Hanne Flinstad Harbo

• Korbmacher, Max; Lie, Ingrid Anne; Wesnes, Kristin; Westman, Eric; Espeseth, Thomas & Andreassen, Ole [Vis alle 13 forfattere av denne artikkelen] (2026). Regional patterns of grey matter volume decline in relapsing-remitting multiple sclerosis relative to healthy ageing. NeuroImage. ISSN 1053-8119. 338, s. 1–9. doi: 10.1016/j.neuroimage.2026.122118. Fulltekst i vitenarkiv Vis sammendrag

  Background: Grey matter volume loss (GM-VL) is an accurate marker of multiple sclerosis (MS)-related progression. However, long-term comparisons of GM-VL between MS and healthy controls (HC) are rare, and the brain regions with most significant GM-VL and their clinical importance still need robust and longitudinal validation. Methods: This multi-cohort longitudinal observational study used two relapsing remitting MS (RRMS) cohorts (N = 386, T1w-scans=940) sampled for up-to-12 years to localise grey matter volume loss (GM-VL) and disease progression (Expanded Disability Status Scale (EDSS), Paced Auditory Serial Addition Test (PASAT), Fatigue Severity Scale (FSS)). The identified region-specific significant GM-VL was compared with 2163 HCs (T1w-scans=4326). Results: The strongest, replicable, significant patterns of brain GM-VL in RRMS were found in the frontal lobes, specifically, in the superior frontal cortex (SFC, βage≤-0.27), pars orbitalis (βage≤-0.25), and thalami (βage≤-0.20). Compared with healthy controls (HCs) >20 years older, MS showed greater GM-VL in the right SFC, caudal-middle frontal cortex, caudate, and left frontal pole (all Z > 2.08, p < 0.019). The overlap of associations between volumetric and clinical outcome changes was limited to EDSS, which was significantly related to left hippocampal volumes βEDSS≤-0.19 in both cohorts. Conclusions: Our findings indicate GM-VL in people with RRMS comparable to 20-year older HC, and stronger in the SFC and thalamus, and cohort-specific relationships with disability-progression.

• Rasmussen, Tilde Harridsleff; Schikora-Rustad, Stine; Lorentzen, Åslaug Rudjord; Tran, Trung; Øverås, Mathias Herstad & Myhr, Kjell-Morten [Vis alle 22 forfattere av denne artikkelen] (2026). Low risk of severe COVID-19 in vaccinated people with multiple sclerosis: a nationwide Norwegian study. BMJ Neurology Open. 8(1). doi: 10.1136/bmjno-2026-001556. Fulltekst i vitenarkiv Vis sammendrag

  Background: We aimed to assess antibody responses and COVID-19 outcomes after vaccination in people with multiple sclerosis (pwMS) receiving disease-modifying therapies. Methods: NevroVAX is a Norwegian multicentre cohort study including 3559 pwMS and 449 healthy controls (HCs) who received at least one dose of BNT162b2 (Pfizer-BioNTech), mRNA-1273 (Moderna) or ChAdOx1 (AstraZeneca/Oxford) between January 2021 and December 2022. Data from records, registries, questionnaires and blood samples collected June 2021–November 2023 were analysed. Primary outcomes were humoral immune responses assessed by seroconversion (anti-spike and anti-receptor-binding domain (RBD) IgG ≥5 binding antibody units/mL). Secondary outcomes included quantitative anti-RBD IgG levels, breakthrough SARS-CoV-2 infection, COVID-19-related hospitalisation and death. Associations with breakthrough infection were evaluated using multivariable logistic regression. Results: Among 3559 pwMS, 1201 received anti-CD20 monoclonal antibodies and 324 sphingosine-1-phosphate receptor (S1PR) modulators. After three vaccine doses, seroconversion was observed in 43.0% of anti-CD20-treated patients and 48.4% of S1PR-treated patients. In multivariable analysis, seroconversion was associated with lower risk of breakthrough infection (OR 0.67, 95% CI 0.58 to 0.78). During follow-up, 58 pwMS (1.6%) were hospitalised for COVID-19; 4 (0.1%) required non-invasive ventilatory support, no patients required invasive ventilation and no deaths occurred. Conclusions: Humoral vaccine responses were impaired in pwMS receiving anti-CD20 or S1PR therapies, but severe COVID-19 was rare. These findings support continued vaccination programmes and tailored protective measures for immunomodulated populations.

• Helland, Gisle Berg; Ihle-Hansen, Håkon; Aamodt, Anne Hege; Leonardsen, Esten Høyland; Kaufmann, Tobias Herbert & Enriquez, Brian Anthony [Vis alle 13 forfattere av denne artikkelen] (2026). Brain age trajectories and cognition after stroke in two longitudinal cohorts. Brain Communications. 8(1). doi: 10.1093/braincomms/fcaf509. Fulltekst i vitenarkiv Vis sammendrag

  Brain age is a promising neuroimaging biomarker, reflecting biological aging, but long-term trajectories and predictive value for cognitive outcomes post-stroke remains unclear. This study aimed to characterize brain aging trajectories over 8 years following a first-ever stroke and to evaluate the predictive value of brain age estimates for long-term cognitive outcomes. We analysed data from working-age (&lt;65 years) ischaemic stroke patients with small- and medium-sized strokes (lesion volumes &lt;70 ml), using two longitudinal stroke cohorts. T1-weighted MRI was acquired in the acute phase and at multiple time points up to 8 years post-stroke. Montreal cognitive assessment (MoCA) was assessed at follow-up sessions. Brain age was estimated using a state-of-the-art deep learning model. Brain-predicted age difference (Brain-PAD) was calculated as estimated brain age minus chronological age and corrected by regressing on age, age² and sex. Linear mixed-effects models examined Brain-PAD over multiple time points (whole-brain, ipsilesional and contralesional). Normalized brain volume was derived from FreeSurfer and included in the whole-brain analysis. Linear regression models evaluated whether brain age was associated with cognitive performance (MoCA) at long-term follow-up. We included 120 patients [n = 50 (42%) female, mean ± SD age at discharge was 54.9 ± 9 and National Institutes of Health Stroke Scale was 3.7 ± 6.4], with a mean follow-up of 3.4 ± 2.5 years. The mean MoCA score at follow-up was 24.7 ± 3.7. Brain-PAD increased significantly over time in the whole-brain analysis (β = 0.6/year, P &lt; 0.01), indicating 60% acceleration in brain aging after stroke, with the association remaining significant after adjusting for normalized brain volume (β = 0.5/year, P &lt; 0.01). Accelerated brain aging was observed in the ipsilesional hemisphere (β = 0.7/year, P &lt; 0.01), but not the contralesional hemisphere (β = 0.3/year, P = 0.12). Higher brain age in the acute phase of stroke predicted lower MoCA scores at follow-up (β = −0.12, P &lt; 0.05), whereas chronological age was not a significant predictor (P = 0.12). The association between brain age estimations and cognitive performance remained significant after adjusting for age, sex and education (β = −0.42, P &lt; 0.01). In this longitudinal study, we found accelerated brain aging following stroke. Furthermore, brain age was associated with cognitive outcomes several years later, highlighting its potential as an early biomarker for long-term cognitive prognosis.

• Pukaj, Albert; Harroud, Adil; Shchetynsky, Klementy; Wirsching, Laura; Peters, Lucy & Andlauer, Till F.M. [Vis alle 52 forfattere av denne artikkelen] (2025). Genetic Risk Variants for Multiple Sclerosis and Other Loci Linked to Intrathecal Immunoglobulin G Synthesis. Neurology: Neuroimmunology and neuroinflammation. 12(6). doi: 10.1212/nxi.0000000000200499. Fulltekst i vitenarkiv Vis sammendrag

  Background and Objectives Intrathecal synthesis of immunoglobulin G (IgG) is a key feature of multiple sclerosis (MS) and a prognostic marker for the disease course. Although previous studies identified 2 genetic regions—the major histocompatibility complex (MHC) region on chromosome 6 and the immunoglobulin heavy chain constant (IGHC) locus on chromosome 14—associated with intrathecal IgG synthesis in MS, the genetic underpinnings remain insufficiently understood. Methods We conducted a genome-wide association study on intrathecal IgG synthesis using the IgG index to identify individuals with (≥0.7) or without (<0.7) quantitative intrathecal synthesis. We used logistic regression models adjusting for sex, age, and population structure. We performed secondary analyses to examine associations between identified loci and the extent of intrathecal IgG synthesis and the presence and extent of intrathecal immunoglobulin A and M synthesis. We further conducted association analyses for imputed human leukocyte antigen alleles and analyzed whether a higher genetic burden for MS risk—quantified through polygenic risk scores—is associated with intrathecal IgG synthesis. Results In the discovery cohort (n = 3,934), we identified a novel genome-wide significant association of the intronic variant rs844586 (p = 1.48 × 10−8) in the sterile alpha motif domain containing 5 (SAMD5) gene on chromosome 6, with intrathecal IgG synthesis. We could confirm this association in a replication cohort (n = 1,094) and demonstrated that it is independent of a previously described association signal at the MHC region. In a subset (n = 1,413), we further identified rs1407 as a potential causal variant (p = 3.80 × 10−11, posterior inclusion probability = 0.92) for the previously reported association signal at the IGHC locus with the extent of intrathecal IgG synthesis. In addition, we demonstrated that a higher genetic burden for MS susceptibility, both within and outside of the MHC region, is associated with a higher likelihood of and a more pronounced intrathecal IgG synthesis. Discussion Our study revealed a previously unknown association between an intronic variant in SAMD5 with intrathecal IgG synthesis and identified a potential causal variant within the IGHC locus. It further provides evidence for possible effects of known MS risk variants on disease severity through their effect on the intrathecal humoral immune response, a prognostic marker for the disease course.

• Skattebøl, Lars; Nygaard, Gro Owren; Leonardsen, Esten Høyland; Kaufmann, Tobias Herbert; Moridi, Thomas & Stawiarz, Leszek [Vis alle 23 forfattere av denne artikkelen] (2025). Brain age in multiple sclerosis: a study with deep learning and traditional machine learning. Brain Communications. 7(3). doi: 10.1093/braincomms/fcaf152. Fulltekst i vitenarkiv Vis sammendrag

  ‘Brain age’ is a numerical estimate of the biological age of the brain and an overall effort to measure neurodegeneration, regardless of disease type. In multiple sclerosis, accelerated brain ageing has been linked to disability accrual. Artificial intelligence has emerged as a promising tool for the assessment and quantification of the impact of neurodegenerative diseases. Despite the existence of numerous AI models, there is a noticeable lack of comparative imaging data for traditional machine learning versus deep learning in conditions such as multiple sclerosis. A retrospective observational study was initiated to analyse clinical and MRI data (4584 MRIs) from various scanners in a large longitudinal cohort (n = 1516) of people with multiple sclerosis collected from two institutions (Karolinska Institute and Oslo University Hospital) using a uniform data post-processing pipeline. We conducted a comparative assessment of brain age using a deep learning simple fully convolutional network and a well-established traditional machine learning model. This study was primarily aimed to validate the deep learning brain age model in multiple sclerosis. The correlation between estimated brain age and chronological age was stronger for the deep learning estimates (r = 0.90, P &lt; 0.001) than the traditional machine learning estimates (r = 0.75, P &lt; 0.001). An increase in brain age was significantly associated with higher expanded disability status scale scores (traditional machine learning: t = 5.3, P &lt; 0.001; deep learning: t = 3.7, P &lt; 0.001) and longer disease duration (traditional machine learning: t = 6.5, P &lt; 0.001; deep learning: t = 5.8, P &lt; 0.001). No significant inter-model difference in clinical correlation or effect measure was found, but significant differences for traditional machine learning-derived brain age estimates were found between several scanners. Our study suggests that the deep learning-derived brain age is significantly associated with clinical disability, performed equally well to the traditional machine learning-derived brain age measures, and may counteract scanner variability.

• Skattebøl, Lars; Lundby, Rigmor; Øverås, Mathias H.; Sowa, Piotr; Celius, Elisabeth G. & Harbo, Hanne-Cathrin Flinstad [Vis alle 9 forfattere av denne artikkelen] (2025). Quantitative susceptibility mapping of paramagnetic rim lesions in early multiple sclerosis: A cross-sectional study of brain age and disability. Neuroimage: Reports. 5(3), s. 100277–100277. doi: 10.1016/j.ynirp.2025.100277. Fulltekst i vitenarkiv
• Aamodt, Anne Hege; Ueland, Thor; Boldingh, Marion Ingeborg; Bezgal, Burcu; Argren, Maria Bengtson Argren & Dunne, Cecilia Adele [Vis alle 29 forfattere av denne artikkelen] (2025). Altered amyloid plasma profile in patients with disabling headaches after SARS-CoV-2 infection and vaccination. BMJ Neurology Open. 7(2). doi: 10.1136/bmjno-2024-001013. Fulltekst i vitenarkiv Vis sammendrag

  Background and objectives Persistent headache has emerged as a symptom following acute COVID-19 and, to a lesser extent, after SARS-CoV-2 vaccination. However, the underlying mechanisms remain poorly understood. This study aimed to evaluate plasma levels of amyloid-related biomarkers in patients experiencing persistent headaches after COVID-19 or SARS-CoV-2 vaccination. Methods In this prospective observational cohort, patients presenting with severe headache as the dominating symptom after COVID-19 (n=29) or SARS-CoV-2 vaccination (n=31) had neurological assessments with reassessments after 6 months. Plasma levels of amyloid precursor protein (APP), pregnancy zone protein (PZP), cathepsin L1 (CTSL) and serum Amyloid A (SAA1) were measured using ELISA and compared with levels in healthy controls (n=16). Results We found a strong and persistent upregulation of APP in patients with headache after COVID-19 as compared with the two other groups. Notably, APP levels remained elevated at both inclusion and after 6 months in individuals with accompanying cognitive symptoms. In contrast, PZP levels were increased in patients with headache after SARS-CoV-2 vaccination at both time points relative to healthy controls. CTSL was only elevated in the post-COVID-19 at baseline, whereas SAA1 showed levels comparable across all groups. Conclusion Altered plasma levels of soluble markers, potentially reflecting changes in amyloid processing, were found in patients with persistent headache following SARS-CoV-2 vaccine, particularly in those with persistent headache after COVID-19. In the latter group, we also found some association with cognitive symptoms. Trial registration numbers NCT04576351 and NCT05235776 .

• Furevik, Liv; Lapina, Oksana; Lindland, Elisabeth Margrete Stokke; Høgestøl, Einar August; Geier, Oliver Marcel & Devik, Kristina [Vis alle 22 forfattere av denne artikkelen] (2025). Brain MRI findings in patients with post COVID-19 condition: frequency and longitudinal changes in a nationwide cohort study. Frontiers in Neurology. 16, s. 1–9. doi: 10.3389/fneur.2025.1662263. Fulltekst i vitenarkiv Vis sammendrag

  Background Prolonged neurological symptoms following COVID-19 are common, yet few longitudinal studies describe brain MRI findings in this patient group. The use of contrast enhanced sequences is particularly lacking. We address this knowledge gap by reporting the frequency and longitudinal changes in brain MRI findings among patients with post COVID-19 condition exhibiting neurological symptoms. Methods This prospective multicenter study included 140 adult patients referred for persistent neurological symptoms following COVID-19. Brain MRI was performed at both 6 and 12 months after infection onset, reporting white matter hyperintensities, cerebral microbleeds, and additional pathological findings including contrast enhancement. White matter hyperintensities were compared with a healthy control group. Results The prevalence of white matter hyperintensities was comparable to healthy controls, and microbleeds were found at rates comparable to population studies, with longitudinal changes being infrequent. Lesions consistent with inflammation or demyelination were present in 4% (5/120) of patients at 6 months. Cranial nerve enhancement was found in 7% (7/94) of patients, persisting up to 12 months, predominantly affecting the oculomotor nerve. However, enhancement occurred without clinically detected ocular muscle paresis. Conclusion Our findings indicate that brain MRI primarily serves to exclude differential diagnoses in post COVID-19 condition, with limited clinical benefit of repeated imaging in the absence of new symptoms. However, signs of long-term inflammatory processes can be observed, and detection is improved by contrast enhanced sequences.

• Høgestøl, Einar August; Rinker, Daniel Allen; Maximov, Ivan; Sowa, Piotr; Celius, Elisabeth Gulowsen & Hope, Tuva Roaldsdatter [Vis alle 26 forfattere av denne artikkelen] (2025). A cross-sectional multicentre study of multishell diffusion MRI in multiple sclerosis. Multiple Sclerosis and Related Disorders. ISSN 2211-0348. 98. doi: 10.1016/j.msard.2025.106435. Fulltekst i vitenarkiv Vis sammendrag

  Background and objectives White matter (WM) microstructural properties from advanced multishell diffusion MRI (dMRI) have been linked to clinical disability in multiple sclerosis (MS). This multicentre study used multishell dMRI to compute WM metrics and test for differences between people with MS (pwMS) and healthy controls (HCs). Methods We included multishell dMRI data from 251 pwMS or clinically isolated syndrome (CIS) (mean age 40.7 years, 72.4 % women, 88.8 % relapsing remitting MS) at six MAGNIMS centres and 543 HCs. Eleven scalar metric maps were estimated from multishell dMRI sequences, based on diffusion tensor imaging (DTI) and restriction spectrum imaging (RSI). The maps were analysed using tract-based spatial statistics (TBSS). The diffusion output was submitted to paired sampled t-tests to test for case-control differences and linear regression models to test for associations with Expanded Disability Status Scale (EDSS) scores, while accounting for confounders. In a sub-sample from Oslo, we tested for correlations between EDSS and dMRI metrics within WM lesions. Results Significant group differences were found in nine out of eleven dMRI metrics. Linear regression models revealed significant correlations between EDSS and fractional anisotropy (FA) fast (β=-4.54, p = 0.01) and apparent diffusion coefficient (ADC) fast (β=10.92, p = 8.7 × 10−3). Conclusions Diffusion MRI based on clinically feasible multishell sequences uncovers WM group differences between pwMS and HCs, but only a selection of the advanced multishell parameters were sensitive to disability, and no statistically significant correlations with disability remained after Bonferroni correction.

• Eriksson, Anna Maria; Emini, Nora; Harbo, Hanne-Cathrin Flinstad & Berge, Tone (2025). Is DEXI a Multiple Sclerosis Susceptibility Gene? International Journal of Molecular Sciences. ISSN 1661-6596. 26(3). doi: 10.3390/ijms26031175. Fulltekst i vitenarkiv
• Pontillo, Giuseppe; Prados, Ferran; Wink, Alle Meije; Kanber, Baris; Bisecco, Alvino & Broeders, Tommy A. A. [Vis alle 43 forfattere av denne artikkelen] (2025). More Than the Sum of Its Parts: Disrupted Core Periphery of Multiplex Brain Networks in Multiple Sclerosis. Human Brain Mapping. ISSN 1065-9471. 46(1). doi: 10.1002/hbm.70107. Fulltekst i vitenarkiv
• Fleischer, Vinzenz; Gonzalez-Escamilla, Gabriel; Pareto, Deborah; Rovira, Alex; Sastre-Garriga, Jaume & Sowa, Piotr [Vis alle 23 forfattere av denne artikkelen] (2024). Prognostic value of single-subject grey matter networks in early multiple sclerosis. Brain. ISSN 0006-8950. 147(1), s. 135–146. doi: 10.1093/brain/awad288. Fulltekst i vitenarkiv Vis sammendrag

  The identification of prognostic markers in early multiple sclerosis (MS) is challenging and requires reliable measures that robustly predict future disease trajectories. Ideally, such measures should make inferences at the individual level to inform clinical decisions. This study investigated the prognostic value of longitudinal structural networks to predict 5-year Expanded Disability Status Scale (EDSS) progression in patients with relapsing-remitting MS (RRMS). We hypothesized that network measures, derived from MRI, outperform conventional MRI measurements at identifying patients at risk of developing disability progression. This longitudinal, multicentre study within the Magnetic Resonance Imaging in MS (MAGNIMS) network included 406 patients with RRMS (mean age = 35.7 ± 9.1 years) followed up for 5 years (mean follow-up = 5.0 ± 0.6 years). EDSS was determined to track disability accumulation. A group of 153 healthy subjects (mean age = 35.0 ± 10.1 years) with longitudinal MRI served as controls. All subjects underwent MRI at baseline and again 1 year after baseline. Grey matter atrophy over 1 year and white matter lesion load were determined. A single-subject brain network was reconstructed from T1-weighted scans based on grey matter atrophy measures derived from a statistical parameter mapping-based segmentation pipeline. Key topological measures, including network degree, global efficiency and transitivity, were calculated at single-subject level to quantify network properties related to EDSS progression. Areas under receiver operator characteristic (ROC) curves were constructed for grey matter atrophy and white matter lesion load, and the network measures and comparisons between ROC curves were conducted. The applied network analyses differentiated patients with RRMS who experience EDSS progression over 5 years through lower values for network degree [H(2) = 30.0, P < 0.001] and global efficiency [H(2) = 31.3, P < 0.001] from healthy controls but also from patients without progression. For transitivity, the comparisons showed no difference between the groups [H(2) = 1.5, P = 0.474]. Most notably, changes in network degree and global efficiency were detected independent of disease activity in the first year. The described network reorganization in patients experiencing EDSS progression was evident in the absence of grey matter atrophy. Network degree and global efficiency measurements demonstrated superiority of network measures in the ROC analyses over grey matter atrophy and white matter lesion load in predicting EDSS worsening (all P-values < 0.05). Our findings provide evidence that grey matter network reorganization over 1 year discloses relevant information about subsequent clinical worsening in RRMS. Early grey matter restructuring towards lower network efficiency predicts disability accumulation and outperforms conventional MRI predictors.

