The clinico-radiological paradox of cognitive function and MRI burden of white matter lesions in people with multiple sclerosis: a systematic review and meta-analysis.

Moderate correlation exists between the imaging quantification of brain white matter lesions and cognitive performance in people with multiple sclerosis (MS). This may reflect the greater importance of other features, including subvisible pathology, or methodological limitations of the primary literature.To summarise the cognitive clinico-radiological paradox and explore the potential methodological factors that could influence the assessment of this relationship.Systematic review and meta-analysis of primary research relating cognitive function to white matter lesion burden.Fifty papers met eligibility criteria for review, and meta-analysis of overall results was possible in thirty-two (2050 participants). Aggregate correlation between cognition and T2 lesion burden was r = -0.30 (95% confidence interval: -0.34, -0.26). Wide methodological variability was seen, particularly related to key factors in the cognitive data capture and image analysis techniques.Resolving the persistent clinico-radiological paradox will likely require simultaneous evaluation of multiple components of the complex pathology using optimum measurement techniques for both cognitive and MRI feature quantification. We recommend a consensus initiative to support common standards for image analysis in MS, enabling benchmarking while also supporting ongoing innovation

Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis

BACKGROUND: Primary and secondary progressive multiple sclerosis (MS), collectively called progressive multiple sclerosis (PMS), is characterized by gradual progression of disability. The current anti-inflammatory treatments for MS have little or no efficacy in PMS in the absence of obvious active inflammation. Optimal biomarkers for phase II PMS trials is unknown. Ibudilast is an inhibitor of macrophage migration inhibitor factor and phosphodiesterases-4 and -10 and exhibits possible neuroprotective properties. The goals of SPRINT-MS study are to evaluate the safety and efficacy of ibudilast in PMS and to directly compare several imaging metrics for utility in PMS trials. METHODS: SPRINT-MS is a randomized, placebo-controlled, phase II trial of ibudilast in patients with PMS. Eligible subjects were randomized 1:1 to receive either ibudilast (100 mg/day) or placebo for 96 weeks. Imaging is conducted every 24 weeks for whole brain atrophy, magnetization transfer ratio, diffusion tensor imaging, cortical brain atrophy, and retinal nerve fiber layer thickness. Clinical outcomes include neurologic disability and patient reported quality of life. Safety assessments include laboratory testing, electrocardiography, and suicidality screening. RESULTS: A total of 331 subjects were enrolled, of which 255 were randomized onto active study treatment. Randomized subjects were 53.7% female and mean age 55.7 (SD 7.3) years. The last subject is projected to complete the study in May 2017. CONCLUSION: SPRINT-MS is designed to evaluate the safety and efficacy of ibudilast as a treatment for PMS while simultaneously validating five different imaging biomarkers as outcome metrics for use in future phase II proof-of-concept PMS trials

Neuroplasticity and functional recovery in multiple sclerosis

The development of therapeutic strategies that promote functional recovery is a major goal of multiple sclerosis (MS) research. Neuroscientific and methodological advances have improved our understanding of the brain's recovery from damage, generating novel hypotheses about potential targets and modes of intervention, and laying the foundation for development of scientifically informed recovery-promoting strategies in interventional studies. This Review aims to encourage the transition from characterization of recovery mechanisms to development of strategies that promote recovery in MS. We discuss current evidence for functional reorganization that underlies recovery and its implications for development of new recovery-oriented strategies in MS. Promotion of functional recovery requires an improved understanding of recovery mechanisms that can be modulated by interventions and the development of robust measurements of therapeutic effects. As imaging methods can be used to measure functional and structural alterations associated with recovery, this Review discusses their use to obtain reliable markers of the effects of interventions