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Modern management of MS targets No Evidence of Disease Activity (NEDA): no clinical relapses, no magnetic resonance imaging (MRI) disease activity and no disability worsening. While MRI is the principal tool available to neurologists for monitoring clinically silent MS disease activity and, where appropriate, escalating treatment, standard radiology reports are qualitative and may be insensitive to the development of new or enlarging lesions. Existing quantitative neuroimaging tools lack adequate clinical validation. In 397 multi-center MRI scan pairs acquired in routine practice, we demonstrate superior case-level sensitivity of a clinically integrated AI-based tool over standard radiology reports (93.3% vs 58.3%), relative to a consensus ground truth, with minimal loss of specificity. We also demonstrate equivalence of the AI-tool with a core clinical trial imaging lab for lesion activity and quantitative brain volumetric measures, including percentage brain volume loss (PBVC), an accepted biomarker of neurodegeneration in MS (mean PBVC -0.32% vs -0.36%, respectively), whereas even severe atrophy (>0.8% loss) was not appreciated in radiology reports. Finally, the AI-tool additionally embeds a clinically meaningful, experiential comparator that returns a relevant MS patient centile for lesion burden, revealing, in our cohort, inconsistencies in qualitative descriptors used in radiology reports. AI-based image quantitation enhances the accuracy of, and value-adds to, qualitative radiology reporting. Scaled deployment of these tools will open a path to precision management for patients with MS., (© 2023. Springer Nature Limited.)

Competing Interests: Competing interests: None declared.

