Multiple sclerosis decreases explicit counterfactual processing and risk taking in decision making.

INTRODUCTION: Deficits in decision making (DM) are commonly associated with prefrontal cortical damage, but may occur with multiple sclerosis (MS). There are no data concerning the impact of MS on tasks evaluating DM under explicit risk, where different emotional and cognitive components can be distinguished. METHODS: We assessed 72 relapsing-remitting MS (RRMS) patients with mild to moderate disease and 38 healthy controls in two DM tasks involving risk with explicit rules: (1) The Wheel of Fortune (WOF), which probes the anticipated affects of decisions outcomes on future choices; and (2) The Cambridge Gamble Task (CGT) which measures risk taking. Participants also underwent a neuropsychological and emotional assessment, and skin conductance responses (SCRs) were recorded. RESULTS: In the WOF, RRMS patients showed deficits in integrating positive counterfactual information (p<0.005) and greater risk aversion (p<0.001). They reported less negative affect than controls (disappointment: p = 0.007; regret: p = 0.01), although their implicit emotional reactions as measured by post-choice SCRs did not differ. In the CGT, RRMS patients differed from controls in quality of DM (p = 0.01) and deliberation time (p = 0.0002), the latter difference being correlated with attention scores. Such changes did not result in overall decreases in performance (total gains). CONCLUSIONS: The quality of DM under risk was modified by MS in both tasks. The reduction in the expression of disappointment coexisted with an increased risk aversion in the WOF and alexithymia features. These concomitant emotional alterations may have implications for better understanding the components of explicit DM and for the clinical support of MS patients.

A phase IIa randomised clinical study of GNbAC1, a humanised monoclonal antibody against the envelope protein of multiple sclerosis-associated endogenous retrovirus in multiple sclerosis patients.

BACKGROUND: GNbAC1 is an immunoglobulin (IgG4) humanised monoclonal antibody against multiple sclerosis-associated retrovirus (MSRV)-Env, a protein of endogenous retroviral origin, expressed in multiple sclerosis (MS) lesions, which is pro-inflammatory and inhibits oligodendrocyte precursor cell differentiation. OBJECTIVE: This is a randomised, double-blind placebo-controlled dose-escalation study followed by a six-month open-label phase to test GNbAC1 in MS patients. The primary objective was to assess GNbAC1 safety in MS patients, and the other objectives were pharmacokinetic and pharmacodynamic assessments. METHODS: Ten MS patients were randomised into two cohorts to receive a single intravenous infusion of GNbAC1/placebo at doses of 2 or 6 mg/kg. Then all patients received five infusions of GNbAC1 at 2 or 6 mg/kg at four-week intervals in an open-label setting. Safety, brain magnetic resonance imaging (MRI), pharmacokinetics, immunogenicity, cytokines and MSRV RNA expression were studied. RESULTS: All patients completed the study. GNbAC1 was well tolerated in all patients. GNbAC1 pharmacokinetics is dose-linear with mean elimination half-life of 27-37 d. Anti-GNbAC1 antibodies were not detected. Cytokine analysis did not indicate an adverse effect. MSRV-transcripts showed a decline after the start of treatment. Nine patients had stable brain lesions at MRI. CONCLUSION: The safety, pharmacokinetic profile, and pharmacodynamic responses to GNbAC1 are favourable in MS patients over a six-month treatment period.

Metabolic gene expression changes in astrocytes in Multiple Sclerosis cerebral cortex are indicative of immune-mediated signaling.

