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OBJECTIVE:To assess the onset of ocrelizumab efficacy on brain MRI measures of disease activity in the phase II study in relapsing-remitting multiple sclerosis (RRMS), and relapse rate in the pooled phase III studies in relapsing multiple sclerosis (RMS). METHODS:Brain MRI activity was determined in the phase II trial at monthly intervals in patients with RRMS receiving placebo, ocrelizumab (600 mg), or intramuscular interferon (IFN) β-1a (30 μg). Annualized relapse rate (ARR; over various epochs) and time to first relapse were analyzed in the pooled population of the phase III OPERA (A Study of Ocrelizumab in Comparison With Interferon Beta-1a [Rebif] in Participants With Relapsing Multiple Sclerosis) I and OPERA II trials in patients with RMS receiving ocrelizumab (600 mg) or subcutaneous IFN-β-1a (44 μg). RESULTS:In patients with RRMS, ocrelizumab reduced the number of new T1 gadolinium-enhancing lesions by week 4 vs placebo (p = 0.042) and by week 8 vs intramuscular IFN-β-1a (p < 0.001). Ocrelizumab also reduced the number of new or enlarging T2 lesions appearing between weeks 4 and 8 vs both placebo and IFN-β-1a (both p < 0.001). In patients with RMS, ocrelizumab significantly reduced ARR (p = 0.005) and the probability of time to first protocol-defined relapse (p = 0.014) vs subcutaneous IFN-β-1a within the first 8 weeks. CONCLUSION:Epoch analysis of MRI-measured lesion activity in the phase II study and relapse rate in the phase III studies consistently revealed a rapid suppression of acute MRI and clinical disease activity following treatment initiation with ocrelizumab in patients with RRMS and RMS, respectively. CLASSIFICATION OF EVIDENCE:This study provides Class II evidence that for patients with RRMS and RMS, ocrelizumab suppressed MRI activity within 4 weeks and clinical disease activity within 8 weeks.

ObjectiveTo summarize current and emerging imaging techniques that can be used to assess neuroprotection and repair in multiple sclerosis (MS), and to provide a consensus opinion on the potential utility of each technique in clinical trial settings.MethodsClinicians and scientists with expertise in the use of MRI in MS convened in Toronto, Canada, in November 2016 at a North American Imaging in Multiple Sclerosis (NAIMS) Cooperative workshop meeting. The discussion was compiled into a manuscript and circulated to all NAIMS members in attendance. Edits and feedback were incorporated until all authors were in agreement.ResultsA wide spectrum of imaging techniques and analysis methods in the context of specific study designs were discussed, with a focus on the utility and limitations of applying each technique to assess neuroprotection and repair. Techniques were discussed under specific themes, and included conventional imaging, magnetization transfer ratio, diffusion tensor imaging, susceptibility-weighted imaging, imaging cortical lesions, magnetic resonance spectroscopy, PET, advanced diffusion imaging, sodium imaging, multimodal techniques, imaging of special regions, statistical considerations, and study design.ConclusionsImaging biomarkers of neuroprotection and repair are an unmet need in MS. There are a number of promising techniques with different strengths and limitations, and selection of a specific technique will depend on a number of factors, notably the question the trial seeks to answer. Ongoing collaborative efforts will enable further refinement and improved methods to image the effect of novel therapeutic agents that exert benefit in MS predominately through neuroprotective and reparative mechanisms.

Background: Advanced magnetic resonance imaging (MRI) methods can provide more specific information about various microstructural tissue changes in multiple sclerosis (MS) brain. Quantitative measurement of T1 and T2 relaxation, and diffusion basis spectrum imaging (DBSI) yield metrics related to the pathology of neuroinflammation and neurodegeneration that occurs across the spectrum of MS. Objective: To use relaxation and DBSI MRI metrics to describe measures of neuroinflammation, myelin and axons in different MS subtypes. Methods: 103 participants (20 clinically isolated syndrome (CIS), 33 relapsing-remitting MS (RRMS), 30 secondary progressive MS and 20 primary progressive MS) underwent quantitative T1, T2, DBSI and conventional 3T MRI. Whole brain, normal-appearing white matter, lesion and corpus callosum MRI metrics were compared across MS subtypes. Results: A gradation of MRI metric values was seen from CIS to RRMS to progressive MS. RRMS demonstrated large oedema-related differences, while progressive MS had the most extensive abnormalities in myelin and axonal measures. Conclusion: Relaxation and DBSI-derived MRI measures show differences between MS subtypes related to the severity and composition of underlying tissue damage. RRMS showed oedema, demyelination and axonal loss compared with CIS. Progressive MS had even more evidence of increased oedema, demyelination and axonal loss compared with CIS and RRMS. [ABSTRACT FROM AUTHOR]

