Value contribution of blood-based neurofilament light chain as a biomarker in multiple sclerosis using multi-criteria decision analysis.

Introduction: Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease that represents a leading cause of non-traumatic disability among young and middle-aged adults. MS is characterized by neurodegeneration caused by axonal injury. Current clinical and radiological markers often lack the sensitivity and specificity required to detect inflammatory activity and neurodegeneration, highlighting the need for better approaches. After neuronal injury, neurofilament light chains (NfL) are released into the cerebrospinal fluid, and eventually into blood. Thus, blood-based NfL could be used as a potential biomarker for inflammatory activity, neurodegeneration, and treatment response in MS. The objective of this study was to determine the value contribution of blood-based NfL as a biomarker in MS in Spain using the Multi-Criteria Decision Analysis (MCDA) methodology. Materials and methods: A literature review was performed, and the results were synthesized in the evidence matrix following the criteria included in the MCDA framework. The study was conducted by a multidisciplinary group of six experts. Participants were trained in MCDA and scored the evidence matrix. Results were analyzed and discussed in a group meeting through reflective MCDA discussion methodology. Results: MS was considered a severe condition as it is associated with significant disability. There are unmet needs in MS as a disease, but also in terms of biomarkers since no blood biomarker is available in clinical practice to determine disease activity, prognostic assessment, and response to treatment. The results of the present study suggest that quantification of blood-based NfL may represent a safe option to determine inflammation, neurodegeneration, and response to treatments in clinical practice, as well as to complement data to improve the sensitivity of the diagnosis. Participants considered that blood-based NfL could result in a lower use of expensive tests such as magnetic resonance imaging scans and could provide cost-savings by avoiding ineffective treatments. Lower indirect costs could also be expected due to a lower impact of disability consequences. Overall, blood-based NfL measurement is supported by high-quality evidence. Conclusion: Based on MCDA methodology and the experience of a multidisciplinary group of six stakeholders, blood-based NfL measurement might represent a high-value-option for the management of MS in Spain.

Defining a standard set of health outcomes for patients with relapsing-remitting multiple sclerosis.

BACKGROUND: Standardizing health outcomes is challenging in clinical management, but it also holds the potential for creating a healthcare system that is both more effective and efficient. The aim of the present study is to define a standardized set of health outcomes for managing Relapsing-Remitting Multiple Sclerosis (RRMS). METHODS: The project was led and coordinated by a multidisciplinary scientific committee (SC), which included a literature review, a patient-focused group, three nominal group meetings, and two SC meetings. RESULTS: 36 outcome variables were included in the standard set: 24 clinical (including weight, smoking habit, comorbidities, disability, mobility, diagnosis of secondary progressive multiple sclerosis, relapsed-related variables, radiological variables, cognitive status and disease-related symptoms), nine treatment-related (pharmacological and non-pharmacological information), and 3 related to the impact of RRMS on the patient's life (quality of life, pregnancy desire, work-related difficulties). In addition, experts also agreed to collect 10 case-mix variables that may affect but cannot be controlled as part of the management of the condition: 4 sociodemographic (age, sex, race, and employment status) and 6 clinical (height, date of diagnosis and first episode, serological status, early symptoms, and number of relapses pre-diagnosis). CONCLUSION: The information provided through the present standard set of outcome variables can improve the management of RRMS and promote patient-centred quality care.

Family Planning in Fertile-Age Patients With Multiple Sclerosis (MS) (ConPlanEM Study): Delphi Consensus Statements.