Emerging as an important correlate of neurological dysfunction in Multiple Sclerosis (MS), extended focal and diffuse gray matter abnormalities have been found and linked to clinical manifestations such as seizures, fatigue and cognitive dysfunction. To investigate possible underlying mechanisms we analyzed the molecular alterations in histopathological normal appearing cortical gray matter (NAGM) in MS. By performing a differential gene expression analysis of NAGM of control and MS cases we identified reduced transcription of astrocyte specific genes involved in the astrocyte-neuron lactate shuttle (ANLS) and the glutamate-glutamine cycle (GGC). Additional quantitative immunohistochemical analysis demonstrating a CX43 loss in MS NAGM confirmed a crucial involvement of astrocytes and emphasizes their importance in MS pathogenesis. Concurrently, a Toll-like/IL-1β signaling expression signature was detected in MS NAGM, indicating that immune-related signaling might be responsible for the downregulation of ANLS and GGC gene expression in MS NAGM. Indeed, challenging astrocytes with immune stimuli such as IL-1β and LPS reduced their ANLS and GGC gene expression in vitro. The detected upregulation of IL1B in MS NAGM suggests inflammasome priming. For this reason, astrocyte cultures were treated with ATP and ATP/LPS as for inflammasome activation. This treatment led to a reduction of ANLS and GGC gene expression in a comparable manner. To investigate potential sources for ANLS and GGC downregulation in MS NAGM, we first performed an adjuvant-driven stimulation of the peripheral immune system in C57Bl/6 mice in vivo. This led to similar gene expression changes in spinal cord demonstrating that peripheral immune signals might be one source for astrocytic gene expression changes in the brain. IL1B upregulation in MS NAGM itself points to a possible endogenous signaling process leading to ANLS and GGC downregulation. This is supported by our findings that, among others, MS NAGM astrocytes express inflammasome components and that astrocytes are capable to release Il-1β in-vitro. Altogether, our data suggests that immune signaling of immune- and/or central nervous system origin drives alterations in astrocytic ANLS and GGC gene regulation in the MS NAGM. Such a mechanism might underlie cortical brain dysfunctions frequently encountered in MS patients.

Multicontrast MRI Quantification of Focal Inflammation and Degeneration in Multiple Sclerosis.

INTRODUCTION: Local microstructural pathology in multiple sclerosis patients might influence their clinical performance. This study applied multicontrast MRI to quantify inflammation and neurodegeneration in MS lesions. We explored the impact of MRI-based lesion pathology in cognition and disability. METHODS: 36 relapsing-remitting MS subjects and 18 healthy controls underwent neurological, cognitive, behavioural examinations and 3 T MRI including (i) fluid attenuated inversion recovery, double inversion recovery, and magnetization-prepared gradient echo for lesion count; (ii) T1, T2, and T2(*) relaxometry and magnetisation transfer imaging for lesion tissue characterization. Lesions were classified according to the extent of inflammation/neurodegeneration. A generalized linear model assessed the contribution of lesion groups to clinical performances. RESULTS: Four lesion groups were identified and characterized by (1) absence of significant alterations, (2) prevalent inflammation, (3) concomitant inflammation and microdegeneration, and (4) prevalent tissue loss. Groups 1, 3, 4 correlated with general disability (Adj-R (2) = 0.6; P = 0.0005), executive function (Adj-R (2) = 0.5; P = 0.004), verbal memory (Adj-R (2) = 0.4; P = 0.02), and attention (Adj-R (2) = 0.5; P = 0.002). CONCLUSION: Multicontrast MRI provides a new approach to infer in vivo histopathology of plaques. Our results support evidence that neurodegeneration is the major determinant of patients' disability and cognitive dysfunction.

A phase IIa randomized clinical study testing GNbAC1, a humanized monoclonal antibody against the envelope protein of multiple sclerosis associated endogenous retrovirus in multiple sclerosis patients - A twelve month follow-up.

GNbAC1 is a humanized monoclonal antibody targeting MSRV-Env, an endogenous retroviral protein, which is expressed in multiple sclerosis (MS) lesions, is pro-inflammatory and inhibits oligodendrocyte precursor cell differentiation. This paper describes the open-label extension up to 12months of a trial testing GNbAC1 in 10 MS patients at 2 and 6mg/kg. The primary objective was to assess GNbAC1 safety, and other objectives were pharmacokinetic and pharmacodynamic assessments. During the extended study, no safety issues occurred in the 8 remaining patients. No anti-GNbAC1 antibodies were detected. GNbAC1 appears well tolerated.

