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Although many regional multiple sclerosis (MS) databases existed in the United States and Canada, there was no single clinician-derived registry that examined this disease as a group across the North American continent. This distinction is important because information that results from such a database can potentially give perspectives about MS that cannot be derived from any single regional registry. A partnership was forged between the pharmaceutical industry and the Consortium of Multiple Sclerosis Centers (CMSC) to create a registry of patients with MS from Canada and the United States, including Puerto Rico. Case report forms were created to collect physician-derived information, and the Patient-Reported Outcomes Measurement Information System (PROMIS) was selected to capture patient-reported outcomes. As of November 2021, 754 of 1000 patients have been enrolled. Completion of recruitment is expected by the end of 2021. Twenty-five centers are participating, with an expected total of 30, including five centers from Canada. Clinical status, health economic outcomes, magnetic resonance images, and, soon, biomarkers relevant to understanding relapses and progression are collected. The short-term goal is to understand and better treat MS disease progression, and the long-term goal is its prevention. The North American Registry for Care and Research in Multiple Sclerosis (NARCRMS) is one of few clinician/patient-generated registries that examines MS across North America, including Puerto Rico. Information derived from the natural history studies should help physicians, the pharmaceutical industry, and regulatory bodies understand MS better and improve quality of life for patients with MS worldwide.

PURPOSE The decomposition of multi-exponential decay data into a T2 spectrum poses substantial challenges for conventional fitting algorithms, including non-negative least squares (NNLS). Based on a combination of the resolution limit constraint and machine learning neural network algorithm, a data-driven and highly tailorable analysis method named spectrum analysis for multiple exponentials via experimental condition oriented simulation (SAME-ECOS) was proposed. THEORY AND METHODS The theory of SAME-ECOS was derived. Then, a paradigm was presented to demonstrate the SAME-ECOS workflow, consisting of a series of calculation, simulation, and model training operations. The performance of the trained SAME-ECOS model was evaluated using simulations and six in vivo brain datasets. The code is available at https://github.com/hanwencat/SAME-ECOS. RESULTS Using NNLS as the baseline, SAME-ECOS achieved over 15% higher overall cosine similarity scores in producing the T2 spectrum, and more than 10% lower mean absolute error in calculating the myelin water fraction (MWF), as well as demonstrated better robustness to noise in the simulation tests. Applying to in vivo data, MWF from SAME-ECOS and NNLS was highly correlated among all study participants. However, a distinct separation of the myelin water peak and the intra/extra-cellular water peak was only observed in the mean T2 spectra determined using SAME-ECOS. In terms of data processing speed, SAME-ECOS is approximately 30 times faster than NNLS, achieving a whole-brain analysis in 3 min. CONCLUSION Compared with NNLS, the SAME-ECOS method yields much more reliable T2 spectra in a dramatically shorter time, increasing the feasibility of multi-component T2 decay analysis in clinical settings.

Background and purpose While diffusely abnormal white matter (DAWM) is a nonlesional MRI abnormality identified in ∼25% of patients with multiple sclerosis (MS), it has yet to be investigated in patients at an earlier disease stage, namely clinically isolated syndrome (CIS). The goals of this study were to (1) determine the prevalence of DAWM in patients with a CIS suggestive of MS, (2) evaluate the association between DAWM and demographic, clinical, and MRI features, and (3) evaluate the prognostic significance of DAWM on conversion from CIS to MS. Methods One hundred and forty-two CIS participants were categorized into DAWM and non-DAWM groups at baseline and followed for up to 24 months or until MS diagnosis. The primary outcome was conversion to MS (2005 McDonald criteria) within 6 months. Results DAWM was present in 27.5% of participants, and was positively associated with brainstem symptom onset, receiving corticosteroids, dissemination in space, and T2 lesion volume. DAWM was associated with an increased risk of conversion to MS over 6 months after adjustment for age and disability (hazard ratio [HR] = 2.24, p = 0.004). This association remained at a trend-level after adjustment for high-risk imaging features (HR = 1.68, p = 0.10). Conclusions DAWM is present in a similar proportion of patients with CIS and clinically definite MS, and it is associated with increased risk of conversion to MS over 6 months.

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.

Standardized magnetic resonance imaging (MRI) protocols are important for the diagnosis and monitoring of patients with multiple sclerosis (MS). The Consortium of Multiple Sclerosis Centers (CMSC) convened an international panel of MRI experts to review and update the current guidelines. The objective was to update the standardized MRI protocol and clinical guidelines for diagnosis and follow-up of MS and develop strategies for advocacy, dissemination, and implementation. Conference attendees included neurologists, radiologists, technologists, and imaging scientists with expertise in MS. Representatives from the CMSC, Magnetic Resonance Imaging in MS (MAGNIMS), North American Imaging in Multiple Sclerosis Cooperative, US Department of Veteran Affairs, National Multiple Sclerosis Society, Multiple Sclerosis Association of America, MRI manufacturers, and commercial image analysis companies were present. Before the meeting, CMSC members were surveyed about standardized MRI protocols, gadolinium use, need for diffusion-weighted imaging, and the central vein sign. The panel worked to make the CMSC and MAGNIMS MRI protocols similar so that the updated guidelines could ultimately be accepted by international consensus. Advocacy efforts will promote the importance of standardized MS MRI protocols. Dissemination will include publications, meeting abstracts, educational programming, webinars, “meet the expert” teleconferences, and examination cards. Implementation will require comprehensive and coordinated efforts to make the protocol easy to access and use. The ultimate vision, and goal, is for the guidelines to be universally useful, usable, and used as the standard of care for patients with MS.

MRI enables detailed in vivo depiction of multiple sclerosis (MS) pathology. Localized areas of MS damage, commonly referred to as lesions, or plaques, have been a focus of clinical and research MRI studies for over four decades. A nonplaque MRI abnormality which is present in at least 25% of MS patients but has received far less attention is diffusely abnormal white matter (DAWM). DAWM has poorly defined boundaries and a signal intensity that is between normal-appearing white matter and classic lesions on proton density and T2 -weighted images. All clinical phenotypes of MS demonstrate DAWM, including clinically isolated syndrome, where DAWM is associated with higher lesion volume, reduced brain volume, and earlier conversion to MS. Advanced MRI metric abnormalities in DAWM tend to be greater than those in NAWM, but not as severe as focal lesions, with myelin, axons, and water-related changes commonly reported. Histological studies demonstrate a primary lipid abnormality in DAWM, with some axonal damage and lesser involvement of myelin proteins. This review provides an overview of DAWM identification, summarizes in vivo and postmortem observations, and comments on potential pathophysiological mechanisms, which may underlie DAWM in MS. Given the prevalence and potential clinical impact of DAWM, the number of imaging studies focusing on DAWM is insufficient. Characterization of DAWM significance and microstructure would benefit from larger longitudinal and additional quantitative imaging efforts. Revisiting data from previous studies that included proton density and T2 imaging would enable retrospective DAWM identification and analysis.