Family planning is essential for establishing Multiple Sclerosis (MS) prognosis, treatment decision, and disease monitoring. We aimed to generate an expert consensus addressing recommendations for family planning in MS patients of childbearing age. Initially, a committee comprising seven neurologists, experts in the MS field, identified the topics to be addressed. Then, the committee elaborated on different evidence-based preliminary statements. Next, using the Delphi methodology, a panel of neurologists manifested their level of agreement on the different statements using a Likert-type scale. Consensus was reached when ⩾70% of respondents expressed an agreement or disagreement using a five-point scale. Consensus was achieved on 47 out of 63 recommendations after three rounds of evaluations. The panel considered it essential to address family planning in all patients of childbearing age. There was also consensus that treatment should not be delayed due to the patient's desire for pregnancy. Additionally, in highly active patients, planning the pregnancy in the medium to long term using depletory drugs such as cladribine or alemtuzumab might represent a useful strategy. However, risks of adverse effects on the fetus due to drug-associated secondary autoimmunity should be addressed when alemtuzumab is considered. Moreover, the maintenance of natalizumab during pregnancy in very active patients reached expert consensus. Also, the panel supported the use of certain disease-modifying treatment (DMT) during lactation in selected cases. Our results identified specific areas of pregnancy planning in MS patients, where different treatment strategies might be considered to facilitate a safe and successful pregnancy while maintaining clinical and radiological stability.

Therapeutic effect of α7 nicotinic receptor activation after ischemic stroke in rats.

Nicotinic acetylcholine α7 receptors (α7 nAChRs) have a well-known modulator effect in neuroinflammation. Yet, the therapeutical effect of α7 nAChRs activation after stroke has been scarcely evaluated to date. The role of α7 nAChRs activation with PHA 568487 on inflammation after brain ischemia was assessed with positron emission tomography (PET) using [18F]DPA-714 and [18F]BR-351 radiotracers after transient middle cerebral artery occlusion (MCAO) in rats. The assessment of brain oedema, blood brain barrier (BBB) disruption and neurofunctional progression after treatment was evaluated with T2 weighted and dynamic contrast-enhanced magnetic resonance imaging (T2 W and DCE-MRI) and neurological evaluation. The activation of α7 nAChRs resulted in a decrease of ischemic lesion, midline displacement and cell neurodegeneration from days 3 to 7 after ischemia. Besides, the treatment with PHA 568487 improved the neurofunctional outcome. Treated ischemic rats showed a significant [18F]DPA-714-PET uptake reduction at day 7 together with a decrease of activated microglia/infiltrated macrophages. Likewise, the activation of α7 receptors displayed an increase of [18F]BR-351-PET signal in ischemic cortical regions, which resulted from the overactivation of MMP-2. Finally, the treatment with PHA 568487 showed a protective effect on BBB disruption and blood brain vessel integrity after cerebral ischemia.

Assessing care-related regret among nurses specialized in multiple sclerosis: A psychometric analysis of a new assessment battery.

Experiences of regret associated with caring for patients with multiple sclerosis (MS) can affect medical decisions. A non-interventional study was conducted to assess the dimensionality and item characteristics of a battery including the Regret Intensity Scale (RIS-10) and 15 items evaluating common situations experienced by nurses in MS care. A total of 97 nurses were included. The RIS-10 showed good internal reliability and a unidimensional structure according to Mokken analysis. All-item homogeneity coefficients exceeded 0.30, whereas scalability for the overall RIS-10 was 0.66, indicating a strong scale. This battery showed adequate psychometric properties to evaluate regret among MS nurses.

Consensus on early detection of disease progression in patients with multiple sclerosis.

Background: Early identification of the transition from relapsing-remitting multiple sclerosis (RRMS) to secondary progressive MS (SPMS) can be challenging for clinicians, as diagnostic criteria for SPMS are primarily based on physical disability and a holistic interpretation. Objective: To establish a consensus on patient monitoring to identify promptly disease progression and the most useful clinical and paraclinical variables for early identification of disease progression in MS. Methods: A RAND/UCLA Appropriateness Method was used to establish the level of agreement among a panel of 15 medical experts in MS. Eighty-three items were circulated to the experts for confidential rating of the grade of agreement and recommendation. Consensus was defined when ≥66% agreement or disagreement was achieved. Results: Consensus was reached in 72 out of 83 items (86.7%). The items addressed frequency of follow-up visits, definition of progression, identification of clinical, cognitive, and radiological assessments as variables of suspected or confirmed SPMS diagnosis, the need for more accurate assessment tools, and the use of promising molecular and imaging biomarkers to predict disease progression and/or diagnose SPMS. Conclusion: Consensus achieved on these topics could guide neurologists to identify earlier disease progression and to plan targeted clinical and therapeutic interventions during the earliest stages of SPMS.