Multicontrast connectometry: A new tool to assess cerebellum alterations in early relapsing-remitting multiple sclerosis.

BACKGROUND: Cerebellar pathology occurs in late multiple sclerosis (MS) but little is known about cerebellar changes during early disease stages. In this study, we propose a new multicontrast "connectometry" approach to assess the structural and functional integrity of cerebellar networks and connectivity in early MS. METHODS: We used diffusion spectrum and resting-state functional MRI (rs-fMRI) to establish the structural and functional cerebellar connectomes in 28 early relapsing-remitting MS patients and 16 healthy controls (HC). We performed multicontrast "connectometry" by quantifying multiple MRI parameters along the structural tracts (generalized fractional anisotropy-GFA, T1/T2 relaxation times and magnetization transfer ratio) and functional connectivity measures. Subsequently, we assessed multivariate differences in local connections and network properties between MS and HC subjects; finally, we correlated detected alterations with lesion load, disease duration, and clinical scores. RESULTS: In MS patients, a subset of structural connections showed quantitative MRI changes suggesting loss of axonal microstructure and integrity (increased T1 and decreased GFA, P < 0.05). These alterations highly correlated with motor, memory and attention in patients, but were independent of cerebellar lesion load and disease duration. Neither network organization nor rs-fMRI abnormalities were observed at this early stage. CONCLUSION: Multicontrast cerebellar connectometry revealed subtle cerebellar alterations in MS patients, which were independent of conventional disease markers and highly correlated with patient function. Future work should assess the prognostic value of the observed damage. Hum Brain Mapp 36:1609-1619, 2015. © 2014 Wiley Periodicals, Inc.

Interleukin-22 is increased in multiple sclerosis patients and targets astrocytes.

BACKGROUND: Increasing evidences link T helper 17 (Th17) cells with multiple sclerosis (MS). In this context, interleukin-22 (IL-22), a Th17-linked cytokine, has been implicated in blood brain barrier breakdown and lymphocyte infiltration. Furthermore, polymorphism between MS patients and controls has been recently described in the gene coding for IL-22 binding protein (IL-22BP). Here, we aimed to better characterize IL-22 in the context of MS. METHODS: IL-22 and IL-22BP expressions were assessed by ELISA and qPCR in the following compartments of MS patients and control subjects: (1) the serum, (2) the cerebrospinal fluid, and (3) immune cells of peripheral blood. Identification of the IL-22 receptor subunit, IL-22R1, was performed by immunohistochemistry and immunofluorescence in human brain tissues and human primary astrocytes. The role of IL-22 on human primary astrocytes was evaluated using 7-AAD and annexin V, markers of cell viability and apoptosis, respectively. RESULTS: In a cohort of 141 MS patients and healthy control (HC) subjects, we found that serum levels of IL-22 were significantly higher in relapsing MS patients than in HC but also remitting and progressive MS patients. Monocytes and monocyte-derived dendritic cells contained an enhanced expression of mRNA coding for IL-22BP as compared to HC. Using immunohistochemistry and confocal microscopy, we found that IL-22 and its receptor were detected on astrocytes of brain tissues from both control subjects and MS patients, although in the latter, the expression was higher around blood vessels and in MS plaques. Cytometry-based functional assays revealed that addition of IL-22 improved the survival of human primary astrocytes. Furthermore, tumor necrosis factor α-treated astrocytes had a better long-term survival capacity upon IL-22 co-treatment. This protective effect of IL-22 seemed to be conferred, at least partially, by a decreased apoptosis. CONCLUSIONS: We show that (1) there is a dysregulation in the expression of IL-22 and its antagonist, IL-22BP, in MS patients, (2) IL-22 targets specifically astrocytes in the human brain, and (3) this cytokine confers an increased survival of the latter cells.

