Meningeal contrast enhancement in multiple sclerosis: Assessment of field strength, acquisition delay, and clinical relevance.

BACKGROUND/PURPOSE: Leptomeningeal enhancement (LME) on post-contrast FLAIR is described as a potential biomarker of meningeal inflammation in multiple sclerosis (MS). Here we report an assessment of the impact of MRI field strength and acquisition timing on meningeal contrast enhancement (MCE). METHODS: This was a cross-sectional, observational study of 95 participants with MS and 17 healthy controls (HC) subjects. Each participant underwent an MRI of the brain on both a 7 Tesla (7T) and 3 Tesla (3T) MRI scanner. 7T protocols included a FLAIR image before, soon after (Gd+ Early 7T FLAIR), and 23 minutes after gadolinium (Gd+ Delayed 7T FLAIR). 3T protocol included FLAIR before and 21 minutes after gadolinium (Gd+ Delayed 3T FLAIR). RESULTS: LME was seen in 23.3% of participants with MS on Gd+ Delayed 3T FLAIR, 47.4% on Gd+ Early 7T FLAIR (p = 0.002) and 57.9% on Gd+ Delayed 7T FLAIR (p < 0.001 and p = 0.008, respectively). The count and volume of LME, leptomeningeal and paravascular enhancement (LMPE), and paravascular and dural enhancement (PDE) were all highest for Gd+ Delayed 7T FLAIR and lowest for Gd+ Delayed 3T FLAIR. Non-significant trends were seen for higher proportion, counts, and volumes for LME and PDE in MS compared to HCs. The rate of LMPE was different between MS and HCs on Gd+ Delayed 7T FLAIR (98.9% vs 82.4%, p = 0.003). MS participants with LME on Gd+ Delayed 7T FLAIR were older (47.6 (10.6) years) than those without (42.0 (9.7), p = 0.008). CONCLUSION: 7T MRI and a delay after contrast injection increased sensitivity for all forms of MCE. However, the lack of difference between groups for LME and its association with age calls into question its relevance as a biomarker of meningeal inflammation in MS.

Meningeal contrast enhancement in multiple sclerosis: assessment of field strength, acquisition delay, and clinical relevance.

Background/Purpose: Leptomeningeal enhancement (LME) on post-contrast FLAIR is described as a potential biomarker of meningeal inflammation in multiple sclerosis (MS). Here we report a comprehensive assessment of the impact of MRI field strength and acquisition timing on meningeal contrast enhancement (MCE). Methods: This was a cross-sectional, observational study of 95 participants with MS and 17 healthy controls (HC) subjects. Each participant underwent an MRI of the brain on both a 7 Tesla (7T) and 3 Tesla (3T) MRI scanner. 7T protocols included a FLAIR image before, soon after (Gd+ Early 7T FLAIR), and 23 minutes after gadolinium (Gd+ Delayed 7T FLAIR). 3T protocol included FLAIR before and 21 minutes after gadolinium (Gd+ Delayed 3T FLAIR). Results: LME was seen in 23.3% of participants with MS on Gd+ Delayed 3T FLAIR, 47.4% on Gd+ Early 7T FLAIR (p = 0.002) and 57.9% on Gd+ Delayed 7T FLAIR (p < 0.001 and p = 0.008, respectively). The count and volume of LME, leptomeningeal and paravascular enhancement (LMPE), and paravascular and dural enhancement (PDE) were all highest for Gd+ Delayed 7T FLAIR and lowest for Gd+ Delayed 3T FLAIR. Non-significant trends were seen for higher proportion, counts, and volumes for LME and PDE in MS compared to HCs. The rate of LMPE was different between MS and HCs on Gd+ Delayed 7T FLAIR (98.9% vs 82.4%, p = 0.003). MS participants with LME on Gd+ Delayed 7T FLAIR were older (47.6 (10.6) years) than those without (42.0 (9.7), p = 0.008). Conclusion: 7T MRI and a delay after contrast injection increased sensitivity for all forms of MCE. However, the lack of difference between groups for LME and its association with age calls into question its relevance as a biomarker of meningeal inflammation in MS.

Imaging chronic active lesions in multiple sclerosis: a consensus statement.

