Publications by authors named "Rogier Q Hintzen"

117 Publications

EBNA-1 titer gradient in families with multiple sclerosis indicates a genetic contribution.

Neurol Neuroimmunol Neuroinflamm 2020 11 13;7(6). Epub 2020 Aug 13.

From the Department of Neurology (J.Y.M., K.L.K.); Department of Viroscience (G.P.N., A.A.E.), Erasmus MC, University Medical Center, Rotterdam, the Netherlands; and Department of Neurology, MS Centre ErasMS, Erasmus MC, Rotterdam, the Netherlands (J.Y.M., K.L.K.).

Objective: In multiplex MS families, we determined the humoral immune response to Epstein-Barr virus nuclear antigen 1 (EBNA-1)-specific immunoglobulin γ (IgG) titers in patients with MS, their healthy siblings, and biologically unrelated healthy spouses and investigated the role of specific genetic loci on the antiviral IgG titers.

Methods: IgG levels against EBNA-1 and varicella zoster virus (VZV) as control were measured. and tagging single-nucleotide polymorphisms (SNPs) were genotyped. We assessed the associations between these SNPs and antiviral IgG titers.

Results: OR for abundant EBNA-1 IgG was the highest in patients with MS and intermediate in their siblings compared with spouses. We confirmed that is associated with abundant EBNA-1 IgG. After stratification for , the EBNA-1 IgG gradient was still significant in patients with MS and young siblings compared with spouses. was not explanatory for EBNA-1 IgG titer gradient. No associations for VZV IgG were found.

Conclusions: In families with MS, the EBNA-1 IgG gradient being the highest in patients with MS, intermediate in their siblings, and lowest in biologically unrelated spouses indicates a genetic contribution to EBNA-1 IgG levels that is only partially explained by carriership.
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http://dx.doi.org/10.1212/NXI.0000000000000872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428359PMC
November 2020

The Role of Autoimmunity-Related Gene in the B Cell Receptor-Mediated HLA Class II Pathway.

J Immunol 2020 Aug 8;205(4):945-956. Epub 2020 Jul 8.

Department of Immunology, Erasmus MC, 3015 CN Rotterdam, the Netherlands;

C-type lectin is located next to , the master transcription factor of HLA class II (HLA-II), at a susceptibility locus for several autoimmune diseases, including multiple sclerosis (MS). We previously found that promotes the biogenesis of HLA-II peptide-loading compartments (MIICs) in myeloid cells. Given the emerging role of B cells as APCs in these diseases, in this study, we addressed whether and how is involved in the BCR-dependent HLA-II pathway. was coexpressed with surface class II-associated invariant chain peptides (CLIP) in human EBV-positive and not EBV-negative B cell lines. Stable knockdown of in EBV-positive Raji B cells resulted in an upregulation of surface HLA-DR and CD74 (invariant chain), whereas CLIP was slightly but significantly reduced. In addition, IgM-mediated uptake was decreased, and MIICs were less clustered in -silenced Raji cells, implying that controls both HLA-DR/CD74 and BCR/Ag processing in MIICs. In primary B cells, was only induced under CLIP-stimulating conditions in vitro and was predominantly expressed in CLIP naive populations. Finally, CLIP-loaded HLA-DR molecules were abnormally enriched, and coregulation with was abolished in blood B cells of patients who rapidly develop MS. These findings demonstrate that CLEC16A participates in the BCR-dependent HLA-II pathway in human B cells and that this regulation is impaired during MS disease onset. The abundance of CLIP already on naive B cells of MS patients may point to a chronically induced stage and a new mechanism underlying B cell-mediated autoimmune diseases such as MS.
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http://dx.doi.org/10.4049/jimmunol.1901409DOI Listing
August 2020

HLA association in MOG-IgG- and AQP4-IgG-related disorders of the CNS in the Dutch population.

Neurol Neuroimmunol Neuroinflamm 2020 05 20;7(3). Epub 2020 Mar 20.

From the Department of Neurology (A.L.B., Y.Y.M.W., E.D.P., R.Q.H., R.F.N., B.H.A.W.), Erasmus University Medical Center, Rotterdam; and Department of Immunohaematology and Blood Transfusion (P.J.E.L., G.W.H., F.H.J.C.), Leiden University Medical Center, the Netherlands.

Objective: To investigate the possible human leukocyte antigen (HLA) association of both myelin oligodendrocyte glycoprotein (MOG-IgG)-associated diseases (MOGAD) and aquaporin-4 antibody (AQP4-IgG)-positive neuromyelitis optica spectrum disorders (NMOSDs) in the Dutch population with European ancestry to clarify similarities or differences in the immunogenetic background of both diseases.

Methods: Blood samples from patients in the Dutch national MS/NMOSD expert clinic were tested for MOG-IgG and AQP4-IgG using a cell-based assay. HLA Class I and II genotyping was performed in 43 MOG-IgG-seropositive and 42 AQP4-IgG-seropositive Dutch patients with European ancestry and compared with those of 5,604 Dutch healthy blood donors.

Results: No significant HLA association was found in MOG-IgG-seropositive patients. The AQP4-IgG-seropositive patients had a significant higher frequency of HLA-A*01 (61.9% vs 33.7%, OR 3.16, 95% CI, 1.707-5.863, after correction [c] = 0.0045), HLA-B*08 (61.9% vs 25.6%, OR 4.66, 95% CI, 2.513-8.643, c < 0.0001), and HLA-DRB1*03 (51.2% vs 27.6%, OR 2.75, 95% CI, 1.495-5.042, c = 0.0199) compared with controls.

Conclusions: The present study demonstrates differences in the immunogenetic background of MOGAD and AQP4-IgG-positive NMOSD. The strong positive association with HLA-A*01, -B*08, and -DRB1*03 is suggestive of a role of this haplotype in the etiology of AQP4-IgG-positive NMOSD in patients with European ancestry, whereas in MOGAD no evidence was found for any HLA association in these disorders.
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http://dx.doi.org/10.1212/NXI.0000000000000702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136059PMC
May 2020

Polygenic Multiple Sclerosis Risk and Population-Based Childhood Brain Imaging.

Ann Neurol 2020 05 27;87(5):774-787. Epub 2020 Mar 27.

Department of Neurology, MS Center ErasMS, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands.

Objective: Multiple sclerosis (MS) is a neurological disease with a substantial genetic component and immune-mediated neurodegeneration. Patients with MS show structural brain differences relative to individuals without MS, including smaller regional volumes and alterations in white matter (WM) microstructure. Whether genetic risk for MS is associated with brain structure during early neurodevelopment remains unclear. In this study, we explore the association between MS polygenic risk scores (PRS) and brain imaging outcomes from a large, population-based pediatric sample to gain insight into the underlying neurobiology of MS.