Background and Purpose: Cognitive impairment is a core symptom in multiple sclerosis (MS). Damage to normal appearing white matter (NAWM) is likely involved. We sought to determine if greater myelin heterogeneity in NAWM is associated with decreased cognitive performance in MS.Methods: A total of 27 participants with MS and 13 controls matched for age, sex, and education underwent myelin water imaging (MWI) from which the myelin water fraction (MWF) was calculated. Corpus callosum, superior longitudinal fasciculus, and cingulum were chosen as regions of interest (ROIs) a priori based on their involvement in MS-related cognitive impairment. Cognitive performance was assessed using the Symbol Digit Modalities Test (SDMT). Pearson ́s product moment correlations were performed to assess relationships between cognitive performance and myelin heterogeneity (variance of MWF within an ROI).Results: In MS, myelin heterogeneity in all three ROIs was significantly associated with performance on the SDMT. These correlations ranged from moderate (r = -.561) to moderately strong (r = -.654) and were highly significant (P values ranged from .001 to .0002). Conversely, myelin heterogeneity was not associated with SDMT performance in controls in any ROI (P > .108).Conclusion: Increased myelin heterogeneity in NAWM is associated with decreased cognitive processing speed performance in MS. [ABSTRACT FROM AUTHOR]

Background: Tissue damage in both multiple sclerosis (MS) lesions and normal-appearing white matter (NAWM) are important contributors to disability and progression. Specific aspects of MS pathology can be measured using advanced imaging. Alemtuzumab is a humanised monoclonal antibody targeting CD52 developed for MS treatment. Objective: To investigate changes over 2 years of advanced magnetic resonance (MR) metrics in lesions and NAWM of MS patients treated with alemtuzumab. Methods: A total of 42 relapsing–remitting alemtuzumab-treated MS subjects were scanned for 2 years at 3 T. T1 relaxation, T2 relaxation, diffusion tensor, MR spectroscopy and volumetric sequences were performed. Mean T1 and myelin water fraction (MWF) were determined for stable lesions, new lesions and NAWM. Fractional anisotropy was calculated for the corpus callosum (CC) and N -acetylaspartate (NAA) concentration was determined from a large NAWM voxel. Brain parenchymal fraction (BPF), cortical thickness and CC area were also calculated. Results: No change in any MR measurement was found in lesions or NAWM over 24 months. BPF, cortical thickness and CC area all showed decreases in the first year followed by stability in the second year. Conclusion: Advanced MR biomarkers of myelin (MWF) and neuron/axons (NAA) show no change in NAWM over 24 months in alemtuzumab-treated MS participants. [ABSTRACT FROM AUTHOR]

Background: Long-term follow-up from the randomized trial of interferon beta-1b (IFNB-1b) permitted the assessment of different definitions of no evidence of disease activity (NEDA) for predicting long-term outcome in multiple sclerosis (MS). Objective: To examine the predictive validity of different NEDA definitions. Methods: Predictive validity for negative disability outcomes (NDOs) at 16 years and survival at 21 years post-randomization were assessed. NEDA in the first 2 years was defined as follows: clinical NEDA: no relapses or Expanded Disability Status Scale (EDSS) progression from baseline to Year 2; NEDA-3a: no relapses, no confirmed ⩾1-point EDSS progression, and no new T2-active lesions; NEDA-3b: no relapses, no EDSS progression, and no increase in T2 burden of disease (T2-BOD); and NEDA-4: no relapses, no EDSS progression, and no increase in T2-BOD or atrophy. NDOs were defined as death, need for wheelchair, EDSS ⩾6, or progressive MS. Results: A total of 245 and 371 patients were evaluated at 16 and 21 years, respectively. Clinical NEDA predicted NDOs (p = 0.0029), as did baseline EDSS (p < 0.0001), baseline T2-BOD (p < 0.0001), and change in T2-BOD (p = 0.0033). IFNB-1b treatment (p = 0.0251), relapse rate in the 2 years before study start (p = 0.0260), T2-BOD at baseline (p = 0.0014), and change in T2-BOD (p = 0.0129) predicted survival at 21 years. Conclusion: Clinical NEDA predicted long-term disability outcome. By contrast, definitions of NEDA that included on-therapy changes in magnetic resonance imaging variables did not increase the predictive validity. [ABSTRACT FROM AUTHOR]