Chronic active lesions (CAL) are an important manifestation of chronic inflammation in multiple sclerosis (MS) and have implications for non-relapsing biological progression. In recent years, the discovery of innovative magnetic resonance imaging (MRI) and PET derived biomarkers has made it possible to detect CAL, and to some extent quantify them, in the brain of persons with MS, in vivo. Paramagnetic rim lesions on susceptibility-sensitive MRI sequences, MRI-defined slowly expanding lesions on T1-weighted (T1-w) and T2-w scans, and 18-kDa translocator protein-positive lesions on PET are promising candidate biomarkers of CAL. While partially overlapping, these biomarkers do not have equivalent sensitivity and specificity to histopathological CAL. Standardization in the use of available imaging measures for CAL identification, quantification, and monitoring is lacking. To fast-forward clinical translation of CAL, the North American Imaging in Multiple Sclerosis Cooperative developed a Consensus Statement, which provides guidance for the radiological definition and measurement of CAL. The proposed manuscript presents this Consensus Statement, summarizes the multistep process leading to it, and identifies the remaining major gaps in knowledge.

Evaluation of the Blood-Brain Barrier, Demyelination, and Neurodegeneration in Paramagnetic Rim Lesions in Multiple Sclerosis on 7 Tesla MRI.

BACKGROUND: Paramagnetic rim lesions (PRLs) are associated with chronic inflammation in multiple sclerosis (MS). 7-Tesla (7T) magnetic resonance imaging (MRI) can evaluate the integrity of the blood-brain barrier (BBB) in addition to the tissue myelination status and cell loss. PURPOSE: To use MRI metrics to investigate underlying physiology and clinical importance of PRLs. STUDY TYPE: Prospective. SUBJECTS: Thirty-six participants (mean-age 47, 23 females, 13 males) of mixed MS subtypes. FIELD STRENGTH/SEQUENCE: 7T, MP2RAGE, MULTI-ECHO 3D-GRE, FLAIR. ASSESSMENT: Lesion heterogeneity; longitudinal changes in lesion counts; comparison of T1, R2*, and χ; association between baseline lesion types and disease progression (2-3 annual MRI visits with additional years of annual clinical follow-up). STATISTICAL TESTS: Two-sample t-test, Wilcoxon Rank-Sum test, Pearson's chi-square test, two-group comparison with linear-mixed-effect model, mixed-effect ANOVA, logistic regression. P-values <0.05 were considered significant. RESULTS: A total of 58.3% of participants had at least one PRL at baseline. Higher male proportion in PRL+ group was found. Average change in PRL count was 0.20 (SD = 2.82) for PRLs and 0.00 (SD = 0.82) for mottled lesions. Mean and median pre-/post-contrast T1 were longer in PRL+ than in PRL-. No differences in mean χ were seen for lesions grouped by PRL (P = 0.310, pre-contrast; 0.086, post-contrast) or PRL/M presence (P = 0.234, pre-contrast; 0.163, post-contrast). Median χ were less negative in PRL+ and PRL/M+ than in PRL- and PRL/M-. Mean and median pre-/post-contrast R2* were slower in PRL+ compared to PRL-. Mean and median pre-/post-contrast R2* were slower in PRL/M+ than in PRL/M-. PRL presence at baseline was associated with confirmed EDSS Plus progression (OR 3.75 [1.22-7.59]) and PRL/M+ at baseline with confirmed EDSS Plus progression (OR 3.63 [1.14-7.43]). DATA CONCLUSION: Evidence of BBB breakdown in PRLs was not seen. Quantitative metrics confirmed prior results suggesting greater demyelination, cell loss, and possibly disruption of tissue anisotropy in PRLs. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

A pilot trial of ocrelizumab for modulation of meningeal enhancement in multiple sclerosis.

