Research in Parkinson’s Disease

Biomarkers and tailored therapies for Parkinson’s disease

PI: Charalampos Tzoulis

Professor Tzoulis is an expert in neurodegeneration, neurogenetics and mitochondrial medicine. His research group, “Neuromics” (http://www.neuromics.org/#research), comprises more than 20 members and integrates molecular, computational and clinical neuroscience, with the overarching aim to decipher the role of mitochondrial dysfunction in Parkinson’s disease (PD), and develop novel biomarkers for patient stratification and tailored therapies.

Charalampos Tzoulis is Professor of Neurology and Neurodegeneration and Consultant of Neurology at the University of Bergen and Haukeland University Hospital, Norway. He is the Director of the Neuromics Research Group, Head of Neurodegeneration Research and Vice Centre Director at the Neuro-SysMed Centre of Excellence for Clinical Research in Neurological Diseases.

During 2020, Professor Tzoulis’ group made keyadvances in their research projects: The NAD-PARK study, a phase-I randomized trial of NADsupplementation therapy with nicotinamide riboside (NR) in PD is completed and shows promising results, including conclusive evidence that NR penetrates the brain and impacts the cerebral metabolic profile.

The NO-PARK study, a phase-II randomized trial of NR in PD, is initiated in four out of seven centres and has already recruited nearly 100 patients. When completed, this study will provide a definite answer to whether NRtherapy can delay the progression of PD.

The STRAT-PARK initiative was also initiated in 2020. STRAT-PARK is a cohort study aiming to stratify PD according to clinical and biological variation, provide mechanistic insight into disease subtypes, and develop clinical biomarkers for patient stratification. So far, approximately 15 patients and controls have been recruited in Bergen, and the project is now starting at partner-centres in Trondheim and London Ontario, Canada.

The ParkOme initiative aims to map the multi-omic profile of PD at the individual and single-cell level. So far, the group has analyzed the genome, DNAmethylome, histone-acetylome (for selected markers), transcriptome, and proteome, for ~100 brain samples. In addition, they mapped the transcriptome in a total of ~1,000 brain samples. Analyses of the ParkOme data have generated novel insights into the genetics and gene-expression profile of PD. Moreover, in the first histone-acetylome-wide study in PD, the group showed that the brain of individuals with PD is characterized by a profound, genome-wide dysregulation of H3K27 acetylation and decoupling from transcription.

Single-cell transcriptomics, using the dedicated 10X-Chromium platform, are also well-underway. The methodology has been established and the data from the first pilot experiments in blood cells and nuclei from brain tissue are currently being analyzed. The group is also experimenting with the potential of long-read sequencing to map “obscure” areas of the genome, assess DNA-methylation natively, and evaluate RNAsplicing. The first samples have been analyzed and the group’s bioinformatics team is currently establishing the analyses pipelines.

Developing and testing mitochondrial therapies as well as biomarkers for patient selection is a central aim of the Neuro-SysMed work led by Professor Tzoulis. A detailed description of the ongoing and planned work can be found in the section for Parkinson’s disease.

Selected Key Publications

1. Haukeland University Hospital. NAD-PARK: A Double-blinded Randomized Pilot Trial of NAD-supplementation in Drug naïve Parkinson’s Disease [Internet]. clinicaltrials.gov; 2020 Feb. Report No.: NCT03816020. Available from: https://clinicaltrials. gov/ct2/show/NCT03816020
2. Haukeland University Hospital. A Randomized Controlled Trial of Nicotinamide Supplementation in Early Parkinson’s Disease: the NOPARK Study [Internet]. clinicaltrials.gov; 2020 Jun. Report No.: NCT03568968. Available from: https://clinicaltrials.gov/ct2/show/NCT03568968
3. Gaare JJ, Nido G, Dölle C, Sztromwasser P, Alves G, Tysnes O-B, et al. Meta-analysis of whole-exome sequencing data from two independent cohorts finds no evidence for rare variant enrichment in Parkinson disease associated loci. PLoS One. 2020;15:e0239824.
4. Nido GS, Dick F, Toker L, Petersen K, Alves G, Tysnes O-B, et al. Common gene expression signatures in Parkinson’s disease are driven by changes in cell composition. Acta Neuropathol Commun. 2020;8:55.
5. Dick F, Nido GS, Alves GW, Tysnes O-B, Nilsen GH, Dölle C, et al. Differential transcript usage in the Parkinson’s disease brain. PLoS Genet [Internet]. 2020 [cited 2020 Nov 29];16. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660910/
6. Dick F, Tysnes O-B, Alves GW, Nido GS, Tzoulis C. Altered transcriptome-proteome coupling indicates aberrant proteostasis in Parkinson’s disease. medRxiv. Cold Spring Harbor Laboratory Press; 2021;2021.03.18.21253875.
7. Toker L, Tran GT, Sundaresan J, Tysnes O-B, Alves G, Haugarvoll K, et al. Genome-wide dysregulation of histone acetylation in the Parkinson’s disease brain. bioRxiv. 2020;785550.
8. Gaare JJ, Nido GS, Sztromwasser P, Knappskog PM, Dahl O, Lund-Johansen M, Alves G, Tysnes OB, Johansson S, Haugarvoll K, Tzoulis C*. No evidence for rare TRAP1 mutations influencing the risk of idiopathic Parkinson’s disease. Brain. 2018 Jan 24.
9. Flønes I, Fernandez-Vizarra E, Lykouri M, Brakedal B, Skeie GO, Miletic H, Lilleng PK, Alves G, Tysnes OB, Haugarvoll H, Dölle C, Zeviani M and Tzoulis C*. Widespread neuronal complex I deficiency in Parkinson’s disease. Acta Neuropathol. 2017 Dec 21.
10. Nido G, Dölle C, Flønes I, Alves G, Tysnes OB, Haugarvoll H and Tzoulis C*. Ultra-deep mapping of neuronal mitochondrial deletions in Parkinson’s disease. Neurobiol Aging. 2017 Dec 8;63:120-127.
11. Brakedal B, Flønes I, Dölle C, Torkildsen Ø, Assmus J, Engeland A, Haugarvoll H and Tzoulis C*. Glitazone use associated with reduced risk of Parkinson’s disease. Movement Disorders, Mov Disord. 2017 Sep 1.
12. Dölle C, Flønes I, Nido G, Miletic H, Kristoffersen S, Lilleng KP, Larsen JP, Tysness OB, Haugarvoll K, Bindoff LA, and Tzoulis C*. Defective mitochondrial DNA homeostasis in the dopaminergic substantia nigra of patients with Parkinson’s disease. Nat Commun. 2016 Nov 22;7:13548.