• Helland, Gisle Berg; Beyer, Mona K.; Enriquez, Brian Anthony; Ihle-Hansen, Hege Beate; Ihle-Hansen, Håkon & Andersson, Stein [Vis alle 13 forfattere av denne artikkelen] (2024). Lesion Volume as a Predictor for Return to Work After Endovascular Treatment: A 4‐Year Prospective Cohort Study. Stroke: Vascular and Interventional Neurology. 4(6). doi: 10.1161/SVIN.124.001494. Fulltekst i vitenarkiv Vis sammendrag

  Background There are no known objective biomarkers for predicting return to work (RTW) in ischemic stroke survivors. This study aims to explore the predictive utility and defines a cutoff value of lesion volume on RTW after endovascular treatment. Methods We included patients aged <65 years undergoing endovascular treatment at Oslo University Hospital between January 2017 and May 2019. Employment status was obtained at both baseline and a 4‐year follow‐up. Stroke lesion volumes were segmented using magnetic resonance imaging scans 24 hours after endovascular treatment. Logistic regression models were conducted to assess the impact of lesion volume on RTW status at follow‐up, adjusted for patients’ characteristics, stroke‐related factors, and treatment. We calculated the receiver operating characteristic curve to determine the optimal lesion volume cutoff. Machine learning regression models were used to assess the predictive abilities of baseline clinical and imaging variables for RTW. Results Of the 109 individuals treated, 81 (74%) were employed at baseline. Among these, 60 completed 4‐year follow‐up with magnetic resonance imaging available for stroke lesion segmentation and were included in the analyses. Mean age at stroke onset was 51.8 years (range, 23.5–64.9 years), and 50% were female. Median lesion volume was 18 mL (interquartile ranges, 45—47 mL). After 4 years, 34 (57%) had successfully RTW. The odds for not RTW increased by 5% for every 1 mL increase in lesion volume (adjusted odds ratio, 1.05 [95% CI, 1.02–1.11]; P = 0.02). A lesion volume cutoff value of 29 cm3 yielded a sensitivity of 0.91 and specificity of 0.65 for predicting RTW. Notably, the most influential feature in the machine learning model for predicting RTW was lesion volume. Conclusion Lesion volume was the most robust predictor of RTW 4 years after endovascular treatment. Our findings suggest that a cutoff of 29 cm3 is suitable to distinguish between those with high and low chance of RTW.

• Lincoln, Matthew R.; Connally, Noah; Axisa, Pierre-Paul; Gasperi, Christiane; Mitrovic, Mitja & Heel, David van [Vis alle 53 forfattere av denne artikkelen] (2024). Genetic mapping across autoimmune diseases reveals shared associations and mechanisms. Nature Genetics. ISSN 1061-4036. 56(5), s. 838–845. doi: 10.1038/s41588-024-01732-8. Fulltekst i vitenarkiv
• Pontillo, Giuseppe; Prados, Ferran; Colman, Jordan; Kanber, Baris; Abdel-Mannan, Omar & Al-Araji, Sarmad [Vis alle 62 forfattere av denne artikkelen] (2024). Disentangling Neurodegeneration From Aging in Multiple Sclerosis Using Deep Learning: The Brain-Predicted Disease Duration Gap. Neurology. ISSN 0028-3878. 103(10). doi: 10.1212/WNL.0000000000209976. Fulltekst i vitenarkiv Vis sammendrag

  Background and Objectives Disentangling brain aging from disease-related neurodegeneration in patients with multiple sclerosis (PwMS) is increasingly topical. The brain-age paradigm offers a window into this problem but may miss disease-specific effects. In this study, we investigated whether a disease-specific model might complement the brain-age gap (BAG) by capturing aspects unique to MS. Methods In this retrospective study, we collected 3D T1-weighted brain MRI scans of PwMS to build (1) a cross-sectional multicentric cohort for age and disease duration (DD) modeling and (2) a longitudinal single-center cohort of patients with early MS as a clinical use case. We trained and evaluated a 3D DenseNet architecture to predict DD from minimally preprocessed images while age predictions were obtained with the DeepBrainNet model. The brain-predicted DD gap (the difference between predicted and actual duration) was proposed as a DD-adjusted global measure of MS-specific brain damage. Model predictions were scrutinized to assess the influence of lesions and brain volumes while the DD gap was biologically and clinically validated within a linear model framework assessing its relationship with BAG and physical disability measured with the Expanded Disability Status Scale (EDSS). Results We gathered MRI scans of 4,392 PwMS (69.7% female, age: 42.8 ± 10.6 years, DD: 11.4 ± 9.3 years) from 15 centers while the early MS cohort included 749 sessions from 252 patients (64.7% female, age: 34.5 ± 8.3 years, DD: 0.7 ± 1.2 years). Our model predicted DD better than chance (mean absolute error = 5.63 years, R2 = 0.34) and was nearly orthogonal to the brain-age model (correlation between DD and BAGs: r = 0.06 [0.00–0.13], p = 0.07). Predictions were influenced by distributed variations in brain volume and, unlike brain-predicted age, were sensitive to MS lesions (difference between unfilled and filled scans: 0.55 years [0.51–0.59], p < 0.001). DD gap significantly explained EDSS changes (B = 0.060 [0.038–0.082], p < 0.001), adding to BAG (ΔR2 = 0.012, p < 0.001). Longitudinally, increasing DD gap was associated with greater annualized EDSS change (r = 0.50 [0.39–0.60], p < 0.001), with an incremental contribution in explaining disability worsening compared with changes in BAG alone (ΔR2 = 0.064, p < 0.001). Discussion The brain-predicted DD gap is sensitive to MS-related lesions and brain atrophy, adds to the brain-age paradigm in explaining physical disability both cross-sectionally and longitudinally, and may be used as an MS-specific biomarker of disease severity and progression.

• Kennedy, Keith E.; Rosbo, Nicole Kerlero de; Uccelli, Antonio; Cellerino, Maria; Ivaldi, Federico & Contini, Paola [Vis alle 37 forfattere av denne artikkelen] (2024). Multiscale networks in multiple sclerosis. PLoS Computational Biology. ISSN 1553-734X. 20(2). doi: 10.1371/journal.pcbi.1010980. Fulltekst i vitenarkiv Vis sammendrag

  Complex diseases such as Multiple Sclerosis (MS) cover a wide range of biological scales, from genes and proteins to cells and tissues, up to the full organism. In fact, any phenotype for an organism is dictated by the interplay among these scales. We conducted a multilayer network analysis and deep phenotyping with multi-omics data (genomics, phosphoproteomics and cytomics), brain and retinal imaging, and clinical data, obtained from a multicenter prospective cohort of 328 patients and 90 healthy controls. Multilayer networks were constructed using mutual information for topological analysis, and Boolean simulations were constructed using Pearson correlation to identified paths within and among all layers. The path more commonly found from the Boolean simulations connects protein MK03, with total T cells, the thickness of the retinal nerve fiber layer (RNFL), and the walking speed. This path contains nodes involved in protein phosphorylation, glial cell differentiation, and regulation of stress-activated MAPK cascade, among others. Specific paths identified were subsequently analyzed by flow cytometry at the single-cell level. Combinations of several proteins (GSK3AB, HSBP1 or RS6) and immune cells (Th17, Th1 non-classic, CD8, CD8 Treg, CD56 neg, and B memory) were part of the paths explaining the clinical phenotype. The advantage of the path identified from the Boolean simulations is that it connects information about these known biological pathways with the layers at higher scales (retina damage and disability). Overall, the identified paths provide a means to connect the molecular aspects of MS with the overall phenotype.

• Martí-Juan, Gerard; Sastre-Garriga, Jaume; Vidal-Jordana, Angela; Martinez-Heras, Eloy; Llufriu, Sara & Groppa, Sergiu [Vis alle 21 forfattere av denne artikkelen] (2024). Conservation of structural brain connectivity in people with multiple sclerosis. Network Neuroscience. 8(4), s. 1545–1562. doi: 10.1162/netn_a_00404. Fulltekst i vitenarkiv
• Lindland, Elisabeth S.; Røvang, Martin S.; Solheim, Anne Marit; Andreassen, Silje; Skarstein, Ingerid & Dareez, Nazeer [Vis alle 17 forfattere av denne artikkelen] (2024). Are white matter hyperintensities associated with neuroborreliosis? The answer is twofold. Neuroradiology. ISSN 0028-3940. 67, s. 37–48. doi: 10.1007/s00234-024-03482-0. Fulltekst i vitenarkiv Vis sammendrag

  Purpose Many consider white matter hyperintensities (WMHs) to be important imaging findings in neuroborreliosis. However, evidence regarding association with WMHs is of low quality. The objective was to investigate WMHs in neuroborreliosis visually and quantitatively. Materials and methods Patients underwent brain MRI within one month of diagnosis and six months after treatment. Healthy controls were recruited. WMHs were counted by visual rating and the volume was calculated from automatic segmentation. Biochemical markers and scores for clinical symptoms and findings were used to explore association with longitudinal volume change of WMHs. Results The study included 74 patients (37 males) with early neuroborreliosis and 65 controls (30 males). Mean age (standard deviation) was 57.4 (13.5) and 57.7 (12.9) years, respectively. Baseline WMH lesion count was zero in 14 patients/16 controls, < 10 in 36/31, 10–20 in 9/7 and > 20 in 13/11, with no difference between groups (p = 0.90). However, from baseline to follow-up the patients had a small reduction in WMH volume and the controls a small increase, median difference 0.136 (95% confidence interval 0.051–0.251) ml. In patients, volume change was not associated with biochemical or clinical markers, but with degree of WMHs (p values 0.002–0.01). Conclusion WMH lesions were not more numerous in patients with neuroborreliosis compared to healthy controls. However, there was a small reduction of WMH volume from baseline to follow-up among patients, which was associated with higher baseline WMH severity, but not with disease burden or outcome. Overall, non-specific WMHs should not be considered suggestive of neuroborreliosis.

• Martí-Juan, Gerard; Sastre-Garriga, Jaume; Martinez-Heras, Eloy; Vidal-Jordana, Angela; Llufriu, Sara & Groppa, Sergiu [Vis alle 20 forfattere av denne artikkelen] (2023). Using The Virtual Brain to study the relationship between structural and functional connectivity in patients with multiple sclerosis: a multicenter study. Cerebral Cortex. ISSN 1047-3211. 33(12), s. 7322–7334. doi: 10.1093/cercor/bhad041. Fulltekst i vitenarkiv
• Wolf, Asia-Sophia Fumika Michaela; Ravussin, Anthony; König, Marton; Øverås, Mathias Herstad; Solum, Guri & Kjønstad, Ingrid Fadum [Vis alle 18 forfattere av denne artikkelen] (2023). T cell responses to SARS-CoV-2 vaccination differ by disease-modifying therapy for multiple sclerosis. JCI Insight. 8(12), s. 1–14. doi: 10.1172/jci.insight.165111. Fulltekst i vitenarkiv Vis sammendrag

  Immune responses in people with multiple sclerosis (pwMS) receiving disease-modifying therapies (DMTs) have been of significant interest throughout the COVID-19 pandemic. Lymphocyte-targeting immunotherapies, including anti-CD20 treatments and sphingosine-1-phosphate receptor (S1PR) modulators, attenuate Ab responses after vaccination. Evaluation of cellular responses after vaccination, therefore, is of particular importance in these populations. In this study, we used flow cytometry to analyze CD4 and CD8 T cell functional responses to SARS-CoV-2 spike peptides in healthy control study participants and pwMS receiving 5 different DMTs. Although pwMS receiving rituximab and fingolimod therapies had low Ab responses after both 2 and 3 vaccine doses, T cell responses in pwMS taking rituximab were preserved after a third vaccination, even when an additional dose of rituximab was administered between vaccine doses 2 and 3. PwMS taking fingolimod had low detectable T cell responses in peripheral blood. CD4 and CD8 T cell responses to SARS-CoV-2 variants of concern Delta and Omicron were lower than to the ancestral Wuhan-Hu-1 variant. Our results indicate the importance of assessing both cellular and humoral responses after vaccination and suggest that, even in the absence of robust Ab responses, vaccination can generate immune responses in pwMS.

• Harroud, Adil; Stridh, Pernilla; McCauley, Jacob L.; Saarela, Janna Saija; Bosch, Aletta M. R. van den & Engelenburg, Hendrik J. [Vis alle 120 forfattere av denne artikkelen] (2023). Locus for severity implicates CNS resilience in progression of multiple sclerosis. Nature. ISSN 0028-0836. 619(7969), s. 323–331. doi: 10.1038/s41586-023-06250-x. Fulltekst i vitenarkiv
• Lindland, Elisabeth Margrete Stokke; Solheim, Anne Marit; Andreassen, Silje; Bugge, Robin Antony Birkeland; Eikeland, Randi & Reiso, Harald [Vis alle 10 forfattere av denne artikkelen] (2023). Dynamic contrast-enhanced MRI shows altered blood–brain barrier function of deep gray matter structures in neuroborreliosis: a case–control study. European Radiology Experimental. 7(1). doi: 10.1186/s41747-023-00365-6. Fulltekst i vitenarkiv Vis sammendrag

  Background Main aim was assessment of regional blood–brain barrier (BBB) function by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in patients with neuroborreliosis. Secondary aim was to study the correlation of BBB function with biochemical, clinical, and cognitive parameters. Methods Regional ethical committee approved this prospective single-center case–control study. Within 1 month after diagnosis of neuroborreliosis, 55 patients underwent DCE-MRI. The patient group consisted of 25 males and 30 females with mean age 58 years, and the controls were 8 males and 7 females with mean age 57 years. Pharmacokinetic compartment modelling with Patlak fit was applied, providing estimates for capillary leakage rate and blood volume fraction. Nine anatomical brain regions were sampled with auto-generated binary masks. Fatigue, severity of clinical symptoms and findings, and cognitive function were assessed in the acute phase and 6 months after treatment. Results Leakage rates and blood volume fractions were lower in patients compared to controls in the thalamus (p = 0.027 and p = 0.018, respectively), caudate nucleus (p = 0.009 for both), and hippocampus (p = 0.054 and p = 0.009). No correlation of leakage rates with fatigue, clinical disease severity or cognitive function was found. Conclusions In neuroborreliosis, leakage rate and blood volume fraction in the thalamus, caudate nucleus, and hippocampus were lower in patients compared to controls. DCE-MRI provided new insight to pathophysiology of neuroborreliosis, and can serve as biomarker of BBB function and regulatory mechanisms of the neurovascular unit in infection and inflammation. Relevance statement DCE-MRI provided new insight to pathophysiology of neuroborreliosis, and can serve as biomarker of blood–brain barrier function and regulatory mechanisms of the neurovascular unit in infection and inflammation.

• Brune-Ingebretsen, Synne; Høgestøl, Einar August; Rosbo, Nicole Kerlero de; Berg-Hansen, Pål; Brunborg, Cathrine & Blennow, Kaj [Vis alle 12 forfattere av denne artikkelen] (2023). Immune cell subpopulations and serum neurofilament light chain are associated with increased risk of disease worsening in multiple sclerosis. Journal of Neuroimmunology. ISSN 0165-5728. 382. doi: 10.1016/j.jneuroim.2023.578175. Fulltekst i vitenarkiv Vis sammendrag

  Changes is lymphocyte subpopulations in peripheral blood have been proposed as biomarkers for evaluation of disease activity in multiple sclerosis (MS). Serum neurofilament light chain (sNfL) is a biomarker reflecting neuro-axonal injury in MS that could be used to monitor disease activity, response to drugs and to prognosticate disease course. Here we show a moderate correlation between sNfL and lymphocyte cell subpopulations, and our data furthermore suggest that sNfL and specific immune cell subpopulations together could predict future disease worsening in MS.

• Andorra, Magi; Freire, Ana; Zubizarreta, Irati; Rosbo, Nicole Kerlero de; Bos, Steffan Daniel & Rinas, Melanie [Vis alle 40 forfattere av denne artikkelen] (2023). Predicting disease severity in multiple sclerosis using multimodal data and machine learning. Journal of Neurology. ISSN 0340-5354. doi: 10.1007/s00415-023-12132-z. Fulltekst i vitenarkiv Vis sammendrag

  Background Multiple sclerosis patients would benefit from machine learning algorithms that integrates clinical, imaging and multimodal biomarkers to define the risk of disease activity. Methods We have analysed a prospective multi-centric cohort of 322 MS patients and 98 healthy controls from four MS centres, collecting disability scales at baseline and 2 years later. Imaging data included brain MRI and optical coherence tomography, and omics included genotyping, cytomics and phosphoproteomic data from peripheral blood mononuclear cells. Predictors of clinical outcomes were searched using Random Forest algorithms. Assessment of the algorithm performance was conducted in an independent prospective cohort of 271 MS patients from a single centre. Results We found algorithms for predicting confirmed disability accumulation for the different scales, no evidence of disease activity (NEDA), onset of immunotherapy and the escalation from low- to high-efficacy therapy with intermediate to high- accuracy. This accuracy was achieved for most of the predictors using clinical data alone or in combination with imaging data. Still, in some cases, the addition of omics data slightly increased algorithm performance. Accuracies were comparable in both cohorts. Conclusion Combining clinical, imaging and omics data with machine learning helps identify MS patients at risk of dis- ability worsening.

• Brorson, Ina Skaara; Eriksson, Anna Maria; Høgestøl, Einar August; Leikfoss, Ingvild Sørum; Harbo, Hanne-Cathrin Flinstad & Berge, Tone [Vis alle 8 forfattere av denne artikkelen] (2022). Global DNA methylation changes in treated and untreated MS patients measured over time. Journal of Neuroimmunology. ISSN 0165-5728. 364. doi: 10.1016/j.jneuroim.2022.577808. Fulltekst i vitenarkiv Vis sammendrag

  Multiple sclerosis (MS) is an autoimmune, neurological disease. We investigated genome-wide DNA methylation profiles of CD4+ and CD8+ T cells from MS patients and healthy controls at baseline and a follow-up visit. Patients were all treatment-naïve at baseline, and either on treatment or remained untreated at the follow-up visit. MS patients show more changes in their T cell DNA methylation profiles as compared to healthy controls over time, with the most pronounced differences observed in the untreated MS patients. These findings underline the potential of DNA methylation as biomarkers in MS.

• Andreassen, Silje; Lindland, Elisabeth Margrete Stokke; Beyer, Mona K.; Solheim, Anne Marit; Ljøstad, Unn & Mygland, Åse Daasvand [Vis alle 13 forfattere av denne artikkelen] (2022). Assessment of cognitive function, structural brain changes and fatigue 6 months after treatment of neuroborreliosis. Journal of Neurology. ISSN 0340-5354. doi: 10.1007/s00415-022-11463-7. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Rise, Henning Hoel; Brune, Synne; Chien, Claudia; Berge, Tone; Bos, Steffan Daniel & Andorrà, Magí [Vis alle 23 forfattere av denne artikkelen] (2022). Brain disconnectome mapping derived from white matter lesions and serum neurofilament light levels in multiple sclerosis: A longitudinal multicenter study. NeuroImage: Clinical. 35, s. 1–11. doi: 10.1016/j.nicl.2022.103099. Fulltekst i vitenarkiv Vis sammendrag

  Background and Objectives Connectivity-based approaches incorporating the distribution and magnitude of the extended brain network aberrations caused by lesions may offer higher sensitivity for axonal damage in patients with multiple sclerosis (MS) than conventional lesion characteristics. Using individual brain disconnectome mapping, we tested the longitudinal associations between putative imaging-based brain network aberrations and levels of serum neurofilament light chain (NfL) as a neuroaxonal injury biomarker. Methods MS patients (n = 312, mean age 42.9 years, 71 % female) and healthy controls (HC) (n = 59, mean age 39.9 years, 78 % female) were prospectively enrolled at four European MS centres, and reassessed after two years (MS, n = 242; HC, n = 30). Post-processing of 3 Tesla (3 T) MRI data was performed at one centre using a harmonized pipeline, and disconnectome maps were calculated using BCBtoolkit based on individual lesion maps. Global disconnectivity (GD) was defined as the average disconnectome probability in each patient’s white matter. Serum NfL concentrations were measured by single molecule array (Simoa). Robust linear mixed models (rLMM) with GD or T2-lesion volume (T2LV) as dependent variables, patient as a random factor, serum NfL, age, sex, timepoint for visit, diagnosis, treatment, and center as fixed factors were run. Results rLMM revealed significant associations between GD and serum NfL (t = 2.94, p = 0.003), age (t = 4.21, p = 2.5 × 10−5), and longitudinal changes in NfL (t = -2.29, p = 0.02), but not for sex (t = 0.63, p = 0.53) or treatments (t = 0.80–0.83, p = 0.41–0.42). Voxel-wise analyses revealed significant associations between dysconnectivity in cerebellar and brainstem regions and serum NfL (t = 7.03, p < 0.001). Discussion In our prospective multi-site MS cohort, rLMMs demonstrated that the extent of global and regional brain disconnectivity is sensitive to a systemic biomarker of axonal damage, serum NfL, in patients with MS. These findings provide a neuroaxonal correlate of advanced disconnectome mapping and provide a platform for further investigations of the functional and potential clinical relevance of brain disconnectome mapping in patients with brain disorders.