Methods: We included 8- to 12-year-old genotyped participants from the Generation R Study in whom T1-weighted volumetric (n = 1,136) and/or diffusion tensor imaging (n = 1,088) had been collected. PRS for MS were calculated based on a large genome-wide association study of MS (n = 41,505) and were regressed on regional volumes, global and tract-specific fractional anisotropy (FA), and global mean diffusivity using linear regression.

Results: No associations were observed for the regional volumes. We observed a positive association between the MS PRS and global FA (β = 0.098, standard error [SE] = 0.030, p = 1.08 × 10 ). Tract-specific analyses showed higher FA and lower radial diffusivity in several tracts. We replicated our findings in an independent sample of children (n = 186) who were scanned in an earlier phase (global FA; β = 0.189, SE = 0.072, p = 9.40 × 10 ).

Interpretation: This is the first study to show that greater genetic predisposition for MS is associated with higher global brain WM FA at an early age in the general population. Our results suggest a preadolescent time window within neurodevelopment in which MS risk variants act upon the brain. ANN NEUROL 2020;87:774-787.
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http://dx.doi.org/10.1002/ana.25717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187244PMC
May 2020

Pediatric autoimmune encephalitis: Recognition and diagnosis.

Neurol Neuroimmunol Neuroinflamm 2020 05 11;7(3). Epub 2020 Feb 11.

From the Department of Neurology (M.A.A.M.d.B., A.L.B., A.E.M.B., A.v.S., P.A.E.S.S., M.J.T.), Department of Immunology (M.W.J.S.), and Department of Pediatric Neurology (R.F.N.), Erasmus MC University Medical Center, Rotterdam; Haga Hospital (A.v.S.), The Hague; and Sophia Children's Hospital (R.F.N.), Rotterdam, the Netherlands. A.v.S. is currently working at Medisch Centrum Haaglanden, The Hague.

Objective: The aims of this study were (1) to describe the incidence of autoimmune encephalitis (AIE) and acute disseminated encephalomyelitis (ADEM) in children, (2) to validate the currently used clinical criteria to diagnose AIE, and (3) to describe pitfalls in the diagnosis of pediatric autoimmune (AI) and inflammatory neurologic disorders.

Methods: This study cohort consists of 3 patient categories: (1) children with antibody-mediated AIE (n = 21), (2) children with ADEM (n = 32), and (3) children with suspicion of an AI etiology of their neurologic symptoms (n = 60). Baseline and follow-up clinical data were used to validate the current guideline to diagnose AIE. In addition, patient files and final diagnoses were reviewed.

Results: One-hundred three of the 113 included patients fulfilled the criteria of possible AIE. Twenty-one children had antibody-mediated AIE, of whom 19 had anti-N-methyl-D-aspartate receptor (NMDAR), 1 had anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, and 1 had anti-leucine-rich glioma-inactivated protein 1 encephalitis. Finally, 34 children had ADEM, and 2 children had Hashimoto encephalopathy. Mean incidence rates were 1.54 children/million (95% CI 0.95-2.35) for antibody-mediated AIE and 2.49 children/million (95% CI 1.73-3.48) for ADEM. Of the other 48 children, treating physicians' diagnoses were reviewed. In 22% (n = 6) of children initially diagnosed as having an AI/inflammatory etiology (n = 27), no support for AI/inflammation was found.

Conclusion: Besides anti-NMDAR encephalitis and ADEM, other AIEs are rare in children. The current guideline to diagnose AIE is also useful in children. However, in children with nonspecific symptoms, it is important to review data critically, to perform complete workup, and to consult specialized neuroinflammatory centers.
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http://dx.doi.org/10.1212/NXI.0000000000000682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051211PMC
May 2020

Serum neurofilament light chain in pediatric MS and other acquired demyelinating syndromes.

Neurology 2019 09 5;93(10):e968-e974. Epub 2019 Aug 5.

From the Department of Neurology, MS Centre ErasMS (Y.Y.M.W., A.L.B., D.v.P., R.Q.H.), Department of Immunology (M.-J.M., A.F.W., R.Q.H.), and Department of Pediatric Neurology (R.F.N.), Erasmus MC, Rotterdam, the Netherlands; and Neurologic Clinic and Policlinic (C.B., Z.M., J.K.), University Hospital Basel, Switzerland.

Objective: To explore the correlation between serum and CSF neurofilament light chain (NfL) and the association of NfL levels and future disease activity in pediatric patients with a first attack of acquired demyelinating syndromes (ADS).

Methods: In total, 102 children <18 years with a first attack of CNS demyelination and 23 age-matched controls were included. Clinically definite multiple sclerosis (CDMS) was set as an endpoint for analysis. CSF NfL was tested by the commercially available ELISA (UmanDiagnostics); serum NfL (sNfL) was tested with a Simoa assay. Hazard ratios (HR) were calculated with Cox regression analysis.

Results: Of the 102 patients, 47 (46%) were tested for CSF NfL. CSF and serum NfL correlated significantly in the total group (ρ 0.532, < 0.001) and even more significantly in the subgroup of patients with future CDMS diagnosis (ρ 0.773, < 0.001). sNfL was higher in patients than in controls (geometric mean 6.1 pg/mL, < 0.001), and was highest in ADS presenting with encephalopathy (acute disseminated encephalomyelitis, n = 28, 100.4 pg/mL), followed by patients without encephalopathy (ADS-) with future CDMS diagnosis (n = 40, 32.5 pg/mL), and ADS- who remained monophasic (n = 34, 17.6 pg/mL). sNfL levels higher than a median of 26.7 pg/mL at baseline are associated with a shorter time to CDMS diagnosis in ADS- ( = 0.045). HR for CDMS diagnosis was 1.09 for each 10 pg/mL increase of sNfL, after correction for age, oligoclonal bands, and MRI measures ( = 0.012).

Conclusion: The significant correlation between CSF and serum NfL strengthens its reliability as a peripheral marker of neuroaxonal damage. Higher sNfL levels at baseline were associated with higher probability of future CDMS diagnosis in ADS-.
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http://dx.doi.org/10.1212/WNL.0000000000008057DOI Listing
September 2019

Induction of brain-infiltrating T-bet-expressing B cells in multiple sclerosis.

Ann Neurol 2019 08 19;86(2):264-278. Epub 2019 Jun 19.

Department of Immunology, MS Center ErasMS, Erasmus Medical Center, University Medical Center, Rotterdam, the Netherlands.

Objective: Results from anti-CD20 therapies demonstrate that B- and T-cell interaction is a major driver of multiple sclerosis (MS). The local presence of B-cell follicle-like structures and oligoclonal bands in MS patients indicates that certain B cells infiltrate the central nervous system (CNS) to mediate pathology. Which peripheral triggers underlie the development of CNS-infiltrating B cells is not fully understood.

