Humoral immunity to SARS-CoV-2 mRNA vaccination in multiple sclerosis: the relevance of time since last rituximab infusion and first experience from sporadic revaccinations.

INTRODUCTION: The effect of disease-modifying therapies (DMT) on vaccine responses is largely unknown. Understanding the development of protective immunity is of paramount importance to fight the COVID-19 pandemic. OBJECTIVE: To characterise humoral immunity after mRNA-COVID-19 vaccination of people with multiple sclerosis (pwMS). METHODS: All pwMS in Norway fully vaccinated against SARS-CoV-2 were invited to a national screening study. Humoral immunity was assessed by measuring anti-SARS-CoV-2 SPIKE RBD IgG response 3-12 weeks after full vaccination, and compared with healthy subjects. RESULTS: 528 pwMS and 627 healthy subjects were included. Reduced humoral immunity (anti-SARS-CoV-2 IgG <70 arbitrary units) was present in 82% and 80% of all pwMS treated with fingolimod and rituximab, respectively, while patients treated with other DMT showed similar rates as healthy subjects and untreated pwMS. We found a significant correlation between time since the last rituximab dose and the development of humoral immunity. Revaccination in two seronegative patients induced a weak antibody response. CONCLUSIONS: Patients treated with fingolimod or rituximab should be informed about the risk of reduced humoral immunity and vaccinations should be timed carefully in rituximab patients. Our results identify the need for studies regarding the durability of vaccine responses, the role of cellular immunity and revaccinations.

Functional connectivity in multiple sclerosis modelled as connectome stability: A 5-year follow-up study.

BACKGROUND: Brain functional connectivity (FC) in multiple sclerosis (MS) is abnormal compared to healthy controls (HCs). More longitudinal studies in MS are needed to evaluate whether FC stability is clinically relevant. OBJECTIVE: To compare functional magnetic resonance imaging (fMRI)-based FC between MS and HC, and to determine the relationship between longitudinal FC changes and structural brain damage, cognitive performance and physical disability. METHODS: T1-weighted MPRAGE and resting-state fMRI (1.5T) were acquired from 70 relapsing-remitting MS patients and 94 matched HC at baseline (mean months since diagnosis 14.0 ± 11) and from 60 MS patients after 5 years. Independent component analysis and network modelling were used to measure longitudinal FC stability and cross-sectional comparisons with HC. Linear mixed models, adjusted for age and sex, were used to calculate correlations. RESULTS: At baseline, patients with MS showed FC abnormalities both within networks and in single connections compared to HC. Longitudinal analyses revealed functional stability and no significant relationships with clinical disability, cognitive performance, lesion or brain volume. CONCLUSION: FC abnormalities occur already at the first decade of MS, yet we found no relevant clinical correlations for these network deviations. Future large-scale longitudinal fMRI studies across a range of MS subtypes and outcomes are required.

Magnetic resonance imaging perfusion is associated with disease severity and activity in multiple sclerosis.

PURPOSE: The utility of perfusion-weighted imaging in multiple sclerosis (MS) is not well investigated. The purpose of this study was to compare baseline normalized perfusion measures in subgroups of newly diagnosed MS patients. We wanted to test the hypothesis that this method can differentiate between groups defined according to disease severity and disease activity at 1 year follow-up. METHODS: Baseline magnetic resonance imaging (MRI) including a dynamic susceptibility contrast perfusion sequence was performed on a 1.5-T scanner in 66 patients newly diagnosed with relapsing-remitting MS. From the baseline MRI, cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) maps were generated. Normalized (n) perfusion values were calculated by dividing each perfusion parameter obtained in white matter lesions by the same parameter obtained in normal-appearing white matter. Neurological examination was performed at baseline and at follow-up approximately 1 year later to establish the multiple sclerosis severity score (MSSS) and evidence of disease activity (EDA). RESULTS: Baseline normalized mean transit time (nMTT) was lower in patients with MSSS >3.79 (p = 0.016), in patients with EDA (p = 0.041), and in patients with both MSSS >3.79 and EDA (p = 0.032) at 1-year follow-up. Baseline normalized cerebral blood flow and normalized cerebral blood volume did not differ between these groups. CONCLUSION: Lower baseline nMTT was associated with higher disease severity and with presence of disease activity 1 year later in newly diagnosed MS patients. Further longitudinal studies are needed to confirm whether baseline-normalized perfusion measures can differentiate between disease severity and disease activity subgroups over time.

Assessment of cognitive function, structural brain changes and fatigue 6 months after treatment of neuroborreliosis.