• Brune, Synne; Høgestøl, Einar August; Benavent, Sigrid Aune de Rodez; Berg-Hansen, Pål; Beyer, Mona K. & Leikfoss, Ingvild Sørum [Vis alle 23 forfattere av denne artikkelen] (2022). Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis. Multiple Sclerosis. ISSN 1352-4585. 28(12), s. 1859–1870. doi: 10.1177/13524585221097296. Fulltekst i vitenarkiv Vis sammendrag

  Background: Serum neurofilament light (sNfL) chain is a promising biomarker reflecting neuro-axonal injury in multiple sclerosis (MS). However, the ability of sNfL to predict outcomes in real-world MS cohorts requires further validation. Objective: The aim of the study is to investigate the associations of sNfL concentration, magnetic resonance imaging (MRI) and retinal optical coherence tomography (OCT) markers with disease worsening in a longitudinal European multicentre MS cohort. Methods: MS patients ( n = 309) were prospectively enrolled at four centres and re-examined after 2 years ( n = 226). NfL concentration was measured by single molecule array assay in serum. The patients’ phenotypes were thoroughly characterized with clinical examination, retinal OCT and MRI brain scans. The primary outcome was disease worsening at median 2-year follow-up. Results: Patients with high sNfL concentrations (⩾8 pg/mL) at baseline had increased risk of disease worsening at median 2-year follow-up (odds ratio (95% confidence interval) = 2.8 (1.5–5.3), p = 0.001). We found no significant associations of MRI or OCT measures at baseline with risk of disease worsening. Conclusion: Serum NfL concentration was the only factor associated with disease worsening, indicating that sNfL is a useful biomarker in MS that might be relevant in a clinical setting.

• Andreassen, Silje; Solheim, Anne Marit; Ljøstad, Unn; Mygland, Åse Daasvand; Lorentzen, Åslaug Rudjord & Reiso, Harald [Vis alle 10 forfattere av denne artikkelen] (2022). Cognitive function in patients with neuroborreliosis: A prospective cohort study from the acute phase to 12 months post treatment. Brain and Behavior. 12(6). doi: 10.1002/brb3.2608. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Cappelletti, Chiara; Eriksson, Anna Maria; Brorson, Ina Skaara; Leikfoss, Ingvild Sørum; Kråbøl, Oda Glomstad & Høgestøl, Einar August [Vis alle 12 forfattere av denne artikkelen] (2022). Quantitative proteomics reveals protein dysregulation during T cell activation in multiple sclerosis patients compared to healthy controls. Clinical Proteomics. ISSN 1542-6416. 19(1), s. 1–17. doi: 10.1186/s12014-022-09361-1. Fulltekst i vitenarkiv Vis sammendrag

  Background Multiple sclerosis (MS) is an autoimmune, neurodegenerative disorder with a strong genetic component that acts in a complex interaction with environmental factors for disease development. CD4+ T cells are pivotal players in MS pathogenesis, where peripherally activated T cells migrate to the central nervous system leading to demyelination and axonal degeneration. Through a proteomic approach, we aim at identifying dysregulated pathways in activated T cells from MS patients as compared to healthy controls. Methods CD4+ T cells were purified from peripheral blood from MS patients and healthy controls by magnetic separation. Cells were left unstimulated or stimulated in vitro through the TCR and costimulatory CD28 receptor for 24 h prior to sampling. Electrospray liquid chromatography-tandem mass spectrometry was used to measure protein abundances. Results Upon T cell activation the abundance of 1801 proteins was changed. Among these proteins, we observed an enrichment of proteins expressed by MS-susceptibility genes. When comparing protein abundances in T cell samples from healthy controls and MS patients, 18 and 33 proteins were differentially expressed in unstimulated and stimulated CD4+ T cells, respectively. Moreover, 353 and 304 proteins were identified as proteins exclusively induced upon T cell activation in healthy controls and MS patients, respectively and dysregulation of the Nur77 pathway was observed only in samples from MS patients. Conclusions Our study highlights the importance of CD4+ T cell activation for MS, as proteins that change in abundance upon T cell activation are enriched for proteins encoded by MS susceptibility genes. The results provide evidence for proteomic disturbances in T cell activation in MS, and pinpoint to dysregulation of the Nur77 pathway, a biological pathway known to limit aberrant effector T cell responses.

• Lie, Ingrid Anne; Wesnes, Kristin; Kvistad, Silje Agnethe Stokke; Brouwer, Iman; Wergeland, Stig & Holmøy, Trygve [Vis alle 20 forfattere av denne artikkelen] (2022). The Effect of Smoking on Long-term Gray Matter Atrophy and Clinical Disability in Patients with Relapsing-Remitting Multiple Sclerosis. Neurology: Neuroimmunology and neuroinflammation. 9(5), s. 1–10. doi: 10.1212/NXI.0000000000200008. Fulltekst i vitenarkiv Vis sammendrag

  Background and Objectives - The relationship between smoking, long-term brain atrophy, and clinical disability in patients with multiple sclerosis (MS) is unclear. Here, we assessed long-term effects of smoking by evaluating MRI and clinical outcome measures after 10 years in smoking and nonsmoking patients with relapsing-remitting MS (RRMS). Methods - We included 85 treatment-naive patients with RRMS with recent inflammatory disease activity who participated in a 10-year follow-up visit after a multicenter clinical trial of 24 months. Smoking status was decided for each patient by 2 separate definitions: by serum cotinine levels measured regularly for the first 2 years of the follow-up (during the clinical trial) and by retrospective patient self-reporting. At the 10-year follow-up visit, clinical tests were repeated, and brain atrophy measures were obtained from MRI using FreeSurfer. Differences in clinical and MRI measurements at the 10-year follow-up between smokers and nonsmokers were investigated by 2-sample t tests or Mann-Whitney tests and linear mixed-effect regression models. All analyses were conducted separately for each definition of smoking status. Results - After 10 years, smoking (defined by serum cotinine levels) was associated with lower total white matter volume (β = −21.74, p = 0.039) and higher logT2 lesion volume (β = 0.22, p = 0.011). When defining smoking status by patient self-reporting, the repeated analyses found an additional association with lower deep gray matter volume (β = −2.35, p = 0.049), and smoking was also associated with a higher score (higher walking impairment) on the log timed 25-foot walk test (β = 0.050, p = 0.039) after 10 years and a larger decrease in paced auditory serial addition test (attention) scores (β = −3.58, p = 0.029). Discussion - Smoking was associated with brain atrophy and disability progression 10 years later in patients with RRMS. The findings imply that patients should be advised and offered aid in smoking cessation shortly after diagnosis, to prevent long-term disability progression.

• Nes, Dragana; Berg-Hansen, Pål; Benavent, Sigrid Aune de Rodez; Høgestøl, Einar August; Beyer, Mona K. & Rinker, Daniel Allen [Vis alle 12 forfattere av denne artikkelen] (2022). Exploring Retinal Blood Vessel Diameters as Biomarkers in Multiple Sclerosis. Journal of Clinical Medicine. 11(11). doi: 10.3390/jcm11113109. Fulltekst i vitenarkiv Vis sammendrag

  We aimed to determine whether retinal vessel diameters and retinal oxygen saturation in newly diagnosed patients with multiple sclerosis (pwMS) are different from those of a healthy population. Retinal blood vessel diameters were measured using imaging with a spectrophotometric non-invasive retinal oximeter. Twenty-three newly diagnosed untreated relapsing-remitting MS (RRMS) patients (mean age: 32.2 ± 7.5 years, age range = 18–50 years, 56.5% female) were measured and compared to 23 age- and sex-matched healthy controls (HCs) (mean age: 34.8 ± 8.1 years). Patients with Optic Neuritis were excluded. Retinal venular diameter (143.8 µm versus 157.8 µm: mean; p = 0.0013) and retinal arteriolar diameter (112.6 µm versus 120.6 µm: mean; p = 0.0089) were smaller in pwMS when compared with HCs, respectively. There was no significant difference in the oxygen saturation in retinal venules and arterioles in pwMS (mean: 60.0% and 93.7%; p = 0.5980) compared to HCs (mean: 59.3% and 91.5%; p = 0.8934), respectively. There was a significant difference in the median low contrast visual acuity (2.5% contrast) between the pwMS and the HC groups (p = 0.0143) Retinal arteriolar and venular diameter may have potential as objective biomarkers for MS.

• Lie, Ingrid Anne; Kacar, Sezgi; Wesnes, Kristin; Brouwer, Iman; Kvistad, Silje Agnethe Stokke & Wergeland, Stig [Vis alle 24 forfattere av denne artikkelen] (2022). Serum neurofilament as a predictor of 10-year grey matter atrophy and clinical disability in multiple sclerosis: a longitudinal study. Journal of Neurology, Neurosurgery and Psychiatry. ISSN 0022-3050. 93(8), s. 849–857. doi: 10.1136/jnnp-2021-328568. Fulltekst i vitenarkiv Vis sammendrag

  Background The predictive value of serum neurofilament light chain (sNfL) on long-term prognosis in multiple sclerosis (MS) is still unclear. Objective Investigate the relation between sNfL levels over a 2-year period in patients with relapsing-remitting MS, and clinical disability and grey matter (GM) atrophy after 10 years. Methods 85 patients, originally enrolled in a multicentre, randomised trial of ω−3 fatty acids, participated in a 10-year follow-up visit. sNfL levels were measured by Simoa quarterly until month 12, and then at month 24. The appearance of new gadolinium-enhancing (Gd+) lesions was assessed monthly between baseline and month 9, and then at months 12 and 24. At the 10-year follow-up visit, brain atrophy measures were obtained using FreeSurfer. Results Higher mean sNfL levels during early periods of active inflammation (Gd+ lesions present or recently present) predicted lower total (β=−0.399, p=0.040) and deep (β=−0.556, p=0.010) GM volume, lower mean cortical thickness (β=−0.581, p=0.010) and higher T2 lesion count (β=0.498, p=0.018). Of the clinical outcomes, higher inflammatory sNfL levels were associated with higher disability measured by the dominant hand Nine-Hole Peg Test (β=0.593, p=0.004). Mean sNfL levels during periods of remission (no Gd+ lesions present or recently present) did not predict GM atrophy or disability progression. Conclusion Higher sNfL levels during periods of active inflammation predicted more GM atrophy and specific aspects of clinical disability 10 years later. The findings suggest that subsequent long-term GM atrophy is mainly due to neuroaxonal degradation within new lesions.

• Leonardsen, Esten Høyland; Peng, Han; Kaufmann, Tobias; Agartz, Ingrid; Andreassen, Ole & Celius, Elisabeth Gulowsen [Vis alle 19 forfattere av denne artikkelen] (2022). Deep neural networks learn general and clinically relevant representations of the ageing brain. NeuroImage. ISSN 1053-8119. 256. doi: 10.1016/j.neuroimage.2022.119210. Fulltekst i vitenarkiv Vis sammendrag

  The discrepancy between chronological age and the apparent age of the brain based on neuroimaging data — the brain age delta — has emerged as a reliable marker of brain health. With an increasing wealth of data, approaches to tackle heterogeneity in data acquisition are vital. To this end, we compiled raw structural magnetic resonance images into one of the largest and most diverse datasets assembled (n=53542), and trained convolutional neural networks (CNNs) to predict age. We achieved state-of-the-art performance on unseen data from unknown scanners (n=2553), and showed that higher brain age delta is associated with diabetes, alcohol intake and smoking. Using transfer learning, the intermediate representations learned by our model complemented and partly outperformed brain age delta in predicting common brain disorders. Our work shows we can achieve generalizable and biologically plausible brain age predictions using CNNs trained on heterogeneous datasets, and transfer them to clinical use cases.

• Wesnes, Kristin; Myhr, Kjell-Morten; Riise, Trond; Kvistad, Silje Agnethe Stokke; Torkildsen, Øivind & Wergeland, Stig [Vis alle 17 forfattere av denne artikkelen] (2021). Low vitamin D, but not tobacco use or high BMI, is associated with long-term disability progression in multiple sclerosis. Multiple Sclerosis and Related Disorders. ISSN 2211-0348. 50:102801, s. 1–7. doi: 10.1016/j.msard.2021.102801. Fulltekst i vitenarkiv Vis sammendrag

  Background: Low vitamin D levels, tobacco use and high body mass index (BMI) have been linked to adverse disease outcomes in multiple sclerosis (MS), but their influence on long-term disability progression remains unclear. Therefore, we explored whether these modifiable lifestyle factors were associated with 10-year clinical disability progression in patients with MS. Methods: In this prospective study, a cohort of 88 patients with relapsing-remitting MS completed a randomized controlled study on ω-3 fatty acids between 2004 and 2008. During 24 months, serum 25-hydroxyvitamin D (25 (OH)D), serum cotinine (nicotine metabolite), and BMI were repeatedly measured. In 2017, a follow-up study was conducted among 80 of the participants, including disability assessment by the Expanded Disability Status Scale (EDSS). Linear regression was used to explore associations between the lifestyle factors and the EDSS change over 10 years. Results: Higher seasonally adjusted 25(OH)D levels were associated with lower 10-year EDSS progression (change in EDSS per 1 SD increase in 25(OH)D in a model adjusted for sex, age and baseline EDSS: -0.45 point, 95% CI: -0.75 to -0.16, p=0.003). Further adjustments for potential confounders related to lifestyle and disease status gave similar results. The association was mainly driven by low 25(OH)D levels during spring, as well as seasonally adjusted levels below 80 nmol/L. No clear association was found for BMI and cotinine. Conclusion: Lower 25(OH)D levels, but apparently not tobacco use or higher BMI, were significantly associated with worse long-term disability progression in MS.

• Creary, Lisa E.; Gangavarapu, Sridevi; Caillier, Stacy J.; Cavalcante, Paola; Frangiamore, Rita & Lie, Benedicte Alexandra [Vis alle 16 forfattere av denne artikkelen] (2021). 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. Frontiers in Immunology. 12, s. 1–14. doi: 10.3389/fimmu.2021.667336. Fulltekst i vitenarkiv Vis sammendrag

  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.

• König, Marton; Lorentzen, Åslaug Rudjord; Torgauten, Hilde Marie; Tran, Trung; Schikora-Rustad, Stine & Vaage, Eline Benno [Vis alle 22 forfattere av denne artikkelen] (2021). 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. Journal of Neurology, Neurosurgery and Psychiatry. ISSN 0022-3050. doi: 10.1136/jnnp-2021-327612. Fulltekst i vitenarkiv Vis sammendrag

  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. This article is made freely available for use in accordance with BMJ’s website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.

• Andreassen, Silje; Lindland, Elisabeth Margrete Stokke; Solheim, Anne Marit; Beyer, Mona K.; Ljøstad, Unn & Mygland, Åse Daasvand [Vis alle 11 forfattere av denne artikkelen] (2021). Cognitive function, fatigue and Fazekas score in patients with acute neuroborreliosis. Ticks and Tick-borne Diseases. ISSN 1877-959X. 12(3), s. 1–5. doi: 10.1016/j.ttbdis.2021.101678. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Aamodt, Anne Hege; Høgestøl, Einar August; Popperud, Trine Haug; Holter, Jan Cato; Dyrhol-Riise, Anne Ma & Tonby, Kristian [Vis alle 15 forfattere av denne artikkelen] (2021). Blood neurofilament light concentration at admittance: a potential prognostic marker in COVID-19. Journal of Neurology. ISSN 0340-5354. doi: 10.1007/s00415-021-10517-6. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Eriksson, Anna Maria; Leikfoss, Ingvild Sørum; Abrahamsen, Greger; Gjerstad, Vibeke Sundvold; Isom, Martine Mesel & Keshari, Pankaj [Vis alle 12 forfattere av denne artikkelen] (2021). Exploring the role of the multiple sclerosis susceptibility gene CLEC16A in T cells. Scandinavian Journal of Immunology. ISSN 0300-9475. 94(1). doi: 10.1111/sji.13050. Fulltekst i vitenarkiv Vis sammendrag

  C-type lectin-like domain family 16 member A (CLEC16A) is associated with autoimmune disorders, including multiple sclerosis (MS), but its functional relevance is not completely understood. CLEC16A is expressed in several immune cells, where it affects autophagic processes and receptor expression. Recently, we reported that the risk genotype of an MS-associated single nucleotide polymorphism in CLEC16A intron 19 is associated with higher expression of CLEC16A in CD4+ T cells. Here, we show that CLEC16A expression is induced in CD4+ T cells upon T cell activation. By the use of imaging flow cytometry and confocal microscopy, we demonstrate that CLEC16A is located in Rab4a-positive recycling endosomes in Jurkat TAg T cells. CLEC16A knock-down in Jurkat cells resulted in lower cell surface expression of the T cell receptor, however, this did not have a major impact on T cell activation response in vitro in Jurkat nor in human, primary CD4+ T cells.

• Høgestøl, Einar August; Ghezzo, Samuele; Nygaard, Gro Owren; Espeseth, Thomas; Sowa, Piotr & Beyer, Mona K. [Vis alle 10 forfattere av denne artikkelen] (2021). Functional connectivity in multiple sclerosis modelled as connectome stability: A 5-year follow-up study. Multiple Sclerosis. ISSN 1352-4585. s. 1–9. doi: 10.1177/13524585211030212. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Brune, Synne; Høgestøl, Einar August; Cengija, Vanja; Berg-Hansen, Pål; Sowa, Piotr & Nygaard, Gro Owren [Vis alle 8 forfattere av denne artikkelen] (2020). LesionQuant for assessment of MRI in multiple sclerosis—A promising supplement to the visual scan inspection. Frontiers in Neurology. 11:546744, s. 1–10. doi: 10.3389/fneur.2020.546744. Fulltekst i vitenarkiv Vis sammendrag

  Background and Goals: Multiple sclerosis (MS) is a central nervous system inflammatory disease where magnetic resonance imaging (MRI) is an important tool for diagnosis and disease monitoring. Quantitative measurements of lesion volume, lesion count, distribution of lesions, and brain atrophy have a potentially significant value for evaluating disease progression. We hypothesize that utilizing software designed for evaluating MRI data in MS will provide more accurate and detailed analyses compared to the visual neuro-radiological evaluation. Methods: A group of 56 MS patients (mean age 35 years, 70% females and 96% relapsing-remitting MS) was examined with brain MRI one and 5 years after diagnosis. The T1 and FLAIR brain MRI sequences for all patients were analyzed using the LesionQuant (LQ) software. These data were compared with data from structured visual evaluations of the MRI scans performed by neuro-radiologists, including assessments of atrophy, and lesion count. The data from LQ were also compared with data from other validated research methods for brain segmentation, including assessments of whole brain volume and lesion volume. Correlations with clinical tests like the timed 25-foot walk test (T25FT) were performed to explore additional value of LQ analyses. Results: Lesion count assessments by LQ and by the neuro-radiologist were significantly correlated one year (cor = 0.92, p = 2.2 × 10 −16 ) and 5 years (cor = 0.84, p = 2.7 × 10 −16 ) after diagnosis. Analyzes of the intra- and interrater variability also correlated significantly (cor = 0.96, p &amp;lt; 0.001, cor = 0.97, p &amp;lt; 0.001). Significant positive correlation was found between lesion volume measured by LQ and by the software Cascade (cor = 0.7, p &amp;lt; 0.001. LQ detected a reduction in whole brain percentile &amp;gt;10 in 10 patients across the time-points, whereas the neuro-radiologist assessment identified six of these. The neuro-radiologist additionally identified five patients with increased atrophy in the follow-up period, all of them displayed decreasing low whole brain percentiles (median 11, range 8–28) in the LQ analysis. Significant positive correlation was identified between lesion volume measured by LQ and test performance on the T25FT both at 1 and 5 years after diagnosis. Conclusion: For the number of MS lesions at both time-points, we demonstrated strong correlations between the assessments done by LQ and the neuro-radiologist. Lesion volume evaluated with LQ correlated with T25FT performance. LQ-analyses classified more patients to have brain atrophy than the visual neuro-radiological evaluation. In conclusion, LQ seems like a promising supplement to the evaluation performed by neuro-radiologists, providing an automated tool for evaluating lesions in MS patients and also detecting early signs of atrophy in both a longitudinal and cross-sectional setting.

