| 1. |
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| 2. |
- Al Nimer, Faiez, et al.
(författare)
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Lipocalin-2 is increased in progressive multiple sclerosis and inhibits remyelination
- 2016
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Ingår i: Neurology. - 2332-7812. ; 3:1
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Tidskriftsartikel (refereegranskat)abstract
- Objective: We aimed to examine the regulation of lipocalin-2 (LCN2) in multiple sclerosis (MS) and its potential functional relevance with regard to myelination and neurodegeneration. Methods: We determined LCN2 levels in 3 different studies: (1) in CSF and plasma from a case-control study comparing patients with MS (n = 147) with controls (n = 50) and patients with relapsing-remitting MS (n = 75) with patients with progressive MS (n = 72); (2) in CSF and brain tissue microdialysates from a case series of 7 patients with progressive MS; and (3) in CSF at baseline and 60 weeks after natalizumab treatment in a cohort study of 17 patients with progressive MS. Correlation to neurofilament light, a marker of neuroaxonal injury, was tested. The effect of LCN2 on myelination and neurodegeneration was studied in a rat in vitro neuroglial cell coculture model. Results: Intrathecal production of LCN2 was increased predominantly in patients with progressive MS (p < 0.005 vs relapsing-remitting MS) and displayed a positive correlation to neurofilament light (p = 0.005). Levels of LCN2 in brain microdialysates were severalfold higher than in the CSF, suggesting local production in progressive MS. Treatment with natalizumab in progressive MS reduced LCN2 levels an average of 13% (p < 0.0001). LCN2 was found to inhibit remyelination in a dose-dependent manner in vitro. Conclusions: LCN2 production is predominantly increased in progressive MS. Although this moderate increase does not support the use of LCN2 as a biomarker, the correlation to neurofilament light and the inhibitory effect on remyelination suggest that LCN2 might contribute to neurodegeneration through myelination-dependent pathways.
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| 3. |
- Anesten, Birgitta, et al.
(författare)
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Blood-brain barrier integrity, intrathecal immunoactivation, and neuronal injury in HIV.
- 2016
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Ingår i: Neurology, Neuroimmunology & Neuroinflammation. - 2332-7812. ; 3:6
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Tidskriftsartikel (refereegranskat)abstract
- Although blood-brain barrier (BBB) impairment has been reported in HIV-infected individuals, characterization of this impairment has not been clearly defined.BBB integrity was measured by CSF/plasma albumin ratio in this cross-sectional study of 631 HIV-infected individuals and 71 controls. We also analyzed CSF and blood HIV RNA and neopterin, CSF leukocyte count, and neurofilament light chain protein (NFL) concentrations. The HIV-infected participants included untreated neuroasymptomatic patients, patients with untreated HIV-associated dementia (HAD), and participants on suppressive antiretroviral treatment (ART).The albumin ratio was significantly increased in patients with HAD compared to all other groups. There were no significant differences between untreated neuroasymptomatic participants, treated participants, and controls. BBB integrity, however, correlated significantly with CSF leukocyte count, CSF HIV RNA, serum and CSF neopterin, and age in untreated neuroasymptomatic participants. In a multiple linear regression analysis, age, CSF neopterin, and CSF leukocyte count stood out as independent predictors of albumin ratio. A significant correlation was found between albumin ratio and CSF NFL in untreated neuroasymptomatic patients and in participants on ART. Albumin ratio, age, and CD4 cell count were confirmed as independent predictors of CSF NFL in multivariable analysis.BBB disruption was mainly found in patients with HAD, where BBB damage correlated with CNS immunoactivation. Albumin ratios also correlated with CSF inflammatory markers and NFL in untreated neuroasymptomatic participants. These findings give support to the association among BBB deterioration, intrathecal immunoactivation, and neuronal injury in untreated neuroasymptomatic HIV-infected individuals.
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| 4. |
- Bergman, Joakim, et al.
(författare)
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Neurofilament light in CSF and serum is a sensitive marker for axonal white matter injury in MS.