Last updated april 15th, 2021 at 11:31 am

Motion biomechanics and biomarkers in Parkinson’s disease

PI: Mandar Jog

Mandar S. Jog, MD, FRCPC, is the Director of the National Parkinson Foundation Centre of Excellence in the Parkinson Disease and Movement Disorders Program at the London Health Sciences Centre, Professor of Neurology at Western University, both in London, Ontario, Canada and one of the PIs of the Neuro-SysMed centre. He is also one of the Associate Directors of the Lawson Health Research Institute.

Professor Jog is an internationally renowned expert in movement disorders, including dystonia, tremor, ataxia and Parkinson’s disease, and runs a state-of-theart centre dedicated to the diagnosis and treatment of patients with these common and debilitating disorders. He is also widely acknowledged as a leader in research and innovation in the fields of movement disorders and neurodegeneration. Professor Jog’s early research advanced the understanding of how neuronal networks function in animal models. He then transferred these findings to the clinic and translated them into novel therapeutic approaches as well as smart technologies to objectify clinical assessment and treatment of patients. His seminal scientific work has made outstanding contributions to improving the care and quality of life of patients with movement disorders.

Prominent examples of Professor Jog’s work include using spinal cord stimulation for gait dysfunction treatment in Parkinson’s disease, with impressive results.
In another major scientific and clinical contribution, Professor Jog and his team established innovative machine learning algorithms improving the outcome of injection therapy for patients with cervical dystonia and tremor. Professor Jog’s lab has recently discovered that brain injections with botulinum toxin (a drug that is already in clinical use for other indications) hold potential as a novel treatment alternative for patients with Parkinson’s disease and potentially other movement disorders. Professor Jog’s work has led to substantial innovation and commercial value generation, including the establishment of several start-up businesses.

Professor Jog has a key role in the design and implementation of clinical cohort studies as well as randomized clinical trials for PD, such as the ongoing NO-PARK, NAD-PARK and STRAT-PARK studies. These trials employ innovative approaches for objective patient assessment, which are enabled by technologies developed by Professor Jog’s lab, such as wireless whole-body wearable sensors with accompanying computational algorithms.

Selected Key Publications

1. Shahtalebi S. et al. PHTNet: Characterization and Deep Mining of Involuntary Pathological Hand Tremor using Recurrent Neural Network Models. Sci Rep. 2020 Feb 10;10(1):2195. PMID: 32042111
2. Hui D. et al. Assessing the effect of current steering on the total electrical energy delivered and ambulation in Parkinson’s disease. Sci Rep. 2020;10(1):8256. 2020 May 19. doi:10.1038/s41598-020-64250-7
3. Jog M. et al. Tolerability and Efficacy of Customized IncobotulinumtoxinA Injections for Essential Tremor: A Randomized, Double-Blind, Placebo-Controlled Study. Toxins (Basel). 2020 Dec 20;12(12):807. doi: 10.3390/toxins12120807. PMID: 33419261; PMCID: PMC7766785.
4. Samotus O. et al. Standardized algorithm for muscle selection and dosing of botulinum toxin for Parkinson tremor using kinematic analysis. Ther Adv Neurol Disord. 2020 Sep 23;13:1756286420954083. doi:10.1177/1756286420954083. PMID: 33014139; PMCID: PMC7517980.
5. Samotus O. et al. Spinal cord stimulation therapy for gait dysfunction in progressive supranuclear palsy patients. J Neurol. 2020 Oct 3. doi: 10.1007/s00415-020-10233-7. Epub ahead of print. PMID: 33011852
6. Knowles T. et al. A Comparison of Speech Amplification and Personal Communication Devices for Hypophonia. J Speech Lang Hear Res. 2020 Aug 10;63(8):2695-2712. doi: 10.1044/2020_JSLHR-20-00085. Epub 2020 Aug 5. PMID: 32755496.
7. Samotus O. et al. Spinal Cord Stimulation Therapy for Gait Dysfunction in Two Corticobasal Syndrome Patients. Can J Neurol Sci. 2020 Jul 10:1-3. doi: 10.1017/cjn.2020.143. Epub ahead of print. PMID: 32646537.
8. Samotus O. et al. Long-term update of the effect of spinal cord stimulation in advanced Parkinson’s disease patients. Brain Stimul. 2020 Sep-Oct;13(5):1196-1197. doi: 10.1016/j.brs.2020.06.004. Epub 2020 Jun 3. PMID: 32504828.
9. Adams S. et al. Efficacy and Acceptance of a Lombardresponse Device for Hypophonia in Parkinson’s Disease. Can J Neurol Sci. 2020 Sep;47(5):634-641. doi: 10.1017/cjn.2020.90. Epub 2020 May 11. PMID: 32389143.
10. Khosravi M. et al. Intraoperative Localization of STN During DBS Surgery Using a Data-Driven Model. IEEE J Transl Eng Health Med. 2020;8:2500309. Published 2020 Jan 30. doi:10.1109/JTEHM.2020.2969152
11. Mittal SO. et al. Novel Botulinum Toxin Injection Protocols for Parkinson Tremor and Essential Tremor – the Yale Technique and Sensor-Based Kinematics Procedure for Safe and Effective Treatment. Tremor Other Hyperkinet Mov (N Y). 2020 Dec 31;10:61. doi: 10.5334/tohm.582. PMID: 33442486; PMCID: PMC7774361.
12. Page AD. et al. Exploring the Psychosocial Impact of Botulinum Toxin Type A Injections for Individuals With Oromandibular Dystonia: A Qualitative Study of Patients’ Experiences. Am J Speech Lang Pathol. 2021 Feb 25:1-15. doi: 10.1044/2020_AJSLP-20-00124. Epub ahead of print. PMID: 33647215.