• Cellerino, Maria; Ivaldi, Frederico; Pardini, Matteo; Rotta, Gianluca; Vila, Gemma & Bäcker-Koduah, Priscilla [Vis alle 23 forfattere av denne artikkelen] (2020). Impact of treatment on cellular immunophenotype in MS: A cross-sectional study. Neurology: Neuroimmunology and neuroinflammation. 7(3), s. 1–13. doi: 10.1212/NXI.0000000000000693. Fulltekst i vitenarkiv Vis sammendrag

  Objective: To establish cytometry profiles associated with disease stages and immunotherapy in MS. Methods: Demographic/clinical data and peripheral blood samples were collected from 227 patients with MS and 82 sex- and age-matched healthy controls (HCs) enrolled in a cross-sectional study at 4 European MS centers (Spain, Italy, Germany, and Norway). Flow cytometry of isolated peripheral blood mononuclear cells was performed in each center using specifically prepared antibody-cocktail Lyotubes; data analysis was centralized at the Genoa center. Differences in immune cell subsets were assessed between groups of untreated patients with relapsing-remitting or progressive MS (RRMS or PMS) and HCs and between groups of patients with RRMS taking 6 commonly used disease-modifying drugs. Results: In untreated patients with MS, significantly higher frequencies of Th17 cells in the RRMS population compared with HC and lower frequencies of B-memory/B-regulatory cells as well as higher percentages of B-mature cells in patients with PMS compared with HCs emerged. Overall, the greatest deviation in immunophenotype in MS was observed by treatment rather than disease course, with the strongest impact found in fingolimod-treated patients. Fingolimod induced a decrease in total CD4+ T cells and in B-mature and B-memory cells and increases in CD4+ and CD8+ T-regulatory and B-regulatory cells. Conclusions: Our highly standardized, multisite cytomics data provide further understanding of treatment impact on MS immunophenotype and could pave the way toward monitoring immune cells to help clinical management of MS individuals.

• Brorson, Ina Skaara; Eriksson, Anna Maria; Leikfoss, Ingvild Sørum; Vitelli, Valeria; Celius, Elisabeth Gulowsen & Luders, Torben [Vis alle 10 forfattere av denne artikkelen] (2020). CD8 + T cell gene expression analysis identifies differentially expressed genes between multiple sclerosis patients and healthy controls. Multiple Sclerosis Journal, Experimental, Translational and Clinical. doi: 10.1177/2055217320978511. Fulltekst i vitenarkiv Vis sammendrag

  Background: Genetic and clinical observations have indicated T cells are involved in MS pathology. There is little insight in how T cells are involved and whether or not these can be used as markers for MS. Objectives: Analysis of the gene expression profiles of circulating CD8þ T cells of MS patients compared to healthy controls. Methods: RNA from purified CD8þ T cells was sequenced and analyzed for differential gene expression. Pathway analyses of genes at several p-value cutoffs were performed to identify putative pathways involved. Results: We identified 36 genes with significant differential gene expression in MS patients. Four genes reached at least 2-fold differences in expression. The majority of differentially expressed genes was higher expressed in MS patients. Genes associated to MS in GWAS showed enrichment amongst the differentially expressed genes. We did not identify enrichment of specific pathways amongst the differentially expressed genes in MS patients. Conclusions: CD8þ T cells of MS patients show differential gene expression, with predominantly higher activity of genes in MS patients. We do not identify specific biological pathways in our study. More detailed analysis of CD8þ T cells and subtypes of these may increase understanding of how T cells are involved in MS.

• Aamodt, Anne Hege; Harbo, Hanne Flinstad; Eldøen, Guttorm; Barratt-Due, Andreas & Aukrust, Pål (2020). Hvordan påvirkes hjernen ved covid-19? Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 140(10), s. 968–969. doi: 10.4045/tidsskr.20.0444. Fulltekst i vitenarkiv
• Elvsåshagen, Torbjørn; Bahrami, Shahram; Meer, Dennis van der; Agartz, Ingrid; Alnæs, Dag & Barch, Deanna M. [Vis alle 76 forfattere av denne artikkelen] (2020). The genetic architecture of human brainstem structures and their involvement in common brain disorders. Nature Communications. 11. doi: 10.1038/s41467-020-17376-1. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Brorson, Ina Skaara; Eriksson, Anna Maria; Leikfoss, Ingvild Sørum; Celius, Elisabeth Gulowsen; Berg-Hansen, Pål & Barcellos, Lisa F [Vis alle 9 forfattere av denne artikkelen] (2019). No differential gene expression for CD4+ T cells of MS patients and healthy controls. Multiple Sclerosis Journal, Experimental, Translational and Clinical. 5(2). doi: 10.1177/2055217319856903. Fulltekst i vitenarkiv
• Berge, Tone; Eriksson, Anna; Brorson, Ina Skaara; Høgestøl, Einar August; Berg-Hansen, Pål & Døskeland, Anne Marie Simonne [Vis alle 10 forfattere av denne artikkelen] (2019). Quantitative proteomic analyses of CD4+ and CD8+ T cells reveal differentially expressed proteins in multiple sclerosis patients and healthy controls. Clinical Proteomics. ISSN 1542-6416. 16:19, s. 1–18. doi: 10.1186/s12014-019-9241-5. Fulltekst i vitenarkiv Vis sammendrag

  Background Multiple sclerosis (MS) is an autoimmune, neuroinflammatory disease, with an unclear etiology. However, T cells play a central role in the pathogenesis by crossing the blood–brain-barrier, leading to inflammation of the central nervous system and demyelination of the protective sheath surrounding the nerve fibers. MS has a complex inheritance pattern, and several studies indicate that gene interactions with environmental factors contribute to disease onset. Methods In the current study, we evaluated T cell dysregulation at the protein level using electrospray liquid chromatography–tandem mass spectrometry to get novel insights into immune-cell processes in MS. We have analyzed the proteomic profiles of CD4+ and CD8+ T cells purified from whole blood from 13 newly diagnosed, treatment-naive female patients with relapsing–remitting MS and 14 age- and sex-matched healthy controls. Results An overall higher protein abundance was observed in both CD4+ and CD8+ T cells from MS patients when compared to healthy controls. The differentially expressed proteins were enriched for T-cell specific activation pathways, especially CTLA4 and CD28 signaling in CD4+ T cells. When selectively analyzing proteins expressed from the genes most proximal to > 200 non-HLA MS susceptibility polymorphisms, we observed differential expression of eight proteins in T cells between MS patients and healthy controls, and there was a correlation between the genotype at three MS genetic risk loci and protein expressed from proximal genes. Conclusion Our study provides evidence for proteomic differences in T cells from relapsing–remitting MS patients compared to healthy controls and also identifies dysregulation of proteins encoded from MS susceptibility genes.

• Rhead, Brooke; Brorson, Ina Skaara; Berge, Tone; Adams, Cameron; Quach, H. & Moen, Stine Marit [Vis alle 18 forfattere av denne artikkelen] (2019). Increased DNA methylation of SLFN12 in CD4+ and CD8+ T cells from multiple sclerosis patients. PLOS ONE. doi: 10.1371/journal.pone.0206511. Fulltekst i vitenarkiv
• Brorson, Ina Skaara; Eriksson, Anna; Leikfoss, Ingvild Sørum; Celius, Elisabeth Gulowsen; Berg-Hansen, Pål & Barcellos, Lisa F. [Vis alle 9 forfattere av denne artikkelen] (2019). No differential gene expression for CD4+ T cells of MS patients and healthy controls. Multiple Sclerosis Journal, Experimental, Translational and Clinical. 5(2). doi: 10.1177/2055217319856903. Fulltekst i vitenarkiv Vis sammendrag

  Background: Multiple sclerosis-associated genetic variants indicate that the adaptive immune system plays an important role in the risk of developing multiple sclerosis. It is currently not well understood how these multiple sclerosis-associated genetic variants contribute to multiple sclerosis risk. CD4þ T cells are suggested to be involved in multiple sclerosis disease processes. Objective: We aim to identify CD4þ T cell differential gene expression between multiple sclerosis patients and healthy controls in order to understand better the role of these cells in multiple sclerosis. Methods: We applied RNA sequencing on CD4þ T cells from multiple sclerosis patients and healthy controls. Results: We did not identify significantly differentially expressed genes in CD4þ T cells from multiple sclerosis patients. Furthermore, pathway analyses did not identify enrichment for specific pathways in multiple sclerosis. When we investigated genes near multiple sclerosis-associated genetic variants, we did not observe significant enrichment of differentially expressed genes. Conclusion: We conclude that CD4þ T cells from multiple sclerosis patients do not show significant differential gene expression. Therefore, gene expression studies of all circulating CD4þ T cells may not result in viable biomarkers. Gene expression studies of more specific subsets of CD4þ T cells remain justified to understand better which CD4þ T cell subsets contribute to multiple sclerosis pathology.

• Madireddy, Lohith; Patsopoulos, Nikolaos A.; Cotsapas, Chris; Bos, Steffan Daniel; Beecham, Ashley & McCauley, Jacob [Vis alle 64 forfattere av denne artikkelen] (2019). A systems biology approach uncovers cell-specific gene regulatory effects of genetic associations in multiple sclerosis. Nature Communications. 10:2236, s. 1–12. doi: 10.1038/s41467-019-09773-y. Fulltekst i vitenarkiv Vis sammendrag

  Genome-wide association studies (GWAS) have identified more than 50,000 unique associations with common human traits. While this represents a substantial step forward, establishing the biology underlying these associations has proven extremely difficult. Even determining which cell types and which particular gene(s) are relevant continues to be a challenge. Here, we conduct a cell-specific pathway analysis of the latest GWAS in multiple sclerosis (MS), which had analyzed a total of 47,351 cases and 68,284 healthy controls and found more than 200 non-MHC genome-wide associations. Our analysis identifies pan immune cell as well as cell-specific susceptibility genes in T cells, B cells and monocytes. Finally, genotype-level data from 2,370 patients and 412 controls is used to compute intraindividual and cell-specific susceptibility pathways that offer a biological interpretation of the individual genetic risk to MS. This approach could be adopted in any other complex trait for which genome-wide data is available.

• Benavent, Sigrid Aune de Rodez; Nygaard, Gro Owren; Nilsen, Kristian Bernhard; Etholm, Lars; Sowa, Piotr & Gustavsen, Marte Wendel [Vis alle 11 forfattere av denne artikkelen] (2019). Neurodegenerative interplay of cardiovascular autonomic dysregulation and the retina in early multiple sclerosis. Frontiers in Neurology. 10, s. 1–9. doi: 10.3389/fneur.2019.00507. Fulltekst i vitenarkiv Vis sammendrag

  Introduction: Autonomic nervous system (ANS) symptoms are prevalent in multiple sclerosis (MS) as is neurodegeneration. Our aim was to explore the occurrence of ANS symptoms and retinal neurodegeneration in a newly diagnosed MS population with tools available in a clinical setting. Methods: Forty-three MS patients and 44 healthy controls took part in the study. We employed a bedside cardiovascular ANS test battery together with classical pupillometry, optical coherence tomography (OCT) evaluation of retinal neurodegeneration in eyes without previous optic neuritis (MSNON) and patients' self-report forms on fatigue, orthostatic and ANS symptoms. Results: Half of the patients presented with ANS symptoms and a high level of fatigue. There was a significant difference in ganglion cell layer thickness (mean GCIPL) evaluated by OCT in MSNON compared to healthy control eyes. We found a negative linearity of mean GCIPL on group level with increasing disease duration. Three patients fulfilled the criteria of postural orthostatic tachycardia syndrome (POTS). Conclusion: Our results demonstrate retinal neurodegeneration in MSNON, a high frequency of fatigue and a high prevalence of ANS symptoms in newly diagnosed patients. Whether neurodegeneration precedes ANS dysfunction or vice versa is still open to debate, but as unveiled by the presence of POTS in this MS population, differences in stress-response regulation add to the understanding of variation in onset-time of ANS dysfunction in early MS.

• Høgestøl, Einar August; Kaufmann, Tobias; Nygaard, Gro Owren; Beyer, Mona K.; Sowa, Piotr & Nordvik, Jan Egil [Vis alle 11 forfattere av denne artikkelen] (2019). Cross-sectional and longitudinal MRI brain scans reveal accelerated brain aging in multiple sclerosis. Frontiers in Neurology. 10:450, s. 1–9. doi: 10.3389/fneur.2019.00450. Fulltekst i vitenarkiv Vis sammendrag

  Multiple sclerosis (MS) is an inflammatory disorder of the central nervous system. By combining longitudinal MRI-based brain morphometry and brain age estimation using machine learning, we tested the hypothesis that MS patients have higher brain age relative to chronological age than healthy controls (HC) and that longitudinal rate of brain aging in MS patients is associated with clinical course and severity. Seventy-six MS patients [71% females, mean age 34.8 years (range 21–49) at inclusion] were examined with brain MRI at three time points with a mean total follow up period of 4.4 years (±0.4 years). We used additional cross-sectional MRI data from 235 HC for case-control comparison. We applied a machine learning model trained on an independent set of 3,208 HC to estimate individual brain age and to calculate the difference between estimated and chronological age, termed brain age gap (BAG). We also assessed the longitudinal change rate in BAG in individuals with MS. MS patients showed significantly higher BAG (4.4 ± 6.6 years) compared to HC (Cohen's D = 0.69, p = 4.0 × 10−6). Longitudinal estimates of BAG in MS patients showed high reliability and suggested an accelerated rate of brain aging corresponding to an annual increase of 0.41 (SE = 0.15) years compared to chronological aging (p = 0.008). Multiple regression analyses revealed higher rate of brain aging in patients with more brain atrophy (Cohen's D = 0.86, p = 4.3 × 10−15) and increased white matter lesion load (WMLL) (Cohen's D = 0.55, p = 0.015). On average, patients with MS had significantly higher BAG compared to HC. Progressive brain aging in patients with MS was related to brain atrophy and increased WMLL. No significant clinical associations were found in our sample, future studies are warranted on this matter. Brain age estimation is a promising method for evaluation of subtle brain changes in MS, which is important for predicting clinical outcome and guide choice of intervention.

• Kaufmann, Tobias; Meer, Dennis van der; Doan, Nhat Trung; Schwarz, Emanuel; Lund, Martina Jonette & Agartz, Ingrid [Vis alle 84 forfattere av denne artikkelen] (2019). Common brain disorders are associated with heritable patterns of apparent aging of the brain. Nature Neuroscience. ISSN 1097-6256. 22(10), s. 1617–1623. doi: 10.1038/s41593-019-0471-7. Fulltekst i vitenarkiv Vis sammendrag

  Common risk factors for psychiatric and other brain disorders are likely to converge on biological pathways influencing the development and maintenance of brain structure and function across life. Using structural MRI data from 45,615 individuals aged 3–96 years, we demonstrate distinct patterns of apparent brain aging in several brain disorders and reveal genetic pleiotropy between apparent brain aging in healthy individuals and common brain disorders.

• Høgestøl, Einar August; Nygaard, Gro Owren; Alnæs, Dag; Beyer, Mona K.; Westlye, Lars Tjelta & Harbo, Hanne Flinstad (2019). Symptoms of fatigue and depression is reflected in altered default mode network connectivity in multiple sclerosis. PLOS ONE. 14(4). doi: 10.1371/journal.pone.0210375. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Patsopoulos, Nikolaos A.; Baranzini, Sergio E.; Santaniello, Adam; Shoostari, Parisa; Cotsapas, Chris & Wong, Garrett [Vis alle 154 forfattere av denne artikkelen] (2019). Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science. ISSN 0036-8075. 365:eaav7188(6460), s. 1–12. doi: 10.1126/science.aav7188. Fulltekst i vitenarkiv Vis sammendrag

  We analyzed genetic data of 47,429 multiple sclerosis (MS) and 68,374 control subjects and established a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 variants within the extended MHC. We used an ensemble of methods to prioritize 551 putative susceptibility genes that implicate multiple innate and adaptive pathways distributed across the cellular components of the immune system. Using expression profiles from purified human microglia, we observed enrichment for MS genes in these brain-resident immune cells, suggesting that these may have a role in targeting an autoimmune process to the central nervous system, although MS is most likely initially triggered by perturbation of peripheral immune responses

• Rhead, Brooke; Brorson, Ina Skaara; Berge, Tone; Adams, Cameron; Quach, Hong & Moen, Stine Marit [Vis alle 18 forfattere av denne artikkelen] (2018). Increased DNA methylation of SLFN12 in CD4+ and CD8+ T cells from multiple sclerosis patients. PLOS ONE. 13(10). doi: 10.1371/journal.pone.0206511. Fulltekst i vitenarkiv Vis sammendrag

  DNA methylation is an epigenetic mark that is influenced by environmental factors and is associated with changes to gene expression and phenotypes. It may link environmental exposures to disease etiology or indicate important gene pathways involved in disease pathogenesis. We identified genomic regions that are differentially methylated in T cells of patients with relapsing remitting multiple sclerosis (MS) compared to healthy controls. DNA methylation was assessed at 450,000 genomic sites in CD4+ and CD8+ T cells purified from peripheral blood of 94 women with MS and 94 healthy women, and differentially methylated regions were identified using bumphunter. Differential DNA methylation was observed near four loci: MOG/ZFP57, HLA-DRB1, NINJ2/LOC100049716, and SLFN12. Increased methylation of the first exon of the SLFN12 gene was observed in both T cell subtypes and remained present after restricting analyses to samples from patients who had never been on treatment or had been off treatment for more than 2.5 years. Genes near the regions of differential methylation in T cells were assessed for differential expression in whole blood samples from a separate population of 1,329 women with MS and 97 healthy women. Gene expression of HLA-DRB1, NINJ2, and SLFN12 was observed to be decreased in whole blood in MS patients compared to controls. We conclude that T cells from MS patients display regions of differential DNA methylation compared to controls, and corresponding gene expression differences are observed in whole blood. Two of the genes that showed both methylation and expression differences, NINJ2 and SLFN12, have not previously been implicated in MS. SLFN12 is a particularly compelling target of further research, as this gene is known to be down-regulated during T cell activation and up-regulated by type I interferons (IFNs), which are used to treat MS.

• Lindland, Elisabeth Margrete Stokke; Solheim, Anne Marit; Andreassen, Silje; Paulsen, Else Quist; Eikeland, Randi & Ljøstad, Unn [Vis alle 12 forfattere av denne artikkelen] (2018). Imaging in Lyme neuroborreliosis. Insights into Imaging. 9(5), s. 833–844. doi: 10.1007/s13244-018-0646-x. Fulltekst i vitenarkiv Vis sammendrag

  Lyme neuroborreliosis (LNB) is a tick-borne spirochetal infection with a broad spectrum of imaging pathology. For individuals who live in or have travelled to areas where ticks reside, LNB should be considered among differential diagnoses when clinical manifestations from the nervous system occur. Radiculitis, meningitis and facial palsy are commonly encountered, while peripheral neuropathy, myelitis, meningoencephalitis and cerebral vasculitis are rarer manifestations of LNB. Cerebrospinal fluid (CSF) analysis and serology are key investigations in patient workup. The primary role of imaging is to rule out other reasons for the neurological symptoms. It is therefore important to know the diversity of possible imaging findings from the infection itself. There may be no imaging abnormality, or findings suggestive of neuritis, meningitis, myelitis, encephalitis or vasculitis. White matter lesions are not a prominent feature of LNB. Insight into LNB clinical presentation, laboratory test methods and spectrum of imaging pathology will aid in the multidisciplinary interaction that often is imperative to achieve an efficient patient workup and arrive at a correct diagnosis. This article can educate those engaged in imaging of the nervous system and serve as a comprehensive tool in clinical cases.

• Page, Christian; Vos, Linda; Rounge, Trine Ballestad; Harbo, Hanne Flinstad & Kulle, Bettina (2018). Assessing genome-wide significance for the detection of differentially methylated regions. Statistical Applications in Genetics and Molecular Biology. 17(6). doi: 10.1515/sagmb-2017-0050. Fulltekst i vitenarkiv Vis sammendrag

  DNA methylation plays an important role in human health and disease, and methods for the identification of differently methylated regions are of increasing interest. There is currently a lack of statistical methods which properly address multiple testing, i.e. control genome-wide significance for differentially methylated regions. We introduce a scan statistic (DMRScan), which overcomes these limitations. We benchmark DMRScan against two well established methods (bumphunter, DMRcate), using a simulation study based on real methylation data. An implementation of DMRScan is available from Bioconductor. Our method has higher power than alternative methods across different simulation scenarios, particularly for small effect sizes. DMRScan exhibits greater flexibility in statistical modeling and can be used with more complex designs than current methods. DMRScan is the first dynamic approach which properly addresses the multiple-testing challenges for the identification of differently methylated regions. DMRScan outperformed alternative methods in terms of power, while keeping the false discovery rate controlled.