- 2016
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Ingår i: Neurology® neuroimmunology & neuroinflammation. - 2332-7812. ; 3:5
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Tidskriftsartikel (refereegranskat)abstract
- In an ongoing, open-label, phase 1b study on the intrathecal administration of rituximab for progressive multiple sclerosis, an intraventricular catheter was inserted for drug delivery. The objective of this study was to characterize the limited white matter axonal injury evoked by catheter insertion by analyzing a panel of markers for tissue damage in CSF and serum.
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| 8. |
- Gafson, Arie R, et al.
(författare)
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Breaking the cycle: Reversal of flux in the tricarboxylic acid cycle by dimethyl fumarate.
- 2019
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Ingår i: Neurology(R) neuroimmunology & neuroinflammation. - 2332-7812. ; 6:3
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Tidskriftsartikel (refereegranskat)abstract
- To infer molecular effectors of therapeutic effects and adverse events for dimethyl fumarate (DMF) in patients with relapsing-remitting MS (RRMS) using untargeted plasma metabolomics.Plasma from 27 patients with RRMS was collected at baseline and 6 weeks after initiating DMF. Patients were separated into discovery (n = 15) and validation cohorts (n = 12). Ten healthy controls were also recruited. Metabolomic profiling using ultra-high-performance liquid chromatography mass spectrometry (UPLC-MS) was performed on the discovery cohort and healthy controls at Metabolon Inc (Durham, NC). UPLC-MS was performed on the validation cohort at the National Phenome Centre (London, UK). Plasma neurofilament concentration (pNfL) was assayed using the Simoa platform (Quanterix, Lexington, MA). Time course and cross-sectional analyses were performed to identify pharmacodynamic changes in the metabolome secondary to DMF and relate these to adverse events.In the discovery cohort, tricarboxylic acid (TCA) cycle intermediates fumarate and succinate, and TCA cycle metabolites succinyl-carnitine and methyl succinyl-carnitine increased 6 weeks following treatment (q < 0.05). Methyl succinyl-carnitine increased in the validation cohort (q < 0.05). These changes were not observed in the control population. Increased succinyl-carnitine and methyl succinyl-carnitine were associated with adverse events from DMF (flushing and abdominal symptoms). pNfL concentration was higher in patients with RRMS than in controls and reduced over 15 months of treatment.TCA cycle intermediates and metabolites are increased in patients with RRMS treated with DMF. The results suggest reversal of flux through the succinate dehydrogenase complex. The contribution of succinyl-carnitine ester agonism at hydroxycarboxylic acid receptor 2 to both therapeutic effects and adverse events requires investigation.
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| 9. |
- Gisslén, Magnus, 1962, et al.
(författare)
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CSF concentrations of soluble TREM2 as a marker of microglial activation in HIV-1 infection
- 2019
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Ingår i: Neurology-Neuroimmunology & Neuroinflammation. - : Ovid Technologies (Wolters Kluwer Health). - 2332-7812. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- Objective To explore changes in CSF sTREM2 concentrations in the evolving course of HIV-1 infection. In this retrospective cross-sectional study, we measured concentrations of the macrophage/ microglial activation marker sTREM2 in CSF samples from 121 HIV-1-infected adults and 11 HIV-negative controls and examined their correlations with other CSF and blood biomarkers of infection, inflammation, and neuronal injury. CSF sTREM2 increased with systemic and CNS HIV-1 disease severity, with the highest levels found in patients with HIV-associated dementia (HAD). In untreated HIV-1-infected patients without an HAD diagnosis, levels of CSF sTREM2 increased with decreasing CD4(+) T-cell counts. CSF concentrations of both sTREM2 and the neuronal injury marker neurofilament light protein (NFL) were significantly associated with age. CSF sTREM2 levels were also independently correlated with CSF NFL. Notably, this association was also observed in HIV-negative controls with normal CSF NFL. HIV-infected patients on suppressive antiretroviral treatment had CSF sTREM2 levels comparable to healthy controls. Elevations in CSF sTREM2 levels, an indicator of macrophage/microglial activation, are a common feature of untreated HIV-1 infection that increases with CD4(+) T-cell loss and reaches highest levels in HAD. The strong and independent association between CSF sTREM2 and CSF NFL suggests a linkage between microglial activation and neuronal injury in HIV-1 infection. CSF sTREM2 has the potential of being a useful biomarker of innate CNS immune activation in different stages of untreated and treated HIV-1 infection.
