Parkinson-noden

Node leader: Charalampos Tzoulis

Charalampos Tzoulis, MD, PhD, is Professor of Neurology and Neurogenetics at the University of Bergen and Haukeland University Hospital, Bergen, Norway. He is also Director for Neurodegeneration at the Neuro-SysMed, and Director of the DECODE-PD, KG Jebsen Centre for Translational Research in Parkinson’s disease. As a clinical neurologist, Professor Tzoulis is an internationally recognised expert on movement disorders and neurodegeneration. His work has made key scientific contributions to the field, especially pertaining to the role of mitochondrial dysfunction and NAD-metabolism in Parkinson’s disease. Professor Tzoulis has pioneered trials of NAD-replenishment with NR for degenerative parkinsonisms and is currently a global leader in this field.

Key node partner: Mandar S. Jog

Professor Mandar S. Jog, MD, FRCPC, is a leader in research and innovation in the fields of movement disorders and neurodegeneration, and is Director of the London Movement Disorders Centre, Ontario, Canada. He is the co-PI of the STRAT-PARK initiative, and Head of the study arm in Canada.

The PD Node is globally acknowledged for implementing full-cycle translation – from the laboratory to the bedside and back – and for being world leaders in NAD-replenishment therapy for neurodegeneration. Their work has been acclaimed by the field and has constituted the foundation for multiple clinical trials across neurodegenerative diseases, at the Centre and across the globe.

Node activities

Basic and translational research at the PD Node has nominated mitochondrial function and NAD metabolism as promising therapeutic targets primarily for PD and, by extension, other neurodegenerative and neuroinflammatory disorders, including Alzheimer’s disease, ALS, and MS. Inspired by these findings, the PD Node conducts multiple clinical trials of NAD-replenishment therapy, with a broad range of
objectives ranging from establishing safety and pharmacokinetic profiles, to determining the optimal biological dose for brain diseases, and testing efficacy
in delaying or preventing PD and other parkinsonisms. Moreover, this research has catalysed several other NAD-replenishment trials at the Centre, targeting Alzheimer’s disease, ALS, and MS (see respective sections). In addition, the PD Node is working actively on setting the foundations for individualised medicine in PD, by running an international initiative aiming to stratify PD according to underlying molecular mechanisms and develop biomarkers for patient selection for tailored therapies. Finally, the PD Node runs world-class translational research aiming to identify novel therapeutic targets and candidate therapies for PD and emerging subtypes thereof.

During 2023, the PD Node made key advances in their clinical research projects, which include six clinical trials, and one prospective cohort study:

• The NR-SAFE study is a phase I randomised, double blinded trial, with the primary objective to assess the safety and tolerability of high dose NR therapy (3000 mg daily) in PD.
• The N-DOSE study is a phase II randomised, double blinded dose-optimisation trial of NR in PD. The primary objective is to determine the optimal biological dose of NR for PD and other brain diseases.
• The NADbrain study is a phase I pharmacokinetic study, aiming to assess the blood and brain NAD kinetics following the consumption of different NADprecursors. Based on the results of NADbrain, the optimal dosing frequency of NAD replenishment therapy will be determined.
• The NO-PARK study is a phase-III randomised, double-blind, multicentre clinical trial, with the primary objective to assess the efficacy of NR as a neuroprotective therapy, delaying the rate of neurodegeneration and clinical disease progression in PD.
• The NO-PARK extension study is a phase-III openlabel, multicentre clinical trial, with the primary objective of assessing the long-term safety of NR therapy in PD.
• The NADAPT study is a phase-II randomised, doubleblind, multicentre trial, aiming to assess the efficacy of NR as a neuroprotective, disease-modifying therapy for atypical parkinsonism, including progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and corticobasal syndrome (CBS).
• The STRAT-PARK initiative is a longitudinal population-based multicentre cohort study aiming to identify biological subtypes of PD and to develop biomarkers enabling patient stratification in clinical practice.

Selected publications from 2023:

1. Flønes IH, Toker L, Sandnes DA, Lura N, Shadad O, Nyland H, Sandnes DA, Fernandez-Vizarra E, Painous C, Pérez-Soriano A, Compta Y, Molina-Porcel L, Alves GW, Tysnes OB, Dölle C, Nido GS, Tzoulis C. Mitochondrial complex I deficiency stratifies idiopathic Parkinson’s disease. Accepted, Nature Communications, Dec 2023.
2. Berven H, Kverneng S, Sheard E, Søgnen M, Af Geijerstam S, Haugarvoll K, Skeie, GO, Dölle C, Tzoulis C. NR-SAFE: a randomized, double-blind safety trial of high dose nicotinamide riboside in Parkinson’s disease. Nat Commun.
   2023 Nov 28;14(1):7793.
3. Neufeld LM, Ho E, Obeid R, Tzoulis C, Green M, Huber LG, Stout M, Griffiths JC. Advancing nutrition science to meet evolving global health needs. Eur J Nutr. 2023 Dec;62(Suppl 1):1-16
4. Gaare JJ, Brügger K, Nido GS, Tzoulis C. DNA methylation age acceleration is not associated with age of onset in Parkinson disease. Mov Disord. 2023 Nov;38(11):2064-2071.
5. Dick F, Gard J, and Tzoulis C. Neuronal loss drives differentially expressed protein-pathways in the PSP globus pallidus. Clin Transl Med. 2023 Jul;13(7):e1280.
6. Toker L, Nido GS, and Tzoulis C. Not every estimate counts. Genome Med. 2023 Jun 7;15(1):41.
7. Gaare JJ, Dölle C, Brakedal B, Brügger K, Haugarvoll K, Nido GS, Tzoulis C. Nicotinamide riboside supplementation is not associated with altered methylation homeostasis in Parkinson`s disease. iScience. 2023 Feb 27;26(3):106278.
8. Dick F, Tysnes OB, Alves GW, Nido GS, and Tzoulis C. Altered transcriptome-proteome coupling indicates aberrant proteostasis in Parkinson’s disease. iScience. 2023 Jan 4;26(2):105925.