• Akhmadeev, Konstantin; Houssein, Aya; Moussaoui, Said; Høgestøl, Einar August; Tutturen, Ingerid Maria Voorham & Harbo, Hanne Flinstad [Vis alle 10 forfattere av denne artikkelen] (2018). SVM-based tool to detect patients with multiple sclerosis using a commercial EMG sensor. Proceedings of the IEEE Sensor Array and Multichannel Signal Processing Workshop. ISSN 1551-2282. 2018-July, s. 376–379. doi: 10.1109/SAM.2018.8448391. Fulltekst i vitenarkiv Vis sammendrag

  Multiple sclerosis (MS) is a major auto-immune disease that is the leading cause of non-traumatic impairment of the central nervous system (CNS) in young adults. Successful treatment of MS patients depends on accurate tools for both the MS diagnosis and the disability progression. In current and upcoming studies the authors aim to explore the capabilities of applying a commercial electromyographic and inertial sensor (MYO Armband by Thalmic Labs Inc.), coupled with a multichannel signal processing tool, to standard neurological examination of MS progression. In this pilot study we formulate a two-class “healthy control” - “having MS” classification problem. A dataset of electromyographic signals and inertial sensor measurements from 71 individuals (31 MS patients and 40 healthy controls) was acquired during standard neurological examination routine. Temporal and spectral features of the signals were extracted in order to train and validate a classification model. Finally, a Support Vector Machine classifier was obtained giving AUROC = 0.94, 95% CI = [0.88, 0.99]. We propose a set of signal descriptors that correlate with objective components of the neurological examination. The proposed signal acquisition and processing technique, being easy to integrate into the traditional neurological exam, may have high potential for aiding in quantifying MS progression.

• Kular, Lara; Liu, Yun; Ruhrmann, Sabrina; Zheleznyakova, Galina; Marabita, Francesco & Gomez-Cabrero, David [Vis alle 48 forfattere av denne artikkelen] (2018). DNA methylation as a mediator of HLA-DRB1 15:01 and a protective variant in multiple sclerosis. Nature Communications. 9(1), s. 1–15. doi: 10.1038/s41467-018-04732-5. Fulltekst i vitenarkiv Vis sammendrag

  The human leukocyte antigen (HLA) haplotype DRB1*15:01 is the major risk factor for multiple sclerosis (MS). Here, we find that DRB1*15:01 is hypomethylated and predominantly expressed in monocytes among carriers of DRB1*15:01. A differentially methylated region (DMR) encompassing HLA-DRB1 exon 2 is particularly affected and displays methylation-sensitive regulatory properties in vitro. Causal inference and Mendelian randomization provide evidence that HLA variants mediate risk for MS via changes in the HLA-DRB1 DMR that modify HLA-DRB1 expression. Meta-analysis of 14,259 cases and 171,347 controls confirms that these variants confer risk from DRB1*15:01 and also identifies a protective variant (rs9267649, p < 3.32 × 10−8, odds ratio = 0.86) after conditioning for all MS-associated variants in the region. rs9267649 is associated with increased DNA methylation at the HLA-DRB1 DMR and reduced expression of HLA-DRB1, suggesting a modulation of the DRB1*15:01 effect. Our integrative approach provides insights into the molecular mechanisms of MS susceptibility and suggests putative therapeutic strategies targeting a methylation-mediated regulation of the major risk gene.

• Sowa, Piotr; Harbo, Hanne Flinstad; White, Nathan S.; Celius, Elisabeth Gulowsen; Bartsch, Hauke & Berg-Hansen, Pål [Vis alle 12 forfattere av denne artikkelen] (2018). Restriction spectrum imaging of white matter and its relation to neurological disability in multiple sclerosis. Multiple Sclerosis. ISSN 1352-4585. s. 1–12. doi: 10.1177/1352458518765671. Fulltekst i vitenarkiv Vis sammendrag

  Background: Restriction spectrum imaging (RSI) is a recently introduced magnetic resonance imaging diffusion technique. The utility of RSI in multiple sclerosis (MS) is unknown. Objective: To investigate the association between RSI-derived parameters and neurological disability in MS. Methods: Seventy-seven relapsing-remitting MS patients were scanned with RSI on a 3-Tesla scanner. RSI-derived parameters: fast and slow apparent diffusion coefficient (sADC), fractional anisotropy, restricted fractional anisotropy, neurite density (ND), cellularity, extracellular water fraction and free water fraction were obtained in white matter lesions (WML) and normal appearing white matter (NAWM). Patients were divided into three groups according to their expanded disability status scale (EDSS): with minimal, low and substantial disability (<2.5, 2.5–3 and >3, respectively). Group comparisons and correlation analyses were performed. Results: All tested RSI-derived parameters differed between WML and NAWM (p<0.001 for all pairwise comparisons). The sADC in WML showed largest difference across disability subgroups (ANOVA: F=5.1, η2=0.12 p=0.008). ND in NAWM showed strongest correlation with disability (ϱ=-0.39, p<0.001). Conclusion: The strongest correlation with EDSS of ND obtained in NAWM indicates that processes outside lesions are important for disability in MS. Our study suggests that RSIderived parameters may help understand the “clinico-radiological paradox” and improve disease monitoring in MS.

• Mitrovic, Mitja; Patsopoulos, Nikolaos A.; Beecham, Ashley H.; Dankowski, Theresa; Goris, An & Dubois, Benedicte [Vis alle 52 forfattere av denne artikkelen] (2018). Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk. Cell. ISSN 0092-8674. 175(6), s. 1679–1687. doi: 10.1016/j.cell.2018.09.049. Fulltekst i vitenarkiv Vis sammendrag

  Multiple sclerosis is a complex neurological disease, with ∼20% of risk heritability attributable to common genetic variants, including >230 identified by genome-wide association studies. Multiple strands of evidence suggest that much of the remaining heritability is also due to additive effects of common variants rather than epistasis between these variants or mutations exclusive to individual families. Here, we show in 68,379 cases and controls that up to 5% of this heritability is explained by low-frequency variation in gene coding sequence. We identify four novel genes driving MS risk independently of common-variant signals, highlighting key pathogenic roles for regulatory T cell homeostasis and regulation, IFNγ biology, and NFκB signaling. As low-frequency variants do not show substantial linkage disequilibrium with other variants, and as coding variants are more interpretable and experimentally tractable than non-coding variation, our discoveries constitute a rich resource for dissecting the pathobiology of MS.

• Olafsson, Sigurgeir; Olafsson, S.; Stridh, Pernilla; Stridh, P.; Bos, Steffan Daniel & Ingason, Andrés [Vis alle 72 forfattere av denne artikkelen] (2017). Fourteen sequence variants that associate with multiple sclerosis discovered by meta-analysis informed by genetic correlations. NPJ GENOMIC MEDICINE. 2. doi: 10.1038/s41525-017-0027-2. Fulltekst i vitenarkiv Vis sammendrag

  A meta-analysis of publicly available summary statistics on multiple sclerosis combined with three Nordic multiple sclerosis cohorts (21,079 cases, 371,198 controls) revealed seven sequence variants associating with multiple sclerosis, not reported previously. Using polygenic risk scores based on public summary statistics of variants outside the major histocompatibility complex region we quantified genetic overlap between common autoimmune diseases in Icelanders and identified disease clusters characterized by autoantibody presence/absence. As multiple sclerosis-polygenic risk scores captures the risk of primary biliary cirrhosis and vice versa (P = 1.6 x 10(-7), 4.3 x 10(-9)) we used primary biliary cirrhosis as a proxy-phenotype for multiple sclerosis, the idea being that variants conferring risk of primary biliary cirrhosis have a prior probability of conferring risk of multiple sclerosis. We tested 255 variants forming the primary biliary cirrhosis-polygenic risk score and found seven multiple sclerosis-associating variants not correlated with any previously established multiple sclerosis variants. Most of the variants discovered are close to or within immune-related genes. One is a low-frequency missense variant in TYK2, another is a missense variant in MTHFR that reduces the function of the encoded enzyme affecting methionine metabolism, reported to be dysregulated in multiple sclerosis brain.

• Hedström, Anna Karin; Katsoulis, Michail; Hössjer, Ola; Bomfim, Izaura L.; Oturai, Annette & Søndergaard, Helle Bach [Vis alle 19 forfattere av denne artikkelen] (2017). The interaction between smoking and HLA genes in multiple sclerosis: replication and refinement. European Journal of Epidemiology (EJE). ISSN 0393-2990. 32 , s. 909–919. doi: 10.1007/s10654-017-0250-2. Fulltekst i vitenarkiv Vis sammendrag

  Interactions between environment and genetics may contribute to multiple sclerosis (MS) development. We investigated whether the previously observed interaction between smoking and HLA genotype in the Swedish population could be replicated, refined and extended to include other populations. We used six independent case–control studies from five different countries (Sweden, Denmark, Norway, Serbia, United States). A pooled analysis was performed for replication of previous observations (7190 cases, 8876 controls). Refined detailed analyses were carried out by combining the genetically similar populations from the Nordic studies (6265 cases, 8401 controls). In both the pooled analyses and in the combined Nordic material, interactions were observed between HLA-DRB*15 and absence of HLA-A*02 and between smoking and each of the genetic risk factors. Two way interactions were observed between each combination of the three variables, invariant over categories of the third. Further, there was also a three way interaction between the risk factors. The difference in MS risk between the extremes was considerable; smokers carrying HLA-DRB1*15 and lacking HLA-A*02 had a 13-fold increased risk compared with never smokers without these genetic risk factors (OR 12.7, 95% CI 10.8–14.9). The risk of MS associated with HLA genotypes is strongly influenced by smoking status and vice versa. Since the function of HLA molecules is to present peptide antigens to T cells, the demonstrated interactions strongly suggest that smoking alters MS risk through actions on adaptive immunity.

• Sowa, Piotr; Nygaard, Gro Owren; Bjørnerud, Atle; Celius, Elisabeth Gulowsen; Harbo, Hanne Flinstad & Beyer, Mona K. (2017). Magnetic resonance imaging perfusion is associated with disease severity and activity in multiple sclerosis. Neuroradiology. ISSN 0028-3940. 59(7), s. 655–664. doi: 10.1007/s00234-017-1849-4. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Benavent, Sigrid Aune de Rodez; Nygaard, Gro Owren; Harbo, Hanne Flinstad; Tønnesen, Siren; Sowa, Piotr & Landrø, Nils Inge [Vis alle 13 forfattere av denne artikkelen] (2017). Fatigue and cognition: Pupillary responses to problem-solving in early multiple sclerosis patients. Brain and Behavior. 7(7). doi: 10.1002/brb3.717. Fulltekst i vitenarkiv Vis sammendrag

  Introduction In early multiple sclerosis (MS) patients, cognitive changes and fatigue are frequent and troublesome symptoms, probably related to both structural and functional brain changes. Whether there is a common cause of these symptoms in MS is unknown. In theory, an altered regulation of central neuropeptides can lead to changes in regulation of autonomic function, cognitive difficulties, and fatigue. Direct measurements of central neuropeptides are difficult to perform, but measurements of the eye pupil can be used as a reliable proxy of function. Methods This study assesses pupil size during problem-solving in early MS patients versus controls. A difference in pupil size to a cognitive challenge could signal altered activity within the autonomic system because of early functional brain changes associated with cognitive load. We recruited MS patients (mean disease duration: 2.6 years, N = 41) and age-matched healthy controls (N = 43) without eye pathology. Neurological impairment, magnetic resonance imaging, visual evoked potentials, depression, and fatigue were assessed in all of the patients. In both groups, we assessed processing speed and retinal imaging. Pupil size was recorded with an eye-tracker during playback of multiplication tasks. Results Both groups performed well on the cognitive test. The groups showed similar pupillary responses with a mean of 0.55 mm dilation in patients and 0.54 mm dilation in controls for all the tasks collapsed together. However, controls (N = 9) with low cognitive scores (LCS) had an increased pupillary response to cognitive tasks, whereas LCS MS patients (N = 6) did not (p < .05). There was a tendency toward a smaller pupillary response in patients with fatigue. Conclusions This is the first study to investigate pupillary responses to cognitive tasks in MS patients. Our results suggest that MS-related changes in cognition and fatigue may be associated with changes in arousal and the autonomic regulation of task-related pupillary responses. This supports the theory of a link between cognition and fatigue in MS.

• Bos, Steffan Daniel; Berge, Tone; Celius, Elisabeth Gulowsen & Harbo, Hanne Flinstad (2016). From genetic associations to functional studies in multiple sclerosis. European Journal of Neurology. ISSN 1351-5101. 23(5), s. 847–853. doi: 10.1111/ene.12981. Fulltekst i vitenarkiv
• Keshavan, Anisha; Paul, Friedemann; Beyer, Mona K.; Zhu, Alyssa H.; Papinutto, Nico & Shinohara, Russell T. [Vis alle 56 forfattere av denne artikkelen] (2016). Power estimation for non-standardized multisite studies. NeuroImage. ISSN 1053-8119. 134, s. 281–294. doi: 10.1016/j.neuroimage.2016.03.051. Fulltekst i vitenarkiv
• Wang, Yunpeng; Bos, Steffan Daniel; Harbo, Hanne Flinstad; Thompson, Wesley K.; Schork, Andrew J. & Bettella, Francesco [Vis alle 14 forfattere av denne artikkelen] (2016). Genetic overlap between multiple sclerosis and several cardiovascular disease risk factors. Multiple Sclerosis. ISSN 1352-4585. 22(14), s. 1783–1793. doi: 10.1177/1352458516635873. Fulltekst i vitenarkiv
• Gustavsen, Marte Wendel; Celius, Elisabeth Gulowsen; Winsvold, Bendik K S; Moen, Stine Marit; Nygaard, Gro Owren & Berg-Hansen, Pål [Vis alle 9 forfattere av denne artikkelen] (2016). Migraine and frequent tension-type headache are not associated with multiple sclerosis in a Norwegian case-control study. Multiple Sclerosis Journal, Experimental, Translational and Clinical. 2, s. 1–4. doi: 10.1177/2055217316682976. Fulltekst i vitenarkiv Vis sammendrag

  Background Inconsistent results have been obtained with regard to headache comorbidity in multiple sclerosis (MS). Objective Investigate the one-year prevalence of migraine and tension-type headache (TTH) in Norwegian MS patients and relate this to clinical parameters. Methods A questionnaire concerning headache was administered to 756 MS patients and 1090 controls and used to determine the one-year prevalence of migraine and frequent TTH. Results No significant differences were seen between patients and controls or between patients with different disease course. Less migraine was observed in patients with Expanded Disability Status Scale score (EDSS) ≥4.0. Conclusions This case-control study does not support an association between migraine or TTH and MS.

• Keshari, Pankaj; Harbo, Hanne Flinstad; Myhr, Kjell-Morten; Aarseth, Jan Harald; Bos, Steffan Daniel & Berge, Tone (2016). Allelic imbalance of multiple sclerosis susceptibility genes IKZF3 and IQGAP1 in human peripheral blood. BMC Genetics. 17(1). doi: 10.1186/s12863-016-0367-4. Fulltekst i vitenarkiv Vis sammendrag

  Background Multiple sclerosis is a chronic inflammatory, demyelinating disease of the central nervous system. Recent genome-wide studies have revealed more than 110 single nucleotide polymorphisms as associated with susceptibility to multiple sclerosis, but their functional contribution to disease development is mostly unknown. Results Consistent allelic imbalance was observed for rs907091 in IKZF3 and rs11609 in IQGAP1, which are in strong linkage disequilibrium with the multiple sclerosis associated single nucleotide polymorphisms rs12946510 and rs8042861, respectively. Using multiple sclerosis patients and healthy controls heterozygous for rs907091 and rs11609, we showed that the multiple sclerosis risk alleles at IKZF3 and IQGAP1 are expressed at higher levels as compared to the protective allele. Furthermore, individuals homozygous for the multiple sclerosis risk allele at IQGAP1 had a significantly higher total expression of IQGAP1 compared to individuals homozygous for the protective allele. Conclusions Our data indicate a possible regulatory role for the multiple sclerosis-associated IKZF3 and IQGAP1 variants. We suggest that such cis-acting mechanisms may contribute to the multiple sclerosis association of single nucleotide polymorphisms at IKZF3 and IQGAP1.

• George, Michaela F.; Briggs, Farren B.S.; Shao, Xiaorong; Gianfrancesco, Milena A.; Kockum, Ingrid & Harbo, Hanne-Cathrin Flinstad [Vis alle 34 forfattere av denne artikkelen] (2016). Multiple sclerosis risk loci and disease severity in 7,125 individuals from 10 studies. Neurology: Genetics. 2(4). doi: 10.1212/NXG.0000000000000087. Fulltekst i vitenarkiv
• Berge, Tone; Leikfoss, Ingvild Sørum; Brorson, Ina Skaara; Bos, Steffan Daniel; Page, Christian & Gustavsen, Marte Wendel [Vis alle 13 forfattere av denne artikkelen] (2016). The multiple sclerosis susceptibility genes TAGAP and IL2RA are regulated by Vitamin D in CD4+ T cells. Genes and Immunity. ISSN 1466-4879. 17(2), s. 118–127. doi: 10.1038/gene.2015.61. Fulltekst i vitenarkiv
• Leikfoss, Ingvild Sørum; Keshari, Pankaj Kumar; Gustavsen, Marte Wendel; Bjølgerud, Anja; Brorson, Ina Skaara & Celius, Elisabeth Gulowsen [Vis alle 10 forfattere av denne artikkelen] (2015). Multiple sclerosis risk allele in CLEC16A acts as an expression quantitative trait locus for CLEC16A and SOCS1 in CD4+ T cells. PLOS ONE. 10>e0132957(7). doi: 10.1371/journal.pone.0132957. Fulltekst i vitenarkiv Vis sammendrag

  For multiple sclerosis, genome wide association studies and follow up studies have identified susceptibility single nucleotide polymorphisms located in or near CLEC16A at chromosome 16p13.13, encompassing among others CIITA, DEXI and SOCS1 in addition to CLEC16A. These genetic variants are located in intronic or intergenic regions and display strong linkage disequilibrium with each other, complicating the understanding of their functional contribution and the identification of the direct causal variant(s). Previous studies have shown that multiple sclerosis-associated risk variants in CLEC16A act as expression quantitative trait loci for CLEC16A itself in human pancreatic β-cells, for DEXI and SOCS1 in thymic tissue samples, and for DEXI in monocytes and lymphoblastoid cell lines. Since T cells are major players in multiple sclerosis pathogenesis, we have performed expression analyses of the CIITA-DEXI-CLEC16A-SOCS1 gene cluster in CD4+ and CD8+ T cells isolated from multiple sclerosis patients and healthy controls. We observed a higher expression of SOCS1 and CLEC16A in CD4+ T cells in samples homozygous for the risk allele of CLEC16A rs12927355. Pair-wise linear regression analysis revealed high correlation in gene expression in peripheral T cells of CIITA, DEXI, CLEC16A and SOCS1. Our data imply a possible regulatory role for the multiple sclerosis-associated rs12927355 in CLEC16A.

• Moutsianas, Loukas; Jostins, Luke; Beecham, Ashley H.; Dilthey, Alexander T.; Xifara, Dionysia K. & Ban, Maria [Vis alle 55 forfattere av denne artikkelen] (2015). Class II HLA interactions modulate genetic risk for multiple sclerosis. Nature Genetics. ISSN 1061-4036. 47(10), s. 1107–1113. doi: 10.1038/ng.3395. Fulltekst i vitenarkiv
• Berg-Hansen, Pål; Moen, Stine Marit; Sandvik, Leiv; Harbo, Hanne Flinstad; Bakken, Inger Johanne & Stoltenberg, Camilla [Vis alle 7 forfattere av denne artikkelen] (2015). Prevalence of multiple sclerosis among immigrants in Norway. Multiple Sclerosis. ISSN 1352-4585. 21(6), s. 695–702. doi: 10.1177/1352458514554055. Fulltekst i vitenarkiv
• Nygaard, Gro Owren; Benavent, Sigrid Aune de Rodez; Harbo, Hanne Flinstad; Laeng, Bruno; Sowa, Piotr & Damangir, Soheil [Vis alle 13 forfattere av denne artikkelen] (2015). Eye and hand motor interactions with the Symbol Digit Modalities Test in early multiple sclerosis. Multiple Sclerosis and Related Disorders. ISSN 2211-0348. 4(6), s. 585–589. doi: 10.1016/j.msard.2015.08.003. Fulltekst i vitenarkiv Vis sammendrag

  Purpose Eye and hand motor dysfunction may be present early in the disease course of relapsing-remitting multiple sclerosis (RRMS), and can affect the results on visual and written cognitive tests. We aimed to test for differences in saccadic initiation time (SI time) between RRMS patients and healthy controls, and whether SI time and hand motor speed interacted with the written version of the Symbol Digit Modalities Test (wSDMT). Methods Patients with RRMS (N=44, age 35.1±7.3 years), time since diagnosis <3 years and matched controls (N=41, age 33.2±6.8 years) were examined with ophthalmological, neurological and neuropsychological tests, as well as structural MRI (white matter lesion load (WMLL) and brainstem lesions), visual evoked potentials (VEP) and eye-tracker examinations of saccades. Results SI time was longer in RRMS than controls (p<0.05). SI time was not related to the Paced Auditory Serial Addition Test (PASAT), WMLL or to the presence of brainstem lesions. 9 hole peg test (9HP) correlated significantly with WMLL (r=0.58, p<0.01). Both SI time and 9HP correlated negatively with the results of wSDMT (r=−0.32, p<0.05, r=−0.47, p<0.01), but none correlated with the results of PASAT. Conclusions RRMS patients have an increased SI time compared to controls. Cognitive tests results, exemplified by the wSDMT, may be confounded by eye and hand motor function.

