Parkinson’s disease

Parkinson’s disease

Parkinson’s disease (PD) affects ~1-2% of the population above the age of 65 and its prevalence increases dramatically as the population ages. Available treatments are purely symptomatic and have no effect on disease progression. Thus, patients confront a future of progressive disability, early institutionalization and premature death. PD has a devastating global socioeconomic impact. In Europe alone, PD affects an estimated 1.2 million people and has a cost of €14 billion per year. Since demographic studies show that patient numbers will continue to grow, effectively doubling by 2040, our failure to make any significant impact to halt or delay disease progression means that PD is now a major challenge to health care and society.

Photo of Charalampos Tzoulis

Head of research

Charalampos Tzoulis

Aims

  • Advance the mechanistic understanding of PD so that new therapeutic targets can be developed
  • Address the disorder’s vast clinical and biological heterogeneity and develop biomarkers enabling patient stratification for tailored therapies
  • Develop and test novel therapies targeting specific molecular pathways

Research

Clinical trials
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. Data analyses are ongoing and the first publication is anticipated during 2020 ir early 2021.

participating centres

  • Haukeland University Hospital

funding

  • The Regional Health Authority of Western Norway
  • Norwegian research council, Neuro- SysMed
  • Haukeland University Hospital

Last updated October 22nd, 2020 at 3:05 pm

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) will be recruited starting 01/10/2020 from eight centres across all four health regions of Norway: 1) Haukeland University Hospital (HUS, leading site), Bergen; 2) Akershus University Hospital (AHUS), Akershus, Oslo; 3) Ullevål University Hospital (UUH), Oslo; 4) Rikshospitalet (RH), Oslo; 5) Drammen Hospital (DH), Drammen; St. Olavs University Hospital (St. Olavs), Trondheim; 6) University Hospital of North Norway (UNN), Tromsø; 7) Dr Karen Herlofson Practice and Arendal Hospital (AH), Arendal; 8) Førde Central Hospital (FCH), Førde

After the initial assessment, participants will be 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.

The primary objective is to determine whether high dose oral NR delays disease progression in PD measured by MDS-UPDRS. Secondary objectives include to determine whether high dose oral NR: a) Improves and/or prevents specific clinical symptoms in PD (e.g. motor and non-motor symptoms, cognitive symptoms, activity of daily living), b) Delays nigrostriatal degeneration (DAT-scan) c) Rectifies NAD metabolism and mitochondrial function, d) Corrects histone hyperacetylation and gene expression profile.

Newsletter 1 (Norwegian)
Newsletter 2 (Norwegian)
Newsletter 3 (Norwegian)
Newsletter 4 (Norwegian)
Newsletter 5 (Norwegian)
Newsletter 6 (Norwegian)

participating centres

  • Haukeland University Hospital, Bergen
  • Akershus University Hospital, Akershus, Oslo
  • Ullevål University Hospital, Oslo
  • Rikshospitalet, Oslo
  • Drammen Hospital, Drammen
  • St. Olavs University Hospital, Trondheim
  • University Hospital of North Norway, Tromsø
  • Dr Karen Herlofson and Arendal Hospital Arendal
  • Førde Central Hospital, Førde

funding

  • The Regional Health Authority of Western Norway
  • Norwegian research council, Neuro- SysMed
  • Haukeland University Hospital
  • Participating hospitals

Last updated June 29th, 2021 at 3:46 pm

Other research

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.

National and international collaborators

We are privileged to have an extensive network of national and international collaborators contributing to our PD research. A few of these are listed below:

Dr. Kari Anne Bjørnarå, Drammen Hospital (DH), Drammen.
Dr Stig Hegrestad, Førde Central Hospital (FCH), Førde.
Dr Karen Herlofson, private practice and Arendal Hospital (AH), Arendal.
Prof. Hallvard Lilleng
, University Hospital of North Norway (UNN), Troms.
Prof. Christofer Lundqvist
, Akershus University Hospital (AHUS), Oslo.
Prof. Mathias Toft
, Oslo University and Ullevål University Hospital.
Prof. Jan Aasly, St. Olavs University Hospital (St. Olavs), Trondheim.

Prof. Kailash Bathia, Sobell Department of Movement Neuroscience at the Institute of Neurology, UCL, Queen Square, London, UK.
Prof. Nikolaos P. Daskalakis, McLean Hospital/Harvard Medical School, Massachusetts, USA.
Prof. Gabor G. Kovacs, currently works at the University of Toronto, Canada.
Dr Lara Kular
, Karolinska Institute, Stockholm.
Prof. Leonidas Stefanis, University of Athens, Greece.

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