The role of NAD supplementation in Parkinson’s disease

15 January 2025
Dr Fahd Al Qureshah
The role of NAD supplementation in Parkinson’s disease

Background

Parkinson’s disease (PD) affects 1–2% of individuals over 65 and lacks treatments that significantly alter disease progression. NAD+ (nicotinamide adenine dinucleotide), essential for energy metabolism, DNA repair, and redox reactions, declines with age and may play a role in neurodegeneration. Nicotinamide riboside (NR), a vitamin B3 derivative, boosts NAD+ levels and has shown neuroprotective potential in preclinical studies. This study evaluates the safety, cerebral NAD+ enhancement, and metabolic effects of NR supplementation in newly diagnosed, treatment-naive PD patients.


Study Design

  • Participants: 30 individuals, randomly assigned to NR (1000 mg/day) or placebo for 30 days.
  • Methods: Cerebral NAD+ levels were assessed using 31P-magnetic resonance spectroscopy (MRS), while metabolic and transcriptomic changes were measured in blood, cerebrospinal fluid (CSF), and muscle tissue. Clinical outcomes were evaluated using the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS).


Key Findings

Cerebral NAD+ Levels:

  • NR significantly increased cerebral NAD+ levels in 10 of 13 participants (p = 0.016).
  • A between-group comparison showed a greater change in NAD+/ATP-a ratio in the NR group compared to placebo (p = 0.025).

Safety and Tolerability:

  • NR was well tolerated with no major adverse effects.
  • Minor adverse events occurred in 7 NR participants versus 3 in the placebo group, all unrelated to treatment.

Clinical Improvements:

  • Among participants with increased NAD+ levels (MRS responders), MDS-UPDRS scores decreased by an average of 2.33 points (p = 0.017), particularly in subsections I (non-motor symptoms) and III (motor symptoms).

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Metabolic and Transcriptomic Effects:

  • Peripheral Tissues:
  • NR increased NAD-related metabolites like N-methyl-2-pyridone-5-carboxamide (Me-2-PY) in CSF, indicating effective cerebral NAD+ replenishment.
  • Muscle and blood showed enhanced NAD+ metabolome activity without significant increases in absolute NAD+ levels.
  • Gene Expression:
  • NR upregulated genes involved in mitochondrial function, lysosomal activity, and oxidative stress response.
  • Key changes included increased expression of mitochondrial respiratory genes (e.g., FARS2, TMEM242) and proteasomal function markers.
  • Inflammation:
  • CSF cytokines linked to inflammation showed significant reductions exclusively in the NR group.

Neurometabolic Patterns:

  • FDG-PET scans revealed a distinct NR-induced metabolic network pattern (NRRP) in the brain, with reduced glucose uptake in the caudate, putamen, and cortical areas.
  • Changes in NRRP expression correlated with motor improvements (r = -0.59, p = 0.026).


Implications

The study demonstrates that oral NR supplementation safely increases brain NAD+ levels and modulates brain metabolism in PD. These changes correlate with mild clinical improvements and suggest NR’s potential as a neuroprotective therapy.

Key insights include:

  • NAD+ augmentation may enhance mitochondrial function and reduce neuroinflammation in PD.
  • Changes in cerebral metabolism, as indicated by the NRRP, point to a more efficient bioenergetic state in NR-treated patients.


Conclusion

The NADPARK study establishes NR as a promising candidate for neuroprotective therapy in PD by enhancing NAD+ levels and modulating neurometabolic pathways. A Phase II trial is underway to evaluate its effects on disease progression (ClinicalTrials.gov: NCT03568968).

For full details, refer to the original article: https://pubmed.ncbi.nlm.nih.gov/35235774/