Initial presentation of ALS varies between affected individuals, and typically presents as spinal-onset disease (muscle weakness of the limbs), or bulbaronset disease (difficulty with speech and swallowing). Sporadic ALS (sALS) accounts for 90% of cases and has no clear etiology, while familial ALS (fALS) accounts for 10% of cases and contains an underlying genetic component. However, while these two forms differ in causation, they appear pathologically and clinically indistinguishable. There is no known cure for ALS. There are two approved medications to treat ALS, riluzole (a glutamate blocker) and edaravone (a free radical scavenger), but with limited efficacy. Riluzole, approved in 1995, is administered orally twice daily and delays time to tracheostomy or death in patients with ALS (Riluzole package insert 2016), prolonging survival by 2-3 months (Miller et al. 2012). Edaravone, approved in the US in 2017, is administered in courses intravenously and shows efficacy in only a small subset of patients with ALS.

Recent research by the group and others indicates that boosting the activity of the histone deacetylate enzymes known as sirtuins, via a combination of nicotinamide riboside (NR) and pterostilbene, has neuroprotective effects in ALS and may delay clinical disease progression.

Based on these preliminary findings, the group hypothesized that oral administration of combination therapy with NR and pterostilbene will inhibit neurodegeneration and increase survival and quality of life in patients with ALS. To test this hypothesis, they are now running a phase-II, multi-centre, double-blinded randomized clinical trial of oral NR and pterostilbene in early ALS (NO-ALS study). Based on their power estimates, a total of 180 patients will be recruited from all over Norway. The study was started in October 2020. By end of February 2021, 20 patients are included in the study. All study centres will be recruiting by end of March 2021.

This novel project has the potential to discover a therapy, modulating disease activity and progression in ALS, thus vastly improving patient care and prognosis. The study has received support from Helse Vest and KLINBEFORSK.