Background and purpose Myelin water fraction (MWF) is a histopathologically validated in vivo myelin marker. As MWF is the proportion of water with a short T2 relative to the total water, increases in water from edema and inflammation may confound MWF determination in multiple sclerosis (MS) lesions. Total water content (TWC) measurement enables calculation of absolute myelin water content (MWC) and can be used to distinguish edema/inflammation from demyelination. We assessed what influence changes in total water might have on MWF by calculating MWC values in new MS lesions. Methods 3T 32-echo T2 relaxation data were collected monthly for 6 months from six relapsing-remitting MS participants. TWC was determined and multiplied with MWF images to calculate corrected MWC images. The effect of this water content correction was examined in 20 new lesions by comparing mean MWF and MWC over time. Results On average, at lesion first appearance, lesion TWC increased by 6.4% (p = .003; range: -1% to +21%), MWF decreased by 24% (p = .006; range: -70% to +12%), and MWC decreased by 20% (p = .026; range: -68% to +21%), relative to prelesion values. Average TWC in lesions then gradually decreased, whereas MWF and MWC remained low. The shape of the MWF and MWC lesion evolution curves was nearly identical, differing only by an offset. Conclusion MWF mirrors MWC and is able to monitor myelin in new lesions. Even after taking into account water content increases, MWC still decreased at lesion first appearance attributed to demyelination.

Background and purpose Acquiring and interpreting quantitative myelin-specific MRI data at an individual level is challenging because of technical difficulties and natural myelin variation in the population. To overcome these challenges, we used multiecho T2 myelin water imaging (MWI) to create T2 metric healthy population atlases that depict the mean and variation of myelin water fraction (MWF), and intra- and extracellular water mobility as described by geometric mean T2 (IEGMT2 ). Methods Cervical cord MWI was performed at 3T on 20 healthy individuals (10M/10F, mean age: 36 years) and 3 relapsing remitting multiple sclerosis (RRMS) participants (1M/2F, age: 39/42/37 years). Anatomical data were collected for the purpose of image segmentation and registration. Atlases were created by coregistering and averaging T2 metrics from all controls. Voxel-wise z-score maps from 3 RRMS participants were produced to demonstrate the preliminary utility of the MWF and IEGMT2 atlases. Results The average MWF atlas provides a representation of myelin in the spinal cord consistent with well-known spinal cord anatomical characteristics. The IEGMT2 atlas also depicted structural variations in the spinal cord. Z-score analysis illustrated distinct abnormalities in MWF and IEGMT2 in the 3 RRMS cases. Conclusions Our findings highlight the potential for using a quantitative T2 relaxation metric atlas to visualize and detect pathology in spinal cord. Our MWF and IEGMT2 atlases (URL: https://sourceforge.net/projects/mwi-spinal-cord-atlases/) can serve as normative references in the cervical spinal cord for other studies.

Women with multiple sclerosis (MS) are often of childbearing age. Thirty-six women with MS who were pregnant (n = 27) or within 6 weeks postpartum (n = 9) were reported in the North American COViMS registry and their COVID-19 outcomes were described. One pregnant and one postpartum woman were hospitalized. No deaths occurred. To compare COVID-19 clinical outcomes in pregnant and postpartum females with females who were not pregnant or postpartum, a 1:2 propensity score match was performed. While not powered to detect small differences, it was reassuring that no increased risks for those with MS who were pregnant/postpartum were revealed.

The traditional approach for measuring myelin-associated water with quantitative magnetic resonance imaging (MRI) uses multi-echo T2 relaxation data to calculate the myelin water fraction (MWF). A fundamentally different approach, abbreviated “mcDESPOT”, uses a more efficient steady-state acquisition to generate an equivalent metric (fM). Although previous studies have demonstrated inherent instability and bias in the complex mcDESPOT analysis procedure, fM has often been used as a surrogate for MWF. We produced and compared multivariate atlases of MWF and fM in healthy human brain and cervical spinal cord (available online) and compared their ability to detect multiple sclerosis pathology. A significant bias was found in all regions (p –5), albeit reversed for spinal cord (fM-MWF = − 3.4%) compared to brain (+ 6.2%). MWF and fM followed an approximately linear relationship for regions with MWF ~ 10%, the relationship broke down and fM no longer increased in tandem with MWF. For multiple sclerosis patients, MWF and fM Z score maps showed overlapping areas of low Z score and similar trends between patients and brain regions, although those of fM generally had greater spatial extent and magnitude of severity. These results will guide future choice of myelin-sensitive quantitative MRI and improve interpretation of studies using either myelin imaging approach.

Myelin water imaging is a quantitative neuroimaging technique that provides the myelin water fraction (MWF), a metric highly specific to myelin content, and the intra-/extra-cellular T2 (IET2), which is related to water and iron content. We coupled high-resolution data from 100 adults with gold-standard methodology to create an optimized anatomical brain template and accompanying MWF and IET2 atlases. We then used the MWF atlas to characterize how myelin content relates to demographic factors. In most brain regions, myelin content followed a quadratic pattern of increase during the third decade of life, plateau at a maximum around the fifth decade, then decrease during later decades. The ranking of mean myelin content between brain regions remained consistent across age groups. These openly available normative atlases can facilitate evaluation of myelin imaging results on an individual basis and elucidate the distribution of myelin content between brain regions and in the context of aging.

