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Multiple sclerosis (MS) is a demyelinating and inflammatory disease of the central nervous system (CNS). The demyelination process can be repaired by the generation of a new sheath of myelin around the axon, a process termed remyelination. In MS patients, the demyelination-remyelination cycles are highly dynamic. Over the years, magnetic resonance imaging (MRI) has been increasingly used in the diagnosis of MS and it is currently the most useful paraclinical tool to assess this diagnosis. However, conventional MRI pulse sequences are not specific for pathological mechanisms such as demyelination and remyelination. Recently, positron emission tomography (PET) with radiotracer [ 11 C]PIB has become a promising tool to measure in-vivo myelin content changes which is essential to push forward our understanding of mechanisms involved in the pathology of MS, and to monitor individual patients in the context of clinical trials focused on repair therapies. However, PET imaging is invasive due to the injection of a radioactive tracer. Moreover, it is an expensive imaging test and not offered in the majority of medical centers in the world. In this work, by using multisequence MRI, we thus propose a method to predict the parametric map of [ 11 C]PIB PET, from which we derived the myelin content changes in a longitudinal analysis of patients with MS. The method is based on the proposed conditional flexible self-attention GAN (CF-SAGAN) which is specifically adjusted for high-dimensional medical images and able to capture the relationships between the spatially separated lesional regions during the image synthesis process. Jointly applying the sketch-refinement process and the proposed attention regularization that focuses on the MS lesions, our approach is shown to outperform the state-of-the-art methods qualitatively and quantitatively. Specifically, our method demonstrated a superior performance for the prediction of myelin content at voxel-wise level. More important, our method for the prediction of myelin content changes in patients with MS shows similar clinical correlations to the PET-derived gold standard indicating the potential for clinical management of patients with MS., (Copyright © 2020. Published by Elsevier Inc.)

Background: Microglia are the resident macrophages of the central nervous system (CNS). In multiple sclerosis (MS) and related experimental models, microglia have either a pro-inflammatory or a pro-regenerative/pro-remyelinating function. Inhibition of Bruton's tyrosine kinase (BTK), a member of the Tec family of kinases, has been shown to block differentiation of pro-inflammatory macrophages in response to granulocyte-macrophage colony-stimulating factor in vitro . However, the role of BTK in the CNS is unknown., Methods: Our aim was to investigate the effect of BTK inhibition on myelin repair in ex vivo and in vivo experimental models of demyelination and remyelination. The remyelination effect of a BTK inhibitor (BTKi; BTKi-1) was then investigated in LPC-induced demyelinated cerebellar organotypic slice cultures and metronidazole-induced demyelinated Xenopus MBP-GFP-NTR transgenic tadpoles., Results: Cellular detection of BTK and its activated form BTK-phospho-Y223 (p-BTK) was determined by immunohistochemistry in organotypic cerebellar slice cultures, before and after lysophosphatidylcholine (LPC)-induced demyelination. A low BTK signal detected by immunolabeling under normal conditions in cerebellar slices was in sharp contrast to an 8.5-fold increase in the number of BTK-positive cells observed in LPC-demyelinated slice cultures. Under both conditions, approximately 75% of cells expressing BTK and p-BTK were microglia and 25% were astrocytes. Compared with spontaneous recovery, treatment of demyelinated slice cultures and MTZ-demyelinated transgenic tadpoles with BTKi resulted in at least a 1.7-fold improvement of remyelination., Conclusion: Our data demonstrate that BTK inhibition is a promising therapeutic strategy for myelin repair., Competing Interests: R. Grenningloh is an employee of EMD Serono, Billerica, MA, USA (a business of Merck KGaA, Darmstadt, Germany). U. Boschert is an employee of Merck Serono S.A., Eysin, Switzerland., (© 2020 – IOS Press and the authors. All rights reserved.)

Importance: Risk factors associated with the severity of coronavirus disease 2019 (COVID-19) in patients with multiple sclerosis (MS) are unknown. Disease-modifying therapies (DMTs) may modify the risk of developing a severe COVID-19 infection, beside identified risk factors such as age and comorbidities., Objective: To describe the clinical characteristics and outcomes in patients with MS and COVID-19 and identify factors associated with COVID-19 severity., Design, Setting, and Participants: The Covisep registry is a multicenter, retrospective, observational cohort study conducted in MS expert centers and general hospitals and with neurologists collaborating with MS expert centers and members of the Société Francophone de la Sclérose en Plaques. The study included patients with MS presenting with a confirmed or highly suspected diagnosis of COVID-19 between March 1, 2020, and May 21, 2020., Exposures: COVID-19 diagnosed with a polymerase chain reaction test on a nasopharyngeal swab, thoracic computed tomography, or typical symptoms., Main Outcomes and Measures: The main outcome was COVID-19 severity assessed on a 7-point ordinal scale (ranging from 1 [not hospitalized with no limitations on activities] to 7 [death]) with a cutoff at 3 (hospitalized and not requiring supplemental oxygen). We collected demographics, neurological history, Expanded Disability Severity Scale score (EDSS; ranging from 0 to 10, with cutoffs at 3 and 6), comorbidities, COVID-19 characteristics, and outcomes. Univariate and multivariate logistic regression models were used to estimate the association of collected variables with COVID-19 outcomes., Results: A total of 347 patients (mean [SD] age, 44.6 [12.8] years, 249 women; mean [SD] disease duration, 13.5 [10.0] years) were analyzed. Seventy-three patients (21.0%) had a COVID-19 severity score of 3 or more, and 12 patients (3.5%) died of COVID-19. The median EDSS was 2.0 (range, 0-9.5), and 284 patients (81.8%) were receiving DMT. There was a higher proportion of patients with a COVID-19 severity score of 3 or more among patients with no DMT relative to patients receiving DMTs (46.0% vs 15.5%; P < .001). Multivariate logistic regression models determined that age (odds ratio per 10 years: 1.9 [95% CI, 1.4-2.5]), EDSS (OR for EDSS ≥6, 6.3 [95% CI. 2.8-14.4]), and obesity (OR, 3.0 [95% CI, 1.0-8.7]) were independent risk factors for a COVID-19 severity score of 3 or more (indicating hospitalization or higher severity). The EDSS was associated with the highest variability of COVID-19 severe outcome (R2, 0.2), followed by age (R2, 0.06) and obesity (R2, 0.01)., Conclusions and Relevance: In this registry-based cohort study of patients with MS, age, EDSS, and obesity were independent risk factors for severe COVID-19; there was no association found between DMTs exposure and COVID-19 severity. The identification of these risk factors should provide the rationale for an individual strategy regarding clinical management of patients with MS during the COVID-19 pandemic.