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| 14. |
- Li, J., et al.
(författare)
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Molecular Level Characterization of Circulating Aquaporin-4 Antibodies in Neuromyelitis Optica Spectrum Disorder
- 2021
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Ingår i: Neurology(R) neuroimmunology & neuroinflammation. - 2332-7812. ; 8:5
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To determine whether distinct aquaporin-4 (AQP4)-IgG lineages play a role in neuromyelitis optica spectrum disorder (NMOSD) pathogenesis, we profiled the AQP4-IgG polyclonal serum repertoire and identified, quantified, and functionally characterized distinct AQP4-IgG lineages circulating in 2 patients with NMOSD. METHODS: We combined high-throughput sequencing and quantitative immunoproteomics to simultaneously determine the constituents of both the B-cell receptor (BCR) and the serologic (IgG) anti-AQP4 antibody repertoires in the peripheral blood of patients with NMOSD. The monoclonal antibodies identified by this platform were recombinantly expressed and functionally characterized in vitro. RESULTS: Multiple antibody lineages comprise serum AQP4-IgG repertoires. Their distribution, however, can be strikingly different in polarization (polyclonal vs pauciclonal). Among the 4 serum AQP4-IgG monoclonal antibodies we identified in 2 patients, 3 induced complement-dependent cytotoxicity in a model mammalian cell line (p < 0.01). CONCLUSIONS: The composition and polarization of AQP4-IgG antibody repertoires may play an important role in NMOSD pathogenesis and clinical presentation. Here, we present a means of coupling both cellular (BCR) and serologic (IgG) antibody repertoire analysis, which has not previously been performed in NMOSD. Our analysis could be applied in the future to clinical management of patients with NMOSD to monitor disease activity over time as well as applied to other autoimmune diseases to facilitate a deeper understanding of disease pathogenesis relative to autoantibody clones. Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
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| 15. |
- Lundblad, Katarina, et al.
(författare)
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CSF Concentrations of CXCL13 and sCD27 Before and After Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis.
- 2023
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Ingår i: Neurology. - 2332-7812. ; 10:5
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND OBJECTIVES: In the past decade, autologous hematopoietic stem cell transplantation (AHSCT) has emerged as a treatment for relapsing-remitting multiple sclerosis (RRMS). How this procedure affects biomarkers of B- and T-cell activation is currently unknown. The objective of this study was to investigate CXCL13 and sCD27 concentrations in CSF before and after AHSCT.METHODS: This prospective cohort study was conducted at a specialized MS clinic in a university hospital. Patients with a diagnosis of RRMS, treated with AHSCT between January 1, 2011, and December 31, 2018, were evaluated for participation. Patients were included if CSF samples from baseline plus at least 1 follow-up were available on June 30, 2020. A control group of volunteers without neurologic disease was included as a reference. CSF concentrations of CXCL13 and sCD27 were measured with ELISA.RESULTS: The study comprised 29 women and 16 men with RRMS, aged 19-46 years at baseline, and 15 women and 17 men, aged 18-48 years, in the control group. At baseline, patients had higher CXCL13 and sCD27 concentrations than controls, with a median (IQR) of 4 (4-19) vs 4 (4-4) pg/mL (p < 0.0001) for CXCL13 and 352 (118-530) vs 63 (63-63) pg/mL (p < 0.0001) for sCD27. After AHSCT, the CSF concentrations of CXCL13 were considerably lower at the first follow-up at 1 year than at baseline, with a median (IQR) of 4 (4-4) vs 4 (4-19) pg/mL (p < 0.0001), and then stable throughout follow-up. The CSF concentrations of sCD27 were also lower at 1 year than at baseline, with a median (IQR) of 143 (63-269) vs 354 (114-536) pg/mL (p < 0.0001). Thereafter, sCD27 concentrations continued to decrease and were lower at 2 years than at 1 year, with a median (IQR) of 120 (63-231) vs 183 (63-290) pg/mL (p = 0.017).DISCUSSION: After AHSCT for RRMS, CSF concentrations of CXCL13 were rapidly normalized, whereas sCD27 decreased gradually over the course of 2 years. Thereafter, the concentrations remained stable throughout follow-up, indicating that AHSCT induced long-lasting biological changes.
