ObjectiveTo report the 5-year risk and to identify risk factors for the development of a seminal acute or progressive clinical event in a multi-national cohort of asymptomatic subjects meeting 2009 RIS Criteria.MethodsRetrospectively identified RIS subjects from 22 databases within 5 countries were evaluated. Time to the first clinical event related to demyelination (acute or 12-month progression of neurological deficits) was compared across different groups by univariate and multivariate analyses utilizing a Cox regression model.ResultsData were available in 451 RIS subjects (F: 354 (78.5%)). The mean age at from the time of the first brain MRI revealing anomalies suggestive of MS was 37.2 years (y) (median: 37.1 y, range: 11–74 y) with mean clinical follow-up time of 4.4 y (median: 2.8 y, range: 0.01–21.1 y). Clinical events were identified in 34% (standard error = 3%) of individuals within a 5-year period from the first brain MRI study. Of those who developed symptoms, 9.6% fulfilled criteria for primary progressive MS. In the multivariate model, age [hazard ratio (HR): 0.98 (95% CI: 0.96–0.99); p = 0.03], sex (male) [HR: 1.93 (1.24–2.99); p = 0.004], and lesions within the cervical or thoracic spinal cord [HR: 3.08 (2.06–4.62); p = <0.001] were identified as significant predictors for the development of a first clinical event.InterpretationThese data provide supportive evidence that a meaningful number of RIS subjects evolve to a first clinical symptom. An age <37 y, male sex, and spinal cord involvement appear to be the most important independent predictors of symptom onset.

Testis-brain RNA-binding protein (TB-RBP), the mouse orthologue of the human protein Translin, is a widely expressed and highly conserved protein with proposed functions in chromosomal translocations, mitotic cell division, and mRNA transport and storage. To better define the biological roles of TB-RBP, we generated mice lacking TB-RBP. Matings between heterozygotes gave rise to viable, apparently normal homozygous mutant mice at a normal Mendelian ratio. The TB-RBP-related and -interacting protein Translin-associated factor X was reduced to 50% normal levels in heterozygotes and was absent in TB-RBP-null animals. The null mice were 10 to 30% smaller than their wild-type or heterozygote littermates at birth and remained so to about 6 to 9 months of age, showed normal B-and T-cell development, and accumulated visceral fat. TB-RBP-null male mice were fertile and sired offspring but had abnormal seminiferous tubules and reduced sperm counts. Null female mice were subfertile and had reduced litter sizes. Microarray analysis of total brain RNA from null and wild-type mice revealed an altered gene expression profile with the up-regulation of 14 genes and the down-regulation of 217 genes out of 12,473 probe sets. Numerous neurotransmitter receptors and ion channels, including ␥-aminobutyric acid A receptor ␣1 and glutamate receptor ␣3, were strongly down-regulated. Behavioral abnormalities were also seen. Compared to littermates, the TB-RBP-null mice appeared docile and exhibited reduced Rota-Rod performance.The mouse nucleic acid-binding protein testis-brain RNAbinding protein (TB-RBP) is the orthologue of the human protein Translin (5, 6, 26). The official nomenclature for the mouse TB-RBP gene is Tsn. Translin/TB-RBP is expressed in many organisms, including fission yeasts, plants, frogs, insects, and mammals. In mammalian tissues, it is ubiquitously expressed, with especially high levels in the brain and testis (18,31,32). Translin is a 228-amino-acid protein encoded by a single-copy gene on human chromosome 2 (3). TB-RBP, encoded by a single-copy gene on mouse chromosome 1, differs from the human protein in three amino acids (3,55,56). Translin has been implicated in DNA rearrangements through binding to single-stranded DNA sequences found at the breakpoint junctions of chromosomal translocations in lymphoid malignancies and solid tumors (26). Electron microscopic and analytical ultracentrifugation studies have revealed multimeric ring structures of Translin which have been proposed to recognize staggered breaks occurring at recombination hot spots in the genome (26,35,45,52). Similar multimeric ring structures are seen when TB-RBP is crystallized (44). Recently, Translin was shown to accelerate cell proliferation when overexpressed in cultured HEK cells (22).In addition to its proposed roles in DNA recombination and cell proliferation, TB-RBP functions in mRNA transport and/or stabilization and in translational regulation (40,41). In the brain and testis, TB-RBP serves as a linker protein binding specific mRNAs t...

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Objective The radiologically isolated syndrome (RIS) represents the earliest detectable pre‐clinical phase of multiple sclerosis (MS). This study evaluated the impact of therapeutic intervention in preventing first symptom manifestation at this stage in the disease spectrum. Methods We conducted a multi‐center, randomized, double‐blinded, placebo‐controlled study involving people with RIS. Individuals without clinical symptoms typical of MS but with incidental brain MRI anomalies consistent with central nervous system (CNS) demyelination were included. Within 12 MS centers in the United States, participants were randomly assigned 1:1 to oral dimethyl fumarate (DMF) 240 mg twice daily or placebo. The primary endpoint was the time to onset of clinical symptoms attributable to a CNS demyelinating event within a follow‐up period of 96 weeks. An intention‐to‐treat analysis was applied to all participating individuals in the primary and safety investigations. The study is registered at http://clinicaltrials.gov, NCT02739542 (ARISE). Results Participants from 12 centers were recruited from March 9, 2016, to October 31, 2019, with 44 people randomized to dimethyl fumarate and 43 to placebo. Following DMF treatment, the risk of a first clinical demyelinating event during the 96‐week study period was highly reduced in the unadjusted Cox proportional‐hazards regression model (hazard ratio [HR] = 0.18, 95% confidence interval [CI] = 0.05–0.63, p = 0.007). More moderate adverse reactions were present in the DMF (34 [32%]) than placebo groups (19 [21%]) but severe events were similar (DMF, 3 [5%]; placebo, 4 [9%]). Interpretation This is the first randomized clinical trial demonstrating the benefit of a disease‐modifying therapy in preventing a first acute clinical event in people with RIS. ANN NEUROL 2023;93:604–614

Study design: Cross-sectional analyses. Objective: To determine whether cervical spinal cord lesions predict the presence of thoracic cord lesions in multiple sclerosis (MS) patients. Setting: Single MS Clinic, AZ, USA. Methods: All MS patients, with MRI studies of the brain, cervical and thoracic spine obtained during a single scanning session, were acquired during a 1-year period. Clinical, demographic and imaging covariates were used in a multivariate regression model to refine predictors of thoracic cord involvement. Results: A total of 687 patients were evaluated, and patients were excluded because of a diagnosis of other neurological disorders, not meeting the 2010 McDonald criteria for MS (n = 222) or incomplete neuraxis imaging (n = 339). The study cohort comprised 126 patients. There was an increase in the odds ratio (OR) of thoracic spine involvement when any cervical spine lesion was present (OR = 6.08, 95% confidence interval (2.21-16.68), Po0.001). The multivariate logistic regression model demonstrated a substantial and significant increase in the odds of thoracic spine involvement when more than two cervical spine lesions were present, two lesions (OR 4.44, (0.91-21.60), P = 0.06), three lesions (OR 19.76,, P = 0.001), four or more lesions (OR 20.49,), P = 0.012) and diffuse lesions (OR 71.94,), P = 0.001), when adjusting for significant covariates including clinical symptoms, brain lesions, disease duration and treatment exposure. Conclusions: Thoracic spinal cord lesions appear to be predicated on the degree of cervical spine involvement in patients with MS, a risk that appears to be independent of brain findings or clinical features.