Background: Adherence and persistence are critical to optimising therapeutic benefit from disease-modifying therapies (DMTs) in relapsing-remitting multiple sclerosis (RRMS). This prospective, open-label, multicentre, observational study (AubPRO), conducted in 13 hospital-based neurology clinics around Australia, describes treatment satisfaction in patients newly initiated on teriflunomide (Aubagio) and evaluates the use of an electronic patient-reported outcome (PRO) tool., Methods: Patients (≥18 years) newly initiated on teriflunomide (14 mg/day) were followed up at 24 and 48 weeks. Patients completed questionnaires and pill counts electronically using MObile Data in Multiple Sclerosis. The primary endpoint was treatment satisfaction, measured by the Treatment Satisfaction Questionnaire for Medication (TSQM, V.1.4), at week 48. Secondary endpoints included treatment satisfaction at week 24, other PRO scales, clinical outcomes, medication adherence and safety., Results: Patients (n=103; 54 (52.4%) treatment naive) were mostly female (n=82 (79.6%)), aged 49.5 (11.8) years, with MS duration since symptom onset of 9.1 (11.8) years and a median Expanded Disability Status Scale score of 1.0. Mean treatment satisfaction scores were high (≥60%) across all domains of the TSQM V.1.4 at week 24 and at week 48. Compared with week 24, week 48 treatment satisfaction increased for patients who were treatment naïve and for those previously on another oral or injectable DMT. Over 48 weeks, PROs remained stable across a range of measures including disability, physical health, emotional health and mobility, and there were improvements in work capacity and daily life activity. Adherence was high throughout the study with mean compliance (pill counts) of 93.2%±6.26%, and 98 of 103 (95.1%) patients remained relapse-free., Conclusion: This cohort of Australian patients with RRMS, newly initiated on teriflunomide, and treated in a real-world clinical practice setting, reported high treatment satisfaction and adherence at 24 and 48 weeks. Patient-reported measures of disability remained stably low, work capacity and daily life activity improved, and most patients remained relapse-free., Competing Interests: Competing interests: TH has received speaking fees or received honoraria for serving on advisory boards for Biogen, Merck, Teva, Novartis, Roche, Bristol Myers Squibb and Sanofi. He is co-editor of Advances in Clinical Neurosciences and Rehabilitation. JP reports grants from Roche, Merck, Sanofi, Biogen and consulting agreements for Roche, Merck, Sanofi, Biogen and Eli-Lilly. MB reports grants from Biogen, grants from Novartis Pharmaceuticals, grants from Sanofi, grants from Merck, outside the submitted work; and MB is a consultant to RxMx and research director at the Sydney Neuroimaging Analysis Centre. HB reports personal fees and other from Biogen, personal fees and other from Novartis, personal fees and other from Sanofi, personal fees and other from Roche, personal fees and other from Merck, outside the submitted work. AL, RGB, RM, NS, WC and CS have nothing to disclose. SB reports grants and speaker fees from Merck, Biogen, Sanofi, Novartis, Bayer, Otuskua, CSL and Roche. MS is an employee of Sanofi and may hold shares and/or stock options in the company. RW is an employee of Sanofi and may hold shares and/or stock options in the company. JM is an employee of Sanofi and may hold shares and/or stock options in the company. SV reports personal fees and other from Biogen Idec and Merck, outside the submitted work., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To investigate potential neuroprotective and pro-remyelinating effects of alemtuzumab in multiple sclerosis (MS), using the visual pathway as a model., Methods: We monitored clinical, multifocal visual evoked potential (mfVEP) and MRI outcomes in 30 patients commencing alemtuzumab for relapsing MS, and a reference group of 20 healthy controls (HCs), over 24 months. Change in mfVEP latency was the primary endpoint; change in optic radiation (OR) lesion diffusion metrics and Mars letter contrast sensitivity over the course of the study were secondary endpoints., Results: In patients, we observed a mean shortening of mfVEP latency of 1.21 ms over the course of the study (95% CI 0.21 to 2.21, p=0.013), not altered by correction for age, gender, disease duration or change in OR T2 lesion volume. Mean mfVEP latency in the HC group increased over the course of the study by 0.72 ms (not significant). Analysis of chronic OR T2 lesions (patients) showed an increase in normalised fractional anisotropy and axial diffusivity between baseline and 24 months (both p<0.01). Mean Mars letter contrast sensitivity was improved at 24 months vs baseline (p<0.001), and driven by an early improvement, in both patients and HC., Conclusion: We found evidence of partial lesion remyelination after alemtuzumab therapy, indicating either natural restoration in the context of a 'permissive' local milieu; or potentially an independent, pro-reparative mechanism of action. The visual system presents a unique opportunity to study function-structure specific effects of therapy and inform the design of future phase 2 MS remyelination trials., Competing Interests: Competing interests: CW has received research fellowship support from Multiple Sclerosis Research Australia, Nerve Research Foundation at the University of Sydney, and is an employee at Sydney Neuroimaging Analysis Centre (SNAC). JB has received honoraria for talks and advisory boards and support for scientific meetings from Sanofi-Genzyme, Novartis, Teva, Merck and Biogen. KK and LL are employees at SNAC. YB is a consulting neuroradiologist for SNAC. HB has received honoraria for presentations and advisory boards; and has received educational travel support from Biogen, Genzyme, Merck, Novartis and/or Roche. SWR has received institutional support from Baxter, Bayer Schering, Biogen Idec, CSL, Genzyme, Grifols, Octapharma, Merck, Novartis, Roche, Sanofi Aventis Genzyme, Servier and TEVA; and is a co-founder of Medical Safety Systems/RxMx. MHB reports grants from Genzyme-Sanofi, during the conduct of the study; grants from Genzyme-Sanofi, Novartis, Biogen and Merck outside the submitted work; and is a co-founder of RxMx, which provides automated laboratory monitoring for patients with MS prescribed immunotherapies; and research director of SNAC. H-PH has received fees for serving on steering and data monitoring committees from Bayer Healthcare, Biogen, Celgene BMS, CSL Behring, GeNeuro, MedImmune, Merck, Novartis, Octapharma, Roche, Sanofi Genzyme, TG Therapeutics and Viela Bio; fees for serving on advisory boards from Biogen, Sanofi Genzyme, Merck, Novartis, Octapharma and Roche; and lecture fees from Biogen, Celgene BMS, Merck, Novartis, Roche and Sanofi Genzyme. MT and AK have nothing to disclose., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Whole brain atrophy (WBA) estimates in multiple sclerosis (MS) correlate more robustly with clinical disability than traditional, lesion-based metrics. We compare Structural Image Evaluation using Normalisation of Atrophy (SIENA) with the icobrain longitudinal pipeline (icobrain long), for assessment of longitudinal WBA in MS patients., Methods: Magnetic resonance imaging (MRI) scan pairs [1.05 (±0.15) year separation] from 102 MS patients were acquired on the same 3T scanner. Three-dimensional (3D) T1-weighted and two-dimensional (2D)/3D fluid-attenuated inversion-recovery sequences were analysed. Percentage brain volume change (PBVC) measurements were calculated using SIENA and icobrain long. Statistical correlation, agreement and consistency between methods was evaluated; MRI brain volumetric and clinical data were compared. The proportion of the cohort with annualized brain volume loss (aBVL) rates ⩾ 0.4%, ⩾0.8% and ⩾0.94% were calculated. No evidence of disease activity (NEDA) 3 and NEDA 4 were also determined., Results: Mean annualized PBVC was -0.59 (±0.65)% and -0.64 (±0.73)% as measured by icobrain long and SIENA. icobrain long and SIENA-measured annualized PBVC correlated strongly, r = 0.805 ( p < 0.001), and the agreement [intraclass correlation coefficient (ICC) 0.800] and consistency (ICC 0.801) were excellent. Weak correlations were found between MRI metrics and Expanded Disability Status Scale scores. Over half the cohort had aBVL ⩾ 0.4%, approximately a third ⩾0.8%, and aBVL was ⩾0.94% in 28.43% and 23.53% using SIENA and icobrain long, respectively. NEDA 3 was achieved in 35.29%, and NEDA 4 in 15.69% and 16.67% of the cohort, using SIENA and icobrain long to derive PBVC, respectively., Discussion: icobrain long quantified longitudinal WBA with a strong level of statistical agreement and consistency compared to SIENA in this real-world MS population. Utility of WBA measures in individuals remains challenging, but show promise as biomarkers of neurodegeneration in MS clinical practice. Optimization of MRI analysis algorithms/techniques are needed to allow reliable use in individuals. Increased levels of automation will enable more rapid clinical translation., Competing Interests: Conflict of interest statement: Heidi Beadnall has received compensation for education travel, speaker honoraria and/or consultant fees from Biogen, Novartis, Merck, Sanofi Genzyme and Roche. Chenyu Wang has nothing to disclose. Wim Van Hecke is the CEO and co-founder of icometrix. Annemie Ribbens and Thibo Billiet are employees of icometrix. Michael H Barnett has received institutional support for research, speaking and/or participation in advisory boards (Biogen, Novartis, and Sanofi Genzyme); research consultant (Medical Safety Systems).

