Parkinson’s disease

The N-DOSE study will recruit a total of 80 patients in Norway with Parkinson’s Disease. We are actively recruiting patients and the study has started in December 2022.

Contact our study nurse Erika Shear to participate:  erika.veslemoy.sheard@helse-bergen.no

NAD-brain is a pharmacokinetic study of brain NAD replenishment therapy. We will try to determine the change in the blood NAD-metabolome and cerebral NAD levels, following the administration of oral NAD replenishment therapy (NRT) with the following NAD precursors: NR 600mg x 2 daily, NMN 600mg x 2 daily.

We will measure the levels of cerebral NAD levels change by MRI and blood samples reputedly during the trial. A total of 10 healthy individuals (5 men and 5 women) and 10 individuals with PD (5 men and 5 women) will undergo repeated blood sampling and 31P-MRS brain scans during two 20-day periods, each of which will start with 8 days of daily intake of NR 600mg x 2, or NMN 600mg x 2. There will be a washout period of 14 days between the periods so total time is 54 days.

This study has completed recruitment and has started in January 2023.

Principal Investigator: Charalampos Tzoulis

We recently completed the NAD-PARK study, a trial of tolerability and cerebral bioavailability of NAD supplementation therapy with NR in PD (ClinicalTrials.gov: NCT03816020). A total of 30 individuals with newly diagnosed, drug naïve PD were randomized to NR 500 mg x2/day or placebo for 30 days. Link to the scientific publication: The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson’s disease – PubMed (nih.gov)

Principal Investigator: Charalampos Tzoulis

To test the potential of NR as a neuroprotective therapy for PD, we will perform NO-PARK (ClinicalTrials.gov: NCT03568968), a multi-centre, phase II randomized double-blinded clinical trial, comparing NR to placebo in individuals with early stage PD. The central hypothesis of NO-PARK is that oral administration of the NAD precursor NR can boost neuronal NAD levels and ameliorate mitochondrial dysfunction in PD. This, in turn, will rectify neuronal metabolism and inhibit neurodegeneration, resulting in amelioration of clinical symptoms and delayed PD progression.

Individuals with PD (n = 400) are being recruited from centres across all four health regions of Norway. After the initial assessment, participants are randomly assigned to either NR 500 mg x 2/day, or placebo and followed with regular clinical examination, brain imaging and blood tests for a total period of one year. This work aims to discover and develop a therapy with the potential to delay the progression of PD.

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This is an open-label extension study offered only to those who have been part of the NO-PARK trial. The primary objective of this study is to monitor NR use for long term safety. The secondary objective is to monitor long term NR use among PD patients and observe the clinical progression of PD.

More info: Clinical Trial on Safety Issues: Nicotinamide Riboside – Clinical Trials Registry – ICH GCP 

Contact: Head Research Nurse Erika V. Sheard: +47 992 04 028, erika.veslemoy.sheard@helse-bergen.no 

A phase I, randomized, double-blinded, safety trial of high-dose nicotinamide riboside (NR) in Parkinson’s Disease. This short trial took place during the first half of 2022 and has been completed. Data are currently being analyzed and a open-access publication will be made available shortly.

Ethics approval body/ID: REK / 379218

More info: NR-SAFE: Safety of High-dose Nicotinamide Riboside (NR) in Parkinson’s Disease – Full Text View – ClinicalTrials.gov 

Contact: Head Research Nurse Erika V. Sheard: +47 992 04 028, erika.veslemoy.sheard@helse-bergen.no

The heterogeneity of Parkinson ́s disease (PD) is a major obstacle preventing the development of patient-tailored therapies. Here, we aim to stratify PD by identifying and characterizing subgroups of patients with distinct clinical and/or molecular characteristics. Moreover, we aim to develop biomarkers enabling patient stratification in clinical practice.

We will establish a population-based cohort from three centres across Norway and Canada. We will follow the cohort yearly and map the longitudinal change of the molecular landscape in clinically accessible tissues of patients and controls. This will elucidate molecular processes implicated in disease initiation and progression and provide an early, crude clustering of patients according to molecular background. Subsequently, we will apply state-of-the-art computational analyses to perform multidimensional integration of our database and identify biomarkers for molecular stratification of PD. Biomarkers will be validated in other appropriate cohorts and assessed for innovation and commercialization potential. Successful biomarkers will enable patient selection for participation in tailored trials.