Last updated april 15th, 2021 at 12:01 pm

Therapeutic target validation and novel drug identification

PI: Aurora Martinez

Aurora Martinez leads the Martinez lab which is part of the Biorecognition Unit at the Department of Biomedicine, UiB. This group investigates the molecular basis of disease, notably in inborn errors of metabolism with neurological impairment such as parkinsonisms, phenylketonuria and porphyria.

A key focus in the lab is studies of proteins involved in dopamine synthesis and transport. The projects combine biochemical, biophysical and structural studies of isolated proteins and protein complexes with assays in cellular and animal models, elucidating the pathogenic role of dysfunctional biomolecular interactions and loss of protein stability on genotypecorrelations and gain-of-function comorbidities. The group is also increasing its research- and innovation focus on drug discovery and development, and contributes to Nor-Openscreen and EU-Openscreen
(Eric and Drive) infrastructure projects for highcapacity screening, chemical biology and drug design, focusing on low molecular weight drug candidates (figure 1). Furthermore, the Martinez lab investigates the characterization and optimization of interactions with selected proteins, notably tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of dopamine, for enzyme stabilization and improved cellular uptake, aiming at development of enzyme replacement therapies (see key publications to the right).

Within the Neuro-SysMed centre, the research of the group is integrated in translational projects with clinical partner groups, focusing on molecular mechanisms involved in the development and progression of Parkinson’s disease, and on the concomitant discovery and evaluation of specific mechanistic-based therapies. The use of highthroughput screening methods and facilities are essential in these projects. Towards this end, the Martinez lab has initiated projects to understand and develop therapies to correct (i) dysfunctional proteinprotein interactions involved in dopamine synthesis and vesicular transport, (ii) proteostasis dysregulation, and (iii) neuronal respiratory complex I deficiency and impaired mitochondrial DNA homeostasis, collaborating with Neuro-SysMed partners Trond Riise, Charalampos Tzoulis and Laurence A. Bindoff.

Selected Key Publications

1. Aubi O, Prestegård KS, Jung-KC K, Shi TS, Ying M, Grindheim AK, Scherer T, Ulvik A, McCann A, Spriet E, Thöny B, Martinez A (2021). The Pah-R261Q mouse reveals oxidative stress associated with amyloid-like hepatic aggregation of mutant phenylalanine hydroxylase. Nat. Commun. DOI: 10.1038/s41467-021-22107-1
2. Bezem MT, Johannessen FG, Kråkenes TA, Sailor MJ, Martinez A. (2021) Relevance of electrostatics for the interaction of tyrosine hydroxylase with porous silicon nanoparticles. Mol Pharm. 18:976-985. DOI: 10.1021/acs.molpharmaceut.0c00960.
3. Flydal MI, Kråkenes TA, Tai MDS, Tran MPA, Teigen K, Martinez A. (2020) Levalbuterol lowers the feedback inhibition by dopamine and delays misfolding and aggregation in tyrosine hydroxylase. Biochimie S0300-9084(20)30322-9. DOI: 10.1016/j.biochi.2020.12.002.
4. Støve SI, Flydal MI, Hausvik E, Underhaug J, Martinez A. Chapter 15 – Differential scanning fluorimetry in the screening and validation of pharmacological chaperones for soluble and membrane proteins. In: Protein Homeostasis Diseases (ed Pey AL). Academic Press (2020). https://doi.org/10.1016/B978-0-12-819132-3.00015-4

Systems bioinformatics

PI: Inge Jonassen

Inge Jonassen has broad expertise within bioinformatics with a focus on development and application of informatics methods for the analysis of molecular biology data. His research interests include methods for the automatic discovery of patterns, data analysis, algorithms and machine learning applied on molecular biology data, and he is Director of the Computational Biology Unit, CBU, a leading hub of bioinformatics research spanning both the basic and applied fields.

In context of Neuro-SysMed, the Jonassen group is working with Tzoulis and colleagues on development and application of methods to analyze omics data for PD patients and controls. The work has benefited from earlier work in the Jonassen group developing novel methods for gene expression deconvolution resulting in the method Deblender, developed in collaboration with the Akslen and Wik groups at the Centre for Cancer Biomarkers (CCBIO), UiB, published in BMC Bioinformatics in 2018. In a later publication in collaboration with Tzoulis and colleagues, the group showed the importance of taking tissue composition into account in analysis of gene expression data, showing that previous expression signatures developed for Parkinson’s disease to a large extent were driven by alterations in cell composition (published in Acta Neuro Comm in 2020).

Further work involve co-analysis of proteomics and transcriptomics level data from the same patients – work that is on-going and not yet published. Jonassen is planning recruitment of a post-doctoral researcher to work between Jonassen/CBU and the Tzoulis group on applying methods for multi-omics analysis on data from PD patients and controls, and an internal proposal for work in this direction has been authored by Jonassen and Kjell Petersen at CBU.

Through his engagement in the pan-European bioinformatics infrastructure ELIXIR and as Head of ELIXIR Norway, Jonassen has also worked to establish infrastructure for controlled sharing of molecular level and clinical data supporting medical biomedical research findings. As one of the first in Europe, ELIXIR Norway is ready to operate a node of the federated European Genome-phenome Archive – enabling controlled sharing of data that due to consent or other legal constraints cannot be deposited in international repositories. Through ELIXIR Norway, the Jonassen group has also worked to provide solutions for analyzing human molecular level data as well as phenotypic data in secure environments and to establish better support for data management and
FAIR data sharing for Norwegian life science research projects.