We assess two modified guidelines for monitoring patient safety in multiple sclerosis (MS) trials. These guidelines flag patients with an increase in contrast enhancing lesion (CEL) count above a threshold over the CEL level 1–2 months earlier. We compare the new guidelines to the original guideline where the threshold is set according to the baseline by applying the guidelines to two previous studies. The odds ratios of a subsequent clinical relapse associated with meeting the CEL threshold based on the modified guidelines are similar to those based on the original guideline. There is a need for patient and cohort specific monitoring procedures. [ABSTRACT FROM PUBLISHER]

Background: Reduced myelin water fraction (MWF, a marker for myelin), increased geometric mean T 2 (ieGMT 2 , reflecting intra/extracellular water properties), and increased T 1 (related to total water content) have been observed in cross-sectional studies of multiple sclerosis (MS) normal-appearing white matter (NAWM)., Objective: To assess longitudinal changes of magnetic resonance (MR) measures in relapsing-remitting MS (RRMS) brain NAWM., Methods: A total of 11 subjects with RRMS and 4 controls were scanned on a 3T MRI at baseline and long-term follow-up (LTFU; 3.2-5.8 years) with a 32-echo T 2 relaxation and an inversion recovery T 1 sequence. For every voxel, MWF, ieGMT 2 , and T 1 were obtained. Mean, peak height, and peak location from NAWM mask-based histograms were determined., Results: In MS subjects, NAWM MWF mean decreased by 8% ( p = 0.0016). No longitudinal changes were measured in T 1 or ieGMT 2 . There was no relationship between change in any MR metric and change in EDSS. Control white matter showed no differences over time in any metric., Conclusion: The decreases we observed in MWF suggest that changes in myelin integrity and loss of myelin may be occurring diffusely and over long time periods in the MS brain. The timescale of these changes indicates that chronic, progressive myelin damage is an evolving process occurring over many years.

Background: Loss of myelin in the spinal cord in multiple sclerosis (MS) is likely an important, and early, contributor to atrophy and associated disability. In vivo measurement of myelin is possible using myelin water fraction (MWF) imaging, but MWF has never been assessed in MS along the entire length of the spinal cord in vivo or in post-mortem tissue., Objective: To assess the feasibility of measuring the distribution of MWF along the entire length of the spinal cord in post-mortem MS tissue using high-field MRI., Methods: One formalin-fixed spinal cord from a female with secondary progressive MS (age: 78 years, disease duration: 25 years) was cut into 104 5-mm-thick cross sections along the entire length of the spinal cord from the cervico-medullary junction to the conus medullaris and imaged using a 64 echo T2 relaxation experiment at 7T., Results: Myelin water maps showed cord anatomy in superb detail, white matter demonstrating a higher MWF than the grey matter. Anatomical variation in myelin distribution along cervical, thoracic and lumbar regions was observed. Lesions demonstrated myelin loss., Conclusion: Post-mortem myelin water imaging of formalin-fixed MS spinal cord is feasible., (© The Author(s), 2016.)

Background: Both multiple sclerosis (MS) and neuromyelitis optica (NMO) can present with transverse myelitis; however, NMO symptoms are usually more severe and may present with more extensive axonal loss. Transcranial magnetic stimulation (TMS)-based input-output recruitment curves can quantitatively assess the excitability of corticospinal tract pathways and myelin water imaging can quantify the amount of myelin within this same pathway., Objective: To compare differential effects of MS and NMO on TMS recruitment curves and myelin water imaging., Methods: Ten healthy controls, 10 individuals with MS and 10 individuals with NMO completed clinical assessments, a TMS assessment and magnetic resonance imaging scan to measure recruitment curves and myelin water fraction in the corticospinal tract., Results: Individuals with NMO had lower recruitment curve slopes (mean 13.6±6 μV/%) than MS (23.6±11 μV/%) and controls (21.9±9 μV/%, analysis of variance (ANOVA) P=0.05). Corticospinal tract myelin water fraction was lower in individuals with NMO (mean 0.17±0.02) compared to MS (0.19±0.02) and controls (0.20±0.02, ANOVA P=0.0006)., Conclusion: Corticospinal pathway damage in individuals with NMO was evident by reduced recruitment curve slope and lower myelin water fraction. These specific measures of corticospinal function and structure may be used to obtain a better understanding and monitor brain injury caused by inflammatory central nervous system disorders., (© The Author(s), 2015.)