To generate and communicate new knowledge on the determinants of cause and neurodegenerative course of MS and its mimics (in children and in adults), while continuously improving care for these patients and their stakeholders.
(MS is the main reason for non-traumatic neurological disability in young adults, and the diseases studied in this ACE constitute 95% of the inflammatory neurodegenerative diseases of the central nervous system seen at the neurology outpatient clinic)
- Clinical translational-adults
- "MS from the very first attack": factors that predict the disease course (PROUD cohort study: PRediciting the OUtcome of a Demyelinating event) (neurology, radiology, immunology, virology, genetics, mass spectometry)
- Search for biomarkers to assess chronic neurodegeneration, focus on mass spectometry
- In depth analysis of T- and B lymphocyte subsets in MS, in blood, brain and CSF, and effect of novel treatments on immune functions and phenotypes (immunology, neurology)
- Nationwide genetic epidemiological study (epidemiology, neurology)
- Novel markers for diagnosis and prognosis of NMO-spectrum disorders (together with Sanquin Amsterdam) (neurology, radiology, Sanquin, genetics)
- investigator-initiated intervention study, VIDEO: High dose vitamin D to treat optic neuritis-using OCT as read out (with dept of Ophtalmology and with OZR)
- Several phase III treatment trials to prevent neurodegeneration (neurology, immunology, companies)
- TREFAMS (ZONMW) Study on fatigue and rehabilitation (ZonMW) (rehabilitation, neurology) Clinical translational-children
- Risk of MS and disease course in children with a first attack of acquired demyelinating syndromes (ADS) – a Dutch nationwide cohort, coupled to international cohorts (neurology, immunology, virology, genetics)
- Cognitive defects and fatigue in Dutch children with acquired demyelinating syndromes (pediatric neurology, neuropsychology)
- Urological problems in children with MS (neurology, urology)
- First trial on oral drug for MS in children (fingolimod) Biological •Specificity of T lymphocytes within the MS lesion (virology, immunology, neurology, Dutch Brain Bank)
- Immortalization of intrathecal and lesional B lymphocytes to unravel their function (together with start-up company AIMM in Amsterdam)
- Functional characterization of recently identified MS risk genes (genetic epidemiology, neurology)
- Pathogenesis and clinical impact of neurotropic virus infections including herpesviruses (virology)
- Identification of novel risk genes in sporadic MS (genetic epidemiology)
- Identification of rare varians in Dutch multiplex families and in a Dutch genetic isolate (Cornelia v Dujjn/Andre Uitterlinden).
- Kinesins as a cause of neurodegeneration (with Neurocience Utrecht, prof. Casper Hoogenraad) National collaborations: VUMC, UMC Groningen, UMC, Sanquin Amsterdam International collaborations: The International MS Genetics Consortium (IMSGC) Prof. Dr. J. Hillert, Stockholm- genetic epidemiology Prof. Dr. T. Olsson, Stockholm-CSF proteomics Prof. Dr. R. Martin, Zurich- ag-recognition of brain derived T-cells Prof. Dr. H. Wiendl and KKMS (German Government supported MS consortium), Muenster, Germany Prof. Dr. G. Giovannoni, London-disease markers, EBV Prof. Dr. X. Montalban, Dr. M. Comabella, Barcelona, CIS and biomarkers Dr. B. Hemmer, Munich-biomarkers, e.g. anti-MOG and anti-aquaporin-4 Prof. Dr. M. Tardieu, Paris-pediatric MS Dr. B. Banwell, Toronto-Philadelphia-pediatric MS Dr. A. Bar-Or, Montreal-pediatric MS Dr Phil de Jager and Dr Nikos Patsopoulos, Harvard/Boston-MS risk genes Dr. Chris Kotsapas and prof. David Hafler, Yale University-rare variants, immunogenetics ErasMS participates in BioMS, a European Network on biomarker discovery in MS (BIOMS)
Education High school level: school student teaching and thesis writing members of MS Centrum Rotterdam contribute to the medical curriculum (bachelor and master level). Paramedical education should not be forgotten: occupational therapists and physical therapists Postdoctoral level The center annually receives a number of requests by international postdoctoral students; and accommodates a few per year.