Key Points Question Is myelin damage in normal-appearing white matter associated with cognitive impairment in participants with multiple sclerosis (MS)? Findings In this cross-sectional study of 73 participants with MS and 22 age-, sex-, and education-matched healthy controls, significant associations were observed in participants with MS between a quantitative neuroimaging measure of myelin and performance on cognitive tests validated for MS. No significant associations were found between myelin measures and cognitive performance in controls. Meaning These findings suggest that myelin damage that is completely invisible on standard clinical images but can be measured using myelin water imaging is involved in MS-related cognitive impairment., This cross-sectional study uses myelin water imaging to examine participants with multiple sclerosis as well as controls to see whether advanced imaging can show myelin damage that does not appear on standard imaging., Importance Cognitive impairment is a debilitating symptom of multiple sclerosis (MS) that affects up to 70% of patients. An improved understanding of the underlying pathology of MS-related cognitive impairment would provide considerable benefit to patients and clinicians. Objective To determine whether there is an association between myelin damage in tissue that appears completely normal on standard clinical imaging, but can be detected by myelin water imaging (MWI), with cognitive performance in MS. Design, Setting, and Participants In this cross-sectional study, participants with MS and controls underwent cognitive testing and magnetic resonance imaging (MRI) from August 23, 2017, to February 20, 2019. Participants were recruited through the University of British Columbia Hospital MS clinic and via online recruitment advertisements on local health authority websites. Cognitive testing was performed in the MS clinic, and MRI was performed at the adjacent academic research neuroimaging center. Seventy-three participants with clinically definite MS fulfilling the 2017 revised McDonald criteria for diagnosis and 22 age-, sex-, and education-matched healthy volunteers without neurological disease were included in the study. Data analysis was performed from March to November 2019. Exposures MWI was performed at 3 T with a 48-echo, 3-dimensional, gradient and spin-echo (GRASE) sequence. Cognitive testing was performed with assessments drawn from cognitive batteries validated for use in MS. Main Outcomes and Measures The association between myelin water measures, a measurement of the T2 relaxation signal from water in the myelin bilayers providing a specific marker for myelin, and cognitive test scores was assessed using Pearson correlation. Three white matter regions of interest—the cingulum, superior longitudinal fasciculus (SLF), and corpus callosum—were selected a priori according to their known involvement in MS-related cognitive impairment. Results For the 95 total participants, the mean (SD) age was 49.33 (11.44) years. The mean (SD) age was 50.2 (10.7) years for the 73 participants with MS and 46.4 (13.5) for the 22 controls. Forty-eight participants with MS (66%) and 14 controls (64%) were women. The mean (SD) years of education were 14.7 (2.2) for patients and 15.8 (2.5) years for controls. In MS, significant associations were observed between myelin water measures and scores on the Symbol Digit Modalities Test (SLF, r = −0.490; 95% CI, −0.697 to −0.284; P

Background Increasing evidence suggests that various inflammatory, immunological and metabolic pathways are altered in the clinically isolated syndrome (CIS) of multiple sclerosis (MS). Moreover, recent diagnostic criteria have made possible the very early diagnosis of MS. We evaluated multiple fluid biomarkers in people with early MS and CIS. Methods We measured blood levels of cytokines, matrix metalloproteinases (MMPs), serum metabolomics and immune cell immunophenotyping in participants in the Trial of Minocycline in a Clinically Isolated Syndrome of Multiple Sclerosis. Results When compared with healthy controls, people with early MS/CIS had higher levels of eotaxin, MCP-3, IL-1 receptor antagonist, IL-1β, IL-9 and IP-10, as well as MMPs 1, 8 and 9. In metabolomics analysis, the alanine, aspartate and glutamate metabolism and the synthesis and degradation of ketone bodies pathways were altered compared to healthy controls. There were no differences in lymphocyte subpopulation numbers. Out of all these biomarkers, only MMP-1 was able to differentiate between early MS and CIS, and was found to correlate with lesion volume and gadolinium enhancing lesions on MRI. Conclusion The immunological and metabolic profile of CIS and early MS is remarkably similar, supporting that these are a continuum of a common underlying pathophysiological process.

Background Neurofilaments are cytoskeletal proteins that are detectable in the blood after neuroaxonal injury. Multiple sclerosis (MS) disease progression, greater lesion volume, and brain atrophy are associated with higher levels of serum neurofilament light chain (NfL), but few studies have examined the relationship between NfL and advanced magnetic resonance imaging (MRI) measures related to myelin and axons. We assessed the relationship between serum NfL and brain MRI measures in a diverse group of MS participants. Methods and Materials 103 participants (20 clinically isolated syndrome, 33 relapsing-remitting, 30 secondary progressive, 20 primary progressive) underwent 3T MRI to obtain myelin water fraction (MWF), geometric mean T2 (GMT2), water content, T1; high angular resolution diffusion imaging (HARDI)-derived axial diffusivity (AD), radial diffusivity (RD), fractional anisotropy (FA); diffusion basis spectrum imaging (DBSI)-derived AD, RD, FA; restricted, hindered, water and fiber fractions; and volume measurements of normalized brain, lesion, thalamic, deep grey matter (GM), and cortical thickness. Multiple linear regressions assessed the strength of association between serum NfL (dependent variable) and each MRI measure in whole brain (WB), normal appearing white matter (NAWM) and T2 lesions (independent variables), while controlling for age, expanded disability status scale, and disease duration. Results Serum NfL levels were significantly associated with metrics of axonal damage (FA: R2WB-HARDI=0.29, R2NAWM-HARDI=0.31, R2NAWM-DBSI=0.30, R2Lesion-DBSI=0.31; AD: R2WB-HARDI=0.31), myelin damage (MWF: R2WB=0.29, R2NAWM=0.30, RD: R2WB-HARDI=0.32, R2NAWM-HARDI=0.34, R2Lesion-DBSI=0.30), edema and inflammation (T1: R2Lesion=0.32; GMT2: R2WB=0.31, R2Lesion=0.31), and cellularity (restricted fraction R2WB=0.30, R2NAWM=0.32) across the entire MS cohort. Higher serum NfL levels were associated with significantly higher T2 lesion volume (R2=0.35), lower brain structure volumes (thalamus R2=0.31; deep GM R2=0.33; normalized brain R2=0.31), and smaller cortical thickness R2=0.31). Conclusion The association between NfL and myelin MRI markers suggest that elevated serum NfL is a useful biomarker that reflects not only acute axonal damage, but also damage to myelin and inflammation, likely due to the known synergistic myelin-axon coupling relationship.

Radiation necrosis mostly occurs in and near the radiation field. We used magnetic resonance imaging to study radiation‐induced necrosis of atypical onset, severity, and extent following stereotactic radiosurgery for a symptomatic arteriovenous malformation. Susceptibility‐sensitive imaging, T1‐relaxation, myelin water imaging, and magnetic resonance spectroscopy were acquired three times up to 52 months postradiosurgery. Increasing water content outside the radiation field, contralateral neuronal loss, and gliosis were detected over time. Our findings suggest that radiation‐induced vasculopathic changes spread more diffusely than previously described. An autoimmune response to brain antigens could underlie white matter changes outside the initial radiation field.