• Page, Christian; Baranzini, Sergio E.; Mevik, Bjørn-Helge; Bos, Steffan Daniel; Harbo, Hanne Flinstad & Kulle, Bettina (2015). Assessing the Power of Exome Chips. PLOS ONE. 10(10). doi: 10.1371/journal.pone.0139642. Fulltekst i vitenarkiv Vis sammendrag

  Genotyping chips for rare and low-frequent variants have recently gained popularity with the introduction of exome chips, but the utility of these chips remains unclear. These chips were designed using exome sequencing data from mainly American-European individuals, enriched for a narrow set of common diseases. In addition, it is well-known that the statistical power of detecting associations with rare and low-frequent variants is much lower compared to studies exclusively involving common variants. We developed a simulation program adaptable to any exome chip design to empirically evaluate the power of the exome chips. We implemented the main properties of the Illumina HumanExome BeadChip array. The simulated data sets were used to assess the power of exome chip based studies for varying effect sizes and causal variant scenarios. We applied two widely-used statistical approaches for rare and low-frequency variants, which collapse the variants into genetic regions or genes. Under optimal conditions, we found that a sample size between 20,000 to 30,000 individuals were needed in order to detect modest effect sizes (0.5% < PAR > 1%) with 80% power. For small effect sizes (PAR <0.5%), 60,000–100,000 individuals were needed in the presence of non-causal variants. In conclusion, we found that at least tens of thousands of individuals are necessary to detect modest effects under optimal conditions. In addition, when using rare variant chips on cohorts or diseases they were not originally designed for, the identification of associated variants or genes will be even more challenging.

• Sundal, Christina Heidemann; Baker, Matt C.; Karrenbauer, Virginija Danylaité; Gustavsen, Marte Wendel; Bedri, Sahl Khalid & Glaser, Anna [Vis alle 15 forfattere av denne artikkelen] (2015). Hereditary diffuse leukoencephalopathy with spheroids with phenotype of primary progressive multiple sclerosis. European Journal of Neurology. ISSN 1351-5101. 22(2), s. 328–333. doi: 10.1111/ene.12572. Fulltekst i vitenarkiv
• Gustavsen, Marte Wendel; Celius, Elisabeth Gulowsen; Moen, Stine Marit; Bjølgerud, Anja; Berg-Hansen, Pål & Nygaard, Gro Owren [Vis alle 9 forfattere av denne artikkelen] (2015). No association between multiple sclerosis and periodontitis after adjusting for smoking habits. European Journal of Neurology. ISSN 1351-5101. 22(3), s. 588–590. doi: 10.1111/ene.12520. Fulltekst i vitenarkiv
• Nygaard, Gro Owren; Celius, Elisabeth Gulowsen; Benavent, Sigrid Aune de Rodez; Sowa, Piotr; Gustavsen, Marte Wendel & Fjell, Anders Martin [Vis alle 9 forfattere av denne artikkelen] (2015). A longitudinal study of disability, cognition and gray matter atrophy in early multiple sclerosis patients according to evidence of disease activity. PLOS ONE. 10(8). doi: 10.1371/journal.pone.0135974. Fulltekst i vitenarkiv Vis sammendrag

  New treatment options may make “no evidence of disease activity” (NEDA: no relapses or disability progression and no new/enlarging MRI lesions, as opposed to “evidence of disease activity” (EDA) with at least one of the former), an achievable goal in relapsing-remitting multiple sclerosis (RRMS). The objective of the present study was to determine whether early RRMS patients with EDA at one-year follow-up had different disability, cognition, treatment and gray matter (GM) atrophy rates from NEDA patients and healthy controls (HC). RRMS patients (mean age 34 years, mean disease duration 2.2 years) were examined at baseline and one-year follow-up with neurological (n = 72), neuropsychological (n = 56) and structural MRI (n = 57) examinations. Matched HC (n = 61) were retested after three years. EDA was found in 46% of RRMS patients at follow-up. EDA patients used more first line and less second line disease modifying treatment than NEDA (p = 0.004). While the patients groups had similar disability levels at baseline, they differed in disability at follow-up (p = 0.010); EDA patients progressed (EDSS: 1.8–2.2, p = 0.010), while NEDA patients improved (EDSS: 2.0–1.7, p<0.001). Cognitive function was stable in both patient groups. Subcortical GM atrophy rates were higher in EDA patients than HC (p<0.001). These results support the relevance of NEDA as outcome in RRMS and indicate that pathological neurodegeneration in RRMS mainly occur in patients with evidence of disease activity.

• Goris, An; Pauwels, Ine; Gustavsen, Marte Wendel; Son, Brechtje Van; Hilven, Kelly & Bos, Steffan Daniel [Vis alle 46 forfattere av denne artikkelen] (2015). Genetic variants are major determinants of CSF antibody levels in multiple sclerosis. Brain. ISSN 0006-8950. 138(3), s. 632–643. doi: 10.1093/brain/awu405. Fulltekst i vitenarkiv
• Seldin, Michael F.; Alkhairy, Omar K; Lee, Annette T.; Lamb, Janine; Sussman, Jon & Pirskanen-Matell, Ritva [Vis alle 19 forfattere av denne artikkelen] (2015). Genome-wide association study of late-onset myasthenia gravis: Confirmation of TNFRSF11A and identification of ZBTB10 and three distinct HLA associations. Molecular medicine (Cambridge, Mass. Print). ISSN 1076-1551. 21, s. 769–781. doi: 10.2119/molmed.2015.00232. Fulltekst i vitenarkiv Vis sammendrag

  To investigate the genetics of late-onset myasthenia gravis (LOMG), we conducted a genome-wide association study imputation of >6 million single nucleotide polymorphisms (SNPs) in 532 LOMG cases (anti–acetylcholine receptor [AChR] antibody positive; onset age ≥50 years) and 2,128 controls matched for sex and population substructure. The data confirm reported TNFRSF11A associations (rs4574025, P = 3.9 × 10–7, odds ratio [OR] 1.42) and identify a novel candidate gene, ZBTB10, achieving genome-wide significance (rs6998967, P = 8.9 × 10–10, OR 0.53). Several other SNPs showed suggestive significance including rs2476601 (P = 6.5 × 10–6, OR 1.62) encoding the PTPN22 R620W variant noted in early-onset myasthenia gravis (EOMG) and other autoimmune diseases. In contrast, EOMG-associated SNPs in TNIP1 showed no association in LOMG, nor did other loci suggested for EOMG. Many SNPs within the major histocompatibility complex (MHC) region showed strong associations in LOMG, but with smaller effect sizes than in EOMG (highest OR ~2 versus ~6 in EOMG). Moreover, the strongest associations were in opposite directions from EOMG, including an OR of 0.54 for DQA1*05:01 in LOMG (P = 5.9 × 10–12) versus 2.82 in EOMG (P = 3.86 × 10–45). Association and conditioning studies for the MHC region showed three distinct and largely independent association peaks for LOMG corresponding to (a) MHC class II (highest attenuation when conditioning on DQA1), (b) HLA-A and (c) MHC class III SNPs. Conditioning studies of human leukocyte antigen (HLA) amino acid residues also suggest potential functional correlates. Together, these findings emphasize the value of subgrouping myasthenia gravis patients for clinical and basic investigations and imply distinct predisposing mechanisms in LOMG.

• Eriksen, Agnete Bratsberg; Berge, Tone; Gustavsen, Marte Wendel; Leikfoss, Ingvild Sørum; Bos, Steffan Daniel & Spurkland, Anne [Vis alle 8 forfattere av denne artikkelen] (2015). Retinoic acid enhances the levelels of IL-10 in TLR-stimulated B cells from patients with relapsing-remitting multiple sclerosis. Journal of Neuroimmunology. ISSN 0165-5728. 278, s. 11–18. doi: 10.1016/j.jneuroim.2014.11.019. Fulltekst i vitenarkiv
• Andreassen, Ole Andreas; Harbo, Hanne Flinstad; Wang, Yunpeng; Thompson, WK; Schork, AJ & Mattingsdal, Morten [Vis alle 18 forfattere av denne artikkelen] (2015). Genetic pleiotropy between multiple sclerosis and schizophrenia but not bipolar disorder: differential involvement of immune-related gene loci. Molecular Psychiatry. ISSN 1359-4184. 20(2), s. 207–214. doi: 10.1038/mp.2013.195. Fulltekst i vitenarkiv Vis sammendrag

  Converging evidence implicates immune abnormalities in schizophrenia (SCZ), and recent genome-wide association studies (GWAS) have identified immune-related single-nucleotide polymorphisms (SNPs) associated with SCZ. Using the conditional false discovery rate (FDR) approach, we evaluated pleiotropy in SNPs associated with SCZ (n=21 856) and multiple sclerosis (MS) (n=43 879), an inflammatory, demyelinating disease of the central nervous system. Because SCZ and bipolar disorder (BD) show substantial clinical and genetic overlap, we also investigated pleiotropy between BD (n=16 731) and MS. We found significant genetic overlap between SCZ and MS and identified 21 independent loci associated with SCZ, conditioned on association with MS. This enrichment was driven by the major histocompatibility complex (MHC). Importantly, we detected the involvement of the same human leukocyte antigen (HLA) alleles in both SCZ and MS, but with an opposite directionality of effect of associated HLA alleles (that is, MS risk alleles were associated with decreased SCZ risk). In contrast, we found no genetic overlap between BD and MS. Considered together, our findings demonstrate genetic pleiotropy between SCZ and MS and suggest that the MHC signals may differentiate SCZ from BD susceptibility.

• Nygaard, Gro Owren; Walhovd, Kristine B; Sowa, Piotr; Chepkoech, Joy-Loi; Bjørnerud, Atle & Due-Tønnessen, Paulina [Vis alle 14 forfattere av denne artikkelen] (2015). Cortical thickness and surface area relate to specific symptoms in early relapsing−remitting multiple sclerosis. Multiple Sclerosis. ISSN 1352-4585. 21(4), s. 402–414. doi: 10.1177/1352458514543811. Fulltekst i vitenarkiv
• Sowa, Piotr; Bjørnerud, Atle; Nygaard, Gro Owren; Damangir, Soheil; Spulber, Gabriela & Celius, Elisabeth Gulowsen [Vis alle 9 forfattere av denne artikkelen] (2015). Reduced perfusion in white matter lesions in multiple sclerosis. European Journal of Radiology. ISSN 0720-048X. 84(12), s. 2605–2612. doi: 10.1016/j.ejrad.2015.09.007. Fulltekst i vitenarkiv
• Westerlind, Helga; Imrell, Kerstin; Ramanujam, Ryan; Myhr, Kjell-Morten; Celius, Elisabeth Gulowsen & Harbo, Hanne Flinstad [Vis alle 13 forfattere av denne artikkelen] (2015). Identity-by-descent mapping in a Scandinavian multiple sclerosis cohort. European Journal of Human Genetics. ISSN 1018-4813. 23(5), s. 688–692. doi: 10.1038/ejhg.2014.155. Fulltekst i vitenarkiv Vis sammendrag

  In an attempt to map chromosomal regions carrying rare gene variants contributing to the risk of multiple sclerosis (MS), we identified segments shared identical-by-descent (IBD) using the software BEAGLE 4.0’s refined IBD analysis. IBD mapping aims at identifying segments inherited from a common ancestor and shared more frequently in case–case pairs. A total of 2106 MS patients of Nordic origin and 624 matched controls were genotyped on Illumina Human Quad 660 chip and an additional 1352 ethnically matched controls typed on Illumina HumanHap 550 and Illumina 1M were added. The quality control left a total of 441 731 markers for the analysis. After identification of segments shared by descent and significance testing, a filter function for markers with low IBD sharing was applied. Four regions on chromosomes 5, 9, 14 and 19 were found to be significantly associated with the risk for MS. However, all markers but for one were located telomerically, including the very distal markers. For methodological reasons, such segments have a low sharing of IBD signals and are prone to be false positives. One marker on chromosome 19 reached genome-wide significance and was not one of the distal markers. This marker was located within the GNA11 gene, which contains no previous association with MS. We conclude that IBD mapping is not sufficiently powered to identify MS risk loci even in ethnically relatively homogenous populations, or that alternatively rare variants are not adequately present.

• Bos, Steffan Daniel; Page, Christian; Kulle, Bettina; Elboudwarej, Emon; Gustavsen, Marte Wendel & Briggs, Farren [Vis alle 12 forfattere av denne artikkelen] (2015). Genome-wide DNA methylation profiles indicate CD8+ T cell hypermethylation in multiple sclerosis. PLOS ONE. 10(3). doi: 10.1371/journal.pone.0117403. Fulltekst i vitenarkiv
• Goris, An; Setten, Jessica Van; Diekstra, Frank; Ripke, Stephan; Patsopoulos, Nikolaos A. & Sawcer, Stephen [Vis alle 141 forfattere av denne artikkelen] (2014). No evidence for shared genetic basis of common variants in multiple sclerosis and amyotrophic lateral sclerosis. Human Molecular Genetics. ISSN 0964-6906. 23(7), s. 1916–1922. doi: 10.1093/hmg/ddt574. Fulltekst i vitenarkiv
• Sundqvist, Emilie; Buck, Dorothea; Warnke, Clemens; Albrecht, Eva; Gieger, Christian & Khademi, Mohsen [Vis alle 41 forfattere av denne artikkelen] (2014). JC Polyomavirus Infection Is Strongly Controlled by Human Leucocyte Antigen Class II Variants. PLoS Pathogens. ISSN 1553-7366. 10(4). doi: 10.1371/journal.ppat.1004084. Fulltekst i vitenarkiv
• Berge, Tone & Harbo, Hanne Flinstad (2014). Fra identifikasjon til karakterisering av CLEC16A – et mottagelighetsgen for multippel sklerose. Best Practice. ISSN 1329-1874. Fulltekst i vitenarkiv
• Avidan, Nili; Panse, Rozen Le; Harbo, Hanne Flinstad; Bernasconi, Pia; Poulas, Konstantinos & Ginzburg, Elizabeta [Vis alle 28 forfattere av denne artikkelen] (2014). VAV1 and BAFF, via NFκB pathway, are genetic risk factors for myasthenia gravis. Annals of clinical and translational neurology. 1(5), s. 329–339. doi: 10.1002/acn3.51. Fulltekst i vitenarkiv
• Damotte, V; Guillot-Noel, Lena; Patsopoulos, Nikolaos A.; Madireddy, L; Behi, M El & Ban, Maria [Vis alle 128 forfattere av denne artikkelen] (2014). A gene pathway analysis highlights the role of cellular adhesion molecules in multiple sclerosis susceptibility. Genes and Immunity. ISSN 1466-4879. 15, s. 126–132. doi: 10.1038/gene.2013.70. Fulltekst i vitenarkiv
• Berg-Hansen, Pål; Moen, Stine Marit; Harbo, Hanne Flinstad & Celius, Elisabeth Gulowsen (2014). High prevalence and no latitude gradient of multiple sclerosis in Norway. Multiple Sclerosis. ISSN 1352-4585. 20(13), s. 1780–1782. doi: 10.1177/1352458514525871. Fulltekst i vitenarkiv
• Gustavsen, Marte Wendel; Page, Christian; Moen, Stine Marit; Bjølgerud, Anja; Berg-Hansen, Pål & Nygaard, Gro Owren [Vis alle 10 forfattere av denne artikkelen] (2014). Environmental exposures and the risk of multiple sclerosis investigated in a Norwegian case-control study. BMC Neurology. 14(1). doi: 10.1186/s12883-014-0196-x. Fulltekst i vitenarkiv Vis sammendrag

  Background: Several environmental exposures, including infection with Epstein-Barr virus, low levels of vitamin D and smoking are established risk factors for multiple sclerosis (MS). Also, high hygienic standard and infection with parasites have been proposed to influence MS risk. The aim of this study was to investigate the influence of various environmental exposures on MS risk in a Norwegian cohort, focusing on factors during childhood related to the hygiene hypothesis. Methods: A questionnaire concerning environmental exposures, lifestyle, demographics and comorbidity was administrated to 756 Norwegian MS patients and 1090 healthy controls. Logistic regression was used to calculate odds ratio (OR) with 95% confidence interval (CI) for the risk of MS associated with the variables infectious mononucleosis, severe infection during childhood, vaccination and animals in the household during childhood. Age, gender, HLA-DRB1*15:01, smoking and infectious mononucleosis were included as covariates. General environmental exposures, including tobacco use, were also evaluated. Results: Infectious mononucleosis was confirmed to be significantly associated with increased MS risk, also after adjusting for the covariates (OR?=?1.79, 95% CI: 1.12-2.87, p?=?0.016). The controls more often reported growing up with a cat and/or a dog in the household, and this was significant for ownership of cat also after adjusting for the covariates (OR?=?0.56, 95% CI: 0.40-0.78, p?=?0.001). More patients than controls reported smoking and fewer patients reported snuff use. Conclusions: In this Norwegian MS case-control study of environmental exposures, we replicate that infectious mononucleosis and smoking are associated with increased MS risk. Our data also indicate a protective effect on MS of exposure to cats during childhood, in accordance with the hypothesis that risk of autoimmune diseases like MS may increase with high hygienic standard.

