Objective Rates of worsening and evolution to secondary progressive multiple sclerosis (MS) may be substantially lower in actively treated patients compared to natural history studies from the pretreatment era. Nonetheless, in our recently reported prospective cohort, more than half of patients with relapsing MS accumulated significant new disability by the 10th year of follow‐up. Notably, “no evidence of disease activity” at 2 years did not predict long‐term stability. Here, we determined to what extent clinical relapses and radiographic evidence of disease activity contribute to long‐term disability accumulation. Methods Disability progression was defined as an increase in Expanded Disability Status Scale (EDSS) of 1.5, 1.0, or 0.5 (or greater) from baseline EDSS = 0, 1.0–5.0, and 5.5 or higher, respectively, assessed from baseline to year 5 (±1 year) and sustained to year 10 (±1 year). Longitudinal analysis of relative brain volume loss used a linear mixed model with sex, age, disease duration, and HLA‐DRB1*15:01 as covariates. Results Relapses were associated with a transient increase in disability over 1‐year intervals ( p = 0.012) but not with confirmed disability progression ( p = 0.551). Relative brain volume declined at a greater rate among individuals with disability progression compared to those who remained stable ( p < 0.05). Interpretation Long‐term worsening is common in relapsing MS patients, is largely independent of relapse activity, and is associated with accelerated brain atrophy. We propose the term silent progression to describe the insidious disability that accrues in many patients who satisfy traditional criteria for relapsing–remitting MS. Ann Neurol 2019;85:653–666

Changes in gut microbiota composition and a diverse role of B cells have recently been implicated in multiple sclerosis (MS), a central nervous system (CNS) autoimmune disease. Immunoglobulin A (IgA) is a key regulator at the mucosal interface. However, whether gut microbiota shape IgA responses and what role IgA+ cells have in neuroinflammation are unknown. Here, we identify IgA-bound taxa in MS and show that IgA-producing cells specific for MS-associated taxa traffic to the inflamed CNS, resulting in a strong, compartmentalized IgA enrichment in active MS and other neuroinflammatory diseases. Unlike previously characterized polyreactive anti-commensal IgA responses, CNS IgA cross-reacts with surface structures on specific bacterial strains but not with brain tissue. These findings establish gut microbiota–specific IgA+ cells as a systemic mediator in MS and suggest a critical role of mucosal B cells during active neuroinflammation with broad implications for IgA as an informative biomarker and IgA-producing cells as an immune subset to harness for therapeutic interventions.

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Background and Purpose-The quantification of spinal cord (SC) atrophy by MRI has assumed an important role in assessment of neuroinflammatory/neurodegenerative diseases and traumatic SC injury. Recent technical advances make possible the quantification of gray matter (GM) and white matter tissues in clinical settings. However, the goal of a reliable diagnostic, prognostic or predictive marker is still elusive, in part due to large inter-subject variability of SC areas. Here, we investigated the sources of this variability and explored effective strategies to reduce it.Methods-129 healthy subjects (mean age: 41.0±15.9) underwent MRI on a Siemens 3T Skyra scanner. 2D PSIR at the C2-C3 vertebral level and a sagittal 1mm 3 3D T1-weighted brain acquisition extended to the upper cervical cord were acquired. Total cross-sectional area and GM area were measured at C2-C3, as well as measures of the vertebra, spinal canal and the skull. Correlations between the different metrics were explored using Pearson product-moment coefficients. The most promising metrics were used to normalize cord areas using multiple regression analyses.Results-The most effective normalization metrics were the V-scale (from SienaX) and the product of the C2-C3 spinal canal diameters. Normalization methods based on these metrics reduced the inter-subject variability of cord areas of up to 17.74%. The measured cord areas had a statistically significant sex difference, while the effect of age was moderate.Conclusions-The present work explored in a large cohort of healthy subjects the source of inter-subject variability of SC areas and proposes effective normalization methods for its reduction.

The third National Health and Nutrition Examination Survey (NHANES III) was conducted to assess the health and nutritional status of the US population. As part of the nutritional status assessment, reliable 24-h dietary recalls were collected for 14,801 examined persons. Mean (+/- SEM) energy intakes are reported for persons aged > or = 2 mo by age, sex, and race-ethnicity. Males had higher mean energy intakes than did females. Energy intakes peaked during late adolescence and young adulthood and declined thereafter. Energy intake patterns were similar among non-Hispanic whites, non-Hispanic blacks, and Mexican Americans. Underreporting was addressed by computing a ratio of energy intake (EI) to estimated basal metabolic rate (BMRest). This ratio (EI:BMRest) was 1.47 for adult males and 1.26 for nonpregnant adult females. Overweight adults had a lower mean EI:BMRest (1.09 in females and 1.28 in males). Underreporting in food consumption surveys remains problematic among females and overweight persons.

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Objective A major challenge in multiple sclerosis (MS) research is the understanding of silent progression and Progressive MS. Using a novel method to accurately capture upper cervical cord area from legacy brain MRI scans we aimed to study the role of spinal cord and brain atrophy for silent progression and conversion to secondary progressive disease (SPMS). Methods From a single‐center observational study, all RRMS (n = 360) and SPMS (n = 47) patients and 80 matched controls were evaluated. RRMS patient subsets who converted to SPMS (n = 54) or silently progressed (n = 159), respectively, during the 12‐year observation period were compared to clinically matched RRMS patients remaining RRMS (n = 54) or stable (n = 147), respectively. From brain MRI, we assessed the value of brain and spinal cord measures to predict silent progression and SPMS conversion. Results Patients who developed SPMS showed faster cord atrophy rates (−2.19%/yr) at least 4 years before conversion compared to their RRMS matches (−0.88%/yr, p < 0.001). Spinal cord atrophy rates decelerated after conversion (−1.63%/yr, p = 0.010) towards those of SPMS patients from study entry (−1.04%). Each 1% faster spinal cord atrophy rate was associated with 69% (p < 0.0001) and 53% (p < 0.0001) shorter time to silent progression and SPMS conversion, respectively. Interpretation Silent progression and conversion to secondary progressive disease are predominantly related to cervical cord atrophy. This atrophy is often present from the earliest disease stages and predicts the speed of silent progression and conversion to Progressive MS. Diagnosis of SPMS is rather a late recognition of this neurodegenerative process than a distinct disease phase. ANN NEUROL 2022;91:268–281