The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson's disease.

Double-blind, randomized, placebo-controlled phase I trial; 30 newly diagnosed, treatment-naive Parkinson's disease patients (15 NR; 15 placebo); mean age ~63 years; mixed sexes; diagnosed by Movement Disorder Society criteria; no dopaminergic therapy at enrollment.

Nicotinamide riboside (NR), 1000 mg/day total, taken orally as 500 mg per dose, twice daily (two 250 mg NR capsules per dose) for 30 days.

NR is safe and increases brain NAD levels (31P-MRS) with a significant NAD/ATP-a rise in the NR group (p=0.016); between-group NAD change difference significant (p=0.025). 10/13 NR recipients showed NAD increases; those with NAD increases exhibited an NR-related metabolic pattern (NRRP) on FDG-PET that correlated with mild UPDRS motor improvement. NR augmented the NAD metabolome in CSF and peripheral tissues and induced transcriptional upregulation of mitochondrial, lysosomal, and proteasomal pathways in blood cells and muscle; inflammatory cytokines decreased in serum and CSF (serum GDF15 decreased; FGF21 unchanged; Nf-L unchanged). Across tissues, NR exposure increased Nam-derived metabolites (e.g., Me-2-PY, Me-Nam, NAMN, NAAD) with no consistent rise in NAD+ or NADH in muscle. Overall, findings support NR as a potential neuroprotective therapy for PD and justify larger, longer trials; phase II (NOPARK, NCT03568968) is underway.

Small sample size; short duration; substantial interindividual variability in NAD response; 3T 31P-MRS limitations in distinguishing NAD+ from NADH; post hoc tissue analyses limited by sample availability; results require confirmation in larger, longer-term trials.