Publications by authors named "Zsolt Illés"

159 Publications

Toll-Like Receptor Homolog CD180 Expression Is Diminished on Natural Autoantibody-Producing B Cells of Patients with Autoimmune CNS Disorders.

J Immunol Res 2021 25;2021:9953317. Epub 2021 May 25.

Department of Immunology and Biotechnology, Clinical Center, University of Pécs Medical School, H-7624 Pécs, Hungary.

Purpose: Decreased expression of TLR homolog CD180 in peripheral blood B cells and its potential role in antibody production have been described in autoimmune diseases. Effectiveness of anti-CD20 therapy in neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) strengthens the role of B cells in the pathogenesis. Therefore, we aimed to investigate the CD180 expression of peripheral blood B cell subsets in NMOSD and MS patients and analyze the levels of natural anti-citrate synthase (CS) IgG autoantibodies and IgG antibodies induced by bacterial infections reported to play a role in the pathogenesis of NMOSD or MS.

Methods: We analyzed the distribution and CD180 expression of peripheral blood B cell subsets, defined by CD19/CD27/IgD staining, and measured anti-CS IgM/G natural autoantibody and antibacterial IgG serum levels in NMOSD, RRMS, and healthy controls (HC).

Results: We found decreased naïve and increased memory B cells in NMOSD compared to MS. Among the investigated four B cell subsets, CD180 expression was exclusively decreased in CD19CD27IgD nonswitched (NS) memory B cells in both NMOSD and MS compared to HC. Furthermore, the anti-CS IgM natural autoantibody serum level was lower in both NMOSD and MS. In addition, we found a tendency of higher anti-CS IgG natural autoantibody levels only in anti-Chlamydia IgG antibody-positive NMOSD and MS patients.

Conclusions: Our results suggest that reduced CD180 expression of NS B cells could contribute to the deficient natural IgM autoantibody production in NMOSD and MS, whereas natural IgG autoantibody levels show an association with antibacterial antibodies.
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http://dx.doi.org/10.1155/2021/9953317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169253PMC
May 2021

Real-world outcomes for a complete nationwide cohort of more than 3200 teriflunomide-treated multiple sclerosis patients in The Danish Multiple Sclerosis Registry.

PLoS One 2021 18;16(5):e0250820. Epub 2021 May 18.

The Danish Multiple Sclerosis Registry, University Hospital Copenhagen, Rigshospitalet, Copenhagen, Denmark.

Objective: Teriflunomide is a once-daily, oral disease-modifying therapy (DMT) for relapsing forms of multiple sclerosis (MS). We studied clinical outcomes in a real-world setting involving a population-based large cohort of unselected patients enrolled in The Danish Multiple Sclerosis Registry (DMSR) who started teriflunomide treatment between 2013-2019.

Methods: This was a complete nationwide population-based cohort study with prospectively enrolled unselected cases. Demographic and disease-specific patient parameters related to treatment history, efficacy outcomes, and discontinuation and switching rates among other clinical variables were assessed at baseline and during follow-up visits.

Results: A total of 3239 patients (65.4% female) started treatment with teriflunomide during the study period, 56% of whom were treatment-naïve. Compared to previously treated patients, treatment-naïve patients were older on average at disease onset, had a shorter disease duration, a lower Expanded Disability Status Scale score at teriflunomide treatment start and more frequently experienced a relapse in the 12 months prior to teriflunomide initiation. In the 3001 patients initiating teriflunomide treatment at least 12 months before the cut-off date, 72.7% were still on treatment one year after treatment start. Discontinuations in the first year were due mainly to adverse events (15.6%). Over the full follow-up period, 47.5% of patients discontinued teriflunomide treatment. Sixty-three percent of the patients treated with teriflunomide for 5 years were relapse-free, while significantly more treatment-naïve versus previously treated patients experienced a relapse during the follow-up (p<0.0001). Furthermore, 85% of the patients with available data were free of disability worsening at the end of follow-up.

Conclusions: Solid efficacy and treatment persistence data consistent with other real-world studies were obtained over the treatment period. Treatment outcomes in this real-world scenario of the population-based cohort support previous findings that teriflunomide is an effective and generally well-tolerated DMT for relapsing MS patients with mild to moderate disease activity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250820PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130956PMC
May 2021

Autoantibodies Against the Complement Regulator Factor H in the Serum of Patients With Neuromyelitis Optica Spectrum Disorder.

Front Immunol 2021 27;12:660382. Epub 2021 Apr 27.

Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disease of the central nervous system (CNS), characterized by pathogenic, complement-activating autoantibodies against the main water channel in the CNS, aquaporin 4 (AQP4). NMOSD is frequently associated with additional autoantibodies and antibody-mediated diseases. Because the alternative pathway amplifies complement activation, our aim was to evaluate the presence of autoantibodies against the alternative pathway C3 convertase, its components C3b and factor B, and the complement regulator factor H (FH) in NMOSD. Four out of 45 AQP4-seropositive NMOSD patients (~9%) had FH autoantibodies in serum and none had antibodies to C3b, factor B and C3bBb. The FH autoantibody titers were low in three and high in one of the patients, and the avidity indexes were low. FH-IgG complexes were detected in the purified IgG fractions by Western blot. The autoantibodies bound to FH domains 19-20, and also recognized the homologous FH-related protein 1 (FHR-1), similar to FH autoantibodies associated with atypical hemolytic uremic syndrome (aHUS). However, in contrast to the majority of autoantibody-positive aHUS patients, these four NMOSD patients did not lack FHR-1. Analysis of autoantibody binding to FH19-20 mutants and linear synthetic peptides of the C-terminal FH and FHR-1 domains, as well as reduced FH, revealed differences in the exact binding sites of the autoantibodies. Importantly, all four autoantibodies inhibited C3b binding to FH. In conclusion, our results demonstrate that FH autoantibodies are not uncommon in NMOSD and suggest that generation of antibodies against complement regulating factors among other autoantibodies may contribute to the complement-mediated damage in NMOSD.
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http://dx.doi.org/10.3389/fimmu.2021.660382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111293PMC
April 2021

Muscle damage in response to a single bout of high intensity concentric exercise in patients with Pompe disease.

Ann Transl Med 2021 Mar;9(5):389

Department of Neurology, Medical School, University of Pécs, Pécs, Hungary.

Background: In Pompe disease, resistance exercise could be an effective treatment to delay motor function impairment, however, the acute effects of this exercise modality are unclear.

Methods: In a prospective cohort study, we compared responses to a single bout of resistance exercise by serum markers of muscle damage and quantitative muscle magnetic resonance imaging (MRI) in patients (n=12) and age- and gender-matched healthy controls (n=12). Participants performed 50 maximal effort concentric knee flexions on a dynamometer.

