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Objective Determine whether a treatment effect of ibudilast on brain atrophy rate differs between participants with primary (PPMS) and secondary (SPMS) progressive multiple sclerosis. Background Progressive forms of MS are both associated with continuous disability progression. Whether PPMS and SPMS differ in treatment response remains unknown. Design/Methods SPRINT‐MS was a randomized, placebo‐controlled 96‐week phase 2 trial in both PPMS (n = 134) and SPMS (n = 121) patients. The effect of PPMS and SPMS phenotype on the rate of change of brain atrophy measured by brain parenchymal fraction (BPF) was examined by fitting a three‐way interaction linear‐mixed model. Adjustment for differences in baseline demographics, disease measures, and brain size was explored. Results Analysis showed that there was a three‐way interaction between the time, treatment effect, and disease phenotype (P

Multiple sclerosis (MS) is a "3C" (complex, chronic, costly) condition that is a common and disabling neurological illness affecting approximately 1 million adults in the United States. MS has been studied at the basic science, individual, and population levels, but not at the system level to assess small-area variation effects on MS population health outcomes. System-level effects have been observed in other 3C conditions including cystic fibrosis, rheumatoid arthritis, and inflammatory bowel disease. The authors report here on system-level variation findings from the baseline period during the first year of the Multiple Sclerosis Continuous Quality Improvement (MS-CQI) study. Stepwise binary logistic regression analyses were conducted to investigate system-level (small-area variation) effects on MS relapses (exacerbations), disease-modifying therapy (DMT) utilization, and brain MRI utilization, controlling for demographics (age and sex) and other potential confounders. Significant differences were observed in people with MS (PwMS) between centers for a number of demographic and disease characteristics, including sex, age, and MS subtype. Controlling for these factors, significant system-level effects were observed on outcomes, including DMT utilization, MRI utilization, and relapses. Significant relationships also were observed between outcomes and urgent care utilization, including emergency department visits and hospitalizations. This initial study provides evidence establishing the presence of system-level variation effects on MS outcomes in a multicenter population study - where PwMS get their care can influence their outcomes. Results support continued systems-level research and improvement initiatives to optimize MS population health outcomes in this challenging and costly complex chronic condition.

Objective To evaluate alterations in apparent axon diameter and axon density obtained by high‐gradient diffusion MRI in the corpus callosum of MS patients and the relationship of these advanced diffusion MRI metrics to neurologic disability and cognitive impairment in MS. Methods Thirty people with MS (23 relapsing‐remitting MS [RRMS], 7 progressive MS [PMS]) and 23 healthy controls were scanned on a human 3‐tesla (3T) MRI scanner equipped with 300 mT/m maximum gradient strength using a comprehensive multishell diffusion MRI protocol. Data were fitted to a three‐compartment geometric model of white matter to estimate apparent axon diameter and axon density in the midline corpus callosum. Neurologic disability and cognitive function were measured using the Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC), and Minimal Assessment of Cognitive Function in MS battery. Results Apparent axon diameter was significantly larger and axon density reduced in the normal‐appearing corpus callosum (NACC) of MS patients compared to healthy controls, with similar trends seen in PMS compared to RRMS. Larger apparent axon diameter in the NACC of MS patients correlated with greater disability as measured by the EDSS (r = 0.555, P = 0.007) and poorer performance on the Symbol Digits Modalities Test (r = ‐0.593, P = 0.008) and Brief Visuospatial Memory Test–Revised (r = −0.632, P

Background: Activated microglia, which can be detected in vivo by 11C-PBR28 positron emission tomography (PET), represent a main component of MS pathology in the brain. Their role in the cerebellum is still unexplored, although cerebellar involvement in MS is frequent and accounts for disability progression. Objectives: We aimed at characterizing cerebellar neuroinflammation in MS patients compared to healthy subjects by combining 11C-PBR28 MRI-Positron Emission Tomography (MR-PET) with 7 Tesla (T) MRI and assessing its relationship with brain neuroinflammation and clinical outcome measures. Methods: Twenty-eight MS patients and 16 healthy controls underwent 11C-PBR28 MR-PET to measure microglia activation in normal appearing cerebellum and lesions segmented from 7 T scans. Patients were evaluated using the Expanded Disability Status Scale and Symbol Digit Modalities Test. 11C-PBR28 binding was assessed in regions of interest using 60–90 minutes standardized uptake values normalized by a pseudo-reference region in the brain normal appearing white matter. Multilinear regression was used to compare tracer uptake in MS and healthy controls and assess correlations with clinical scores. Results: In all cerebellar regions examined, MS patients showed abnormally increased tracer uptake, which correlated with cognitive and neurological disability. Conclusion: Neuroinflammation is widespread in the cerebellum of patients with MS and related to neurological disability and cognitive impairment.

Strong gradient systems can improve the signal-to-noise ratio of diffusion MRI measurements and enable a wider range of acquisition parameters that are beneficial for microstructural imaging. We present a comprehensive diffusion MRI dataset of 26 healthy participants acquired on the MGH-USC 3 T Connectome scanner equipped with 300 mT/m maximum gradient strength and a custom-built 64-channel head coil. For each participant, the one-hour long acquisition systematically sampled the accessible diffusion measurement space, including two diffusion times (19 and 49 ms), eight gradient strengths linearly spaced between 30 mT/m and 290 mT/m for each diffusion time, and 32 or 64 uniformly distributed directions. The diffusion MRI data were preprocessed to correct for gradient nonlinearity, eddy currents, and susceptibility induced distortions. In addition, scan/rescan data from a subset of seven individuals were also acquired and provided. The MGH Connectome Diffusion Microstructure Dataset (CDMD) may serve as a test bed for the development of new data analysis methods, such as fiber orientation estimation, tractography and microstructural modelling., Measurement(s)brain measurementTechnology Type(s)diffusion magnetic resonance imagingFactor Type(s)diffusion time • gradient strength • directionSample Characteristic - OrganismHomo sapiens Machine-accessible metadata file describing the reported data: 10.6084/m9.figshare.16910290

Background and purpose Cognitive dysfunction is common in multiple sclerosis (MS). The dorsal anterior insula (dAI) is a key hub of the salience network (SN) orchestrating access to critical cognitive brain regions. The aim of this study was to assess whole-brain dAI intrinsic functional connectivity (iFC) using resting-state functional MRI (rs-fMRI) in people with MS and healthy controls (HC) and test the relationship between cognitive reserve (CR) and dAI iFC in people with MS. Methods We studied 28 people with relapsing-remitting MS and 28 HC. CR index was quantified by combining premorbid IQ, leisure activities, and education level. For whole-brain iFC analyses, the bilateral dAI were used as seeds. Individual subject correlation maps were entered into general linear models for group comparison and to analyze the effect of CR index on dAI iFC, controlling for multiple comparisons. The correlation between CR index and iFC was assessed using a linear regression model. Results rs-fMRI analyses revealed a negative relationship between CR index and iFC within the left dAI and a left occipital cluster in people with MS including regions of the cuneus, superior occipital gyrus, and parieto-occipital sulcus. The regression analysis showed that people with MS and a higher CR index had a statistically significantly reduced iFC within the left dAI and the cluster. Conclusions CR is relevant to functional connectivity within one of the main nodes of the SN, the dAI, and occipital regions in MS. These results have implications for how CR may modulate the susceptibility to cognitive dysfunction in MS.