Background and purpose Multiple sclerosis (MS) diffusely abnormal white matter (DAWM) is a mildly hyperintense magnetic resonance imaging abnormality distinct from typical lesions. Our goal was to investigate the prevalence and natural history of DAWM in a large cohort (n = 348) of relapsing-remitting MS (RRMS) patients. Methods The presence of DAWM and relationship to changes in T2 burden of disease (BOD), brain volume (brain fractional ratio, BFR), and disability (Expanded Disability Status Scale, EDSS) were investigated at baseline and year 7-8 (long-term follow-up, LTF). Results DAWM was present in 25.3% (88 of 348) of patients at baseline. At LTF, DAWM was unchanged in 69.3% (61 of 88), decreased in 28.4% (25 of 88), and increased in 2.3% (2 of 88) of patients. Baseline BOD and change in BOD did not significantly differ between patients with and without DAWM. DAWM was associated with greater reduction in BFR at LTF (P = .038). DAWM and DAWM change did not predict EDSS or EDSS progression. Conclusions DAWM is present in a quarter of RRMS patients, and rarely increases or develops de novo. DAWM predicts brain atrophy but does not predict physical disability. Because of its posterior periventricular location, further investigation is warranted to evaluate its relationship to other measures of disability, including visual spatial processing and cognitive function.

ObjectiveTo determine the safety and efficacy of balloon vs sham venoplasty of narrowing of the extracranial jugular and azygos veins in multiple sclerosis (MS).MethodsPatients with relapsing or progressive MS were screened using clinical and ultrasound criteria. After confirmation of >50% narrowing by venography, participants were randomized 1:1 to receive balloon or sham venoplasty of all stenoses and were followed for 48 weeks. Participants and research staff were blinded to intervention allocation. The primary safety outcome was the number of adverse events (AEs) during 48 weeks. The primary efficacy outcome was the change from baseline to week 48 in the patient-reported outcome MS Quality of Life–54 (MSQOL-54) questionnaire. Standardized clinical and MRI outcomes were also evaluated.ResultsOne hundred four participants were randomized (55 sham; 49 venoplasty) and 103 completed 48 weeks of follow-up. Twenty-three sham and 21 venoplasty participants reported at least 1 AE; one sham (2%) and 5 (10%) venoplasty participants had a serious AE. The mean improvement in MSQOL-54 physical score was +1.3 (sham) and +1.4 (venoplasty) (p = 0.95); MSQOL-54 mental score was +1.2 (sham) and −0.8 (venoplasty) (p = 0.55).ConclusionsOur data do not support the continued use of venoplasty of extracranial jugular and/or azygous venous narrowing to improve patient-reported outcomes, chronic MS symptoms, or the disease course of MS.ClinicalTrials.gov identifierNCT01864941.Classification of evidenceThis study provides Class I evidence that for patients with MS, balloon venoplasty of extracranial jugular and azygous veins is not beneficial in improving patient-reported, standardized clinical, or MRI outcomes.

Background and purpose Quantitative T1 and diffusion tensor imaging (DTI) may provide information about pathological changes underlying disability and progression in diseases like multiple sclerosis (MS). Imaging the corpus callosum (CC), a primary site of damage in MS with a critical role in interhemispheric connectivity, may be useful for assessing overall brain health, prognosis, and therapy efficacy. We assessed the feasibility of multisite clinical trials using advanced MRI by examining the intra and intersite reproducibility of T1 and DTI measurements in the CC and segmented white matter (WM). Methods Five healthy volunteers were scanned twice within 24 hours at six 3T sites. Coefficients of variation (COVs) and intraclass correlation coefficients (ICCs) for CC and WM T1 , fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (Dax ), and radial diffusivity (Drad ) assessed intrasite and intersite reliability. Results CC and WM T1 showed excellent intrasite reproducibility with low COVs (mean = .90% and .89%, respectively) and good ICCs (CC = .78, WM = .90). T1 also demonstrated intersite reliability (low COVs: CC = 2.4%, WM = 1.8%; moderate ICCs: CC = .43, WM = .69). DTI had low intrasite COVs (CC: FA = 1.3%, MD = 1.5%, Dax = 1.4%, Drad = 2.2%; WM: FA = .9%, MD = .9%, Dax = .7%, Drad = 1.2%) and high intrasite ICCs (CC: FA = .95, MD = .97, Dax = .94, Drad = .97; CC: FA = .9, MD = .66, Dax = .88, Drad = .63), indicating excellent intrasite reproducibility. DTI also showed excellent intersite reliability with low COVs (CC: FA = 2.1%, MD = 4.1%, Dax = 3.4%, Drad = 5.3%, WM: FA = 1.3%, MD = 1.9%, Dax = 1.8%, Drad = 2.1%,) and good ICCs (CC: FA = .90, MD = .84, Dax = .72, Drad = .90; WM: FA = .83, MD = .34, Dax = .62, Drad = .41). Conclusions T1 and DTI measures are reproducible using equivalent MRI scanners and sequence protocols. Using a similar MR system, it is feasible to carry out multicenter studies using T1 and DTI to evaluate changes within the CC and WM.

Background: Nifedipine is a generic, well-known and commonly-prescribed dihydropyridine calcium channel blocker used in the treatment of hypertension and Prinzmetal’s angina. A known but very rare and serious adverse effect of nifedipine is clinically-apparent hepatitis which can take months to resolve. Case presentation: Here we present a case of nifedipine-induced hepatitis in a 78-year-old Caucasian female with no prior history of liver or autoimmune disease. We discuss our investigative and management approach, and present a review of prior cases. We offer an approach for patients who present with signs of acute liver injury with jaundice and high elevations in serum transaminases. Conclusion: Not much is known about nifedipine-induced hepatitis due to its rare occurrence. Its prevalence is unknown. The disease appears to afflict older men and women. It can present acutely (within days) or subacutely (within 4–8 weeks after medication start) and in an idiosyncratic manner. Chronic or latent cases have also been described, some diagnosed as late as 3 years after medication start. Common symptoms include jaundice, nausea, chills, rigors, diaphoresis, fatigue, and abdominal pain. Laboratory investigations often reveal profound elevations in AST, ALT, GGT, and conjugated bilirubin. Peripheral blood smear may demonstrate eosinophilia. Histology from liver biopsy typically demonstrates infiltration of immune cells, cholestasis, and a picture of steatohepatitis. Treatment involves immediate discontinuation of the drug with supportive care. Thus far, all published instances of nifedipine-induced hepatitis were self-limiting without mortality due to fulminant liver failure. However, this disease can take months to resolve. There is no randomized evidence for other treatments such as corticosteroids.