BACKGROUND: Autopsy data suggests that meningeal inflammation in multiple sclerosis (MS) is driven by CD20+ B-cells. Ocrelizumab is an anti-CD20 monoclonal antibody, and thus could potentially ameliorate meningeal inflammation in MS. Leptomeningeal enhancement (LME) on MRI is suggested as a surrogate biomarker of meningeal inflammation in MS, and thus may be a way of monitoring for this treatment effect. OBJECTIVES: To determine if ocrelizumab impacts meningeal enhancement (ME) on 7T MRI in MS. METHODS: Twenty-two patients with MS started on ocrelizumab by their treating physician were enrolled into this single-center, open-label, prospective trial. Participants underwent 7T MRI of the brain prior to first infusion, with screening for the presence of LME. Fourteen patients (48 ± 11 years; 11 women) had LME on the baseline scan and were invited to return for an additional 7T MRI after 1 year of treatment. Fourteen MS patients (49 ± 10 years; 11 women) on non-CD20 treatment from a separate observational cohort of annual 7T MRIs were used for comparison - matched for LME at baseline, age, and sex. Post-contrast FLAIR and subtraction images were reviewed for LME and paravascular and dural enhancement (PDE). RESULTS: All subjects in the ocrelizumab and comparison groups had LME and PDE on their baseline scan. At the beginning of the study the mean number of foci of LME and PDE in the study group were 2.3 ± 1.7 and 6.6 ± 3.9 respectively. Mean LME and PDE count for the comparison group were 1.7 ± 1.5 and 7.8 ± 5.5. Mean volume of LME in the study group was 50.5 mm3 ± 65.0 mm3 and that of the PDE was 866 mm3 ± 937.9. Mean volume of LME and PDE for comparison group were 28.4 mm3 ± 36.0 and 885 mm3 ± 947.7 respectively. At follow-up, the number of patients with LME decreased to 8 (57 %) in both groups, whereas the proportion of patients with PDE was unchanged. Minimal mean change in the number of LME after 1 year were seen in both the study group (0.07 ± 2.9, p = 0.97) and comparison group (-0.71 ± 1.5, p = 0.08). Minimal mean change was seen in the volume of LME in both the study group (-21.91 mm3 ± 77.66, p = 0.27) and comparison group (3.4 mm3 ± 32.11, p = 0.77). There was minimal change in the mean number of foci of PDE after 1 year in both the study group (-0.71 ± 2.36, p = 0.32) and in the comparison group (-0.17 ± 3.89, p = 0.15). Mean change in volume of PDE was measurable, but not significant in both the study group (-397.1 mm3 ±959.6, p = 0.80) and in the comparison group (-417.0 mm3 ± 922.7) (p = 0.80). Comparisons between the changes in foci count and volume for both LME and PDE in the study versus comparison groups showed no significant differences. CONCLUSION: In this small pilot trial, ocrelizumab did not significantly reduce the number or volume of foci of LME or PDE in MS patients.

Cellular-Level Visualization of Retinal Pathology in Multiple Sclerosis With Adaptive Optics.

Purpose: To apply adaptive optics-optical coherence tomography (AO-OCT) to quantify multiple sclerosis (MS)-induced changes in axonal bundles in the macular nerve fiber layer, ganglion cell somas, and macrophage-like cells at the vitreomacular interface. Methods: We used AO-OCT imaging in a pilot study of MS participants (n = 10), including those without and with a history of optic neuritis (ON, n = 4), and healthy volunteers (HV, n = 9) to reveal pathologic changes to inner retinal cells and structures affected by MS. Results: We found that nerve fiber layer axonal bundles had 38% lower volume in MS participants (1.5 × 10-3 mm3) compared to HVs (2.4 × 10-3 mm3; P < 0.001). Retinal ganglion cell (RGC) density was 51% lower in MS participants (12.3 cells/mm2 × 1000) compared to HVs (25.0 cells/mm2 × 1000; P < 0.001). Spatial differences across the macula were observed in RGC density. RGC diameter was 15% higher in MS participants (11.7 µm) compared to HVs (10.1 µm; P < 0.001). A nonsignificant trend of higher density of macrophage-like cells in MS eyes was also observed. For all AO-OCT measures, outcomes were worse for MS participants with a history of ON compared to MS participants without a history of ON. AO-OCT measures were associated with key visual and physical disabilities in the MS cohort. Conclusions: Our findings demonstrate the utility of AO-OCT for highly sensitive and specific detection of neurodegenerative changes in MS. Moreover, the results shed light on the mechanisms that underpin specific neuronal pathology that occurs when MS attacks the retina. The new findings support the further development of AO-based biomarkers for MS.

Imaging of the meningeal lymphatic network in healthy adults: A 7T MRI study.

BACKGROUND AND PURPOSE: Meningeal lymphatic vessels (MLVs) along the dural venous sinuses are suspected to be important in connecting the glymphatic and peripheral lymphatic system. Understanding the topography of MLVs may clarify the role of the glymphatic system in neurological diseases. The aim of this analysis was to use high resolution pre- and post-contrast FLAIR 7T MRI to identify and characterize the morphology of MLV in a cohort of healthy volunteers. MATERIALS AND METHODS: MRI examinations of seventeen healthy volunteers enrolled as controls in a larger 7T MRI study were reviewed. Pre- and post-contrast 3-D FLAIR subtractions and MP2RAGE sequences were spatially normalized and reviewed for signal intensity and enhancement patterns within putative MLVs along pre-determined dural and venous structures. Frequency of occurrence of MLVs at the above-described locations and patterns of their enhancement were analyzed. RESULTS: Putative MLVs are commonly located along the superior sagittal sinus (SSS) and cortical veins. A "fixed enhancement" signal pattern was more frequent at these locations (p<.05). The morphology of MLVs along the SSS qualitatively changes in an antero-posterior direction. Lack of signal was more frequent along the straight and transverse sinuses (p<.05). CONCLUSION: Putative MLVs in healthy individuals are concentrated along the SSS and cortical veins. FLAIR signal and enhancement characteristics suggest these structures may transport proteinaceous fluid. Pathways connecting MLVs to cervical lymph nodes however remain unclear.