The STRAT-PARK study represents a vast clinical endeavour, co-led by Neuro-SysMed PIs Charalampos Tzoulis in Norway and Mandar Jog in Canada. A total of 1,500-2,000 patients and controls will be recruited from three clinical centres: Haukeland University Hospital (HUS) in Bergen, St. Olavs University Hospital in Trondheim and The London Movement Disorders Centre (LMDC), Ontario, Canada. Subjects will be followed at yearly visits with repeated clinical investigations, neuroimaging, blood and cerebrospinal fluid sampling and muscle biopsy. We are particularly interested in the muscle specimens as this is a post mitotic tissue that may express epigenetic, mitochondrial and other molecular markers of disease that are undetectable in blood. As part of our clinical characterization, we will implement novel methods of objective motor assessment using body suits with integrated movement sensors, implemented in collaboration with co-PI Prof. Mandar Jog, who is leading world expert in motion biomechanics for PD and related movement disorders.

Principal Investigator: Laurence Bindoff

In projects led by Prof. Bindoff, we have generated cell and mouse models of impaired mtDNA homeostasis. Impaired mtDNA homeostasis due to POLG mutations results in the same pattern of mitochondrial dysfunction as seen in the brain with aging and multiple CNS disorders including PD, dementia, ALS and MS. We have induced pluripotent stem cells (iPSC) derived neurons and astrocytes from patients with POLG mutations. By co-culturing these, we will construct a cell model of mtDNA damage in the CNS and use it to screen for compounds that reverse/slow the development of mtDNA abnormalities. Outcome measures will include mitochondrial membrane potential and the amount of TFAM (which reflects the amount of mtDNA/cell) in flow-based assays. In addition to iPSC, we have a mouse model with a neurological phenotype and impaired neuronal mtDNA maintenance due to POLG mutations.

Principal Investigator: Charalampos Tzoulis, Inge Jonassen, Kristoffer Haugarvoll

We are currently in the process of establishing the ParkOme database, a multidimensional molecular atlas of PD at unprecedented resolution. We are mapping the molecular landscape of PD in key-regions of fresh-frozen post-mortem brain (n > 1,000). In each bulk-tissue sample, we are constructing a multilayer molecular map combining the genome, DNA-methylation, selected histone modifications, chromatin accessibility, transcriptome and proteome. To mitigate the confounder of cellular heterogeneity, we are conducting additional studies in single cells using a dual strategy: 1) High-throughput single-cell analyses, using our 10X Genomics platform. 2) Pathology-guided single-cell transcriptomics to elucidate the selective neuronal vulnerability to PD-associated pathology such as α-synuclein aggregation, mitochondrial or lysosomal dysfunction.

We will interrogate the ParkOme using a combination of powerful supervised and unsupervised computational analyses (including artificial intelligence). Molecular signatures defining PD and its subclasses will be identified and translated into: 1) Disease models recapitulating subclasses of human disease. These will be developed and characterized in our cell model workflow (section 2.4), 2) Precision biomarkers for patient stratification in clinical practice and 3) Therapeutic targets tailored to the molecular profile of patients. Biomarkers and therapies emerging from this work will trigger clinical studies at the Neuro-SysMed Centre. The ParkOme data analyses are being carried out by the bioinformatics unit of the Tzoulis group in collaboration with Prof. Inge Jonassen and Dr Kjell Petersen at the computational Biology Unit (CBU) of the UiB, and Microsoft.

The “end-users” in our research are the patients with PD, their families and the health services, all of who will directly benefit from a positive study outcome. Patients/families are regularly updated on the progress of our research and are recruited for our studies via our website, popular and social media, and regular open meetings organized in collaboration with the Norwegian PD association. Together with our head of administration, Magnus Alvestad, our PD team ensures that the projects adhere to the Responsible Research and Innovation (RRI) framework laid down by the Research Council of Norway (as outlined by Stilgoe et al.) and have a major focus on inclusion and active user participation.

A user panel has been assembled comprising a representative of the PD patient association (Ellen Tove Lindblom), and convenes regularly with the following agenda: 1) Sharing of latest research findings and potential impacts; 2) Information on upcoming studies and call for participant recruitment; 3) User input on prioritization of research directions and ethics; 4) User-initiated research.

Standardized care pathway for PD diagnosis, follow-up and treatment
The project will develop a care pathway that will become active at first contact with the neurology department at Haukeland. It will be built on interviews with patient, family members, and representatives of all the different disciplines involved at the hospital.
The standard care pathway will be based on evidence, but with an opportunity to adjust for the clinical needs and preferences of individual patients. This approach will optimize healthcare for PD by ensuring every task is done efficiently, and without redundancy, and it will create better opportunities for networking and cooperation within and across healthcare institutions and other related assets including the industry.