Management of Fulminant Multiple Sclerosis With Rituximab: A Case Report.

INTRODUCTION: Malignant variant is a rare subtype of multiple sclerosis (MS) that is rapidly progressive and may lead to significant disability or even death. No consensus exists on best management of this disorder, although corticosteroids and plasmapheresis are commonly used in the acute phase, followed either by MS-specific disease-modifying therapy or an immunosuppressant. CASE REPORT: The patient is a 30-year-old man with relapsing-remitting MS previously well controlled with natalizumab, who has developed fulminant disease activity upon natalizumab cessation. In the acute phase, patient had a suboptimal response to multiple corticosteroid treatments but responded very well to plasmapheresis. Patient continued to have worsening disease activity despite fingolimod treatment. Disease control has been eventually achieved by switching to rituximab. CONCLUSION: Rituximab treatment should be considered for a patient with fulminant MS who responded well to plasmapheresis.

Revue de la littérature 2011 : neuropathies dysimmunitaires [2011: What's new in dysimmune neuropathies].

There are strong research activities in the field of dysimmune neuropathies. In Guillain-Barré syndrome, new pathophysiological mechanisms have been demonstrated with the potential development of new therapies, a clinical prediction model is applicable early in the course of disease, and under investigation are new treatment strategies with adapted intravenous Ig dosages. In chronic inflammatory demyelinating polyneuropathies, current diagnostic tests are discussed but biomarkers are needed, such as histological changes or differential gene expression in nerve or skin biopsies. The exploration of novel therapeutic approaches including monoclonal antibodies and oral immunosuppressants, known from multiple sclerosis studies, suggests new approaches to treatment. Changes of the peripheral nerves on MR imaging are better known and the usefulness of serum antibodies is reviewed.

Patterns of pain-free response in 497 cases of classic trigeminal neuralgia treated with Gamma Knife surgery and followed up for least 1 year.

Object The goal of this study was to establish whether clear patterns of initial pain freedom could be identified when treating patients with classic trigeminal neuralgia (TN) by using Gamma Knife surgery (GKS). The authors compared hypesthesia and pain recurrence rates to see if statistically significant differences could be found. Methods Between July 1992 and November 2010, 737 patients presenting with TN underwent GKS and prospective evaluation at Timone University Hospital in Marseille, France. In this study the authors analyzed the cases of 497 of these patients, who participated in follow-up longer than 1 year, did not have megadolichobasilar artery- or multiple sclerosis-related TN, and underwent GKS only once; in other words, the focus was on cases of classic TN with a single radiosurgical treatment. Radiosurgery was performed with a Leksell Gamma Knife (model B, C, or Perfexion) using both MR and CT imaging targeting. A single 4-mm isocenter was positioned in the cisternal portion of the trigeminal nerve at a median distance of 7.8 mm (range 4.5-14 mm) anterior to the emergence of the nerve. A median maximum dose of 85 Gy (range 70-90 Gy) was delivered. Using empirical methods and assisted by a chart with clear cut-off periods of pain free distribution, the authors were able to divide patients who experienced freedom from pain into 3 separate groups: patients who became pain free within the first 48 hours post-GKS; those who became pain free between 48 hours and 30 days post-GKS; and those who became pain free more than 30 days after GKS. Results The median age in the 497 patients was 68.3 years (range 28.1-93.2 years). The median follow-up period was 43.75 months (range 12-174.41 months). Four hundred fifty-four patients (91.34%) were initially pain free within a median time of 10 days (range 1-459 days) after GKS. One hundred sixty-nine patients (37.2%) became pain free within the first 48 hours (Group PF(≤ 48 hours)), 194 patients (42.8%) between posttreatment Day 3 and Day 30 (Group PF((>48 hours, ≤ 30 days))), and 91 patients (20%) after 30 days post-GKS (Group PF(>30 days)). Differences in postoperative hypesthesia were found: in Group PF(≤ 48 hours) 18 patients (13.7%) developed postoperative hypesthesia, compared with 30 patients (19%) in Group PF((>48 hours, ≤ 30 days)) and 22 patients (30.6%) in Group PF(>30 days) (p = 0.014). One hundred fifty-seven patients (34.4%) who initially became free from pain experienced a recurrence of pain with a median delay of 24 months (range 0.62-150.06 months). There were no statistically significant differences between the patient groups with respect to pain recurrence: 66 patients (39%) in Group PF(≤ 48 hours) experienced pain recurrence, compared with 71 patients (36.6%) in Group PF((>48 hours, ≤ 30 days)) and 27 patients (29.7%) in Group PF(>30 days) (p = 0.515). Conclusions A substantial number of patients (169 cases, 37.2%) became pain free within the first 48 hours. The rate of hypesthesia was higher in patients who became pain free more than 30 days after GKS, with a statistically significant difference between patient groups (p = 0.014).