Present and future of the diagnostic work-up of multiple sclerosis: the imaging perspective.

In recent years, the use of magnetic resonance imaging (MRI) for the diagnostic work-up of multiple sclerosis (MS) has evolved considerably. The 2017 McDonald criteria show high sensitivity and accuracy in predicting a second clinical attack in patients with a typical clinically isolated syndrome and allow an earlier diagnosis of MS. They have been validated, are evidence-based, simplify the clinical use of MRI criteria and improve MS patients' management. However, to limit the risk of misdiagnosis, they should be applied by expert clinicians only after the careful exclusion of alternative diagnoses. Recently, new MRI markers have been proposed to improve diagnostic specificity for MS and reduce the risk of misdiagnosis. The central vein sign and chronic active lesions (i.e., paramagnetic rim lesions) may increase the specificity of MS diagnostic criteria, but further effort is necessary to validate and standardize their assessment before implementing them in the clinical setting. The feasibility of subpial demyelination assessment and the clinical relevance of leptomeningeal enhancement evaluation in the diagnostic work-up of MS appear more limited. Artificial intelligence tools may capture MRI attributes that are beyond the human perception, and, in the future, artificial intelligence may complement human assessment to further ameliorate the diagnostic work-up and patients' classification. However, guidelines that ensure reliability, interpretability, and validity of findings obtained from artificial intelligence approaches are still needed to implement them in the clinical scenario. This review provides a summary of the most recent updates regarding the application of MRI for the diagnosis of MS.

Correction: Blood-brain barrier breakdown in non-enhancing multiple sclerosis lesions detected by 7-Tesla MP2RAGE ΔT1 mapping.

[This corrects the article DOI: 10.1371/journal.pone.0249973.].

Association of retinal atrophy with cortical lesions and leptomeningeal enhancement in multiple sclerosis on 7T MRI.

BACKGROUND: Retinal atrophy in multiple sclerosis (MS) as measured by optical coherence tomography (OCT) correlates with demyelinating lesions and brain atrophy, but its relationship with cortical lesions (CLs) and meningeal inflammation is not well known. OBJECTIVES: To evaluate the relationship of retinal layer atrophy with leptomeningeal enhancement (LME) and CLs in MS as visualized on 7 Tesla (7T) magnetic resonance imaging (MRI). METHODS: Forty participants with MS underwent 7T MRI of the brain and OCT. Partial correlation and mixed-effects regression evaluated relationships between MRI and OCT findings. RESULTS: All participants had CLs and 32 (80%) participants had LME on post-contrast MRI. Ganglion cell/inner plexiform layer (GCIPL) thickness correlated with total CL volume (r =-0.45, p < 0.01). Participants with LME at baseline had thinner macular retinal nerve fiber layer (mRNFL; p = 0.01) and GCIPL (p < 0.01). Atrophy in various retinal layers was faster in those with certain patterns of LME. For example, mRNFL declined -1.113 (-1.974, -0.252) µm/year faster in those with spread/fill-pattern LME foci at baseline compared with those without (p = 0.01). CONCLUSION: This study associates MRI findings of LME and cortical pathology with thinning of retinal layers as measured by OCT, suggesting a common link between meningeal inflammation, CLs, and retinal atrophy in MS.

Blood-brain barrier breakdown in non-enhancing multiple sclerosis lesions detected by 7-Tesla MP2RAGE ΔT1 mapping.