Highlights • Optic radiation (OR) white matter damage is associated with retinal thinning in MS. • Axonal water fraction (AWF) reflects axonal damage in the OR of MS patients. • AWF in the OR shows a tract-specific association with retinal thinning., Introduction White matter damage in the visual pathway is common in multiple sclerosis (MS) and is associated with retinal thinning, although the underlying mechanism of association remains unclear. The goal of this work was to evaluate the presence and extent of white matter tract integrity (WMTI) alterations in the optic radiation (OR) in people with MS and to investigate the association between WMTI metrics and retinal thinning in the eyes of MS patients without a history of optic neuritis (ON) as measured by optical coherence tomography (OCT). We hypothesized that WMTI metrics would reflect axonal damage that occurs in the OR in MS, and that axonal alterations revealed by WMTI would be associated with retinal thinning. Methods Twenty-nine MS patients without previous ON in at least one eye and twenty-nine age-matched healthy controls (HC) were scanned on a dedicated high-gradient 3-Tesla MRI scanner with 300 mT/m maximum gradient strength using a multi-shell diffusion MRI protocol (b = 800, 1500, 2400 s/mm2). The patients were divided into two subgroups according to history without ON (N = 18) or with ON in one eye (N = 11). Diffusion tensor imaging (DTI) metrics and WMTI metrics derived from diffusion kurtosis imaging were assessed in normal-appearing white matter (NAWM) of the OR and in focal lesions. Retinal thickness in the eyes of MS patients was measured by OCT. Student’s t-test was used to assess group differences between MRI metrics. Linear regression was used to study the relationship between OCT metrics, including retinal nerve fiber layer (RNFL) and combined ganglion cell and inner plexiform layer thickness (GCL/IPL), visual acuity measures and DTI and WMTI metrics. Results OR NAWM in MS showed significantly decreased axonal water fraction (AWF) compared to HC (0.36 vs 0.39, p

Introduction: While monophasic and relapsing forms of myelin oligodendrocyte glycoprotein antibody associated disorders (MOGAD) are increasingly diagnosed world-wide, consensus on management is yet to be developed. Objective: To survey the current global clinical practice of clinicians treating MOGAD. Method: Neurologists worldwide with expertise in treating MOGAD participated in an online survey (February–April 2019). Results: Fifty-two responses were received (response rate 60.5%) from 86 invited experts, comprising adult (78.8%, 41/52) and paediatric (21.2%, 11/52) neurologists in 22 countries. All treat acute attacks with high dose corticosteroids. If recovery is incomplete, 71.2% (37/52) proceed next to plasma exchange (PE). 45.5% (5/11) of paediatric neurologists use IV immunoglobulin (IVIg) in preference to PE. Following an acute attack, 55.8% (29/52) of respondents typically continue corticosteroids for ≥ 3 months; though less commonly when treating children. After an index event, 60% (31/51) usually start steroid-sparing maintenance therapy (MT); after ≥ 2 attacks 92.3% (48/52) would start MT. Repeat MOG antibody status is used by 52.9% (27/51) to help decide on MT initiation. Commonly used first line MTs in adults are azathioprine (30.8%, 16/52), mycophenolate mofetil (25.0%, 13/52) and rituximab (17.3%, 9/52). In children, IVIg is the preferred first line MT (54.5%; 6/11). Treatment response is monitored by MRI (53.8%; 28/52), optical coherence tomography (23.1%; 12/52) and MOG antibody titres (36.5%; 19/52). Regardless of monitoring results, 25.0% (13/52) would not stop MT. Conclusion: Current treatment of MOGAD is highly variable, indicating a need for consensus-based treatment guidelines, while awaiting definitive clinical trials.

BackgroundThere are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood-brain barrier, with potential salutary effects in progressive multiple sclerosis.MethodsWe enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (≤100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis.ResultsOf 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was -0.0010 per year with ibudilast and -0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression.ConclusionsIn a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders and Stroke and others; NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942 .).

Background: Cerebellar lesions are often reported in relapsing-remitting multiple sclerosis (RRMS) and have been associated with impaired motor function and cognitive status. However, prior research has primarily focused on summary measures of cerebellar involvement (e.g. total lesion load, gray/white matter volume) and not on the effect of lesion load within specific regions of cerebellar white matter. Objective: Spatially map the probability of cerebellar white matter lesion (CWML) occurrence in RRMS and explore the relationship between cognitive impairment and lesion (CWML) location within the cerebellum. Methods: High-resolution structural magnetic resonance imaging (MRI) was acquired on 16 cognitively impaired (CI) and 15 cognitively preserved (CP) RRMS subjects at 3T and used for lesion identification and voxel-based lesion-symptom mapping (VLSM). Results: CI RRMS demonstrated a predilection for the middle cerebellar peduncle (MCP). VLSM results indicate that lesions of the MCP are significantly associated with CI in RRMS. Measures of cerebellar lesion load were correlated with age at disease onset but not disease duration. Conclusion: A specific pattern of cerebellar lesions involving the MCP, rather than the total CWML load, contributes to cognitive dysfunction in RRMS. Cerebellar lesion profiles may provide a biomarker of current or evolving risk for cognitive status change in RRMS.

Axon diameter mapping using diffusion MRI in the living human brain has attracted growing interests with the increasing availability of high gradient strength MRI systems. A systematic assessment of the consistency of axon diameter estimates within and between individuals is needed to gain a comprehensive understanding of how such methods extend to quantifying differences in axon diameter index between groups and facilitate the design of neurobiological studies using such measures. We examined the scan-rescan repeatability of axon diameter index estimation based on the spherical mean technique (SMT) approach using diffusion MRI data acquired with gradient strengths up to 300 mT/m on a 3T Connectom system in 7 healthy volunteers. We performed statistical power analyses using data acquired with the same protocol in a larger cohort consisting of 15 healthy adults to investigate the implications for study design. Results revealed a high degree of repeatability in voxel-wise restricted volume fraction estimates and tract-wise estimates of axon diameter index derived from high-gradient diffusion MRI data. On the region of interest (ROI) level, across white matter tracts in the whole brain, the Pearson's correlation coefficient of the axon diameter index estimated between scan and rescan experiments was r = 0.72 with an absolute deviation of 0.18 μm. For an anticipated 10% effect size in studies of axon diameter index, most white matter regions required a sample size of less than 15 people to observe a measurable difference between groups using an ROI-based approach. To facilitate the use of high-gradient strength diffusion MRI data for neuroscientific studies of axonal microstructure, the comprehensive multi-gradient strength, multi-diffusion time data used in this work will be made publicly available, in support of open science and increasing the accessibility of such data to the greater scientific community.

