Learning Myelin Content in Multiple Sclerosis from Multimodal MRI through Adversarial Training

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS). A reliable measure of the tissue myelin content is therefore essential for the understanding of the physiopathology of MS, tracking progression and assessing treatment efficacy. Positron emission tomography (PET) with [^{11} \mbox{C}] \mbox{PIB} has been proposed as a promising biomarker for measuring myelin content changes in-vivo in MS. However, PET imaging is expensive and invasive due to the injection of a radioactive tracer. On the contrary, magnetic resonance imaging (MRI) is a non-invasive, widely available technique, but existing MRI sequences do not provide, to date, a reliable, specific, or direct marker of either demyelination or remyelination. In this work, we therefore propose Sketcher-Refiner Generative Adversarial Networks (GANs) with specifically designed adversarial loss functions to predict the PET-derived myelin content map from a combination of MRI modalities. The prediction problem is solved by a sketch-refinement process in which the sketcher generates the preliminary anatomical and physiological information and the refiner refines and generates images reflecting the tissue myelin content in the human brain. We evaluated the ability of our method to predict myelin content at both global and voxel-wise levels. The evaluation results show that the demyelination in lesion regions and myelin content in normal-appearing white matter (NAWM) can be well predicted by our method. The method has the potential to become a useful tool for clinical management of patients with MS.Comment: Accepted by MICCAI201

Imaging Characteristics of Choroid Plexuses in Presymptomatic Multiple Sclerosis. A Retrospective Study

Background and Objectives Recent imaging studies have suggested a possible involvement of the choroid plexus (CP) in multiple sclerosis (MS). Here, we investigated whether CP changes are already detectable at the earliest stage of MS, preceding symptom onset. Methods This study is a retrospective analysis of 27 patients with presymptomatic MS, 97 patients with clinically definite MS (CDMS), and 53 healthy controls (HCs) who underwent a cross-sectional 3T-MRI acquisition; of which, 22 MS, 19 HCs, and 1 presymptomatic MS (evaluated 8 months before conversion to CDMS) also underwent translocator protein (TSPO) F-18-DPA-714 PET and were included in the analysis. CPs were manually segmented on 3D T1-weighted images for volumetric analysis. CP F-18-DPA-714 uptake, reflecting inflammation, was calculated as the average standardized uptake value (SUV). Multivariable regressions adjusted for age, sex, and ventricular and brain volume were fitted to test CP volume differences between presymptomatic patients and MS or HCs. For the presymptomatic case who also had F-18-DPA-714 PET, CP SUV differences with MS and HCs were assessed through Crawford-Howell tests. To provide further insight into the interpretation of F-18-DPA-714-PET uptake at the CP level, a postmortem analysis of CPs in MS vs HCs was performed to characterize the cellular localization of TSPO expression. Results Compared with HCs, patients with presymptomatic MS had 32% larger CPs (beta = 0.38, p = 0.001), which were not dissimilar to MS CPs (p = 0.69). Moreover, in the baseline scan of the presymptomatic case who later on developed MS, TSPO PET showed 33% greater CP inflammation vs HCs (p = 0.04), although no differences in F-18-DPA-714 uptake were found in parenchymal regions vs controls. CP postmortem analysis identified a population of CD163(+) mononuclear phagocytes expressing TSPO in MS, possibly contributing to the increased F-18-DPA-714 uptake. Discussion We identified an imaging signature in CPs at the presymptomatic MS stage using MRI; in addition, we found an increased CP inflammation with PET in a single presymptomatic patient. These findings suggest a role of CP imaging as an early biomarker and argue for the involvement of the blood-CSF barrier dysfunction in disease development

Mécanismes biologiques à l'origine de la neurodégénérescence dans la Sclérose en Plaques : une approche in vivo associant tomographie par émission de positrons et imagerie par résonance magnétique à haut champ