• Gustavsen, Marte Wendel; Viken, Marte K; Celius, Elisabeth Gulowsen; Berge, Tone; Mero, Inger-Lise & Berg-Hansen, Pål [Vis alle 17 forfattere av denne artikkelen] (2014). Oligoclonal band phenotypes in MS differ in their HLA class II association, while specific KIR ligands at HLA class I show association to MS in general. Journal of Neuroimmunology. ISSN 0165-5728. 274(1-2), s. 174–179. doi: 10.1016/j.jneuroim.2014.06.024. Fulltekst i vitenarkiv
• Harbo, Hanne Flinstad; Isobe, Noriko; Berg-Hansen, Pål; Bos, Steffan Daniel; Caillier, Stacy & Gustavsen, Marte Wendel [Vis alle 11 forfattere av denne artikkelen] (2014). Oligoclonal bands and age at onset correlate with genetic risk score in multiple sclerosis. Multiple Sclerosis. ISSN 1352-4585. 20(6), s. 660–668. doi: 10.1177/1352458513506503. Fulltekst i vitenarkiv
• Maniaol, Angelina; Boldingh, Marion Ingeborg; Brunborg, Cathrine; Harbo, Hanne Flinstad & Tallaksen, Chantal (2013). Smoking and socio-economic status may affect myasthenia gravis. European Journal of Neurology. ISSN 1351-5101. 20(3), s. 453–460. doi: 10.1111/j.1468-1331.2012.03843.x. Fulltekst i vitenarkiv
• Berg-Hansen, Pål; SMESTAD, CATHRINE; Sandvik, Leiv; Harbo, Hanne Flinstad & Celius, Elisabeth Gulowsen (2013). Increased disease severity in non-Western immigrants with multiple sclerosis in Oslo, Norway. European Journal of Neurology. ISSN 1351-5101. 20(12), s. 1546–1552. doi: 10.1111/ene.12227. Fulltekst i vitenarkiv
• Harbo, Hanne Flinstad; Gold, Ralf & Tintore, Mar (2013). Sex and gender issues in multiple sclerosis. Therapeutic Advances in Neurological Disorders (TAND). ISSN 1756-2856. 6(4), s. 237–248. doi: 10.1177/1756285613488434. Fulltekst i vitenarkiv
• Leone, Maurizio A.; Barizzone, Nadia; Esposito, Federica; Lucenti, Ausiliatrice; Harbo, Hanne Flinstad & Goris, An [Vis alle 21 forfattere av denne artikkelen] (2013). Association of genetic markers with CSF oligoclonal bands in multiple sclerosis patients. PLOS ONE. 8(6). doi: 10.1371/journal.pone.0064408. Fulltekst i vitenarkiv
• Mero, Inger-Lise; Gustavsen, Marte Wendel; Sæther, Hanne Skarpodde; Flåm, Siri Tennebø; Berg-Hansen, Pål & Søndergaard, Helle Bach [Vis alle 22 forfattere av denne artikkelen] (2013). Oligoclonal band status in Scandinavian multiple sclerosis patients is associated with specific genetic risk alleles. PLOS ONE. 8(3). doi: 10.1371/journal.pone.0058352. Fulltekst i vitenarkiv
• Isobe, Noriko; Gourraud, Pierre-Antoine; Harbo, Hanne Flinstad; Caillier, Stacy; Santaniello, A & Khankhanian, Pouya [Vis alle 17 forfattere av denne artikkelen] (2013). Genetic risk variants in African Americans With multiple sclerosis. Neurology. ISSN 0028-3878. 81(3), s. 219–227. doi: 10.1212/WNL.0b013e31829bfe2f. Fulltekst i vitenarkiv
• Baranzini, SE; Celius, E.G.; Elovaara, I; Harbo, HF; Hillert, J & Myhr, Kjell-Morten [Vis alle 84 forfattere av denne artikkelen] (2013). Network-based multiple sclerosis pathway analysis with GWAS data from 15,000 cases and 30,000 controls. American Journal of Human Genetics. ISSN 0002-9297. s. 854–865. doi: 10.1016/j.ajhg.2013.04.019. Fulltekst i vitenarkiv
• Leikfoss, Ingvild Sørum; Mero, Inger-Lise; Dahle, Maria Krudtaa; Lie, Benedicte Alexandra; Harbo, Hanne Flinstad & Spurkland, Anne [Vis alle 7 forfattere av denne artikkelen] (2013). Multiple sclerosis-associated single-nucleotide polymorphisms in CLEC16A correlate with reduced SOCS1 and DEXI expression in the thymus. Genes and Immunity. ISSN 1466-4879. 14(1), s. 62–66. doi: 10.1038/gene.2012.52. Fulltekst i vitenarkiv
• Beecham, Ashley H.; Patsopoulos, NA; Xifara, DK; Davis, MF; Kemppinen, A & Cotsapas, C [Vis alle 193 forfattere av denne artikkelen] (2013). Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nature Genetics. ISSN 1061-4036. 45(11), s. 1353–1360. doi: 10.1038/ng.2770. Fulltekst i vitenarkiv
• Berge, Tone; Leikfoss, Ingvild Sørum & Harbo, Hanne Flinstad (2013). From Identification to Characterization of the Multiple Sclerosis Susceptibility Gene CLEC16A. International Journal of Molecular Sciences. ISSN 1661-6596. 14(3), s. 4476–4497. doi: 10.3390/ijms14034476. Fulltekst i vitenarkiv
• Ban, Maria; Caillier, Stacy; Mero, Inger-Lise; Myhr, Kjell-Morten; Celius, Elisabeth Gulowsen & Aarseth, Jan Harald [Vis alle 12 forfattere av denne artikkelen] (2013). No evidence of association between mutant alleles of the CYP27B1 gene and multiple sclerosis. Annals of Neurology. ISSN 0364-5134. 73(3), s. 430–432. doi: 10.1002/ana.23833. Fulltekst i vitenarkiv
• Rosella, Mechelli; Renato, Umeton; Policano, Claudia; Annibali, Viviana; Giulia, Coarelli & Ricigliano, Vito A. G. [Vis alle 55 forfattere av denne artikkelen] (2013). A ‘‘candidate-interactome’’ aggregate analysis of genome-wide association data in multiple sclerosis. PLOS ONE. 8(5). doi: 10.1371/journal.pone.0063300. Fulltekst i vitenarkiv
• Høglund, Rune Alexander; Holmøy, Trygve; Harbo, Hanne Flinstad & Maghazachi, Azzam (2013). A One Year Follow-Up Study of Natural Killer and Dendritic Cells Activities in Multiple Sclerosis Patients Receiving Glatiramer Acetate (GA). PLOS ONE. 8(4). doi: 10.1371/journal.pone.0062237. Fulltekst i vitenarkiv
• Gourraud, Pierre-Antoine; Harbo, Hanne Flinstad; Hauser, Stephen L & Baranzini, Sergio E. (2012). The genetics of multiple sclerosis: an up-to-date review. Immunological Reviews. ISSN 0105-2896. 248, s. 87–103. doi: 10.1111/j.1600-065X.2012.01134.x. Fulltekst i vitenarkiv
• Link, Jenny; Kockum, Ingrid; Lorentzen, Åslaug Rudjord; Lie, Benedicte Alexandra; Celius, Elisabeth Gulowsen & Westerlind, Helga [Vis alle 12 forfattere av denne artikkelen] (2012). Importance of human leukocyte antigen (HLA) class I and II alleles on the risk of multiple sclerosis. PLOS ONE. 7(5:e36779). doi: 10.1371/journal.pone.0036779. Fulltekst i vitenarkiv
• Gregersen, Peter K.; Kosoy, Roman; Lee, Annette T.; Lamb, Janine; Sussman, Jon & McKee, David [Vis alle 29 forfattere av denne artikkelen] (2012). Risk for Myasthenia Gravis Maps to a 151Pro!Ala Change in TNIP1 and to Human Leukocyte Antigen-B*08. Annals of Neurology. ISSN 0364-5134. 72(6), s. 927–935. doi: 10.1002/ana.23691. Fulltekst i vitenarkiv
• Brambilla, Paola; Esposito, Federica; Lindström, Eva S.; Sorosina, Melissa; Giacalone, Giacomo & Clarelli, Ferdinando [Vis alle 22 forfattere av denne artikkelen] (2012). Association between DPP6 polymorphism and the risk of progressive multiple sclerosis in Northern and Southern Europeans. Neuroscience Letters. ISSN 0304-3940. 530(2), s. 155–160. doi: 10.1016/j.neulet.2012.10.008. Fulltekst i vitenarkiv
• Harbo, Hanne Flinstad & Mero, Inger-Lise (2012). From genes to characteristics of multiple sclerosis. Acta Neurologica Scandinavica. ISSN 0001-6314. 126, s. 76–83. doi: 10.1111/ane.12027. Fulltekst i vitenarkiv
• Mero, Inger-Lise; SMESTAD, CATHRINE; Lie, Benedicte Alexandra; Lorentzen, Åslaug Rudjord; Sandvik, Leiv & Landrø, Nils Inge [Vis alle 10 forfattere av denne artikkelen] (2012). Polymorphisms of the BDNF gene show neither association with multiple sclerosis susceptibility nor clinical course. Journal of Neuroimmunology. ISSN 0165-5728. 244(1-2), s. 107–110. doi: 10.1016/j.jneuroim.2012.01.011. Fulltekst i vitenarkiv
• Maniaol, Angelina; Elsais, Ahmed; Lorentzen, Åslaug Rudjord; Owe, Jone Furulund; Viken, Marte K & Sæther, Hanne Skarpodde [Vis alle 17 forfattere av denne artikkelen] (2012). Late onset myasthenia gravis is associated with HLA DRB1*15:01 in the Norwegian population. PLOS ONE. 7(5). doi: 10.1371/journal.pone.0036603. Fulltekst i vitenarkiv Vis sammendrag

  Background: Acquired myasthenia gravis (MG) is a rare antibody-mediated autoimmune disease caused by impaired neuromuscular transmission, leading to abnormal muscle fatigability. The aetiology is complex, including genetic risk factors of the human leukocyte antigen (HLA) complex and unknown environmental factors. Although associations between the HLA complex and MG are well established, not all involved components of the HLA predisposition to this heterogeneous disease have been revealed. Well-powered and comprehensive HLA analyses of subgroups in MG are warranted, especially in late onset MG. Methodology/Principal Findings: This case-control association study is of a large population-based Norwegian cohort of 369 MG patients and 651 healthy controls. We performed comprehensive genotyping of four classical HLA loci (HLA-A, -B, -C and -DRB1) and showed that the DRB1*15:01 allele conferred the strongest risk in late onset MG (LOMG; onset ≥60years) (OR 2.38, pc7.4×10−5). DRB1*13:01 was found to be a protective allele for both early onset MG (EOMG) and LOMG (OR 0.31, pc 4.71×10−4), a finding not previously described. No significant association was found to the DRB1*07:01 allele (pnc = 0.18) in a subset of nonthymomatous anti-titin antibody positive LOMG as reported by others. HLA-B*08 was mapped to give the strongest contribution to EOMG, supporting previous studies. Conclusion: The results from this study provide important new information concerning the susceptibility of HLA alleles in Caucasian MG, with highlights on DRB1*15:01 as being a major risk allele in LOMG.

• Martinelli-Boneschi, Filippo; Esposito, Federica; Brambilla, Paola; Lindström, Eva S.; Lavorgna, Giovanni & Stankovich, Jim [Vis alle 23 forfattere av denne artikkelen] (2012). A genome-wide association study in progressive multiple sclerosis. Multiple Sclerosis. ISSN 1352-4585. 18(10), s. 1384–1394. doi: 10.1177/1352458512439118. Fulltekst i vitenarkiv
• Harbo, Hanne Flinstad & Mero, Inger-Lise (2012). From genes to characteristics of multiple sclerosis. Acta Neurologica Scandinavica, Supplementum. ISSN 0065-1427. 126, s. 76–83. doi: 10.1111/ane.12027. Fulltekst i vitenarkiv
• Mero, Inger-Lise; Ban, Maria; Lorentzen, Åslaug Rudjord; SMESTAD, CATHRINE; Celius, Elisabeth Gulowsen & Sæther, Hanne Skarpodde [Vis alle 18 forfattere av denne artikkelen] (2011). Exploring the CLEC16A gene reveals a MS-associated variant with correlation to the relative expression of CLEC16A isoforms in thymus. Genes and Immunity. ISSN 1466-4879. 12(3), s. 191–198. doi: 10.1038/gene.2010.59. Fulltekst i vitenarkiv
• Burgunder, Jean-Marc; Schöls, Ludger; Baets, Jonathan; Andersen, Peter Munch; Gasser, Thomas & Szolnoki, Zoltan [Vis alle 18 forfattere av denne artikkelen] (2011). EFNS guidelines for the molecular diagnosis of neurogenetic disorders: motoneuron, peripheral nerve and muscle disorders. European Journal of Neurology. ISSN 1351-5101. 18(2), s. 207–E20. doi: 10.1111/j.1468-1331.2010.03069.x. Fulltekst i vitenarkiv
• Pandya, Abhilash D.; Al-Jaderi, Zaidoon; Høglund, Rune Alexander; Holmøy, Trygve; Harbo, Hanne Flinstad & Norgauer, Johannes [Vis alle 7 forfattere av denne artikkelen] (2011). Identification of Human NK17/NK1 Cells. PLOS ONE. 6(10). doi: 10.1371/journal.pone.0026780. Fulltekst i vitenarkiv Vis sammendrag

  Background Natural killer (NK) cells have both cytolytic and immunoregulatory functions. We recently described that these cells release the inflammatory cytokines IL-17 and IFN-γ. However, the precise identity of the NK cell subset(s) that secrete these cytokines is not known. Methodology/Principal Findings To isolate the cells secreting IL-17 and IFN-γ, we took advantage of the findings that Th17/Th1 cells express chemokine receptors. Therefore, CD56+NK cells were stained with antibodies against various chemokine receptors and intracellularly with antibodies toward IL-17 and IFN-γ. Consequently, we identified previously unrecognized subset of NK cells generated from normal human peripheral blood after activation with IL-2 but not PMA plus ionomycin. The cells are characterized by the expression of CD56+ and CCR4+, produce IL-17 and IFN-γ and are consequently named NK17/NK1 cells. They also express CD161, NKp30, NKp44, NKp46, NKG2D, CD158, CCL22, IL-2Rβ and the common γ chain but not CD127 or IL-23R. Further, they possess T-bet and RORγt transcription factors. Antibodies to IL-1β, IL-6, IL-21, or TGF-β1 do not inhibit IL-2-induced generation of NK17/NK1 cells, suggesting that IL-2 has the capacity to polarize these cells. Notably, NK17/NK1 cells are abundant in the cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS) without activation, and are generated from the peripheral blood of these patients after activation with IL-2. Conclusions/Significance NK17/NK1 cells identified here have not been previously described in healthy or MS patients. © 2011 Pandya et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

• Sawcer, S; Hellenthal, G; Pirinen, M; Spencer, CCA; Patsopoulos, NA & Moutsianas, L [Vis alle 242 forfattere av denne artikkelen] (2011). Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. ISSN 0028-0836. 476(7359), s. 214–219. doi: 10.1038/nature10251. Fulltekst i vitenarkiv
• Lundström, Wangko; Greiner, Eva; Lundmark, Frida; Westerlind, Helga; SMESTAD, CATHRINE & Lorentzen, Åslaug Rudjord [Vis alle 13 forfattere av denne artikkelen] (2011). No influence on disease progression of non-HLA susceptibility genes in MS. Journal of Neuroimmunology. ISSN 0165-5728. 237(1-2), s. 98–100. doi: 10.1016/j.jneuroim.2011.05.003. Fulltekst i vitenarkiv
• Hansen, Bettina; Oturai, Annette Bang; Harbo, Hanne Flinstad; Celius, Elisabeth Gulowsen; Nissen, Kari K. & Laska, Magdalena J. [Vis alle 9 forfattere av denne artikkelen] (2011). Genetic Association of Multiple Sclerosis with the Marker rs391745 near the Endogenous Retroviral Locus HERV-Fc1: Analysis of Disease Subtypes. PLOS ONE. 6(10). doi: 10.1371/journal.pone.0026438. Fulltekst i vitenarkiv
• Harbo, Hanne Flinstad; Lorentzen, Åslaug Rudjord; Lie, Benedicte Alexandra; Celius, Elisabeth Gulowsen & Spurkland, Anne (2011). Nytt genkart for multippel sklerose. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 131(21), s. 2126–2130. doi: 10.4045/tidsskr.10.0823. Fulltekst i vitenarkiv
• Søndergaard, Helle Bach; Sellebjerg, Finn; Hillert, Jan; Olsson, Tomas; Kockum, Ingrid & Lindén, Magdalena [Vis alle 14 forfattere av denne artikkelen] (2011). Alterations in KLRB1 gene expression and a Scandinavian multiple sclerosis association study of the KLRB1 SNP rs4763655. European Journal of Human Genetics. ISSN 1018-4813. 19(10), s. 1100–1103. doi: 10.1038/ejhg.2011.88. Fulltekst i vitenarkiv
• Jakkula, Eveliina; Leppa, Virpi; Sulonen, Anna-Maija; Varilo, Teppo; Kallio, Suvi & Kemppinen, Anu [Vis alle 29 forfattere av denne artikkelen] (2010). Genome-wide Association Study in a High-Risk Isolate for Multiple Sclerosis Reveals Associated Variants in STAT3 Gene. American Journal of Human Genetics. ISSN 0002-9297. 86(2), s. 285–291. doi: 10.1016/j.ajhg.2010.01.017. Fulltekst i vitenarkiv
• Mero, Inger-Lise; Lorentzen, Åslaug Rudjord; SMESTAD, CATHRINE; Ban, Maria; Celius, Elisabeth Gulowsen & Aarseth, Jan [Vis alle 22 forfattere av denne artikkelen] (2010). A rare variant of the TYK2 gene is confirmed to be associated with multiple sclerosis. European Journal of Human Genetics. ISSN 1018-4813. 18(4), s. 502–504. doi: 10.1038/ejhg.2009.195. Fulltekst i vitenarkiv
• Burgunder, JM; al, More authors Et; Tallaksen, Chantal & Harbo, Hanne Flinstad (2010). EFNS guidelines for the molecular diagnosis of neurodegenerative disorders:motoneuron, peripheral nerve and muscle disorders. European Journal of Neurology. ISSN 1351-5101. 18, s. 207–217. doi: 10.1111/j.468-1331.2010.03069.x. Fulltekst i vitenarkiv
• Lorentzen, Åslaug Rudjord; Melum, Espen; Ellinghaus, Eva; Smestad, Cathrine; Mero, Inger-Lise & Aarseth, Jan Harald [Vis alle 12 forfattere av denne artikkelen] (2010). Association to the Glypican-5 gene in multiple sclerosis. Journal of Neuroimmunology. ISSN 0165-5728. 226(1-2), s. 194–197. doi: 10.1016/j.jneuroim.2010.07.003. Fulltekst i vitenarkiv
• Link, Jenny; Lorentzen, Åslaug Rudjord; Kochum, Ingrid; Duvefelt, Kristina; Lie, Benedicte Alexandra & Celius, Elisabeth Gulowsen [Vis alle 9 forfattere av denne artikkelen] (2010). Two HLA class I genes independently associated with multiple sclerosis. Journal of Neuroimmunology. ISSN 0165-5728. 226(1-2), s. 172–176. doi: 10.1016/j.jneuroim.2010.07.006. Fulltekst i vitenarkiv
• Beyeen, AD; Adzemovic, Milena Z.; Öckinger, Johan; Sridh, Pernilla; al, More authors Et & Becanovic, Kristina [Vis alle 16 forfattere av denne artikkelen] (2010). IL-22RA2 Associates with Multiple Sclerosis and Macrophage Effector Mechanisms in Experimental Neuroinflammation. Journal of Immunology. ISSN 0022-1767. 185(11), s. 6883–6890. doi: 10.4049/jimmunol.1001392. Fulltekst i vitenarkiv
• Esposito, Floriana; Patsopoulos, NA; Cepok, Sabine; Kockum, I; Leppa, V & Booth, DR [Vis alle 69 forfattere av denne artikkelen] (2010). IL12A, MPHOSPH9/CDK2AP1 and RGS1 are novel multiple sclerosis susceptibility loci. Genes and Immunity. ISSN 1466-4879. 11(5), s. 397–405. doi: 10.1038/gene.2010.28. Fulltekst i vitenarkiv
• Gasser, T; Finsterer, Josef; Baets, J; Broeckhoven, C Van; Donato, S Di & Fontaine, B [Vis alle 18 forfattere av denne artikkelen] (2010). EFNS guidelines on the molecular diagnosis of ataxias and spastic paraplegias. European Journal of Neurology. ISSN 1351-5101. 17(2), s. 179–188. doi: 10.1111/j.1468-1331.2009.02873.x. Fulltekst i vitenarkiv
• Burgunder, J-M.; Finsterer, J.; Szolnoki, Z.; Fontaine, B.; Baets, J. & Broeckhoven, C. Van [Vis alle 17 forfattere av denne artikkelen] (2010). EFNS guidelines on the molecular diagnosis of channelopathies, epilepsies, migraine, stroke, and dementias. European Journal of Neurology. ISSN 1351-5101. 17(5), s. 641–648. doi: 10.1111/j.1468-1331.2010.02985.x. Fulltekst i vitenarkiv
• Harbo, Hanne Flinstad; Riccio, Maria Elena; Lorentzen, Åslaug Rudjord; Utsi, Egil; Myhr, Kjell-Morten & Mellgren, Svein Ivar [Vis alle 10 forfattere av denne artikkelen] (2010). Norwegian Sami differs significantly from other Norwegians according to their HLA profile. Tissue Antigens. ISSN 0001-2815. 75(3), s. 207–217. doi: 10.1111/j.1399-0039.2009.01425.x. Fulltekst i vitenarkiv
• Nohra, R; Beyeen, A.D.; Guo, JP; Khademi, M; Sundqvist, E & Hedreul, M [Vis alle 17 forfattere av denne artikkelen] (2010). RGMA and IL21R show association with experimental inflammation and multiple sclerosis. Genes and Immunity. ISSN 1466-4879. 11(4), s. 279–293. doi: 10.1038/gene.2009.111. Fulltekst i vitenarkiv
• Ban, Maria; Booth, David R; Heard, Robert N; Stewart, Graeme J; Goris, An & Dobosi, Rita [Vis alle 33 forfattere av denne artikkelen] (2009). The expanding genetic overlap between multiple sclerosis and type I diabetes. Genes and Immunity. ISSN 1466-4879. 10(1), s. 11–14. doi: 10.1038/gene.2008.83. Fulltekst i vitenarkiv Vis sammendrag

  Familial clustering of autoimmune disease is well recognized and raises the possibility that some susceptibility genes may predispose to autoimmunity in general. In light of this observation, it might be expected that some of the variants of established relevance in one autoimmune disease may also be relevant in other related conditions. On the basis of this hypothesis, we tested seven single nucleotide polymorphisms (SNPs) that are known to be associated with type I diabetes in a large multiple sclerosis data set consisting of 2369 trio families, 5737 cases and 10,296 unrelated controls. Two of these seven SNPs showed evidence of association with multiple sclerosis; that is rs12708716 from the CLEC16A gene (P=1.6 x 10(-16)) and rs763361 from the CD226 gene (P=5.4 x 10(-8)). These findings thereby identify two additional multiple sclerosis susceptibility genes and lend support to the notion of autoimmune susceptibility genes.

