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Background: MRI assessment in multiple sclerosis (MS) focuses on the presence of typical white matter (WM) lesions. Neurodegeneration characterised by brain atrophy is recognised in the research field as an important prognostic factor. It is not routinely reported clinically, in part due to difficulty in achieving reproducible measurements. Automated MRI quantification of WM lesions and brain volume could provide important clinical monitoring data. In general, lesion quantification relies on both T1 and FLAIR input images, while tissue volumetry relies on T1. However, T1-weighted scans are not routinely included in the clinical MS protocol, limiting the utility of automated quantification., Objectives: We address an aspect of this important translational challenge by assessing the performance of FLAIR-only lesion and brain segmentation, against a conventional approach requiring multi-contrast acquisition. We explore whether FLAIR-only grey matter (GM) segmentation yields more variability in performance compared with two-channel segmentation; whether this is related to field strength; and whether the results meet a level of clinical acceptability demonstrated by the ability to reproduce established biological associations., Methods: We used a multicentre dataset of subjects with a CIS suggestive of MS scanned at 1.5T and 3T in the same week. WM lesions were manually segmented by two raters, 'manual 1' guided by consensus reading of CIS-specific lesions and 'manual 2' by any WM hyperintensity. An existing brain segmentation method was adapted for FLAIR-only input. Automated segmentation of WM hyperintensity and brain volumes were performed with conventional (T1/T1 + FLAIR) and FLAIR-only methods., Results: WM lesion volumes were comparable at 1.5T between 'manual 2' and FLAIR-only methods and at 3T between 'manual 2', T1 + FLAIR and FLAIR-only methods. For cortical GM volume, linear regression measures between conventional and FLAIR-only segmentation were high (1.5T: α = 1.029, R 2  = 0.997, standard error (SE) = 0.007; 3T: α = 1.019, R 2  = 0.998, SE = 0.006). Age-associated change in cortical GM volume was a significant covariate in both T1 (p = 0.001) and FLAIR-only (p = 0.005) methods, confirming the expected relationship between age and GM volume for FLAIR-only segmentations., Conclusions: FLAIR-only automated segmentation of WM lesions and brain volumes were consistent with results obtained through conventional methods and had the ability to demonstrate biological effects in our study population. Imaging protocol harmonisation and validation with other MS phenotypes could facilitate the integration of automated WM lesion volume and brain atrophy analysis as clinical tools in radiological MS reporting., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: The novel PET tracer [ 11 C]SMW139 binds with high affinity to the P2X 7 receptor, which is expressed on pro-inflammatory microglia. The purposes of this first in-man study were to characterise pharmacokinetics of [ 11 C]SMW139 in patients with active relapsing remitting multiple sclerosis (RRMS) and healthy controls (HC) and to evaluate its potential to identify in vivo neuroinflammation in RRMS., Methods: Five RRMS patients and 5 age-matched HC underwent 90-min dynamic [ 11 C]SMW139 PET scans, with online continuous and manual arterial sampling to generate a metabolite-corrected arterial plasma input function. Tissue time activity curves were fitted to single- and two-tissue compartment models, and the model that provided the best fits was determined using the Akaike information criterion., Results: The optimal model for describing [ 11 C]SMW139 kinetics in both RRMS and HC was a reversible two-tissue compartment model with blood volume parameter and with the dissociation rate k 4 fixed to the whole-brain value. Exploratory group level comparisons demonstrated an increased volume of distribution (V T ) and binding potential (BP ND ) in RRMS compared with HC in normal appearing brain regions. BP ND in MS lesions was decreased compared with non-lesional white matter, and a further decrease was observed in gadolinium-enhancing lesions. In contrast, increased V T was observed in enhancing lesions, possibly resulting from disruption of the blood-brain barrier in active MS lesions. In addition, there was a high correlation between parameters obtained from 60- to 90-min datasets, although analyses using 60-min data led to a slight underestimation in regional V T and BP ND values., Conclusions: This first in-man study demonstrated that uptake of [ 11 C]SMW139 can be quantified with PET using BP ND as a measure for specific binding in healthy controls and RRMS patients. Additional studies are warranted for further clinical evaluation of this novel neuroinflammation tracer.