Methods: Ex vivo flow cytometry was used to assess chemokine receptor profiles of B cells in blood, cerebrospinal fluid, meningeal, and brain tissues of MS patients (n = 10). Similar analyses were performed for distinct memory subsets in the blood of untreated and natalizumab-treated MS patients (n = 38). To assess T-bet(CXCR3) B-cell differentiation, we cultured B cells from MS patients (n = 21) and healthy individuals (n = 34) under T helper 1- and TLR9-inducing conditions. Their CNS transmigration capacity was confirmed using brain endothelial monolayers.

Results: CXC chemokine receptor 3 (CXCR3)-expressing B cells were enriched in different CNS compartments of MS patients. Treatment with the clinically effective drug natalizumab prevented the recruitment of CXCR3 IgG1 subsets, corresponding to their increased ability to cross CNS barriers in vitro. Blocking of interferon-γ (IFNγ) reduced the transmigration potential and antigen-presenting function of these cells. IFNγ-induced B cells from MS patients showed increased T-bet expression and plasmablast development. Additional TLR9 triggering further upregulated T-bet and CXCR3, and was essential for IgG1 switching.

Interpretation: This study demonstrates that T-bet IgG1 B cells are triggered by IFNγ and TLR9 signals, likely contributing to enhanced CXCR3-mediated recruitment and local reactivity in the CNS of MS patients. ANN NEUROL 2019;86:264-278.
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http://dx.doi.org/10.1002/ana.25508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771938PMC
August 2019

Time Is Brain and Spine-Reply.

JAMA Neurol 2019 05;76(5):623-624

Department of Neurology, MS Center ErasMS, Erasmus MC, Rotterdam, the Netherlands.

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http://dx.doi.org/10.1001/jamaneurol.2019.0149DOI Listing
May 2019

Real-world validation of the 2017 McDonald criteria for pediatric MS.

Neurol Neuroimmunol Neuroinflamm 2019 03 14;6(2):e528. Epub 2018 Dec 14.

Department of Neurology (Y.Y.M.W., C.L.d.M., R.M.v.d.V.d.V., E.D.v.P., I.A.K., R.Q.H.), MS Centre ErasMS, Erasmus MC, Rotterdam, The Netherlands; and Department of Pediatric Neurology (C.E.C.-B., R.F.N.), Erasmus MC, Rotterdam, The Netherlands.

Objective: To compare the diagnostic accuracy of the McDonald 2017 vs the McDonald 2010 criteria to predict a second attack of MS (clinically definite MS [CDMS]) at the first attack of acquired demyelinating syndromes (ADS).

Methods: One hundred sixty-four children (aged <18 years) with an incident attack of ADS were included in a prospective multicenter study between June 2006 and December 2016. Brain (and spinal if available) MRI was performed ≤3 months after symptom onset. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were compared at baseline between the 2010 and 2017 criteria.

Results: Among the 164 patients, 110 patients (67%) presented without encephalopathy (ADS-, female 63%; median age 14.8 years, IQR 11.3-16.1years) and 54 (33%) with encephalopathy (acute disseminated encephalomyelitis [ADEM], female 52%; median age 4.0 years, IQR 2.6-6.1 years). Of the 110 ADS- patients, 52 (47%) were diagnosed with CDMS within a median follow-up of 4.5 years (IQR 2.6-6.7 years). The sensitivity was higher for the 2017 criteria than for the 2010 criteria (83%; 95% CI 67-92, vs 49%; 95% CI 33-65; < 0.001), but the specificity was lower (73%; 95% CI 59-84 vs 87%; 95% CI 74-94, = 0.02). At baseline, 48 patients fulfilled the 2017 criteria compared with 27 patients when using the 2010 criteria. The results for children aged <12 years without encephalopathy were similar. In patients with ADEM, 8% fulfilled the 2010 criteria and 10% the 2017 criteria at baseline but no patient fulfilled the criteria for CDMS.

Conclusions: The McDonald 2017 criteria are more sensitive than the McDonald 2010 criteria for predicting CDMS at baseline. These criteria can also be applied in children aged <12 years without encephalopathy but not in children with ADEM.

Classification Of Evidence: This study provides Class II evidence that in children with ADS, the 2017 McDonald criteria are more sensitive but less specific than the 2010 McDonald criteria for predicting CDMS.
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http://dx.doi.org/10.1212/NXI.0000000000000528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340337PMC
March 2019

Paediatric multiple sclerosis: early diagnosis as a first step.

Authors:
Rogier Q Hintzen

Lancet Child Adolesc Health 2018 03 1;2(3):161-162. Epub 2018 Feb 1.

MS Centre ErasMS, Dept of Neurology, Erasmus MC, 3000 CA Rotterdam, Netherlands. Electronic address:

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http://dx.doi.org/10.1016/S2352-4642(18)30028-2DOI Listing
March 2018

The macrophage migration inhibitory factor pathway in human B cells is tightly controlled and dysregulated in multiple sclerosis.

Eur J Immunol 2018 11 25;48(11):1861-1871. Epub 2018 Sep 25.

Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.

In MS, B cells survive peripheral tolerance checkpoints to mediate local inflammation, but the underlying molecular mechanisms are relatively underexplored. In mice, the MIF pathway controls B-cell development and the induction of EAE. Here, we found that MIF and MIF receptor CD74 are downregulated, while MIF receptor CXCR4 is upregulated in B cells from early onset MS patients. B cells were identified as the main immune subset in blood expressing MIF. Blocking of MIF and CD74 signaling in B cells triggered CXCR4 expression, and vice versa, with separate effects on their proinflammatory activity, proliferation, and sensitivity to Fas-mediated apoptosis. This study reveals a new reciprocal negative regulation loop between CD74 and CXCR4 in human B cells. The disturbance of this loop during MS onset provides further insights into how pathogenic B cells survive peripheral tolerance checkpoints to mediate disease activity in MS.
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http://dx.doi.org/10.1002/eji.201847623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282801PMC
November 2018

Application of the 2017 Revised McDonald Criteria for Multiple Sclerosis to Patients With a Typical Clinically Isolated Syndrome.

JAMA Neurol 2018 11;75(11):1392-1398

Department of Neurology, MS Center ErasMS, Erasmus MC, Rotterdam, the Netherlands.

Importance: In 2017, the International Panel on Diagnosis of Multiple Sclerosis revised the McDonald 2010 criteria for the diagnosis of multiple sclerosis (MS). The new criteria are easier to apply and could lead to more and earlier diagnoses. It is important to validate these criteria globally for their accuracy in clinical practice.

Objective: To evaluate the diagnostic accuracy of the 2017 criteria vs the 2010 criteria in prediction of clinically definite MS in patients with a typical clinically isolated syndrome (CIS).

