Sirtuin Pathway Dysfunction Validation in Parkinson's Disease

SUMMARY

# Sirtuin Pathway Dysfunction Validation in Parkinson's Disease ## Background and Rationale This groundbreaking multi-phase clinical study investigates the role of sirtuin pathway dysfunction as a fundamental mechanism underlying Parkinson's disease pathogenesis and evaluates NAD+ repletion strategies as novel disease-modifying therapeutics. Sirtuins are NAD+-dependent deacetylases that regulate cellular metabolism, mitochondrial function, and stress responses - all processes critically impaired

METHODOLOGY NOTES

**Phase 1: Biomarker Validation and Patient Stratification (Months 1-12)** Recruit 300 participants: 150 Parkinson's disease patients (50 early-stage H&Y 1-2, 50 moderate H&Y 2.5-3, 50 advanced H&Y 3-4), 75 atypical parkinsonisms controls, and 75 healthy age-matched controls. Inclusion criteria include clinical diagnosis per Movement Disorder Society criteria, age 50-80 years, and stable medication regimen for ≥3 months. Collect blood samples for comprehensive NAD+ metabolome analysis using LC-MS/MS, measuring NAD+, NADH, nicotinamide, nicotinic acid, and NAD+/NADH ratios. Analyze peripheral blood mononuclear cells (PBMCs) for sirtuin enzyme activity (SIRT1, SIRT3, SIRT6) using fluorometric assays and Western blot for protein expression levels. Perform skin biopsies for α-synuclein aggregation analysis and mitochondrial function assessment in peripheral autonomic fibers. **Phase 2: Neuroimaging and CSF Sirtuin Pathway Assessment (Months 6-18)** Conduct [18F]FDG-PET imaging to assess