Selected Key Publications

1. Association of SNCA Parkinson’s Disease Risk Polymorphisms With Disease Progression in Newly Diagnosed Patients. Szwedo AA, Pedersen CC, Ushakova A, Forsgren L, Tysnes OB, Counsell CE, Alves G, Lange J, Macleod AD, Maple-Grødem J. Front Neurol. 2021 Feb 10;11:620585. doi: 10.3389/fneur.2020.620585. eCollection 2020.PMID: 33643180 Free PMC article.
2. Letter to the editor in response to the letter from the EPIPARK Study Group regarding the publication ‘Progression of fatigue in Parkinson’s disease – a 9-year follow-up’ (Eur J Neurol 2021. doi:10.1111/ene.14520). Ongre SO, Dalen I, Tysnes OB, Alves G, Herlofson K.Eur J Neurol. 2021 Feb 5. doi: 10.1111/ene.14765. Online ahead of print.PMID: 33547699
3. Association of GBA Genotype With Motor and Functional Decline in Patients With Newly Diagnosed Parkinson Disease. MapleGrødem J, Dalen I, Tysnes OB, Macleod AD, Forsgren L, Counsell CE, Alves G.Neurology. 2021 Feb 16;96(7):e1036-e1044. doi: 10.1212/WNL.0000000000011411. Epub 2020 Dec 21.PMID: 33443131
4. Differential transcript usage in the Parkinson’s disease brain. Dick F, Nido GS, Alves GW, Tysnes OB, Nilsen GH, Dölle C, Tzoulis C.PLoS Genet. 2020 Nov 2;16(11):e1009182. doi: 10.1371/journal.pgen.1009182. eCollection 2020 Nov.PMID: 33137089 Free PMC article.
5. Differences in the Presentation and Progression of Parkinson’s Disease by Sex. Iwaki H, Blauwendraat C, Leonard HL, Makarious MB, Kim JJ, Liu G, Maple-Grødem J, Corvol JC, Pihlstrøm L, van Nimwegen M, Smolensky L, Amondikar N, Hutten SJ, Frasier M, Nguyen KH, Rick J, Eberly S, Faghri F, Auinger P, Scott KM, Wijeyekoon R, Van Deerlin VM, Hernandez DG, Gibbs RJ, Day-Williams AG, Brice A, Alves G, Noyce AJ, Tysnes OB, Evans JR, Breen DP, Estrada K, Wegel CE, Danjou F, Simon DK, Andreassen OA, Ravina B, Toft M, Heutink P, Bloem BR, Weintraub D, Barker RA, Williams-Gray CH, van de Warrenburg BP, Van Hilten JJ, Scherzer CR, Singleton AB, Nalls MA.Mov Disord. 2021 Jan;36(1):106-117. doi: 10.1002/mds.28312. Epub 2020 Oct 1.PMID: 33002231
6. Meta-analysis of whole-exome sequencing data from two independent cohorts finds no evidence for rare variant enrichment in Parkinson disease associated loci. Gaare JJ, Nido G, Dölle C, Sztromwasser P, Alves G, Tysnes OB, Haugarvoll K, Tzoulis C.PLoS One. 2020 Oct 1;15(10):e0239824. doi: 10.1371/journal.pone.0239824. eCollection 2020.PMID: 33002040 Free PMC article.
7. Progression of fatigue in Parkinson’s disease – a 9-year follow-up. Ongre SO, Dalen I, Tysnes OB, Alves G, Herlofson K.Eur J Neurol. 2021 Jan;28(1):108-116. doi: 10.1111/ene.14520. Epub 2020 Oct 16.PMID: 32920893
8. Genetic risk scores and hallucinations in patients with Parkinson disease. Kusters CDJ, Paul KC, Duarte Folle A, Keener AM, Bronstein JM, Dobricic V, Tysnes OB, Bertram L, Alves G, Sinsheimer JS, Lill CM, Maple-Grødem J, Ritz BR.Neurol Genet. 2020 Jul 20;6(5):e492. doi: 10.1212/NXG.0000000000000492. eCollection 2020 Oct.PMID: 32802953 Free PMC article.
9. Impulsive and compulsive behaviors in Parkinson’s disease: Impact on quality of and satisfaction with life, and caregiver burden. Erga AH, Alves G, Tysnes OB, Pedersen KF.Parkinsonism Relat Disord. 2020 Sep;78:27-30. doi: 10.1016/j. parkreldis.2020.07.007. Epub 2020 Jul 9.PMID: 32679528 Free article.
10. Validation of a UPDRS-/MDS-UPDRS-based definition of functional dependency for Parkinson’s disease. Ramsay N, Macleod AD, Alves G, Camacho M, Forsgren L, Lawson RA, Maple-Grødem J, Tysnes OB, Williams-Gray CH, Yarnall AJ, Counsell CE; Parkinson’s Incidence Cohorts Collaboration; PINE Study; CamPaIGN study; PICNICS study; NYPUM Study; ParkWest Study: ParkWest Principal investigators; Study personnel; ICICLE-PD Study.Parkinsonism Relat Disord. 2020 Jul;76:49-53. doi:10.1016/j.parkreldis.2020.05.034. Epub 2020 May 30.PMID: 32645619
11. Common gene expression signatures in Parkinson’s disease are driven by changes in cell composition. Nido GS, Dick F, Toker L, Petersen K, Alves G, Tysnes OB, Jonassen I, Haugarvoll K, Tzoulis C.Acta Neuropathol Commun. 2020 Apr 21;8(1):55. doi: 10.1186/s40478-020-00932-7.PMID: 32317022 Free PMC article.
12. Targeting NAD+ in translational research to relieve diseases and conditions of metabolic stress and ageing. Gilmour BC, Gudmundsrud R, Frank J, Hov A, Lautrup S, Aman Y, Røsjø H, Brenner C, Ziegler M, Tysnes OB, Tzoulis C, Omland T, Søraas A, Holmøy T, Bergersen LH, Storm-Mathisen J, Nilsen H, Fang EF.Mech Ageing Dev. 2020 Mar;186:111208. doi: 10.1016/j. mad.2020.111208. Epub 2020 Jan 15.PMID: 31953124 Review.
13. Evolution of impulsive-compulsive behaviors and cognition in Parkinson’s disease. Erga AH, Alves G, Tysnes OB, Pedersen KF.J Neurol. 2020 Jan;267(1):259-266. doi: 10.1007/s00415-019-09584-7. Epub 2019 Oct 18.PMID: 31628533 Free PMC article.

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.

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.

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