We perform a randomized trial to test the impact of electronic pill bottles with audiovisual reminders on oral disease modifying therapy (DMT) adherence in people with MS (PwMS).Adults with multiple sclerosis (MS) taking an oral DMT were randomized 1:1 for 90 days to remote smartphone app- and pill bottle-based (a) adherence monitoring, or (b) adherence monitoring with audiovisual medication reminders. Optimal adherence was defined as the proportion of doses taken ±3 h of the scheduled time. Numbers of missed pills and pills taken early, on time, late, and extra were recorded. A multivariable regression model tested possible associations between optimal adherence and age, MS duration, cognitive functioning, and number of daily prescription pills.85 participants (66 female; mean age 44.9 years) took dimethyl/diroximel fumarate (n = 49), fingolimod (n = 26), or teriflunomide (n = 10). Optimal adherence was on average higher in the monitoring with reminders arm (71.4%) than the monitoring only arm (61.6%; p = 0.033). In a multivariable model, optimal adherence was less likely in younger participants (p 0.001) and those taking more daily prescription pills (p 0.001). In the monitoring only arm, 4.0% of doses were taken early, 61.6% on time, 5.6% late, 4.4% in excess, and 24.4% were missed. In the reminders arm, these proportions were 3.4%, 71.4%, 3.7%, 8.7%, and 12.8%, respectively.We map real-world oral DMT adherence patterns using mHealth technology. PwMS who received medication reminders had higher optimal adherence. Nonadherence was more nuanced than simply missing pills. Developing strategies to improve adherence remains important in longitudinal MS care.

Purpose Recent MRI techniques have been introduced that can extract microstructural information in the white matter, such as the density or macromolecular content. Translating quantitative MRI to the clinic raises many challenges in terms of acquisition strategy, modeling of the MRI signal, artifact corrections, and metric extraction (template registration and partial volume effects). In this work, we investigated the scan-rescan repeatability of several quantitative MRI techniques in the human spinal cord. Methods AxCaliber metrics, macromolecular tissue volume, and the fiber g-ratio were estimated in the spinal cord of eight healthy subjects, scanned and rescanned the same day in two different sessions. Results Scan-rescan repeatability deviation was 3% for all metrics, in average in the white matter of all subjects. Intraclass correlation coefficient was up to 0.9. A three-way analysis of variance showed significant effects of white matter pathway, laterality, and subject. Conclusion The present study suggests that quantitative MRI gives stable measurements of white matter microstructure in the spinal cord of healthy subjects. Our findings remain to be evaluated in diseased populations. Magn Reson Med 79:2759-2765, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

The fiber g-ratio is defined as the ratio of the inner to the outer diameter of the myelin sheath. This ratio provides a measure of the myelin thickness that complements axon morphology (diameter and density) for assessment of demyelination in diseases such as multiple sclerosis. Previous work has shown that an aggregate g-ratio map can be computed using a formula that combines axon and myelin density measured with quantitative MRI. In this work, we computed g-ratio weighted maps in the cervical spinal cord of nine healthy subjects. We utilized the 300mT/m gradients from the CONNECTOM scanner to estimate the fraction of restricted water (fr) with high accuracy, using the CHARMED model. Myelin density was estimated using the lipid and macromolecular tissue volume (MTV) method, derived from normalized proton density (PD) mapping. The variability across spinal level, laterality and subject were assessed using a three-way ANOVA. The average g-ratio value obtained in the white matter was 0.76+/-0.03, consistent with previous histology work. Coefficients of variation of fr and MTV were respectively 4.3% and 13.7%. fr and myelin density were significantly different across spinal tracts (p=3×10-7 and 0.004 respectively) and were positively correlated in the white matter (r=0.42), suggesting shared microstructural information. The aggregate g-ratio did not show significant differences across tracts (p=0.6). This study suggests that fr and myelin density can be measured in vivo with high precision and that they can be combined to produce a g-ratio-weighted map robust to free water pool contamination from cerebrospinal fluid or veins. Potential applications include the study of early demyelination in multiple sclerosis, and the quantitative assessment of remyelination drugs.

Axon diameter and density are important microstructural metrics that offer valuable insight into the structural organization of white matter throughout the human brain. We report the systematic acquisition and analysis of a comprehensive diffusion MRI data set acquired with 300 mT/m maximum gradient strength in a cohort of 20 healthy human subjects that yields distinct and consistent patterns of axon diameter index in white matter tracts of arbitrary orientation. We use a straightforward, previously validated approach to estimating indices of axon diameter and volume fraction that involves interpolating the diffusion signal perpendicular to the principal fiber orientation and fitting a three-compartment model of intra-axonal, extra-axonal and free water diffusion. The resultant maps confirm the presence of larger diameter indices in the body of corpus callosum compared to the genu and splenium, as previously reported, and show larger axon diameter index in the corticospinal tracts compared to adjacent white matter tracts such as the cingulum. An anterior-to-posterior gradient in axon diameter index is also observed, with smaller diameter indices in the frontal lobes and larger diameter indices in the parieto-occipital white matter. These observations are consistent with known trends from prior histologic studies in humans and non-human primates. Rather than serving as fully quantitative measures of axon diameter and density, our results may be considered as axon diameter- and volume fraction-weighted images that appear to be modulated by the underlying microstructure and may capture broad trends in axonal size and packing density, acknowledging that the precise origin of such modulation requires further investigation that will be facilitated by the availability of high gradient strengths for in vivo human imaging.

