Glymphatic-Circadian Axis Enhancement Therapy for Parkinson's Disease

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