Parkinson’s disease (PD) affects 1%–2% of the population above the age of 65 and is a major cause of death and disability, with a rapidly growing global socioeconomic impact. Current treatments for PD can provide partial symptomatic relief, mainly for motor symptoms but make no substantial impact on disease progression. Despite several candidate neuroprotective therapies showing encouraging preclinical results, these have failed to show disease-modifying effects in clinical trials.
A growing body of evidence supports that boosting cellular levels of nicotinamide adenine dinucleotide (NAD) may confer neuroprotective effects in both healthy aging and neurodegeneration. NAD is reversibly interconverted between its oxidized (NAD+) and reduced (NADH) state and thereby constitutes an essential cofactor for metabolic redox reactions, including mitochondrial respiration. Furthermore, NAD+ is substrate to vital signaling reactions involved in DNA repair, histone and other protein deacylation reactions, and second messenger generation. NAD can be replenished via supplementation of nicotinamide riboside, a vitamin B3 molecule and biosynthetic precursor of NAD. Nicotinamide riboside can be found in foods like fruits, vegetables, meat, and milk. It is also used as a nutritional supplement to boost cellular levels of NAD (nicotinamide adenine dinucleotide). Nicotinamide riboside has undergone extensive preclinical testing. this evidence suggests that Nicotinamide riboside may hold promise as a potential neuroprotective agent for PD. However, several critical knowledge gaps have yet to be addressed. Specifically, it needs to be established whether Nicotinamide riboside is well tolerated, augments cerebral NAD levels, and affects cerebral metabolism in patients with PD.
To address these questions, scientists at Haukeland University Hospital and the University of Bergen led by Prof. Charalampos Tzoulis conducted a double-blinded, randomized, placebo-controlled phase I study of nicotinamide riboside in newly diagnosed PD patients, naive to dopaminergic therapy. The study was designed to have primary outcomes the detection of cerebral penetration and metabolic response, measured by 31phospohorous-magnetic resonance spectroscopy (31P-MRS), cerebrospinal fluid (CSF) metabolomics, and 18fluoro-deoxyglucose positron emission tomography (FDG-PET). The original research article is now published in Cell Metabolism.
The research team found that nicotinamide riboside supplementation was well tolerated with no adverse effects. Treatment increased brain NAD levels, as well as related metabolites in the CSF and peripheral tissues. At the individual level, the increase in cerebral NAD was not universal but evident in 10/13 nicotinamide riboside recipients from whom data were available. The Nicotinamide riboside recipients who showed increased brain NAD levels exhibited altered cerebral metabolism, inducing a specific treatment-related metabolic network that overlapped with key elements of the PD-related spatial covariance pattern and were associated with mild clinical improvement.
The authors findings suggest that Nicotinamide riboside may target multiple processes implicated in the pathophysiology of the disease by upregulating the expression of genes involved in mitochondrial respiration, oxidative damage response, lysosomal and proteasomal function, and downregulating inflammatory cytokines in the central nervous system. In addition, it is possible that Nicotinamide riboside may mitigate epigenomic dysregulation in PD by regulating histone acetylation.
In a nutshell, a total of 30 individuals with early Parkinson’s disease received either 1,000 mg nicotinamide riboside or placebo for a total of 30 days. The Belgian clinical study showed that Nicotinamide riboside supplementation significantly increased NAD levels in the patient brain, and resulted in altered cerebral metabolism and decreased markers of inflammation in the fluid surrounding the brain and spinal cord. Moreover, a mild but significant improvement of Parkinson’s disease symptoms was seen in participants who showed substantially increased brain NAD levels, and this correlated with the change in the brain’s energy metabolism pattern. According to the authors Nicotinamide riboside may be useful as a neuroprotective therapy in PD, pending further investigation in a phase II study.
Brakedal B, Dölle C, Riemer F, Ma Y, Nido GS, Skeie GO, Craven AR, Schwarzlmüller T, Brekke N, Diab J, Sverkeli L, Skjeie V, Varhaug K, Tysnes OB, Peng S, Haugarvoll K, Ziegler M, Grüner R, Eidelberg D, Tzoulis C. The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson’s disease. Cell Metab. 2022 Mar 1;34(3):396-407.e6. doi: 10.1016/j.cmet.2022.02.001. PMID: 35235774.Go To Cell Metab