Dimethyl fumarate for treatment of multiple sclerosis : clinical effects and mechanisms

Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system (CNS). Dimethyl fumarate (DMF) is one of the more recent additions to a rapidly expanding treatment repertoire for MS. While DMF has proven beneficial for relapsing-remitting MS (RRMS) patients, its clinical profile in relation to current alternatives as well as its immunological effects are less known. The overarching aim of the thesis was to assess the clinical effects of DMF for MS patients and investigate the underlying immunological mechanisms. Since both DMF and physical exercise is known to elicit an antioxidative response through the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), we further explored their immunological commonalities. In Paper I, we showed that treatment discontinuations with DMF were lower than with interferons, the main existing initial drug choice, among newly diagnosed MS patients in Stockholm and Västerbotten Counties. Risks of having persistent disease activity, as shown by relapses and/or magnetic resonance imaging (MRI), were similar to fingolimod and natalizumab; two more recent disease modulatory therapies (DMTs). The main finding of the article, however, was that the comparator treatment, rituximab (Mabthera®; RTX), had a superior clinical effect compared to all other DMTs in terms of both clinical effect and treatment discontinuation. In Paper II, we used Swedish nationwide data to compare DMF to interferons and glatiramer acetate, two common initial DMT choices, and fingolimod, which mainly is used as an escalation treatment. DMF proved more effective and had better drug survival in the first line comparison with interferons and glatiramer acetate but was less well tolerated than fingolimod when used second line. In Paper III, we explored the immunological mechanisms of DMF treatment in humans underlying the clinical effects we observed in Paper I and II. We observed that DMF increased production of reactive oxygen species (ROS) in monocytes and that methylation changes occurred earlier in monocytes than in T cells. In addition, monocyte counts and levels of oxidized fat in blood were higher among treatment responders compared to non-responders, supporting the notion that DMF act by increasing oxidative burst in myeloid cells. In Paper IV, we investigated the effects of aerobic exercise of moderate and high intensity on immune protein markers and kynurenine pathway (KP) metabolites in cerebrospinal fluid (CSF) and plasma of healthy participants. Participants in the high intensity group displayed changes in concentration of several immune markers and KP metabolites in both CSF and plasma, whereas participants in the moderate intensity group displayed few changes, suggesting a dose-response relationship. A separate comparison with DMF treated MS patients revealed few overlapping immune markers despite indications of overlapping mechanisms. In conclusion, by affecting Nrf2 and oxidative burst, DMF has a unique mode of action among existing DMT options for RRMS, however, with limited overlap to effects mediated by physical exercise. Its clinical effectiveness is superior to traditional DMTs for newly diagnosed patients, but inferior to RTX. As an escalation DMT, it is less well tolerated than existing alternatives

Memory-reliant Post-error Slowing Is Associated with Successful Learning and Fronto-occipital Activity

Negative feedback after an action in a cognitive task can lead to devaluing that action on future trials as well as to more cautious responding when encountering that same choice again. These phenomena have been explored in the past by reinforcement learning theories and cognitive control accounts, respectively. Yet, how cognitive control interacts with value updating to give rise to adequate adaptations under uncertainty is less clear. In this fMRI study, we investigated cognitive control-based behavioral adjustments during a probabilistic reinforcement learning task and studied their influence on performance in a later test phase in which the learned value of items is tested. We provide support for the idea that functionally relevant and memory-reliant behavioral adjustments in the form of post-error slowing during reinforcement learning are associated with test performance. Adjusting response speed after negative feedback was correlated with BOLD activity in right inferior frontal gyrus and bilateral middle occipital cortex during the event of receiving the feedback. Bilateral middle occipital cortex activity overlapped partly with activity reflecting feedback deviance from expectations as measured by unsigned prediction error. These results suggest that cognitive control and feature processing cortical regions interact to implement feedback-congruent adaptations beneficial to learning

Electron effective mass in Sn-doped monoclinic single crystal β\beta-gallium oxide determined by mid-infrared optical Hall effect

The isotropic average conduction band minimum electron effective mass in Sn-doped monoclinic single crystal $\beta$-Ga$_2$O$_3$ is experimentally determined by mid-infrared optical Hall effect to be $(0.284\pm0.013)m_{0}$ combining investigations on ($010$) and ($\bar{2}01$) surface cuts. This result falls within the broad range of values predicted by theoretical calculations for undoped $\beta$-Ga$_2$O$_3$. The result is also comparable to recent density functional calculations using the Gaussian-attenuation-Perdue-Burke-Ernzerhof hybrid density functional, which predict an average effective mass of $0.267m_{0}$ (arXiv:1704.06711 [cond-mat.mtrl-sci]). Within our uncertainty limits we detect no anisotropy for the electron effective mass, which is consistent with most previous theoretical calculations. We discuss upper limits for possible anisotropy of the electron effective mass parameter from our experimental uncertainty limits, and we compare our findings with recent theoretical results

