The project activities of the Multiple Sclerosis (MS) Research Group aim to support and meet the main objective of Neuro-SysMed to generate improved and tailored treatment strategies for patients with MS. Some projects are a direct result from the NeuroSysMed funding, and others are a part of the longterm commitment of the group for improved therapy and care for MS patients, and thus are important prerequisites for the Neuro-SysMed centre.

The group is currently recruiting patients into four investigator sponsored clinical trials. The RAM-MS study evaluates the safety and efficacy of autologous hematopoietic stem cell transplantation (HSCT) compared to high-efficacy disease modifying therapies (DMT) in relapsing-remitting MS (RRMS) patient with breakthrough disease activity. The OVERLORD-MS study evaluates and compares the efficacy and safety of rituximab and ocrelizumab in newly diagnosed RRMS patients. The COVID-19 vaccine response study evaluates the impact of various DMTs on the vaccination response in MS patients. The SMARTMS study aims to evaluate the regenerative effect of mesenchymal autologous stem cells in progressive MS. This latter study has received approval from the Norwegian Medical Agency and the Ethical Committee, but the start is put on hold due to COVID-19 restrictions for the partner in Ulm, Germany. The group is however pre-screening patients to be ready for the start-up. In addition, they are also national coordinator for three industry sponsored multicentre randomized clinical trials, and recruiting site for another.

In collaboration with the biomarker group, the MS group is currently phenotyping stem cells and immune cells from patients included in the ongoing clinical trials, aiming to identify biomarkers for tailored dosing or patient selection. In other studies, they have evaluated biomarkers of treatment response of natalizumab as well as dimethyl fumarate and teriflunomide. similarly, the use of neurofilament (NFL) and magnetic resonance imaging (MRI) are used to evaluate treatment response and disease progression. The impact of modifiable lifestyle factors are also evaluated, related to treatment efficacy and long-term prognoses, aiming for improved and personalised treatment strategies in MS.

A sensitive and clinical practical screening instrument for early detection of disabling symptoms like cognitive dysfunction is another important research focus with direct impact for the clinical trial efficacy endpoints. Thus, the Norwegian translation of the brief international cognitive assessment for multiple sclerosis (BICAMS) is currently included in the clinical trials.

Registry and epidemiological studies to evaluate possible risk factors and comorbidities have been a long-term commitment for the research group. Recent data on cancer frequency in MS calls or further studies both on the aetiology of the disease, and risk stratification for immunotherapy.

Preclinical studies evaluating effects from vitamin D on remyelination (repair) in animal models, as well as biomarker discovery studies in these animal models and the cerebrospinal fluid from MS patients are other prioritized projects in the group. They also use animal models in feasibility studies of mesenchymal stem cells as a regenerative therapy in progressive MS.

Selected Key Publications

1. Bringeland GH, Blaser N, Myhr KM, Vedeler CA, Gavasso S. Wearing-off at the end of natalizumab dosing intervals is associated with low receptor occupancy. Neurol Neuroimmunol Neuroinflamm. 2020;7:e678. PMID: 32019768
2. Bringeland GH, Myhr KM, Vedeler CA, Gavasso S. Wearing-off at the end of natalizumab dosing interval and risk of MS disease activity: A prospective 1-year follow-up study. J Neurol Sci 2020;415:116880. PMID: 32413799
3. Norborg H, Riise T, Myhr KM, Grytten N, Wergeland S. Real-world discontinuation of teriflunomide and dimethyl fumarate in multiple sclerosis. Mult Scler J Exp Transl Clin 2020/2021 – in press.
4. Varhaug KN, Torkildsen Ø, Myhr KM, Vedeler CA. Neurofilament Light Chain as a Biomarker in Multiple Sclerosis. Front Neurol 2019;10:338. PMID: 31024432
5. Lie IA, Weeda MM, Mattiesing RM, Mol MAE, Pouwels PJW, Barkhof F, Torkildsen Ø, Bø L, Myhr KM, Vrenken H. The relationship between white matter lesions and grey matter atrophy in multiple sclerosis. Neurology 2020/2021, submitted
6. Wesnes K, Myhr KM, Riise T, Kvistad SS, Torkildsen Ø, Wergeland S, Holmøy T, Midgard R, Bru A, Edland A, Eikeland R, Gosal S, Harbo HF, Kleveland G, Sørenes YS, Øksendal N, Bjørnevik K. Low vitamin D, but not tobacco use or high BMI, is associated with long-term disability progression in multiple sclerosis. Mult Scler Relat Disord 2021;50:102801. PMID: 33636616
7. Skorve E, Lundervold AJ, Torkildsen Ø, Myhr KM. A two-year longitudinal follow-up of cognitive performance assessed by BICAMS in newly diagnosed patients with MS. Mult Scler Relat Disord 2020;46:102577. PMID: 33296975
8. Grytten N, Myhr KM, Celius EG, Benjaminsen E, Kampman M, Midgard R, Vatne A, Aarseth JH, Riise T, Torkildsen Ø. Risk of cancer among multiple sclerosis patients, siblings, and population controls: A prospective cohort study. Mult Scler 2020;26:1569-1580. PMID: 31573834
9. Grytten N, Myhr KM, Celius EG, Benjaminsen E, Kampman MT, Midgard R, Vatne A, Aarseth JH, Riise T, Torkildsen Ø. Incidence of cancer in multiple sclerosis before and after the treatment era– a registry- based cohort study. Mult Scler J Exp Transl Clin 2020/2021 – submitted.
10. Nystad AE, Lereim RR, Wergeland S, Oveland E, Myhr KM, Bø L, Torkildsen Ø. Fingolimod downregulates brain sphingosine-1-phosphate receptor 1 levels but does not promote remyelination or neuroprotection in the cuprizone model. J Neuroimmunol 2020;339:577091. PMID: 31739156
11. Oveland E, Ahmad I, Lereim RR, Kroksveen AC, Barsnes H, Guldbrandsen A, Myhr KM, Bø L, Berven FS, Wergeland S. Cuprizone and EAE mouse frontal cortex proteomics revealed proteins altered in multiple sclerosis. Sci Rep 2020/2021 in press
12. Mosleth EF, Vedeler CA, Liland KH, McLeod A, Bringeland GH, Kroondijk L, Berven FS, Lysenko A, Rawlings CJ, Eid KE, Opsahl JA, Gjertsen BT, Myhr KM, Gavasso S. Cerebrospinal fluid proteome shows disrupted neuronal development in multiple sclerosis. Sci Rep 2021;11:4087. PMID: 33602999

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).

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