Design, Setting And Patients: A total of 251 patients at Erasmus MC, Rotterdam, the Netherlands, in collaboration with several regional hospitals, fulfilled the inclusion criteria. Thirteen patients received another diagnosis early in the diagnostic process and therefore were excluded from the analyses. Nine patients with CIS declined to participate in the study. This left 229 patients who were included between March 2006 and August 2016 in this prospective CIS cohort. Patients underwent a baseline magnetic resonance imaging scan within 3 months after onset of symptoms and, if clinically required, a lumbar puncture was performed. Data were analyzed between December 2017 and January 2018.

Main Outcomes And Measures: Sensitivity, specificity, accuracy, and positive and negative predictive value were calculated after 1, 3, and 5 years for the 2017 vs the 2010 criteria.

Results: Among the 229 patients with CIS, 167 were women (73%), and the mean (SD) age was 33.5 (8.2) years. One hundred thirteen patients (49%) were diagnosed as having CDMS during a mean (SD) follow-up time of 65.3 (30.9) months. Sensitivity for the 2017 criteria was higher than for the 2010 criteria (68%; 95% CI, 57%-77% vs 36%; 95% CI, 27%-47%; P < .001), but specificity was lower (61%; 95% CI, 50%-71% vs 85%; 95% CI, 76%-92%; P < .001). Using the 2017 criteria, more MS diagnoses could be made at baseline (n = 97 [54%]; 95% CI, 47%-61% vs n = 46 [26%]; 95% CI, 20%-32%; P < .001). In the group with at least 5 years of follow-up, 33% of patients who were diagnosed as having MS using the 2017 criteria did not experience a second attack during follow-up vs 23% when using the 2010 criteria.

Conclusions And Relevance: The 2017 revised McDonald criteria are associated with greater sensitivity but less specificity for a second attack than the previous 2010 criteria. The tradeoff is that it leads to a higher number of MS diagnoses in patients with a less active disease course.
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http://dx.doi.org/10.1001/jamaneurol.2018.2160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6248116PMC
November 2018

Chemical and genetic control of IFNγ-induced MHCII expression.

EMBO Rep 2018 09 18;19(9). Epub 2018 Jul 18.

Department of Cell and Chemical Biology, LUMC, Leiden, The Netherlands

The cytokine interferon-γ (IFNγ) can induce expression of MHC class II (MHCII) on many different cell types, leading to antigen presentation to CD4 T cells and immune activation. This has also been linked to anti-tumour immunity and graft-versus-host disease. The extent of MHCII upregulation by IFNγ is cell type-dependent and under extensive control of epigenetic regulators and signalling pathways. Here, we identify novel genetic and chemical factors that control this form of MHCII expression. Loss of the oxidative stress sensor Keap1, autophagy adaptor p62/SQSTM1, ubiquitin E3-ligase Cullin-3 and chromatin remodeller BPTF impair IFNγ-mediated MHCII expression. A similar phenotype is observed for arsenite, an oxidative stressor. Effects of the latter can be reversed by the inhibition of HDAC1/2, linking oxidative stress conditions to epigenetic control of MHCII expression. Furthermore, dimethyl fumarate, an antioxidant used for the treatment of several autoimmune diseases, impairs the IFNγ response by manipulating transcriptional control of MHCII We describe novel pathways and drugs related to oxidative conditions in cells impacting on IFNγ-mediated MHCII expression, which provide a molecular basis for the understanding of MHCII-associated diseases.
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http://dx.doi.org/10.15252/embr.201745553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123650PMC
September 2018

T-cell activation marker sCD27 is associated with clinically definite multiple sclerosis in childhood-acquired demyelinating syndromes.

Mult Scler 2018 11 18;24(13):1715-1724. Epub 2018 Jul 18.

Department of Neurology, Erasmus MC, Rotterdam, The Netherlands/Department of Immunology, Erasmus MC, Rotterdam, The Netherlands.

Background: Cerebrospinal fluid (CSF) levels of T-cell activation marker soluble CD27 (sCD27) are associated with subsequent disease activity after a first attack of suspected MS in adults. The predictive value for disease course in children with acquired demyelinating syndromes (ADS) is unknown.

Objectives: To assess the predictive value of sCD27 levels for clinically definite multiple sclerosis (CDMS) diagnosis in childhood ADS.

Methods: Children <18 years with a first demyelinating event were prospectively included and followed. Soluble CD27 was determined in CSF using an enzyme-linked immunosorbent assay (ELISA). Cox regression analyses were used to calculate hazard ratios (HRs) for CDMS.

Results: A total of 94 ADS children were included (ADS with encephalopathy (ADS+) n = 33 and ADS without encephalopathy (ADS-) n = 61). Of the 61 ADS- children, 21 (48%) were diagnosed with CDMS during follow-up. At baseline, sCD27 levels were higher in patients with a future CDMS diagnosis ( n = 29) than in monophasic ADS+ ( n = 30), monophasic ADS- ( n = 28) and relapsing non-MS patients ( n = 7; p < 0.001). In ADS- patients, sCD27 was associated with CDMS (HR = 1.8 per 100 U/mL increase in sCD27 levels, p = 0.031), after adjustments for age, oligoclonal bands and the presence of dissemination in space on baseline magnetic resonance imaging (MRI).

Conclusion: CSF sCD27 levels at first attack of demyelination were associated with CDMS diagnosis in children. This makes sCD27 a potential clinically relevant quantitative marker when performing routine CSF diagnostics.
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http://dx.doi.org/10.1177/1352458518786655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6238180PMC
November 2018

Linkage analysis and whole exome sequencing identify a novel candidate gene in a Dutch multiple sclerosis family.

Mult Scler 2019 06 6;25(7):909-917. Epub 2018 Jun 6.

Department of Neurology, MS Center ErasMS, Erasmus Medical Centre, Rotterdam, The Netherlands.

Background: Multiple sclerosis (MS) is a complex disease resulting from the joint effect of many genes. It has been speculated that rare variants might explain part of the missing heritability of MS.

Objective: To identify rare coding genetic variants by analyzing a large MS pedigree with 11 affected individuals in several generations.

Methods: Genome-wide linkage screen and whole exome sequencing (WES) were performed to identify novel coding variants in the shared region(s) and in the known 110 MS risk loci. The candidate variants were then assessed in 591 MS patients and 3169 controls.

Results: Suggestive evidence for linkage was obtained to 7q11.22-q11.23. In WES data, a rare missense variant p.R183C in FKBP6 was identified that segregated with the disease in this family. The minor allele frequency was higher in an independent cohort of MS patients than in healthy controls (1.27% vs 0.95%), but not significant (odds ratio (OR) = 1.33 (95% confidence interval (CI): 0.8-2.4), p = 0.31).

Conclusion: The rare missense variant in FKBP6 was identified in a large Dutch MS family segregating with the disease. This association to MS was not found in an independent MS cohort. Overall, genome-wide studies in larger cohorts are needed to adequately investigate the role of rare variants in MS risk.
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http://dx.doi.org/10.1177/1352458518777202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545620PMC
June 2019

High neurofilament levels are associated with clinically definite multiple sclerosis in children and adults with clinically isolated syndrome.