The treatment of multiple sclerosis has been transformed by the successful development of immunotherapies that efficiently reduce disease activity and related clinical relapses during the relapsing-remitting phase of the disease. However, the prevention of disability progression, which is due to axonal and neuronal damage and loss, has yet to be achieved and is therapeutically challenging, particularly during the progressive phase of the disease. One strategy to counteract neurodegeneration is to promote neuroprotection by enhancing myelin regeneration, hence restoring nerve conduction and metabolic support to the axon. Animal studies have provided targets for interventions to improve brain and spinal cord remyelination, paving the way for the translation of this research to humans. From these initial and promising forays, further problems have emerged, including questions on how best to design these clinical trials and appropriately measure the outcomes. Solving these problems will need additional work before efficacious pro-remyelination therapies will be ready for people with multiple sclerosis, but there is a real sense of hope that researchers are getting closer to a successful therapy., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Our objective was to develop a novel approach to generate individual maps of white matter (WM) innate immune cell activation using 18 F-DPA-714 translocator protein PET and to explore the relationship between these maps and individual trajectories of worsening disability in patients with multiple sclerosis (MS). Methods: Patients with MS ( n = 37), whose trajectories of worsening disability over the 2 y preceding study entry were calculated, and healthy controls ( n = 19) underwent MRI and 18 F-DPA-714 PET. A threshold for significant activation of 18 F-DPA-714 binding was calculated with a voxelwise randomized permutation-based comparison between patients and controls and used to classify each WM voxel in all subjects as characterized by a significant activation of innate immune cells (DPA+) or not. Individual maps of innate immune cell activation in the WM were used to calculate the extent of activation in WM regions of interests and to classify each WM lesion as DPA-active, DPA-inactive, or unclassified. Results: Compared with the WM of healthy controls, patients with MS had a significantly higher percentage of DPA+ voxels in the normal-appearing WM (NAWM) (NAWM in patients, 24.6% ± 1.4%; WM in controls, 14.6% ± 2.0%; P < 0.001). In patients with MS, the percentage of DPA+ voxels increased significantly from the NAWM to the perilesional areas, T2 hyperintense lesions, and T1 hypointense lesions (38.1% ± 2.6%, 45.0% ± 2.6%, 51.8% ± 2.6%, respectively; P < 0.001). Among the 1,379 T2 lesions identified, 512 were defined as DPA-active and 258 as DPA-inactive. A higher number of lesions classified as DPA-active (odds ratio, 1.13; P = 0.009), a higher percentage of DPA+ voxels in the NAWM (odds ratio, 1.16; P = 0.009), and a higher percentage of DPA+ voxels in T1 spin-echo lesions (odds ratio, 1.06; P = 0.036) were significantly associated with a retrospectively more severe clinical trajectory in patients with MS. Conclusion: A more severe trajectory of disability worsening in MS is associated with innate immune cell activation inside and around WM lesions. 18 F-DPA-714 PET may provide a promising biomarker to identify patients at risk of a severe clinical trajectory., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Primary Sjögren's syndrome (pSS) is a common systemic autoimmune disease characterised by exocrinopathy resulting in dryness of the mouth and eyes, unexplained fatigue and diffuse pain. Neurological involvement is uncommon in pSS, involving the central nervous system in 2-5% of cases and more frequently the peripheral nervous system in 5-15% of cases. The diagnosis of pSS is to be considered when confronted with symptoms such as mouth and eye dryness, fatigue and pain, the most frequent of pSS symptoms. Objective measures of oral and eye dryness may help assert the diagnosis of pSS, as well as ACR/EULAR criteria. Differential diagnoses have to be excluded in patients exhibiting neurological symptoms, such as cryoglobulinaemic vasculitis or multiple sclerosis, before considering a neurological involvement specific to pSS. The treatment of these neurological manifestations takes into account different parameters, such as the presence of cryoglobulinaemic vasculitis, the severity of the symptoms, a rapidly progressing evolution and the failure of previous symptomatic treatments.

The 2019 ECTRIMS Congress, in Stockholm, has had record-breaking figures for both attendance and scientific production. There were 9361 participants from 100 different countries for a total of 1541 abstracts. Upon invitation of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) executive committee, the authors of this meeting report assessed abstracts from all poster and oral presentations for novelty, scientific quality and relevance for basic and clinical multiple sclerosis (MS) research. The objective of this report is to highlight a selection of basic, translational and clinical studies out of the many outstanding projects that were presented. Abstracts and references cited in our report were chosen at the discretion of the authors and all co-authors and the ECTRIMS executive committee agreed on the selection. In the event of discrepancies between the abstract and the uploaded poster or presentation, we aimed to present data derived from the poster or presentation. All abstracts are accessible through the ECTRIMS online library ( https://onlinelibrary.ectrimscongress.eu/ectrims/#!*menu=36*browseby=3*sortby=2*ce&#95;id=160 ) and also published in this journal (Volume 25 Issue 2&#95;suppl, September 2019; https://journals.sagepub.com/toc/msja/25/2&#95;suppl ). A few additional references from the literature were added but were restricted to the ones that authors considered as absolutely required for an optimized understanding of the topics highlighted.

Regenerative medicines that promote remyelination in multiple sclerosis (MS) are making the transition from laboratory to clinical trials. While animal models provide the experimental flexibility to analyze mechanisms of remyelination, here we discuss the challenges in understanding where and how remyelination occurs in MS., Competing Interests: Declarations of Interest R.J.M.F. is a scientific advisory board member of Frequency Therapeutics, Rewind Therapeutics, and Biogen and has received research funding from Biogen. D.S.R. has received research funding from Vertex Pharmaceuticals. C.L. is an advisory board member of Merck-Serono, Roche, Rewind Therapeutics, and Biogen., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disorder of the brain caused by reactivation of the JC virus (JCV), a polyomavirus that infects at least 60% of the population but is asymptomatic or results in benign symptoms in most people. PML occurs as a secondary disease in a variety of disorders or as a serious adverse event from immunosuppressant agents, but is mainly found in three groups: HIV-infected patients, patients with hematological malignancies, or multiple sclerosis (MS) patients on the immunosuppressant therapy natalizumab. It is severely debilitating and is deadly in ~50% HIV cases, ~90% of hematological malignancy cases, and ~24% of MS-natalizumab cases. A PML risk prediction test would have clinical utility in all at risk patient groups but would be particularly beneficial in patients considering therapy with immunosuppressant agents known to cause PML, such as natalizumab, rituximab, and others. While a JC antibody test is currently used in the clinical decision process for natalizumab, it is suboptimal because of its low specificity and requirement to periodically retest patients for seroconversion or to assess if a patient's JCV index has increased. Whereas a high specificity genetic risk prediction test comprising host genetic risk variants (i.e., germline variants occurring at higher frequency in PML patients compared to the general population) could be administered one time to provide clinicians with additional risk prediction information that is independent of JCV serostatus. Prior PML case reports support the hypothesis that PML risk is greater in patients with a genetically caused immunodeficiency disorder. To identify germline PML risk variants, we performed exome sequencing on 185 PML cases (70 in a discovery cohort and 115 in a replication cohort) and used the gnomAD variant database for interpretation. Our study yielded 19 rare variants (maximum allele frequency of 0.02 in gnomAD ethnically matched populations) that impact 17 immune function genes (10 are known to cause inborn errors of immunity). Modeling of these variants in a PML genetic risk test for MS patients considering natalizumab treatment indicates that at least a quarter of PML cases may be preventable., (Copyright © 2020 Eis, Bruno, Richmond, Koralnik, Hanson, Major, Chow, Hendel-Chavez, Stankoff, Gasnault, Taoufik and Hatchwell.)