BACKGROUND: Complete recovery after adequately treated neuroborreliosis is common, but studies report that some patients experience persistent symptoms like self-reported cognitive problems and fatigue. Persisting symptoms are often termed post-Lyme disease syndrome, of which etiology is not clearly understood. The aim of this study was to investigate cognitive function, possible structural changes in brain regions and level of fatigue. We have not found previous studies on neuroborreliosis that use standardized neuropsychological tests and MRI with advanced image processing to investigate if there are subtle regional changes in cortical thickness and brain volumes after treatment. METHODS: We examined 68 patients treated for neuroborreliosis 6 months earlier and 66 healthy controls, with a comprehensive neuropsychological test protocol, quantitative structural MRI analysis of the brain and Fatigue Severity Scale. RESULTS: We found no differences between the groups in either cognitive function, cortical thickness or brain volumes. The patients had higher score on Fatigue Severity Scale 3.8 vs. 2.9 (p = 0.001), and more patients (25.4%) than controls (5%) had severe fatigue (p = 0.002), but neither mean score nor proportion of patients with severe fatigue differed from findings in the general Norwegian population. CONCLUSION: The prognosis regarding cognitive function, brain MRI findings and fatigue after adequately treated neuroborreliosis is favorable.

Cognitive function in patients with neuroborreliosis: A prospective cohort study from the acute phase to 12 months post treatment.

BACKGROUND: Long-term cognitive problems after neuroborreliosis treatment remain a subject of debate. We have previously shown that cognitive problems are not present in the acute phase of neuroborreliosis, although fatigue is common. The aim of this study was to re-assess the same patient cohort and evaluate long-term outcomes. METHODS: In this follow-up, we re-assessed 58 patients with well-characterized neuroborreliosis 12 months after completing treatment. The same protocol with eight subtests measuring attention and processing speed and the Fatigue Severity Scale (FSS) were used to compare the results from the acute phase to 12 months post treatment. RESULTS: We found no changes in attention or processing speed but a reduction in the level of fatigue (median score on FSS: 4.9 vs. 3.9, p < .001) from the acute phase to 12 months post treatment. CONCLUSION: The patient group did not develop problems with attention or processing speed post treatment, while the level of fatigue decreased.

Cognitive function, fatigue and Fazekas score in patients with acute neuroborreliosis.

Long-term cognitive problems and fatigue after adequately treated neuroborreliosis has caused uncertainty and debate among patients and health care workers for years. Despite several studies, the prevalence, cause and severity of such complaints are still not clarified. More knowledge about cognitive function, fatigue and MRI findings in the acute phase of neuroborreliosis could possibly contribute to clarification. In the current study, we therefore aimed to address this. Patients with well-characterized acute neuroborreliosis (n = 72) and a matched control group (n = 68) were screened with eight subtests from three different neuropsychological test batteries assessing attention, working memory and processing speed, and with Fatigue Severity Scale. Fazekas score was used to grade white matter hyperintensities on MRI. We found no differences in mean scores on the neuropsychological tests between the groups. The patient group reported significantly higher level of fatigue (Fatigue Severity Scale: 4.8 vs. 2.9, p < .001). There was no significant difference in Fazekas score between the groups. Neuroborreliosis does not seem to affect cognitive functions in the acute state of the disease, while fatigue is common.

Blood neurofilament light concentration at admittance: a potential prognostic marker in COVID-19.

OBJECTIVE: To test the hypotheses that blood biomarkers for nervous system injury, serum concentrations of neurofilament light chain protein (NfL) and glial fibrillary acidic protein (GFAp) can serve as biomarkers for disease severity in COVID-19 patients. METHODS: Forty-seven inpatients with confirmed COVID-19 had blood samples drawn on admission for assessing serum biomarkers of CNS injury by Single molecule array (Simoa), NfL and GFAp. Concentrations of NfL and GFAp were analyzed in relation to symptoms, clinical signs, inflammatory biomarkers and clinical outcomes. We used multivariate linear models to test for differences in biomarker concentrations in the subgroups, accounting for confounding effects. RESULTS: In total, 21% (n = 10) of the patients were admitted to an intensive care unit, and the overall mortality rate was 13% (n = 6). Non-survivors had higher serum concentrations of NfL (p < 0.001) upon admission than patients who were discharged alive both in adjusted analyses (p = 2.6 × 10-7) and unadjusted analyses (p = 0.001). The concentrations of NfL in non-survivors increased over repeated measurements; whereas, the concentrations in survivors were stable. The GFAp concentration was also significantly higher in non-survivors than survivors (p = 0.02). CONCLUSION: Increased concentrations of NfL and GFAp in COVID-19 patients on admission may indicate increased mortality risk. Measurement of blood biomarkers for nervous system injury can be useful to detect and monitor CNS injury in COVID-19.