Results: Twenty-four hours after exercise, levels of serum creatine kinase, lactate dehydrogenase and myoglobin increased in controls. In contrast, only myoglobin level increased in patients. All elevated serum markers declined by 48 hours after exercise in both groups. Mild soreness developed at 24 hours, which disappeared at 48 hours in both groups. In controls, MRI R2* relaxation rate reduced immediately and 24 hours after exercise, indicating increased water content and muscle perfusion. In patients, exercise had no effect on R2* values. The resistance exercise did not induce acute strength deficit in patients, rather, patients increased their strength by 24 hours. When serum marker changes were normalized to the magnitude of knee flexor tension developed during exercise, lactate dehydrogenase response was greater in patients.

Conclusions: Late-onset Pompe disease did not exacerbate exercise-induced muscle damage, however, lactate dehydrogenase may be monitored to screen high responders during high intensity resistance exercise interventions.
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http://dx.doi.org/10.21037/atm-20-3114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033309PMC
March 2021

Microstructural and functional brain abnormalities in multiple sclerosis predicted by osteopontin and neurofilament light.

Mult Scler Relat Disord 2021 Mar 24;51:102923. Epub 2021 Mar 24.

Department of Neurology, Medical School, University of Pecs, Pecs, Hungary; Department of Neurology, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, Denmark. Electronic address:

Background: Osteopontin (OPN) is a proinflammatory biomarker, and neurofilament light chain (NFL) levels reflect axonal damage. Resting-state functional MRI (rs-fMRI) defines brain networks during wakeful rest.

Objective: To examine, if levels of OPN and NFL are associated on the long term with (i) lesion evolution, (ii) changes in normal-appearing white matter (NAWM) microstructure and (iii) functional connectivity in multiple sclerosis (MS).

Methods: Concentration of NFL and OPN in the blood and CSF were related to MRI findings 10.3 ± 2.8 years later in 53 patients with MS. NFL was examined by Simoa method, OPN by ELISA. Lesion volume in the brain and cervical spinal cord was examined by 3D FLAIR images. Voxel-wise images of fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD) were examined by tract-based spatial statistics corrected for gender, age and lesion volume. Metabolites were examined by single-voxel MR-spectroscopy in the NAWM. Fifty-five default mode network connections were examined by rs-fMRI corrected for gender, age, MS subtype and current therapy as covariates.

Results: While NFL in paired serum and CSF positively correlated (p = 0.019), there was no correlation between serum and CSF OPN. Higher OPN levels in the CSF but not in the serum showed association with increased brain WM lesion volume (p = 0.009) in 10.3 ± 2.8 years. Higher OPN in the CSF was associated with reduced FA, increased MD, and reduced RD in different NAWM areas 10.3 ± 2.8 years later. Higher OPN in the serum and CSF were associated with increased connectivity strength between the medial prefrontal cortex (MPFC) and other regions except with inferior parietal lobule. NFL in the CSF and in the serum was associated with decreased connectivity strength except for ventral MPFC-hippocampal formation. Neither serum OPN nor NFL at the time of the MRI were associated with functional connectivity changes.

Conclusion: While serum NFL levels reflects CNS production, OPN in serum and CSF may have different cellular sources. OPN within the CSF but not in the serum may forecast development of lesions and microstructural abnormalities in 10 years, indicating the detrimental role of CNS inflammation on the long-term. Although both OPN and NFL in the CSF were associated with functional connectivity changes in 10 years, NFL was associated with decreased strength possibly indicating general axonal loss. In contrast, the positive association of OPN levels in the CSF with increased connectivity strength in 10 years may point to adaptive re-organization due to inflammatory WM lesions and microstructural changes.
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http://dx.doi.org/10.1016/j.msard.2021.102923DOI Listing
March 2021

Alemtuzumab treatment in Denmark: A national study based on the Danish Multiple Sclerosis Registry.

Mult Scler 2021 Mar 29:13524585211003291. Epub 2021 Mar 29.

Department of Neurology, Odense University Hospital, Odense, Denmark/Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.

Objective: To investigate clinical outcomes in a real-world setting in the complete population-based cohort of alemtuzumab-treated MS patients in Denmark.

Methods: Data were retrieved from The Danish Multiple Sclerosis Registry between 2009 and 2019. Demographic and disease-specific patient parameters related to treatment history, efficacy, and safety outcomes were assessed at baseline and during follow-up visits.

Results: A total of 209 patients (78% female) started treatment with alemtuzumab during the study period with 3.1 ± 1.4 years follow-up. After 2 years, 75% of patients were relapse-free compared to 48% the year before alemtuzumab ( < 0.001). The annual number of relapses was reduced by 69% in year 4 compared with the year prior alemtuzumab. More active disease before alemtuzumab increased the annual hazard rate for relapse (HR: 2.88,  < 0.001). The Expanded Disability Status Scale (EDSS) score remained stable or improved in 81% of patients after 2 years. The need for an additional treatment course was associated with higher number of relapses in the year before alemtuzumab (odds ratio (OR) = 1.95,  = 0.001).

Conclusion: In a country with primarily escalation strategy, relapse rate reduction was maintained for 5 years, and EDSS stabilized/improved in majority of patients. Higher relapse rate 1 year before alemtuzumab increased the odds for additional courses. Novel serious AEs were not observed.
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http://dx.doi.org/10.1177/13524585211003291DOI Listing
March 2021

Clinical Characteristics and Outcome of Neuronal Surface Antibody-Mediated Autoimmune Encephalitis Patients in a National Cohort.

Front Neurol 2021 9;12:611597. Epub 2021 Mar 9.

Department of Immunology and Biotechnology, Clinical Center, University of Pécs Medical School, Pécs, Hungary.

In our previous single-center study of autoimmune encephalitis (AE) related autoantibody test results we found positivity in 60 patients out of 1,034 with suspected AE from 2012 through 2018 as part of a Hungarian nationwide program. In our current multicenter retrospective study, we analyzed the clinical characteristics and outcome of AE patients with positive neuronal cell surface autoantibody test results. A standard online questionnaire was used to collect demographic and clinical characteristics, laboratory and imaging data, therapy and prognosis of 30 definitive AE patients in four major clinical centers of the region. In our study, 19 patients were positive for anti-NMDAR (63%), 6 patients (20%) for anti-LGI1, 3 patients for anti-GABABR (10%) and 3 patients for anti-Caspr2 (10%) autoantibodies. Most common prodromal symptoms were fever or flu-like symptoms (10/30, 33%). Main clinical features included psychiatric symptoms (83%), epileptic seizures (73%) and memory loss (50%). 19 patients (63%) presented with signs of central nervous system (CNS) inflammation, which occurred more frequently in elder individuals ( = 0.024), although no significant differences were observed in sex, tumor association, time to diagnosis, prognosis and immunotherapy compared to AE patients without CNS inflammatory markers. Anti-NMDAR encephalitis patients were in more severe condition at the disease onset ( = 0.028), although no significant correlation between mRS score, age, sex and immunotherapy was found. 27% of patients ( = 8) with associated tumors had worse outcome ( = 0.045) than patients without tumor. In most cases, immunotherapy led to clinical improvement of AE patients (80%) who achieved a good outcome (mRS ≤ 2; median follow-up 33 months). Our study confirms previous publications describing characteristics of AE patients, however, differences were observed in anti-NMDAR encephalitis that showed no association with ovarian teratoma and occurred more frequently among young males. One-third of AE patients lacked signs of inflammation in both CSF and brain MRI, which emphasizes the importance of clinical symptoms and autoantibody testing in diagnostic workflow for early introduction of immunotherapy, which can lead to favorable outcome in AE patients.
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http://dx.doi.org/10.3389/fneur.2021.611597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985080PMC
March 2021

Population-based head-to-head comparison of the clinical characteristics and epidemiology of AQP4 antibody-positive NMOSD between two European countries.