Purpose: Drugs promoting myelin repair represent a promising therapeutic approach in multiple sclerosis and several candidate molecules are currently being evaluated, fostering the need of a quantitative method to specifically measure myelin content in vivo. PET using the benzothiazole derivative 11 C-PiB has been successfully used to quantify myelin content changes in humans. Stilbene derivatives, such as 11 C-MeDAS, have also been shown to bind to myelin in animals and are considered a promising radiopharmaceutical class for myelin imaging. Fluorinated compounds from both classes are now commercially available and thus should constitute clinically useful myelin radiotracers. The aim of this study is to provide a head-to-head comparison of 18 F-florbetaben, 18 F-florbetapir, 18 F-flutemetamol, 11 C-MeDAS, and 11 C-PiB with regard to brain kinetics and binding in white matter (WM)., Methods: Four baboons underwent a 90-min dynamic PET scan for each radioligand. Arterial blood samples were collected during the exam for each radiotracer, except for 18 F-florbetapir, to obtain a radiometabolite-corrected input function. Standardized uptake value ratio between 75 at 90 min (SUVR 75-90 ), binding potential (BP) estimated with Logan method with input function, and distribution volume ratio (DVR) estimated with Logan reference method (using cerebellar gray matter as reference region) were calculated in WM and compared between tracers using mixed effect models., Results: In WM, 18 F-florbetapir had the highest SUVR 75-90 (1.38 ± 0.03), followed by 18 F-flutemetamol (1.34 ± 0.02), 18 F-florbetaben (1.32 ± 0.07), 11 C-MeDAS (1.27 ± 0.04), and 11 C-PiB (1.25 ± 0.07). With regard to BP, 18 F-florbetaben had the highest value (0.32 ± 0.06) compared with 18 F-flutemetamol (0.20 ± 0.03), 11 C-MeDAS (0.17 ± 0.03), and 11 C-PiB (0.16 ± 0.03). No difference in DVR was detected between 18 F-florbetaben (1.26 ± 0.06) and 18 F-florbetapir (1.27 ± 0.03), but both were significantly higher in DVR than 18 F-flutemetamol (1.17 ± 0.02), 11 C-MeDAS (1.16 ± 0.03), and 11 C-PiB (1.14 ± 0.02)., Conclusions: Given their higher binding and longer half-life, our study indicates that 18 F-florbetapir and 18 F-florbetaben are promising tracers for myelin imaging which are readily available for clinical application in demyelinating diseases.

The care of multiple sclerosis (MS) in France is based on two complementary interlinked networks: MS expert centers in university hospitals and regional networks of neurologists. The routine use of European database for multiple sclerosis (EDMUS) in all those centers has paved the way for the constitution of a national registry, designated as Observatoire Français de la Sclérose En Plaques (OFSEP). It promotes a prospective, standardized, high-quality, and multimodal collection of data. On June 2018, there were 68.097 files, with 71.1% females, representing 761,185 person-years. This huge database is open to the scientific community and might contribute exploring unresolved issues and unmet needs in MS.

Importance: Risk of developing progressive multifocal leukoencephalopathy (PML) is the major barrier to using natalizumab for patients with multiple sclerosis (MS). To date, the association of risk stratification with PML incidence has not been evaluated., Objective: To describe the temporal evolution of PML incidence in France before and after introduction of risk minimization recommendations in 2013., Design, Setting, and Participants: This observational study used data in the MS registry OFSEP (Observatoire Français de la Sclérose en Plaques) collected between April 15, 2007, and December 31, 2016, by participating MS expert centers and MS-dedicated networks of neurologists in France. Patients with an MS diagnosis according to current criteria, regardless of age, were eligible, and those exposed to at least 1 natalizumab infusion (n = 6318) were included in the at-risk population. A questionnaire was sent to all centers, asking for a description of their practice regarding PML risk stratification. Data were analyzed in July 2018., Exposures: Time from the first natalizumab infusion to the occurrence of PML, natalizumab discontinuation plus 6 months, or the last clinical evaluation., Main Outcomes and Measures: Incidence was the number of PML cases reported relative to the person-years exposed to natalizumab. A Poisson regression model for the 2007 to 2016 period estimated the annual variation in incidence and incidence rate ratio (IRR), adjusted for sex and age at treatment initiation and stratified by period (2007-2013 and 2013-2016)., Results: In total, 6318 patients were exposed to natalizumab during the study period, of whom 4682 (74.1%) were female, with a mean (SD [range]) age at MS onset of 28.5 (9.1 [1.1-72.4]) years; 45 confirmed incident cases of PML were diagnosed in 22 414 person-years of exposure. The crude incidence rate for the whole 2007 to 2016 period was 2.00 (95% CI, 1.46-2.69) per 1000 patient-years. Incidence significantly increased by 45.3% (IRR, 1.45; 95% CI, 1.15-1.83; P = .001) each year before 2013 and decreased by 23.0% (IRR, 0.77; 95% CI, 0.61-0.97; P = .03) each year from 2013 to 2016., Conclusions and Relevance: The results of this study suggest, for the first time, a decrease in natalizumab-associated PML incidence since 2013 in France that may be associated with a generalized use of John Cunningham virus serologic test results; this finding appears to support the continuation and reinforcement of educational activities and risk-minimization strategies in the management of disease-modifying therapies for multiple sclerosis.

Multiple sclerosis (MS) is the most common demyelinating disease. In MS, demyelination occurs in the white matter of the brain and in the spinal cord. It is thus essential to measure the tissue myelin content to understand the physiopathology of MS, track progression and assess treatment efficacy. Positron emission tomography (PET) with [ 11 C]PIB is a reliable method to measure myelin content in vivo. However, the availability of PET in clinical centers is limited. Moreover, it is expensive to acquire and invasive due to the injection of a radioactive tracer. By contrast, MR imaging is non-invasive, less expensive and widely available, but conventional MRI sequences cannot provide a direct and reliable measure of myelin. In this work, we therefore propose, to the best of our knowledge for the first time, a method to predict the PET-derived myelin content map from multimodal MRI. To that purpose, we introduce a new approach called Sketcher-Refiner generative adversarial networks (GANs) with specifically designed adversarial loss functions. The first network (Sketcher) generates global anatomical and physiological information. The second network (Refiner) refines and generates the tissue myelin content. A visual attention saliency map is also proposed to interpret the attention of neural networks. Our approach is shown to outperform the state-of-the-art methods in terms of image quality and myelin content prediction. Particularly, our prediction results show similar results to the PET-derived gold standard at both global and voxel-wise levels indicating the potential for clinical management of patients with MS., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Cerebrospinal fluid (CSF) plays an important role in solute clearance and maintenance of brain homeostasis. 11 C-Pittsburgh compound B (PiB) PET was recently proposed as a tool for detection of CSF clearance alterations in Alzheimer disease. The current study investigates the magnitude of 11 C-PiB PET signal in the lateral ventricles of an independent group of Alzheimer and mild cognitive impairment subjects. We have also evaluated multiple sclerosis as a model of disease with CSF clearance alterations without amyloid-β tissue accumulation. Methods: A set of 11 Alzheimer and 12 mild cognitive impairment subjects and a set of 20 multiple sclerosis subjects with matched controls underwent MRI and dynamic 11 C-PiB PET. Lateral ventricle regions of interest were generated manually from MRI data. PET data were analyzed using cerebellum or a supervised reference region for the Alzheimer and multiple sclerosis data sets, respectively. The magnitude of 11 C-PiB signal in the lateral ventricles was calculated as area under the curve from 35 to 80 min and SUV ratio (SUVR) from 50 to 70 min. Compartmental modeling analysis was performed on a separate data set containing 11 Alzheimer and matched control subjects; this analysis included an arterial input function, to further understand the kinetics of the lateral ventricular 11 C-PiB signal. Results: ANOVA revealed significant group differences in lateral ventricular SUVR across the Alzheimer, mild cognitive impairment, and healthy control groups ( P = 0.004). Pairwise comparisons revealed significantly lower lateral ventricular SUVR in Alzheimer subjects than in healthy controls ( P < 0.001) or mild cognitive impairment subjects ( P = 0.029). Lateral ventricular SUVR was significantly lower in multiple sclerosis subjects than in healthy controls ( P = 0.008). Compartmental modeling analysis revealed significantly lower uptake rates of 11 C-PiB signal from blood ( P = 0.005) and brain tissue ( P = 0.004) to the lateral ventricles and significantly lower 11 C-PiB signal clearance out of the lateral ventricles ( P = 0.002) in Alzheimer subjects than in healthy controls. Conclusion: These results indicate that dynamic 11 C-PiB PET can be used to observe pathologic changes in CSF dynamics. We have replicated previous work demonstrating CSF clearance deficits in Alzheimer disease associated with amyloid-β deposits and have extended the observations to include ventricular CSF clearance deficits in mild cognitive impairment and multiple sclerosis., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Specific magnetic resonance imaging (MRI) markers of myelin are critical for the evaluation and development of regenerative therapies for demyelinating diseases. Several MRI methods have been developed for myelin imaging, based either on acquisition schemes or on mathematical modeling of the signal. They generally showed good sensitivity but validation for specificity toward myelin is still warranted to allow a reliable interpretation in an in vivo complex pathological environment. Experimental models of dys-/demyelination are characterized by various levels of myelin disorders, axonal damage, gliosis and inflammation, and offer the opportunity for powerful correlative studies between imaging metrics and histology. Here, we review how ultrahigh field MRI markers have been correlated with histology in these models and provide insights into the trends for future developments of MRI tools in human myelin diseases. To this end, we present the biophysical basis of the main MRI methods for myelin imaging based on T 1 , T 2 , water diffusion, and magnetization transfer signal, the characteristics of animal models used and the outcomes of histological validations. To date such studies are limited, and demonstrate partial correlations with immunohistochemical and electron microscopy measures of myelin. These MRI metrics also often correlate with axons, glial, or inflammatory cells in models where axonal degeneration or inflammation occur as potential confounding factors. Therefore, the MRI markers' specificity for myelin is still perfectible and future developments should improve mathematical modeling of the MR signal based on more complex systems or provide multimodal approaches to better disentangle the biological processes underlying the MRI metrics., (© 2018 Wiley Periodicals, Inc.)