Sick leave and occupational burnout among nurses caring for patients with multiple sclerosis.

BACKGROUND: Sick leave is a common problem among healthcare professionals. Nurses play a critical role in the multidisciplinary management of multiple sclerosis (MS). However, limited information is available on the phenomenon of sick leave among MS nurses. OBJECTIVE: The aim of this study was to assess the presence of sick leave among nurses caring for patients with MS and to identify associated factors. METHODS: We conducted a multicenter, non-interventional, cross-sectional, web-based study. Nurses involved in MS care from across Spain answered a survey composed of demographic characteristics, professional background, questions about their standard practice, and a behavioral battery including the Maslach Burnout Inventory - Human Services Survey (MBI-HSS). A multivariable logistic regression analysis was conducted to determine the association between nurses' characteristics and sick leave. RESULTS: Ninety-six nurses were included in the study. Mean age (SD) was 44.6 (9.8) years, and 91.7% were female. Participants had a median of 6 (IQR 3.0, 11.0) years of expertise in MS managing a median of 15 (5.0, 35.0) patients per week. Sixteen participants (16.7%) had been on sick leave in the last 6 months, with a median absence of 14.5 days (7.0, 30.0). Sixteen nurses (16.7%) reported severe burnout. Participants on sick leave had higher levels of emotional exhaustion (mean MBI-HSS scores of 22.3 and 16.0, p=0.01) and inadequate interactions with their colleagues (mean Practice Environment Scale - Nursing Work Index scores of 11.8 and 13.1, p=0.01) than their counterparts. Burnout was associated with higher risk of sick leave in the multivariable analysis (OR=1.06 [95% CI 1.00, 1.13], p=0.04) after adjustment for confounders. CONCLUSIONS: Occupational burnout is associated with increased risk of sick leave among nurses managing patients with MS. Identifying burnout may be critical for implementing specific intervention strategies to maintain an adequate functioning of MS care units.

Disease modifying therapy switching in relapsing multiple sclerosis: A Delphi consensus of the demyelinating expert group of the Spanish society of neurology.

BACKGROUND: The increase in available disease modifying therapies (DMTs) for multiple sclerosis has led to greater emphasis on improving treatment sequencing paradigms. This article summarises the opinions from a panel of 25 experts on treatment switching approaches in relapsing multiple sclerosis (RMS). METHODS: A modified Delphi consensus process was carried out to develop clinically relevant statements for aiding treatment decisions in patients with RMS between the 16th January and the 9th October 2019. A sub-group of two experts (core group) carried out an extensive review of the literature and formulated 106 statements for the expert panel to evaluate. RESULTS: From a total number of 106 statements that were submitted to the expert panel for critical evaluation, consensus (at least 80% of the panelists agreed) was reached on 99 of them. These statements cover treatment objectives, reasons for DMT switching, suboptimal response criteria, strategies for treatment change and washout periods. CONCLUSION: The agreed statements provide up-to-date guidance on DMT sequencing for optimal patient management.

Neuropsychological Profile of Hereditary Ataxias: Study of 38 Patients.

Hereditary ataxias are a heterogeneous group of disorders characterized by degeneration of the cerebellum and its connections. It is known that patients with ataxia can manifest a broad spectrum of motor symptoms; however, current research has emphasized the relevance of cognitive disturbances. The aim of this study is to analyze the presence of cognitive impairment in a heterogeneous cohort of patients with hereditary ataxia (HA). A group of 38 patients with HA of different etiologies and a matched group of 38 healthy controls were recruited and evaluated through a comprehensive battery of neuropsychological tests. The findings show a worse performance in ataxic patients on planning, visuospatial skills, naming, and Theory of Mind tasks, regardless their physical and psychological symptomatology. The influence of clinical status as well as functional ability-related variables on their performance were analyzed, showing that the level of disability and motor disturbances have a significant effect on verbal memory, verbal fluency, and working memory. These findings suggest that patients with HA can manifest cognitive and neuropsychiatric symptoms as part of their clinical features, which demands its inclusion for the diagnosis and management of the disease.