Mult Scler Relat Disord 2021 Mar 3;51:102879. Epub 2021 Mar 3.

Department of Neurology, Odense University Hospital, Odense, Denmark; Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.

Background: Population-based clinical studies in neuromyelitis optica spectrum disorder (NMOSD) and epidemiological and clinical comparisons of White ethnicities are missing. In a large population-based international cohort, we extensively characterized aquaporin-4 antibody seropositive (AQP4-Ab+) NMOSD, and also compared the clinical, radiological and epidemiological features between two European populations residing in different areas.

Methods: Between self-reported Danish and Hungarian ethnicities, we compared the population-based clinical features, disability outcomes, and death of 134 AQP4-Ab+ NMOSD cases fulfilling the 2015 International Panel for NMO Diagnosis (IPND) criteria. For precise comparison of epidemiology, we conducted a population-based head-to-head comparative study of the age-standardized prevalence (January 1, 2014) and incidence (2007-2013) of AQP4-Ab+ NMO/NMOSD among adults (≥16 years) in Denmark (4.6 million) and Hungary (6.4 million) by applying 2015 IPND (NMOSD) criteria and 2006 Wingerchuk (NMO).

Results: Danes were more likely to present with transverse myelitis and were more affected by spinal cord damage on long-term disability. Hungarians presented most often with optic neuritis, although visual outcome was similar in the groups. No differences were observed in sex, disease course, relapse rate, autoimmune comorbidity, mortality, brain MRI, and treatment strategies. The age-standardized prevalence estimates of AQP4-Ab+ NMOSD (2015 IPND criteria) in Denmark vs. Hungary were 0.66 vs. 1.43 (/100,000) while incidence rates were 0.04 vs. 0.11 (/100,000 person-years); similar differences were found based on the 2006 NMO criteria.

Conclusions: This head-to-head comparative study indicates different disease characteristics and epidemiology among White populations in Europe, and substantiates the need for population-based genetic and environmental studies in NMOSD.
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http://dx.doi.org/10.1016/j.msard.2021.102879DOI Listing
March 2021

Comparison of neurofilament light chain results between two independent facilities.

BMJ Neurol Open 2020 19;2(2):e000063. Epub 2020 Oct 19.

Department of Neurology, University of Southern Denmark, Odense, Denmark.

Objectives: To examine levels of neurofilament light chain (NFL) in identical cerebrospinal fluid (CSF) and blood samples at two different facilities, and how differences affect interpretation of levels within and above the normal range.

Methods: CSF and plasma from patients with multiple sclerosis (MS) and healthy controls (HCs) were analysed by Simoa (Quanterix) for levels of NFL providing a total of 165 CSF samples (119 from MS) and 225 plasma samples (180 from MS).

Results: CSF and plasma concentrations highly correlated between NFL laboratory facilities (R: 0.92 and 0.84, <0.0001, respectively), and there were no differences between facilities. A bias between the two sites for plasma was -0.95 pg/mL and for CSF -73.53 pg/mL. The cut-offs for CSF were 807.5 and 571.0 pg/mL at site 1 and site 2, respectively; the cut-offs for plasma were 13.0 and 11.8 pg/mL, respectively. Seven out of 180 plasma samples (3.9%) and 3 out of 119 CSF samples (2.5%) from MS patients could be reclassified as normal/abnormal, that is, below/above cut-off, when measured at different facilities.

Conclusion: Our study demonstrates that results of NFL in CSF and blood measured with SIMOA are comparable between facilities. Nevertheless, healthcare practitioners should consider reference values at different laboratories, since different sensitivity/specificity can affect interpretation when low values are adjacent to cut-offs.
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http://dx.doi.org/10.1136/bmjno-2020-000063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871722PMC
October 2020

Elevated Neurofilament Light Chain in Cerebrospinal Fluid and Plasma Reflect Inflammatory MRI Activity in Neurosarcoidosis.

Brain Sci 2021 Feb 14;11(2). Epub 2021 Feb 14.

Rheumatology Research Unit, Odense University Hospital, J.B. Winsloewsvej 4, 5000 Odense, Denmark.

Background: Damage to axonal cells releases neurofilament light chain (NFL) into the cerebrospinal fluid and plasma. The objective of this study was to investigate NFL as a potential biomarker of disease activity in neurosarcoidosis. MRIs were graded according to enhancing lesions at different central nervous system (CNS) sites.

Results: In cerebrospinal fluid, levels of NFL were higher in neurosarcoidosis patients ( = 20) median 2304 pg/mL (interquartile range (IQR) 630-19,612) compared to 426 pg/mL (IQR 261-571) in extra-neurologic sarcoidosis patients ( = 20) and 336 pg/mL (IQR 194-402) in healthy controls ( = 11) ( = 0.0002). In plasma, levels of NFL were higher in neurosarcoidosis patients median 28.2 pg/mL (IQR 11.5-49.3) compared to 6.2 pg/mL (IQR 4.3-8.2) in extra-neurologic sarcoidosis patients and 7.1 pg/mL (IQR 6.2-9.0) in healthy controls ( = 0.0001). Levels in both cerebrospinal fluid and plasma were higher in neurosarcoidosis patients with moderate/severe enhancement than patients with mild enhancement on MRI ( = 0.009 and = 0.005, respectively). To distinguish neurosarcoidosis patients from extra-neurologic patients and healthy controls, a cut-off level of 630 pg/mL in cerebrospinal fluid had 94% specificity and 79% sensitivity, while a cut-off level of 11.4 pg/mL in plasma had 97% specificity and 75% sensitivity.

Conclusions: NFL levels in cerebrospinal fluid and plasma are significantly higher in neurosarcoidosis patients compared to extra-neurologic patients and healthy controls, and the levels correlate to the extent of inflammation on MRI.
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http://dx.doi.org/10.3390/brainsci11020238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918492PMC
February 2021

The levels of the serine protease HTRA1 in cerebrospinal fluid correlate with progression and disability in multiple sclerosis.

J Neurol 2021 Mar 4. Epub 2021 Mar 4.

Department of Molecular Medicine- Neurobiology Research, University of Southern Denmark, J.B. Winsløws Vej 21, 5000, Odense, Denmark.