Objective: In this study, we compared the effectiveness of teriflunomide (TRF) and dimethyl fumarate (DMF) on both clinical and MRI outcomes in patients followed prospectively in the Observatoire Français de la Sclérose en Plaques., Methods: A total of 1,770 patients with relapsing-remitting multiple sclerosis (RRMS) (713 on TRF and 1,057 on DMF) with an available baseline brain MRI were included in intention to treat. The 1- and 2-year postinitiation outcomes were relapses, increase of T2 lesions, increase in Expanded Disability Status Scale score, and reason for treatment discontinuation. Propensity scores (inverse probability weighting) and logistic regressions were estimated., Results: The confounder-adjusted proportions of patients were similar in TRF- compared to DMF-treated patients for relapses and disability progression after 1 and 2 years. However, the adjusted proportion of patients with at least one new T2 lesion after 2 years was lower in DMF compared to TRF (60.8% vs 72.2%, odds ratio [OR] 0.60, p < 0.001). Analyses of reasons for treatment withdrawal showed that lack of effectiveness was reported for 8.5% of DMF-treated patients vs 14.5% of TRF-treated patients (OR 0.54, p < 0.001), while adverse events accounted for 16% of TRF-treated patients and 21% of DMF-treated patients after 2 years (OR 1.39, p < 0.001)., Conclusions: After 2 years of treatment, we found similar effectiveness of DMF and TRF in terms of clinical outcomes, but with better MRI-based outcomes for DMF-treated patients, resulting in a lower rate of treatment discontinuation due to lack of effectiveness., Classification of Evidence: This study provides Class III evidence that for patients with RRMS, TRF and DMF have similar clinical effectiveness after 2 years of treatment., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

The 18 kDa translocator protein (TSPO) is a marker of microglia activation and the main target of positron emission tomography (PET) ligands for neuroinflammation. Previous works showed that accounting for TSPO endothelial binding improves PET quantification for [ 11 C]PBR28, [ 18 F]DPA714 and [ 11 C]-R-PK11195. It is still unclear, however, whether the vascular signal is tracer-dependent. This work aims to explore the relationship between the TSPO vascular and tissue components for PET tracers with varying affinity, also assessing the impact of affinity towards the differentiability amongst kinetics and the ensuing ligand amenability to cluster analysis for the extraction of a reference region. First, we applied the compartmental model accounting for vascular binding to [ 11 C]-R-PK11195 data from six healthy subjects. Then, we compared the [ 11 C]-R-PK11195 vascular binding estimates with previously published values for [ 18 F]DPA714 and [ 11 C]PBR28. Finally, we determined the suitability for reference region extraction by calculating the angle between grey and white matter kinetics. Our results showed that endothelial binding is common to all TSPO tracers and proportional to their affinity. By consequence, grey and white matter kinetics were most similar for the radioligand with the highest affinity (i.e. [ 11 C]PBR28), hence poorly suited for the extraction of a reference region using supervised clustering.

Objective: To investigate the efficacy of rituximab as rescue therapy in patients with relapsing-remitting multiple sclerosis (RRMS) and persistent disease activity confirmed by magnetic resonance imaging (MRI) despite immunosuppressive disease-modifying therapy (DMT)., Methods: In this observational nationwide retrospective multicenter study, we first identified 351 off-label rituximab-treated patients through a cohort of 15,984 RRMS patients. In this group, we identified patients with disease activity prior to rituximab confirmed by MRI (one or more new T2 lesion and/or gadolinium-enhancing lesion) despite immunosuppressive DMT (fingolimod, natalizumab, or mitoxantrone) with a follow-up after rituximab initiation longer than 6 months. Outcome data were collected from the French Observatory of Multiple Sclerosis (OFSEP) register and medical charts., Results: A total of 50 patients were identified. Median rituximab treatment duration was 1.1 (0.5-6.4) year. Mean annualized relapse rate significantly decreased from 0.8 during last immunosuppressive DMT to 0.18 after rituximab ( p < 0.0001). While 72% of patients showed gadolinium-enhancing lesions on the last MRI performed during last immunosuppressive DMT, 8% of them showed gadolinium-enhancing lesions on the first MRI performed 6.1 (range 1.4-18.4) months after rituximab ( p < 0.0001)., Conclusion: This study provides level IV evidence that rituximab reduces clinical and MRI disease activity in patients with active RRMS despite immunosuppressive DMT.

Multiple sclerosis (MS) is a white matter (WM) disease characterized by the formation of WM lesions, which can be visualized by magnetic resonance imaging (MRI). The fluid-attenuated inversion recovery (FLAIR) MRI pulse sequence is used clinically and in research for the detection of WM lesions. However, in clinical settings, some MRI pulse sequences could be missed because of various constraints. The use of the three-dimensional fully convolutional neural networks is proposed to predict FLAIR pulse sequences from other MRI pulse sequences. In addition, the contribution of each input pulse sequence is evaluated with a pulse sequence-specific saliency map. This approach is tested on a real MS image dataset and evaluated by comparing this approach with other methods and by assessing the lesion contrast in the synthetic FLAIR pulse sequence. Both the qualitative and quantitative results show that this method is competitive for FLAIR synthesis.

The biological mechanisms driving disability worsening in multiple sclerosis (MS) are only partly understood. Monitoring changes in lesion load on MRI has a limited predictive value on the progression of clinical disability, and there is an essential need for novel imaging markers specific for the main candidate mechanisms underlying neurodegeneration which include failing myelin repair, innate immune cell activation and gray matter neuronal damage. Positron Emission Tomography (PET) is an imaging technology based on the injection of radiotracers directed against specific molecular targets, which has recently allowed the selective quantification in-vivo of the key biological mechanisms relevant to MS pathophysiology. Pilot PET studies performed in patients with all forms of MS allowed to revisit the contribution of MS lesions to disability worsening and showed that the evolution of lesions toward chronic activation, together with their remyelination profile were relevant predictors of disability worsening. PET offers the opportunity to bridge a critical gap between neuropathology and in-vivo imaging. This technique provides an original approach to disentangle some of the most relevant pathological components driving MS progression, to follow-up their temporal evolution, to investigate their clinical relevance and to evaluate novel therapeutics aimed to prevent disease progression., (© 2018 International Society of Neuropathology.)