Etalage stage Dutch neurology residents Supervision and training of PhD students The center actively participates within the master programs: masters NIHES, masters Neuroscience and masters Infection/Immunity, sometimes in other national academic centres. Every year there are visiting (postdoc ) scientists from worldwide.
Furthermore members participate in weekly teaching for PhD's and for AIOS neurology, rehabilitation and ophtalmology. -International courses on MS for postdocs and medical students with strong emphasis on translational medicine. Patients and lay audience Information to the general public, patients, and MS specialists at national and international levels. Public information events together with the three MS care and research organisations. Annually, we organise an informative festivity for pediatric MS patients and their families (in 2013 for the 8th consecutive year). Initiation of a patient stakeholder organization for NMO The centre is active in the media (radio, TV, newspapers, journals, websites) Training and research with biotech industry business alliance for companies, on pre-clinical trials on anti-CD20, anti-CD40, anti-IL-7, NOGO, anti-IL12/p40 and on stem cell transplantation.
Societal Relevance to Research, Education and Patient Care
1. Patent number: P85588PC00 susceptibility markers for MS: KIF1B as a risk and outcome gene in MS.
2. Patent number: PCT/NL2008/000020, Methods and markers for detecting multiple sclerosis. Guidelines and care standards have been developed by the centre: pediatric MS, adult MS, neurogenic bladder, international consensus on treatment of pediatric MS, international consensus on treatment for Neuromyelitis Optica.
Short informative films for general audience (YouTube; Wetenschap voor Patienten by prof. Hintzen and by Dr van Pelt). Members active in development of masters Infection & Immunity, and contribute to other master curriculums (NIHES and Neuroscience).
Regarding innovational education:
Twitter: ACE MS Centrum Rotterdam on https://twitter.com/erasms
Two Facebook accounts for ACE MS Centrum Rotterdam :
On YouTube; "Wetenschap voor patienten" by prof. Hintzen and by Dr. van Pelt. The contribution of the ACE to public health (prevention and therapeutics).
MS Centrum Rotterdam is continuously working on identification for biomarkers for prognosis, preclinical identification of novel therapies, and assessment of efficacy and safety of novel neuroprotective drugs in MS. Next, the Nationwide gene-environment study gives support to changes in lifestyle for MS patients: smoking influences the disease course, as well as low sunlight and vitamin D. Early councelling and start of treatment seems of benefit for patients.
Viability of Research, Education and Patient Care
There are regular internal meetings, presentations, discussions with staff and PhD. 60% of the Pi's have international experience. One is also professor in Hannover (GV). 40% of the PhD's has significant experience abroad (Harvard, UCSF, University of British Columbia). All stayed in the Netherlands after PhD.
MS Centrum Rotterdam receives continuous requests for a position by young scientists interested in MS research, at both national and international levels. Some of them we can accommodate. Every year we have at least one student from abroad, for research in translational aspects of MS or NMO. PhD students and post-docs attend international conferences and publish in international top journals. Talents are encouraged to gain experience abroad, and are assisted in obtaining funding.
Preference is given to personal funding, e.g. NWO, Erasmus MC grants. -ErasMS participates actively and extensively in the European neuroimmunology network (European School for Neuroimmunology; ESNI. Prof. Hintzen is a board member of ESNI and of the International Society of Neuroimmunology (ISNI), Neurologist Dorine Siepman has replaced him as a Dutch representative within ECTRIMS. Hintzen is a member of the scientific committee of the US-initiated study group on pediatric MS (headed by Dr Brenda Banwell, Toronto) and since 2012 member of the steering committee of the International Pediatric MS Study Group-IPMSSG (MSIF Coordinating Consultant: Jon Temme). At a national level, Hintzen is chairman of the research committee of the Dutch society for Neurology (Commissie wetenschappelijk onderzoek Neurologie).
Both Siepman and Hintzen are members of the "werkgroep MS" of the Dutch Neurology association and are academic advisors in the regional network MS group South-West Netherlands.