BACKGROUND AND PURPOSE: Remyelination represents an area of great therapeutic interest in multiple sclerosis but currently lacks a robust imaging marker. The purpose of this study was to use high-gradient diffusion MRI and macromolecular tissue volume imaging to obtain estimates of axonal volume fraction, myelin volume fraction, and the imaging g-ratio in patients with MS and healthy controls and to explore their relationship to neurologic disability in MS. MATERIALS AND METHODS: Thirty individuals with MS (23 relapsing-remitting MS, 7 progressive MS) and 19 age-matched healthy controls were scanned on a 3T MRI scanner equipped with 300 mT/m maximum gradient strength using a comprehensive multishell diffusion MRI protocol. Macromolecular tissue volume imaging was performed to quantify the myelin volume fraction. Diffusion data were fitted to a 3-compartment model of white matter using a spheric mean approach to yield estimates of axonal volume fraction. The imaging g-ratio was calculated from the ratio of myelin volume fraction and axonal volume fraction. Imaging metrics were compared between groups using 2-sided t tests with a Bonferroni correction. RESULTS: The mean g-ratio was significantly elevated in lesions compared with normal-appearing WM (0.74 vs 0.67, P CONCLUSIONS: The imaging g-ratio may serve as a biomarker for the relative degree of axonal and myelin loss in MS.

Objective to develop a resource of systematically collected, longitudinal clinical data and biospecimens for assisting in the investigation into neuromyelitis optica spectrum disorder (NMOSD) epidemiology, pathogenesis, and treatment. Methods to illustrate its research-enabling purpose, epidemiologic patterns and disease phenotypes were assessed among enrolled subjects, including age at disease onset, annualized relapse rate (ARR), and time between the first and second attacks. Results as of December 2017, the Collaborative International Research in Clinical and Longitudinal Experience Study (CIRCLES) had enrolled more than 1,000 participants, of whom 77.5% of the NMOSD cases and 71.7% of the controls continue in active follow-up. Consanguineous relatives of patients with NMOSD represented 43.6% of the control cohort. Of the 599 active cases with complete data, 84% were female, and 76% were anti-AQP4 seropositive. The majority were white/Caucasian (52.6%), whereas blacks/African Americans accounted for 23.5%, Hispanics/Latinos 12.4%, and Asians accounted for 9.0%. The median age at disease onset was 38.4 years, with a median ARR of 0.5. Seropositive cases were older at disease onset, more likely to be black/African American or Hispanic/Latino, and more likely to be female. Conclusions collectively, the CIRCLES experience to date demonstrates this study to be a useful and readily accessible resource to facilitate accelerating solutions for patients with NMOSD., The Guthy-Jackson Charitable Foundation, The CIRCLES Project

Axon diameter mapping using high-gradient diffusion MRI has generated great interest as a noninvasive tool for studying trends in axonal size in the human brain. One of the main barriers to mapping axon diameter across the whole brain is accounting for complex white matter fiber configurations (e.g., crossings and fanning), which are prevalent throughout the brain. Here, we present a framework for generalizing axon diameter index estimation to the whole brain independent of the underlying fiber orientation distribution using the spherical mean technique (SMT). This approach is shown to significantly benefit from the use of real-valued diffusion data with Gaussian noise, which reduces the systematic bias in the estimated parameters resulting from the elevation of the noise floor when using magnitude data with Rician noise. We demonstrate the feasibility of obtaining whole-brain orientationally invariant estimates of axon diameter index and relative volume fractions in six healthy human volunteers using real-valued diffusion data acquired on a dedicated high-gradient 3-Tesla human MRI scanner with 300 mT/m maximum gradient strength. The trends in axon diameter index are consistent with known variations in axon diameter from histology and demonstrate the potential of this generalized framework for revealing coherent patterns in axonal structure throughout the living human brain. The use of real-valued diffusion data provides a viable solution for eliminating the Rician noise floor and should be considered for all spherical mean approaches to microstructural parameter estimation.

Cerebral white matter exhibits age-related degenerative changes during the course of normal aging, including decreases in axon density and alterations in axonal structure. Noninvasive approaches to measure these microstructural alterations throughout the lifespan would be invaluable for understanding the substrate and regional variability of age-related white matter degeneration. Recent advances in diffusion magnetic resonance imaging (MRI) have leveraged high gradient strengths to increase sensitivity toward axonal size and density in the living human brain. Here, we examined the relationship between age and indices of axon diameter and packing density using high-gradient strength diffusion MRI in 36 healthy adults (aged 22–72) in well-defined central white matter tracts in the brain. A recently validated method for inferring the effective axonal compartment size and packing density from diffusion MRI measurements acquired with 300 mT/m maximum gradient strength was applied to the in vivo human brain to obtain indices of axon diameter and density in the corpus callosum, its sub-regions, and adjacent anterior and posterior fibers in the forceps minor and forceps major. The relationships between the axonal metrics, corpus callosum area and regional gray matter volume were also explored. Results revealed a significant increase in axon diameter index with advancing age in the whole corpus callosum. Similar analyses in sub-regions of the corpus callosum showed that age-related alterations in axon diameter index and axon density were most pronounced in the genu of the corpus callosum and relatively absent in the splenium, in keeping with findings from previous histological studies. The significance of these correlations was mirrored in the forceps minor and forceps major, consistent with previously reported decreases in FA in the forceps minor but not in the forceps major with age. Alterations in the axonal imaging metrics paralleled decreases in corpus callosum area and regional gray matter volume with age. Among older adults, results from cognitive testing suggested an association between larger effective compartment size in the corpus callosum, particularly within the genu of the corpus callosum, and lower scores on the Montreal Cognitive Assessment, largely driven by deficits in short-term memory. The current study suggests that high-gradient diffusion MRI may be sensitive to the axonal substrate of age-related white matter degeneration reflected in traditional DTI metrics and provides further evidence for regionally selective alterations in white matter microstructure with advancing age.

Increased synchrony within neuroanatomical networks is often observed in neurophysiologic studies of human brain disease. Most often, this phenomenon is ascribed to a compensatory process in the face of injury, though evidence supporting such accounts is limited. Given the known dependence of resting-state functional connectivity (rsFC) on underlying structural connectivity (SC), we examine an alternative hypothesis: that topographical changes in SC, specifically particular patterns of disconnection, contribute to increased network rsFC. We obtain measures of rsFC using fMRI and SC using probabilistic tractography in 50 healthy and 28 multiple sclerosis subjects. Using a computational model of neuronal dynamics, we simulate BOLD using healthy subject SC to couple regions. We find that altering the model by introducing structural disconnection patterns observed in those multiple sclerosis subjects with high network rsFC generates simulations with high rsFC as well, suggesting that disconnection itself plays a role in producing high network functional connectivity. We then examine SC data in individuals. In multiple sclerosis subjects with high network rsFC, we find a preferential disconnection between the relevant network and wider system. We examine the significance of such network isolation by introducing random disconnection into the model. As observed empirically, simulated network rsFC increases with removal of connections bridging a community with the remainder of the brain. We thus show that structural disconnection known to occur in multiple sclerosis contributes to network rsFC changes in multiple sclerosis and further that community isolation is responsible for elevated network functional connectivity.