Objective: We employed diffusion-weighted magnetic resonance spectroscopy (DW-MRS), which allows to measure in vivo the diffusion properties of metabolites, to explore the functional neuro-axonal damage and the ongoing energetic dysregulation in multiple sclerosis (MS)., Methods: Twenty-five patients with MS and 18 healthy controls (HC) underwent conventional magnetic resonance imaging (MRI) and DW-MRS. The apparent diffusion coefficient (ADC) of total N-acetyl-aspartate (tNAA) and creatine-phosphocreatine (tCr) were measured in the parietal normal-appearing white matter (NAWM) and in the thalamic grey matter (TGM). Multiple regressions were used to compare metabolite ADCs between groups and to explore clinical correlations., Results: In patients compared with HCs, we found a reduction in ADC(tNAA) in the TGM, reflecting functional and structural neuro-axonal damage, and in ADC(tCr) in both NAWM and TGM, possibly reflecting a reduction in energy supply in neurons and glial cells. Metabolite ADCs did not correlate with tissue atrophy, lesional volume or metabolite concentrations, while in TGM metabolite ADCs correlated with clinical scores., Conclusion: DW-MRS showed a reduction in tCr diffusivity in the normal-appearing brain of patients with MS, which might reflect a state of ongoing energy dysregulation affecting neurons and/or glial cells. Reversing this energy dysregulation before neuro-axonal degeneration arises may become a key objective in future neuroprotective strategies.

There is a great need for a non-invasive methodology enabling the quantification of translocator protein overexpression in PET clinical imaging. [ 18 F]DPA-714 has emerged as a promising translocator protein radiotracer as it is fluorinated, highly specific and returned reliable quantification using arterial input function. Cerebellum gray matter was proposed as reference region for simplified quantification; however, this method cannot be used when inflammation involves cerebellum. Here we adapted and validated a supervised clustering (supervised clustering algorithm (SCA)) for [ 18 F]DPA-714 analysis. Fourteen healthy subjects genotyped for translocator protein underwent an [ 18 F]DPA-714 PET, including 10 with metabolite-corrected arterial input function and three for a test-retest assessment. Two-tissue compartmental modelling provided [Formula: see text] estimates that were compared to either [Formula: see text] or [Formula: see text] generated by Logan analysis (using supervised clustering algorithm extracted reference region or cerebellum gray matter). The supervised clustering algorithm successfully extracted a pseudo-reference region with similar reliability using classes that were defined using either all subjects, or separated into HAB and MAB subjects. [Formula: see text], [Formula: see text] and [Formula: see text] were highly correlated (ICC of 0.91 ± 0.05) but [Formula: see text] were ∼26% higher and less variable than [Formula: see text]. Reproducibility was good with 5% variability in the test-retest study. The clustering technique for [ 18 F]DPA-714 provides a simple, robust and reproducible technique that can be used for all neurological diseases.

18 F-DPA-714 is a second-generation tracer for PET imaging of the 18-kDa translocator protein (TSPO), a marker of neuroinflammation. Analysis and interpretation of TSPO PET are challenging, especially because of the basal expression of TSPO. The aim of this study was to evaluate a compartmental model that accounts for the effect of endothelial TSPO binding on the quantification of 18 F-DPA-714 PET scans from a cohort of healthy subjects. Methods: Fifteen healthy subjects (9 high-affinity binders and 6 mixed-affinity binders) underwent 18 F-DPA-714 PET scans with arterial blood sampling and metabolite analysis. The kinetic parameters were quantified using a 2-tissue compartmental model (2TC) as well as a 2TC with an extra, irreversible, compartment for endothelial binding (2TC-1K). These regional parameters and messenger RNA (mRNA) expression specific to endothelial cells were correlated with regional TSPO mRNA expression. Results: The 2TC-1K model was more appropriate than the 2TC for 81% of fits. The total volume of distribution was significantly reduced by 21% ± 12% across all regions with the 2TC-1K, compared with the 2TC. The endothelial binding parameter K b varied highly across brain regions. K b strongly and significantly correlated with all 3 probes extracted for TSPO mRNA expression ( r = 0.80, r = 0.79, and r = 0.90), but no correlation was seen with the other binding parameters from the 2TC-1K. For the 2TC, there was a lower but significant correlation between the volume of distribution and one of the TSPO mRNA probes ( r = 0.65). A strong, significant correlation was seen between mRNA for TSPO and genes specific to endothelial cells. Conclusion: Accounting for endothelial TSPO in the kinetic model improved the fit of PET data. The high correlation between K b and TSPO mRNA suggests that the 2TC-1K model reveals more biologic information about the regional density of TSPO than the 2TC. The correlation between TSPO and endothelial cell mRNA supports the relationship between the regional variation of K b and endothelial TSPO. These results can improve the estimation of binding parameter estimates from 18 F-DPA-714 PET, especially in diseases that induce vascular change., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

The [ 11 C]PIB PET tracer, originally developed for amyloid imaging, has been recently repurposed to quantify demyelination and remyelination in multiple sclerosis (MS). Myelin PET imaging, however, is limited by its low resolution that deteriorates the quantification accuracy of white matter (WM) lesions. Here, we introduce a novel partial volume correction (PVC) method called Multiresolution-Multimodal Resolution-Recovery (MM-RR), which uses the wavelet transform and a synergistic statistical model to exploit MRI structural images to improve the resolution of [ 11 C]PIB PET myelin imaging. MM-RR performance was tested on a phantom acquisition and in a dataset comprising [ 11 C]PIB PET and MR T1- and T2-weighted images of 8 healthy controls and 20 MS patients. For the control group, the MM-RR PET images showed an average increase of 5.7% in WM uptake while the grey-matter (GM) uptake remained constant, resulting in +31% WM/GM contrast. Furthermore, MM-RR PET binding maps correlated significantly with the mRNA expressions of the most represented proteins in the myelin sheath (R 2  = 0.57 ± 0.09). In the patient group, MM-RR PET images showed sharper lesion contours and significant improvement in normal-appearing tissue/WM-lesion contrast compared to standard PET (contrast improvement > +40%). These results were consistent with MM-RR performances in phantom experiments.

Objective: To evaluate the effectiveness and tolerance of mycophenolate mofetil (MMF) as a first-line treatment in neuromyelitis optica spectrum disorder (NMOSD)., Methods: In all, 67 NMOSD patients treated by MMF as first-line therapy, from the NOMADMUS cohort were included. A total of 65 fulfilled 2015 NMOSD criteria, and 5 were myelin oligodendrocyte glycoprotein (MOG)-immunoglobulin G (IgG) positive. Effectiveness was evaluated on percentage of patients continuing MMF, percentage of patients free of relapse, pre- and post-treatment change in the annualized relapse rate (ARR), and Expanded Disability Status Scale (EDSS)., Results: Among 67 patients, 40 (59.7%) continued treatment till last follow-up. A total of 33 (49.3%) were relapse-free. The median ARR decreased from one pre-treatment to zero post-treatment. Of 53 patients with complete EDSS data, the score improved or stabilized in 44 (83%; p < 0.05). Effectiveness was observed in aquaporin-4 (AQP4)-IgG (57.8% continued treatment, 46.7% relapse-free), MOG-IgG (3/5 continued treatment, 4/5 relapse-free), and seronegative NMOSD (64.7% continued treatment, 61.3% relapse-free). In 16 patients with associated steroids, 13 (81.2%) continued MMF till last follow-up versus 15 of 28 (53.6%) in the non-steroid group. Nine patients discontinued treatment for tolerability purpose., Conclusion: MMF showed effectiveness and good tolerability as a first-line therapy in NMOSD, whatever the AQP4-IgG status. Concomitant use of oral steroids at start could limit the risk of treatment failure.