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| 16. |
- Molin, Carl Johan, et al.
(författare)
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Thymectomy lowers the myasthenia gravis biomarker miR-150-5p
- 2018
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Ingår i: Neurology. - 2332-7812. ; 5:3
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The aim of the study was to analyze the effect of thymectomy on the proposed disease-specific microRNA (miRNA) biomarkers miR-150-5p and miR-21-5p in patients from the prospective randomized trial of thymectomy in myasthenia gravis (MGTX trial) and to evaluate the longitudinal changes in clinical patterns compared with these miRNA levels.Methods: Serum samples were obtained from 80 patients with MG who were included in the MGTX trial. Thirty-eight patients were randomized to thymectomy plus prednisone treatment, and 42 patients were randomized to prednisone treatment. Serum samples were analyzed for the expression of miR-150-5p and miR-21-5p, with quantitative reverse transcriptase PCR at baseline and at 12, 24, and 36 months after randomization. The inclusion criteria for participation in the MGTX trial were age 18-65 years, generalized myasthenia gravis (Myasthenia Gravis Foundation of America Class II-IV), disease duration of less than 5 years, and seropositivity for acetylcholine receptor antibodies (AChR+).Results: Patients treated with thymectomy had lower levels of miR-150-5p at 24 months, both compared with baseline values (p = 0.0011) and the prednisone group (p = 0.04). No change in miRNA levels was found in the prednisone group. Levels of miR-21-5p displayed a negative correlation with the prednisone dose within the prednisone-only group (p ≤ 0.001).Conclusions: Thymectomy lowers the levels of the proposed biomarker miR-150-5p, which strengthens its position as a potential disease-specific biomarker for AChR+ MG.
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| 17. |
- Montgomery, Scott M., 1961-, et al.
(författare)
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Multiple sclerosis and risk of young-adult-onset Hodgkin lymphoma
- 2016
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Ingår i: Neurology. - Philadelphia, USA : Lippincott Williams & Wilkins. - 2332-7812. ; 3:3
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To determine whether there is an association between multiple sclerosis (MS) and young-adult-onset Hodgkin lymphoma (YAHL) as this will signal etiologic similarities relevant both to inherited characteristics and environmental exposures in childhood.Methods: Swedish general population registers identified a cohort of 29,617 with an MS diagnosis between 1968 and 2012, matched with a cohort of 296,164 without MS. Cox regression was used to assess the association of MS with subsequent YAHL (defined as onset between ages 15 and 39 years; n = 20), with adjustment, for age/period, sex, county of residence, and level of education.Results: The adjusted hazard ratio (and 95% confidence interval) for the association of MS with YAHL is 3.30 (1.01-10.73), resulting from 4 and 16 events in the MS and non-MS cohorts, respectively. All 4 of the YAHL diagnoses in MS occurred in women, and the association of MS with YAHL has a hazard ratio of 4.04 (1.17-13.94) among women. There was no notable association of MS with older-onset Hodgkin lymphoma.Conclusion: There may be common risks for YAHL and MS, consistent with an etiologic role in MS for early-life exposures, such as to infectious agents.
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| 18. |
- Muller, J., et al.