Selected Key Publications

1. X Zhang, I Jonassen, RASflow: an RNA-Seq analysis workflow with Snakemake, BMC bioinformatics 21 (1), 1-9
2. Gonzalo S Nido, Fiona Dick, Lilah Toker, Kjell Petersen, Guido Alves, Ole-Bjørn Tysnes, Inge Jonassen, Kristoffer Haugarvoll, Charalampos Tzoulis, Common gene expression signatures in Parkinson’s disease are driven by changes in cell composition, Acta neuropathologica communications 8, 1-14
3. Mitra Parissa Barzine, Karlis Freivalds, James C Wright, Mārtiņš Opmanis, Darta Rituma, Fatemeh Zamanzad Ghavidel, Andrew F Jarnuczak, Edgars Celms, Kārlis Čerāns, Inge Jonassen, Lelde Lace, Juan Antonio Vizcaíno, Jyoti Sharma Choudhary, Alvis Brazma, Juris Viksna, Using Deep Learning to Extrapolate Protein Expression Measurements, Proteomics 20 (21-22)
4. Xiaokang Zhang, Inge Jonassen, An Ensemble Feature Selection Framework Integrating Stability, 2019 IEEE International Conference on Bioinformatics and Biomedicine (BIBM), 2792-2798

Home care, digital phenotyping and nursing home medicine

PI: Bettina Husebø

The Centre for Elderly and Nursing Home Medicine (SEFAS) is a part of the Department of Global Public Health and Primary Care at the Faculty of Medicine, University of Bergen. The centre is led by Professor Bettina Husebø, established in collaboration with the GC Rieber Foundations and financed by the Norwegian Government. The group’s focus is research, teaching and implementation of research results based on national and international multidisciplinary collaboration.

SEFAS is a part of the Section for Elderly Medicine, Social Pharmacy and Interprofessional Work-Place Learning (FEST). SEFAS staff currently counts five permanent positions funded by a grant from the Norwegian Directorate of Health, with administrative and research functions including co-research and user representation. The remaining positions are related to ongoing projects, constituting a vibrant research environment with a total of five postdoctoral researchers, nine PhD candidates, and three master students, in 2020. Most positions are financed by the Research Council of Norway (RCN).

SEFAS is directly linked to Neuro-SysMed by the DIGI.PARK project. Other national collaboration partners include the Alrek Health Cluster, the municipality of Bergen, Western Norway University of Applied Sciences, the Centre for International Health, and the Norwegian Smart Care Cluster, among others. The group has ongoing international collaboration with researchers from USA (Yale University; Harvard Medical School, McLean Hospital), the Netherlands (University of Leiden), Austria (Joanneum Research, Graz), Romania (Politehnica University of Bucharest),and Japan (Tohoku University), among others. In 2020, this resulted in three applications for project funding led by SEFAS and submitted to EU Horizon 2020, ERC, and the RCN.

Despite the COVID-19 related restrictions, SEFAS held high activity levels during 2020; their annual report is available at www.uib.no/sefas. SEFAS also figured among the top 10 from the faculty of Medicine, UiB, most frequently featured in media communications in 2020 (Faculty’s Annual Communications Report). Further, two international students have won awards after their stay in Bergen and publications based on COSMOS data. Erika Ito, Tohoku University, investigated the impact of psychotropic drug use on quality of life in people with dementia. Paulien van
Dam, University of Leiden, investigated analgesic treatment and quality of life in this population. As a cultural highlight, the group contributed to the Bergen Festival’s opening day with the Bergen International Summit. The focus of this day was on culture, activity, and health in elderly care.

SEFAS currently has two major ongoing research projects. LIVE@Home.Path is a mixed-method stepped wedge randomized controlled trial including home dwelling persons with dementia and their informal caregivers (dyads) in Bergen, Bærum and Kristiansand. Funded by the RCN, the trial investigates the impact of a complex intervention to improve resource utilization and caregiver burden.

In the initial phase of the COVID-19 restrictions, SEFAS nested a new study, PAN.DEM (PANdemic in people with DEMentia) into the ongoing LIVE@Home.Path trial and interviewed caregivers on their perceptions of the situation and how the pandemic influences the health care service, neuropsychiatric symptoms, use of assistive technology, and social contact. Several articles are published or in preparation, and the research group is actively related to the newly established Pandemic Centre at UiB. Results were also presented digitally at the Technology in Psychiatry Summit, McLean Hospital (28.-30.10.2020):www.vimeo.com/470492759 2020 also marks the initial steps of the ActiveAgeing approach, a collaborative effort between SEFAS, Neuro-SysMed, the GC Rieber Foundations and Helgetun Living Lab. Helgetun is a senior housing project aiming to promote mental, social and physical activity, creativity and healthy ageing, consisting of 31 apartments in rural surroundings near Bergen. ActiveAgeing will investigate the current possibilities for enhanced activity and quality of life in healthy elderly and people with e.g. Parkinson’s disease (PD). Using innovative home-based sensors, the ActiveAgeing project will produce big data to develop AI-based algorithms that can describe and predict function and activity in elderly people. ActiveAgeing also aims to determine how smart housing and health systems can be used to promote healthy ageing and empower individuals to stay active in health and disease. In DIGI.PARK, the group investigates the use of wearable and sensor technology to determine symptom trajectories and prognosis in people with PD, working closely with NeuroSysMed and including participants in parallel with the planned STRAT-PARK study. Collaboration with the Group for Artificial Intelligence, UiB, and the upcoming Incubator, UiB, is established.