Purpose of Review: Studies of large longitudinal cohorts of patients with multiple sclerosis (MS) have emphasized the prognostic value of conventional MRI markers, at least during early stages. Advanced imaging metrics derived from quantitative MRI and PET provide relevant information about microstructural damage within and outside visible lesions that may be more sensitive to predict long-term disability. Here, we summarize the most recent findings regarding the prognostic value of imaging markers throughout MS stages., Recent Findings: In clinically isolated syndrome, the presence of at least one brain or spinal cord T2 lesion strongly increases the risk of conversion to clinically definite MS (hazard ratio ranging from 5 to 11). Similarly, the occurrence of new white matter lesions is strongly predictive of subsequent relapse rate and response to current disease modifying therapies. Beyond white matter lesions, volumetric changes in the grey matter and normal-appearing tissue damage are more sensitive prognostic markers for physical and cognitive disability, especially in progressive MS., Summary: Although white matter lesion number and volume still remains the imaging metric used in daily clinical practice, further development of advanced imaging predictors of long-term disability should allow a better stratification of patients in future clinical trials aimed at promoting repair or neuroprotection.

Objective: To describe the clinico-radiologic outcome of MS patients with natalizumab-related progressive multifocal leukoencephalopathy (Nz-PML) surviving and receiving disease-modifying therapy (DMT)., Methods: We describe clinical and radiologic evolution of Nz-PML survivors in an observational retrospective multicenter cohort to clarify the effect of different subsequent MS DMT strategies. Twenty-three patients from 11 centers were analyzed. Outcomes were (1) clinical efficacy of post-PML MS DMT, (2) radiologic efficacy of post-PML MS DMT, (3) radiologic evolution of PML lesion, and (4) disability progression., Results: There was no clinical worsening of PML symptoms with a stability of Expanded Disability Status Scale at the last follow-up. No relapse was reported with fingolimod and dimethyl fumarate. No radiologic worsening of Nz-PML lesion was observed at the end of the follow-up., Conclusion: In this large cohort of patients with Nz-PML, MS therapies given after Nz discontinuation were not associated with PML worsening. A larger cohort with longer follow-up will be necessary to confirm this therapeutic strategy.

One major challenge in multiple sclerosis is to understand the cellular and molecular mechanisms leading to disease severity progression. The recently demonstrated correlation between disease severity and remyelination emphasizes the importance of identifying factors leading to a favourable outcome. Why remyelination fails or succeeds in multiple sclerosis patients remains largely unknown, mainly because remyelination has never been studied within a humanized pathological context that would recapitulate major events in plaque formation such as infiltration of inflammatory cells. Therefore, we developed a new paradigm by grafting healthy donor or multiple sclerosis patient lymphocytes in the demyelinated lesion of nude mice spinal cord. We show that lymphocytes play a major role in remyelination whose efficacy is significantly decreased in mice grafted with multiple sclerosis lymphocytes compared to those grafted with healthy donors lymphocytes. Mechanistically, we demonstrated in vitro that lymphocyte-derived mediators influenced differentiation of oligodendrocyte precursor cells through a crosstalk with microglial cells. Among mice grafted with lymphocytes from different patients, we observed diverse remyelination patterns reproducing for the first time the heterogeneity observed in multiple sclerosis patients. Comparing lymphocyte secretory profile from patients exhibiting high and low remyelination ability, we identified novel molecules involved in oligodendrocyte precursor cell differentiation and validated CCL19 as a target to improve remyelination. Specifically, exogenous CCL19 abolished oligodendrocyte precursor cell differentiation observed in patients with high remyelination pattern. Multiple sclerosis lymphocytes exhibit intrinsic capacities to coordinate myelin repair and further investigation on patients with high remyelination capacities will provide new pro-regenerative strategies., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.)

The central cholinergic system undergoes changes during the physiological process of aging and the pathologic process of Alzheimer disease (AD). We aimed to analyze the impairment of cholinergic pathways by positron emission tomography using the [F]-F-A-85380 (FA85) tracer, which has a high affinity for nicotinic acetylcholine receptors (nAChRs). Aging was assessed by comparing young (n=10) and elderly (n=4) healthy subjects, and the pathologic process of AD was assessed by comparing elderly controls and age-matched AD patients (n=8). We measured an index of the nAChR density in the cortex and the hippocampus and the total number of FA85-binding sites by taking into account the volume changes. In AD, the nAChR density was preserved in both the cortex and hippocampus. The total estimated number of FA85-binding sites was decreased in the hippocampus despite the lack of a significant loss of volume, whereas the difference in the cortex did not withstand the adjustment for multiple comparisons despite a significant loss of volume. In contrast, in aging, the estimated number of FA85-binding sites was decreased in both the cortex and hippocampus with significant hippocampal atrophy. These findings suggest a preferential impairment of cholinergic pathways in the cortex during aging, whereas in AD, this damage predominated in the hippocampus with a potential compensatory cholinergic effect in the cortex.

Positron Emission Tomography (PET), an imaging technique based on the injection of radiotracers directed against specific biological targets within brain tissues, within brain tissues, is a specific and sensitive technique which offers the unique opportunity to quantify myelin dynamics in the central nervous system. Several stilbene and benzothiazole derivatives have been repurposed to image myelin by PET. In demyelinating and dysmyelinating models, selected radiotracers were shown to reliably quantify demyelination and remyelination, allowing a translational approach in humans. A pilot study in subjects with active relapsing MS using PET and the most available benzothiazole derivative, [ 11 C]PIB, supported the hypothesis that this technique is able to quantify myelin content in multiple sclerosis (MS) lesions and to capture dynamic demyelination and remyelination over time. This study highlighted for the first time in vivo the prognostic value of individual profiles of remyelination on the disease course. In future, the clinical application of myelin PET will be pushed forward thanks to the availability of novel fluorinated tracers for myelin, together with the setting up of non invasive quantification procedures and the use of powerful PET-MR systems. This will enable to address in vivo critical unanswered questions about the pathogenesis of remyelination, and to measure the efficacy of emerging promyelinating drugs in early-phase therapeutic trials.

Objective: To assess disease activity within 12 months after natalizumab (NZ) discontinuation in a large French postmarketing cohort., Methods: In France, patients exposed at least once to NZ were included in the TYSEDMUS observational and multicenter cohort, part of the French NZ Risk Management Plan. Clinical disease activity during the year following NZ discontinuation was assessed in this cohort. Time to first relapse after NZ stop was analyzed using Kaplan-Meier method and potentially associated factors were studied using a multivariate Cox model., Results: Out of the 4,055 patients with multiple sclerosis (MS) included in TYSEDMUS, 1,253 discontinued NZ and 715 of them had relevant data for our study. The probability of relapse within the year after NZ stop was estimated at 45% (95% confidence interval 0.41-0.49)., Conclusions: This large and systematic survey of patients with MS after NZ withdrawal allows quantifying the risk of increased disease activity following treatment discontinuation. This study provides large-scale, multicenter, systematic data after NZ cessation in real-life settings.

Myelin is a component of the nervous system that is disrupted in multiple sclerosis, resulting in neuro-axonal degeneration. The longitudinal effect of chronic cuprizone-induced demyelination was investigated in the cerebral gray and white matter of treated mice and the spontaneous remyelination upon treatment interruption. Multimodal Magnetic Resonance Imaging and a Cryoprobe were used at 11.7T to measure signal intensity ratios, T 2 values and diffusion metrics. The results showed significant and reversible modifications in white matter and gray matter regions such as in the rostral and caudal corpus callosum, the external capsule, the cerebellar peduncles, the caudate putamen, the thalamus, and the somatosensory cortex of treated mice. T 2 and radial diffusivity metrics appeared to be more sensitive than fractional anisotropy, axial diffusivity or mean diffusivity to detect those cuprizone-induced changes. In the gray matter, only signal and T 2 metrics and not diffusion metrics were sensitive to detect any changes. Immunohistochemical qualitative assessments in the same regions confirmed demyelination and remyelination processes. These multimodal data will provide better understanding of the dynamics of cuprizone-induced de- and remyelination in white and gray matter structures, and will be the basis to test therapies in experimental models.