Behavioral aspects of nurse practitioners associated with optimal multiple sclerosis care in Spain.

BACKGROUND: Nurse practitioners (NPs) play a critical role in the multidisciplinary management of patients with multiple sclerosis (MS). Neurologists´ behavioral characteristics have been associated with suboptimal clinical decisions. However, limited information is available on their impact among NPs involved in MS care. The aim of this study was to assess nurses´ therapeutic choices to understand behavioral factors influencing their decision making process. METHODS: A non-interventional, cross-sectional, web-based study was conducted. NPs actively involved in the care of patients with MS were invited to participate in the study by the Spanish Society of Neurology Nursing. Participants answered questions regarding their standard practice and therapeutic management of seven simulated relapsing-remitting MS (RRMS) case scenarios. A behavioral battery was used to measure participants´ life satisfaction, mood, positive social behaviors, feeling of helpfulness, attitudes toward adoption of evidence-based innovations, occupational burnout, and healthcare-related regret. The outcome of interest was therapeutic inertia (TI), defined as the lack of treatment escalation when there is clinical and radiological evidence of disease activity. A score to quantify TI was created based on the number of simulated scenarios where treatment intensification was warranted. RESULTS: Overall, 331 NPs were invited to participate, 130 initiated the study, and 96 (29%) completed the study. The mean age (SD) was 44.6 (9.8) years and 91.7% were female. Seventy-three participants (76.0%) felt their opinions had a significant influence on neurologists´ therapeutic decisions. Sixteen NPs (16.5%) showed severe emotional exhaustion related to work and 13 (13.5%) had depressive symptoms. The mean (SD) TI score was 0.97 (1.1). Fifty-six of NPs showed TI in at least one case scenario. Higher years of nursing experience (p = 0.014), feeling of helpfulness (p = 0.014), positive attitudes toward innovations (p = 0.046), and a higher intensity of care-related regret (p = 0.021) were associated with a lower risk of TI (adjusted R2 = 0.28). Burnout was associated with higher risk of TI (p = 0.001). CONCLUSIONS: Although NPs cannot prescribe MS treatments in Spain, their behavioral characteristics may influence the management of patients with RRMS. Continuing education and specific strategies for reducing occupational burnout may lead to better management skills and improve MS care.

Regret and Therapeutic Decisions in Multiple Sclerosis Care: Literature Review and Research Protocol.

Background: Decisions based on erroneous assessments may result in unrealistic patient and family expectations, suboptimal advice, incorrect treatment, or costly medical errors. Regret is a common emotion in daily life that involves counterfactual thinking when considering alternative choices. Limited information is available on care-related regret affecting healthcare professionals managing patients with multiple sclerosis (MS). Methods: We reviewed identified gaps in the literature by searching for the combination of the following keywords in Pubmed: "regret and decision," "regret and physicians," and "regret and nurses." An expert panel of neurologists, a nurse, a psychiatrist, a pharmacist, and a psychometrics specialist participated in the study design. Care-related regret will be assessed by a behavioral battery including the standardized questionnaire Regret Intensity Scale (RIS-10) and 15 new specific items. Six items will evaluate regret in the most common social domains affecting individuals (financial, driving, sports-recreation, work, own health, and confidence in people). Another nine items will explore past and recent regret experiences in common situations experienced by healthcare professionals caring for patients with MS. We will also assess concomitant behavioral characteristics of healthcare professionals that could be associated with regret: coping strategies, life satisfaction, mood, positive social behaviors, occupational burnout, and tolerance to uncertainty. Planned Outcomes: This is the first comprehensive and standardized protocol to assess care-related regret and associated behavioral factors among healthcare professionals managing MS. These results will allow to understand and ameliorate regret in healthcare professionals. Spanish National Register (SL42129-20/598-E).

Gene Expression Analysis of Astrocyte and Microglia Endocannabinoid Signaling during Autoimmune Demyelination.

