Association of Initial Side of Brain Atrophy With Clinical Features and Disease Progression in Patients With Frontotemporal Dementia.

Background And Objectives: Pathogenic variants in the gene cause frontotemporal dementia (FTD-) with marked brain asymmetry. This study aims to assess whether the disease progression of FTD- depends on the initial side of the atrophy. We also investigated the potential use of brain asymmetry as a biomarker of the disease.

Large-scale network analysis of the cerebrospinal fluid proteome identifies molecular signatures of frontotemporal lobar degeneration.

The pathophysiological mechanisms driving disease progression of frontotemporal lobar degeneration (FTLD) and corresponding biomarkers are not fully understood. We leveraged aptamer-based proteomics (> 4,000 proteins) to identify dysregulated communities of co-expressed cerebrospinal fluid proteins in 116 adults carrying autosomal dominant FTLD mutations () compared to 39 noncarrier controls. Network analysis identified 31 protein co-expression modules.

Genetics of multiple sclerosis: lessons from polygenicity.

Large-scale mapping studies have identified 236 independent genetic variants associated with an increased risk of multiple sclerosis. However, none of these variants are found exclusively in patients with multiple sclerosis. They are located throughout the genome, including 32 independent variants in the MHC and one on the X chromosome.

Effects of Vitamin D and Body Mass Index on Disease Risk and Relapse Hazard in Multiple Sclerosis: A Mendelian Randomization Study.

Background And Objectives: Decreased vitamin D levels and obesity are associated with an increased risk for multiple sclerosis (MS). However, whether they also affect the disease course after onset remains unclear. With larger data sets now available, we used Mendelian randomization (MR) to determine whether serum 25-hydroxyvitamin D (25OHD) and body mass index (BMI) are causally associated with MS risk and, moving beyond susceptibility toward heterogeneity, with relapse hazard.

Body Mass Index, Interleukin-6 Signaling and Multiple Sclerosis: A Mendelian Randomization Study.

Objectives: We explored whether genetically predicted increased body mass index (BMI) modulates multiple sclerosis (MS) risk through interleukin-6 (IL-6) signaling.

Methods: We performed a two-sample Mendelian randomization (MR) study using multiple genome-wide association studies (GWAS) datasets for BMI, IL-6 signaling, IL-6 levels and c-reactive protein (CRP) levels as exposures and estimated their effects on risk of MS from GWAS data from the International Multiple Sclerosis Genetics Consortium (IMSGC) in 14,802 MS cases and 26,703 controls.

Results: In univariable MR analyses, genetically predicted increased BMI and IL-6 signaling were associated with higher risk of MS (BMI: odds ratio (OR) = 1.

Environmental risk factors in multiple sclerosis: bridging Mendelian randomization and observational studies.

Multiple sclerosis (MS) is a complex disease with both genetic variants and environmental factors involved in disease susceptibility. The main environmental risk factors associated with MS in observational studies include obesity, vitamin D deficiency, Epstein-Barr virus infection and smoking. As modifying these environmental and lifestyle factors may enable prevention, it is important to pinpoint causal links between these factors and MS.

Genetic Variation in WNT9B Increases Relapse Hazard in Multiple Sclerosis.

Objective: Many multiple sclerosis (MS) genetic susceptibility variants have been identified, but understanding disease heterogeneity remains a key challenge. Relapses are a core feature of MS and a common primary outcome of clinical trials, with prevention of relapses benefiting patients immediately and potentially limiting long-term disability accrual. We aim to identify genetic variation associated with relapse hazard in MS by analyzing the largest study population to date.

Quantitative MRI phenotypes capture biological heterogeneity in multiple sclerosis patients.

Magnetization transfer ratio (MTR) and brain volumetric imaging are (semi-)quantitative MRI markers capturing demyelination, axonal degeneration and/or inflammation. However, factors shaping variation in these traits are largely unknown. In this study, we collected a longitudinal cohort of 33 multiple sclerosis (MS) patients and extended it cross-sectionally to 213.

Smoking and multiple sclerosis risk: a Mendelian randomization study.

Background: Striking changes in the demographic pattern of multiple sclerosis (MS) strongly indicate an influence of modifiable exposures, which lend themselves well to intervention. It is important to pinpoint which of the many environmental, lifestyle, and sociodemographic changes that have occurred over the past decades, such as higher smoking and obesity rates, are responsible. Mendelian randomization (MR) is an elegant tool to overcome limitations inherent to observational studies and leverage human genetics to inform prevention strategies in MS.

CHIT1 at Diagnosis Reflects Long-Term Multiple Sclerosis Disease Activity.

Objective: Evidence for a role of microglia in the pathogenesis of multiple sclerosis (MS) is growing. We investigated association of microglial markers at time of diagnostic lumbar puncture (LP) with different aspects of disease activity (relapses, disability, magnetic resonance imaging parameters) up to 6 years later in a cohort of 143 patients.

Methods: In cerebrospinal fluid (CSF), we measured 3 macrophage and microglia-related proteins, chitotriosidase (CHIT1), chitinase-3-like protein 1 (CHI3L1 or YKL-40), and soluble triggering receptor expressed on myeloid cells 2 (sTREM2), as well as a marker of neuronal damage, neurofilament light chain (NfL), using enzyme-linked immunosorbent assay and electrochemiluminescence.

Machine learning identifies an immunological pattern associated with multiple juvenile idiopathic arthritis subtypes.

Objectives: Juvenile idiopathic arthritis (JIA) is the most common class of childhood rheumatic diseases, with distinct disease subsets that may have diverging pathophysiological origins. Both adaptive and innate immune processes have been proposed as primary drivers, which may account for the observed clinical heterogeneity, but few high-depth studies have been performed.

Methods: Here we profiled the adaptive immune system of 85 patients with JIA and 43 age-matched controls with indepth flow cytometry and machine learning approaches.

Genetic Architecture of Adaptive Immune System Identifies Key Immune Regulators.

The immune system is highly diverse, but characterization of its genetic architecture has lagged behind the vast progress made by genome-wide association studies (GWASs) of emergent diseases. Our GWAS for 54 functionally relevant phenotypes of the adaptive immune system in 489 healthy individuals identifies eight genome-wide significant associations explaining 6%-20% of variance. Coding and splicing variants in PTPRC and COMMD10 are involved in memory T cell differentiation.

Genetic basis for relapse rate in multiple sclerosis: Association with LRP2 genetic variation.

Background: In contrast to successes for multiple sclerosis (MS) susceptibility, the genetic basis for clinical heterogeneity remains largely unresolved.

Objectives: We investigate the first reported genetic association with relapse rate.

Methods: We genotyped variant rs12988804 in LRP2 in a homogeneous study population of 527 Belgian MS patients with 970 documented relapses.