BACKGROUND AND PURPOSE Late-onset adult Krabbe disease is a very rare demyelinating leukodystrophy, affecting less than 1 in a million people. Hematopoietic stem cell transplantation (HSCT) strategies can stop the accumulation of toxic metabolites that damage myelin-producing cells. We used quantitative advanced imaging metrics to longitudinally assess the impact of HSCT on brain abnormalities in adult-onset Krabbe disease. METHODS A 42-year-old female with late-onset Krabbe disease and an age/sex-matched healthy control underwent annual 3T MRI (baseline was immediately prior to HSCT for the Krabbe subject). Imaging included conventional scans, myelin water imaging, diffusion tensor imaging, and magnetic resonance spectroscopy. RESULTS Brain abnormalities far beyond those visible on conventional imaging were detected, suggesting a global pathological process occurs in Krabbe disease with adult-onset etiology, with myelin being more affected than axons, and evidence of wide-spread gliosis. After HSCT, our patient showed clinical stability in all measures, as well as improvement in gait, dysarthria, and pseudobulbar affect at 7.5 years post-transplant. No MRI evidence of worsening demyelination and axonal loss was observed up to 4 years post-allograft. CONCLUSIONS Clinical evidence and stability of advanced MR measures related to myelin and axons supports HSCT as an effective treatment strategy for stopping progression associated with late-onset Krabbe disease.

Myelin imaging is a form of quantitative magnetic resonance imaging (MRI) that measures myelin content and can potentially allow demyelinating diseases such as multiple sclerosis (MS) to be detected earlier. Although focal lesions are the most visible signs of MS pathology on conventional MRI, it has been shown that even tissues that appear normal may exhibit decreased myelin content as revealed by myelin-specific images (i.e., myelin maps). Current methods for analyzing myelin maps typically use global or regional mean myelin measurements to detect abnormalities, but ignore finer spatial patterns that may be characteristic of MS. In this paper, we present a machine learning method to automatically learn, from multimodal MR images, latent spatial features that can potentially improve the detection of MS pathology at early stage. More specifically, 3D image patches are extracted from myelin maps and the corresponding T1-weighted (T1w) MRIs, and are used to learn a latent joint myelin-T1w feature representation via unsupervised deep learning. Using a data set of images from MS patients and healthy controls, a common set of patches are selected via a voxel-wise t-test performed between the two groups. In each MS image, any patches overlapping with focal lesions are excluded, and a feature imputation method is used to fill in the missing values. A feature selection process (LASSO) is then utilized to construct a sparse representation. The resulting normal-appearing features are used to train a random forest classifier. Using the myelin and T1w images of 55 relapse-remitting MS patients and 44 healthy controls in an 11-fold cross-validation experiment, the proposed method achieved an average classification accuracy of 87.9% (SD = 8.4%), which is higher and more consistent across folds than those attained by regional mean myelin (73.7%, SD = 13.7%) and T1w measurements (66.7%, SD = 10.6%), or deep-learned features in either the myelin (83.8%, SD = 11.0%) or T1w (70.1%, SD = 13.6%) images alone, suggesting that the proposed method has strong potential for identifying image features that are more sensitive and specific to MS pathology in normal-appearing brain tissues., Graphical Abstract, Highlights • Deep-learning method to detect MS pathology on normal-appearing brain tissue on MRI • Unsupervised deep learning and random forest applied to myelin and T1w images • Deep learning of myelin maps has not been previously attempted. • Deep-learned features yield more accurate detection (88%) than regional means (74%). • Joint deep learning improves pathology detection over modality-specific features.

Prolonged spin-spin relaxation times in tumour tissue have been observed since some of the earliest nuclear magnetic resonance investigations of the brain. Over the last three decades, numerous studies have sought to characterize tumour morphology and malignancy using quantitative assessment of T 2 relaxation times, although attempts to categorize and differentiate tumours have had limited success. However, previous work must be interpreted with caution as relaxation data were typically acquired using a variety of multiple echo sequences with a range of echoes and T 2 decay curves and were frequently fit with monoexponential analysis. We defined the distribution of T 2 components in three different human brain tumours (glioblastoma, oligodendroglioma, meningioma) using a multi-echo sequence with a greater number of echoes and a longer acquisition window than previously used (48 echoes, data collection out to 1120 ms) with no a priori assumptions about the number of exponential components contributing to the T 2 decay. T 2 relaxation times were increased in tumour tissue and each tumour showed a distinct T 2 distribution profile. Tumours have complex and unique compartmentalization characteristics. Quantitative assessment of T 2 relaxation in brain cancer may be useful in evaluating different grades of brain tumours on the basis of their T 2 distribution profile, and has the potential to be a non-invasive diagnostic tool which may also be useful in monitoring therapy. Further study with a larger sample size and varying grades of tumours is warranted.

Multiple sclerosis (MS) is a neurological disease with an early course that is characterised by attacks of clinical worsening, separated by variable periods of remission. The ability to predict the...

Spinal cord pathology is a feature of both neuromyelitis optica spectrum disorder (NMOSD) and relapsing-remitting multiple sclerosis (MS). While subclinical disease activity has been described in MS using quantitative magnetic resonance imaging measures, current evidence suggests that neurodegeneration is absent between relapses in NMOSD, although most evidence comes from brain studies. We aimed to assess cross-sectional differences and longitudinal changes in myelin integrity in relapse-free MS and NMOSD subjects over one year. 15 NMOSD, 15 MS subjects, and 17 healthy controls were scanned at 3 T using a cervical cord mcDESPOT protocol. A subset of 8 NMOSD, 11 MS subjects and 14 controls completed follow-up. Measures of the myelin water fraction (fM) within lesioned and non-lesioned cord segments were collected. At baseline, fM in lesioned and non-lesioned segments was significantly reduced in MS (lesioned: p = 0.002; non-lesioned: p = 0.03) and NMOSD (lesioned: p = 0.0007; non-lesioned: p = 0.002) compared to controls. Longitudinally, fM decreased within non-lesioned cord segments in the MS group (− 7.3%, p = 0.02), but not in NMOSD (+ 5.8%, p = 0.1), while change in lesioned segments fM did not differ from controls' in either patient group. These results suggest that degenerative changes outside of lesioned areas can be observed over a short time frame in MS, but not NMOSD, and support the use of longitudinal myelin water imaging for the assessment of pathological changes in the cervical cord in demyelinating diseases., Highlights • MS and NMOSD subjects underwent longitudinal cervical cord myelin water imaging. • Reduced myelin water fraction in MS and NMOSD normal-appearing and lesioned areas • Decrease in myelin in normal-appearing tissue over 1 year in MS, but not NMOSD • Further evidence that disease progression is absent between relapses in NMOSD.