Purpose of Review: Following the establishment of a number of successful immunomodulatory treatments for multiple sclerosis, current research focuses on the repair of existing damage., Recent Findings: Promotion of regeneration is particularly important for demyelinated areas with degenerated or functionally impaired axons of the central nervous system's white and gray matter. As the protection and generation of new oligodendrocytes is a key to the re-establishment of functional connections, adult oligodendrogenesis and myelin reconstitution processes are of primary interest. Moreover, understanding, supporting and promoting endogenous repair activities such as mediated by resident oligodendroglial precursor or adult neural stem cells are currently thought to be a promising approach toward the development of novel regenerative therapies., Summary: This review summarizes recent developments and findings related to pharmacological myelin repair as well as to the modulation/application of stem cells with the aim to restore defective myelin sheaths.

Purpose of Review: Despite major progress in multiple sclerosis (MS) treatment, to date, accumulation of irreversible clinical disability is not sufficiently prevented with immunotherapies. In this context, repair strategies aimed at reducing axonal damage are becoming a very active field of preclinical and clinical research., Recent Findings: Improved understanding of the cellular and molecular mechanisms of myelin repair, together with the emergence of new therapeutic candidates are paving the way for novel therapeutic strategies in MS. In parallel, there is a very active development of imaging methods to assess lesions ongoing remyelination that are crucially needed to evaluate therapeutic efficacy., Summary: The current development of a very dynamic and multidisciplinary research on remyelination should accelerate the development of myelin repair strategies in MS, to prevent disability progression.

Background: Quantitative in vivo imaging of myelin loss and repair in patients with multiple sclerosis (MS) is essential to understand the pathogenesis of the disease and to evaluate promyelinating therapies. Selectively binding myelin in the central nervous system white matter, Pittsburgh compound B ([ 11 C]PiB) can be used as a positron emission tomography (PET) tracer to explore myelin dynamics in MS., Methods: Patients with active relapsing-remitting MS (n = 20) and healthy controls (n = 8) were included in a longitudinal trial combining PET with [ 11 C]PiB and magnetic resonance imaging. Voxel-wise maps of [ 11 C]PiB distribution volume ratio, reflecting myelin content, were derived. Three dynamic indices were calculated for each patient: the global index of myelin content change; the index of demyelination; and the index of remyelination., Results: At baseline, there was a progressive reduction in [ 11 C]PiB binding from the normal-appearing white matter to MS lesions, reflecting a decline in myelin content. White matter lesions were characterized by a centripetal decrease in the tracer binding at the voxel level. During follow-up, high between-patient variability was found for all indices of myelin content change. Dynamic remyelination was inversely correlated with clinical disability (p = 0.006 and beta-coefficient = -0.67 with the Expanded Disability Status Scale; p = 0.003 and beta-coefficient = -0.68 with the MS Severity Scale), whereas no significant clinical correlation was found for the demyelination index., Interpretation: [ 11 C]PiB PET allows quantification of myelin dynamics in MS and enables stratification of patients depending on their individual remyelination potential, which significantly correlates with clinical disability. This technique should be considered to assess novel promyelinating drugs. Ann Neurol 2016;79:726-738., (© 2016 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)

An accurate in vivo measure of myelin content is essential to deepen our insight into the mechanisms underlying demyelinating and dysmyelinating neurological disorders, and to evaluate the effects of emerging remyelinating treatments. Recently [(11)C]PIB, a positron emission tomography (PET) tracer originally conceived as a beta-amyloid marker, has been shown to be sensitive to myelin changes in preclinical models and humans. In this work, we propose a reference-region methodology for the voxelwise quantification of brain white-matter (WM) binding for [(11)C]PIB. This methodology consists of a supervised procedure for the automatic extraction of a reference region and the application of the Logan graphical method to generate distribution volume ratio (DVR) maps. This approach was assessed on a test-retest group of 10 healthy volunteers using a high-resolution PET tomograph. The [(11)C]PIB PET tracer binding was shown to be up to 23% higher in WM compared with gray matter, depending on the image reconstruction. The DVR estimates were characterized by high reliability (outliers <1%) and reproducibility (intraclass correlation coefficient (ICC) >0.95). [(11)C]PIB parametric maps were also found to be significantly correlated (R(2)>0.50) to mRNA expressions of the most represented proteins in the myelin sheath. On the contrary, no correlation was found between [(11)C]PIB imaging and nonmyelin-associated proteins.

Objective: Using positron emission tomography (PET) with [(11) C]flumazenil ([(11) C]FMZ), an antagonist of the central benzodiazepine site located within the GABAA receptor, we quantified and mapped neuronal damage in the gray matter (GM) of patients with multiple sclerosis (MS) at distinct disease stages. We investigated the relationship between neuronal damage and white matter (WM) lesions and evaluated the clinical relevance of this neuronal PET metric., Methods: A cohort of 18 MS patients (9 progressive and 9 relapsing-remitting) was compared to healthy controls and underwent neurological and cognitive evaluations, high-resolution dynamic [(11) C]FMZ PET imaging and brain magnetic resonance imaging. [(11) C]FMZ binding was estimated using the partial saturation protocol providing voxel-wise absolute quantification of GABAA receptor concentration. PET data were evaluated using a region of interest (ROI) approach as well as on a vertex-by-vertex basis., Results: [(11) C]FMZ binding was significantly decreased in the cortical GM of MS patients, compared to controls (-10%). Cortical mapping of benzodiazepine receptor concentration ([(11) C]FMZ Bmax) revealed significant intergroup differences in the bilateral parietal cortices and right frontal areas. ROI analyses taking into account GM volume changes showed extensive decrease in [(11) C]FMZ binding in bilateral parietal, cingulate, and insular cortices as well as in the thalami, amygdalae, and hippocampi. These changes were significant in both progressive and relapsing-remitting forms of the disease and correlated with WM T2-weighted lesion load. [(11) C]FMZ cortical binding correlated with cognitive performance., Interpretation: This pilot study showed that PET with [(11) C]FMZ could be a promising and sensitive quantitative marker to assess and map the neuronal substrate of GM pathology in MS., (© 2015 American Neurological Association.)

Background: Children with untreated biotinidase deficiency can experience variable symptoms depending on their age of presentation. Older children and adolescents can exhibit predominant neurological deficits including para- or tetraparesis and vision loss., Methods: We report the first case of delayed-onset biotinidase deficiency in a young adult., Results: A 22-year-old man presented with a disabling extensive myelopathy and bilateral optic neuropathy which mimicked the findings of a (seronegative) neuromyelitis optica. Imaging investigations were characterized by an MRI T2 hyper-intensity involving the spinal cord, the optic nerves, the fornix and the mammillar bodies, together with an increased (18)F-FDG uptake on positron emission tomography. He was ultimately shown to have profound biotinidase deficiency due to a novel missense mutation and was partly improved by oral biotin therapy., Conclusion: This individual exemplifies the need to include biotinidase deficiency in the differential diagnosis of patients with extensive myelopathy and/or bilateral optic neuropathy and argues for newborn screening for the disorder., (© The Author(s), 2015.)

