exhaustive history or discovery priority claim.",
  "milestones": [
    {
      "pmid": "22896675",
      "year": "2012",
      "title": "A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β.",
      "doi": "10.1126/scitranslmed.3003748",
      "url": "https://pubmed.ncbi.nlm.nih.gov/22896675/",
      "interpretation": "Tracer and AQP4 experiments establish a restricted perivascular transport mechanism."
    },
    {
      "pmid": "24136970",
      "year": "2013",
      "title": "Sleep drives metabolite clearance from the adult brain.",
      "doi": "10.1126/science.1241224",
      "url": "https://pubmed.ncbi.nlm.nih.gov/24136970/",
      "interpretation": "Sleep-state experiments associate larger interstitial space with increased clearance in mice."
    },
    {
      "pmid": "28826498",
      "year": "2017",
      "title": "Test of the 'glymphatic' hypothesis demonstrates diffusive and aquaporin-4-independent solute transport in rodent brain parenchyma.",
      "doi": "10.7554/eLife.27679",
      "url": "https://pubmed.ncbi.nlm.nih.gov/28826498/",
      "interpretation": "Direct diffusion and AQP4-independent measurements challenge uniform parenchymal convection."
    },
    {
      "pmid": "29220873",
      "year": "2018",
      "title": "Effect of sleep on overnight cerebrospinal fluid amyloid β kinetics.",
      "doi": "10.1002/ana.25117",
      "url": "https://pubmed.ncbi.nlm.nih.gov/29220873/",
      "interpretation": "Human isotope kinetics distinguishes amyloid production from fractional clearance."
    },
    {
      "pmid": "35212707",
      "year": "2022",
      "title": "Glymphatic system clears extracellular tau and protects from tau aggregation and neurodegeneration.",
      "doi": "10.1084/jem.20211275",
      "url": "https://pubmed.ncbi.nlm.nih.gov/35212707/",
      "interpretation": "AQP4 loss worsens pathology in a mutant-tau mouse model."
    },
    {
      "pmid": "38741022",
      "year": "2024",
      "title": "Brain clearance is reduced during sleep and anesthesia.",
      "doi": "10.1038/s41593-024-01638-y",
      "url": "https://pubmed.ncbi.nlm.nih.gov/38741022/",
      "interpretation": "Small-dye experiments report reduced clearance during sleep and anesthesia."
    },
    {
      "pmid": "39788123",
      "year": "2025",
      "title": "Norepinephrine-mediated slow vasomotion drives glymphatic clearance during sleep.",
      "doi": "10.1016/j.cell.2024.11.027",
      "url": "https://pubmed.ncbi.nlm.nih.gov/39788123/",
      "interpretation": "Noradrenergic oscillations link sleep microarchitecture to fluid transport."
    },
    {
      "pmid": "42214342",
      "year": "2026",
      "title": "Physiological brain clearance architecture revealed by neuronal protein tracing.",
      "doi": "10.1016/j.cell.2026.04.048",
      "url": "https://pubmed.ncbi.nlm.nih.gov/42214342/",
      "interpretation": "Endogenous neuronal protein tracing resolves compartment-specific exit routes."
    }
  ],
  "gaps": [
    "Influx, redistribution, degradation and net export need independent mass-balance measurements.",
    "Opposite sleep results require matched injection recovery, solute size, compartment and physiological state.",
    "AQP4 affects water homeostasis and cell function beyond the proposed route.",
    "Human device/model estimates need held-out orthogonal clearance validation; plasma changes alone do not identify the route.",
    "A clearance-specific human disease-trajectory intervention and directionally valid genetic instrument remain unverified."
  ],
  "decisive_experiment": "Prospectively register a selective adult pathway manipulation in a predefined aging/neurodegeneration setting, measure endogenous-solute production and net export with independent methods, and follow neuronal/functional trajectory. Match circadian timing, natural sleep, vascular dynamics and delivery pressure; add mediator rescue or epistasis before translating the physiological target to a human clinical trial."
}