Atomic-resolution spectroscopic imaging of ensembles of nanocatalyst particles across the life of a fuel cell

The thousandfold increase in data-collection speed enabled by aberration-corrected optics allows us to overcome an electron microscopy paradox - how to obtain atomic-resolution chemical structure in individual nanoparticles, yet record a statistically significant sample from an inhomogeneous population. This allowed us to map hundreds of Pt-Co nanoparticles to show atomic-scale elemental distributions across different stages of the catalyst aging in a proton-exchange-membrane fuel cell, and relate Pt-shell thickness to treatment, particle size, surface orientation, and ordering.Comment: 28 pages, 5 figures, accepted, nano letter

Differential effects on blood and cerebrospinal fluid immune protein markers and kynurenine pathway metabolites from aerobic physical exercise in healthy subjects

Mounting evidence shows that physical exercise modulates systemic inflammation. However, its effect on cerebrospinal fluid (CSF) immune-marker profiles in man are largely unknown. We here report a study on healthy subjects (n=27, males=12, mean age 28.7, range 22-52) allocated to either an acute exercise setting over four consecutive days, or a training intervention over 4 weeks. Paired plasma and CSF samples collected at baseline, after 7 days of exercise abstention, and the day after completion of the exercise interventions, were analyzed for protein inflammation markers using a multiplex proximity extension assay and neurotransmitters and kynurenine pathway (KP) metabolites using liquid chromatography, respectively. Routine cell counts, and albumin, immunoglobulin G and neurofilament light chain concentrations in CSF remained unchanged in both paradigms, while several inflammatory proteins became upregulated after acute exercise. However, only changes in three CSF (vascular endothelial growth factor-A, interleukin-7 and matrix metalloproteinase-10) and 12 plasma proteins reached significance levels after adjustment for multiple comparisons and exclusion of less stable proteins. Similarly, KP metabolites only changed among participants after acute exercise, while neurotransmitter levels, except for increased CSF serine, remained stable. Both in plasma and CSF changes in KP metabolites and inflammatory proteins correlated, suggesting that these processes are functionally linked. These findings suggest that acute aerobic physical exercise affects immune markers and KP metabolites systemically and in the CSF

A novel, robust method for quantification of multiple kynurenine pathway metabolites in the cerebrospinal fluid

Aim: Kynurenine metabolites are potential modulators of psychiatric disease. We aimed to develop a highly sensitive biochemical analysis of cerebrospinal fluid (CSF) tryptophan (TRP) metabolites, to investigate the stability of metabolites and to confirm our previous findings of aberrant CSF quinolinic acid (QUIN) and picolinic acid (PIC) in suicide attempters using this method. Methodology & results: Ten CSF TRP metabolites were analyzed with ultraperformance LC-MS/MS. The method showed small intra- and interassay variation. Metabolites were stable following freeze-thaw cycles. A decreased CSF PIC/QUIN ratio was found in suicide attempters. Conclusion: The feasibility of reliably determining CSF TRP metabolites were demonstrated, including separation of the two isomers PIC and nicotinic acid (NA) and the finding of a reduced PIC/QUIN ratio replicated in suicide attempters

Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis associates with ROS pathway in monocytes

Dimethyl fumarate (DMF) is a first-line-treatment for relapsing-remitting multiple sclerosis (RRMS). The redox master regulator Nrf2, essential for redox balance, is a target of DMF, but its precise therapeutic mechanisms of action remain elusive. Here we show impact of DMF on circulating monocytes and T cells in a prospective longitudinal RRMS patient cohort. DMF increases the level of oxidized isoprostanes in peripheral blood. Other observed changes, including methylome and transcriptome profiles, occur in monocytes prior to T cells. Importantly, monocyte counts and monocytic ROS increase following DMF and distinguish patients with beneficial treatment-response from non-responders. A single nucleotide polymorphism in the ROS-generating NOX3 gene is associated with beneficial DMF treatment-response. Our data implicate monocyte-derived oxidative processes in autoimmune diseases and their treatment, and identify NOX3 genetic variant, monocyte counts and redox state as parameters potentially useful to inform clinical decisions on DMF therapy of RRMS.Funding Agencies|Swedish Medical Research Council [2017-03054]; Stockholm County [20170216]; Biogen; Hjarnfonden; NEURO Forbundet; Karolinska Thematic Center in Inflammation</p