Next-Generation Sequencing Identifies Extended HLA Class I and II Haplotypes Associated With Early-Onset and Late-Onset Myasthenia Gravis in Italian, Norwegian, and Swedish Populations.

Genetic susceptibility to myasthenia gravis (MG) associates with specific HLA alleles and haplotypes at the class I and II regions in various populations. Previous studies have only examined alleles at a limited number of HLA loci that defined only broad serotypes or alleles defined at the protein sequence level. Consequently, genetic variants in noncoding and untranslated HLA gene segments have not been fully explored but could also be important determinants for MG. To gain further insight into the role of HLA in MG, we applied next-generation sequencing to analyze sequence variation at eleven HLA genes in early-onset (EO) and late-onset (LO) non-thymomatous MG patients positive for the acetylcholine receptor (AChR) antibodies and ethnically matched controls from Italy, Norway, and Sweden. For all three populations, alleles and haplotype blocks present on the ancestral haplotype AH8.1 were associated with risk in AChR-EOMG patients. HLA-B*08:01:01:01 was the dominant risk allele in Italians (OR = 3.28, P = 1.83E-05), Norwegians (OR = 3.52, P = 4.41E-16), and in Swedes HLA-B*08:01 was the primary risk allele (OR = 4.24, P <2.2E-16). Protective alleles and haplotype blocks were identified on the HLA-DRB7, and HLA-DRB13.1 class II haplotypes in Italians and Norwegians, whereas in Swedes HLA-DRB7 exhibited the main protective effect. For AChR-LOMG patients, the HLA-DRB15.1 haplotype and associated alleles were significantly associated with susceptibility in all groups. The HLA-DR13-HLA-DR-HLA-DQ haplotype was associated with protection in all AChR-LOMG groups. This study has confirmed and extended previous findings that the immunogenetic predisposition profiles for EOMG and LOMG are distinct. In addition, the results are consistent with a role for non-coding HLA genetic variants in the pathogenesis of MG.

The genetic architecture of human brainstem structures and their involvement in common brain disorders.

Brainstem regions support vital bodily functions, yet their genetic architectures and involvement in common brain disorders remain understudied. Here, using imaging-genetics data from a discovery sample of 27,034 individuals, we identify 45 brainstem-associated genetic loci, including the first linked to midbrain, pons, and medulla oblongata volumes, and map them to 305 genes. In a replication sample of 7432 participants most of the loci show the same effect direction and are significant at a nominal threshold. We detect genetic overlap between brainstem volumes and eight psychiatric and neurological disorders. In additional clinical data from 5062 individuals with common brain disorders and 11,257 healthy controls, we observe differential volume alterations in schizophrenia, bipolar disorder, multiple sclerosis, mild cognitive impairment, dementia, and Parkinson's disease, supporting the relevance of brainstem regions and their genetic architectures in common brain disorders.

Symptoms of fatigue and depression is reflected in altered default mode network connectivity in multiple sclerosis.

BACKGROUND: Fatigue and depression are frequent and often co-occurring symptoms in multiple sclerosis (MS). Resting-state functional magnetic resonance imaging (rs-fMRI) represents a promising tool for disentangling differential associations between depression and fatigue and brain network function and connectivity. In this study we tested for associations between symptoms of fatigue and depression and DMN connectivity in patients with MS. MATERIALS AND METHODS: Seventy-four MS patients were included on average 14 months after diagnosis. They underwent MRI scanning of the brain including rs-fMRI, and symptoms of fatigue and depression were assessed with Fatigue Severity Scale (FSS) and Beck Depression Inventory II (BDI). A principal component analysis (PCA) on FSS and BDI scores was performed, and the component scores were analysed using linear regression models to test for associations with default mode network (DMN) connectivity. RESULTS: We observed higher DMN connectivity with higher scores on the primary principal component reflecting common symptom burden for fatigue and depression (Cohen's f2 = 0.075, t = 2.17, p = 0.03). The secondary principal component reflecting a pattern of low fatigue scores with high scores of depression was associated with lower DMN connectivity (Cohen's f2 = 0.067, t = -2.1, p = 0.04). Using continuous mean scores of FSS we also observed higher DMN connectivity with higher symptom burden (t = 3.1, p = 0.003), but no significant associations between continuous sum scores of BDI and DMN connectivity (t = 0.8, p = 0.4). CONCLUSION: Multivariate decomposition of FSS and BDI data supported both overlapping and unique manifestation of fatigue and depression in MS patients. Rs-fMRI analyses showed that symptoms of fatigue and depression were reflected in altered DMN connectivity, and that higher DMN activity was seen in MS patients with fatigue even with low depression scores.