Background: High Temperature Requirement Serine Protease A1 (HTRA1) degrades extracellular matrix molecules (ECMs) and growth factors. It interacts with several proteins implicated in multiple sclerosis (MS), but has not previously been linked to the disease.

Objective: Investigate the levels of HTRA1 in cerebrospinal fluid (CSF) in different subtypes of MS and brain tissue.

Methods: Using ELISA, HTRA1 levels were compared in CSF from untreated patients with relapsing-remitting MS (RRMS, n = 23), secondary progressive MS (SPMS, n = 26) and healthy controls (HCs, n = 26). The effect of disease modifying therapies (DMTs) were examined in both patient groups. Cellular distribution in human brain was studied using immunochemistry and the oligointernode database, based on a single-nuclei RNA expression map.

Results: HTRA1 increased in RRMS and SPMS compared to HCs. DMT decreased HTRA1 levels in both types of MS. Using ROC analysis, HTRA1 cut-offs could discriminate HCs from RRMS patients with 100% specificity and 82.6% sensitivity. In the brain, HTRA1 was expressed in glia and neurons.

Conclusion: HTRA1 is a promising CSF biomarker for MS correlating with disease- and disability progression. Most cell species of the normal and diseased CNS express HTRA1 and the expression pattern could reflect pathological processes involved in MS pathogenesis.
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http://dx.doi.org/10.1007/s00415-021-10489-7DOI Listing
March 2021

CSF proteome in multiple sclerosis subtypes related to brain lesion transcriptomes.

Sci Rep 2021 Feb 18;11(1):4132. Epub 2021 Feb 18.

Department of Neurology, Odense University Hospital, J.B. Winslowsvej 4, 5000, Odense C, Denmark.

To identify markers in the CSF of multiple sclerosis (MS) subtypes, we used a two-step proteomic approach: (i) Discovery proteomics compared 169 pooled CSF from MS subtypes and inflammatory/degenerative CNS diseases (NMO spectrum and Alzheimer disease) and healthy controls. (ii) Next, 299 proteins selected by comprehensive statistics were quantified in 170 individual CSF samples. (iii) Genes of the identified proteins were also screened among transcripts in 73 MS brain lesions compared to 25 control brains. F-test based feature selection resulted in 8 proteins differentiating the MS subtypes, and secondary progressive (SP)MS was the most different also from controls. Genes of 7 out these 8 proteins were present in MS brain lesions: GOLM was significantly differentially expressed in active, chronic active, inactive and remyelinating lesions, FRZB in active and chronic active lesions, and SELENBP1 in inactive lesions. Volcano maps of normalized proteins in the different disease groups also indicated the highest amount of altered proteins in SPMS. Apolipoprotein C-I, apolipoprotein A-II, augurin, receptor-type tyrosine-protein phosphatase gamma, and trypsin-1 were upregulated in the CSF of MS subtypes compared to controls. This CSF profile and associated brain lesion spectrum highlight non-inflammatory mechanisms in differentiating CNS diseases and MS subtypes and the uniqueness of SPMS.
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http://dx.doi.org/10.1038/s41598-021-83591-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892884PMC
February 2021

Unbiased examination of genome-wide human endogenous retrovirus transcripts in MS brain lesions.

Mult Scler 2021 Jan 19:1352458520987269. Epub 2021 Jan 19.

Department of Neurology, Odense University Hospital, Odense, Denmark/Neurology Research Unit, Department of Clinical Research, University of Southern Denmark, Odense, Denmark/Neurobiology Research Unit, Department of Molecular Medicine, University of Southern Denmark, Odense, Denmark.

Background: Human endogenous retrovirus (HERV) expression in multiple sclerosis (MS) brain lesions may contribute to chronic inflammation, but expression of genome-wide HERVs in different MS lesions is unknown.

Objective: We examined the HERV expression landscape in different MS lesions compared to control brains.

Methods: Transcripts from 71 MS brain samples and 25 control WM were obtained by next-generation RNA sequencing and mapped against HERV transcripts across the human genome. Differential expression of mapped HERV-W and HERV-H reads between MS lesion types and controls was analysed.

Results: Out of 6.38 billion high-quality paired end reads, 174 million reads (2.73%) mapped to HERV transcripts. There was no difference in HERVs expression level between MS and control brains, but HERV-W transcripts were significantly reduced in chronic active lesions. Of the four HERV-W transcripts exclusively present in MS, ERV3633503 located on chromosome 7q21.13 close to the MS genetic risk locus had the highest number of reads. In the HERV-H family, 75% of transcripts located to nearby 7q21-22 were overrepresented in MS, and ERV3643914 was expressed more than 16 times in MS compared to control brains.

Conclusion: Novel HERV-W and HERV-H transcripts located at chromosome 7 regions were uniquely expressed in MS lesions, indicating their potential role in brain lesion evolution.
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http://dx.doi.org/10.1177/1352458520987269DOI Listing
January 2021

Factors influencing daily treatment choices in multiple sclerosis: practice guidelines, biomarkers and burden of disease.

Ther Adv Neurol Disord 2020 7;13:1756286420975223. Epub 2020 Dec 7.

Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.

At two meetings of a Central European board of multiple sclerosis (MS) experts in 2018 and 2019 factors influencing daily treatment choices in MS, especially practice guidelines, biomarkers and burden of disease, were discussed. The heterogeneity of MS and the complexity of the available treatment options call for informed treatment choices. However, evidence from clinical trials is generally lacking, particularly regarding sequencing, switches and escalation of drugs. Also, there is a need to identify patients who require highly efficacious treatment from the onset of their disease to prevent deterioration. The recently published European Committee for the Treatment and Research in Multiple Sclerosis/European Academy of Neurology clinical practice guidelines on pharmacological management of MS cover aspects such as treatment efficacy, response criteria, strategies to address suboptimal response and safety concerns and are based on expert consensus statements. However, the recommendations constitute an excellent framework that should be adapted to local regulations, MS center capacities and infrastructure. Further, available and emerging biomarkers for treatment guidance were discussed. Magnetic resonance imaging parameters are deemed most reliable at present, even though complex assessment including clinical evaluation and laboratory parameters besides imaging is necessary in clinical routine. Neurofilament-light chain levels appear to represent the current most promising non-imaging biomarker. Other immunological data, including issues of immunosenescence, will play an increasingly important role for future treatment algorithms. Cognitive impairment has been recognized as a major contribution to MS disease burden. Regular evaluation of cognitive function is recommended in MS patients, although no specific disease-modifying treatment has been defined to date. Finally, systematic documentation of real-life data is recognized as a great opportunity to tackle unresolved daily routine challenges, such as use of sequential therapies, but requires joint efforts across clinics, governments and pharmaceutical companies.
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http://dx.doi.org/10.1177/1756286420975223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724259PMC
December 2020

Worldwide Incidence and Prevalence of Neuromyelitis Optica: A Systematic Review.

Neurology 2021 01 11;96(2):59-77. Epub 2020 Dec 11.