ObjectiveTo assess the onset of ocrelizumab efficacy on brain MRI measures of disease activity in the phase II study in relapsing-remitting multiple sclerosis (RRMS), and relapse rate in the pooled phase III studies in relapsing multiple sclerosis (RMS).MethodsBrain MRI activity was determined in the phase II trial at monthly intervals in patients with RRMS receiving placebo, ocrelizumab (600 mg), or intramuscular interferon (IFN) β-1a (30 μg). Annualized relapse rate (ARR; over various epochs) and time to first relapse were analyzed in the pooled population of the phase III OPERA (A Study of Ocrelizumab in Comparison With Interferon Beta-1a [Rebif] in Participants With Relapsing Multiple Sclerosis) I and OPERA II trials in patients with RMS receiving ocrelizumab (600 mg) or subcutaneous IFN-β-1a (44 μg).ResultsIn patients with RRMS, ocrelizumab reduced the number of new T1 gadolinium-enhancing lesions by week 4 vs placebo (p = 0.042) and by week 8 vs intramuscular IFN-β-1a (p < 0.001). Ocrelizumab also reduced the number of new or enlarging T2 lesions appearing between weeks 4 and 8 vs both placebo and IFN-β-1a (both p < 0.001). In patients with RMS, ocrelizumab significantly reduced ARR (p = 0.005) and the probability of time to first protocol-defined relapse (p = 0.014) vs subcutaneous IFN-β-1a within the first 8 weeks.ConclusionEpoch analysis of MRI-measured lesion activity in the phase II study and relapse rate in the phase III studies consistently revealed a rapid suppression of acute MRI and clinical disease activity following treatment initiation with ocrelizumab in patients with RRMS and RMS, respectively.Classification of evidenceThis study provides Class II evidence that for patients with RRMS and RMS, ocrelizumab suppressed MRI activity within 4 weeks and clinical disease activity within 8 weeks.

Background and purpose Myelin water imaging (MWI) and diffusion tensor imaging (DTI) provide information about myelin and axon-related brain microstructure, which can be useful for investigating normal brain development and many childhood brain disorders. While pediatric DTI atlases exist, there are no pediatric MWI atlases available for the 9-10 years old age group. As myelination and structural development occurs throughout childhood and adolescence, studies of pediatric brain pathologies must use age-specific MWI and DTI healthy control data. We created atlases of myelin water fraction (MWF) and DTI metrics for healthy children aged 9-10 years for use as normative data in pediatric neuroimaging studies. Methods 3D-T1 , DTI, and MWI scans were acquired from 20 healthy children (mean age: 9.6 years, range: 9.2-10.3 years, 4 females). ANTs and FSL registration were used to create quantitative MWF and DTI atlases. Region of interest (ROI) analysis in nine white matter regions was used to compare pediatric MWF with adult MWF values from a recent study and to investigate the correlation between pediatric MWF and DTI metrics. Results Adults had significantly higher MWF than the pediatric cohort in seven of the nine white matter ROIs, but not in the genu of the corpus callosum or the cingulum. In the pediatric data, MWF correlated significantly with mean diffusivity, but not with axial diffusivity, radial diffusivity, or fractional anisotropy. Conclusions Normative MWF and DTI metrics from a group of 9-10 year old healthy children provide a resource for comparison to pathologies. The age-specific atlases are ready for use in pediatric neuroimaging research and can be accessed: https://sourceforge.net/projects/pediatric-mri-myelin-diffusion/.

Purpose: Based on a deep learning neural network (NN) algorithm, a super fast and easy to implement data analysis method was proposed for myelin water imaging (MWI) to calculate the myelin water fraction (MWF). Methods: A NN was constructed and trained on MWI data acquired by a 32-echo 3D gradient and spin echo (GRASE) sequence. Ground truth labels were created by regularized non-negative least squares (NNLS) with stimulated echo corrections. Voxel-wise GRASE data from 5 brains (4 healthy, 1 multiple sclerosis (MS)) were used for NN training. The trained NN was tested on 2 healthy brains, 1 MS brain with segmented lesions, 1 healthy spinal cord, and 1 healthy brain acquired from a different scanner. Results: Production of whole brain MWF maps in approximately 33 ​s can be achieved by a trained NN without graphics card acceleration. For all testing regions, no visual differences between NN and NNLS MWF maps were observed, and no obvious regional biases were found. Quantitatively, all voxels exhibited excellent agreement between NN and NNLS (all R2>0.98, p ​

BACKGROUND AND PURPOSE Myelin water imaging (MWI) is a magnetic resonance imaging technique that quantifies myelin in-vivo. Although MWI has been extensively applied to study myelin-related diseases in groups, clinical use in individual patients is challenging mainly due to population heterogeneity. The purpose of this study was twofold: (1) create a normative brain myelin water atlas depicting the population mean and regional variability of myelin content; and (2) apply the myelin atlas to assess the degree of demyelination in individuals with multiple sclerosis (MS). METHODS 3T MWI was performed on 50 healthy adults (25 M/25 F, mean age 25 years [range 17-42 years]). The myelin water atlas was created by averaging coregistered myelin water fraction (MWF) maps from all healthy individuals. To illustrate the preliminary utility of the atlas, white matter (WM) regional MWF variations were evaluated and voxel-wise z-score maps (z < -1.96) from the MWI of three MS participants were produced to assess individually the degree of demyelination. RESULTS The myelin water atlas demonstrated significant MWF variation across control WM. No significant MWF differences were found between male and female healthy participants. MS z-score maps revealed diffuse regions of demyelination in the two participants with Expanded Disability Status Scale (EDSS) = 2.0 but not in the participant with EDSS = 0. CONCLUSIONS The myelin water atlas can be used as a reference (URL: https://sourceforge.net/projects/myelin-water-atlas/) to demonstrate areas of demyelination in individual MS participants. Future studies will expand the atlas age range, account for education, and other variables that may affect myelination.

