Search

Leptomeningeal inflammation in multiple sclerosis is associated with worse clinical outcomes and greater cortical pathology. Despite progress in identification of this process in multiple sclerosis patients using post-contrast FLAIR imaging, early trials attempting to target meningeal inflammation have been unsuccessful. There is a lack of appropriate model systems to screen potential therapeutic agents targeting meningeal inflammation. We utilized ultra-high field (11.7 Tesla) MRI to perform post-contrast FLAIR imaging in SJL/J mice with experimental autoimmune encephalomyelitis induced using immunization with proteolipid protein peptide (PLP139-151) and complete Freund’s adjuvant. Imaging was performed in both a cross-sectional and longitudinal fashion at time-points ranging from 2 to 14 weeks post-immunization. Following imaging, we euthanized animals and collected tissue for pathological evaluation, which identified dense cellular infiltrates corresponding to areas of contrast-enhancement involving the leptomeninges. These areas of meningeal inflammation contained B cells (B220+), T cells (CD3+) and myeloid cells (Mac2+). We also noted features consistent with tertiary lymphoid tissue within these areas – presence of peripheral node addressin (PNAd) positive structures, CXCL13 producing cells and FDC-M1+ follicular dendritic cells. In the cortex adjacent to areas of meningeal inflammation we identified astrocytosis, microgliosis, demyelination and evidence of axonal stress/damage. Since areas of meningeal contrast enhancement persisted over several weeks in longitudinal experiments, we utilized this model to test the effects of a therapeutic intervention on established meningeal inflammation. We randomized mice with evidence of meningeal contrast enhancement on MRI scans performed at 6 weeks post-immunization, to treatment with either vehicle or evobrutinib (a Bruton’s tyrosine kinase inhibitor) for a period of 4 weeks. These mice underwent serial imaging and we examined the effect of treatment on the areas of meningeal contrast enhancement and noted a significant reduction in the evobrutinib group compared to vehicle (30% reduction versus 5% increase; P = 0.003). We utilized ultra-high field MRI imaging to identify areas of meningeal inflammation and to track them over time in SJL/J mice with experimental autoimmune encephalomyelitis and then utilized this model to identify Bruton’s tyrosine kinase inhibition as a novel therapeutic approach to target meningeal inflammation. The results of this study provide support for future studies in multiple sclerosis patients with imaging evidence of meningeal inflammation.

Multiple sclerosis (MS) lesions that do not resolve in the months after they form harbour ongoing demyelination and axon degeneration, and are identifiable in vivo by their paramagnetic rims on MRI scans1-3. Here, to define mechanisms underlying this disabling, progressive neurodegenerative state4-6 and foster development of new therapeutic agents, we used MRI-informed single-nucleus RNA sequencing to profile the edge of demyelinated white matter lesions at various stages of inflammation. We uncovered notable glial and immune cell diversity, especially at the chronically inflamed lesion edge. We define 'microglia inflamed in MS' (MIMS) and 'astrocytes inflamed in MS', glial phenotypes that demonstrate neurodegenerative programming. The MIMS transcriptional profile overlaps with that of microglia in other neurodegenerative diseases, suggesting that primary and secondary neurodegeneration share common mechanisms and could benefit from similar therapeutic approaches. We identify complement component 1q (C1q) as a critical mediator of MIMS activation, validated immunohistochemically in MS tissue, genetically by microglia-specific C1q ablation in mice with experimental autoimmune encephalomyelitis, and therapeutically by treating chronic experimental autoimmune encephalomyelitis with C1q blockade. C1q inhibition is a potential therapeutic avenue to address chronic white matter inflammation, which could be monitored by longitudinal assessment of its dynamic biomarker, paramagnetic rim lesions, using advanced MRI methods.

Accumulating evidence corroborates the role of the "central vein sign" in the radiological diagnosis of multiple sclerosis (MS). Here, we report human magnetic resonance imaging (MRI) and corresponding pathological data that inflammation-dependent intracerebral remodeling of the vessel wall is directly associated with the prominence of intralesional veins on susceptibility-based MRI. In adult marmosets with experimental autoimmune encephalomyelitis, vessel-wall fibrosis was detected early in the demyelinating process, even in lesions

This cross-sectional study examines paramagnetic rim sign positivity in patients with radiologically isolated syndrome.

Highlights • This is an overview of preclinical MRI studies in neuroinflammatory diseases. • We summarized experimental setup, MRI methodology, and risk of bias of these studies. • We propose guidelines to improve standardization of preclinical MRI studies. • Implementing these reporting guidelines could facilitate clinical translation. • This study can serve as a framework for future preclinical studies using MRI., Magnetic resonance imaging (MRI) is the most important paraclinical tool for assessing drug response in multiple sclerosis (MS) clinical trials. As such, MRI has also been widely used in preclinical research to investigate drug efficacy and pathogenic aspects in MS animal models. Keeping track of all published preclinical imaging studies, and possible new therapeutic approaches, has become difficult considering the abundance of studies. Moreover, comparisons between studies are hampered by methodological differences, especially since small differences in an MRI protocol can lead to large differences in tissue contrast. We therefore provide a comprehensive qualitative overview of preclinical MRI studies in the field of neuroinflammatory and demyelinating diseases, aiming to summarize experimental setup, MRI methodology, and risk of bias. We also provide estimates of the effects of tested therapeutic interventions by a meta-analysis. Finally, to improve the standardization of preclinical experiments, we propose guidelines on technical aspects of MRI and reporting that can serve as a framework for future preclinical studies using MRI in MS animal models. By implementing these guidelines, clinical translation of findings will be facilitated, and could possibly reduce experimental animal numbers.

Background: The central vein sign (CVS) has been shown to help in the differential diagnosis of multiple sclerosis (MS), but most prior studies are retrospective. Objectives: To prospectively assess the diagnostic predictive value of the CVS in diagnostically difficult cases. Methods: In this prospective multicenter study, 51 patients with suspected MS who had clinical, imaging, or laboratory “red flags” (i.e. features atypical for MS) underwent 3T fluid-attenuated inversion recovery (FLAIR*) magnetic resonance imaging (MRI) for CVS assessment. After the diagnostic work-up, expert clinicians blinded to the results of the CVS assessment came to a clinical diagnosis. The value of the CVS to prospectively predict an MS diagnosis was assessed. Results: Of the 39 patients who received a clinical diagnosis by the end of the study, 27 had MS and 12 received a non-MS diagnosis that included systemic lupus erythematosus, sarcoidosis, migraine, Sjögren disease, SPG4-spastic-paraparesis, neuromyelitis optica, and Susac syndrome. The percentage of perivenular lesions was higher in MS (median = 86%) compared to non-MS (median = 21%; p < 0.0001) patients. A 40% perivenular lesion cutoff was associated with 97% accuracy and a 96% positive/100% negative predictive value. Conclusion: The CVS detected on 3T FLAIR* images can accurately predict an MS diagnosis in patients suspected to have MS, but with atypical clinical, laboratory, and imaging features., SCOPUS: ar.j, info:eu-repo/semantics/published

Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system. Although it has been extensively studied, the proximate trigger of the immune response remains uncertain. Experimental autoimmune encephalomyelitis in the common marmoset recapitulates many radiological and pathological features of focal multiple sclerosis lesions in the cerebral white matter, unlike traditional experimental autoimmune encephalomyelitis in rodents. This provides an opportunity to investigate how lesions form as well as the relative timing of factors involved in lesion pathogenesis, especially during early stages of the disease. We used MRI to track experimental autoimmune encephalomyelitis lesions in vivo to determine their age, stage of development, and location, and we assessed the corresponding histopathology post-mortem. We focused on the plasma protein fibrinogen-a marker for blood-brain barrier leakage that has also been linked to a pathogenic role in inflammatory demyelinating lesion development. We show that fibrinogen has a specific spatiotemporal deposition pattern, apparently deriving from the central vein in early experimental autoimmune encephalomyelitis lesions

Objectives In multiple sclerosis (MS), magnetic resonance imaging (MRI) is a sensitive tool for detecting white matter lesions, but its diagnostic specificity is still suboptimal; ambiguous cases are frequent in clinical practice. Detection of perivenular lesions in the brain (the "central vein sign") improves the pathological specificity of MS diagnosis, but comprehensive evaluation of this MRI biomarker in MS-mimicking inflammatory and/or autoimmune diseases, such as central nervous system (CNS) inflammatory vasculopathies, is lacking. In a multicenter study, we assessed the frequency of perivenular lesions in MS versus systemic autoimmune diseases with CNS involvement and primary angiitis of the CNS (PACNS). Methods In 31 patients with inflammatory CNS vasculopathies and 52 with relapsing-remitting MS, 3-dimensional T2*-weighted and T2-fluid-attenuated inversion recovery images were obtained during a single MRI acquisition after gadolinium injection. For each lesion, the central vein sign was evaluated according to consensus guidelines. For each patient, lesion count, volume, and brain location, as well as fulfillment of dissemination in space MRI criteria, were assessed. Results MS showed higher frequency of perivenular lesions (median = 88%) than did inflammatory CNS vasculopathies (14%), without overlap between groups or differences between 3T and 1.5T MRI. Among inflammatory vasculopathies, Behcet disease showed the highest median frequency of perivenular lesions (34%), followed by PACNS (14%), antiphospholipid syndromes (12%), Sjogren syndrome (11%), and systemic lupus erythematosus (0%). When a threshold of 50% perivenular lesions was applied, central vein sign discriminated MS from inflammatory vasculopathies with a diagnostic accuracy of 100%. Interpretation The central vein sign differentiates inflammatory CNS vasculopathies from MS at standard clinical magnetic field strengths. Ann Neurol 2018;83:283-294.

Background: Detection of a “central vein sign” (CVS) on FLAIR* magnetic resonance imaging (MRI) is highly specific and sensitive for multiple sclerosis (MS). We evaluated the specificity and sensitivity of simplified CVS algorithms for MS diagnosis. Methods: MRIs from 10 participants with MS without additional comorbidities for MRI white matter abnormalities; 10 with MS and additional comorbidities for white matter abnormalities; 10 with migraine, white matter abnormalities, and no additional comorbidities; and 10 who had previously been erroneously diagnosed with MS were evaluated. 3T MRI T2-FLAIR and T2*-weighted sequences were acquired to create FLAIR* images. Three MS physician reviewers, blinded to diagnosis, evaluated two different algorithms: (1) three lesions pre-selected on FLAIR were subsequently evaluated for CVS on FLAIR*( select3). (2) FLAIR* was evaluated for up to three lesions with CVS ( select3*). Results: For select3, average specificity across reviewers for MS was 0.98 and sensitivity 0.52 and a correct prediction of diagnosis demonstrated kappa = 0.29. For select3*, specificity was 0.81, sensitivity was 0.83, and kappa was 0.31. Conclusion: A simplified determination of CVS in three white matter lesions on 3T FLAIR* MRI demonstrated good specificity and sensitivity and fair inter-rater reliability for a diagnosis of MS and with further study, may be a candidate for clinical application.

Inflammatory destruction of iron-rich myelin is characteristic of multiple sclerosis (MS). Although iron is needed for oligodendrocytes to produce myelin during development, its deposition has also been linked to neurodegeneration and inflammation, including in MS. We report perivascular iron deposition in multiple sclerosis lesions that was mirrored in 72 lesions from 13 marmosets with experimental autoimmune encephalomyelitis. Iron accumulated mainly inside microglia/macrophages from 6 weeks after demyelination. Consistently, expression of transferrin receptor, the brain's main iron-influx protein, increased as lesions aged. Iron was uncorrelated with inflammation and postdated initial demyelination, suggesting that iron is not directly pathogenic. Iron homeostasis was at least partially restored in remyelinated, but not persistently demyelinated, lesions. Taken together, our results suggest that iron accumulation in the weeks after inflammatory demyelination may contribute to lesion repair rather than inflammatory demyelination per se.

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

Importance In multiple sclerosis (MS), chronic active lesions, which previously could only be detected at autopsy, can now be identified on susceptibility-based magnetic resonance imaging (MRI) in vivo as non–gadolinium-enhancing lesions with paramagnetic rims. Pathologically, they feature smoldering inflammatory demyelination at the edge, remyelination failure, and axonal degeneration. To our knowledge, the prospect of long-term in vivo monitoring makes it possible for the first time to determine their contribution to disability and value as a treatment target. Objective To assess whether rim lesions are associated with patient disability and long-term lesion outcomes. Design, Setting, Participants We performed 3 studies at the National Institutes of Health Clinical Center: (1) a prospective clinical/radiological cohort of 209 patients with MS (diagnosis according to the 2010 McDonald revised MS criteria, age ≥18 years, with 7-T or 3-T susceptibility-based brain MRI results) who were enrolled from January 2012 to March 2018 (of 209, 17 patients [8%] were excluded because of uninterpretable MRI scans); (2) a radiological/pathological analysis of expanding lesions featuring rims; and (3) a retrospective longitudinal radiological study assessing long-term lesion evolution in 23 patients with MS with yearly MRI scans for 10 years or more (earliest scan, 1992). Main Outcomes and Measures (1) Identification of chronic rim lesions on 7-T or 3-T susceptibility-based brain MRI in 192 patients with MS and the association of rim counts with clinical disability (primary analysis) and brain volume changes (exploratory analysis). (2) Pathological characterization of 10 expanding lesions from an adult with progressive MS who came to autopsy after 7 years of receiving serial in vivo MRI scans. (3) Evaluation of annual lesion volume change (primary analysis) and T1 times (exploratory analysis) in 27 rim lesions vs 27 rimless lesions. Results Of 209 participants, 104 (50%) were women and 32 (15%) were African American. One hundred seventeen patients (56%) had at least 1 rim lesion regardless of prior or ongoing treatment. Further, 84 patients (40%) had no rims (mean [SD] age, 47 [14] years), 66 (32%) had 1 to 3 rims (mean [SD] age, 47 [11] years), and 42 (20%) had 4 rims or more (mean [SD] age, 44 [11] years). Individuals with 4 rim lesions or more reached motor and cognitive disability at an earlier age. Normalized volumes of brain, white matter, and basal ganglia were lower in those with rim lesions. Whereas rimless lesions shrank over time (−3.6%/year), rim lesions were stable in size or expanded (2.2%/year;P Conclusions and Relevance Chronic active lesions are common, are associated with more aggressive disease, exert ongoing tissue damage, and occur even in individuals treated with effective disease-modifying therapies. These results prompt the planning of MRI-based clinical trials aimed at treating perilesional chronic inflammation in MS.