Unlabelled: Translocator protein (TSPO) is expressed at a low level in healthy brain and is upregulated during inflammatory processes that may occur in neurodegenerative diseases. Thus, TSPO may be a suitable in vivo indicator of neurodegeneration. Here, we quantified the (18)F-DPA-714 radioligand in healthy TSPO-genotyped volunteers and developed a method to eliminate the need for invasive arterial blood sampling., Methods: Ten controls (7 high-affinity binders [HABs] and 3 mixed-affinity binders [MABs]) underwent (18)F-DPA-714 PET with arterial and venous sampling. (18)F-DPA-714 binding was quantified with a metabolite-corrected arterial plasma input function, using the 1- and 2-tissue-compartment models (TCMs) as well as the Logan analysis to estimate total volume distribution (V(T)) in the regions of interest. Alternative quantification methods were tested, including tissue-to-plasma ratio or population-based input function approaches normalized by late time points of arterial or venous samples., Results: The distribution pattern of (18)F-DPA-714 was consistent with the known distribution of TSPO in humans, with the thalamus displaying the highest binding and the cerebellum the lowest. The 2-TCM best described the regional kinetics of (18)F-DPA-714 in the brain, with good identifiability (percentage coefficient of variation < 5%). For each region of interest, V(T) was 47.6% ± 6.3% higher in HABs than in MABs, and estimates from the 2-TCM and the Logan analyses were highly correlated. Equilibrium was reached at 60 min after injection. V(T) calculated with alternative methods using arterial samples was strongly and significantly correlated with that calculated by the 2-TCM. Replacement of arterial with venous sampling in these methods led to a significant but lower correlation., Conclusion: Genotyping of subjects is a prerequisite for a reliable quantification of (18)F-DPA-714 PET images. The 2-TCM and the Logan analyses are accurate methods to estimate (18)F-DPA-714 V(T) in the human brain of both HAB and MAB individuals. Population-based input function and tissue-to-plasma ratio with a single arterial sample are promising alternatives to classic arterial plasma input function. Substitution with venous samples is promising but still requires methodologic improvements., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Conventional MR imaging techniques still lack specificity for the underlying central nervous system tissue damage in multiple sclerosis (MS), impeding a comprehensive investigation of the key mechanisms responsible for neurological disability such as myelin damage and repair, neurodegeneration and neuroinflammation. A range of novel and advanced imaging tools, using quantitative magnetic resonance (MR) or positron emission tomography (PET) technologies are now emerging and open the perspective to obtain unique insights into the disease mechanisms. Both can be employed either in experimental models or in patients with MS, and they have already allowed to obtain imaging metrics that significantly correlate with clinical scores. In this review, we summarize the main evidence supporting the use of quantitative MR and PET as essential investigation tools to explore myelin changes, neuronal damage and compartmentalized inflammation in MS. The clinical translation of these imaging techniques has the potential to improve the design of future clinical trials and to allow the measurement of the effects of new drugs aimed at enhancing myelin repair and reducing neurodegeneration and neuroinflammation., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Natalizumab (NTZ), a monoclonal antibody recognizing the alpha4 integrin chain, has been approved for the treatment of active multiple sclerosis, but expose to the onset of a rare side effect, progressive multifocal leukoencephalopathy (PML). Estimating the individual risk of PML in NTZ-treated patients is a major challenge, and therapeutic strategies are mainly guided by the overall PML risk assessed by identified risk factors: JC virus (JCV) seropositivity, treatment duration (with peak incidence after 24 months), and the previous use of immunosuppressive therapies. Given that this stratification does not yet allow a precise individual prediction of PML, other predictive markers are needed, and several immunological biomarkers have been described. Quantification of anti-JCV antibody levels may improve individual predictive value, with higher baseline titers indicating increased risk. Other immunological biomarkers such as leukocyte cell membrane markers (CD49d, CD11a, and CD62L), detection of circulating JCV-specific activated T effector memory cells (TEM) or genetic screening have been proposed. In this review, we discuss how recent progress in immunology has paved the way for «new combined monitoring», which will include immunological screening, in NTZ-treated patients.

Multiple sclerosis (MS) is a complex disease of the central nervous system (CNS), characterized by CNS-restricted inflammation with subsequent demyelination and neurodegeneration. Current disease-modifying therapies efficiently reduce relapse rate and new lesions appearance, but still fail to impact the progressive course of the disease. There is a great need for the avenue of new therapies aimed at promoting myelin repair or reducing neurodegeneration that should result in the prevention of neurological disability in this chronic disease. This review will focus on the potentials and limitations of biotherapies that are currently developed for the promotion of CNS repair in MS, either monoclonal antibodies targeting axonal growth and remyelination, or cell therapies aimed at replacing the depleted myelinating cells within the CNS. As other researches aimed at promoting neuroprotection or remyelination are following a classical pharmacological approach, they will not be described in this review, which will focus on antibody-based therapies and cell therapies., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Background and Objective: Cognitive and behavioural symptoms are common in multiple sclerosis (MS), but they are rarely the inaugural and predominant manifestation of the disease. Our objective is to characterize the clinical and radiological features of cognitive-multiple sclerosis (cog-MS), defined as MS subjects who entered into the disease with cognitive symptoms, which subsequently remain the predominant manifestation., Methods: We describe the disease course, and clinical and radiological features of 18 subjects with a cognitive form of MS., Results: Memory loss and behavioural changes were the primary symptoms at disease onset. They remained prominent and led to severe cognitive impairment during disease course. The main associated manifestations were depression, pathological laughing and/or crying, urinary incontinence and gait disturbance suggestive of high-level gait disorder. Motor, sensory or cerebellar abnormalities were uncommon. During disease course, superimposed neurological relapses occurred in 61% of cases. Brain MRI revealed multiple periventricular lesions that were extensive and confluent in half of cases, and a severe atrophy measured as an increase in the third ventricular width compared to age-matched healthy controls. Gadolinium-enhancing lesions were common (72%). The mean diagnosis delay from disease onset was 2 years. A principal component analysis on the neuropsychological results revealed that verbal memory assessment is complementary to global cognitive functioning evaluation in these patients with severe cognitive deficit. Verbal memory deficit was associated with high EDSS., Conclusions: cog-MS patients might represent a challenging diagnosis, which needs to be individualized for an early management., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Severe cognitive impairment involving multiple cognitive domains can occur early during the course of multiple sclerosis (MS). We investigated resting state functional connectivity changes in large-scale brain networks and related structural damage underlying cognitive dysfunction in patients with early MS. Patients with relapsing MS (3-5 years disease duration) were prospectively assigned to two groups based on a standardized neuropsychological evaluation: (1) cognitively impaired group (CI group, n = 15), with abnormal performances in at least 3 tests; (2) cognitively preserved group (CP group, n = 20) with normal performances in all tests. Patients and age-matched healthy controls underwent a multimodal 3T magnetic resonance imaging (MRI) including anatomical T1 and T2 images, diffusion imaging and resting state functional MRI. Structural MRI analysis revealed that CI patients had a higher white matter lesion load compared to CP and a more severe atrophy in gray matter regions highly connected to networks involved in cognition. Functional connectivity measured by integration was increased in CP patients versus controls in attentional networks (ATT), while integration was decreased in CI patients compared to CP both in the default mode network (DMN) and ATT. An anatomofunctional study within the DMN revealed that functional connectivity was mostly altered between the medial prefrontal cortex (MPFC) and the posterior cingulate cortex (PCC) in CI patients compared to CP and controls. In a multilinear regression model, functional correlation between MPFC and PCC was best predicted by PCC atrophy. Disconnection in the DMN and ATT networks may deprive the brain of compensatory mechanisms required to face widespread structural damage., (Copyright © 2014 Wiley Periodicals, Inc.)