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

Importance Emergence of SARS-CoV-2 causing COVID-19 prompted the need to gather information on clinical outcomes and risk factors associated with morbidity and mortality in patients with multiple sclerosis (MS) and concomitant SARS-CoV-2 infections. Objective To examine outcomes and risk factors associated with COVID-19 clinical severity in a large, diverse cohort of North American patients with MS. Design, Setting, and Participants This analysis used deidentified, cross-sectional data on patients with MS and SARS-CoV-2 infection reported by health care professionals in North American academic and community practices between April 1, 2020, and December 12, 2020, in the COVID-19 Infections in MS Registry. Health care professionals were asked to report patients after a minimum of 7 days from initial symptom onset and after sufficient time had passed to observe the COVID-19 disease course through resolution of acute illness or death. Data collection began April 1, 2020, and is ongoing. Exposures Laboratory-positive SARS-CoV-2 infection or highly suspected COVID-19. Main Outcomes and Measures Clinical outcome with 4 levels of increasing severity: not hospitalized, hospitalization only, admission to the intensive care unit and/or required ventilator support, and death. Results Of 1626 patients, most had laboratory-positive SARS-CoV-2 infection (1345 [82.7%]), were female (1202 [74.0%]), and had relapsing-remitting MS (1255 [80.4%]). A total of 996 patients (61.5%) were non-Hispanic White, 337 (20.8%) were Black, and 190 (11.7%) were Hispanic/Latinx. The mean (SD) age was 47.7 (13.2) years, and 797 (49.5%) had 1 or more comorbidity. The overall mortality rate was 3.3% (95% CI, 2.5%-4.3%). Ambulatory disability and older age were each independently associated with increased odds of all clinical severity levels compared with those not hospitalized after adjusting for other risk factors (nonambulatory: hospitalization only, odds ratio [OR], 2.8 [95% CI, 1.6-4.8]; intensive care unit/required ventilator support, OR, 3.5 [95% CI, 1.6-7.8]; death, OR, 25.4 [95% CI, 9.3-69.1]; age [every 10 years]: hospitalization only, OR, 1.3 [95% CI, 1.1-1.6]; intensive care unit/required ventilator support, OR, 1.3 [95% CI, 0.99-1.7]; death, OR, 1.8 [95% CI, 1.2-2.6]). Conclusions and Relevance In this registry-based cross-sectional study, increased disability was independently associated with worse clinical severity including death from COVID-19. Other risk factors for worse outcomes included older age, Black race, cardiovascular comorbidities, and recent treatment with corticosteroids. Knowledge of these risk factors may improve the treatment of patients with MS and COVID-19 by helping clinicians identify patients requiring more intense monitoring or COVID-19 treatment.

Purpose Myelin water imaging (MWI) using multi-echo T2 relaxation is a quantitative MRI technique that can be used as an in vivo biomarker for myelin in the central nervous system. MWI using a multi-echo spin echo sequence currently takes more than 20 min to acquire eight axial slices (5 mm thickness) in the cervical spinal cord, making spinal cord MWI impractical for implementation in clinical studies. Methods In this study, an accelerated gradient and spin echo sequence (GRASE), previously validated for brain MWI, was adapted for spinal cord MWI. Ten healthy volunteers were scanned with the GRASE sequence (acquisition time 8.5 min) and compared with the multi-echo spin echo sequence (acquisition time 23.5 min). Results Using region of interest analysis, myelin estimates obtained from the two sequences were found to be in good agreement (mean difference = −0.0092, 95% confidence interval = − 0.0092 ± 0.061; regression slope = 1.01, ρ = 0.9). MWI using GRASE was shown to be highly reproducible with an average coefficient of variation of 6.1%. Conclusion The results from this study show that MWI can be performed in the cervical spinal cord in less than 10 min, allowing for practical implementation in multimodal clinical studies. Magn Reson Med 78:1482–1487, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Background The role that dietary interventions can play in multiple sclerosis (MS) management is of huge interest amongst patients and researchers but data evaluating this is limited. Possible effects of a very-low-fat, plant-based dietary intervention on MS related progression and disease activity as measured by brain imaging and MS related symptoms have not been evaluated in a randomized-controlled trial. Despite use of disease modifying therapies (DMT), poor quality of life (QOL) in MS patients can be a significant problem with fatigue being one of the common disabling symptoms. Effective treatment options for fatigue remain limited. Emerging evidence suggests diet and vascular risk factors including obesity and hyperlipidemia may influence MS disease progression and improve QOL. Objectives To evaluate adherence, safety and effects of a very-low-fat, plant-based diet (Diet) on brain MRI, clinical [MS relapses and disability, body mass index (BMI)] and metabolic (blood lipids and insulin) outcomes, QOL [Short Form-36 (SF-36)], and fatigue [Fatigue Severity Scale (FSS) and Modified Fatigue Impact Scale (MFIS)], in relapsing-remitting MS (RRMS). Methods This was a randomized-controlled, assessor-blinded, one-year long study with 61 participants assigned to either Diet (N=32) or wait-listed (Control, N=29) group. Results The mean age (years) [Control−40.9±8.48; Diet−40.8±8.86] and the mean disease duration (years) [Control −5.3±3.86; Diet−5.33±3.63] were comparable between the two groups. There was a slight difference between the two study groups in the baseline mean expanded disability status scale (EDSS) score [Control−2.22±0.90; Diet−2.72±1.05]. Eight subjects withdrew (Diet, N=6; Control, N=2). Adherence to the study diet based on monthly Food Frequency Questionnaire (FFQ) was excellent with the diet group showing significant difference in the total fat caloric intake compared to the control group [total fat intake/total calories averaged ~15% (Diet) versus ~40% (Control)]. The two groups showed no differences in brain MRI outcomes, number of MS relapses or disability at 12 months. The diet group showed improvements at six months in low-density lipoprotein cholesterol (Δ=−11.99mg/dL; p =0.031), total cholesterol (Δ=−13.18mg/dL; p =0.027) and insulin (Δ=−2.82mg/dL; p =0.0067), mean monthly reductions in BMI (Rate=−1.125kg/m2 per month; p p =0.0010); MFIS (Rate=−0.233 points/month; p =0.0011)] during the 12-month period. Conclusions While a very-low fat, plant-based diet was well adhered to and tolerated, it resulted in no significant improvement on brain MRI, relapse rate or disability as assessed by EDSS scores in subjects with RRMS over one year. The diet group however showed significant improvements in measures of fatigue, BMI and metabolic biomarkers. The study was powered to detect only very large effects on MRI activity so smaller but clinically meaningful effects cannot be excluded. The diet intervention resulted in a beneficial effect on the self-reported outcome of fatigue but these results should be interpreted cautiously as a wait-list control group may not completely control for a placebo effect and there was a baseline imbalance on fatigue scores between the groups. If maintained, the improved lipid profile and BMI could yield long-term vascular health benefits. Longer studies with larger sample sizes are needed to better understand the long-term health benefits of this diet.