From the Department of Neurology (V.P., Z.I.), Odense University Hospital; Danish Multiple Sclerosis Center (M.M.), Copenhagen University Hospital, Rigshospitalet, Denmark; Department of Neurology (O.A.), Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany; Department of Neurology (T.B.), Medical University of Vienna, Austria; Menzies Health Institute Queensland (S.A.B.), Griffith University, Gold Coast; Department of Neurology (S.A.B.), Gold Coast University Hospital, Australia; Department of Neurology (P.C.), Fort-de-France University Hospital Center, Pierre Zobda Quitman Hospital, Fort-de-France, Martinique, France; Department of Neurology (A.J.), The Walton Centre, Liverpool, UK; Cleveland Clinic (A.J.), Abu Dhabi, United Arab Emirates; Departments of Neurology (J.K., J.P.), Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Nuffield Department of Clinical Neurosciences (M.I.L., J.P.), John Radcliffe Hospital, University of Oxford, UK; Service de Neurologie (R.M.), Sclérose en Plaques, Pathologies de la Myéline et Neuro-Inflammation, et Centre de Référence des Maladies Inflammatoires Rares du Cerveau et de la Moelle (MIRCEM), Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Bron, France; Department of Neurology (K.M.), Kindai University Graduate School of Medicine, Osaka, Japan; Center of Neuroimmunology (A.S., M.S.), Service of Neurology, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Spain; Department of Neurology (O.S.), Karolinska University Hospital and Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Institute of Clinical Research (Z.I.), University of Southern Denmark, Odense, Denmark; and Institute of Molecular Medicine (Z.I.), University of Southern Denmark, Odense.

Objective: Since the last epidemiologic review of neuromyelitis optica/neuromyelitis optica spectrum disorder (NMO/NMOSD), 22 additional studies have been conducted. We systematically review the worldwide prevalence, incidence, and basic demographic characteristics of NMOSD and provide a critical overview of studies.

Methods: PubMed, Ovid MEDLINE, and Embase using Medical Subject Headings and keyword search terms and reference lists of retrieved articles were searched from 1999 until August 2019. We collected data on the country; region; methods of case assessment and aquaporin-4 antibody (AQP4-Ab) test; study period; limitations; incidence (per 100,000 person-years); prevalence (per 100,000 persons); and age-, sex-, and ethnic group-specific incidence or prevalence.

Results: We identified 33 relevant articles. The results indicated the highest estimates of incidence and prevalence of NMOSD in Afro-Caribbean region (0.73/100 000 person-years [95% CI: 0.45-1.01] and 10/100 000 persons [95% CI: 6.8-13.2]). The lowest incidence and prevalence of NMOSD were found in Australia and New Zealand (0.037/100 000 person-years [95% CI: 0.036-0.038] and 0.7/100,000 persons [95% CI: 0.66-0.74]). There was prominent female predominance in adults and the AQP4-Ab-seropositive subpopulation. The incidence and prevalence peaked in middle-aged adults. African ethnicity had the highest incidence and prevalence of NMOSD, whereas White ethnicity had the lowest. No remarkable trend of incidence was described over time.

Conclusion: NMOSD is a rare disease worldwide. Variations in prevalence and incidence have been described among different geographic areas and ethnicities. These are only partially explained by different study methods and NMO/NMOSD definitions, highlighting the need for specifically designed epidemiologic studies to identify genetic effects and etiologic factors.
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http://dx.doi.org/10.1212/WNL.0000000000011153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905781PMC
January 2021

Recent progress in maintenance treatment of neuromyelitis optica spectrum disorder.

J Neurol 2020 Oct 3. Epub 2020 Oct 3.

Department of Clinical Medicine, University of Bergen, Bergen, Norway.

Background: Treatment of neuromyelitis optica spectrum disorder (NMOSD) has so far been based on retrospective case series. The results of six randomized clinical trials including five different monoclonal antibodies targeting four molecules and three distinct pathophysiological pathways have recently been published.

Methods: Literature search on clinical trials and case studies in NMOSD up to July 10. 2020.

Results: We review mechanism of action, efficacy and side effects, and consequences for reproductive health from traditional immunosuppressants and monoclonal antibodies including rituximab, inebilizumab, eculizumab, tocilizumab and satralizumab.

Conclusion: In NMOSD patients with antibodies against aquaporin 4, monoclonal antibodies that deplete B cells (rituximab and inebilizumab) or interfere with interleukin 6 signaling (tocilizumab and satralizumab) or complement activation (eculizumab) have superior efficacy compared to placebo. Tocilizumab and rituximab were also superior to azathioprine in head-to-head studies. Rituximab, tocilizumab and to some extent eculizumab have well-known safety profiles for other inflammatory diseases, and rituximab and azathioprine may be safe during pregnancy.
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http://dx.doi.org/10.1007/s00415-020-10235-5DOI Listing
October 2020

Paraneoplastic anti-NMDA receptor encephalitis in 1830?

Neurol Neuroimmunol Neuroinflamm 2020 11 25;7(6). Epub 2020 Sep 25.

From the Department of Neurology (D.T., N.K., J.J.), University of Pécs, Medical School, Hungary; National Institute of Clinical Neuroscience (A.S.), Budapest, Hungary; MTA-PTE Clinical Neuroscience MRI Research Group (N.K., J.J.), Hungary; Department of Neurology (Z.I.), Odense University Hospital, Denmark; and Department of Clinical Research (Z.I.), University of Southern Denmark, Odense.

Objective: Our aim was to identify patients with probable anti-NMDA receptor encephalitis among historical medical cases.

Method: A case report published in leading Hungarian-, German- and Italian-language medical journals in the early 1840s was revisited.

Results: In 1830, an 18-year-old, healthy woman suffered epileptic seizures, followed by a 6-day-long state characterized by catalepsy, unresponsiveness, motionless, and light breathing. Her symptoms regularly returned in the following 1.5 years. Meanwhile, a progressively growing huge abdominal tumor appeared. One day, she suddenly started vomiting a large amount of foul-smelling pus mixed with blood, accompanied by bone fragments. Pus mixed blood with some membranous substance was also evacuated through the anus and vagina. After this event, she completely recovered; 1.5 years later, she married and later gave birth to 3 healthy children. The patient remained healthy during the 11-year follow-up.

Conclusions: We suggest that in the description of a paraneoplastic case, an anti-NMDA receptor encephalitis can be dated back as far as to the 19th century, with an especially rare type of resolution: the disappearance of the symptoms after the spontaneous elimination of an ovarian teratoma.
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http://dx.doi.org/10.1212/NXI.0000000000000887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577529PMC
November 2020

Multiple Sclerosis Atlas: A Molecular Map of Brain Lesion Stages in Progressive Multiple Sclerosis.

Netw Syst Med 2020 27;3(1):122-129. Epub 2020 Aug 27.

Neurology Research Unit, Department of Neurology, Odense University Hopsital, Odense, Denmark.