Neuroaxonal pathology is a main determinant of disease progression in multiple sclerosis; however, its underlying pathophysiological mechanisms, including its link to inflammatory demyelination and temporal occurrence in the disease course are still unknown. We used ultra-high field (7 T), ultra-high gradient strength diffusion and T1/T2-weighted myelin-sensitive magnetic resonance imaging to characterize microstructural changes in myelin and neuroaxonal integrity in the cortex and white matter in early stage multiple sclerosis, their distribution in lesional and normal-appearing tissue, and their correlations with neurological disability. Twenty-six early stage multiple sclerosis subjects (disease duration ≤5 years) and 24 age-matched healthy controls underwent 7 T T2*-weighted imaging for cortical lesion segmentation and 3 T T1/T2-weighted myelin-sensitive imaging and neurite orientation dispersion and density imaging for assessing microstructural myelin, axonal and dendrite integrity in lesional and normal-appearing tissue of the cortex and the white matter. Conventional mean diffusivity and fractional anisotropy metrics were also assessed for comparison. Cortical lesions were identified in 92% of early multiple sclerosis subjects and they were characterized by lower intracellular volume fraction (P = 0.015 by paired t-test), lower myelin-sensitive contrast (P = 0.030 by related-samples Wilcoxon signed-rank test) and higher mean diffusivity (P = 0.022 by related-samples Wilcoxon signed-rank test) relative to the contralateral normal-appearing cortex. Similar findings were observed in white matter lesions relative to normal-appearing white matter (all P < 0.001), accompanied by an increased orientation dispersion (P < 0.001 by paired t-test) and lower fractional anisotropy (P < 0.001 by related-samples Wilcoxon signed-rank test) suggestive of less coherent underlying fibre orientation. Additionally, the normal-appearing white matter in multiple sclerosis subjects had diffusely lower intracellular volume fractions than the white matter in controls (P = 0.029 by unpaired t-test). Cortical thickness did not differ significantly between multiple sclerosis subjects and controls. Higher orientation dispersion in the left primary motor-somatosensory cortex was associated with increased Expanded Disability Status Scale scores in surface-based general linear modelling (P < 0.05). Microstructural pathology was frequent in early multiple sclerosis, and present mainly focally in cortical lesions, whereas more diffusely in white matter. These results suggest early demyelination with loss of cells and/or cell volumes in cortical and white matter lesions, with additional axonal dispersion in white matter lesions. In the cortex, focal lesion changes might precede diffuse atrophy with cortical thinning. Findings in the normal-appearing white matter reveal early axonal pathology outside inflammatory demyelinating lesions.

Objective:To study the effect of pregnancy on the frequency of neuromyelitis optica spectrum disorder (NMOSD) relapse and evaluate rates of pregnancy-related complications in an international multicenter setting.Methods:We administered a standardized survey to 217 women with NMOSD from 7 medical centers and reviewed their medical records. We compared the annualized relapse rate (ARR) during a baseline period 2 years prior to a participant's first pregnancy to that during pregnancy and to the 9 months postpartum. We also assessed pregnancy-related complications.Results:There were 46 informative pregnancies following symptom onset in 31 women with NMOSD. Compared to baseline (0.17), ARR was increased both during pregnancy (0.44; p = 0.035) and during the postpartum period (0.69; p = 0.009). The highest ARR occurred during the first 3 months postpartum (ARR 1.33). A total of 8 of 76 (10.5%) with onset of NMOSD prior to age 40 experienced their initial symptom during the 3 months postpartum, 2.9 times higher than expected.Conclusions:The postpartum period is a particularly high-risk time for initial presentation of NMOSD. In contrast to published observations in multiple sclerosis, in neuromyelitis optica, relapse rate during pregnancy was also increased, although to a lesser extent than after delivery.

Purpose of review This article summarizes the use of MRI in the diagnosis and treatment of multiple sclerosis (MS). Current and emerging imaging techniques are reviewed pertaining to their utility in MS. Recent findings Conventional T1-weighted and T2-weighted sequences are used to identify and characterize disease pathology in MS. T2 lesion burden, postcontrast enhancement, T1 hypointensities, and regional and global atrophy are all informative and correlate to clinical measures, such as disease disability, to a variable extent. Newer techniques such as diffusion tensor imaging, magnetization transfer imaging, and MR spectroscopy are increasingly being incorporated into clinical trials and may provide improved specificity to the underlying pathology. Double inversion recovery and ultrahigh-field-strength MRI have direct application in MS for evaluating cortical pathology. Newer functional MRI techniques such as resting-state functional connectivity are increasingly being applied in MS. Summary Conventional and emerging imaging techniques greatly inform our understanding of MS. These techniques are integral in diagnosis, in evaluating new treatments for MS, and for following patients in the clinical setting.

This study assessed the tissue integrity of major cervical cord tracts by using diffusion tensor imaging (DTI) to determine the relationship with specific clinical functions carried by those tracts.This was a cross-sectional study of 37 patients with multiple sclerosis or neuromyelitis optica with remote cervical cord disease. Finger vibratory thresholds, 25-foot timed walk (25FTW), 9-hole peg test (9HPT), and Expanded Disability Status Scale were determined. DTI covered cervical regions C1 through C6 with 17 5-mm slices (0.9 × 0.9 mm in-plane resolution). Regions of interest included posterior columns (PCs) and lateral corticospinal tracts (CSTs). Hierarchical linear mixed-effect modeling included covariates of disease subtype (multiple sclerosis vs neuromyelitis optica), disease duration, and sex.Vibration thresholds were associated with radial diffusivity (RD) and fractional anisotropy (FA) in the PCs (both p0.01), but not CSTs (RD, p = 0.29; FA, p = 0.14). RD and FA in PCs, and RD in CSTs were related to 9HPT (each p0.0001). 25FTW was associated with RD and FA in PCs (p0.0001) and RD in CSTs (p = 0.008). Expanded Disability Status Scale was related to RD and FA in PCs and CSTs (p0.0001). Moderate/severe impairments in 9HPT (p = 0.006) and 25FTW (p = 0.017) were more likely to show combined moderate/severe tissue injury within both PCs and CSTs by DTI.DTI can serve as an imaging biomarker of spinal cord tissue injury at the tract level. RD and FA demonstrate strong and consistent relationships with clinical outcomes, specific to the clinical modality.