Although the blood-brain barrier (BBB) is altered in most multiple sclerosis (MS) lesions, gadolinium enhancement is seen only in acute lesions. In this study, we aimed to investigate gadolinium-induced changes in T1 relaxation time in MS lesions on 7-tesla (7T) MRI as a means to quantify BBB breakdown in non-enhancing MS lesions. Forty-seven participants with MS underwent 7T MRI of the brain with a magnitude-prepared rapid acquisition of 2 gradient echoes (MP2RAGE) sequence before and after contrast. Subtraction of pre- and post-contrast T1 maps was used to measure T1 relaxation time change (ΔT1) from gadolinium. ΔT1 values were interrogated in enhancing white matter lesions (ELs), non-enhancing white matter lesions (NELs), and normal appearing white matter (NAWM) and metrics were compared to clinical data. ΔT1 was measurable in NELs (median: -0.139 (-0.304, 0.174) seconds; p < 0.001) and was negligible in NAWM (median: -0.001 (-0.036, 0.155) seconds; p = 0.516). Median ΔT1 in NELs correlated with disability as measured by Expanded Disability Status Scale (EDSS) (rho = -0.331, p = 0.026). Multiple measures of NEL ΔT1 variability also correlated with EDSS. NEL ΔT1 values were greater and more variable in patients with progressive forms of MS and greater in those not on MS treatment. Measurement of the changes in T1 relaxation time caused by contrast on 7T MP2RAGE reveals clinically relevant evidence of BBB breakdown in NELs in MS. This data suggests that NEL ΔT1 should be evaluated further as a potential biomarker of persistently disrupted BBB in MS.Although the blood-brain barrier (BBB) is altered in most multiple sclerosis (MS) lesions, gadolinium enhancement is seen only in acute lesions. In this study, we aimed to investigate gadolinium-induced changes in T1 relaxation time in MS lesions on 7-tesla (7T) MRI as a means to quantify BBB breakdown in non-enhancing MS lesions. Forty-seven participants with MS underwent 7T MRI of the brain with a magnitude-prepared rapid acquisition of 2 gradient echoes (MP2RAGE) sequence before and after contrast. Subtraction of pre- and post-contrast T1 maps was used to measure T1 relaxation time change (ΔT1) from gadolinium. ΔT1 values were interrogated in enhancing white matter lesions (ELs), non-enhancing white matter lesions (NELs), and normal appearing white matter (NAWM) and metrics were compared to clinical data. ΔT1 was measurable in NELs (median: -0.139 (-0.304, 0.174) seconds; p < 0.001) and was negligible in NAWM (median: -0.001 (-0.036, 0.155) seconds; p = 0.516). Median ΔT1 in NELs correlated with disability as measured by Expanded Disability Status Scale (EDSS) (rho = -0.331, p = 0.026). Multiple measures of NEL ΔT1 variability also correlated with EDSS. NEL ΔT1 values were greater and more variable in patients with progressive forms of MS and greater in those not on MS treatment. Measurement of the changes in T1 relaxation time caused by contrast on 7T MP2RAGE reveals clinically relevant evidence of BBB breakdown in NELs in MS. This data suggests that NEL ΔT1 should be evaluated further as a potential biomarker of persistently disrupted BBB in MS.

Deep grey matter injury in multiple sclerosis: a NAIMS consensus statement.

Although multiple sclerosis has traditionally been considered a white matter disease, extensive research documents the presence and importance of grey matter injury including cortical and deep regions. The deep grey matter exhibits a broad range of pathology and is uniquely suited to study the mechanisms and clinical relevance of tissue injury in multiple sclerosis using magnetic resonance techniques. Deep grey matter injury has been associated with clinical and cognitive disability. Recently, MRI characterization of deep grey matter properties, such as thalamic volume, have been tested as potential clinical trial end points associated with neurodegenerative aspects of multiple sclerosis. Given this emerging area of interest and its potential clinical trial relevance, the North American Imaging in Multiple Sclerosis (NAIMS) Cooperative held a workshop and reached consensus on imaging topics related to deep grey matter. Herein, we review current knowledge regarding deep grey matter injury in multiple sclerosis from an imaging perspective, including insights from histopathology, image acquisition and post-processing for deep grey matter. We discuss the clinical relevance of deep grey matter injury and specific regions of interest within the deep grey matter. We highlight unanswered questions and propose future directions, with the aim of focusing research priorities towards better methods, analysis, and interpretation of results.

Multi-layer analysis of quantitative 7 T magnetic resonance imaging in the cortex of multiple sclerosis patients reveals pathology associated with disability.

BACKGROUND: Cortical demyelination is a relevant aspect of tissue damage in multiple sclerosis (MS). Microstructural changes may affect each layer in the cortex differently. OBJECTIVES: To evaluate the sensitivity of quantitative magnetic resonance imaging (qMRI) measurements on cortical layers as clinically accessible biomarkers of grey matter (GM) pathology. METHODS: Forty-five participants with MS underwent 7 T magnetic resonance imaging (MRI) of the brain. Magnetization prepared two rapid acquisition gradient echoes (MP2RAGE) was processed for T1-weighted images and a T1 map. Multi-echo gradient echo images were processed for quantitative susceptibility and R2* maps. Cortical GM volumes were segmented into four cortical layers, and relaxometry metrics were calculated within and between these layers. RESULTS: Significant correlations were found for disability scales and multi-layer metrics, for example, Expanded Disability Status Scale (EDSS) and peak height (PH) in the subpial (T1: ρ = -0.372, p < 0.050) and inner (R2*: ρ = -0.359, p < 0.050) cortical layers. Multivariate regression showed interdependency between atrophy and cortical metrics in some instances, but an independent relationship between cortical metrics and disability in others. CONCLUSION: Cortical layer 7 T qMRI analyses reveal layer-specific relationships with disability in MS and allow emergence of clinically relevant associations that are hidden when analysing the full cortex.

