Detection and kinetics of persistent neutralizing anti-interferon-beta antibodies in patients with multiple sclerosis. Results from the ABIRISK prospective cohort study.

Two validated assays, a bridging ELISA and a luciferase-based bioassay, were compared for detection of anti-drug antibodies (ADA) against interferon-beta (IFN-β) in patients with multiple sclerosis. Serum samples were tested from patients enrolled in a prospective study of 18 months. In contrast to the ELISA, when IFN-β-specific rabbit polyclonal and human monoclonal antibodies were tested, the bioassay was the more sensitive to detect IFN-β ADA in patients' sera.

Serum heat shock protein 70 levels as a biomarker for inflammatory processes in multiple sclerosis.

Background: Inflammatory and neurodegenerative processes are hallmarks of multiple sclerosis (MS). The synthesis of the major stress-inducible heat shock protein 70 (Hsp70) is induced by inflammation.

Objective: The purpose of this study is to determine whether Hsp70 in serum can serve as a potential biomarker to distinguish inflammatory and neurodegenerative processes in MS.

Effect of HLA-DRB1 alleles and genetic variants on the development of neutralizing antibodies to interferon beta in the BEYOND and BENEFIT trials.

Background: Treatment of multiple sclerosis (MS) with interferon β can lead to the development of antibodies directed against interferon β that interfere with treatment efficacy. Several observational studies have proposed different HLA alleles and genetic variants associated with the development of antibodies against interferon β.

Objective: To validate the proposed genetic markers and to identify new markers.

Interferon-beta specific T cells are associated with the development of neutralizing antibodies in interferon-beta treated multiple sclerosis patients.

Beta-interferons are still among the most commonly used drugs to treat Multiple Sclerosis (MS). The use of beta-interferons is limited by the development of anti-drug antibodies (ADA), which may abrogate the treatment effect of the drug. Although the antibody response has been well studied, little is known about the T cell response to interferon-beta (IFN-β).

Cortical pathology in multiple sclerosis detected by the T1/T2-weighted ratio from routine magnetic resonance imaging.

Objective: In multiple sclerosis, neuropathological studies have shown widespread changes in the cerebral cortex. In vivo imaging is critical, because the histopathological substrate of most measurements is unknown.

Methods: Using a novel magnetic resonance imaging analysis technique, based on the ratio of T1- and T2-weighted signal intensities, we studied the cerebral cortex of a large cohort of patients in early stages of multiple sclerosis.

Fatigue in multiple sclerosis: Associations with clinical, MRI and CSF parameters.

Background: Damage of different brain structures has been related to fatigue. Alternatively, functional alterations of central nervous system (CNS) cells by the inflammatory milieu within the CNS may be responsible for the development of fatigue.

Aim: To investigate the effect of structural brain damage and inflammatory cerebrospinal fluid (CSF) changes on fatigue in multiple sclerosis (MS).

Clinical practice of analysis of anti-drug antibodies against interferon beta and natalizumab in multiple sclerosis patients in Europe: A descriptive study of test results.

Antibodies against biopharmaceuticals (anti-drug antibodies, ADA) have been a well-integrated part of the clinical care of multiple sclerosis (MS) in several European countries. ADA data generated in Europe during the more than 10 years of ADA monitoring in MS patients treated with interferon beta (IFNβ) and natalizumab have been pooled and characterized through collaboration within a European consortium. The aim of this study was to report on the clinical practice of ADA testing in Europe, considering the number of ADA tests performed and type of ADA assays used, and to determine the frequency of ADA testing against the different drug preparations in different countries.

Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation.

We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci.

The farnesoid-X-receptor in myeloid cells controls CNS autoimmunity in an IL-10-dependent fashion.

Innate immune responses by myeloid cells decisively contribute to perpetuation of central nervous system (CNS) autoimmunity and their pharmacologic modulation represents a promising strategy to prevent disease progression in Multiple Sclerosis (MS). Based on our observation that peripheral immune cells from relapsing-remitting and primary progressive MS patients exhibited strongly decreased levels of the bile acid receptor FXR (farnesoid-X-receptor, NR1H4), we evaluated its potential relevance as therapeutic target for control of established CNS autoimmunity. Pharmacological FXR activation promoted generation of anti-inflammatory macrophages characterized by arginase-1, increased IL-10 production, and suppression of T cell responses.

Successful Replication of GWAS Hits for Multiple Sclerosis in 10,000 Germans Using the Exome Array.

Genome-wide association studies (GWAS) successfully identified various chromosomal regions to be associated with multiple sclerosis (MS). The primary aim of this study was to replicate reported associations from GWAS using an exome array in a large German study. German MS cases (n = 4,476) and German controls (n = 5,714) were genotyped using the Illumina HumanExome v1-Chip.

Prevalence of neuropathic pain in early multiple sclerosis.

Background: Pain is considered a frequent symptom in multiple sclerosis. Neuropathic pain is the type of pain most closely related to the pathology of multiple sclerosis and its prevalence estimates vary largely.

Objective: We prospectively assessed the prevalence of neuropathic pain in patients with early multiple sclerosis and investigated the association of neuropathic pain with other clinical parameters.

Optical coherence tomography indicates disease activity prior to clinical onset of central nervous system demyelination.

Background: Establishing biomarkers for predicting disease activity in demyelinating disease of the central nervous system is crucial for designing appropriate disease modifiying treatment strategies.

Objective: To investigate retinal findings and disease activity in patients with radiologically isolated and clinically isolated syndromes.