Objective:To assess the prevalence and the specificity of leptomeningeal enhancement (LME) on postcontrast T2–fluid-attenuated inversion recovery (FLAIR) MRI in multiple sclerosis (MS) compared to a variety of inflammatory and noninflammatory neurologic conditions assessed in 2 academic research hospitals.Methods:On 3T postcontrast T2-FLAIR images, the presence of focal gadolinium enhancement was evaluated in the leptomeningeal compartment in 254 people with non-MS neurologic conditions or neurotropic viral infections. Based on their clinical diagnosis, patients were grouped as follows: (1) other-than-MS inflammatory neurologic diseases; (2) noninflammatory neurologic diseases; (3) human T-lymphotropic virus (HTLV)–infected; (4) HIV-infected; (5) healthy volunteers.Results:LME was detected in 56/254 non-MS cases (22%) vs 74/299 (25%) of MS cases. LME was nearly 4-fold more frequent in non-MS inflammatory neurologic conditions (18/51 cases, 35%) than in noninflammatory neurologic conditions (3/38, 8%) and healthy volunteers (5/66, 8%). The highest prevalence of LME was detected in HTLV infection (17/38 cases, 45%), particularly in the setting of HTLV-associated myelopathy (14/25 cases, 56%). LME also frequently occurred in HIV infection (13/61 cases, 21%). Unlike in MS, LME is not associated with lower brain and cortical volumes in non-MS inflammatory neurologic conditions, including HTLV and HIV infection.Conclusions:Despite its relevance to MS pathogenesis and cortical pathology, LME is not specific to MS, occurring frequently in non-MS inflammatory neurologic conditions and especially in those patients with HTLV-associated myelopathy. Overall, this strengthens the notion that LME localizes inflammation-related focal disruption of the blood–meninges barrier and associated scarring.

Interfacing magnetic resonance imaging (MRI) and pathology is critically important for understanding the pathological basis of MRI signal changes in vivo and for clinicopathological correlations. Postmortem MRI is an intermediate step in this process; unfortunately, however, relating the data to standard pathological sections, which are relatively thick and often non-parallel, is both time consuming and insufficiently accurate. The aim of this project was to develop technology to integrate postmortem, high-resolution, whole-brain MRI into the planning and execution of the pathological analysis through precise localization of the target and coordinates of cut. Compared to standard pathological sectioning, the use of an individualized 3D-printed cutting-box, designed based on postmortem MRI of formalin-fixed whole brains, improved the speed, quality, and accuracy of radiological-pathological correlation and, specifically, the histopathological localization of imaging findings. The technology described herein is easily implemented, applicable to any brain disorder, and potentially extendable to other organs. From the point of view of the pathologist this technique can improve localization of small or subtle abnormalities, whereas from the point of view of the radiologist it has the potential to improve understanding of MRI signal changes observed in disease.

Background: At autopsy, 20%–40% of chronic multiple sclerosis (MS) lesions are labeled “slowly expanding” and feature myelin phagocytosis at the lesion edge. As pathological lesion classification relies on a single, terminal time point, the rate of lesion expansion cannot be directly measured. Objective: To study long-term volume changes in individual MS lesions. Methods: Volumes of individual lesions on proton density magnetic resonance imaging (MRI) acquired between 1992 and 2015 were measured in 22 individuals (one lesion per person). After correction for acquisition protocol, a mixed model evaluated lesion volume changes. Results: The mean (standard deviation) lesion volume at baseline was 142 (82) mL, falling to 74 (51) mL after 16 (3) years. All lesions shrank over time. Change in lesion volume did not correlate with change in supratentorial brain volume ( p = 0.33). In simulations, the results could be explained by a process of slow radial expansion superimposed on substantially more rapid resorption of damaged tissue. Conclusion: We noted sustained radiological contraction of MS lesions, a surprising result given that fresh myelin breakdown products within chronic active lesions are observed relatively frequently at autopsy. Therefore, the primary pathological process in chronic lesions, even those described as “slowly expanding,” is likely to be tissue loss.

Over the past few decades, MRI-based visualization of demyelinated CNS lesions has become pivotal to the diagnosis and monitoring of multiple sclerosis (MS). In this Review, we outline current efforts to correlate imaging findings with the pathology of lesion development in MS, and the pitfalls that are being encountered in this research. Multimodal imaging at high and ultra-high magnetic field strengths is yielding biologically relevant insights into the pathophysiology of blood-brain barrier dynamics and both active and chronic inflammation, as well as mechanisms of lesion healing and remyelination. Here, we parallel the results in humans with advances in imaging of a primate model of MS - experimental autoimmune encephalomyelitis (EAE) in the common marmoset - in which demyelinated lesions resemble their human counterparts far more closely than do EAE lesions in the rodent. This approach holds promise for the identification of innovative biological markers, and for next-generation clinical trials that will focus more on tissue protection and repair.

BACKGROUND. In some active multiple sclerosis (MS) lesions, a strong immune reaction at the lesion edge may contain growth and thereby isolate the lesion from the surrounding parenchyma. Our previous studies suggest that this process involves opening of the blood-brain barrier in capillaries at the lesion edge, seen on MRI as centripetal contrast enhancement and a colocalized phase rim. We hypothesized that using these features to characterize early lesion evolution will allow in vivo tracking of tissue degeneration and/or repair, thus improving the evaluation of potential therapies for chronic active lesions. METHODS. Centripetally and centrifugally enhancing lesions were studied in 17 patients with MS using 7-tesla MRI. High-resolution, susceptibility-weighted, T1-weighted (before/after gadolinium), and dynamic contrast–enhanced scans were acquired at baseline and months 1, 3, 6, and 12. For each lesion, time evolution of the phase rim, lesion volume, and T1 hypointensity were assessed. In autopsies of 3 progressive MS cases, the histopathology of the phase rim was determined. RESULTS. In centripetal lesions, a phase rim colocalized with initial contrast enhancement. In 12 of 22, this phase rim persisted after enhancement resolved. Compared with centripetal lesions with transient rim, those with persistent rim had less volume shrinkage and became more T1 hypointense between months 3 and 12. No centrifugal lesions developed phase rims at any time point. Pathologically, persistent rims corresponded to an iron-laden inflammatory myeloid cell population at the edge of chronic demyelinated lesions. CONCLUSION. In early lesion evolution, a persistent phase rim in lesions that shrink least and become more T1 hypointense over time suggests that the rim might mark failure of early lesion repair and/or irreversible tissue damage. In later stages of MS, phase rim lesions continue to smolder, exerting detrimental effects on affected brain tissue. TRIAL REGISTRATION. NCT00001248. FUNDING. The Intramural Research Program of NINDS supported this study.