(författare)
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Choroid Plexus Volume in Multiple Sclerosis vs Neuromyelitis Optica Spectrum Disorder A Retrospective, Cross-sectional Analysis
- 2022
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Ingår i: Neurology-Neuroimmunology & Neuroinflammation. - : Ovid Technologies (Wolters Kluwer Health). - 2332-7812. ; 9:3
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objectives The choroid plexus has been shown to play a crucial role in CNS inflammation. Previous studies found larger choroid plexus in multiple sclerosis (MS) compared with healthy controls. However, it is not clear whether the choroid plexus is similarly involved in MS and in neuromyelitis optica spectrum disorder (NMOSD). Thus, the aim of this study was to compare the choroid plexus volume in MS and NMOSD. Methods In this retrospective, cross-sectional study, patients were included by convenience sampling from 4 international MS centers. The choroid plexus of the lateral ventricles was segmented fully automatically on T1-weighted MRI sequences using a deep learning algorithm (Multi-Dimensional Gated Recurrent Units). Uni- and multivariable linear models were applied to investigate associations between the choroid plexus volume, clinically meaningful disease characteristics, and MRI parameters. Results We studied 180 patients with MS and 98 patients with NMOSD. In total, 94 healthy individuals and 47 patients with migraine served as controls. The choroid plexus volume was larger in MS (median 1,690 mu L, interquartile range [IQR] 648 mu L) than in NMOSD (median 1,403 mu L, IQR 510 mu L), healthy individuals (median 1,533 mu L, IQR 570 mu L), and patients with migraine (median 1,404 mu L, IQR 524 mu L; all p < 0.001), whereas there was no difference between NMOSD, migraine, and healthy controls. This was also true when adjusted for age, sex, and the intracranial volume. In contrast to NMOSD, the choroid plexus volume in MS was associated with the number of T2-weighted lesions in a linear model adjusted for age, sex, total intracranial volume, disease duration, relapses in the year before MRI, disease course, Expanded Disability Status Scale score, disease-modifying treatment, and treatment duration (beta 4.4; 95% CI 0.78-8.1; p = 0.018). Discussion This study supports an involvement of the choroid plexus in MS in contrast to NMOSD and provides clues to better understand the respective pathogenesis.
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| 19. |
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| 20. |
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| 21. |
- Olesen, Mads Nikolaj, et al.
(författare)
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Inflammatory profiles relate to survival in subtypes of amyotrophic lateral sclerosis
- 2020
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Ingår i: Neurology. - : Wolters Kluwer. - 2332-7812. ; 7:3
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate inflammatory cytokines in patients with motor neuron disease (MND) evaluating the putative contribution of amyotrophic lateral sclerosis (ALS)-causing gene variants.Methods: This study is a retrospective case series with prospective follow-up (1994–2016) of 248 patients with MND, of whom 164 had ALS who were screened for mutations in the genes for SOD1 and C9orf72. Paired CSF and plasma were collected at the diagnostic evaluation before treatment. A panel of cytokines were measured blindly via digital ELISA on the Simoa platform.Results: Time from disease onset to death was longer for patients with ALS-causing SOD1 mutations (mSOD1, n = 24) than those with C9orf72 hexanucleotide repeat expansion (C9orf72HRE) ALS (n = 19; q = 0.001) and other ALS (OALS) (n = 119; q = 0.0008). Patients with OALS had higher CSF tumor necrosis factor alpha (TNF-α) compared with those with C9orf72HRE ALS (q = 0.014). Patients with C9orf72HRE ALS had higher CSF interferon alpha compared with those with OALS and mSOD1 ALS (q = 0.042 and q = 0.042). In patients with ALS, the survival was negatively correlated with plasma interleukin (IL) 10 (hazard ratio [HR] 1.17, 95% CI 1.05–1.30). Plasma TNF-α, IL-10, and TNF-related apoptosis-inducing ligand (TRAIL) (HR 1.01 [1.00–1.02], 1.15 [1.02–1.30], and 1.01 [1.00–1.01], respectively) of patients with OALS, plasma IL-1β (HR 5.90 [1.27–27.5]) of patients with C9orf72HRE ALS, and CSF TRAIL (10.5 [1.12–98.6]) of patients with mSOD1 ALS all correlated negatively with survival.Conclusions: Differences in survival times in ALS subtypes were correlated with cytokine levels, suggesting specific immune responses related to ALS genetic variants.