Methods: We performed retinal optical coherence tomography and cerebral magnetic resonance imaging in healthy control individuals (n=19), in individuals with non-specific white matter lesions (n=18), and in patients with clinically isolated syndromes (n=18) and radiologically isolated syndromes (n=20).

Class II HLA interactions modulate genetic risk for multiple sclerosis.

Association studies have greatly refined the understanding of how variation within the human leukocyte antigen (HLA) genes influences risk of multiple sclerosis. However, the extent to which major effects are modulated by interactions is poorly characterized. We analyzed high-density SNP data on 17,465 cases and 30,385 controls from 11 cohorts of European ancestry, in combination with imputation of classical HLA alleles, to build a high-resolution map of HLA genetic risk and assess the evidence for interactions involving classical HLA alleles.

Mapping CSF biomarker profiles onto NIA-AA guidelines for Alzheimer's disease.

The National Institute on Aging-Alzheimer's Association (NIA-AA) guidelines for Alzheimer's disease (AD) propose the categorization of individuals according to their biomarker constellation. Though the NIA-AA criteria for preclinical AD and AD dementia have already been applied in conjunction with imaging AD biomarkers, the application of the criteria using comprehensive cerebrospinal fluid (CSF) biomarker information has not been thoroughly studied yet. The study included a monocentric cohort with healthy (N = 41) and disease (N = 22) controls and patients with AD dementia (N = 119), and a multicentric sample with healthy controls (N = 116) and patients with AD dementia (N = 102).

Genetic variants are major determinants of CSF antibody levels in multiple sclerosis.

Immunological hallmarks of multiple sclerosis include the production of antibodies in the central nervous system, expressed as presence of oligoclonal bands and/or an increased immunoglobulin G index-the level of immunoglobulin G in the cerebrospinal fluid compared to serum. However, the underlying differences between oligoclonal band-positive and -negative patients with multiple sclerosis and reasons for variability in immunoglobulin G index are not known. To identify genetic factors influencing the variation in the antibody levels in the cerebrospinal fluid in multiple sclerosis, we have performed a genome-wide association screen in patients collected from nine countries for two traits, presence or absence of oligoclonal bands (n = 3026) and immunoglobulin G index levels (n = 938), followed by a replication in 3891 additional patients.

Atrophy and structural variability of the upper cervical cord in early multiple sclerosis.

Background: Despite agreement about spinal cord atrophy in progressive forms of multiple sclerosis (MS), data on clinically isolated syndrome (CIS) and relapsing-remitting MS (RRMS) are conflicting.

Objective: To determine the onset of spinal cord atrophy in the disease course of MS.

Methods: Structural brain magnetic resonance imaging (MRI) was acquired from 267 patients with CIS (85) or RRMS (182) and 64 healthy controls (HCs).

JC polyomavirus infection is strongly controlled by human leucocyte antigen class II variants.

JC polyomavirus (JCV) carriers with a compromised immune system, such as in HIV, or subjects on immune-modulating therapies, such as anti VLA-4 therapy may develop progressive multifocal leukoencephalopathy (PML) which is a lytic infection of oligodendrocytes in the brain. Serum antibodies to JCV mark infection occur only in 50-60% of infected individuals, and high JCV-antibody titers seem to increase the risk of developing PML. We here investigated the role of human leukocyte antigen (HLA), instrumental in immune defense in JCV antibody response.

Biomarkers of treatment response in multiple sclerosis.

Multiple sclerosis (MS) is considered a heterogeneous disease with respect to disease progression and treatment response, which have both remained highly unpredictable. With an increasing number of available disease modifying therapies, strategies for treatment allocation in the individual patient or subgroup of patients has become more important. Therefore biomarkers, which will identify subgroups of MS patients and predict treatment response early in the course of the disease, are urgently needed.

Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.

Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls.

Review of the pharmacoeconomics of early treatment of multiple sclerosis using interferon beta.

Multiple sclerosis (MS) is a common neurological disease with increasing incidence and prevalence. Onset of disease is most frequently in young adulthood when productivity is usually highest; it is of chronic nature and, in the majority of patients, it will result in accumulation of disability. Due to loss of productivity in patients and caregivers as well as high expenses for medical treatment, MS is considered a disease with high economic burden for patients and society.

L-selectin is a possible biomarker for individual PML risk in natalizumab-treated MS patients.

Objective: To find biomarkers identifying patients at risk for the development of progressive multifocal leukoencephalopathy (PML) during natalizumab treatment.

Methods: Patients were recruited from 10 European and US cohorts. Of 289 patients with multiple sclerosis (MS), 224 had been treated with natalizumab (18-80 months), 21 received other immune-modulatory treatments, and 28 were untreated.

Fully Bayesian inference for structural MRI: application to segmentation and statistical analysis of T2-hypointensities.

Aiming at iron-related T2-hypointensity, which is related to normal aging and neurodegenerative processes, we here present two practicable approaches, based on Bayesian inference, for preprocessing and statistical analysis of a complex set of structural MRI data. In particular, Markov Chain Monte Carlo methods were used to simulate posterior distributions. First, we rendered a segmentation algorithm that uses outlier detection based on model checking techniques within a Bayesian mixture model.

White-matter lesions drive deep gray-matter atrophy in early multiple sclerosis: support from structural MRI.

Background: In MS, the relationship between lesions within cerebral white matter (WM) and atrophy within deep gray matter (GM) is unclear.

Objective: To investigate the spatial relationship between WM lesions and deep GM atrophy.

Methods: We performed a cross-sectional structural magnetic resonance imaging (MRI) study (3 Tesla) in 249 patients with clinically-isolated syndrome or relapsing-remitting MS (Expanded Disability Status Scale score: median, 1.