Mult Scler 2019 06 18;25(7):958-967. Epub 2018 May 18.

Department of Neurology, MS Centre ErasMS, Erasmus MC, Rotterdam, The Netherlands.

Background: A promising biomarker for axonal damage early in the disease course of multiple sclerosis (MS) is neurofilament light chain (NfL). It is unknown whether NfL has the same predictive value for MS diagnosis in children as in adults.

Objective: To explore the predictive value of NfL levels in cerebrospinal fluid (CSF) for MS diagnosis in paediatric and adult clinically isolated syndrome (CIS) patients.

Methods: A total of 88 adult and 65 paediatric patients with a first attack of demyelination were included and followed (mean follow up-time in adults: 62.8 months (standard deviation (SD) ±38.7 months) and 43.8 months (SD ±27.1 months) in children). Thirty control patients were also included. Lumbar puncture was done within 6 months after onset of symptoms. NfL was determined in CSF using enzyme-linked immunosorbent assay (ELISA). COX regression analyses were used to calculate hazard ratios (HR) for clinically definite multiple sclerosis (CDMS) diagnosis.

Results: After adjustments for age, oligoclonal bands (OCB), and asymptomatic T2 lesions on baseline magnetic resonance imaging (MRI), increased NfL levels in both paediatric and adult CIS patients were associated with a shorter time to CDMS diagnosis (children HR = 3.7; p = 0.007, adults HR = 2.1; p = 0.032). For CIS patients with a future CDMS diagnosis, children showed higher NfL levels than adults (geometric mean 4888 vs 2156 pg/mL; p = 0.007).

Conclusion: CSF NfL levels are associated with CDMS diagnosis in children and adults with CIS. This makes NfL a promising predictive marker for disease course with potential value in clinical practice.
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http://dx.doi.org/10.1177/1352458518775303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545618PMC
June 2019

T helper 17.1 cells associate with multiple sclerosis disease activity: perspectives for early intervention.

Brain 2018 05;141(5):1334-1349

Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.

Interleukin-17-expressing CD4+ T helper 17 (Th17) cells are considered as critical regulators of multiple sclerosis disease activity. However, depending on the species and pro-inflammatory milieu, Th17 cells are functionally heterogeneous, consisting of subpopulations that differentially produce interleukin-17, interferon-gamma and granulocyte macrophage colony-stimulating factor. In the current study, we studied distinct effector phenotypes of human Th17 cells and their correlation with disease activity in multiple sclerosis patients. T helper memory populations single- and double-positive for C-C chemokine receptor 6 (CCR6) and CXC chemokine receptor 3 (CXCR3) were functionally assessed in blood and/or cerebrospinal fluid from a total of 59 patients with clinically isolated syndrome, 35 untreated patients and 24 natalizumab-treated patients with relapsing-remitting multiple sclerosis, and nine patients with end-stage multiple sclerosis. Within the clinically isolated syndrome group, 23 patients had a second attack within 1 year and 26 patients did not experience subsequent attacks during a follow-up of >5 years. Low frequencies of T helper 1 (Th1)-like Th17 (CCR6+CXCR3+), and not Th17 (CCR6+CXCR3-) effector memory populations in blood strongly associated with a rapid diagnosis of clinically definite multiple sclerosis. In cerebrospinal fluid of clinically isolated syndrome and relapsing-remitting multiple sclerosis patients, Th1-like Th17 effector memory cells were abundant and showed increased production of interferon-gamma and granulocyte macrophage colony-stimulating factor compared to paired CCR6+ and CCR6-CD8+ T cell populations and their blood equivalents after short-term culturing. Their local enrichment was confirmed ex vivo using cerebrospinal fluid and brain single-cell suspensions. Across all pro-inflammatory T helper cells analysed in relapsing-remitting multiple sclerosis blood, Th1-like Th17 subpopulation T helper 17.1 (Th17.1; CCR6+CXCR3+CCR4-) expressed the highest very late antigen-4 levels and selectively accumulated in natalizumab-treated patients who remained free of clinical relapses. This was not found in patients who experienced relapses during natalizumab treatment. The enhanced potential of Th17.1 cells to infiltrate the central nervous system was supported by their predominance in cerebrospinal fluid of early multiple sclerosis patients and their preferential transmigration across human brain endothelial layers. These findings reveal a dominant contribution of Th1-like Th17 subpopulations, in particular Th17.1 cells, to clinical disease activity and provide a strong rationale for more specific and earlier use of T cell-targeted therapy in multiple sclerosis.
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http://dx.doi.org/10.1093/brain/awy069DOI Listing
May 2018

Smoking at time of CIS increases the risk of clinically definite multiple sclerosis.

J Neurol 2018 May 20;265(5):1010-1015. Epub 2018 Feb 20.

Department of Neurology, MS Centre ErasMS, Erasmus MC, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands.

Background: Cigarette smoking is a modifiable risk factor that influences the disease course of patients with multiple sclerosis (MS). However, in patients with a clinically isolated syndrome (CIS), there are conflicting results about the association between smoking and the risk of a subsequent MS diagnosis. The aim of this study was to determine the risk of clinically definite MS (CDMS) in smoking and non-smoking patients at time of a first demyelinating event.

Methods: Two hundred and fifty patients, aged 18-50 years, were included in our prospective CIS cohort. At time of the first neurological symptoms, patients completed a questionnaire about smoking habits. Cox regression analyses were performed to calculate univariate and multivariate hazard ratios for CDMS diagnosis in smoking and non-smoking CIS patients.

Results: One hundred and fourteen (46%) CIS patients were diagnosed with CDMS during a mean follow-up of 58 months. In total, 79 (32%) patients smoked at time of CIS. Sixty-seven % of the smoking CIS patients were diagnosed with CDMS during follow-up compared to 36% of the non-smoking CIS patients (p < 0.001). Smoking at time of CIS was an independent predictor for CDMS diagnosis (HR 2.3; p = 0.002). Non-smoking CIS patients who had a history of smoking did not have a higher risk for CDMS than those who had never smoked.

Conclusions: Smoking at time of CIS was an independent risk factor for a future CDMS diagnosis. This is an additional argument to quit smoking at time of the first attack of suspected MS.
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http://dx.doi.org/10.1007/s00415-018-8780-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5937895PMC
May 2018

Elevated EBNA-1 IgG in MS is associated with genetic MS risk variants.

Neurol Neuroimmunol Neuroinflamm 2017 Nov 12;4(6):e406. Epub 2017 Oct 12.