Multiple sclerosis (MS) is a chronic disorder of the central nervous system with an untreatable late progressive phase. Molecular maps of different stages of brain lesion evolution in patients with progressive multiple sclerosis (PMS) are missing but critical for understanding disease development and to identify novel targets to halt progression. The MS Atlas database comprises comprehensive high-quality transcriptomic profiles of 98 white matter (WM) brain samples of different lesion types (normal-appearing WM [NAWM], active, chronic active, inactive, remyelinating) from ten progressive MS patients and 25 WM areas from five non-neurological diseased cases. We introduce the first MS brain lesion atlas (msatlas.dk), developed to address the current challenges of understanding mechanisms driving the fate on a lesion basis. The MS Atlas gives means for testing research hypotheses, validating biomarkers and drug targets. It comes with a user-friendly web interface, and it fosters bioinformatic methods for network enrichment to extract mechanistic markers for specific lesion types and pathway-based lesion type comparison. We describe examples of how the MS Atlas can be used to extract systems medicine signatures and demonstrate the interface of MS Atlas. This compendium of mechanistic PMS WM lesion profiles is an invaluable resource to fuel future MS research and a new basis for treatment development.
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http://dx.doi.org/10.1089/nsm.2020.0006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500075PMC
August 2020

Detection of silent cerebral microcirculatory abnormalities in patients with manifest ischemic coronary disease: a perfusion brain MRI study combined with dipyridamole stress.

Scand Cardiovasc J 2021 Apr 18;55(2):97-101. Epub 2020 Sep 18.

Department of Neurology, Odense University Hospital, Odense, Denmark.

Objectives: Intravenous dipyridamole (DP) can induce transient perfusion abnormalities in the heart but also the brain indicated by brain SPECT. L-arginine can regulate the vascular tone nitric oxide (NO). Therefore, we examined cerebral blood volume (CBV) by perfusion MRI and L-arginine level before and after DP stress in patients, who developed transient neurological signs, and compared these to unaffected patients.

Design: A total of nine patients with ischemic coronary disease after myocardial perfusion scintigraphy were selected for this prospective pilot study. Four had DP-induced transient mild neurologic signs during myocardial perfusion scintigraphy, while five had no neurological signs. By using perfusion MRI in both groups in a second stage, we examined CBV in identical areas of the two hemispheres before and during DP stress. Besides, pre-and post-stress L-arginine serum levels were also analyzed by high-performance liquid chromatography. Trial registration: NCT03688815.

Results: CBV in the sensory-motor area at baseline was significantly higher in patients with DP-induced transient neurological signs compared to patients without signs ( = 0.028). Intravenous DP normalized the higher perfusion by decreasing CBV, and also increased serum L-arginine level ( = 0.001).

Conclusions: Intravenous DP changed the CBV accompanied by a systemic elevation of L-arginine: this indicates a direct vasorelaxing effect on brain vessels, and an indirect vasodilator effect through L-arginine release presumably NO. In areas with decreased CBV before DP, such double effects caused transient neurological symptoms presumably due to steal phenomenon. Therefore, intravenous DP may have a potential to identify patients with high risk for cerebral ischemia.
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http://dx.doi.org/10.1080/14017431.2020.1821911DOI Listing
April 2021

Mechanisms of sex hormones in autoimmunity: focus on EAE.

Biol Sex Differ 2020 09 7;11(1):50. Epub 2020 Sep 7.

School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE, 68583, USA.

Sex-related differences in the occurrence of autoimmune diseases is well documented, with females showing a greater propensity to develop these diseases than their male counterparts. Sex hormones, namely dihydrotestosterone and estrogens, have been shown to ameliorate the severity of inflammatory diseases. Immunologically, the beneficial effects of sex hormones have been ascribed to the suppression of effector lymphocyte responses accompanied by immune deviation from pro-inflammatory to anti-inflammatory cytokine production. In this review, we present our view of the mechanisms of sex hormones that contribute to their ability to suppress autoimmune responses with an emphasis on the pathogenesis of experimental autoimmune encephalomyelitis.
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http://dx.doi.org/10.1186/s13293-020-00325-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475723PMC
September 2020

Life threatening rare lymphomas presenting as longitudinally extensive transverse myelitis: a diagnostic challenge.

Ideggyogy Sz 2020 Jul;73(7-08):275-285

Department of Pathology, Markusovszky University Teaching Hospital, Szombathely.

Background and aims - Description of two cases of rare intravascular large B-cell lymphoma and secondary T-cell lymphoma diagnosed postmortem, that manifested clinically as longitudinally extensive transverse myelitis (LETM). We discuss causes of diagnostic difficulties, deceptive radiological and histological investigations, and outline diagnostic procedures based on our and previously reported cases. Case reports - Our first case, a 48-year-old female was admitted to the neurological department due to paraparesis. MRI suggested LETM, but the treatments were ineffective. She died after four weeks because of pneumonia and untreatable polyserositis. Pathological examination revealed intravascular large B-cell lymphoma (IVL). Our second case, a 61-year-old man presented with headache and paraparesis. MRI showed small bitemporal lesions and lesions suggesting LETM. Diagnostic investigations were unsuccessful, including tests for possible lymphoma (CSF flow cytometry and muscle biopsy for suspected IVL). Chest CT showed focal inflammation in a small area of the lung, and adrenal adenoma. Brain biopsy sample from the affected temporal area suggested T-cell mediated lymphocytic (paraneoplastic or viral) meningoencephalitis and excluded diffuse large B-cell lymphoma. The symptoms worsened, and the patient died in the sixth week of disease. The pathological examination of the presumed adenoma in the adrenal gland, the pancreatic tail and the lung lesions revealed peripheral T-cell lymphoma, as did the brain and spinal cord lesions. Even at histological examination, the T-cell lymphoma had the misleading appearance of inflammatory condition as did the MRI. Conclusion - Lymphoma can manifest as LETM. In cases of etiologically unclear atypical LETM in patients older than 40 years, a random skin biopsy (with subcutaneous adipose tissue) from the thigh and from the abdomen is strongly recommended as soon as possible. This may detect IVL and provide the possibility of prompt chemotherapy. In case of suspicion of lymphoma, parallel examination of the CSF by flow cytometry is also recommended. If skin biopsy is negative but lymphoma suspicion remains high, biopsy from other sites (bone marrow, lymph nodes or adrenal gland lesion) or from a simultaneously existing cerebral lesion is suggested, to exclude or prove diffuse large B-cell lymphoma, IVL, or a rare T-cell lymphoma.
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http://dx.doi.org/10.18071/isz.73.0275DOI Listing
July 2020

Associations between serum L-arginine and ficolins in the early phase of acute ischemic stroke - A pilot study.

J Stroke Cerebrovasc Dis 2020 Aug 5;29(8):104951. Epub 2020 Jun 5.

Department of Neurology, Odense University Hospital, Odense, Denmark; Institute of Clinical Research, University of Southern Denmark, Odense, Denmark. Electronic address:

Introduction: Activation of both the L-arginine and the lectin pathway contributes to the pathophysiology and the outcome of acute ischemic stroke (AIS). However, the interplay between the two systems has not yet been examined.