Multiple Sclerosis (MS), an inflammatory and demyelinating disease of the central nervous system, is the leading cause of non-traumatic neurological disability in young adults in western countries. It is now well accepted that neurodegeneration is the key mechanism underlying disability progression in this disease. The biological mechanisms leading to neurodegeneration remains poorly understood in vivo, but pathological post-mortem studies have pointed the potential contribution of a persisting inflammation involving the innate immune system together with a failure of endogenous repair in white matter (WM) and cortical lesions. This thesis aimed at developing imaging tools able to quantify and map innate immune cell activation and myelin dynamics though a combination of positron emission tomography (PET) and advanced high field magnetic resonance imaging (MRI) in patients with MS. For this purpose I have first developed a post processing methodology that allows the generation of individual and regional maps of tissue damage and repair, which was used for the quantification of innate immune cell activation as well as for the investigation of demyelination/remyelination in WM lesions and in the cortex. We have combined TSPO PET with [18F]-DPA714, targeting mainly activated innate immune cells, and multimodal 3T MRI, assessing structural damage, in a cohort of MS patients with either a relapsing or a progressive form of the disease. I showed that patients with MS were characterized by a very heterogeneous level of neuroinflammation, and that a large subset of WM lesions considered as inactive on MRI were actually very active on PET, a finding suggestive of chronic active lesions. I further showed that this persisting inflammation correlated with individual trajectories of disability. Then, I have questioned whether the proximity to the cerebrospinal fluid (CSF) could influence innate immune cells in the deep white and grey matter. I demonstrated a clear gradient of innate immune cells activation in vicinity to ventricular CSF, which correlated with the periventricular gradient of microstructural damage, and could also explain part of clinical disability. Aiming to quantify myelin dynamics in the cortex I have applied Magnetization Transfer Imaging and generated individual maps of demyelination and remyelination in cortical tissues. I then showed that cortical and WM individual remyelination profiles were heterogeneous among subjects, and were synergistically contributing to disability in MS. Finally, I have applied for the first time the parallel transmission using dynamic RF-shimming on a 7T MRI system to visualize cortical lesions at the whole brain level, paving the way for an improved detection of these lesions in future studies. Results acquired in this work should allow to apply new imaging tools mapping the mechanisms that drive neurodegeneration in MS in future studies, opening the perspective of patient stratification, novel design for repair and neuroprotection trials, and optimization of care.La sclérose en plaques (SEP) est une maladie inflammatoire démyélinisante du système nerveux central, qui représente la première cause de handicap non-traumatique du jeune adulte. Il a été démontré que le principal mécanisme impliqué dans la progression du handicap était une atteinte neuronale dégénérative. Les mécanismes à l’origine de la neurodégénérescence sont cependant peu connus in vivo. Des études post-mortem ont mis en évidence le rôle d’une inflammation persistante impliquant le système immunitaire innée, en association avec un échec de la remyélination dans la substance blanche ainsi que les lésions corticales. Cette thèse a pour objectif de développer des techniques d’imagerie permettant de quantifier et cartographier l’activation des cellules de l’immunité innée ainsi que les changements en myéline, en combinant la tomographie par émission de positons (TEP) et l’IRM à haut champ. À cette fin, j'ai tout d'abord mis au point une méthodologie de post-traitement permettant de générer des cartes individuelles et régionales de l’atteinte et de la réparation des tissus, utilisée pour la quantification de l'activation des cellules immunitaires innées ainsi que pour l’étude de la démyélinisation/remyélinisation dans les lésions de la substance blanche ainsi que dans le cortex. J’ai combiné la TEP au [18F]-DPA714, ciblant principalement les cellules immunitaires innées activées, et l’IRM multimodale à 3T évaluant les dommages structurels dans une cohorte de patients SEP présentant une forme rémittente ou progressive de la maladie. J'ai montré que les patients SEP étaient caractérisés par un niveau de neuroinflammation très hétérogène et qu'un grand sous-ensemble de lésions de la substance blanche considérées comme inactives en IRM étaient en réalité très actives en TEP, suggérant des lésions actives chroniques. J'ai montré que cette inflammation persistante était en lien avec les trajectoires individuelles du handicap. Ensuite, j’ai étudié si la proximité du liquide céphalo-rachidien (LCR) pouvait influencer les cellules immunitaires innées des substances blanche et grise profondes. J'ai démontré la présence d’un gradient d'activation des cellules immunitaires innées à proximité du LCR ventriculaire, corrélé au gradient périventriculaire d’atteintes microstructurales, pouvant également expliquer en partie du handicap clinique. Dans le but de quantifier la dynamique de la myéline dans le cortex, j'ai appliqué l'imagerie par transfert de magnétisation et généré des cartes individuelles de démyélinisation et de remyélinisation dans les tissus corticaux. J'ai ensuite montré que les profils individuels de remyélinisation de la substance blanche étaient hétérogènes selon les sujets et contribuaient au handicap des patients SEP. Enfin, j'ai appliqué pour la première fois la transmission parallèle utilisant la modulation RF dynamique sur un système IRM 7T afin de visualiser les lésions corticales au niveau du cerveau entier, ouvrant ainsi la voie à une meilleure détection de ces lésions dans les études futures. Les résultats acquis dans ce travail devraient permettre d’appliquer de nouveaux outils d’imagerie permettant de cartographier les mécanismes à l’origine de la neurodégénérescence dans la SEP dans les études futures, d’ouvrir la perspective de la stratification du patient, de concevoir de nouvelles méthodes d’essais de réparation et de neuroprotection et d’optimiser les soins

Predicting PET-derived Demyelination from Multimodal MRI using Sketcher-Refiner Adversarial Training for Multiple Sclerosis

International audienceMultiple 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 [11C]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

FLAIR MR Image Synthesis By Using 3D Fully Convolutional Networks for Multiple Sclerosis

International audienceSynopsis. Fluid-attenuated inversion recovery (FLAIR) MRI pulse sequence is used clinically and in research for the detection of WM lesions. However,in a clinical setting, some MRI pulse sequences can be missing because of patient or time constraints. We propose 3D fully convolutional neural networks to predict a FLAIR MRI pulse sequence from other MRI pulse sequences. We evaluate our approach on a real multiple sclerosis disease dataset by assessing the lesion contrast and by comparing our approach to other methods. Both the qualitative and quantitative results show that our method is competitive for FLAIR prediction

