SUMMARY
# Glymphatic-Circadian Axis Enhancement Therapy for Parkinson's Disease
## Background and Rationale
This Phase 1b/2a clinical trial targets the emerging connection between glymphatic system dysfunction and circadian rhythm disruption in Parkinson's disease pathogenesis. The glymphatic system, responsible for brain waste clearance including α-synuclein aggregates, operates primarily during sleep and is regulated by circadian mechanisms. In Parkinson's disease, both glymphatic dysfunction and circ
METHODOLOGY NOTES
**Phase 1: Screening and Baseline Assessment (Days -28 to -1)**
• Screen 120 early-stage Parkinson's patients (Hoehn-Yahr stages 1-2.5) aged 45-75 years
• Conduct comprehensive neurological evaluation including MDS-UPDRS Parts I-IV
• Perform baseline glymphatic function assessment via diffusion tensor imaging along perivascular spaces (DTI-ALPS)
• Establish circadian rhythm profiles using 14-day actigraphy and salivary melatonin sampling
• Obtain baseline CSF biomarkers (α-synuclein, tau, Aβ42) via lumbar puncture
• Conduct sleep polysomnography and cognitive assessment battery (MoCA, detailed neuropsych testing)
**Phase 2: Randomization and Treatment Initiation (Days 0-7)**
• Randomize 80 eligible participants to four arms (n=20 each): combination therapy, glymphatic enhancement only, circadian therapy only, placebo
• Glymphatic enhancement: Transcranial focused ultrasound (tFUS) 3x/week targeting perivascular spaces
• Circadian therapy: Bright light therapy (10,000 lux, 30 min morni