BACKGROUND AND PURPOSE: VBM is widely applied to characterize regional differences in brain volume among groups of subjects. The aim of this study was to develop and validate a method for voxelwise statistical analysis of cord volume and to test, with this method, the correlation between cord tissue loss and aging. MATERIALS AND METHODS: 3D T1-weighted scans of the spinal cord were acquired from 90 healthy subjects spanning several decades of life. Using an AS method, we outlined the cord surface and created output images reformatted with image planes perpendicular to the estimated cord centerline. Unfolded cervical cord images were coregistered into a common standard space, and smoothed cord binary masks, produced by using the cord outlines estimated by the AS approach, were used as input images for spatial statistics. RESULTS: High spatial correlation between normalized images was observed. Averaging of the normalized scans allowed the creation of a cervical cord template and of a standardized region-of-interest atlas. VBM analysis showed some significant associations between a decreased probability of cord tissue and aging. Results were robust across different smoothing levels, but the use of an anisotropic Gaussian kernel gave the optimal trade-off between spatial resolution and the requirements of the Gaussian random field theory. CONCLUSIONS: VBM analysis of the cervical cord was feasible and holds great promise for accurate localization of regional cord atrophy in several neurologic conditions.

Background/Objective We aimed to investigate whether cervical cord damage and dysfunction is associated with the presence and severity of fatigue in multiple sclerosis (MS) using a multiparametric magnetic resonance (MR) approach. Methods: Cervical cord functional magnetic resonance imaging (fMRI) during a tactile stimulation of the right hand, and structural brain and cord MRI were acquired from 20 controls, 15 MS patients without fatigue (NF) and 20 MS patients with fatigue (F). Between-group differences in the extent of focal lesions and diffusivity abnormalities in the brain and cord, cord-normalized cross-sectional area (CSAn) and fMRI activity were assessed. Results: All structural MRI measures differed significantly among groups, except for cord lesion number and CSAn. Compared with controls, NF-MS patients experienced higher cord recruitment ( p=0.04). Compared with F-MS, NF-MS patients had a lower brain normal-appearing white matter average fractional anisotropy ( p=0.001) and increased cord recruitment ( p=0.02). In patients with MS, the extent of cord recruitment was correlated with the severity of fatigue ( r=-0.34, p=0.04). Compared with the other two groups, F-MS patients had a more diffuse recruitment of cord quadrants on the axial and longitudinal planes. Conclusions: Abnormalities of function, but not of structure, of the cervical cord are likely to contribute to the pathogenesis of fatigue in MS.

To apply voxelwise analysis of diffusion-tensor (DT) magnetic resonance (MR) tractography and T2-weighted MR lesion measurements to characterize intrinsic damage to the brain white matter (WM) tracts and the relation of this damage to the presence and location of focal lesions among the main clinical phenotypes of multiple sclerosis (MS).The study was conducted with institutional review board approval. Written informed consent was obtained from each participant. Brain dual-echo and DT MR images were obtained in 172 patients with MS (22 [13%] with clinically isolated syndromes [CIS] suggestive of MS, 51 [30%] with relapsing-remitting [RR] MS, 44 [26%] with secondary progressive MS, 20 [12%] with benign MS, 35 [20%] with primary progressive MS) and 46 healthy control subjects. Probability maps of the major brain WM tracts were produced. Between-group comparisons were assessed by using analysis of covariance.Compared with the healthy control subjects, the patients with CIS had significantly increased (P.001) mean diffusivity, axial diffusivity, and radial diffusivity in the majority of WM tracts. The primary progressive MS group showed diffuse increases in mean, axial, and radial diffusivity, with fractional anisotropy (FA) damage involving the majority of WM tracts. No relevant difference in diffusivity measures was found between the CIS and RR-MS groups. Compared with the benign MS group, the RR-MS group had reduced FA values in all WM tracts and decreased axial diffusivity in the majority of tracts. The secondary progressive MS group had pronounced damage to the majority of tracts and, compared with the benign MS group, pronounced FA alteration of the tracts relevant for motor impairment.Voxelwise assessment of DT MR index abnormalities is a rewarding strategy for understanding the heterogeneity of clinical MS phenotypes.

Cervical cord damage is likely to contribute to the accumulation of disability in multiple sclerosis (MS) and can be quantified in vivo using MRI. We used conventional and diffusion tensor (DT) MRI to: (a) define the temporal evolution of intrinsic tissue injury and atrophy in the cervical cord from MS patients, (b) investigate how these two aspects of cord damage are interrelated and (c) assess the correlation of cord MRI metrics with concomitant brain damage and disability. Conventional and DT MRI of the brain and cervical cord were obtained from 42 MS patients and 9 healthy controls at baseline and after a mean follow-up of 2.4 years. At each time-point, we measured: cervical cord lesion number, cross-sectional area, mean diffusivity (MD) and fractional anisotropy (FA). Brain T2 lesion volume, grey matter MD, normal appearing white matter (NAWM) MD and FA, as well as longitudinal normalized percentage brain volume changes were also measured. In MS patients, cervical cord cross-sectional area ( P < 0.001) and FA ( P = 0.01) decreased, and cervical cord MD increased ( P < 0.001) during follow-up. Cord FA decrease, but not cord cross-sectional area and MD, was significantly higher ( P = 0.05) in primary progressive MS patients than in those with either relapsing–remitting or secondary progressive MS. At baseline and follow-up, moderate correlations were found between intrinsic cord diffusivity abnormalities and cord cross-sectional area ( r values ranging from 0.34 to 0.58), but not between their changes over time. No cross-sectional and longitudinal correlations were found between these MRI metrics and the number of cord T2-visible lesions. Brain NAWM MD ( P = 0.03) and brain volume ( P < 0.001) also changed in patients. There was no significant correlation between cord and brain MRI metrics at both time-points, as well as between their changes occurred over the follow-up. Baseline cord cross-sectional area ( r = −0.40, P = 0.01) and FA ( r = −0.40, P = 0.03) correlated with increase in disability at follow-up. This study shows that both progressive tissue loss and injury to the remaining tissue occur in the cervical cord of MS patients, and that these two components of cord damage are not strictly interrelated, thus suggesting that a multiparametric MRI approach is needed to achieve more accurate estimates of such a damage. MS cord pathology also seems to be independent of concomitant brain changes, to develop at different rates according to disease phenotype, and to be associated to medium-term disability accrual.

Objective: To evaluate clinical fluid-attenuated inversion recovery (FLAIR)* 3T magnetic resonance imaging (MRI), which is sensitive to perivenular inflammatory demyelinating lesions, in diagnosing multiple sclerosis (MS). Background: Central veins may be a distinguishing feature of MS lesions. FLAIR*, a combined contrast derived from clinical MRI scans, has not been studied as a clinical tool for diagnosing MS. Methods: Two experienced MS neurologists evaluated 87 scan pairs (T2-FLAIR/FLAIR*), separately and side-by-side, from 68 MS cases, 8 healthy volunteers, and 11 individuals with other neurological diseases. Raters judged cases based on experience, published criteria, and a visual assessment of the “40% rule,” whereby MS is favored if >40% of lesions demonstrate a central vein. Diagnostic accuracy was determined with area under the receiver operating characteristic curve (AUC), and inter-rater reliability was assessed with Cohen’s kappa (κ). Results: Diagnostic accuracy was high: rater 1, AUC 0.94 (95% confidence interval: 0.89, 0.97) for T2-FLAIR, 0.95 (0.92, 0.98) for FLAIR*; rater 2, 0.94 (0.90, 0.98) and 0.90 (0.85, 0.95). AUC improved when images were considered together: rater 1, 0.99 (0.98, 1.00); rater 2, 0.98 (0.96, 0.99). Inter-rater agreement was substantial for T2-FLAIR (κ = 0.68) and FLAIR* (κ = 0.74), despite low agreement on the 40% rule (κ = 0.47) ([Formula: see text] in all cases). Conclusions: Joint clinical evaluation of T2-FLAIR and FLAIR* images modestly improves diagnostic accuracy for MS and does not require counting lesions with central veins.