Selected Key Publications

1. Husebo, BS, Kerns, RD, Han, L, et al. Pain, Complex Chronic Conditions and Potential Inappropriate Medication in People with Dementia. Lessons Learnt for Pain Treatment Plans Utilizing Data from the Veteran Health Administration. Brain Sci 2021;11:86.
2. Gedde, MH, Husebo, BS, Erdal, A, et al. Access to and interest in assistive technology for home-dwelling people with dementia during the COVID-19 pandemic (PAN.DEM), Int Rev Psychiatry
2021;1-8.
3. Wagatsuma, S, Yamaguchi, T, Berge, LI, et al. How, Why and Where it Hurts—Breaking Down Pain Syndrome Among Nursing Home Patients With Dementia: A Cross-Sectional Analysis of the COSMOS Trial, Pain Manag Nursing 2021
4. van Dam, PH, Achterberg, WP, Husebo, BS, et al. Does paracetamol improve quality of life, discomfort, pain and neuropsychiatric symptoms in persons with advanced dementia living in long-term care facilities? A randomised double-blind placebo-controlled crossover (Q-PID) trial. BMCMed 2020;18:407.
5. Jong‐Schmit, BEM, Poortvliet, RKE, Böhringer, S, et al. Blood Pressure, Antihypertensive Medication and Neuropsychiatric Symptoms in Older People with Dementia: The COSMOS Study. Int J Geriatr Psychiatry 2021;36:46-53.
6. Vroomen JLMN, Kjellstadli C, Allore HG, et al. Reform influences location of death: Interrupted time-series analysis on older adults and persons with dementia. PLoS ONE 2020;15:e0241132.
7. Gedde, MH, Husebo, BS, Mannseth, J, et al. Less Is More: The Impact of Deprescribing Psychotropic Drugs on Behavioral and Psychological Symptoms and Daily Functioning in Nursing Home Patients. Results From the Cluster-Randomized Controlled COSMOS Trial. Am J Geriatr Psychiatry 2021;29:304-15.
8. Husebo, BS, Berge, LI. Intensive Medicine and Nursing Home Care in Times of SARS CoV-2: A Norwegian Perspective. Am J Geriatr Psychiatry 2020;28:792-3.
9. Husebo, BS, Allore, H, Achterberg, WP, et al. LIVE@Home.Path- Innovating the Clinical Pathway for Home-Dwelling Peoplewith Dementia and Their Caregivers: Study Protocol for a
Mixed-Method, Stepped-Wedge, Randomized Controlled Trial. Trials 2020;21:510.
10. Kjellstadli, C, Allore, H, Husebo, BS, et al. General practitioners’ provision of end-of-life care and associations with dying at home: a registry-based longitudinal study. Family Practice
2020; 37:340-7.
11. Ito, E, Berge, LI, Husebo, BS, et al. The Negative Impact of Psychotropic Drug Use on Quality of Life in Nursing Home Patients at Different Stages of Dementia: Cross-Sectional Analyses from the COSMOS Trial. J Am Med Dir Assoc 2020;21:1623-28.
12. Eriksen, S, Grov, EK, Lichtwarck, B, et al. Palliative treatment and care for dying nursing home patients with COVID-19. Tidsskr Nor Laegeforen 2020;23:140(8).

Stem-cell derived disease models

PI: Laurence Bindoff

The MMN group performs clinical and basic research primarily focussed on mitochondria and their role in disease. To this end, the group studies primary mitochondrial diseases such as those caused by mutations in POLG and mitochondrial DNA, and mitochondrial dysfunction in other diseases, e.g. Parkinson’s and other neurodegenerative disorders.

Whilst the link between primary mitochondrial defects and disease is clear, multiple lines of evidence link mitochondrial dysfunction and neurodegeneration so that no one mechanism prevails. This suggests that either mitochondrial dysfunction is a “common” final pathway for all forms of neurodegeneration, or that mitochondrial promiscuity, i.e. their involvement in almost any cellular process, means that these changes are secondary, and are either not involved in the disease process or only partly so.

The group has established a robust model system to investigate disease related changes in mitochondrial function. Reprogramming patient fibroblasts to induced pluripotent stem cells (iPSC) provides a substrate from which any cell type/tissue can be generated. For example, the group has generated neuronal lineages including dopaminergic neurones, motor neurones, glial cells such as astrocytes and oligodendrocytes and mesenchymal cells such as cardiomyocytes. MMN’s role in Neuro-SysMed is to provide this expertise in generating stem cell models in appropriate cell lineages (e.g. neuronal or glial). MNN is now extending its work into generating complex structures called organoids. The group has successfully generated cortical organoids (“brains in dish”) from patients with mitochondrial disease and controls.

The group’s studies with stem cell models show that it is possible to replicate findings such as respiratory chain complex I deficiency and mtDNA depletion in neural stem cells (NSC), progenitors committed to the neuronal lineage, but with retained ability to divide. The group published their findings in NSC with POLG mutations in EMBO Molecular Medicine. They have also submitted work showing that astrocytes from POLG patients also manifest a phenotype, but more interestingly, they become toxic for neurones. Astrocyte involvement in neurodegeneration is an exciting new area and these groundbreaking findings suggest that mitochondrial dysfunction may be a common stimulus driving astrocyte conversion from normal to the toxic A1 type that damage and potentially kills neurones. This work is under review. Lastly, the group has been looking at various candidate compounds for treating mitochondrial dysfunction. They found that N-acetylcysteine amide was able to reduce oxidative stress and improve mitochondrial function in iPSC derived dopaminergic neurones. This was published in Experimental Neurology.

The MMN group has also generated cardiomyocytes from iPSC and done this in a 96 well format. This method was published in Scientific Reports. The importance of this work is that it confirms our ability to generate a wide range of differentiated cell types, something that can be important in the future.