Exosomes are nano-sized extracellular vesicles released by many cells that contain molecules characteristic of their cell of origin, including microRNA. Exosomes released by glioblastoma cross the blood-brain barrier into the peripheral circulation and carry molecular cargo distinct to that of "free-circulating" miRNA. In this pilot study, serum exosomal microRNAs were isolated from glioblastoma ( n  = 12) patients and analyzed using unbiased deep sequencing. Results were compared to sera from age- and gender-matched healthy controls and to grade II-III ( n  = 10) glioma patients. Significant differentially expressed microRNAs were identified, and the predictive power of individual and subsets of microRNAs were tested using univariate and multivariate analyses. Additional sera from glioblastoma patients ( n  = 4) and independent sets of healthy ( n  = 9) and non-glioma ( n  = 10) controls were used to further test the specificity and predictive power of this unique exosomal microRNA signature. Twenty-six microRNAs were differentially expressed in serum exosomes from glioblastoma patients relative to healthy controls. Random forest modeling and data partitioning selected seven miRNAs (miR-182-5p, miR-328-3p, miR-339-5p, miR-340-5p, miR-485-3p, miR-486-5p, and miR-543) as the most stable for classifying glioblastoma. Strikingly, within this model, six iterations of these miRNA classifiers could distinguish glioblastoma patients from controls with perfect accuracy. The seven miRNA panel was able to correctly classify all specimens in validation cohorts ( n  = 23). Also identified were 23 dysregulated miRNAs in IDH MUT gliomas, a partially overlapping yet distinct signature of lower-grade glioma. Serum exosomal miRNA signatures can accurately diagnose glioblastoma preoperatively. miRNA signatures identified are distinct from previously reported "free-circulating" miRNA studies in GBM patients and appear to be superior., Competing Interests: The authors declare no competing interests.

The availability of effective therapies for patients with relapsing-remitting multiple sclerosis (RRMS) has prompted a re-evaluation of the most appropriate way to measure treatment response, both in clinical trials and clinical practice. Traditional parameters of treatment efficacy such as annualized relapse rate, magnetic resonance imaging (MRI) activity, and disability progression have an important place, but their relative merit is uncertain, and the role of other factors such as brain atrophy is still under study. More recently, composite measures such as "no evidence of disease activity" (NEDA) have emerged as new potential treatment targets, but NEDA itself has variable definitions, is not well validated, and may be hard to implement as a treatment goal in a clinical setting. We describe the development of NEDA as an outcome measure in MS, discuss definitions including NEDA-3 and NEDA-4, and review the strengths and limitations of NEDA, indicating where further research is needed., (Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.)

Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). There is currently no single definitive test for MS. Circulating exosomes represent promising candidate biomarkers for a host of human diseases. Exosomes contain RNA, DNA, and proteins, can cross the blood-brain barrier, and are secreted from almost all cell types including cells of the CNS. We hypothesized that serum exosomal miRNAs could present a useful blood-based assay for MS disease detection and monitoring. Exosome-associated microRNAs in serum samples from MS patients (n = 25) and matched healthy controls (n = 11) were profiled using small RNA next generation sequencing. We identified differentially expressed exosomal miRNAs in both relapsing-remitting MS (RRMS) (miR-15b-5p, miR-451a, miR-30b-5p, miR-342-3p) and progressive MS patient sera (miR-127-3p, miR-370-3p, miR-409-3p, miR-432-5p) in relation to controls. Critically, we identified a group of nine miRNAs (miR-15b-5p, miR-23a-3p, miR-223-3p, miR-374a-5p, miR-30b-5p, miR-433-3p, miR-485-3p, miR-342-3p, miR-432-5p) that distinguished relapsing-remitting from progressive disease. Eight out of nine miRNAs were validated in an independent group (n = 11) of progressive MS cases. This is the first demonstration that microRNAs associated with circulating exosomes are informative biomarkers not only for the diagnosis of MS, but in predicting disease subtype with a high degree of accuracy.