Key and relevant publications of the last five years
- D Buljevac, HZ Flach, WCJ Hop, D Hijdra, JD Laman, HFJ Savelkoul, FGA van der Meché, PA van Doorn and RQ Hintzen. Prospective study on the relationship between infections and multiple sclerosis exacerbations. Brain 125:952-960 (2002)
- van Nierop GP, Janssen M, Mitterreiter JG, van de Vijver DA, de Swart RL,Haagmans BL,Verjans GM, Hintzen RQ.Intrathecal CD4(+) and CD8(+) T-cell responses to endogenously synthesized candidate disease-associated human autoantigens in multiple sclerosis patients. Eur J Immunol. 2016 Feb;46(2):347-53.
- van Luijn MM, Kreft KL, Jongsma ML, Mes SW, Wierenga-Wolf AF, van Meurs M, Melief MJ, der Kant Rv, Janssen L, Janssen H, Tan R, Priatel JJ, Neefjes J, Laman JD, Hintzen RQ.Multiple sclerosis-associated CLEC16A controls HLA class II expression via late endosome biogenesis. Brain. 2015 Jun;138(Pt 6):1531-47.
- International Multiple Sclerosis Genetics Consortium (IMSGC) Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis Nat Genet 45:1353-1360 (2013)
- NA Patsopoulos, et al. Fine-mapping the genetic association of the major istocompatibility complex in multiple sclerosis: HLA and non-HLA effects PLoS Genet 9:e1003926 (2013)
- ED van Pelt et al. Application of the 2012 revised diagnostic definitions for paediatric multiple sclerosis and immune-mediated central nervous system demyelination disorders J Neurol Neurosurg Psychiatry (2013) Dec doi: 10.1136/jnnp-2013-306850
- Stern JNH et al. B Cells Populating the Multiple Sclerosis Brain Mature in the Draining Cervical Lymph Nodes. Science Translational Medicine. Aug. 2014;6(248)
- GM Verjans, RQ Hintzen, JM van Dun, A Poot, JC Milikan, JD Laman, AW Langerak, PR Kinchington and AD Osterhaus. Selective retention of herpes simplex virus-specific T cells in latently infected human trigeminal ganglia. Proc Natl Acad Sci USA 104:3496-3501 (2007)
- Utomo E, Groen J, Blok BF. Surgical management of functional bladder outlet obstruction in adults with neurogenic bladder dysfunction. Cochrane Database Syst Rev. 2014; 24:CD004927.
- Blikman L.J.M., Huisstede B.M.A., Kooijmans H., Stam H.J., Bussmann J.B.J., van Meeteren J. Effectiveness of Energy-Conservation Management treatment in reducing fatigue in Multiple Sclerosis: a systematic review and meta-analysis. Arch Phys Med Rehabil 2013; 94: 1360-1376.
PhD theses of the last five years
- Vaibhav Singh, Identification of potential biomarkers in multiple sclerosis, September 29th 2015, Promotor: RQ Hintzen, ISBN: 978-94-6169-714-1
- Tessel Runia, Multiple sclerosis – predicting the next attack, January 23rd 2015, Promotor: RQ Hintzen, ISBN: 978-90-5335-978-5
- Immy Ketelslegers, Acquired demyelinating syndromes and pediatric multiple sclerosis, January 22nd 2014, Promotor: RQ Hintzen, ISBN: 978-94-6169-46-1
- Karim Kreft, Functional immunogenetics of MS, January 8th 2014, Promotores: RQ Hintzen and JD Laman, ISBN: 978-90-5335-777-4
- RF Neuteboom, Two special situations in multiple sclerosis: MS and pregnancy and childhood onset of MS, April 12th 2012, Promotores: RQ Hintzen and JD Laman, ISBN: 978-90-5335-520-6
- N Jafari, Risk factors in cause and course of multiple sclerosis, Promotion date: January 20th 2012, Promotor: RQ Hintzen, ISBN: 978-90-5335-501-5
- IA Hoppenbrouwers, Genetic epidemiological studies of multiple sclerosis, January 11th 2011, Promotores: CM van Duijn, RQ Hintzen, BA Oostra ISBN: 978-90-5335-354-7
- SA Jagessar, Mechanistic refinement of the common marmoset model for multiple sclerosis, Promotores: JD Laman and BA ‘t Hart ISBN: 978-94-6182-100-3
- Lisette 't Hoen, Outcome measures in functional urology 2015.
- Velzen van M, Herpes simplex virus type 1 infection: features of Immune surveillance and antiviral resistance 2013