The group’s recent clinical work has focussed on greater understanding of POLG related disease and the elaboration of biomarkers with which to diagnose and follow mitochondrial diseases. studies of POLG related disease have used the POLG registry that now contains >180 patients, both living and dead. This unique material has allowed them to generate a simplified classification of POLG related disease, to investigate the impact of gender and pregnancy on disease course and outcome, and to study mental health and quality of life in affected individuals. Intriguingly, they found clear gender differences: males tended to present and die earlier than females and onset and worsening in females was associated with onset of menarche and pregnancy.

The search for biomarkers has focussed on two areas: novel mitochondrial disease markers and studies to investigate how best to use known biomarkers. Neurofilament light chain (NF-L) released by damage to neurones has been used as a marker to follow disease progression in multiple sclerosis. The group asked the question whether it could be useful also in mitochondrial disease, and performed a study comparing it with other known mitochondrial biomarkers, namely FGF21 and GDF15. In their pilot study, they showed that NF-L could be useful in detecting central nervous system involvement in patients with systemic mitochondrial disease. In those with disease restricted to skeletal muscle, FGF21 and GDF15 were more sensitive. They also investigated the detection of mtDNA deletions and showed that urine sediment cells were an appropriate source of DNA, thus obviating the need for muscle biopsy in these patients.

Selected Key Publications

1. Hytönen MK, Sarviaho R, Jackson CB, Syrjä P, Jokinen T, Matiasek K, Rosati M, Quintero I, Arumilli M, Donner J, Anttila M, Bindoff LA, Suomalainen A, Lohi H. In-frame deletion in canine PITRM1 is associated with a severe early-onset epilepsy, mitochondrial dysfunction and neurodegeneration. Hum Genet. Under review. This work is a follow up on the human studies performed with Professor Zeviani (Padua) and confirms that mitochondria are involved in amyloid beta metabolism.
2. Liang KX, Vatne GH, Kristiansen CK, Levglevskyi O, Kondratskaya E, Glover JC, Chen A, Sullivan GJ, Bindoff LA. N-acetylcysteine amide ameliorates mitochondrial dysfunction and reduces oxidative stress in hiPSC-derived dopaminergic neurons with POLG mutation. Exp Neurol. 2020 Nov 29;337:113536. doi: 10.1016/j.expneurol.2020.113536.
3. Balafkan N, Mostafavi S, Schubert M, Siller R, Liang KX, Sullivan G, Bindoff LA. A method for differentiating human induced pluripotent stem cells toward functional cardiomyocytes in 96-well microplates. Sci Reports, 2020 28;10(1):18498. doi: 10.1038/s41598-020-73656-2.
4. Liang KX, Kristiansen CK, Mostafavi S, Vatne GH, Zantingh GA, Kianian A, Tzoulis C, Høyland LE, Ziegler M, Perez RM, Furriol J, Zhang Z, Balafkan N, Hong Y, Siller R, Sullivan GJ, Bindoff LA. Disease-specific phenotypes in iPSC-derived neural stem cells with POLG mutations. EMBO Mol Med 2020 Oct 7;12(10):e12146. doi: 10.15252/emmm.202012146.
5. Lehtonen JM, Auranen M, Darin N, Sofou K, Bindoff LA, Hikmat O, Uusimaa J, Vieira P, Tulinius M, Lönnqvist T, de Coo IF, Suomalainen A, Isohanni P. Diagnostic value of serum biomarkers FGF21 and GDF15 compared to muscle sample in mitochondrial disease. J Inherit Metab Dis. 2020 Aug 28. doi: 10.1002/jimd.1
6. Varhaug, KN, Nido,GS, de Coo I, Isohanni P, Suomalainen A, Tzoulis C, Knappskog P, Bindoff LA. Using urine to diagnose large-scale mtDNA deletions in adult patients. Ann Clin Transl Neurol. 2020 Aug;7(8):1318-1326. doi: 10.1002/acn3.51119.
7. Hikmat O, Naess K, Engvall M, Klingenberg C, Rasmussen M, Tallaksen CM, Brodtkorb E, Ostergaard E, de Coo IFM, PiasPeleteiro L, Isohanni P, Uusimaa J, Darin N, Rahman S, Bindoff LA. Simplifying the clinical classification of polymerase gamma (POLG) disease based on age of onset; studies using a cohort of 155 cases. J Inherit Metab Dis. 2020 Jul;43(4):726-736. doi: 10.1002/jimd.12211.
8. Liang X, Kristiansen, CK, Vatne GH, Hong Y, Bindoff LA. Patient-specific neural progenitor cells derived from induced pluripotent stem cells offer a promise of good models for mitochondrial disease. Cell Tissue Res. 2020 Apr;380(1):15-30.

Molecular Bioenergetics and Signaling

PI: Mathias Ziegler

Professor Ziegler is a world leading expert on mitochondrial biology and NAD-metabolism, and leads the Molecular Bioenergetics and Signaling Group at the UiB Department of Biomedicine. Metabolic alterations are hallmarks of many diseases. Perturbations of energy metabolism are particularly critical in neurodegenerative processes, owing to the impairment of mitochondrial functions often caused by altered mitochondrial DNA homeostasis.

Decreased oxidative phosphorylation leads to ATP deficiency, accumulation of reactive oxygen species and depletion of neuronal NAD+, one of the most critical molecules for bioenergetic conversions and signalling in human cells. Modulation of mitochondrial bioenergetics may be an effective therapeutic strategy to counteract neurodegeneration, and drugs boosting mitochondrial biogenesis and function have indeed been associated with decreased incidence of Parkinson’s disease and dementia in various independent studies. Based on these findings, the group propose that therapies promoting mitochondrial function via replenishing the NAD+ pool can shield neurons against the neurodegenerative processes and delay disease progression. Nicotinamide riboside (NR) is a well-established precursor which effectively elevates NAD+ synthesis and is non-toxic in animals and humans. It is fully approved for human use, has good oral bioavailability, crosses the blood-brain barrier and has been shown to extend lifespan in yeast and to have strong neuroprotective effects in animals. Therefore, the group believes that NR is an excellent candidate for correcting NAD+ deficiency and rectifying the metabolic impairment in neurodegeneration.