Objective: To determine the frequency and nature of leptomeningeal contrast enhancement in multiple sclerosis (MS) via in vivo 3-tesla postcontrast T2-weighted, fluid-attenuated inversion recovery (FLAIR) MRI and 7-tesla postmortem MRI–pathology correlation. Methods: Brain MRI, using the postcontrast T2-weighted, FLAIR technique, was prospectively collected in 299 MS cases and 37 age-matched neurologically healthy controls. Expert raters evaluated focal gadolinium enhancement in the leptomeningeal compartment. Two progressive MS cases came to autopsy after in vivo MRI characterization. Pathologic and immunohistochemical examination assessed the association of enhancement with leptomeningeal inflammation and adjacent cortical demyelination. Results: Focal contrast enhancement was detected in the leptomeningeal compartment in 74 of 299 MS cases (25%) vs 1 of 37 neurologically healthy controls (2.7%; p = 0.001). Enhancement was nearly twice as frequent ( p = 0.009) in progressive MS (39/118 cases, 33%) as in relapsing-remitting MS (35/181, 19%). Enhancing foci generally remained stable throughout the evaluation period (up to 5.5 years). Pathology showed perivascular lymphocytic and mononuclear infiltration in the enhancing areas in association with flanking subpial cortical demyelination. Conclusion: Leptomeningeal contrast enhancement occurs frequently in MS and is a noninvasive, in vivo marker of inflammation and associated subpial demyelination. It might therefore enable testing of new treatments aimed at eliminating this inflammation and potentially arresting progressive MS.

Objectives: To detect and localize MRI signal changes prior to the parenchymal contrast enhancement that classically defines the radiologic onset of the developing white matter lesion in multiple sclerosis (MS). Methods: We reviewed 308 high-resolution (≤1 mm3 voxels) MRI scans at 3T and 7T in 29 patients with active MS. The presence of pre-parenchymal enhancement abnormalities before the appearance of parenchymal enhancement was evaluated in all available scans. Results: Pre-enhancement signal changes were noted in 26 of 162 enhancing lesions (16%) as linear enhancement of the central vein and/or perivenular hyperintense signal on T2 fluid-attenuated inversion recovery or T2* images. They occur up to 2 months before focal enhancement within the parenchyma in 10% of cases. Conclusions: In some lesions, the abrupt opening of the blood-brain barrier, detected by contrast enhancement on MRI, can have directly visible antecedent MRI changes centered on the central vein. We propose that these findings might be the basis for prior reports of subtle pre-parenchymal enhancement changes in quantitative MRI indices. In line with the venulocentric model of lesion development, our findings are consistent with the centrality of early perivenular events in lesion formation in vivo.

Active motor functional magnetic resonance imaging (fMRI) studies have shown that pediatric multiple sclerosis (MS) patients have a strictly lateralized pattern of activations and a preserved functional connectivity (FC) within the motor system when compared to age-matched healthy controls. However, it is still not clear whether a preserved FC in pediatric MS is present only in the motor system, or involves other relevant functional system. Resting-state (RS) fMRI is a valuable tool for an unbiased investigation of FC abnormalities of multiple networks. This study explored abnormalities of RS FC within and between large-scale neuronal networks from 44 pediatric MS patients and 27 controls and their correlation with clinical, neuropsychological, and conventional MRI measures. Compared to controls, pediatric MS patients had a decreased FC of several regions of the sensorimotor, secondary visual, default-mode (DMN), executive control, and bilateral working memory (WMN) networks. They also experienced an increased FC in the right medial frontal gyrus of the attention network, which was correlated with T2 lesion volume. Cognitively impaired patients had decreased RS FC of the right precuneus of the left WMN. An increased FC between the sensorimotor network and the DMN, and between the L WMN and the attention network as well as a decreased FC between L WMN and the DMN were also found. A distributed pattern of FC abnormalities within large-scale neuronal networks occurs in pediatric MS patients, contributes to their cognitive status, and is partially driven by focal white matter lesions. Internetwork connectivity is relatively preserved in these patients. Hum Brain Mapp 35:4180–4192, 2014. © 2014 Wiley Periodicals, Inc.

Objective In multiple sclerosis (MS), accurate, in vivo characterization of dynamic inflammatory pathological changes occurring in newly forming lesions could have major implications for understanding disease pathogenesis and mechanisms of tissue destruction. Here, we investigated the potential of ultrahigh-field magnetic resonance imaging (MRI; 7T), particularly phase imaging combined with dynamic contrast enhancement, to provide new insights in acute MS lesions. Methods Sixteen active MS patients were studied at 7T. Noncontrast, high-resolution T2* magnitude and phase scans, T1 scans before/after gadolinium contrast injection, and dynamic contrast-enhanced (DCE) T1 scans were acquired. T2*/phase features and DCE pattern were determined for acute and chronic lesions. When possible, 1-year follow-up 7T MRI was performed. Results Of 49 contrast-enhancing lesions, 44 could be analyzed. Centrifugal DCE lesions appeared isointense or hypointense on phase images, whereas centripetal DCE lesions showed thin, hypointense phase rims that clearly colocalized with the initial site of contrast enhancement. This pattern generally disappeared once enhancement resolved. Conversely, in 43 chronic lesions also selected for the presence of hypointense phase rims, the findings were stable over time, and the rims were typically thicker and darker. These considerations suggest different underlying pathological processes in the 2 lesion types. Interpretation Ultrahigh-field MRI and, especially, phase contrast, are highly sensitive to tissue changes in acute MS lesions, which differ from the patterns seen in chronic lesions. In acute lesions, the hypointense phase rim reflects the expanding inflammatory edge and may directly correspond to inflammatory byproducts and sequelae of blood–brain barrier opening. Ann Neurol 2013;74:669–678

Using resting state (RS) functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI), we identified the predictors of clinical improvement following constraint-induced movement therapy (CIMT) in pediatric patients with chronic hemiplegia.From 14 children with congenital or acquired brain injury and 10 sex- and age-matched healthy controls, brain dual-echo, DTI and RS fMRI sequences were acquired before CIMT. The Quality of Upper Extremities Skills Test and the Gross Motor Function Measure (GMFM) were administered at baseline, at the end of CIMT (10 weeks), and after 6 months. Mean diffusivity and fractional anisotropy (FA) were measured in the lesion responsible for the clinical symptomatology, the affected and unaffected corticospinal tract (CST), motor transcallosal fibers, and uncinate fasciculus (as an internal control). Independent component analysis was used to identify the sensorimotor RS network. The ability of baseline MRI variables to predict clinical changes over time was assessed using multivariate linear models. At baseline, patients had increased mean diffusivity in the symptomatic lesion and decreased FA in the symptomatic lesion, affected corticospinal tract, and motor transcallosal fibers. A reduced RS functional connectivity was found in the bilateral cerebellum, left precentral gyrus, and right secondary sensorimotor cortex. At follow up, Quality of Upper Extremities Skills Test and GMFM scales improved significantly. Baseline average lesion FA predicted clinical improvement at week 10, and baseline functional connectivity of the right secondary sensorimotor cortex and cerebellum predicted GMFM improvement at month 6. DTI and RS fMRI offer promising and objective markers to predict clinical outcomes following CIMT in pediatric patients with congenital or acquired hemiplegia.