Background Primary and secondary progressive multiple sclerosis (MS), collectively called progressive multiple sclerosis (PMS), is characterized by gradual progression of disability. The current anti-inflammatory treatments for MS have little or no efficacy in PMS in the absence of obvious active inflammation. Optimal biomarkers for phase II PMS trials is unknown. Ibudilast is an inhibitor of macrophage migration inhibitor factor and phosphodiesterases-4 and − 10 and exhibits possible neuroprotective properties. The goals of SPRINT-MS study are to evaluate the safety and efficacy of ibudilast in PMS and to directly compare several imaging metrics for utility in PMS trials. Methods SPRINT-MS is a randomized, placebo-controlled, phase II trial of ibudilast in patients with PMS. Eligible subjects were randomized 1:1 to receive either ibudilast (100 mg/day) or placebo for 96 weeks. Imaging is conducted every 24 weeks for whole brain atrophy, magnetization transfer ratio, diffusion tensor imaging, cortical brain atrophy, and retinal nerve fiber layer thickness. Clinical outcomes include neurologic disability and patient reported quality of life. Safety assessments include laboratory testing, electrocardiography, and suicidality screening. Results A total of 331 subjects were enrolled, of which 255 were randomized onto active study treatment. Randomized subjects were 53.7% female and mean age 55.7 (SD 7.3) years. The last subject is projected to complete the study in May 2017. Conclusion SPRINT-MS is designed to evaluate the safety and efficacy of ibudilast as a treatment for PMS while simultaneously validating five different imaging biomarkers as outcome metrics for use in future phase II proof-of-concept PMS trials.

Objective In multiple sclerosis (MS), using simultaneous magnetic resonance-positron emission tomography (MR-PET) imaging with 11C-PBR28, we quantified expression of the 18kDa translocator protein (TSPO), a marker of activated microglia/macrophages, in cortex, cortical lesions, deep gray matter (GM), white matter (WM) lesions and normal-appearing WM (NAWM) to investigate the in vivo pathological and clinical relevance of neuroinflammation. Methods Fifteen secondary-progressive MS (SPMS) and 12 relapsing-remitting MS (RRMS) cases, and 14 matched healthy controls underwent 11C-PBR28 MR-PET. MS subjects underwent 7 Tesla T2*-weighted imaging for cortical lesions segmentation; neurological and cognitive evaluation. 11C-PBR28 binding was measured using normalized 60-90-minutes standardized uptake values and volume of distribution ratios. Results Relative to controls, MS subjects exhibited abnormally high 11C-PBR28 binding across the brain, the greatest increases being in cortex and cortical lesions, thalamus, hippocampus, and NAWM. MS WM lesions showed relatively modest TSPO increases. With the exception of cortical lesions, where TSPO expression was similar, 11C-PBR28 uptake across the brain was greater in SPMS than in RRMS. In MS, increased 11C-PBR28 binding in cortex, deep GM, and NAWM correlated with neurological disability and impaired cognitive performance; cortical thinning correlated with increased thalamic TSPO levels. Interpretation In MS, neuroinflammation is present in the cortex, cortical lesions, deep GM, and NAWM, and closely linked to poor clinical outcome and, at least partly, to neurodegeneration. Distinct inflammatory-mediated factors may underlie accumulation of cortical and WM lesions. Quantification of TSPO levels in MS could prove a sensitive tool for evaluating in vivo the inflammatory component of GM pathology, particularly in cortical lesions. This article is protected by copyright. All rights reserved.

Purpose To evaluate the ability of high-gradient-diffusion magnetic resonance (MR) imaging by using gradient strengths of up to 300 mT/m to depict axonal disease in lesions and normal-appearing white matter (NAWM) in patients with multiple sclerosis (MS) and to compare high-gradient-diffusion MR findings in these patients with those in healthy control subjects. Materials and Methods In this HIPAA-compliant institutional review board-approved prospective study in which all subjects provided written informed consent, six patients with relapsing-remitting MS and six healthy control subjects underwent diffusion-weighted imaging with a range of diffusion weightings performed with a 3-T human MR imager by using gradient strengths of up to 300 mT/m. A model of intra-axonal, extra-axonal, and free water diffusion was fitted to obtain estimates of axon diameter and density. Differences in axon diameter and density between lesions and NAWM in patients with MS were assessed by using the nonparametric Wilcoxon matched-pairs signed rank test, and differences between NAWM in subjects with MS and white matter in healthy control subjects were assessed by using the Mann-Whitney U test. Results MS lesions showed increased mean axon diameter (10.3 vs 7.9 μm in the genu, 10.4 vs 9.3 μm in the body, and 10.6 vs 8.2 μm in the splenium; P.05) and decreased axon density ([0.48 vs 1.1] × 10(10)/m(2) in the genu, [0.40 vs 0.70] × 10(10)/m(2) in the body, and [0.35 vs 1.1] × 10(10)/m(2) in the splenium; P.05) compared with adjacent NAWM. No significant difference in mean axon diameter or axon density was detected between NAWM in subjects with MS and white matter in healthy control subjects. Conclusion High-gradient-diffusion MR imaging using gradient strengths of up to 300 mT/m can be used to characterize axonal disease in patients with MS, with results that agree with known trends from neuropathologic data showing increased axon diameter and decreased axon density in MS lesions when compared with NAWM. (©) RSNA, 2016 Online supplemental material is available for this article.

Background: Multiple sclerosis (MS) and neuromyelitis optica (NMO) both affect spinal cord with notable differences in pathology. Objective: Determine the utility of diffusion tensor imaging (DTI) to differentiate the spinal cord lesions of NMO from MS within and outside T2 lesions. Methods: Subjects greater than or equal to 12 months from a clinical episode of transverse myelitis underwent a novel transaxial cervical spinal cord DTI sequence. Ten subjects with NMO, 10 with MS and 10 healthy controls were included. Results: Within T2 affected white matter regions, radial diffusivity was increased in both NMO and MS compared with healthy controls ( pConclusions: Higher radial diffusivity within spinal cord white matter tracts derived from diffusion tensor imaging were appreciated in NMO compared with MS, consistent with the known greater tissue destruction seen in NMO. DTI also detected tissue alterations outside T2 lesions and may be a surrogate of anterograde and retrograde degeneration.

The functional organization of the human brain consists of a high degree of connectivity between interhemispheric homologous regions. The degree of homotopic organization is known to vary across the cortex and homotopic connectivity is high in regions that share cross-hemisphere structural connections or are activated by common input streams (e.g., the visual system). Damage to one or both regions, as well as damage to the connections between homotopic regions, could disrupt this functional organization. Here were introduce and test a computationally efficient technique, surface-based homotopic interhermispheric connectivity (sHIC), that leverages surface-based registration and processing techniques in an attempt to improve the spatial specificity and accuracy of cortical interhemispheric connectivity estimated with resting state functional connectivity. This technique is shown to be reliable both within and across subjects. sHIC is also characterized in a dataset of nearly 1000 subjects. We confirm previous results showing increased interhemispheric connectivity in primary sensory regions, and reveal a novel rostro-caudal functionally defined network level pattern of sHIC across the brain. In addition, we demonstrate a structural-functional relationship between sHIC and atrophy of the corpus callosum in multiple sclerosis (r = 0.2979, p = 0.0461). sHIC presents as a sensitive and reliable measure of cortical homotopy that may prove useful as a biomarker in neurologic disease. Hum Brain Mapp 37:2849-2868, 2016. © 2016 Wiley Periodicals, Inc.