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| 22. |
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| 23. |
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| 26. |
- Rosadas, C., et al.
(författare)
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Neurofilament Light in CSF and Plasma Is a Marker of Neuronal Damage in HTLV-1-Associated Myelopathy and Correlates With Neuroinflammation
- 2021
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Ingår i: Neurology-Neuroimmunology & Neuroinflammation. - : Ovid Technologies (Wolters Kluwer Health). - 2332-7812. ; 8:6
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objectives To evaluate the usefulness of CSF and plasma neurofilament light (Nf-L) as a biomarker for human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy (HAM). Methods Nf-L, CXCL10, and neopterin were measured by ELISA in 83 CSF samples obtained from 49 individuals living with HTLV-1/2. Plasma Nf-L was also measured by single molecule array. Results were correlated with duration of disease, age, mobility, CSF cell counts, CSF protein, and HTLV-1 proviral load. Results Nf-L was detected in all CSF samples (median [range] = 575 [791.8-2,349] pg/mL) and positively correlated with markers of inflammation (CXCL10 (r = 0.733), neopterin (r = 0.499), cell count (r = 0.403), and protein levels (r = 0.693) in CSF; p < 0.0015). There was an inverse correlation between Nf-L and duration of disease (r = -0.584, p < 0.0001). Wheelchair-dependent patients had high concentrations of markers of inflammation and neuronal damage. Concentrations of CXCL10, neopterin, and Nf-L remained elevated in follow-up samples (mean follow-up 5.2 years). Nf-L in plasma correlated with concentration of Nf-L, neopterin, CXCL10, and protein in CSF. Conclusions Nf-L in plasma and CSF has potential to be used as a biomarker of disease activity in HAM. Neuronal damage seems to be more intense early in disease but persists long term. Wheelchair-dependent patients have ongoing neuroinflammation.
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| 27. |
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| 28. |
- Smith, JB, et al.
(författare)
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Rituximab, MS, and pregnancy
- 2020
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Ingår i: Neurology(R) neuroimmunology & neuroinflammation. - 2332-7812. ; 7:4
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Tidskriftsartikel (refereegranskat)
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| 29. |
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| 30. |
- Svenningsson, Anders, et al.
(författare)
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Rapid depletion of B lymphocytes by ultra-low-dose rituximab delivered intrathecally
- 2015
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Ingår i: Neurology. - : Lippincott Williams & Wilkins. - 2332-7812. ; 2:2
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Tidskriftsartikel (refereegranskat)abstract
- Objective: We are conducting an open-label phase 1b study on the efficacy of intrathecal (IT) administration of rituximab, provided via an Ommaya reservoir, for the treatment of progressive multiple sclerosis (PMS). The objective of this initial study was to monitor B lymphocytes in peripheral blood (PB) and CSF from the first 10 patients 1 year posttreatment.Methods: Dose titration was performed with daily escalation from 1 mg to 25 mg IT rituximab (n=3). Lymphocyte subpopulations were monitored daily during dose escalation in PB by flow cytometry and subsequently every 3 months for 1 year, after a total dose of 3 x 25 mg. PB B-lymphocyte subpopulations for the remaining patients (n = 7) were monitored at regular intervals. CSF lymphocyte subpopulations for all patients were monitored by flow cytometry every 2-3 months.Results: The PB B-lymphocyte count dropped rapidly after the first 2 injections (total dose of 3.5 mg IT rituximab) to undetectable levels. Three 25-mg doses given once per week depleted peripheral B lymphocytes entirely for the following 3-6 month period.Conclusions: Monoclonal antibodies seem to rapidly redistribute to the peripheral compartment following IT injection. Ultra-low doses of rituximab given IT are sufficient to cause complete depletion of peripheral B lymphocytes, indicating that low-dose IT treatment has the potential to be effective in both the CNS and systemic compartments.Classification of evidence: This study provides Class IV evidence that for patients with PMS, rituximab provided via an Ommaya reservoir depletes peripheral blood B lymphocytes.
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| 32. |
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| 33. |
- Williams, Thomas E, et al.