Methods: A total of 44 patients with AIS were recruited into this study. Serial measurement of serum L-arginine, asymmetric and symmetric dimethylarginine (ADMA, SDMA), and hsCRP, ficolin-2, ficolin-3, MAP-1, MASP-3 and mannose-binding lectin (MBL) were analyzed within 6 h after onset of stroke and 72 h later. Outcomes were assessed as National Institutes of Health Stroke Scale (NIHSS) worsening by 24 h, poststroke infection, and death by 1 month.

Results: In the hyperacute stage of AIS, ficolin-3, MAP-1 and MBL were positively correlated with L-arginine within 6 h after onset of symptoms (p<0.05 respectively). Significantly lower ficolin-3 and MASP-3 levels were found at 72 h in patients, who developed post-stroke infection after day 4, when compared to patients without post-stroke infections (p=0.03 and p=0.009). At 72 hours, ficolin-3 levels negatively correlated with S100B (p=0.01). Ficolin-3 at 72 post-stroke hours remained an independent predictor of post-stroke infection, while only hsCRP was an independent predictor of 30-day mortality.

Conclusion: Early consumption of ficolin-3 is associated with complications such as post-stroke infections. In the hyperacute phase of AIS, the positive correlation between ficolins and the NO donor L-arginine may reflect the protective role of L-arginine presumably by improving the cerebral microcirculation in a prothrombotic environment induced by complement activation.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.104951DOI Listing
August 2020

Initial high-efficacy disease-modifying therapy in multiple sclerosis: A nationwide cohort study.

Neurology 2020 08 7;95(8):e1041-e1051. Epub 2020 Jul 7.

From the Danish Multiple Sclerosis Registry (M.D.B., T.A.C., M.M.) and Danish Multiple Sclerosis Center (M.D.B., T.A.C., F.S., J.R.C., R.C., P.S.S., M.M.), Department of Neurology, Rigshospitalet; Department of Neurology (I.B., V.H., J.S.), Aalborg University Hospital; Department of Neurology (M.K.C., T.P., P.V.R.), Aarhus University Hospital; Department of Neurology (Z.I., V.P., Á.T.), Odense University Hospital; Brain and Nerve Diseases (H.B.J.), Lillebaelt Hospital, Kolding; Institute of Regional Health Research (H.B.J.), University of Southern Denmark, Odense; Department of Neurology (M.K.), Hospital of Southern Jutland, Sønderborg; and Department of Neurology (A.W.), Herlev Hospital, Denmark.

Objective: To determine the effectiveness of high-efficacy disease-modifying therapies (heDMTs) vs medium-efficacy disease-modifying therapies (meDMT) as the first treatment choice in treatment-naive patients with multiple sclerosis (MS) on disability worsening and relapses. We assessed this using a nationwide population-based MS registry.

Methods: We identified all patients starting a heDMT as first-time treatment from the Danish Multiple Sclerosis Registry and compared treatment outcomes with a propensity score matched sample of patients starting meDMT.

Results: We included 388 patients in the study: 194 starting initial therapy with heDMT matched to 194 patients starting meDMT. At 4 years of follow-up, the probabilities of a 6-month confirmed Expanded Disability Status Scale (EDSS) score worsening were 16.7% (95% confidence interval [CI] 10.4%-23.0%) and 30.1% (95% CI 23.1%-37.1%) for heDMT and meDMT initiators, respectively (hazard ratio [HR] 0.53, 95% CI 0.33-0.83, = 0.006). Patients initiating heDMT also had a lower probability of a first relapse (HR 0.50, 95% CI 0.37-0.67). Results were similar after pairwise censoring and in subgroups with high baseline activity, diagnosis after 2006, or information on baseline T2 lesion load.

Conclusion: We found a lower probability of 6-month confirmed EDSS score worsening and lower probability of a first relapse in patients starting a heDMT as first therapy, compared to a matched sample starting meDMT.

Classification Of Evidence: This study provides Class III evidence that for patients with MS, starting heDMT lowers the risk of EDSS worsening and relapses compared to starting meDMT.
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http://dx.doi.org/10.1212/WNL.0000000000010135DOI Listing
August 2020

Absence of miRNA-146a Differentially Alters Microglia Function and Proteome.

Front Immunol 2020 5;11:1110. Epub 2020 Jun 5.

Department of Neurology, Odense University Hospital, Odense, Denmark.

MiR-146a is an important regulator of innate inflammatory responses and is also implicated in cell death and survival. By sorting CNS resident cells, microglia were the main cellular source of miR-146a. Therefore, we investigated microglia function and phenotype in miR-146a knock-out (KO) mice, analyzed the proteome of KO and wild-type (WT) microglia by LC-MS/MS, and examined miR-146a expression in different brain lesions of patients with multiple sclerosis (MS). When stimulated with LPS or myelin , microglia from KO mice expressed higher levels of IL-1β, TNF, IL-6, IL-10, CCL3, and CCL2 compared to WT. Stimulation increased migration and phagocytosis of WT but not KO microglia. CD11c microglia were induced by cuprizone (CPZ) in the WT mice but less in the KO. The proteome of microglia was not different in miR-146a KO compared to WT mice, but CPZ treatment induced differential and reduced protein responses in the KO: GOT1, COX5b, CRYL1, and cystatin-C were specifically changed in KO microglia. We explored discriminative features of microglia proteomes: sparse Partial Least Squares-Discriminant Analysis showed the best discrimination when control and CPZ-treated conditions were compared. Cluster of ten proteins separated WT and miR-146a KO microglia after CPZ: among them were sensomes allowing to perceive the environment, Atp1a3 that belongs to the signature of CD11c microglia, and proteins related to inflammatory responses (S100A9, Ppm1g). Finally, we examined the expression of miR-146a and its validated target genes in different brain lesions of MS patients. MiR-146 was upregulated in all lesion types, and the highest expression was in active lesions. Nineteen of 88 validated target genes were significantly changed in active lesions, while none were changed in NAWM. Our data indicated that microglia is the major source of miR-146a in the CNS. The absence of miR-146a differentially affected microglia function and proteome, and miR-146a may play an important role in gene regulation of active MS lesions.
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http://dx.doi.org/10.3389/fimmu.2020.01110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292149PMC
April 2021

Patient Attitudes to Routine Cognitive Testing in Multiple Sclerosis.

Patient Prefer Adherence 2020 2;14:693-704. Epub 2020 Apr 2.

Department of Neurology, Odense University Hospital, Odense, Denmark.

Background And Aim: In recent years, cognitive dysfunction (CD) in multiple sclerosis (MS) has received increased attention. Neuropsychological tests have been developed allowing to monitor changes in patients' cognitive functions. Knowledge is lacking, however, about patients' attitudes towards introducing routine cognitive testing. It was the aim of this qualitative study to explore this.