A 25-year-old man who emigrated from Mexico 5 years ago presented with headache, altered mental status, and left hemiparesis. Initial history obtained from collateral sources indicated the patient had complained of a headache of increasing severity for the past 2 months. Two weeks prior to presentation, he experienced malaise, decreased appetite, nausea and vomiting, visual changes, and gait difficulties resulting in 2 falls. The day of presentation, he developed acute onset left upper and lower extremity weakness prompting emergency evaluation. On arrival he was lethargic, disoriented, and did not follow commands. Following intubation in the emergency department, he was transferred to the neurologic intensive care unit (ICU). He was febrile and tachycardic on arrival to the ICU. Upon cessation of sedation, the patient was ill-appearing but awake and able to cooperate with the neurologic examination. He was oriented to hospital name and year and was able to follow one-step commands. His pupils were equal, round, and reactive to light and accommodation. Bedside funduscopic examination showed normal discs and vessels. His extraocular movements were full except for the inability to adduct his right eye. He blinked to threat bilaterally but had left-sided visual neglect with a right gaze preference. He had left lower facial weakness. On motor examination, he had left flaccid paralysis as well as mild decreased strength in his right upper and lower extremities (4+/5) that might have been attributable to incomplete cooperation. Sensation was intact to light touch on the right but only to noxious painful nail bed stimulation on the left. Reflexes were brisk on the right and diminished on the left. He had a left Babinski sign. Head CT revealed 2 foci of hemorrhage in the right frontal and parietal lobes with associated vasogenic edema (figure 1). Figure 1 CT findings Two foci of hemorrhage are …

Determine the utility of optical coherence tomography (OCT) to detect clinical and subclinical remote optic neuritis (ON), its relationship to clinical characteristics of ON and visual function, and whether the retinal nerve fiber layer (RNFL) thickness functions as a surrogate marker of global disease severity.Cross-sectional study of 65 subjects with at least 1 clinical ON episode at least 6 months prior. Measures included clinical characteristics, visual acuity (VA), contrast sensitivity (CS), OCT, and visual evoked potentials (VEP).Ninety-six clinically affected optic nerves were studied. The sensitivity of OCT RNFL after ON was 60%, decreasing further with mild onset and good recovery. VEP sensitivity was superior at 81% (p = 0.002). Subclinical ON in the unaffected eye was present in 32%. VEP identified 75% of all subclinically affected eyes, and OCT identified20%. RNFL thickness demonstrated linear correlations with VA (r = 0.65) and CS (r = 0.72) but was unable to distinguish visual categories20/50. RNFL was thinner with severe onset and disease recurrence but was unaffected by IV glucocorticoids. OCT measurements were not related to overall disability, ethnicity, sex, or age at onset. The greatest predictor for RNFL in the unaffected eye was the RNFL in the fellow affected eye.Visual evoked potentials (VEP) remains the preferred test for detecting clinical and subclinical optic neuritis. Optical coherence tomography (OCT) measures were unrelated to disability and demographic features predicting a worse prognosis in multiple sclerosis. OCT may provide complementary information to VEP in select cases, and remains a valuable research tool for studying optic nerve disease in populations.

Neuromyelitis optica (NMO) is an inflammatory and demyelinating disease characterized by recurrent attacks of optic neuritis (ON) and longitudinally extensive transverse myelitis (LETM).1 NMO is associated with antibodies against the aquaporin-4 (AQP4) water channel.2 NMO–immunoglobulin G (IgG) predicts a relapsing course and is a supportive criterion for NMO.3–5 The high risk of relapse, sometimes with devastating effects, makes early diagnosis important. Early identification permits counseling and consideration for immunosuppressive therapy. The serum NMO-IgG assay, using indirect immunofluorescence, is 73% sensitive and 91% specific for clinically defined NMO.6 While helpful when positive, the sensitivity is insufficient to exclude the diagnosis. We describe 3 of 26 patients with NMO at our institution with NMO-IgG positivity restricted to CSF. ### Case reports. #### Case 1. A 25-year-old African American woman presented with leg numbness and mild tetraparesis that resolved over 1 month. Two months later, she developed a midthoracic sensory level, again with recovery. The next month, bilateral leg weakness impaired her ability to ambulate. MRI (figure, A–C) demonstrated T2 hyperintensities (T2H) and patchy enhancement spanning the medulla through C7 and T2–T11. Brain MRI revealed a single nonspecific T2H. Visual evoked potentials (VEPs) were normal. Serum NMO-IgG was negative but CSF NMO-IgG was positive. IgG index was elevated to 0.79, CSF leukocytes were 24/μL, but albumin index, IgG synthesis, and oligoclonal bands (OCBs) were normal. Serum antinuclear antibodies (ANA) were negative. Treatment included IV glucocorticoids and rituximab with no further exacerbations. After 8 months of disease, Expanded Disability Status Scale (EDSS) was 6.0. Figure Neuroimaging of CSF antibody-positive neuromyelitis optica Case 1: Sagittal T2-weighted STIR …

CXCL13, a B-cell chemokine, has been proposed as a biomarker in a variety of conditions, some of which can mimic multiple sclerosis and can have very high levels. In this case-control study, cerebrospinal fluid (CSF) CXCL13 was elevated in multiple sclerosis, neuromyelitis optica and other inflammatory neurological controls compared with noninflammatory controls. Levels did not differentiate disease groups. For all subjects taken together, CSF CXCL13 correlated with CSF WBC, oligoclonal band numbers, CSF protein, EDSS, and neurofilament levels. In subgroup analyses, CSF CXCL13 correlated with CSF WBC in neuromyelitis optica and IgG index in multiple sclerosis. Additionally, serum CXCL13 was elevated in neuromyelitis optica.