Department of Neurology (K.L.K., G.P.V.N., M.J., R.Q.H.), MS Center ErasMS (K.L.K., M.J., R.Q.H.), Department of Viroscience (G.P.V.N., S.M.J.S., G.M.G.M.V.), and Department of Immunology (M.J., R.Q.H.), Erasmus MC, University Medical Center, Rotterdam, The Netherlands.

Objective: To assess whether MS genetic risk polymorphisms (single nucleotide polymorphism [SNP]) contribute to the enhanced humoral immune response against Epstein-Barr virus (EBV) infection in patients with MS.

Methods: Serum anti-EBV nuclear antigen 1 (EBNA-1) and early antigen D (EA-D) immunoglobulin γ (IgG) levels were quantitatively determined in 668 genotyped patients with MS and 147 healthy controls. Anti-varicella-zoster virus (VZV) IgG levels were used as a highly prevalent, non-MS-associated control herpesvirus. Associations between virus-specific IgG levels and MS risk SNPs were analyzed.

Results: IgG levels of EBNA-1, but not EA-D and VZV, were increased in patients with MS compared with healthy controls. Increased EBNA-1 IgG levels were significantly associated with risk alleles of SNP rs2744148 (SOX8), rs11154801 (MYB), rs1843938 (CARD11), and rs7200786 (CLEC16A/CIITA) in an interaction model and a trend toward significance for rs3135388 (HLA-DRB1*1501). In addition, risk alleles of rs694739 (PRDX5/BAD) and rs11581062 (VCAM1) were independently associated and interacted with normal EBNA-1 IgG levels. None of these interactions were associated with EA-D and VZV IgG titers.

Conclusions: Several MS-associated SNPs significantly correlated with differential IgG levels directed to a latent, but not a lytic EBV protein. The data suggest that the aforementioned immune-related genes orchestrate the aberrant EBNA-1 IgG levels.
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http://dx.doi.org/10.1212/NXI.0000000000000406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5778394PMC
November 2017

Specific myelopathy diagnoses using advancing diagnostics: Idiopathic no more.

Neurology 2018 01 15;90(2):51-52. Epub 2017 Dec 15.

From the Department of Pediatrics (Neurology) (E.A.Y.), SickKids Research Institute, Division of Neurosciences and Mental Health, Hospital for Sick Children, University of Toronto, Canada; and Departments of Neurology and Immunology (R.Q.H.), Erasmus MC, Rotterdam, the Netherlands.

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http://dx.doi.org/10.1212/WNL.0000000000004812DOI Listing
January 2018

Regulator of oligodendrocyte maturation, miR-219, a potential biomarker for MS.

J Neuroinflammation 2017 Dec 4;14(1):235. Epub 2017 Dec 4.

Department of Neurology, Donders Institute for Brain Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.

Background: Multiple sclerosis (MS) is a demyelinating and degenerative disease of the central nervous system. Normally, demyelination is followed by remyelination, which requires repopulation of a demyelinated area by oligodendrocyte precursor cells. Although large numbers of precursor cells are present in MS lesions, remyelination often fails, in part by the inability of precursor cells to differentiate into mature myelin-forming cells. In mouse and rat, miR-219 is required for this differentiation. Previously, we identified decreased miR-219 expression in tissue of MS patients compared to controls. Cell-free miRNAs have been detected in many different body fluids including cerebrospinal fluid (CSF) and may reflect disease processes going on in the central nervous system. This prompted us to investigate the biomarker performance of CSF miR-219 for MS diagnosis.

Methods: Quantitative PCR was performed measuring miR-219 levels in CSF of MS patients and controls in three independent cohorts.

Results: All three cohorts of MS patients and controls revealed that absence of miR-219 detection in CSF is consistently associated with MS.

Conclusions: We have been able to identify and validate absence of miR-219 detection in CSF of MS patients compared to controls, suggesting that it may emerge as a candidate biomarker for MS diagnosis.
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http://dx.doi.org/10.1186/s12974-017-1006-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716023PMC
December 2017

Decreased Neuro-Axonal Proteins in CSF at First Attack of Suspected Multiple Sclerosis.

Proteomics Clin Appl 2017 Dec 23;11(11-12). Epub 2017 Oct 23.

Departments of Neurology, Erasmus MC, Rotterdam, the Netherlands.

The pathology of multiple sclerosis is located in the central nervous system, therefore cerebrospinal fluid (CSF) is an attractive biofluid for biomarker research for proteins related to the early stages of this disease. In this study, the CSF proteome of patients with a clinically isolated syndrome of demyelination (CIS, a first attack of multiple sclerosis) is compared to the CSF proteome of control patients to identify differentially abundant proteins. CSF samples of 47 CIS patients and 45 control subjects are enzymatically digested and subsequently measured by LC-MS/MS (LTQ-Orbitrap). Following mass spectrometry differential abundances of the identified proteins between groups are investigated. A total of 3159 peptides are identified, relating to 485 proteins. One protein is significantly more abundant in CSF of CIS patients than in controls: Ig kappa chain C region. In contrast, 35 proteins are significantly lower in CIS patients than controls, most of them with functions in nervous system development and function, such as amyloid-like protein 1 (validated by ELISA in an independent sample set (p < 0.01)), contactin 1, contactin 2 and neuronal cell adhesion molecule. A remarkably lower abundance of neuro-axonal proteins is observed in patients with a first demyelinating event compared to controls.
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http://dx.doi.org/10.1002/prca.201700005DOI Listing
December 2017

Phenotypic and functional characterization of T cells in white matter lesions of multiple sclerosis patients.

Acta Neuropathol 2017 Sep 17;134(3):383-401. Epub 2017 Jun 17.

Department of Viroscience, Erasmus MC, University Medical Center, Room Ee1720a, 's-Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands.

T cells are considered pivotal in the pathology of multiple sclerosis (MS), but their function and antigen specificity are unknown. To unravel the role of T cells in MS pathology, we performed a comprehensive analysis on T cells recovered from paired blood, cerebrospinal fluid (CSF), normal-appearing white matter (NAWM) and white matter lesions (WML) from 27 MS patients with advanced disease shortly after death. The differentiation status of T cells in these compartments was determined by ex vivo flow cytometry and immunohistochemistry. T-cell reactivity in short-term T-cell lines (TCL), generated by non-specific stimulation of T cells recovered from the same compartments, was determined by intracellular cytokine flow cytometry. Central memory T cells predominated in CSF and effector memory T cells were enriched in NAWM and WML. WML-derived CD8 T cells represent chronically activated T cells expressing a cytotoxic effector phenotype (CD95L and granzyme B) indicative for local antigenic stimulation (CD137). The same lesions also contained higher CD8 T-cell frequencies expressing co-inhibitory (TIM3 and PD1) and co-stimulatory (ICOS) T-cell receptors, yet no evidence for T-cell senescence (CD57) was observed. The oligoclonal T-cell receptor (TCR) repertoire, particularly among CD8 T cells, correlated between TCL generated from anatomically separated WML of the same MS patient, but not between paired NAWM and WML. Whereas no substantial T-cell reactivity was detected towards seven candidate human MS-associated autoantigens (cMSAg), brisk CD8 T-cell reactivity was detected in multiple WML-derived TCL towards autologous Epstein-Barr virus (EBV) infected B cells (autoBLCL). In one MS patient, the T-cell response towards autoBLCL in paired intra-lesional TCL was dominated by TCRVβ2CD8 T cells, which were localized in the parenchyma of the respective tissues expressing a polarized TCR and CD8 expression suggesting immunological synapse formation in situ. Collectively, the data suggest the involvement of effector memory cytotoxic T cells recognizing antigens expressed by autoBLCL, but not the assayed human cMSAg, in WML of MS patients.
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http://dx.doi.org/10.1007/s00401-017-1744-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5563341PMC
September 2017

Burden of genetic risk variants in multiple sclerosis families in the Netherlands.