To (a) apply an active surface method to map the regional distribution of cord atrophy across levels and sectors in a relatively large group of patients with multiple sclerosis (MS), (b) compare the anatomic location of cord atrophy between patients with relapsing-remitting (RR) MS and those with secondary progressive (SP) MS, and (c) assess correlations between atrophy and disability.This study was approved by the local ethical committee, and written informed consent was obtained from each participant. High-spatial-resolution magnetic resonance (MR) images of the cervical cord were acquired from 45 patients with RR MS, 26 patients with SP MS, and 67 age-matched healthy control subjects. The active surface method segmented the cord surface from C1 to C7 and created output images reformatted in planes perpendicular to the estimated cord center line. These unfolded cervical cord images were coregistered into a common standard space, and smoothed cord binary masks were used as input images for spatial statistics. Voxel-wise between-group comparisons and the correlation between regional cord atrophy versus clinical and conventional MR imaging variables were assessed with software.Compared with control subjects, patients with RR MS showed localized clusters of atrophy in the posterior cord. Conversely, patients with SP MS showed a widespread pattern of cord atrophy, predominantly in the posterior and lateral cord columns. In patients with MS, cervical cord atrophy was correlated with clinical disability, disease duration, and, to a lesser extent, conventional MR imaging measures of brain injury. No correlation was found between cord atrophy and the presence of focal cord lesions.Voxel-wise assessment of the regional distribution of damage in the cervical cord is feasible and might improve our understanding of the mechanisms related to the development of irreversible clinical disability in MS.

Migraine patients with multiple brain white matter hyperintensities (WMHs) may represent a diagnostic challenge. Using double inversion recovery (DIR) imaging, we studied whether cortical lesions (CLs) could be seen in these patients. Approval of the institutional review boards and written informed consent were obtained from each participant. CLs and WM lesions were assessed on brain scans from 32 migraine patients with WMHs (17 patients with and 15 without aura), and in two control groups, consisting of 15 relapsing-remitting multiple sclerosis (RRMS) patients and 20 healthy controls, matched for age and gender. By definition, brain WM lesions were detected in all migraine and RRMS patients. The number and volume of WM lesions were lower in migraine versus RRMS patients (p < 0.0001). No CLs were identified in migraine patients and healthy controls, whereas 20 CLs were seen in 9 (60 %) RRMS patients. The application of DIR imaging to assess focal cortical involvement seems to be useful in the diagnostic workup of patients with WMHs of unknown etiology, including those with migraine.

"Abstract Primary progressive multiple sclerosis (PPMS) is characterized by a steady progression of irreversible disability from the onset of the disease. Although magnetic resonance imaging (MRI) is a valuable tool to quantify the disease burden in the brain and spinal cord of patients with MS, measures derived from conventional MRI, including T2-visible lesions, gadolinium-enhancing lesions and atrophy, are correlated only weakly with the clinical manifestations of PPMS. On the contrary, advanced MRI techniques are contributing significantly to the understanding of the mechanisms underlying the irreversible accumulation of disability in PPMS patients. Data from quantitative MRI studies suggest that the extent and topography of ‘‘diffuse’’ damage in different central nervous system (CNS) compartments (i.e. normal-appearing brain white matter and grey matter and the spinal cord) is associated with the severity of disability in PPMS and can predict subsequent medium-term disease evolution. Functional MRI studies have shown that the impairment of the adaptive capacity of the cortex to limit the clinical consequences of structural CNS damage is yet another factor contributing to the manifestations of this condition."

Comi, Giancarlo Jeffery, Douglas Kappos, Ludwig Montalban, Xavier Boyko, Alexey Rocca, Maria A Filippi, Massimo ALLEGRO Study Group Clinical Trial, Phase III Multicenter Study Randomized Controlled Trial Research Support, Non-U.S. Gov't United States The New England journal of medicine N Engl J Med. 2012 Mar 15;366(11):1000-9.; BACKGROUND: Two proof-of-concept clinical trials have provided evidence that laquinimod reduces disease activity in patients with relapsing-remitting multiple sclerosis. METHODS: We conducted a randomized, double-blind, phase 3 study at 139 sites in 24 countries. A total of 1106 patients with relapsing-remitting multiple sclerosis were randomly assigned in a 1:1 ratio to receive oral laquinimod at a dose of 0.6 mg once daily or placebo for 24 months. The primary end point was the annualized relapse rate during the 24-month period. Secondary end points included confirmed disability progression (defined as an increase in the score on the Expanded Disability Status Scale that was sustained for at least 3 months) and the cumulative number of gadolinium-enhancing lesions and new or enlarging lesions on T(2)-weighted magnetic resonance imaging. RESULTS: Treatment with laquinimod as compared with placebo was associated with a modest reduction in the mean (+/-SE) annualized relapse rate (0.30+/-0.02 vs. 0.39+/-0.03, P=0.002) and with a reduction in the risk of confirmed disability progression (11.1% vs. 15.7%; hazard ratio, 0.64; 95% confidence interval, 0.45 to 0.91; P=0.01). The mean cumulative numbers of gadolinium-enhancing lesions and new or enlarging lesions on T(2)-weighted images were lower for patients receiving laquinimod than for those receiving placebo (1.33+/-0.14 vs. 2.12+/-0.22 and 5.03+/-0.08 vs. 7.14+/-0.07, respectively; P

Objective: Aim of this study was to compare tactile-associated cervical cord fMRI activity between primary progressive (PP) and secondary progressive (SP) MS patients and to investigate whether cord recruitment was associated with structural brain and cord damage. Experimental Design: Cervical cord fMRI during a tactile stimulation of the right hand was acquired from 17 healthy controls, 18 SPMS patients, and 16 PPMS patients. Average fMRI activity and its topographical distribution in cord sectors (left vs. right, posterior vs. anterior) were assessed. Correlations between cord recruitment and structural cord and brain MRI were estimated. Principal Observations: Progressive MS patients showed an increased cord recruitment compared with controls (P = 0.003). Despite a similar structural cord damage, cord activity was increased in SPMS compared to PPMS patients (P = 0.05). Regional analysis showed a non-lateralized pattern of cord recruitment in MS patients. Compared to PPMS, SPMS patients had grey matter (GM) atrophy in several cortical and subcortical regions. In SPMS patients, atrophy of the left postcentral gyrus was correlated with cord activity (r = −0.48, P = 0.04). Conclusions: Patients with progressive MS had an over-recruitment of the cervical cord, which was more pronounced in SPMS than PPMS, despite similar cord structural damage. The alteration of the complex modulation of spinal cord interneurons possibly due to a loss of supratentorial inhibition secondary to brain injury might contribute to explain the observed functional cord abnormalities. Hum Brain Mapp 33:2072–2080, 2012. © 2011 Wiley Periodicals, Inc.