7T MPFLAIR versus MP2RAGE for Quantifying Lesion Volume in Multiple Sclerosis.

BACKGROUND AND PURPOSE: Use of fluid-attenuated inversion recovery (FLAIR) scans to quantify multiple sclerosis (MS) lesion volume on 7 Tesla (7T) magnetic resonance imaging (MRI) has many downsides, including poor image homogeneity. There are little data about the relative benefit of alternative modalities. The purpose of this paper is to investigate if magnetization-prepared 2 rapid acquisition gradient echo (MP2RAGE) is a viable alternative to FLAIR for robust lesion volume measurement and disability correlations. METHODS: Forty-seven participants with MS underwent annual brain 7T MRIs. Magnetization-prepared FLAIR (MPFLAIR) and MP2RAGE (both at .7 mm3 isotropic resolution) sequences from a total of 80 MRI scans from 47 subjects were reviewed. White matter lesion (WML) masks were manually constructed from MPFLAIR and T1 maps (from MP2RAGE). Lesion volumes (normalized to intracranial volume) were compared to clinical characteristics and disability scales scores by Pearson or Spearman correlation, as appropriate. Relative correlation strength was compared by Fisher r- to z-transformation. RESULTS: Normalized lesion volume was greater in MPFLAIR masks (median .005 [range, .001-.030]) than from T1 maps (median .003 [range, .000-.015]). However, lesion volumes between MPFLAIR and T1 maps were highly correlated (rho = .87, P < .001). WML masks from both modalities correlated with most disability measures with no significant difference in the strength of correlation. CONCLUSIONS: 7T MPFLAIR and MP2RAGE T1 map-based WML volumes are highly intercorrelated and both correlate with disability. Thus, MP2RAGE may be a viable alternative to FLAIR-based methods for WML measurement on 7T MRI in MS research.

Imaging Mechanisms of Disease Progression in Multiple Sclerosis: Beyond Brain Atrophy.

Clinicians involved with different aspects of the care of persons with multiple sclerosis (MS) and scientists with expertise on clinical and imaging techniques convened in Dallas, TX, USA on February 27, 2019 at a North American Imaging in Multiple Sclerosis Cooperative workshop meeting. The aim of the workshop was to discuss cardinal pathobiological mechanisms implicated in the progression of MS and novel imaging techniques, beyond brain atrophy, to unravel these pathologies. Indeed, although brain volume assessment demonstrates changes linked to disease progression, identifying the biological mechanisms leading up to that volume loss are key for understanding disease mechanisms. To this end, the workshop focused on the application of advanced magnetic resonance imaging (MRI) and positron emission tomography (PET) imaging techniques to assess and measure disease progression in both the brain and the spinal cord. Clinical translation of quantitative MRI was recognized as of vital importance, although the need to maintain a relatively short acquisition time mandated by most radiology departments remains the major obstacle toward this effort. Regarding PET, the panel agreed upon its utility to identify ongoing pathological processes. However, due to costs, required expertise, and the use of ionizing radiation, PET was not considered to be a viable option for ongoing care of persons with MS. Collaborative efforts fostering robust study designs and imaging technique standardization across scanners and centers are needed to unravel disease mechanisms leading to progression and discovering medications halting neurodegeneration and/or promoting repair.

No association between cortical lesions and leptomeningeal enhancement on 7-Tesla MRI in multiple sclerosis.