The endocannabinoid system is associated with protective effects in multiple sclerosis (MS) that involve attenuated innate immune cell responses. Astrocytes and microglia are modulated by endocannabinoids and participate in the biosynthesis and metabolism of these compounds. However, the role of neuroglial cells as targets and mediators of endocannabinoid signaling in MS is poorly understood. Here we used a microfluidic RT-qPCR screen to assess changes in the expression of the main endocannabinoid signaling genes in astrocytes and microglia purified from female mice during the time-course of experimental autoimmune encephalomyelitis (EAE). We show that astrocytes and microglia upregulate the expression of genes encoding neurotoxic A1 and pro-inflammatory molecules at the acute disease with many of these transcripts remaining elevated during the recovery phase. Both cell populations exhibited an early onset decrease in the gene expression levels of 2-arachidonoylglycerol (2-AG) hydrolytic enzymes that persisted during EAE progression as well as cell-type-specific changes in the transcript levels for genes encoding cannabinoid receptors and molecules involved in anandamide (AEA) signaling. Our results demonstrate that astrocytes and microglia responses to autoimmune demyelination involve alterations in the expression of multiple endocannabinoid signaling-associated genes and suggest that this system may regulate the induction of neurotoxic and pro-inflammatory transcriptional programs in both cell types during MS.

Positive oligoclonal bands and CSF pleocytosis in narcolepsy type 1: A case report supporting the immune-mediated hypothesis.

Narcolepsy-type 1 is a neurological sleep-disorder caused by a selective loss of hypothalamic orexin/hypocretin-producing neurons whose underlying mechanism is considered to be immune-mediated. We report the case of a 16 year-old girl with excessive daytime sleepiness, hypnagogic/hypnopompic hallucinations and cataplexy, fulfilling narcolepsy-type 1 diagnostic criteria. She was HLA-DQB1*06:02/DQA1*01:02 positive. CSF analysis demonstrated positive IgG oligoclonal bands, pleocytosis and hypocretin-1 below detection limit. Other autoimmune processes were excluded, including autoimmune encephalitis. After treatment with intravenous immunoglobulins sleep-related hallucinations transiently improved for a month. This case's CSF inflammatory findings support the role of neuroinflammation in narcolepsy-type 1 development in genetically predisposed patients.

Exome sequencing study in patients with multiple sclerosis reveals variants associated with disease course.

BACKGROUND: It remains unclear whether disease course in multiple sclerosis (MS) is influenced by genetic polymorphisms. Here, we aimed to identify genetic variants associated with benign and aggressive disease courses in MS patients. METHODS: MS patients were classified into benign and aggressive phenotypes according to clinical criteria. We performed exome sequencing in a discovery cohort, which included 20 MS patients, 10 with benign and 10 with aggressive disease course, and genotyping in 2 independent validation cohorts. The first validation cohort encompassed 194 MS patients, 107 with benign and 87 with aggressive phenotypes. The second validation cohort comprised 257 patients, of whom 224 patients had benign phenotypes and 33 aggressive disease courses. Brain immunohistochemistries were performed using disease course associated genes antibodies. RESULTS: By means of single-nucleotide polymorphism (SNP) detection and comparison of allele frequencies between patients with benign and aggressive phenotypes, a total of 16 SNPs were selected for validation from the exome sequencing data in the discovery cohort. Meta-analysis of genotyping results in two validation cohorts revealed two polymorphisms, rs28469012 and rs10894768, significantly associated with disease course. SNP rs28469012 is located in CPXM2 (carboxypeptidase X, M14 family, member 2) and was associated with aggressive disease course (uncorrected p value < 0.05). SNP rs10894768, which is positioned in IGSF9B (immunoglobulin superfamily member 9B) was associated with benign phenotype (uncorrected p value < 0.05). In addition, a trend for association with benign phenotype was observed for a third SNP, rs10423927, in NLRP9 (NLR family pyrin domain containing 9). Brain immunohistochemistries in chronic active lesions from MS patients revealed expression of IGSF9B in astrocytes and macrophages/microglial cells, and expression of CPXM2 and NLRP9 restricted to brain macrophages/microglia. CONCLUSIONS: Genetic variants located in CPXM2, IGSF9B, and NLRP9 have the potential to modulate disease course in MS patients and may be used as disease activity biomarkers to identify patients with divergent disease courses. Altogether, the reported results from this study support the influence of genetic factors in MS disease course and may help to better understand the complex molecular mechanisms underlying disease pathogenesis.