Fluid-attenuated inversion recovery MRI synthesis from multisequence MRI using three-dimensional fully convolutional networks for multiple sclerosis

International audienceMultiple 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 can be missing because of various constraints. We propose to use 3D fully convolutional neural networks to predict FLAIR pulse sequences from other MRI pulse sequences. In addition, we evaluate the contribution of each input pulse sequence with a pulse-sequence-specific saliency map. Our approach is tested on a real multiple sclerosis image dataset and evaluated by comparing our approach to other methods and by assessing the lesion contrast in the synthetic FLAIR pulse sequence. Both the qualitative and quantitative results show that our method is competitive for FLAIR synthesis

Predicting PET-derived Myelin Content from Multisequence MRI for Individual Longitudinal Analysis in Multiple Sclerosis

International audienceMultiple sclerosis (MS) is a demyelinating and inflammatory disease of the central nervous system (CNS). The de-myelination 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 par-aclinical 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 radio-tracer [ 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 [11C]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

Periventricular remyelination failure in multiple sclerosis: a substrate for neurodegeneration

In multiple sclerosis, spontaneous remyelination is generally incomplete and heterogenous across patients. A high heterogeneity in remyelination may also exist across lesions within the same individual, suggesting the presence of local factors interfering with myelin regeneration. In this study we explored in-vivo the regional distribution of myelin repair and investigated its relationship with neurodegeneration. We first took advantage of the myelin binding property of the amyloid radiotracer [11C]PiB to conduct a longitudinal [11C]PiB positron emission tomography study in an original cohort of 19 participants with a relapsing-remitting form of multiple sclerosis, followed-up over a period of 1-4 months. We then replicated our results on an independent cohort of 40 people with multiple sclerosis followed-up over one year with magnetization transfer imaging, an MRI metrics sensitive to myelin content. For each imaging method, voxel-wise maps of myelin content changes were generated according to modality-specific thresholds. We demonstrated a selective failure of remyelination in periventricular white matter lesions of people with multiple sclerosis in both cohorts. In both the original and the replication cohort, we estimated that the probability of demyelinated voxels to remyelinate over the follow-up increased significantly as a function of the distance from ventricular cerebro-spinal fluid. Enlarged choroid plexus, a recently discovered biomarker linked to neuroinflammation, was found to be associated with the periventricular failure of remyelination in the two cohorts (r=-0.79, p = 0.0018; r=-0.40, p = 0.045 respectively), suggesting a role of the brain-cerebrospinal fluid barrier in affecting myelin repair in surrounding tissues. In both cohorts, the failure of remyelination in periventricular white matter lesions was associated with lower thalamic volume (r = 0.86, p < 0.0001; r = 0.33; p = 0.069 respectively) an imaging marker of neurodegeneration. Interestingly, we also showed an association between the periventricular failure of remyelination and regional cortical atrophy that was mediated by the number of cortex-derived tracts passing through periventricular white matter lesions, especially in patients at the relapsing-remitting stage. Our findings demonstrate that lesion proximity to ventricles is associated with a failure of myelin repair and support the hypothesis that a selective periventricular remyelination failure in combination with the large number of tracts connecting periventricular lesions with cortical areas is a key mechanism contributing to cortical damage in multiple sclerosis

Simultaneous proton density, T1 , T2 , and flip‐angle mapping of the brain at 7 T using multiparametric 3D SSFP imaging and parallel‐transmission universal pulses

International audiencePurpose: Performing simultaneous quantitative MRI at ultra-high field is challenging, as B0 and B1 + heterogeneities as well as Specific Absorption Rate increase. Too large deviations of flip angle from the target can induce biases and impair signal-to-noise ratio in the quantification process. In this work, we use calibration-free parallel transmission, a dedicated pulse sequence parameter optimization and signal fitting to recover 3D proton density, flip angle, T1 and T2 maps over the whole brain, in a clinically suitable time. Methods: Eleven optimized contrasts were acquired with an unbalanced Steady-State Free Precession sequence by varying flip angle amplitude and radiofrequency phase cycling increment, at a 1.0x1.0x3.0mm 3 resolution. Acquisition time was of 16min36sec for the whole brain. Parallel transmission and Universal Pulses were used to mitigate B1 + heterogeneity to improve the results' reliability over six healthy volunteers (3 females/males, age 22.6±2.7 years-old). Quantification of the physical parameters was performed by fitting acquired contrasts to the simulated ones using the Bloch-Torrey equations with a realistic diffusion coefficient. Results: Whole-brain 3D maps of effective flip angle, PD and relaxation times were estimated. Parallel transmission improved the robustness of the results at 7T. Results were in accordance with literature and with measurements from standard methods. Conclusion: These preliminary results show robust PD, FA, T1 and T2 map retrieval. Other parameters, such as Apparent Diffusion Coefficient, could be assessed. With further optimization in the acquisition, scan time could be reduced and spatial resolution increased to bring this multi-parametric quantification method to clinical research routine at 7-tesla