Mult Scler J Exp Transl Clin 2016 Jan-Dec;2:2055217316648721. Epub 2016 May 6.

Department of Neurology, Erasmus Medical Centre, the Netherlands.

Background: Approximately 20% of multiple sclerosis patients have a family history of multiple sclerosis. Studies of multiple sclerosis aggregation in families are inconclusive.

Objective: To investigate the genetic burden based on currently discovered genetic variants for multiple sclerosis risk in patients from Dutch multiple sclerosis multiplex families versus sporadic multiple sclerosis cases, and to study its influence on clinical phenotype and disease prediction.

Methods: Our study population consisted of 283 sporadic multiple sclerosis cases, 169 probands from multiplex families and 2028 controls. A weighted genetic risk score based on 102 non-human leukocyte antigen loci and was calculated.

Results: The weighted genetic risk score based on all loci was significantly higher in familial than in sporadic cases. The contributed significantly to the difference in genetic burden between the groups. A high weighted genetic risk score was significantly associated with a low age of disease onset in all multiple sclerosis patients, but not in the familial cases separately. The genetic risk score was significantly but modestly better in discriminating familial versus sporadic multiple sclerosis from controls.

Conclusion: Familial multiple sclerosis patients are more loaded with the common genetic variants than sporadic cases. The difference is mainly driven by . The predictive capacity of genetic loci is poor and unlikely to be useful in clinical settings.
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http://dx.doi.org/10.1177/2055217316648721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5433503PMC
May 2016

Fatigue after a first attack of suspected multiple sclerosis.

Mult Scler 2018 06 23;24(7):974-981. Epub 2017 May 23.

MS Centrum ErasMS, Department of Neurology, Erasmus MC, Rotterdam, The Netherlands.

Background: Fatigue is reported by more than 75% of multiple sclerosis (MS) patients. In an earlier study, we showed that fatigue is not only a common symptom in patients at time of clinically isolated syndrome (CIS; fatigued 46%) but also predicts subsequent diagnosis of clinically definite multiple sclerosis (CDMS). The course of fatigue after CIS is unknown.

Objective: We aimed to explore the long-term course of fatigue after CIS.

Methods: In this study, 235 CIS patients, aged 18-50 years, were prospectively followed. Patients filled in the Krupp's Fatigue Severity Scale (FSS) and the Hospital Anxiety and Depression Scale (HADS) at baseline and annually. After reaching CDMS diagnosis, Expanded Disability Status Scale (EDSS) was obtained annually. Mixed-effects models were used to analyse longitudinal FSS measurements.

Results: Fatigue at baseline was an independent predictor for CDMS diagnosis (hazard ratio (HR): 2.6, 95% confidence interval (CI): 1.6-4.4). The evolution of FSS was the same in CIS patients who remained monophasic and patients who were diagnosed with CDMS during follow-up. However, FSS increased by 0.86 units after reaching CDMS diagnosis ( p = 0.01). After this increase, the FSS course remained unaltered ( p = 0.44).

Conclusion: Fatigue, which is often present at time of CIS, probably persists over time and increases after a second attack.
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http://dx.doi.org/10.1177/1352458517709348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6027780PMC
June 2018

Fatigue and physical functioning in children with multiple sclerosis and acute disseminated encephalomyelitis.

Mult Scler 2018 06 26;24(7):982-990. Epub 2017 Apr 26.

Department of Pediatric Neurology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.

Background And Objective: Fatigue and physical impairments are a major concern in children with multiple sclerosis (MS) and after acute disseminated encephalomyelitis (post-ADEM). We here aimed to evaluate the interaction between fatigue, exercise capacity, motor performance, neurological status, and quality of life (HRQoL).

Methods: In this cross-sectional study, data of 38 children (MS n = 22, post-ADEM n = 16), aged 4-17 years attending our national pediatric MS center, were studied. Fatigue was measured with the Pediatric Quality of Life Multidimensional Fatigue Scale, exercise capacity with the Bruce Protocol, motor performance with the Movement Assessment Battery for Children second edition, HRQoL with the Pediatric Quality of Life Questionnaire, and extent of disability with the Expanded Disability Status Scale (EDSS).

Results: Children with MS and post-ADEM experienced more fatigue ( p < 0.001), reduced exercise capacity ( p < 0.001), and impaired motor performance ( p < 0.001), despite low scores on the EDSS. Fatigue, but not the other parameters, was significantly correlated with HRQoL. Fatigue was not correlated with exercise capacity.

Conclusion: We confirm the major impact of fatigue on quality of life in children with MS and post-ADEM. Fatigue was not explained by reduced exercise capacity or impaired motor performance. An important finding for clinical practice is that the low EDSS score did not reflect the poor physical functioning.
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http://dx.doi.org/10.1177/1352458517706038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6027779PMC
June 2018

Axonal transport deficits in multiple sclerosis: spiraling into the abyss.

Acta Neuropathol 2017 07 18;134(1):1-14. Epub 2017 Mar 18.

Department Of Neurology, Erasmus MC Rotterdam, Rotterdam, The Netherlands.

The transport of mitochondria and other cellular components along the axonal microtubule cytoskeleton plays an essential role in neuronal survival. Defects in this system have been linked to a large number of neurological disorders. In multiple sclerosis (MS) and associated models such as experimental autoimmune encephalomyelitis (EAE), alterations in axonal transport have been shown to exist before neurodegeneration occurs. Genome-wide association (GWA) studies have linked several motor proteins to MS susceptibility, while neuropathological studies have shown accumulations of proteins and organelles suggestive for transport deficits. A reduced effectiveness of axonal transport can lead to neurodegeneration through inhibition of mitochondrial motility, disruption of axoglial interaction or prevention of remyelination. In MS, demyelination leads to dysregulation of axonal transport, aggravated by the effects of TNF-alpha, nitric oxide and glutamate on the cytoskeleton. The combined effect of all these pathways is a vicious cycle in which a defective axonal transport system leads to an increase in ATP consumption through loss of membrane organization and a reduction in available ATP through inhibition of mitochondrial transport, resulting in even further inhibition of transport. The persistent activity of this positive feedback loop contributes to neurodegeneration in MS.
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http://dx.doi.org/10.1007/s00401-017-1697-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5486629PMC
July 2017

Genetic susceptibility to multiple sclerosis: Brain structure and cognitive function in the general population.