Integrative group-based cognitive rehabilitation efficacy in multiple sclerosis: a randomized clinical trial.

PURPOSE: This study aimed to determine the efficacy of the integrative group-based cognitive rehabilitation programme, REHACOP, on improving cognitive functions in multiple sclerosis (MS). METHODS: Fourty-two MS patients were randomized to the treatment programme REHACOP (n = 21) or waiting list control condition (n = 21). The REHACOP group received cognitive rehabilitation in group format for three months focused on attention, processing speed, learning and memory, language, executive functioning, and social cognition. Patients completed a neuropsychological assessment at baseline and follow-up, which included tests of attention, processing speed, working memory, verbal memory, verbal fluency, and executive functioning. Repeated measures multivariate analysis of covariance (MANCOVA) was used to determine the efficacy of the cognitive rehabilitation programme. RESULTS: Group × Time interactions revealed significant improvements in the REHACOP group as compared with the control group for processing speed (p = 0.011, np2 = 0.16), working memory (p = 0.014, np2 = 0.15), verbal memory (p = 0.025, np2 = 0.13), and executive functioning (p = 0.024, np2 = 0.13), showing medium-large effect sizes. CONCLUSIONS: Patients receiving REHACOP showed improvements in several cognitive domains. This preliminary study thus provides evidence supporting the efficacy of this integrative group-based cognitive rehabilitation intervention in MS. Future research should confirm these findings, examine the impact of the treatment on everyday life functioning and explore the presence of brain changes associated with cognitive rehabilitation. Implications for rehabilitation This study provides initial evidence for integrative group-based cognitive rehabilitation efficacy in MS patients through the implementation of the REHACOP cognitive rehabilitation programme. Patients received cognitive rehabilitation for three months (3 one-hour-sessions per week) focused on training attention, learning and memory, language, executive functioning, and social cognition. Patients attending REHACOP sessions showed medium to large and statistically significant improvements in processing speed, working memory, verbal memory, and executive functioning.

Effects of FTY720 on brain neurogenic niches in vitro and after kainic acid-induced injury.

BACKGROUND: FTY720 (fingolimod, Gilenya™) is an oral, blood-brain barrier (BBB)-passing drug approved as immunomodulatory treatment for relapsing-remitting form of the multiple sclerosis (MS). In addition, FTY720 exerts several effects in the central nervous system (CNS), ranging from neuroprotection to reduction of neuroinflammation. However, the neurogenic and oligodendrogenic potential of FTY720 has been poorly investigated. In this study, we assessed the effect of FTY720 on the production of new neurons and oligodendrocytes from neural stem/precursor cells both in vitro and in vivo. METHODS: Neural stem cells (NSCs) derived from the young rat subventricular zone (SVZ) were exposed to FTY720 (10, 100 nM), and their differentiation into neurons and oligodendrocytes was measured using immunofluorescence for anti-ß-III tubulin or CNPase (2',3'-cyclic nucleotide 3'-phosphodiesterase) as markers of mature neurons or oligodendrocytes, respectively. In addition, intracerebroventricular (icv) administration of kainic acid (KA; 0.5 µg/2 µl) in Sprague-Dawley rats was used as an in vivo model of neuronal death and inflammation. FTY720 was applied icv (1 µg/2 µl), together with KA, plus intraperitoneally (ip; 1 mg/kg) 24 h before, and daily, until sacrifice 8 days after KA injection. To visualize cell proliferation in the hippocampus and in white matter regions, rats were administered 5-bromo-2-deoxyuridine (BrdU) 100 mg/kg, ip injected every 2 days. Immunohistochemical analyses were performed on rat brain slices to measure the production of new neuronal precursors (doublecortin/DCX+ cells) and new oligodendrocytes precursors (proteoglycan/NG2+ cells). RESULTS: In this study, we observed that FTY720 increased postnatal NSCs differentiation into both neurons and oligodendrocytes in vitro. In turn, in adult animals, FTY720 enhanced the percentage of BrdU+ cells coexpressing DCX marker, both in basal (FTY720 alone) and in neurodegenerative (FTY720 + KA) conditions. However, FTY720 had only a partial effect on proliferation and differentiation of oligodendrocyte progenitor cell (OPC) population in vivo. CONCLUSIONS: FTY720 promotes neurogenesis and oligodendrogenesis in vitro under basal conditions. In addition, it increases the generation of neuroblasts and oligodendrocytes after excitotoxic brain injury. This suggests that FTY720 has the potential to activate the neurogenic niche and thus favour tissue repair after lesion.