To contrast differences in pain and treatment outcomes between neuromyelitis optica (NMO) and multiple sclerosis (MS).Retrospective, cross-sectional cohort study.Academic MS center.Complete ascertainment of an academic MS center cohort of NMO and an MS comparison sample cohort.Current pain was quantified by a 10-point scale and the McGill Pain Questionnaire.Expanded Disability Status Scale score and number of involved spinal cord levels were collected in addition to testing for cognition, fatigue, depression, and quality of life. Number and types of pain medications were tabulated.Current pain was more common in subjects with NMO (n=29) vs MS (n=66) (86.2% vs 40.9%; P.001)and more severe on a 10-point scale (5.38 vs 1.85;P.001). Pain remained more common after controlling for disability and number of spinal cord segments(P=.03). Prescription pain medication was used more frequently in subjects with NMO compared with subjects with MS(75.9% vs 37.8%; P.001), often requiring more than 1 medication (65.5% vs 15.2%; P.001). No subject with NMO taking pain medication (22 of 29) rated their current pain as 0 of 10, whereas almost half of those taking pain medication with MS were currently free of pain (0% vs 48%; P=.006).Neuromyelitis optica is frequently associated with severe pain that appears insufficiently controlled by pharmacologic interventions. Future studies should evaluate the efficacy of a multidisciplinary and multimodal approach to pain management.

We describe a cardiac gated high in-plane resolution axial human cervical spinal cord diffusion tensor imaging (DTI) protocol. Multiple steps were taken to optimize both image acquisition and image processing. The former includes slice-by-slice cardiac triggering and individually tiltable slices. The latter includes (i) iterative 2D retrospective motion correction, (ii) image intensity outlier detection to minimize the influence of physiological noise, (iii) a non-linear DTI estimation procedure incorporating non-negative eigenvalue priors, and (iv) tract-specific region-of-interest (ROI) identification based on an objective geometry reference. Using these strategies in combination, radial diffusivity (λ(⊥)) was reproducibly measured in white matter (WM) tracts (adjusted mean [95% confidence interval]=0.25 [0.22, 0.29] μm(2)/ms), lower than previously reported λ(⊥) values in the in vivo human spinal cord DTI literature. Radial diffusivity and fractional anisotropy (FA) measured in WM varied from rostral to caudal as did mean translational motion, likely reflecting respiratory motion effect. Given the considerable sensitivity of DTI measurements to motion artifact, we believe outlier detection is indispensable in spinal cord diffusion imaging. We also recommend using a mixed-effects model to account for systematic measurement bias depending on cord segment.

Objective To describe the clinical and imaging characteristics of spinal cord ring enhancement in multiple sclerosis (MS). Design Clinical case series. Setting Academic referral center. Patients Twenty patients with MS who had spinal cord ring enhancement were retrospectively identified from 322 cervical and thoracic spinal cord magnetic resonance imaging studies during a 3-year period. Main Outcome Measures Demographics, disability, and pattern of enhancement on spinal cord and concomitant brain magnetic resonance imaging results. Results Ring enhancement was seen in 20 patients with spinal cord enhancement, most commonly in the cervical cord. Incomplete or “open” ring enhancement was the dominant pattern in 19 of the 20 patients (95%). Concurrent enhancing brain lesions were present in 14 patients, 8 of which (57%) exhibited a ring pattern of enhancement. At the time of imaging, the Expanded Disability Status Scale scores ranged from 1.0 to 7.0 (median score, 3.0). Conclusions Ring enhancement is not an uncommon pattern for spinal cord lesions in MS, occurring with a prevalence of 6.2% (20 of 322 imaging studies). The most common pattern is incomplete ring enhancement in the cervical spinal cord. Recognition of this pattern may improve and expedite the diagnosis of MS and preclude the need for invasive diagnostic interventions.

Objective To evaluate antibodies to myelin oligodendrocyte glycoprotein (MOG) in the serum and cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS) and control individuals. Design Prospective case-control series. Setting Academic referral center. Patients Twenty-six controls with noninflammatory neurologic disease and 35 patients with MS donated serum and CSF for recombinant MOG (rMOG) antibody determination. Main Outcome Measures Serum and CSF rMOG antibody and albumin levels were used to calculate an rMOG index. Clinical disability, CSF markers, and magnetic resonance metrics were correlated with the rMOG index. Results The rMOG index was elevated in MS patients compared with controls ( P = .01). Patients with progressive MS exhibited elevated rMOG indexes compared with patients with relapsing-remitting MS ( P = .04). The rMOG index was inferior to the IgG index in differentiating MS patients from controls. However, 7 of 16 patients with MS who had normal immunoglobulin G indexes had an elevated rMOG index. The rMOG index did not correlate with clinical disability, other CSF markers, or radiographic outcome measures. Conclusions The rMOG index, a marker of intrathecal MOG antibody production, may provide complementary information to routine CSF testing in the diagnosis of MS. Furthermore, intrathecal anti-MOG antibody production may be more pronounced in progressive than in relapsing forms of MS.

We used 7 T MRI to: (i) characterize the grey and white matter pathology in the cervical spinal cord of patients with early relapsing-remitting and secondary progressive multiple sclerosis; (ii) assess the spinal cord lesion spatial distribution and the hypothesis of an outside-in pathological process possibly driven by CSF-mediated immune cytotoxic factors; and (iii) evaluate the association of spinal cord pathology with brain burden and its contribution to neurological disability. We prospectively recruited 20 relapsing-remitting, 15 secondary progressive multiple sclerosis participants and 11 age-matched healthy control subjects to undergo 7 T imaging of the cervical spinal cord and brain as well as conventional 3 T brain acquisition. Cervical spinal cord imaging at 7 T was used to segment grey and white matter, including lesions therein. Brain imaging at 7 T was used to segment cortical and white matter lesions and 3 T imaging for cortical thickness estimation. Cervical spinal cord lesions were mapped voxel-wise as a function of distance from the inner central canal CSF pool to the outer subpial surface. Similarly, brain white matter lesions were mapped voxel-wise as a function of distance from the ventricular system. Subjects with relapsing-remitting multiple sclerosis showed a greater predominance of spinal cord lesions nearer the outer subpial surface compared to secondary progressive cases. Inversely, secondary progressive participants presented with more centrally located lesions. Within the brain, there was a strong gradient of lesion formation nearest the ventricular system that was most evident in participants with secondary progressive multiple sclerosis. Lesion fractions within the spinal cord grey and white matter were related to the lesion fraction in cerebral white matter. Cortical thinning was the primary determinant of the Expanded Disability Status Scale, white matter lesion fractions in the spinal cord and brain of the 9-Hole Peg Test and cortical thickness and spinal cord grey matter cross-sectional area of the Timed 25-Foot Walk. Spinal cord lesions were localized nearest the subpial surfaces for those with relapsing-remitting and the central canal CSF surface in progressive disease, possibly implying CSF-mediated pathogenic mechanisms in lesion development that may differ between multiple sclerosis subtypes. These findings show that spinal cord lesions involve both grey and white matter from the early multiple sclerosis stages and occur mostly independent from brain pathology. Despite the prevalence of cervical spinal cord lesions and atrophy, brain pathology seems more strongly related to physical disability as measured by the Expanded Disability Status Scale.