The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson’s disease
Authors: Lars Sverkeli
Kristoffer Haugarvoll
Thomas Schwarzlmüller
Geir Olve Skeie
Alexander R Craven
Joseph Diab
Frank Riemer
Vivian Skjeie
Yilong Ma
Kristin Varhaug
Gonzalo S Nido
Ole-Bjørn Tysnes
Brage Brakedal
Renate Grüner
Shichun Peng
Charalampos Tzoulis
Njål Brekke
Mathias Ziegler
David Eidelberg
Christian Dölle
Journal: Cell Metabolism (2022)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: NAD; NR; disease modifying; experimental therapy; mitochondria
Affiliations: Neuro-SysMed, Department of Neurology, Haukeland University Hospital, Bergen, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway., Neuro-SysMed, Department of Neurology, Haukeland University Hospital, Bergen, Norway; Mohn Medical Imaging and Visualization Centre (MMIV), Department of Radiology, Haukeland University Hospital, Bergen, Norway., Center for Neurosciences, Institute of Molecular Medicine, The Feinstein Institutes for Medical Research, Manhasset, NY, USA., Mohn Medical Imaging and Visualization Centre (MMIV), Department of Radiology, Haukeland University Hospital, Bergen, Norway; Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway; Department of Clinical Engineering, Haukeland University Hospital, Bergen, Norway., Department of Clinical Medicine, University of Bergen, Bergen, Norway; Department of Radiology, Haukeland University Hospital, Bergen, Norway., Mohn Medical Imaging and Visualization Centre (MMIV), Department of Radiology, Haukeland University Hospital, Bergen, Norway., Department of Biomedicine, University of Bergen, Bergen, Norway., Department of Radiology, Haukeland University Hospital, Bergen, Norway., Neuro-SysMed, Department of Neurology, Haukeland University Hospital, Bergen, Norway; Department of Biomedicine, University of Bergen, Bergen, Norway., Neuro-SysMed, Department of Neurology, Haukeland University Hospital, Bergen, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway. Electronic address: .

Abstract:  We conducted a double-blinded phase I clinical trial to establish whether nicotinamide adenine dinucleotide (NAD) replenishment therapy, via oral intake of nicotinamide riboside (NR), is safe, augments cerebral NAD levels, and impacts cerebral metabolism in Parkinson's disease (PD). Thirty newly diagnosed, treatment-naive patients received 1,000 mg NR or placebo for 30 days. NR treatment was well tolerated and led to a significant, but variable, increase in cerebral NAD levels-measured by 31phosphorous magnetic resonance spectroscopy-and related metabolites in the cerebrospinal fluid. NR recipients showing increased brain NAD levels exhibited altered cerebral metabolism, measured by 18fluoro-deoxyglucose positron emission tomography, and this was associated with mild clinical improvement. NR augmented the NAD metabolome and induced transcriptional upregulation of processes related to mitochondrial, lysosomal, and proteasomal function in blood cells and/or skeletal muscle. Furthermore, NR decreased the levels of inflammatory cytokines in serum and cerebrospinal fluid. Our findings nominate NR as a potential neuroprotective therapy for PD, warranting further investigation in larger trials. 