The influence of posterior visual pathway damage on visual information processing speed in multiple sclerosis.

BACKGROUND: The injury of visual pathway and abnormalities of visual processing speed (VPS) are frequent in MS, but their association remains unexplored. OBJECTIVE: To evaluate the impact of posterior visual pathway structural and functional integrity on VPS of MS patients. METHODS: Cross-sectional study of 30 MS patients and 28 controls, evaluating the association of a VPS tests composite (Salthouse Perceptual Comparison test, Trail Making Test A and Symbol Digit Modalities Test) with 3T MRI visual cortex thickness, optic radiations (OR) diffusion tensor imaging indexes, and medial visual component (MVC) functional connectivity (FC) (MVC-MVC FC (iFC) and MVC-brain FC (eFC)) by linear regression, removing the effect of premorbid IQ, fatigue, and depression. RESULTS: V2 atrophy, lower OR fractional anisotropy (FA) and MVC FC significantly influenced VPS in MS (at none or lesser extent in controls), even after removing the effect of Expanded Disability Status Scale and previous optic neuritis (V2 ( r2 = 0.210): ß = +0.366, p = 0.046; OR FA ( r2 = 0.243): ß = +0.378, p = 0.034; MVC iFC, for example, left cuneus ( r2 = 0.450): ß = -0.613, p < 0.001; MVC eFC, for example, right precuneus-postcentral gyrus ( r2 = 0.368): ß = -0.466, p = 0.002). CONCLUSION: Posterior visual pathway integrity, structural (V2 thickness and OR FA) and functional (MVC FC), may explain respectively up to 24% and 45% of VPS variability in MS.

Pharmacogenomic study in patients with multiple sclerosis: Responders and nonresponders to IFN-ß.

OBJECTIVES: We aimed to investigate the association between polymorphisms located in type I interferon (IFN)-induced genes, genes belonging to the toll-like receptor (TLR) pathway, and genes encoding neurotransmitter receptors and the response to IFN-ß treatment in patients with multiple sclerosis (MS). METHODS: In a first or screening phase of the study, 384 polymorphisms were genotyped in 830 patients with MS classified into IFN-ß responders (n = 416) and nonresponders (n = 414) according to clinical criteria. In a second or validation phase, the most significant polymorphisms associated with IFN-ß response were genotyped in an independent validation cohort of 555 patients with MS (281 IFN-ß responders and 274 nonresponders). RESULTS: Seven single nucleotide polymorphisms (SNPs) were selected from the screening phase for further validation: rs832032 (GABRR3; p = 0.0006), rs6597 (STUB1; p = 0.019), rs3747517 (IFIH1; p = 0.010), rs2277302 (PELI3; p = 0.017), rs10958713 (IKBKB; p = 0.003), rs2834202 (IFNAR1; p = 0.030), and rs4422395 (CXCL1; p = 0.017). None of these SNPs were significantly associated with IFN-ß response when genotyped in an independent cohort of patients. Combined analysis of these SNPs in all patients with MS (N = 1,385) revealed 2 polymorphisms associated with IFN-ß response: rs2277302 (PELI3; p = 0.008) and rs832032 (GABRR3; p = 0.006). CONCLUSIONS: These findings do not support an association between polymorphisms located in genes related to the type I IFN or TLR pathways or genes encoding neurotransmitter receptors and the clinical response to IFN-ß. Nevertheless, additional genetic and functional studies of PELI3 and GABRR3 are warranted.