Aim: We assessed the pattern of regional white matter and grey matter abnormalities in patients with cluster headache (CH), using tract-based spatial statistics (TBSS) and voxel-based morphometry (VBM). Methods: Using a 3.0 Tesla scanner, dual-echo, diffusion tensor and 3D T1-weighted scan were acquired from 15 patients with episodic CH and 19 healthy controls. TBSS analysis was performed using the FMRIB's Diffusion Toolbox. VBM was performed on the 3D T1-weighted images using SPM8. Results: No diffusivity and volumetry abnormalities of brain white matter were detected in CH patients. Compared with controls, CH patients showed decreased grey matter volume in the right thalamus, head of the right caudate nucleus, right precentral gyrus, right posterior cingulate cortex, bilateral middle frontal gyrus, right middle temporal gyrus, left inferior parietal lobule and left insula (p Conclusion: CH patients experience tissue abnormalities of grey matter regions that are part of the antinociceptive system, which is shared with other chronic pain conditions.

Objective: Double inversion recovery (DIR) sequences have improved the detection of cortical lesions (CLs) in adult patients with multiple sclerosis (MS). We evaluated the presence and frequency of CLs in pediatric patients with relapsing-remitting MS (RRMS) in comparison to adult patients with MS with the same clinical phenotype. Methods: Using a 3.0-T scanner, brain DIR, dual-echo, and 3-dimensional T1-weighted scans were acquired from 24 pediatric patients with RRMS, 15 adult patients with RRMS, and 10 pediatric healthy controls. CLs and white matter (WM) lesions were identified, and their volumes measured. Brain gray matter and WM volumes were also calculated. Between-group comparisons were performed using χ 2 , Mann-Whitney, and analysis of variance tests. Poisson regressions for count data were used to model the number of lesions of the 2 groups of patients. Results: Compared to adults, pediatric patients had shorter disease duration and lower disability. WM lesion number and volume did not differ between pediatric and adult patients with MS. CLs were detected in 2 (8%) pediatric and 10 (66%) adult patients. Median CL volume was lower in pediatric than adult patients with RRMS ( p = 0.0003). Regression analysis showed that pediatric patients had a lower number of CLs than adults ( p = 0.0003), after adjusting for age, gender, Expanded Disability Status Scale score, and disease duration. Conclusion: CLs are rare in pediatric patients with MS. Since pediatric patients with MS have a clinical onset closer to the biological onset of the disease than adult patients with MS, our findings indicate that CL formation is likely not to be an initial event in this disease.

Objective: This study explores default-mode network (DMN) abnormalities in patients with secondary progressive (SP) and primary progressive (PP) multiple sclerosis (MS) and whether such abnormalities correlate with cognitive impairment and damage to selected white matter (WM) fiber bundles, quantified using diffusion tensor (DT) MRI tractography. Methods: Resting state (RS) functional MRI and DT MRI data were acquired from 33 patients with SPMS, 24 patients with PPMS, and 24 controls. Independent component analysis (ICA) was used to identify the DMN. SPM5 was used to assess within- and between-group activations. Results: Between-group differences in DMN activity were found in the left medial prefrontal cortex (mPFC), left precentral gyrus (PcG), and anterior cingulate cortex (ACC). Compared to controls, patients with SPMS had reduced activity in the mPFC ( p = 0.01) and PcG ( p = 0.02), while patients with PPMS had reduced activity in the PcG ( p = 0.008) and the ACC ( p = 0.002). Compared to patients with PPMS, patients with SPMS had increased ACC activity ( p = 0.04). Reduction of RS activity in the ACC was more pronounced in cognitively impaired vs cognitively preserved patients with MS ( p = 0.02). In patients with MS, DMN abnormalities correlated with the PASAT and word list test scores ( r values ranging from 0.35 to 0.45) and DT MRI changes in the corpus callosum and the cingulum ( r values ranging from 0.82 to 0.87). Conclusion: These results suggest that a dysfunction of the anterior components of the default-mode network may be among the factors responsible for the accumulation of cognitive deficits in patients with progressive multiple sclerosis.

To elucidate the factors associated with the preservation of function in relapsing-remitting (RR) multiple sclerosis (MS) by investigating effective connectivity changes of the sensorimotor network in pediatric RR MS patients in comparison with adult patients with either clinically isolated syndromes (CIS) suggestive of MS or RR MS and in adult healthy control subjects by using functional magnetic resonance imaging (MR) imaging and a dynamic causal model approach and to assess the correlation between effective connectivity changes and structural damage to the corpus callosum and the corticospinal tracts (CSTs).The study was conducted with institutional review board approval. Written informed consent was obtained from each participant. Dual-echo, diffusion-tensor, and functional MR images were acquired from 17 pediatric RR MS patients, 16 adult patients with CIS, 14 adult RR MS patients, and 10 age-matched pediatric healthy control subjects during a simple motor task. Whole-brain, corpus callosum, and CST T2 lesion loads, as well as corpus callosum and CST diffusivity measures were determined. Functional MR imaging data were analyzed by using statistical parametric mapping.Coefficients of effective connectivity of the sensorimotor network were similar in control subjects and pediatric MS patients. In adult patients with CIS and even more evidently in those with RR MS, an increase of intra- and interhemispheric strengths of coefficients of effective connectivity was found (P = .05-.008). The increases in such coefficients were correlated with corpus callosum and CST damage, in terms of T2 lesion load and diffusion-tensor MR imaging quantities (r = -0.34 to 0.40).The preservation of brain adaptive properties might explain the favorable medium-term clinical outcome of pediatric MS patients. The progressive recruitment of cortical networks over time in patients with the adult RR forms of the disease might result in a loss of their plastic reservoir, thus possibly contributing to subsequent disease evolution.

Objective To characterise, using conventional and diffusion tensor (DT) MRI, the nature and distribution of lesions and the extent of damage in the brain normal-appearing white matter (NAWM) and grey matter (GM) from a relatively large population of paediatric multiple sclerosis (MS) patients. Methods Brain conventional and DT MRI scans were acquired from 48 patients with paediatric MS (10 clinically isolated syndromes (CIS), 38 relapsing remitting (RR) MS), 30 adult CIS, 27 adult RRMS, 15 paediatric healthy controls (HC) and 18 adult HC. T2-lesion probability maps and DT MRI of lesions, NAWM and GM were compared among controls and MS groups. Results T2-visible lesion volumes did not differ among patient groups, but T2 lesions were more frequently located in the posterior periventricular regions in adult RRMS patients than in adult CIS and paediatric RRMS patients. Adult RRMS patients had a significantly higher lesion average mean diffusivity than paediatric RRMS patients. No DT MRI changes in the NA tissues were found in paediatric and adult CIS patients. DT MRI abnormalities were limited to the NAWM in paediatric RRMS patients, while they involved the NAWM and GM in adult RRMS patients. The extent of NAWM involvement was similar between adult and paediatric RRMS patients and was significantly correlated with T2-visible lesion burden. Conclusions A less severe intrinsic lesion damage, a less frequent lesion occurrence in the posterior periventricular WM and the sparing of GM may help to explain the favourable short-/medium-term disease outcome of paediatric MS.