• Jagodic, Maja; Colacios, Celine; Nohra, Rita; Dejean, Anne S.; Beyeen, Amennai Daniel & Khademi, Mohsen [Vis alle 37 forfattere av denne artikkelen] (2009). A Role for VAV1 in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis. Science Translational Medicine. ISSN 1946-6234. 1(10). doi: 10.1126/scitranslmed.3000278. Fulltekst i vitenarkiv
• Ban, M; Goris, A; Lorentzen, Åslaug Rudjord; Baker, A; Mihalova, T & Ingram, G [Vis alle 31 forfattere av denne artikkelen] (2009). Replication analysis identifies TYK2 as a multiple sclerosis susceptibility factor. European Journal of Human Genetics. ISSN 1018-4813. 17(10), s. 1309–1313. doi: 10.1038/ejhg.2009.41. Fulltekst i vitenarkiv
• Mero, Inger Lise; Lorentzen, Åslaug Rudjord; Ban, Maria; SMESTAD, CATHRINE; Celius, Elisabeth G & Aarseth, Jan [Vis alle 21 forfattere av denne artikkelen] (2009). A rare variant of the TYK2 gene is confirmed to be associated with multiple sclerosis. European Journal of Human Genetics. ISSN 1018-4813. doi: 10.1038/ejhg.2009.195. Fulltekst i vitenarkiv
• Kallio, SP; Jakkula, E; Purcell, S; Suvela, M; Koivisto, K & Tienari, PJ [Vis alle 22 forfattere av denne artikkelen] (2009). Use of a genetic isolate to identify rare disease variants: C7 on 5p associated with MS. Human Molecular Genetics. ISSN 0964-6906. 18(9), s. 1670–1683. doi: 10.1093/hmg/ddp073. Fulltekst i vitenarkiv
• Kemppinen, Anu; Suvela, M; Tienari, PJ; Elovaara, I; Koivisto, K & Pirttila, T [Vis alle 18 forfattere av denne artikkelen] (2009). MYO9B polymorphisms in multiple sclerosis. European Journal of Human Genetics. ISSN 1018-4813. 17(6), s. 840–843. doi: 10.1038/ejhg.2008.251. Fulltekst i vitenarkiv
• Harbo, Hanne Flinstad; Finsterer, J; Baets, J; Broeckhoven, C Van; Donato, S Di & Fontaine, B [Vis alle 18 forfattere av denne artikkelen] (2009). EFNS guidelines on the molecular diagnosis of neurogenetic disorders: general issues, Huntington's disease, Parkinson's disease and dystonias. European Journal of Neurology. ISSN 1351-5101. 16(7), s. 777–785. doi: 10.1111/j.1468-1331.2009.02646.x. Fulltekst i vitenarkiv
• Lorentzen, Åslaug Rudjord; Karlsen, TH; Olsson, M; Smestad, C; Mero, IL & Woldseth, B [Vis alle 13 forfattere av denne artikkelen] (2009). Killer Immunoglobulin-like Receptor Ligand HLA-Bw4 Protects Against Multiple Sclerosis. Annals of Neurology. ISSN 0364-5134. 65(6), s. 658–666. doi: 10.1002/ana.21695. Fulltekst i vitenarkiv
• Finsterer, Josef; Harbo, Hanne Flinstad; Baets, J; Broeckhoven, Cathrine Van; Donato, S Di & Fontaine, B [Vis alle 18 forfattere av denne artikkelen] (2009). EFNS guidelines on the molecular diagnosis of mitochondrial disorders. European Journal of Neurology. ISSN 1351-5101. 16(12), s. 1255–1264. doi: 10.1111/j.1468-1331.2009.02811.x. Fulltekst i vitenarkiv
• Harbo, Hanne Flinstad; Riccio, ME; Lorentzen, Åslaug Rudjord; Utsi, E; Myhr, Kjell Morten & Mellgren, Svein Ivar [Vis alle 10 forfattere av denne artikkelen] (2009). Norwegian Sami differs significantly from other Norwegians according to their HLA profile. Tissue Antigens. ISSN 0001-2815. doi: 10.1111/j.1399-0039.2009.01425.x. Fulltekst i vitenarkiv

Se alle arbeider i NVA

• Helseth, Eirik; Rootwelt, Terje & Harbo, Hanne Flinstad (2019). Nevrologi og nevrokirurgi. Fra barn til voksen, 7. utg. Fagbokforlaget. ISBN 9788245024739. 1000 s. Fulltekst i vitenarkiv
• Helseth, Eirik; Rootwelt, Terje & Harbo, Hanne Flinstad (2019). Nevrologi og nevrokirurgi ; fra barn til voksen. Fagbokforlaget. ISBN 9788245024739. 582 s. Fulltekst i vitenarkiv

Se alle arbeider i NVA

• Sandset, Tony Joakim Ananiassen; Kristensen, Solveig; Amundsen, Marthe & Harbo, Hanne-Cathrin Flinstad (2026). Likestilling og mangfold som kvalitetspolitikk i akademia. Fulltekst i vitenarkiv
• Dyb, Grete Anita; Løberg, Magnus; Feiring, Eli; Bjaalie, Jan G. & Harbo, Hanne-Cathrin Flinstad (2025). Revidert regelverk for ph.d.utdanningen. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 14(14). doi: 10.4045/tidsskr.25.0652. Fulltekst i vitenarkiv
• Bjaalie, Jan G.; Løberg, Magnus; Haugaa, Kristina Ingrid Helena Hermann; Nebb, Hilde Irene & Harbo, Hanne-Cathrin Flinstad (2025). Innovation – the final leg in the research relay race. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. doi: 10.4045/tidsskr.25.0553. Fulltekst i vitenarkiv
• Harbo, Hanne-Cathrin Flinstad; Bakke, Per; Forsmo, Siri; Svineng, Gunbjørg; Dyb, Grete & Bakke, Marit [Vis alle 8 forfattere av denne artikkelen] (2024). Norge trenger kunnskaps­beredskap når kriser inntreffer. Fulltekst i vitenarkiv Vis sammendrag

  Terrorangrep har flere ganger rystet det norske samfunnet, og vi har nylig opplevd en alvorlig pandemi. Det er krig i mange deler av verden, også i Europa. Det er nå vi må legge grunnlaget for å håndtere neste pandemi og neste katastrofe ved å utvikle en tydelig kunnskapsberedskap i Norge.

• Grødeland, Gunnveig; Harbo, Hanne-Cathrin Flinstad; Diaz, Esperanza; Dyb, Grete Anita; Berg, Are Stuwitz & Svineng, Gunbjørg [Vis alle 13 forfattere av denne artikkelen] (2024). Pandemi, krig og terror: Helsefakultetenes betydning for beredskap. Fulltekst i vitenarkiv
• Feiring, Eli; Løberg, Magnus; Bjaalie, Jan G.; Dyb, Grete Anita & Harbo, Hanne-Cathrin Flinstad (2023). Kjønn og helse, utdanning og forskning. 143(11). doi: 10.4045/tidsskr.23.0408. Fulltekst i vitenarkiv
• Rasmussen, Tilde; König, Marton; Lorentzen, Åslaug Rudjord; Schikora-Rustad, Stine; Berge, Tone & Holmøy, Trygve [Vis alle 17 forfattere av denne artikkelen] (2022). Safety of a third SARS CoV 2 mRNA vaccine dose in people with multiple sclerosis. Fulltekst i vitenarkiv
• König, Marton; Wolf, Asia-Sophia Fumika Michaela; Ravussin, Anthony; Chopra, Adity; Tran, Trung & Torgauten, Hilde Marie [Vis alle 28 forfattere av denne artikkelen] (2022). Immunogenicity and efficacy of mRNA-COVID-19 vaccines in people with multiple sclerosis. Fulltekst i vitenarkiv
• Nygaard, Gro Owren; Schikora-Rustad, Stine; Lie, Ingeborg Haugesag; Aase, Audun; Leiknes, Ingvild Jullum & König, Marton [Vis alle 15 forfattere av denne artikkelen] (2021). Humoral immune response to the influenza vaccine in multiple sclerosis patients treated with cladribine or rituximab. Fulltekst i vitenarkiv
• König, Marton; Lorentzen, Åslaug Rudjord; Torgauten, Hilde Marie; Tran, The Trung; Schikora-Rustad, Stine & Vaage, Eline Benno [Vis alle 22 forfattere av denne artikkelen] (2021). Humoral Immunity to SARS-CoV-2 mRNA Vaccination in People with Multiple Sclerosis using High-Efficacy Disease Modifying Therapies. Fulltekst i vitenarkiv
• Kaufmann, Tobias; Meer, Dennis van der; Doan, Nhat Trung; Schwarz, Emanuel; Lund, Martina Jonette & Agartz, Ingrid [Vis alle 97 forfattere av denne artikkelen] (2020). Publisher Correction: Common brain disorders are associated with heritable patterns of apparent aging of the brain (Nature Neuroscience, (2019), 22, 10, (1617-1623), 10.1038/s41593-019-0471-7). Nature Neuroscience. ISSN 1097-6256. 23(2), s. 295–295. doi: 10.1038/s41593-019-0553-6. Fulltekst i vitenarkiv
• Bos, Steffan Daniel; Brorson, Ina Skaara; Eriksson, Anna; Leikfoss, Ingvild Sørum; Vitelli, Valeria & Celius, Elisabeth Gulowsen [Vis alle 10 forfattere av denne artikkelen] (2019). Differential gene expression analysis of CD8+ T cells from multiple sclerosis patients and healthy controls. Fulltekst i vitenarkiv
• Madireddy, Lohith; Patsopoulos, Nikolaos A.; Cotsapas, Chris; Bos, Steffan Daniel; Beecham, Ashley H. & McCauley, Jacob [Vis alle 64 forfattere av denne artikkelen] (2019). Author Correction: A systems biology approach uncovers cell-specific gene regulatory effects of genetic associations in multiple sclerosis (Nature Communications, (2019), 10, 1, (2236), 10.1038/s41467-019-09773-y). Nature Communications. 10(1). doi: 10.1038/s41467-019-10951-1. Fulltekst i vitenarkiv
• Glover, Joel; Tysnes, Ole-Bjørn; Myhr, Kjell-Morten; Bråthen, Geir; Sandvig, Ioanna & Høyer, Helle [Vis alle 9 forfattere av denne artikkelen] (2019). Hvor står ALS-forskningen i Norge? Fulltekst i vitenarkiv
• Bajwa, Simranjit Kaur; Nilsen, Kristian Bernhard; Erichsen, Erik Aksel Spendrup; Berg-Hansen, Pål & Harbo, Hanne Flinstad (2018). En mann i 50-årene med svimmelhet, dobbeltsyn og gangvansker. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 138(3). doi: 10.4045/tidsskr.16.1109. Fulltekst i vitenarkiv
• Brorson, Ina Skaara; Rhead, Brooke; Berge, Tone; Lea, Rodney A.; Burnard, Sean & Scott, Rodney J. [Vis alle 10 forfattere av denne artikkelen] (2018). Differently methylated regions in multiple sclerosis CD4+ and CD8+ T cells. Fulltekst i vitenarkiv
• Berge, Tone; Eriksson, Anna; Brorson, Ina Skaara; Høgestøl, Einar August; Bos, Steffan Daniel & Harbo, Hanne Flinstad [Vis alle 7 forfattere av denne artikkelen] (2018). Proteomic profiling of CD4+ and CD8+ T cells from multiple sclerosis patients and healthy controls. Fulltekst i vitenarkiv
• Berge, Tone; Brorson, Ina Skaara; Høgestøl, Einar August; Bos, Steffan Daniel; Harbo, Hanne Flinstad & Berven, Frode (2018). Proteomic profiling of CD4+ and CD8+ T cells from multiple sclerosis patients and healthy controls. Fulltekst i vitenarkiv
• Eriksson, Anna; Brorson, Ina Skaara; Høgestøl, Einar August; Bos, Steffan Daniel; Harbo, Hanne Flinstad & Berven, Frode [Vis alle 7 forfattere av denne artikkelen] (2018). Proteomic profiling of CD4+ T cells from MS patients show increased activity of T cell activation pathways (compared to healthy controls). Fulltekst i vitenarkiv
• Cellerino, Maria; Pardini, Matteo; Campi, Cristina; Ivaldi, Frederico; Vila, Gemma & Berge, Tone [Vis alle 13 forfattere av denne artikkelen] (2018). Personalizing health care in Multiple Sclerosis using systems medicine tools: Presentation of the cytomics data. Fulltekst i vitenarkiv
• Leikfoss, Ingvild Sørum; Bos, Steffan Daniel; Berg-Hansen, Pål; Berge, Tone; Beyer, Mona K. & Celius, Elisabeth Gulowsen [Vis alle 8 forfattere av denne artikkelen] (2018). The EU Horizon2020 Project MultipleMS: Improved Personalized Medicine for Multiple Sclerosis. Fulltekst i vitenarkiv
• Rhead, Brooke; Brorson, Ina Skaara; Berge, Tone; Adams, Cameron; Quach, Hong & Sangurdekar, Dipen [Vis alle 15 forfattere av denne artikkelen] (2018). Differential DNA methylation and expression of SLFN12 in multiple sclerosis patients’ CD4+ and CD8+ T cells. Fulltekst i vitenarkiv
• Brorson, Ina Skaara; Rhead, Brooke; Berge, Tone; Adams, Cameron; Quach, Hong & Sangurdekar, Dipen [Vis alle 18 forfattere av denne artikkelen] (2018). SLFN12 is differentially methylated in multiple sclerosis CD4+ and CD8+ T cells. Fulltekst i vitenarkiv
• Zubizarreta, Irati; Rosbo, Nicole Kerlero de; Rinas, Melanie; Høgestøl, Einar August; Benavent, Sigrid Aune de Rodez & Bos, Steffan Daniel [Vis alle 17 forfattere av denne artikkelen] (2018). The Sys4MS project: Personalizing health care in Multiple Sclerosis using systems medicine tools. Fulltekst i vitenarkiv
• Berge, Tone; Eriksson, Anna; Brorson, Ina Skaara; Høgestøl, Einar August; Harbo, Hanne Flinstad & Bos, Steffan Daniel [Vis alle 7 forfattere av denne artikkelen] (2018). Proteomic profiling of T cells from multiple sclerosis patients and healthy controls. Fulltekst i vitenarkiv
• Bos, Steffan Daniel; Brorson, Ina Skaara; Høgestøl, Einar August; Berge, Tone; Saez-Rodriguez, Julio & Uccelli, Antonio [Vis alle 9 forfattere av denne artikkelen] (2018). Multiple Sclerosis genetic burden score in a systems biology study of MS patients from four countries. Fulltekst i vitenarkiv
• Cellerino, Maria; Pardini, Matteo; Ivaldi, Frederico; Vila, Gemma; Berge, Tone & Koduah, Priscilla [Vis alle 14 forfattere av denne artikkelen] (2018). Personalizing health care in Multiple Sclerosis using systems medicine tools: presentation of the cytomics data from the Sys4MS project. Fulltekst i vitenarkiv
• Brorson, Ina Skaara; Rhead, Brooke; Quach, Hong; Berg-Hansen, Pål; Berge, Tone & Harbo, Hanne Flinstad [Vis alle 8 forfattere av denne artikkelen] (2017). DNA methylation differences in CD4+ and CD8+ T cells of multiple sclerosis patients and healthy controls. Fulltekst i vitenarkiv
• Bos, Steffan Daniel; Brorson, Ina Skaara; Barcellos, Lisa F; Berge, Tone & Harbo, Hanne Flinstad (2017). Gene expression profiling of CD4+ T cells from multiple sclerosis patients and healthy controls. Fulltekst i vitenarkiv
• Mo, Ingrid; Eriksson, Anna; Brorson, Ina Skaara; Ledsaak, Marit; Harbo, Hanne Flinstad & Gabrielsen, Odd Stokke [Vis alle 7 forfattere av denne artikkelen] (2017). Identifying protein interaction partners for DEXI - encoded by the dexamethasone-induced gene, DEXI. Fulltekst i vitenarkiv
• Fernanda, Kropf Correia; Brorson, Ina Skaara; Eriksson, Anna; Bos, Steffan Daniel; Harbo, Hanne Flinstad & Berge, Tone (2017). Molecular characterization of TAGAP – a GTPase-activating protein encoded by a multiple sclerosis susceptibility gene. Fulltekst i vitenarkiv
• Brorson, Ina Skaara; Eriksson, Anna; Baranzini, Sergio; Berge, Tone; Harbo, Hanne Flinstad & Bos, Steffan Daniel (2017). Gene expression in pathways enriched with MS associated risk loci. Fulltekst i vitenarkiv
• Moen, Stine Marit; Harbo, Hanne Flinstad; Celius, Elisabeth Gulowsen; Sowa, Piotr; Nygaard, Gro Owren & Beyer, Mona K. (2016). S.M. Moen og medarbeidere svarer. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 136(20), s. 1702–1702. doi: 10.4045/tidsskr.16.0865. Fulltekst i vitenarkiv
• Moen, Stine Marit; Harbo, Hanne Flinstad; Sowa, Piotr; Celius, Elisabeth Gulowsen; Nygaard, Gro Owren & Beyer, Mona K. (2016). MR-undersøkelser ved multippel sklerose. 136(16), s. 1373–1376. doi: 10.4045/tidsskr.15.1361. Fulltekst i vitenarkiv
• Moen, Stine Marit; Harbo, Hanne Flinstad; Celius, Elisabeth Gulowsen; Sowa, Piotr; Nygaard, Gro Owren & Beyer, Mona K. (2016). S.M. Moen og medarbeidere svarer. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 136(19), s. 1608–1608. doi: 10.4045/tidsskr.16.0826. Fulltekst i vitenarkiv
• Berg-Hansen, Pål; Moen, Stine Marit; Harbo, Hanne Flinstad & Celius, Elisabeth Gulowsen (2015). Comments on the review article 'Time trends in the incidence and prevalence of multiple sclerosis in Norway during eight decades'. Acta Neurologica Scandinavica. ISSN 0001-6314. 132(5), s. 364–367. doi: 10.1111/ane.12489. Fulltekst i vitenarkiv
• Nygaard, Gro Owren; Harbo, Hanne Flinstad; Celius, Elisabeth Gulowsen & Landro, N. I. (2013). Does the Brief International Cognitive Assessment for MS (BICAMS) catch the cognitive problems of a sample of well-educated recently diagnosed MS patients in Oslo? Multiple Sclerosis. ISSN 1352-4585. 19(7), s. 970–971. Fulltekst i vitenarkiv
• Berge, Tone; Leikfoss, Ingvild Sørum; Spurkland, Anne; Lie, Benedicte Alexandra & Harbo, Hanne Flinstad (2012). Multiple sclerosis-associated single nucleotide polymorphisms in CLEC16A correlate with reduced SOCS1 and DEXI expression in thymic tissue. Fulltekst i vitenarkiv
• Leikfoss, Ingvild Sørum; Berge, Tone; Harbo, Hanne Flinstad & Spurkland, Anne (2012). Multiple sclerosis-associated single nucleotide polymorphisms in CLEC16A correlate with reduced SOCS1 and DEXI expression in thymic tissue. Fulltekst i vitenarkiv
• Leikfoss, Ingvild S; Mero, Inger-Lise; Dahle, Maria Krudtaa; Lie, Benedicte Alexandra; Harbo, Hanne Flinstad & Spurkland, Anne [Vis alle 7 forfattere av denne artikkelen] (2012). Multiple Sclerosis Associated Single Nucleotide Polymorphisms in CLEC16A Correlate with Reduced SOCS1 and DEXI Expression in Thymic Samples. Scandinavian Journal of Immunology. ISSN 0300-9475. 76(2), s. 196–196. Fulltekst i vitenarkiv
• Link, J.; Kockum, I.; Lorentzen, Åslaug Rudjord; Lie, Benedicte Alexandra; Celius, Elisabeth Gulowsen & Schaffer, M. [Vis alle 9 forfattere av denne artikkelen] (2011). Investigation of HLA genes in multiple sclerosis in Scandinavia. Journal of Neurology. ISSN 0340-5354. 258, s. 196–196. Fulltekst i vitenarkiv
• Sørum, Ingvild; Mero, Inger-Lise; Gustavsen, Marte Wendel; Muggerud, Aslaug; Sæther, Hanne Skarpodde & Lie, Benedicte Alexandra [Vis alle 9 forfattere av denne artikkelen] (2011). Molecular Characterization of the Multiple Sclerosis Susceptibility Gene CLEC16A. Scandinavian Journal of Immunology. ISSN 0300-9475. 73(4), s. 377–377. Fulltekst i vitenarkiv
• Maniaol, Angelina; Boldingh, Marion Ingeborg; Brunborg, Cathrine; Harbo, Hanne Flinstad & Tallaksen, Chantal (2011). A POPULATION-BASED DESCRIPTIVE EPIDEMIOLOGIC STUDY OF MYASTHENIA GRAVIS IN NORWAY. European Journal of Neurology. ISSN 1351-5101. 18(S2), s. 276–276. Fulltekst i vitenarkiv
• Lorentzen, Åslaug Rudjord; Melum, Espen; Buchert, Eva; SMESTAD, CATHRINE; Mero, Inger-Lise & Aarseth, Jan Harald [Vis alle 12 forfattere av denne artikkelen] (2010). Trend of association to the Glypican 5 gene region to multiple sclerosis. European Journal of Neurology. ISSN 1351-5101. 17, s. 221–221. Fulltekst i vitenarkiv
• Holmøy, Trygve; Harbo, Hanne Flinstad & Celius, Elisabeth Gulowsen (2010). Behandling av multippel sklerose. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 130(9), s. 923–923. Fulltekst i vitenarkiv
• Booth, DR; Heard, RN; Stewart, GJ; Cox, M; Scott, RJ & Lechner-Scott, J [Vis alle 42 forfattere av denne artikkelen] (2010). Lack of support for association between the KIF1B rs10492972[C] variant and multiple sclerosis. Nature Genetics. ISSN 1061-4036. 42(6), s. 469–470. Fulltekst i vitenarkiv
• Brorson, Ina Skaara; Rhead, Brooke; Berge, Tone; Adams, Cameron; Quach, Hong & Sangurdekar, Dipen [Vis alle 18 forfattere av denne artikkelen] (2010). SLFN12 is differentially methylated in multiple sclerosis CD4+ and CD8+ T cells. Fulltekst i vitenarkiv
• Gustavsen, Marte Wendel; Berge, Tone & Harbo, Hanne Flinstad (2015). Genetic, clinical and environmental aspects of multiple sclerosis. Universitetet i Oslo. ISSN 9788283331417. Fulltekst i vitenarkiv

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