Marked differences in prevalence of multiple sclerosis between ethnic groups in Oslo, Norway.

OBJECTIVES: Oslo, the capital of Norway, has a high prevalence of multiple sclerosis (MS). In recent decades there has been substantial immigration to Oslo from Asia, the Middle East and Africa. The aim of the study was to estimate the prevalence of MS among non-Western immigrants living in Oslo, adjusted for duration of residence. METHODS: Data were obtained from the MS registry at Ullevål University Hospital. The prevalence of MS was adjusted for ethnicity, age and duration of residence in Norway. RESULTS: A total of 786 definite MS patients were alive and resident in Oslo on 31 December 2005, yielding a crude prevalence of 148/10(5). Twenty-seven patients were of non-Western origin: Middle East 14, Asia 9, Africa 4. The non-Western patients' mean age at migration was 20. The crude prevalence (95 % CI) of MS patients was 170/10(5) (159-182) for the Norwegian/Western, 85/10(5) (50-143) for the Middle East, 21/10(5) (11-41) for the Asian, and 20/10(5) (7-53) for the African cohorts. The high MS prevalence in the Middle East cohort and the low prevalence among Asian/African immigrants were also pronounced after adjustment for age and duration of residence. CONCLUSIONS: The Middle East immigrants had a markedly higher prevalence of MS despite a shorter duration of residence than other non-Western patients. These findings suggest that people from the Middle East have a greater genetic disposition for MS. Furthermore, the high age at migration among the non-Western immigrants indicates that possible environmental factors affecting MS risk may also act on adults.

Refining the linkage analysis on chromosome 10 in 449 sib-pairs with multiple sclerosis.

Genome-wide screens for linkage in multiplex families with multiple sclerosis (MS) from United Kingdom, Sardinia, Italy and the Nordic countries (Denmark, Finland, Norway and Sweden) have each shown suggestive or potential linkage on chromosome 10. The partially overlapping regions identified by these studies encompass around 60 cM of the chromosome. In order to explore this region further, we typed 13 microsatellite markers in the same 449 families originally studied in the individual screens. This additional genotyping increased the information extraction in the region from 52% to 79% and revealed increased support for linkage (MLS 2.5) peaking at 10p15.

[Multiple sclerosis--a disease with complex genetics]. / Multippel sklerose--en sykdom med kompleks genetikk.

BACKGROUND: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system, characterised by demyelinisation, gliosis and various degrees of axonal damage. The cause of the disease is unknown though there is evidence that MS is an immune mediated disease in which genetic, environmental and stochastic factors are involved. MATERIAL AND METHODS: Evidence of genetic influence in MS is reviewed. RESULTS: About 20% of patients have other family members with MS. First-degree relatives of MS patients have increased risk (2-5%) of developing MS compared to the risk in the general population (0.1%). The concordance rate in monozygotic twins (25-30%) is higher than in dizygotic twins (2-5%). Genetic analysis has shown association and linkage of MS to the HLA-DR2, DQ6 haplotype. Genome-wide screens have shown chromosome regions of potential importance. CONCLUSION: MS is a complex disease in which several genes are involved. Despite extensive candidate gene studies and genome-wide linkage screens, the HLA-DR2, DQ6 haplotype is the only genetic region that has shown unequivocal association and linkage to the disease. Further studies aimed at defining other MS susceptibility and disease-modifying genes are in progress.

Concordance for disease course and age of onset in Scandinavian multiple sclerosis coaffected sib pairs.

BACKGROUND: Investigation of coaffected sib pairs is one method to determine the genetic influence on the clinical presentation of many complex diseases, such as multiple sclerosis (MS). Investigation of the clinical concordance in coaffected sib pairs may be a prerequisite to identify genes that modify the clinical outcome. The aim of this study was to investigate a possible genetic influence on selected demographic and clinical variables among familial Scandinavian MS cases. MATERIAL AND METHODS: We identified 136 Caucasian Scandinavian families with MS coaffected sib pairs from Denmark, Norway and Sweden. Cohen's kappa coefficient and the intraclass correlation coefficient were used to assess concordances in sib pairs. Furthermore, clinical features and HLA-DR2 carrier status were compared among the probands of sib pairs. RESULTS: We found significant concordance of the disease course (kappa = 0.28, P < 0.001) and adjusted age of onset (r = 0.23, P = 0.028). Among probands of sib pairs, HLA-DR2 carrier patients had a younger age of onset (P = 0.024). CONCLUSION: Analyses of Scandinavian coaffected sib pairs suggest that disease course and age of onset are partly under genetic control. Furthermore, HLA-DR2 in probands of sib pairs suggests importance for age of onset.