Objective To investigate whether (1) the tactile-associated cord functional MRI (fMRI) changes vary in the different clinical stages of relapse-onset multiple sclerosis (MS), and (2) the pattern of cord fMRI changes relates to severity of MS clinical disability. Methods Cervical cord fMRI was acquired from 49 MS patients (30 relapsing-remitting (RR), 19 secondary progressive (SP)), and 19 controls, during a tactile stimulation of the right hand. Task-related cord mean signal change and occurrence of fMRI activity at each cord quadrant and level were measured. MRI quantities were compared between groups using an univariate analysis. Between-group differences in topographical distribution of fMRI activity were evaluated using random-effect logistic regression models. Results Compared with controls, both RRMS (p=0.05) and secondary progressive multiple sclerosis (p=0.02) patients showed a higher cord fMRI activity, whereas no difference was found between patient groups. Severely disabled patients (26/49) showed a cord overactivation relative to controls (p=0.004) and patients with mild disability (p=0.04). Both controls and MS patients showed a functional lateralisation of cord activity, which was predominant in the cord side ipsilateral to the stimulus, and a more frequent activation of the posterior than of the anterior cord quadrants. Discussion This study shows that tactile-associated cervical cord fMRI activity is increased in relapse-onset MS patients. Such an overactivation is more prominent in patients with more severe locomotor disability. This suggests that an abnormality of cord functional properties may be among the factors associated with the clinical status of MS patients.

To assess the extent of tactile-associated cervical spinal cord activation in patients with primary progressive (PP) multiple sclerosis (MS) and to investigate the relationship between spinal cord functional activation and the severity of cervical spinal cord and brain structural damage by using magnetic resonance (MR) images.The study was conducted with institutional review board approval. Written informed consent was obtained from each participant. Cervical spinal cord functional MR images were obtained in 23 patients with PP MS and 18 healthy control subjects during tactile stimulation of the right hand. Conventional and diffusion-tensor MR images of the brain and spinal cord were also acquired. Mean stimulus-related signal intensity change for all activated voxels and the distribution of functional MR activity at each spinal cord level were obtained. Univariate analysis was used to compare MR findings between groups. Between-group differences in topographic distribution of functional MR activity were evaluated by using random-effects logistic regression models.Patients with PP MS had higher mean spinal cord activity on functional MR images than did controls. A higher occurrence of functional MR activation in the right versus left side of the spinal cord and in the posterior versus anterior section of the spinal cord was found in both control subjects and patients with PP MS. Patients who were mildly disabled had a pattern of functional MR activity distribution similar to that of controls, but patients who were more severely disabled did not show differential activation between the right and left sides of the spinal cord. A higher occurrence of functional MR activity in the anterior section of the right side of the spinal cord at the level of the C6-7 intervertebral disk (P = .05) and the left side of the spinal cord at the level of the C7-T1 intervertebral disk (P = .03) was found in patients with PP MS than in control subjects. Mean spinal cord functional MR imaging signal intensity change correlated with spinal cord fractional anisotropy.Patients with PP MS showed tactile-associated cervical spinal cord overactivation. Spinal cord functional changes, possibly owing to injured interneurons, likely contribute to the complex process that leads to the accumulation of irreversible disability in patients with PP MS.

Objective: We used voxel-based morphometry (VBM) to assess the pattern of regional gray matter (GM) loss in patients with pediatric multiple sclerosis (MS) and its relation with the Expanded Disability Status Scale (EDSS) score, disease duration, and the extent of T2 lesion load (LL). Methods: From 28 patients with pediatric relapsing-remitting MS (16 girls; mean age = 14.4 years, range = 7 to 16 years) and 21 matched controls, dual-echo and three-dimensional T1-weighted magnetization prepared rapid acquisition gradient echo sequences were acquired. T2 LL was measured using a local thresholding segmentation technique. Data were analyzed using an optimized VBM analysis and statistical parametric mapping. Results: In pediatric patients with MS, mean brain T2 LL was 7.8 mL ± 11.3. Intracranial volume did not differ between patients and controls. Compared to controls, patients with pediatric MS had significant GM loss in the thalamus, bilaterally, which was significantly correlated with T2 LL (r = −0.80 for the right thalamus, r = −0.74 for the left thalamus, p Conclusions: In patients with pediatric multiple sclerosis (MS), differently from what happens in adult-onset MS, gray matter (GM) atrophy seems to involve the thalamus only, with sparing of the cortex and other deep GM nuclei. The correlation found between atrophy and T2 lesion load suggests transsynaptic and Wallerian degenerations as the most likely substrate of tissue loss in the thalamus of these patients. GLOSSARY: DT = diffusion tensor; EDSS = Expanded Disability Status Scale; FA = flip angle; FOV = field of view; LL = lesion load; GM = gray matter; ICV = intracranial volume; MP-RAGE = magnetization prepared rapid acquisition gradient echo; MS = multiple sclerosis; MT = magnetization transfer; NAWM = normal-appearing white matter; NBV = normalized brain volume; NGM = normalized GM; RR = relapsing-remitting; TE = echo time; TR = repetition time; TSE = turbo spin-echo; VBM = voxel-based morphometry.

Gray matter (GM) damage, in terms of focal lesions,[1][1] “diffuse” tissue injury, and atrophy is a well-known feature of multiple sclerosis (MS). Recently, T1-hyperintensity on unenhanced T1-weighted sequences has been found in the dentate nuclei of patients with MS with severe disability and

TRIAL REGISTRATION: The ALLEGRO trial identifier number with clinicaltrials.gov is NCT00509145.; International audience; OBJECTIVE: In Assessment of OraL Laquinimod in PrEventing ProGRession in Multiple SclerOsis (ALLEGRO), a phase III study in relapsing-remitting multiple sclerosis (RRMS), oral laquinimod slowed disability and brain atrophy progression, suggesting laquinimod may reduce tissue damage in MS. MRI techniques sensitive to the most destructive aspects of the disease were used to further investigate laquinimod's potential effects on inflammation and neurodegeneration.METHODS: 1106 RRMS patients were randomised 1:1 to receive once-daily oral laquinimod (0.6 mg) or placebo for 24 months. White matter (WM), grey matter (GM) and thalamic fractions were derived at months 0, 12 and 24. Also assessed were evolution of gadolinium-enhancing and/or new T2 lesions into permanent black holes (PBH); magnetisation transfer ratio (MTR) of normal-appearing brain tissue (NABT), WM, GM and T2 lesions; and N-acetylaspartate/creatine (NAA/Cr) levels in WM.RESULTS: Compared with placebo, laquinimod-treated patients showed lower rates of WM at months 12 and 24 (p=0.004 and p=0.035) and GM (p=0.004) atrophy at month 12 and a trend for less GM atrophy at month 24 (p=0.078). Laquinimod also slowed thalamic atrophy at month 12 (p=0.005) and month 24 (p=0.003) and reduced the number of PBH at 12 and 24 months evolving from active lesions (all p