Mult Scler 2017 Nov 21;23(13):1697-1706. Epub 2016 Dec 21.

Department of Epidemiology, Erasmus University Medical Center (Erasmus MC), Rotterdam, The Netherlands/Department of Radiology, Erasmus University Medical Center (Erasmus MC), Rotterdam, The Netherlands.

Background: Multiple sclerosis (MS) affects brain structure and cognitive function and has a heritable component. Over a 100 common genetic risk variants have been identified, but most carriers do not develop MS. For other neurodegenerative diseases, risk variants have effects outside patient populations, but this remains uninvestigated for MS.

Objectives: To study the effect of MS-associated genetic variants on brain structure and cognitive function in the general population.

Methods: We studied middle-aged and elderly individuals (mean age = 65.7 years) from the population-based Rotterdam Study. We determined 107 MS variants and additionally created a risk score combining all variants. Magnetic resonance imaging ( N = 4710) was performed to obtain measures of brain macrostructure, white matter microstructure, and gray matter voxel-based morphometry. A cognitive test battery ( N = 7556) was used to test a variety of cognitive domains.

Results: The MS risk score was associated with smaller gray matter volume over the whole brain (β = -0.016; p = 0.044), but region-specific analyses did not survive multiple testing correction. Similarly, no significant associations with brain structure were observed for individual variants. For cognition, rs2283792 was significantly associated with poorer memory (β = -0.064; p = 3.4 × 10).

Conclusion: Increased genetic susceptibility to MS may affect brain structure and cognition in persons without disease, pointing to a "hidden burden" of MS.
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http://dx.doi.org/10.1177/1352458516682104DOI Listing
November 2017

Soluble CD27 Levels in Cerebrospinal Fluid as a Prognostic Biomarker in Clinically Isolated Syndrome.

JAMA Neurol 2017 03;74(3):286-292

Department of Neurology, MS Center ErasMS, Erasmus MC, Rotterdam, the Netherlands.

Importance: There is a growing number of therapies that could be administered after the first symptom of central nervous system demyelination. These drugs can delay multiple sclerosis (MS) diagnosis and slow down future disability. However, treatment of patients with benign course may not be needed; therefore, there is a need for biomarkers to predict long-term prognosis in patients with clinically isolated syndrome (CIS).

Objective: To investigate whether the T-cell activation marker soluble CD27 (sCD27) measured in cerebrospinal fluid of patients at time of a first attack is associated with a subsequent diagnosis of MS and a higher relapse rate.

Design, Setting, And Participants: This prospective study included 77 patients with CIS between March 2002 and May 2015 in a tertiary referral center for multiple sclerosis, in collaboration with several regional hospitals. Patients with CIS underwent a lumbar puncture and magnetic resonance imaging scan within 6 months after first onset of symptoms.

Main Outcomes And Measures: Soluble CD27 levels were determined in cerebrospinal fluid using a commercially available enzyme-linked immunosorbent assay. Cox regression analyses was used to calculate univariate and multivariate hazard ratios for MS diagnosis. Association between sCD27 levels and relapse rate was assessed using a negative binomial regression model.

Results: Among 77 patients with CIS, 50 were female (79.5%), and mean (SD) age was 32.7 (7.4) years. Mean (SD) age in the control individuals was 33.4 (9.5) years, and 20 were female (66.7%).Patients with CIS had higher cerebrospinal fluid sCD27 levels than control individuals (geometric mean, 31.3 U/mL; 95% CI, 24.0-40.9 vs mean, 4.67 U/mL; 95% CI, 2.9-7.5; P < .001). During a mean (SD) follow-up of 54.8 (35.1) months, 39 of 77 patients (50.6%) were diagnosed as having MS. In a model adjusted for magnetic resonance imaging and cerebrospinal fluid measurements, sCD27 levels were associated with a diagnosis of MS (hazard ratio, 2.4 per 100 U/mL increase in sCD27 levels; 95% CI, 1.27-4.53; P = .007). Additionally, patients with MS with high sCD27 levels (median, >31.4 U/mL) at the time of CIS had a 5.5 times higher annualized relapse rate than patients with low sCD27 levels (annualized relapse rate, 0.06 vs 0.33; P = .02).

Conclusions And Relevance: Soluble CD27 in cerebrospinal fluid of patients with CIS was associated with MS diagnosis and a high relapse rate. Therefore, sCD27 is an activation molecule directly related to the immunopathology of the disease and is a potential clinical marker to help in treatment decisions after a first attack of suspected MS.
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http://dx.doi.org/10.1001/jamaneurol.2016.4997DOI Listing
March 2017

Evolution of MRI abnormalities in paediatric acute disseminated encephalomyelitis.

Eur J Paediatr Neurol 2017 Mar 6;21(2):300-304. Epub 2016 Sep 6.

Department of Neurology, MS Centre ErasMS, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, The Netherlands; Department of Paediatric Neurology, Erasmus MC-Sophia, PO Box 2060, 3000 CB Rotterdam, The Netherlands. Electronic address:

Objective: Acute disseminating encephalomyelitis (ADEM) is an inflammatory demyelinating disease affecting the central nervous system and mainly occurs in young children. Children who initially presented with ADEM can be diagnosed with multiple sclerosis (MS) in case new non-encephalopathic clinical symptoms occur with new lesions on MRI at least three months after onset of ADEM. We aim to study the timing of MRI abnormalities related to the evolution of clinical symptoms in our Dutch paediatric ADEM cohort.

Methods: The Dutch database for acquired demyelinating syndromes (ADS) was screened for children under age eighteen fulfilling the international consensus diagnostic criteria for ADEM. Children were eligible when the first MRI was performed within the first three months after onset of clinical symptoms and at least one brain follow-up MRI was available for evaluation. Forty-two children with ADEM were included (median age four years two months). All available MRIs and medical records were assessed and categorised as 'improved', 'deteriorated' and 'unchanged'.

Results: We found that during clinical recovery, new lesions and enlargement of existing MRI lesions occurred in the first three months in about 50% of the performed MRIs. In contrast, this was rarely seen more than three months after first onset of ADEM.

Conclusion: We recommend to perform a brain MRI as a reference scan three months after onset. Follow-up imaging should be compared with this scan in order to prevent an incorrect diagnosis of MS after ADEM.
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http://dx.doi.org/10.1016/j.ejpn.2016.08.014DOI Listing
March 2017