Using various cell systems and state-of-the-art metabolomics approaches, the group is studying the impact of NAD+ deficiency on major cellular bioenergetics and signalling systems. Previously, they have been able to set up the analytical technologies to measure the NAD+ metabolome and its dynamics in biological samples. They have established cellular NAD+ turnover rates in human cell lines and identified metabolic adjustments evoked by chronic NAD+ deficiency. These measurements require the use of stable isotope-labeled NAD+ precursors and highresolution mass spectrometry. In turn, the group needed to develop suitable algorithms enabling appropriate correction for naturally occurring isotopes. This has been achieved in a way applicable to a wide
range of biomolecules (preprint Dietze et al., https://doi.org/10.1101/2020.10.31.361725).

In cellular model systems, the group has mimicked age-dependent decline of NAD levels using genetic engineering to introduce NAD consuming enzyme activities into various subcellular compartments. Phenotypic and mechanistic studies revealed a tight regulation of total cellular NAD turnover, independent of the organelle targeted and the actual total cellular NAD concentration. Based on cell biological analyses, fluxomics and mathematical modelling, they propose that mitochondria serve as cellular NAD buffer. This function requires a mitochondrial NAD carrier as well as a mitochondrial enzyme which reversibly converts NAD to NMN and ATP (preprint vanLinden et al., doi. org/10.21203/rs.3.rs-116850/v1). A key contribution to develop this hypothesis was the discovery of a mitochondrial NAD carrier to which the group made major contributions (Luongo et al.).

The group will now extend their efforts and use the developed methodology to analyze the potential metabolic effect of NR supplementation in patients with Parkinson’s disease as part of the NAD-PARK and NOPARK clinical studies.

Selected Key Publications

1. Chiarugi, A., Dölle, C., Felici, R., and Ziegler, M. (2012) The NAD metabolome – a key determinant of cancer cell biology. Nat Rev Cancer 12, 741-752
2. VanLinden MR, Dölle C, Pettersen IK, Kulikova VA, Niere M, Agrimi G, Dyrstad SE, Palmieri F, Nikiforov AA, Tronstad KJ, Ziegler M. (2015) Subcellular Distribution of NAD+ between Cytosol and Mitochondria Determines the Metabolic Profile of Human Cells. J Biol Chem. Nov 290, 27644-27659
3. Love NR, Pollak N, Dölle C, Niere M, Chen Y, Oliveri P, Amaya E, Patel S, Ziegler M. (2015) NAD kinase controls animal NADP biosynthesis and is modulated via evolutionarily divergent calmodulin-dependent mechanisms. Proc Natl Acad Sci U S A. 112, 1386-1391
4. Buonvicino D, Mazzola F, Zamporlini F, Resta F, Ranieri G, Camaioni E, Muzzi M, Zecchi R, Pieraccini G, Dölle C, Calamante M, Bartolucci G, Ziegler M, Stecca B, Raffaelli N, Chiarugi A. (2018) Identification of the Nicotinamide Salvage Pathway as a New Toxification Route for Antimetabolites. Cell Chem Biol. 25, 471-482
5. Bockwoldt M, Houry D, Niere M, Gossmann TI, Reinartz I, Schug A, Ziegler M, Heiland I. (2019) Identification of evolutionary and kinetic drivers of NAD-dependent signaling. Proc Natl Acad Sci U S A. 116, 15957-15966
6. Ziegler M, Nikiforov, AA (2020) NAD on the rise again. Nat Metabolism 2, 291-292
7. Luongo TS, Eller JM, Lu MJ, Niere M, Raith F, Perry C, Bornstein MR, Oliphint P, Wang L, McReynolds MR, Migaud ME, Rabinowitz JD, Johnson FB, Johnsson K, Ziegler M, Cambronne XA, Baur JA. (2020) SLC25A51 is a mammalian mitochondrial NAD+ transporter. Nature 588, 174-179.

Registry-based in silico drug screening and epidemiology

PI: Trond Riise

The project aims to develop new and effective treatments for the neurological diseases Parkinson’s disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD). Principal Investigator Trond Riise has a background in mathematics/statistics and works as a professor in epidemiology at the University of Bergen, Norway.

Trond Riise’s research has been related to epidemiological studies of neurological diseases including Parkinson’s disease and multiple sclerosis. The focus has been to identify environmental factors that, by their own or in combinations, significantly change the disease risk. Dr. Riise has an extensive collaboration with researchers at Harvard University, where he previously was a visiting professor. He is also currently a core investigator of the Center for Parkinson Precision Neurology at Brigham and Women’s Hospital and Harvard University. Riise has also been a visiting professor at the Universities of Ferrara and Bologna, Italy. Riise’s international collaborators are key researchers in this Neuro-SysMed project. Dr. Riise is Head of Research of a comprehensive drug-screening project which involves screening of all prescriptions given to all Norwegians since 2004. These prescriptions (about 800 mill) are linked to the incidence of Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). The overall objective of the project is to evaluate whether existing drugs (molecules) can be repurposed as effective treatment of PD, ALS and MS.

The group is introducing an initial screening phase in humans that will form the basis for new hypotheses that in a second phase will be tested and validated in mechanistic experiments using human iPSC-derived neurons and animal models. This approach might be referred to as “inverse translational research” and represents a novel use of Norwegian health registries.