Retracted: No

PubPeer comments:
 **Bradekal et al. The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinsonu2019s disease. Cell Metab VOLUME 34, ISSUE 3, P396-407.E6, MARCH 01, 2022** This phase I clinical trial assesses the effect of nicotinamide riboside (NR), an NAD+ precursor, in a panel (n=15 placebo, n=15 NR) of patients with sporadic (monogenic etiology excluded) Parkinsonu2019s disease (PD). Although NR administration has shown neuroprotective effects in various animal models of neurodegeneration and neuronal damage, it seems strange to me that Bradekal et al. do not discuss the implications of the (few) earlier preclinical clinical Parkinsonu2019s studies that touch NAD+ metabolism (see references below). They also omit the literature on monogenic forms of Parkinsonu2019s disease and the connections to mitochondria therein. In the absence of a hypothesis for a dopamine neuron-specific biological mechanism it is difficult to understand the rationale of this trial. Harrison et al. The histone deacetylase inhibitor nicotinamide exacerbates neurodegeneration in the lactacystin rat model of Parkinson s disease. J Neurochem. 2019 Jan;148(1):136-156. doi: 10.1111 jnc.14599. Epub 2018 Nov 26. PMID: 30269333; PMCID: PMC6487684. Chong et al. Niacin Enhancement for Parkinson s Disease: An Effectiveness Trial. Front Aging Neurosci. 2021 Jun 17;13:667032. doi: 10.3389 fnagi.2021.667032. PMID: 34220485; PMCID: PMC8245760. Wakade C, Chong R, Seamon M, Purohit S, Giri B, Morgan JC. Low-Dose Niacin Supplementation Improves Motor Function in US Veterans with Parkinson s Disease: A Single-Center, Randomized, Placebo-Controlled Trial. Biomedicines. 2021 Dec 10;9(12):1881. doi: 10.3390 biomedicines9121881. PMID: 34944695; PMCID: PMC8698595. **Figure 1D**. The MRS analysis of total NAD NADH in brain shows a very modest mean increase pre (=v1) post (=v2) administration. The increase in mean NAD ATPalpha ratio is visually only 10-15% of the variation in this parameter in both groups combined, and the post-administration values fall within the range of values in the placebo group. How can an effect this small be clinically significant? Moreover, there appears to be a significant baseline difference between the groups (standard deviation and the mean ratio). **Table 2**. The authors do not comment on the NR effect size on UPDRS (Unified Parkinson s Disease Rating Scale) compared to the effect sizes typically seen in the standard levodopa test. The clinical relevance of a novel proposed treatment effect should be judged against that of existing treatments. The data do not support the conclusion  NR-induced increase in cerebral NAD is associated with clinical improvement of PD because the effect on both parameters was minimal. **Figure 3, S4**. These data show increase in the degradation products and metabolites of NR in leukocytes, muscle biopsies and, for Me-2-PY, in CSF, after administration of large doses of NR. Such spectrum of metabolites has been published in several preclinical trials and also in humans and is evidence for the absorption of orally administered NR. However, all main endogenous pyridine nucleotides including NAD+ were unchanged by NR in these data, so the conclusion that u201cNR supplementation augments the NAD metabolomeu201d is misleading. It should read e.g. u201cMetabolite data show that oral NR was absorbed and metabolized in the subjectsu201d. **Figure 4, S6** present data on a number of secreted growth factors and cytokines (see examples in screenshots below), but the authors donu2019t explain if and which of these have been shown to be linked to Parkinsonu2019s disease pathogenesis in either preclinical models or clinically and what are the plasma CSF reference values (if any) for each, i.e. what is the value of the data in this context. For plasma, 2 23 were statistically significantly changed on NR only, 9 23 on placebo only and 8 23 on both. Curiously, for the CSF, 5 20 cytokines were highly statistically significantly changed in the placebo group only, and for all cytokines the magnitude of change was similar or smaller than the difference in the mean baseline between placebo and NR. The changes in the pre post concentration for all of these are very small, for some apparently 10%, and the effects are also only a fraction of the variation for each cytokine, again calling into question the biological significance. In summary, the data do not support the authorsu2019 conclusion that u201cNR modulates biomarkers of inflammation and mitochondrial dysfunctionu201d. ![file] ![file] **Supplementary data**: Iu2019m puzzled by the transcriptomics data analysis and conclusions thereof. The authors have performed pre- and post-treatment RNAseq from muscle biopsies and leukocytes (peripheral blood mononuclear cells) and show that, e.g. for PBMCs, the expression of just 13 genes was statistically significantly changed. Yet the functional enrichment analysis shows 373 statistically significantly (p 0.05) altered gene ontology classes of which a large proportion with very small p value. Let us presume this is a formally correct analysis statistically, but what is the heuristic value of such changes when only 13 genes were robustly changed? Also for the muscle RNAseq the number (58) of significantly changed genes sound very small for meaningful pathway analysis. The conclusion u201cNR therapy induces the expression of mitochondrial, antioxidant, and proteostatic processesu201d seems greatly exaggerated in the light of these data. In the u201cLimitations of the studyu201d section the authors donu2019t comment on this at all but continue to imply that the RNAseq data show changes in mitochondrial function and that these changes in skeletal muscle and leukocytes are relevant for the CNS pathology. I would like experts on bioinformatics to comment on this. The authorsu2019 conclusion (in the first chapter of the discussion) that the trial met its primary outcome parameters seems correct. However, all other conclusions are, in my view, erroneous or misleading in the light of the presented data. That these were not actual preregistered outcome parameters does not justify questionable conclusions. , 
 I would like to draw the authors attention to this very recent paper about the caveats in functional enrichment analyses. The bioinfomaticians who have analyzed the transcriptomics data for Bradekal et al. should outline the details of their analyses, the outcome of which looks very suprising to me given the very small number of genes with significantly altered expression. Wijesooriya K, Jadaan SA, Perera KL, Kaur T, Ziemann M. Urgent need for consistent standards in functional enrichment analysis. PLoS Comput Biol. 2022 Mar 9;18(3):e1009935. doi: 10.1371 journal.pcbi.1009935. PMID: 35263338. ,