Background: Natalizumab is an effective treatment for relapsing-remitting multiple sclerosis (RRMS). Data on clinical and imaging measures predictive of disease activity and progression during treatment is limited., Objective: To determine clinical and imaging predictors of long-term inflammatory disease activity and disability progression in RRMS patients on natalizumab., Methods: Patients (n = 135) were selected from our prospective observational natalizumab cohort and monitored using brain MRI and extensive clinical testing. Progression and improvement on the Expanded Disability Status Scale (EDSS), no evidence of disease activity (NEDA) and no evidence of progression or active disease (NEPAD) status were determined using measurements after the initial phase of inflammation and the early anti-inflammatory impact of natalizumab., Results: EDSS progression was seen in 43.7% of patients and EDSS improvement in 17.8%. Median follow-up was 4.9 years (IQR 3.6-6.0). Patients with a longer disease duration at natalizumab initiation have a higher hazard for earlier EDSS progression (HR 1.05, CI 1.00-1.09, p = 0.037) and a higher pre-baseline relapse rate predicted a longer NEPAD status (HR 1.70, CI 1.06-2.72, p = 0.028)., Conclusion: The results suggest that starting natalizumab early, during active inflammatory disease results in a more favourable outcome. When taking into account early inflammation and the impact of natalizumab on disease activity during the initial treatment phase, a higher than expected proportion of patients showed disability progression., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Over the past decades, positron emission tomography (PET) imaging has become an increasingly useful research modality in the field of multiple sclerosis (MS) research, as PET can visualise molecular processes, such as neuroinflammation, in vivo. The second generation PET radioligand [ 18 F]DPA714 binds with high affinity to the 18-kDa translocator-protein (TSPO), which is mainly expressed on activated microglia. The aim of this proof of concept study was to evaluate this in vivo marker of neuroinflammation in primary and secondary progressive MS., Methods: All subjects were genotyped for the rs6971 polymorphism within the TSPO gene, and low-affinity binders were excluded from participation in this study. Eight patients with progressive MS and seven age and genetic binding status matched healthy controls underwent a 60 min dynamic PET scan using [ 18 F]DPA714, including both continuous on-line and manual arterial blood sampling to obtain metabolite-corrected arterial plasma input functions., Results: The optimal model for quantification of [ 18 F]DPA714 kinetics was a reversible two-tissue compartment model with additional blood volume parameter. For genetic high-affinity binders, a clear increase in binding potential was observed in patients with MS compared with age-matched controls. For both high and medium affinity binders, a further increase in binding potential was observed in T2 white matter lesions compared with non-lesional white matter. Volume of distribution, however, did not differentiate patients from healthy controls, as the large non-displaceable compartment of [ 18 F]DPA714 masks its relatively small specific signal., Conclusion: The TSPO radioligand [ 18 F]DPA714 can reliably identify increased focal and diffuse neuroinflammation in progressive MS when using plasma input-derived binding potential, but observed differences were predominantly visible in high-affinity binders.

Objective: In the work-up of patients presenting with a clinically isolated syndrome (CIS), 3T MRI might offer a higher lesion detection than 1.5T, but it remains unclear whether this affects the fulfilment of the diagnostic criteria for multiple sclerosis (MS)., Methods: We recruited 66 patients with CIS within 6 months from symptom onset and 26 healthy controls in 6 MS centers. All participants underwent 1.5T and 3T brain and spinal cord MRI at baseline according to local optimized protocols and the MAGNIMS guidelines. Patients who had not converted to MS during follow-up received repeat brain MRI at 3-6 months and 12-15 months. The number of lesions per anatomical region was scored by 3 raters in consensus. Criteria for dissemination in space (DIS) and dissemination in time (DIT) were determined according to the 2017 revisions of the McDonald criteria., Results: Three-Tesla MRI detected 15% more T2 brain lesions compared to 1.5T ( p < 0.001), which was driven by an increase in baseline detection of periventricular (12%, p = 0.015), (juxta)cortical (21%, p = 0.005), and deep white matter lesions (21%, p < 0.001). The detection rate of spinal cord lesions and gadolinium-enhancing lesions did not differ between field strengths. Three-Tesla MRI did not lead to a higher number of patients fulfilling the criteria for DIS or DIT, or subsequent diagnosis of MS, at any of the 3 time points., Conclusion: Scanning at 3T does not influence the diagnosis of MS according to McDonald diagnostic criteria., (© 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)