Materials And Methods: Based on a literature study, semi-structured interview guides were designed and used in qualitative interviews with 12 Danish patients. Participants were selected to represent different perspectives on CD and included patients with relapsing-remitting MS (RRMS) and secondary-progressive MS (SPMS), women and men with varying time since diagnosis and cognitive test scores using the Symbol Digit Modalities Test (SDMT). The data were analysed using a constructivist approach in order to identify significant relations between the quality of life (QoL) impact of CD, and attitudes towards routine cognitive testing.

Results: Most participants reported several subtypes of CD, yet objective CD did not coincide with subjective CD nor did it translate directly into poorer QoL. Overall, CD appeared to have larger impact on the QoL of patients with RRMS and higher SDMT scores, compared to patients with SPMS and lower SDMT scores. The QoL impact of CD manifested itself in the encounter between individual symptoms, expectations, coping and meaningful activities. All patients supported an introduction of routine cognitive testing, but patients with RRMS and SPMS had different main reasons to do so. These were related to supporting research, optimising treatment decisions, and providing documentation of this invisible MS symptom.

Conclusion: All aspects of MS patients' QoL may be affected by CD. Introducing routine cognitive testing was widely supported by patients in all phases of MS calling for comprehensive care taking both physical and cognitive difficulties into account.
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http://dx.doi.org/10.2147/PPA.S245623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7135142PMC
April 2020

Induction of aquaporin 4-reactive antibodies in Lewis rats immunized with aquaporin 4 mimotopes.

Acta Neuropathol Commun 2020 04 15;8(1):49. Epub 2020 Apr 15.

Department Neuroimmunology, Medical University Vienna, Center for Brain Research, Spitalgasse 4, A-1090, Vienna, Austria.

Most cases of neuromyelitis optica spectrum disorders (NMOSD) harbor pathogenic autoantibodies against the water channel aquaporin 4 (AQP4). Binding of these antibodies to AQP4 on astrocytes initiates damage to these cells, which culminates in the formation of large tissue destructive lesions in the central nervous system (CNS). Consequently, untreated patients may become permanently blind or paralyzed. Studies on the induction and breakage of tolerance to AQP4 could be of great benefit for NMOSD patients. So far, however, all attempts to create suitable animal models by active sensitization have failed. We addressed this challenge and identified peptides, which mimic the conformational AQP4 epitopes recognized by pathogenic antibodies of NMOSD patients. Here we show that these mimotopes can induce the production of AQP4-reactive antibodies in Lewis rats. Hence, our results provide a conceptual framework for the formation of such antibodies in NMOSD patients, and aid to improve immunization strategies for the creation of animal models suitable for tolerance studies in this devastating disease.
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http://dx.doi.org/10.1186/s40478-020-00920-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160927PMC
April 2020

Proteomic changes during experimental de- and remyelination in the corpus callosum.

PLoS One 2020 9;15(4):e0230249. Epub 2020 Apr 9.

Department of Biochemistry and Medical Chemistry, University of Pécs Medical School, Pécs, Hungary.

Background: In the cuprizone model of multiple sclerosis, de- and remyelination can be studied without major interference from the adaptive immune responses. Since previous proteomic studies did not focus on the corpus callosum, where cuprizone causes the most pronounced demyelination, we performed a bottom up proteomic analysis on this brain region.

Methods: Eight week-old mice treated with 0.2% cuprizone, for 4 weeks and controls (C) were sacrificed after termination of the treatment (4wD), and 2 (2dR) or 14 (2wR) days later. Homogenates of dissected corpus callosum were analysed by quantitative proteomics. For data processing, clustering, gene ontology analysis, and regulatory network prediction, we used Perseus, PANTHER and Ingenuity Pathway Analysis softwares, respectively.

Results: We identified 4886 unmodified, single- or multi phosphorylated and/or gycosylated (PTM) proteins. Out of them, 191 proteins were differentially regulated in at least one experimental group. We found 57 proteins specific for demyelination, 27 for early- and 57 for late remyelinationwhile 36 proteins were affected in two, and 23 proteins in all three groups. Phosphorylation represented 92% of the post translational modifications among differentially regulated modified (PTM) proteins with decreased level, while it was only 30% of the PTM proteins with increased level. Gene ontology analysis could not classify the demyelination specific proteins into any biological process category, while allocated the remyelination specific ones to nervous system development and myelination as the most specific subcategory. We also identified a protein network in experimental remyelination, and the gene orthologues of the network were differentially expressed in remyelinating multiple sclerosis brain lesions consistent with an early remyelination pattern.

Conclusion: Proteomic analysis seems more informative for remyelination than demyelination in the cuprizone model.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230249PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145428PMC
July 2020

Molecular signature of different lesion types in the brain white matter of patients with progressive multiple sclerosis.

Acta Neuropathol Commun 2019 12 11;7(1):205. Epub 2019 Dec 11.

Department of Neurology, Odense University Hospital, J.B. Winslowsvej 4, DK-5000, Odense C, Denmark.

To identify pathogenetic markers and potential drivers of different lesion types in the white matter (WM) of patients with progressive multiple sclerosis (PMS), we sequenced RNA from 73 different WM areas. Compared to 25 WM controls, 6713 out of 18,609 genes were significantly differentially expressed in MS tissues (FDR < 0.05). A computational systems medicine analysis was performed to describe the MS lesion endophenotypes. The cellular source of specific molecules was examined by RNAscope, immunohistochemistry, and immunofluorescence. To examine common lesion specific mechanisms, we performed de novo network enrichment based on shared differentially expressed genes (DEGs), and found TGFβ-R2 as a central hub. RNAscope revealed astrocytes as the cellular source of TGFβ-R2 in remyelinating lesions. Since lesion-specific unique DEGs were more common than shared signatures, we examined lesion-specific pathways and de novo networks enriched with unique DEGs. Such network analysis indicated classic inflammatory responses in active lesions; catabolic and heat shock protein responses in inactive lesions; neuronal/axonal specific processes in chronic active lesions. In remyelinating lesions, de novo analyses identified axonal transport responses and adaptive immune markers, which was also supported by the most heterogeneous immunoglobulin gene expression. The signature of the normal-appearing white matter (NAWM) was more similar to control WM than to lesions: only 465 DEGs differentiated NAWM from controls, and 16 were unique. The upregulated marker CD26/DPP4 was expressed by microglia in the NAWM but by mononuclear cells in active lesions, which may indicate a special subset of microglia before the lesion develops, but also emphasizes that omics related to MS lesions should be interpreted in the context of different lesions types. While chronic active lesions were the most distinct from control WM based on the highest number of unique DEGs (n = 2213), remyelinating lesions had the highest gene expression levels, and the most different molecular map from chronic active lesions. This may suggest that these two lesion types represent two ends of the spectrum of lesion evolution in PMS. The profound changes in chronic active lesions, the predominance of synaptic/neural/axonal signatures coupled with minor inflammation may indicate end-stage irreversible molecular events responsible for this less treatable phase.
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http://dx.doi.org/10.1186/s40478-019-0855-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6907342PMC
December 2019