BACKGROUND: Autopsy data suggest a causative link between meningeal inflammation and cortical lesions (CLs) in multiple sclerosis (MS). OBJECTIVE: To use leptomeningeal enhancement (LME) and CLs on 7-Tesla (7T) magnetic resonance imaging (MRI) to investigate associations between meningeal inflammation and cortical pathology. METHODS: Forty-one participants with MS underwent 7T MRI of the brain. CLs and foci of LME were quantified. RESULTS: All MS participants had CLs; 27 (65.8%) had >1 focus of LME. Except for hippocampal CL count (ρ = 0.32 with spread/fill-sulcal pattern LME, p = 0.042), no significant correlations were seen between LME and CLs. Mean cortical thickness correlated with the number of LME foci (ρ = -0.43, p = 0.005). Participants with relapsing-remitting multiple sclerosis (RRMS) showed no correlation with neocortical CLs, but significant correlations were seen between LME and hippocampal lesion count (ρ = 0.39, p = 0.030), normalized cortical gray matter (GM) volume (ρ = -0.49, p = 0.005), and mean cortical thickness (ρ = -0.59, p < 0.001). CONCLUSION: This study supports a relationship between LME and cortical GM atrophy but does not support an association of LME and neocortical CLs. This may indicate that meningeal inflammation is involved with neurodegenerative inflammatory processes, rather than focal lesion development.

Leptomeningeal Enhancement at 7T in Multiple Sclerosis: Frequency, Morphology, and Relationship to Cortical Volume.

BACKGROUND AND PURPOSE: Perform an investigation of the frequency and distribution of leptomeningeal enhancement on postgadolinium magnetization-prepared FLAIR (MPFLAIR) in multiple sclerosis (MS) on 7 Tesla (7T) MRI and to relate this finding to measures of brain structure and lesion volumes. METHODS: Twenty-nine participants with MS underwent 7T MRI of the brain. Three healthy volunteers (HVs) were scanned for comparison. Areas of postcontrast leptomeningeal enhancement were identified. Images were segmented for brain structure and lesion volumes. The relationship between leptomeningeal enhancement and clinical and volumetric data was explored. RESULTS: Two patterns of enhancement were found: "nodular" (discrete, spherical nodules at the pial surface or subarachnoid space) and "spread/fill" (appearance of contrast spread through the local subarachnoid space). Twenty-six of 29 (90%) MS participants had at least one focus of leptomeningeal enhancement. Nodular foci were present in 15 of 29 (51%) MS participants. Spread/fill foci were present in 22 of 29 (76%) MS participants. Two HVs had examples of nodular foci, but none had spread/fill enhancement. MS participants with spread/fill foci were older (48.9 years [SD 8.3]) than those without (33.3 years [SD 11.5], P = .005). MS participants with spread/fill foci had reduced cortical gray matter volume compared to those without (P = .020). CONCLUSIONS: Leptomeningeal enhancement on postcontrast 7T MPFLAIR is more prevalent than prior reports at 3T-occurring at frequencies closer to histopathologic data. Spread/fill foci are associated with reduced cortical gray matter volumes and may represent blood-meningeal barrier breakdown near sites of meningeal inflammation, whereas nodular foci may be a normal variant.

Magnetic susceptibility contrast variations in multiple sclerosis lesions.

PURPOSE: Recent magnetic resonance imaging (MRI) studies have revealed heterogeneous magnetic susceptibility contrasts in multiple sclerosis (MS) lesions. Due to its sensitivity to disease-related iron and myelin changes, magnetic susceptibility-based measures may better reflect some pathological features of MS lesions. Hence, we sought to characterize MS lesions using combined R2* mapping and quantitative susceptibility mapping (QSM). MATERIALS AND METHODS: In all, 306 MS lesions were selected from 24 MS patients who underwent 7T MRI. Maps of R2*, frequency, and quantitative susceptibility were calculated using acquired multiecho gradient echo (GRE) phase data. Lesions were categorized based on their image intensity or their anatomical locations. R2* and susceptibility values were quantified in each lesion based on manually drawn lesion masks and compared between lesion groups showing different contrast patterns. Correlations between R2* and susceptibility were also tested in these lesion groups. RESULTS: In 38% of selected lesions the frequency map did not show the same contrast pattern as the susceptibility map. While most lesions (93%) showed hypointensity on R2*, the susceptibility contrast in lesions varied, with 40% being isointense and 58% being hyperintense in the lesion core. Significant correlations (r = 0.31, P < 0.001) between R2* and susceptibility were found in susceptibility hyperintense lesions, but not in susceptibility isointense lesions. In addition, a higher proportion (74%) of periventricular lesions was found to be susceptibility hyperintense as compared to subcortical (53%) or juxtacortical (38%) lesions. CONCLUSION: Combining R2* and QSM is useful to characterize heterogeneity in MS lesions.

Association of Cortical Lesion Burden on 7-T Magnetic Resonance Imaging With Cognition and Disability in Multiple Sclerosis.