Selected Key Publications

1. Antonazzo IC, Poluzzi E, Forcesi E, Riise T, Bjørnevik K, Baldin E, Muratori L, De Ponti F, Raschi E. Liver injury with drugs used for multiple sclerosis: A contemporary analysis of the FDA Adverse Event Reporting System. Multiple Sclerosis 2019;25:1633-40.
2. Olsen AL, Riise T, Scherzer C. Promise for Parkinson’s: Discovering new benefits from old drugs with big data. Editorial. JAMA Neurology 2018;75(8):917-20.
3. Cortese M, Riise T, Engeland A, Ascherio A, Bjørnevik K. Urate and the risk of Parkinson’s disease in men and women. Parkinsonism and Related Disorders 2018;52:76-82.
4. Mittal S, Bjørnevik K, Im DS, Flierl A, Dong X, Locascio JJ, Abo KM, Long E, Jin M, Xu B, Xiang YK, Rochet JC, Engeland A, Rizzu P, Heutink P, Bartels T, Selkoe DJ, Caldarone BJ , Glicksman MA, Khurana V, Schüle B, Park DS, Riise T, Scherzer CR. β2-Adrenoreceptor is a Regulator of the α-Synuclein Gene Driving Risk of Parkinson’s Disease. Science 2017;357:891-8.

The Philosophy of Neurodegeneration

PI: Jan Reinert Karlsen

Jan Reinert Karlsen is Associate Professor at the Centre for the Study of the Sciences and the Humanities (SVT), an inter-disciplinary and inter-faculty research unit at the University of Bergen. In his affiliation to NeuroSysMed, his project will contribute to a better understanding of philosophical issues in precision medicine in severe chronic neurological diseases. A central issue which will be studied is the concept of suffering. Developing new perspectives on suffering, the group will use this concept as a frame for developing novel interdisciplinary approaches to understanding the characteristics of suffering in patients with severe chronic neurological diseases and how these can be alleviated.

Jan Reinert Karlsen is Associate Professor at the Centre for the Study of the Sciences and the Humanities (SVT), an inter-disciplinary and inter-faculty research unit at the University of Bergen. In his affiliation to NeuroSysMed, his project will contribute to a better understanding of philosophical issues in precision medicine in severe chronic neurological diseases. A central issue which will be studied is the concept of suffering. Developing new perspectives on suffering, the group will use this concept as a frame for developing novel interdisciplinary approaches to understanding the characteristics of suffering in patients with severe chronic neurological diseases and how these can be alleviated.

The project will focus on the four diseases studied at Neuro-SysMed: Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). To enable more precise articulations of the philosophical problems to be studied, the aim is to establish and develop collaborations across the various groups and activities at the centre.

The philosophical and methodological issues to be studied are:

  1. Issues related to the nature of severe chronic neurological diseases with a special focus on the problems of heterogeneity and complexity in disease stratification and classification.
  2. Issues related to the limits and goals of the systems / precision medicine paradigm in severe chronic neurological diseases with a special focus on the intersection between data and algorithmic driven science, clinical research, and clinical practice.
  3. Issues related to conceptualization of suffering and the nature and characteristics of suffering in patients with severe chronic neurological diseases, including their co-sufferers, e.g. next of kin.
  4. Issues related to broader societal aspects, expectations, and concerns with regard to precision medicine in severe chronic neurological diseases, including the models for studying these broader aspects (e.g., ethical legal and social aspects (ELSA), responsible research and innovation (RRI), technology assessment (TA), and ethics of science and technology).

The group plans to organize interdisciplinary discussion and reflection fora at Neuro-SysMed that will seek integration across the different groups. Here, topical philosophical, societal, and ethical issues in relation to the centre’s activities will be discussed. The group will contribute to public understanding and debate about these issues.

The activities of the group in 2020 have been restricted by the fact that the PI has been on two consecutive sabbaticals, the first was a research sabbatical committed to a project at SVT during the spring and the second was a parental leave during most of the fall. However, important progress was made at the conclusion of the year in relation to understanding foundational aspects of the concept of suffering, and a new research project was articulated, i.e. “The philosophy of severe chronic neurological diseases”. The PI will continue this work while awaiting the employment of a postdoc to this project. The concept of suffering will serve as a key analytic frame and heuristic entry point of this research project.

During 2020, the group established contact with a recognized international publishing house for writing a book based on this research project. The book proposal will be written in cooperation with the postdoc. Before the March 12th lockdown, Jan Reinert Karlsen contributed to a popular science debate about philosophical aspects of the science of aging organized by The Students’ Society of Bergen. After the lockdown, the Interdisciplinary Seminar about Suffering was reorganized as a ‘peripathetic seminar’ (i.e. walk–think–talk’ seminars) on a weekly basis. These ambulating seminars continued throughout 2020.

Selected Key Publications

1. Karlsen, JR; Solbakk, JH. A waste of time: the problem of common morality in Principles of Biomedical Ethics. Journal of Medical Ethics 2011;37 p. 588-591
2. Karlsen, JR; Solbakk, JH; Holm, S. Ethical Endgames: Broad Consent for Narrow Interests; Open Consent for Closed Minds. Cambridge Quarterly of Healthcare Ethics 2011;20(4) p. 572-583
3. Karlsen, JR; Strand, R. Annexation of Life: The Biopolitics of Industrial Biology. In: Solbakk, JH; Holm, S; Hofmann, B. (eds.) The Ethics of Research Biobanking. Springer 2009 ISBN 978-0-387- 93871-4. p. 315329
4. Karlsen, JR; Solbakk, JH; Strand, R. In the Ruins of Babel: Should Biobank Regulations be Harmonized? In: Solbakk, JH; Holm, S; Hofmann, B. (eds.) The Ethics of Research Biobanking. Springer 2009 ISBN 9780-387- 93871-4. p. 337-349
5. Karlsen, JR; Strand, R. The Ethical Topography of Research Biobanking. In: Ethics, Law and Society Volume IV. Ashgate 2009 ISBN 978-0-7546-7646-1. p. 127-148
6. Karlsen, JR; De Faria, PL; Solbakk, JH. To know the value of everything: a critical commentary to B. Björkman and S.O. Hansson’s ‘Bodily rights and property rights’. Journal of Medical Ethics 2006;(32) p. 21521

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