Programming Hippocampal Neural Stem/Progenitor Cells into Oligodendrocytes Enhances Remyelination in the Adult Brain after Injury.

Demyelinating diseases are characterized by a loss of oligodendrocytes leading to axonal degeneration and impaired brain function. Current strategies used for the treatment of demyelinating disease such as multiple sclerosis largely rely on modulation of the immune system. Only limited treatment options are available for treating the later stages of the disease, and these treatments require regenerative therapies to ameliorate the consequences of oligodendrocyte loss and axonal impairment. Directed differentiation of adult hippocampal neural stem/progenitor cells (NSPCs) into oligodendrocytes may represent an endogenous source of glial cells for cell-replacement strategies aiming to treat demyelinating disease. Here, we show that Ascl1-mediated conversion of hippocampal NSPCs into mature oligodendrocytes enhances remyelination in a diphtheria-toxin (DT)-inducible, genetic model for demyelination. These findings highlight the potential of targeting hippocampal NSPCs for the treatment of demyelinated lesions in the adult brain.

Direct angiotensin type 2 receptor (AT2R) stimulation attenuates T-cell and microglia activation and prevents demyelination in experimental autoimmune encephalomyelitis in mice.

In the present study, we evaluated stimulation of the angiotensin type 2 receptor (AT2R) by the selective non-peptide agonist Compound 21 (C21) as a novel therapeutic concept for the treatment of multiple sclerosis using the model of experimental autoimmune encephalomyelitis (EAE) in mice. C57BL-6 mice were immunized with myelin-oligodendrocyte peptide and treated for 4 weeks with C21 (0.3 mg/kg/day i.p.). Potential effects on myelination, microglia and T-cell composition were estimated by immunostaining and FACS analyses of lumbar spinal cords. The in vivo study was complemented by experiments in aggregating brain cell cultures and microglia in vitro. In the EAE model, treatment with C21 ameliorated microglia activation and decreased the number of total T-cells and CD4+ T-cells in the spinal cord. Fluorescent myelin staining of spinal cords further revealed a significant reduction in EAE-induced demyelinated areas in lumbar spinal cord tissue after AT2R stimulation. C21-treated mice had a significantly better neurological score than vehicle-treated controls. In aggregating brain cell cultures challenged with lipopolysaccharide (LPS) plus interferon-γ (IFNγ), AT2R stimulation prevented demyelination, accelerated re-myelination and reduced the number of microglia. Cytokine synthesis and nitric oxide production by microglia in vitro were significantly reduced after C21 treatment. These results suggest that AT2R stimulation protects the myelin sheaths in autoimmune central nervous system inflammation by inhibiting the T-cell response and microglia activation. Our findings identify the AT2R as a potential new pharmacological target for demyelinating diseases such as multiple sclerosis.