IMPORTANCE: Cortical lesions (CLs) contribute to physical and cognitive disability in multiple sclerosis (MS). Accurate methods for visualization of CLs are necessary for future clinical studies and therapeutic trials in MS. OBJECTIVE: To evaluate the clinical relevance of measures of CL burden derived from high-field magnetic resonance imaging (MRI) in MS. DESIGN, SETTING, AND PARTICIPANTS: An observational clinical imaging study was conducted at an academic MS center. Participants included 36 individuals with MS (30 relapsing-remitting, 6 secondary or primary progressive) and 15 healthy individuals serving as controls. The study was conducted from March 10, 2010, to November 23, 2012, and analysis was performed from June 1, 2011, to September 30, 2014. Seven-Tesla MRI of the brain was performed with 0.5-mm isotropic resolution magnetization-prepared rapid acquisition gradient echo (MPRAGE) and whole-brain, 3-dimensional, 1.0-mm isotropic resolution magnetization-prepared, fluid-attenuated inversion recovery (MPFLAIR). Cortical lesions, seen as hypointensities on MPRAGE, were manually segmented. Lesions were classified as leukocortical, intracortical, or subpial. Images were segmented using the Lesion-TOADS (Topology-Preserving Anatomical Segmentation) algorithm, and brain structure volumes and white matter (WM) lesion volume were reported. Volumes were normalized to intracranial volume. MAIN OUTCOMES AND MEASURES: Physical disability was measured by the Expanded Disability Status Scale (EDSS). Cognitive disability was measured with the Minimal Assessment of Cognitive Function in MS battery. RESULTS: Cortical lesions were noted in 35 of 36 participants (97%), with a median of 16 lesions per participant (range, 0-99). Leukocortical lesion volume correlated with WM lesion volume (ρ = 0.50; P = .003) but not with cortical volume; subpial lesion volume inversely correlated with cortical volume (ρ = -0.36; P = .04) but not with WM lesion volume. Total CL count and volume, measured as median (range), were significantly increased in participants with EDSS scores of 5.0 or more vs those with scores less than 5.0 (count: 29 [11-99] vs 13 [0-51]; volume: 2.81 × 10-4 [1.30 × 10-4 to 7.90 × 10-4] vs 1.50 × 10-4 [0 to 1.01 × 10-3]) and in cognitively impaired vs unimpaired individuals (count: 21 [0-99] vs 13 [1-54]; volume: 3.51 × 10-4 [0 to 1.01 × 10-4] vs 1.19 × 10-4 [0 to 7.17 × 10-4]). Cortical lesion volume correlated with EDSS scores more robustly than did WM lesion volume (ρ = 0.59 vs 0.36). Increasing log[CL volume] conferred a 3-fold increase in the odds of cognitive impairment (odds ratio [OR], 3.36; 95% CI, 1.07-10.59; P = .04) after adjustment for age and sex and a 14-fold increase in odds after adjustment for WM lesion volume and atrophy (OR, 14.26; 95% CI, 1.06-192.37; P = .045). Leukocortical lesions had the greatest effect on cognition (OR for log [leukocortical lesion volume], 9.65; 95% CI, 1.70-54.59, P = .01). CONCLUSIONS AND RELEVANCE: This study provides in vivo evidence that CLs are associated with cognitive and physical disability in MS and that leukocortical and subpial lesion subtypes have differing clinical relevance. Quantitative assessments of CL burden on high-field MRI may further our understanding of the development of disability and progression in MS and lead to more effective treatments.

Thalamic lesions in multiple sclerosis by 7T MRI: Clinical implications and relationship to cortical pathology.

OBJECTIVE: Pathology in both cortex and deep gray matter contribute to disability in multiple sclerosis (MS). We used the increased signal-to-noise ratio of 7-tesla (7T) MRI to visualize small lesions within the thalamus and to relate this to clinical information and cortical lesions. METHODS: We obtained 7T MRI scans on 34 MS cases and 15 healthy volunteers. Thalamic lesion number and volume were related to demographic data, clinical disability measures, and lesions in cortical gray matter. RESULTS: Thalamic lesions were found in 24/34 of MS cases. Two lesion subtypes were noted: discrete, ovoid lesions, and more diffuse lesional areas lining the periventricular surface. The number of thalamic lesions was greater in progressive MS compared to relapsing-remitting (mean ±SD, 10.7 ±0.7 vs. 3.0 ±0.7, respectively, p < 0.001). Thalamic lesion burden (count and volume) correlated with EDSS score and measures of cortical lesion burden, but not with white matter lesion burden or white matter volume. CONCLUSIONS: Using 7T MRI allows identification of thalamic lesions in MS, which are associated with disability, progressive disease, and cortical lesions. Thalamic lesion analysis may be a simpler, more rapid estimate of overall gray matter lesion burden in MS.