FTY720 attenuates excitotoxicity and neuroinflammation.

BACKGROUND: FTY720 (fingolimod, Gilenya™), a structural analog of sphingosine-1-phosphate (S1P), is the first oral drug approved for treatment the relapsing-remitting form of multiple sclerosis (MS), and its efficacy has been related to induced lymphopenia and consequent immunosuppression via modulation of S1P1 receptors (S1P1R). However, due to its lipophilic nature, FTY720 crosses the blood brain barrier (BBB) and could act directly on neural cells. In this study, we investigated the effectiveness of FTY720 as a neuroprotective agent using in vitro and in vivo models of excitotoxic neuronal death and examined if FTY720 exerts a direct action on neurons, or/and an indirect modulation of inflammation-mediated neurodegeneration as a possible mechanism of neuroprotection. METHODS: Primary neuronal and organotypic cortical cultures were treated with N-methyl-D-aspartic acid (NMDA) to induce excitotoxic cell death (measured by lactate dehydrogenase (LDH) assay or propidium iodide uptake, respectively). The effects of FTY720 treatment (10, 100 and 1,000 nM) on neuronal survival were examined. As an in vivo model of neuronal death and inflammation, we used intracerebroventricular (icv) administration of kainic acid (KA; 0.5 µg/2 µl) in Sprague-Dawley rats. FTY720 was applied icv (1 µg/2 µl), together with KA, plus intraperitoneally (ip; 1 mg/kg) 24 h before, and daily, until sacrifice 3 days after icv. Rats were evaluated for neurological score, neuronal loss in CA3 hippocampal region and activation of microglia at the lesion site. In addition, we tested FTY720 as a modulator of microglia responses using microglial cell cultures activated with lipopolysaccharide (LPS) and its effects in stress signalling pathways using western blotting for p38 and JNK1/2 mitogen-activated protein kinases (MAPKs). RESULTS: FTY720 was able to reduce excitotoxic neuronal death in vitro. Moreover, in vivo repeated FTY720 administration attenuated KA-induced neurodegeneration and microgliosis at the CA3 lesion site. Furthermore, FTY720 negatively modulates p38 MAPK in LPS-activated microglia, whereas it had no effect on JNK1/2 activation. CONCLUSIONS: These data support a role for FTY720 as a neuroprotective agent against excitotoxin-induced neuronal death and as a negative modulator of neuroinflammation by targeting the p38 MAPK stress signalling pathway in microglia.

Cell-specific effects in different immune subsets associated with SOCS1 genotypes in multiple sclerosis.

BACKGROUND: Single nucleotide polymorphisms (SNPs) near SOCS1 are associated with multiple sclerosis (MS), but the most important SNPs in the area and mechanisms by which they influence the disease are unknown. METHODS: A haplotype-tagging association study was performed covering 60.5kbp around SOCS1, and the index SNP was validated in a total of 2292 individuals. mRNA expression of SOCS1 and nearby genes was measured in MS patients with different disease courses and healthy controls. SOCS1 protein expression was studied by flow cytometry in a separate cohort of patients and controls. Differentiation and maturation of monocyte-derived dendritic cells (moDCs) were also studied. RESULTS: One SNP, rs423674, reached genome-wide significance. No genotype-specific mRNA expression differences were seen, but, by flow cytometry, significant interactions were observed between genotypes for rs423674 and disease activity (relapse or remission) in B cells and regulatory T cells. Furthermore, homozygotes for the risk allele (GG) showed higher levels of CD1a and CD86 than carriers of the protective allele (GT) in immature moDCs and a greater increase of HLA-DR+ cell percentage than GT heterozygotes upon maturation. CONCLUSIONS: rs423674, or its genetic proxies, may influence MS risk by modulating SOCS1 expression in a cell-specific manner and by influencing dendritic cell function.