(författare)
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Assessing Neurofilaments as Biomarkers of Neuroprotection in Progressive Multiple Sclerosis: From the MS-STAT Randomized Controlled Trial.
- 2022
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Ingår i: Neurology(R) neuroimmunology & neuroinflammation. - 2332-7812. ; 9:2
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Tidskriftsartikel (refereegranskat)abstract
- Improved biomarkers of neuroprotective treatment are needed in progressive multiple sclerosis (PMS) to facilitate more efficient phase 2 trial design. The MS-STAT randomized controlled trial supported the neuroprotective potential of high-dose simvastatin in secondary progressive MS (SPMS). Here, we analyze serum from the MS-STAT trial to assess the extent to which neurofilament light (NfL) and neurofilament heavy (NfH), both promising biomarkers of neuroaxonal injury, may act as biomarkers of simvastatin treatment in SPMS.The MS-STAT trial randomized patients to 80 mg simvastatin or placebo. Serum was analyzed for NfL and NfH using Simoa technology. We used linear mixed models to investigate the treatment effects of simvastatin compared with placebo on NfL and NfH. Additional models examined the relationships between neurofilaments and MRI and clinical measures of disease severity.A total of 140 patients with SPMS were included. There was no evidence for a simvastatin treatment effect on NfL or NfH: compared with placebo, NfL was 1.2% lower (95% CI 10.6% lower to 9.2% higher; p = 0.820) and NfH was 0.4% lower (95% CI 18.4% lower to 21.6% higher; p = 0.969) in the simvastatin treatment group. Secondary analyses suggested that higher NfL was associated with greater subsequent whole brain atrophy, higher T2 lesion volume, and more new/enlarging T2 lesions in the previous 12 months, as well as greater physical disability. There were no significant associations between NfH and MRI or clinical variables.We found no evidence of a simvastatin treatment effect on serum neurofilaments. While confirmation of the neuroprotective benefits of simvastatin is awaited from the ongoing phase 3 study (NCT03387670), our results suggest that treatments capable of slowing the rate of whole brain atrophy in SPMS, such as simvastatin, may act via mechanisms largely independent of neuroaxonal injury, as quantified by NfL. This has important implications for the design of future phase 2 clinical trials in PMS.MS-STAT: NCT00647348.This study provides class I evidence that simvastatin treatment does not have a large impact on either serum NfL or NfH, as quantified in this study, in SPMS.
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| 34. |
- Willis, M., et al.
(författare)
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An observational study of alemtuzumab following fingolimod for multiple sclerosis
- 2017
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Ingår i: Neurology-Neuroimmunology & Neuroinflammation. - : Ovid Technologies (Wolters Kluwer Health). - 2332-7812. ; 4:2
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To describe a series of patients with relapsing multiple sclerosis (MS) who experienced significant and unexpected disease activity within the first 12 months after switching from fingolimod to alemtuzumab. Methods: Patients with relapsing MS treated sequentially with fingolimod then alemtuzumab who experienced significant subsequent disease activity were identified by personal communication with 6 different European neuroscience centers. Results: Nine patients were identified. Median disease duration to alemtuzumab treatment was 94 (39-215) months and follow-up from time of first alemtuzumab cycle 20 (14-21) months. Following first alemtuzumab infusion cycle, 8 patients were identified by at least 1 clinical relapse and radiologic disease activity and 1 by significant radiologic disease activity alone. Conclusions: We acknowledge the potential for ascertainment bias; however, these cases may illustrate an important cause of reduced efficacy of alemtuzumab in a vulnerable group of patients with MS most in need of disease control. We suggest that significant and unexpected subsequent disease activity after alemtuzumab induction results from prolonged sequestration of autoreactive lymphocytes following fingolimod withdrawal, allowing these cells to be concealed from the usual biological effect of alemtuzumab. Subsequent lymphocyte egress then provokes disease reactivation. Further animal studies and clinical trials are required to confirm these phenomena and in the meantime careful consideration should be given to mode of action of individual therapies and sequential treatment effects in MS when designing personalized treatment regimens.
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