Purpose To determine whether differences in hydration state, which could arise from routine clinical procedures such as overnight fasting, affect brain total water content (TWC) and brain volume measured with magnetic resonance imaging (MRI). Materials and Methods Twenty healthy volunteers were scanned with a 3T MR scanner four times: day 1, baseline scan; day 2, hydrated scan after consuming 3L of water over 12 hours; day 3, dehydrated scan after overnight fasting of 9 hours, followed by another scan 1 hour later for reproducibility. The following MRI data were collected: T2 relaxation (for TWC measurement), inversion recovery (for T1 measurement), and 3D T1-weighted (for brain volumes). Body weight and urine specific gravity were also measured. TWC was calculated by fitting the T2 relaxation data with a nonnegative least-squares algorithm, with corrections for T1 relaxation and image signal inhomogeneity and normalization to ventricular cerebrospinal fluid. Brain volume changes were measured using SIENA. TWC means were calculated within 14 tissue regions. Results Despite indications of dehydration as demonstrated by increases in urine specific gravity (P = 0.03) and decreases in body weight (P = 0.001) between hydrated and dehydrated scans, there was no measurable change in TWC (within any brain region) or brain volume between hydration states. Conclusion We demonstrate that within a range of physiologic conditions commonly encountered in routine clinical scans (no pretreatment with hydration, well hydrated before MRI, and overnight fasting), brain TWC and brain volumes are not substantially affected in a healthy control cohort. J. Magn. Reson. Imaging 2016;44:296–304.

BACKGROUND Magnetic resonance relaxometry studies in multiple sclerosis (MS) have suggested that iron accumulates within deep gray matter (DGM) structures early in the disease course. However, the commonly utilized mean R2* and magnetic susceptibility measures reflect regional iron concentration but not a structure's total iron content. Thus, tissue atrophy could impact mean R2* and magnetic susceptibility estimates. PURPOSE To demonstrate that both average iron concentration and total iron content need to be reported in order to distinguish between atrophy-related and definite magnetic susceptibility changes. STUDY TYPE Observational. POPULATION The study was performed on 30 healthy controls (HCs) and 39 people with definite MS. FIELD STRENGTH/SEQUENCE 3T Philips Achieva using an 8-channel SENSE head coil. R2* data were acquired using a multiecho gradient echo sequence and diffusion tensor imaging data were acquired using an echo-planar sequence. ASSESSMENT Total iron content in DGM structures was assessed by calculating the sum of all R2* values within a region (denoted as R2mass* ) and compared to the mean R2* as a measure of iron concentration. STATISTICAL TEST Significant group differences were investigated in a linear regression model. All DGM structures were assessed individually and the significance threshold was adjusted using the Bonferroni-Holm correction for multiple comparisons. RESULTS There was an increased mean DGM R2* in MS patients compared to HCs (significant in the pallidus, P = 0.0051). In contrast, R2mass* in patients was found to be lower in the thalamus and the caudate (P = 0.0011) compared to HCs, and similar between the two cohorts in the other DGM regions. DATA CONCLUSION An increase in mean R2* may not necessarily reflect increased iron accumulation. We propose R2mass* as an additional metric to account for the effects of tissue atrophy when assessing tissue content changes, such as iron deposition or loss. LEVEL OF EVIDENCE 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;50:201-208.

Background Imaging measurement of structure alignment has shown increasing importance in determining tissue properties. It is not known if a similar ability for characterizing neuropathology exists. New methods This study aimed to validate a new alignment-assessing method for measuring myelin and axonal properties using quantitative histological metrics. The new method involved analysis of the Fourier transform (FT) power spectrum in standard magnetic resonance imaging (MRI). T2-weighted MRI were collected from 10 post-mortem multiple sclerosis (MS) brain samples. Three tissue types were examined: lesions, diffusely abnormal white matter, and normal appearing white matter. MRI analysis included computing the FT power spectrum; extracting alignment histograms; and calculating dominant orientation and alignment complexity (angular entropy). Post MRI, the brain samples were processed for myelin and axonal staining, and the stained images were used to derive quantitative orientation measures using structure tensor analysis for MRI comparison. Results There were significant differences in orientation metrics between tissue types in both MRI and histology, and MRI measurements correlated strongly with histological indices. Moreover, the joint effect of myelin and axonal entropy explained over 95% of the variance of MRI angular entropy. Comparison with existing method There is no established method for characterizing myelin and axonal pathology using standard MRI. Advanced MRI methods have the potential to do this but are still in research development and are not yet routinely acquired in clinical practice. Conclusions Alignment measurement using clinical MRI scans may become a valuable new method for characterizing myelin and axonal properties in MS patients.

Background On-treatment magnetic resonance imaging lesions may predict long-term clinical outcomes in patients receiving interferon β-1a. This study aimed to assess the effect of active T2 and T1 gadolinium-enhancing (Gd+) lesions on relapses and 3-month confirmed Expanded Disability Status Scale (EDSS) progression in the PRISMS clinical trial. Methods Exploratory analyses assessed whether active T2 and T1 Gd + lesions at Month 6, or active T2 lesions at Month 12, predicted clinical outcomes over 4 years in PRISMS. Results Mean active T2 lesion number at Month 6 was significantly lower with interferon beta-1a given subcutaneously (IFN β-1a SC) 44 μg and 22 μg 3×/week (tiw) than with placebo (p

BACKGROUND AND PURPOSE: Dose-dependent association between hyperintensity in deep brain structures on unenhanced T1WIs and gadolinium-based contrast agent administrations has been demonstrated with subsequent histopathological confirmation of gadolinium deposition. Our aim was to determine whether greater exposure to linear gadolinium-based contrast agent administration is associated with higher signal intensity in deep brain structures on unenhanced T1-weighted MR imaging. Secondary objective was to compare signal intensity differences between ionic and nonionic linear gadolinium-based contrast agents. MATERIALS AND METHODS: Subjects with secondary-progressive MS originally enrolled in a multicenter clinical trial were studied retrospectively. Eighty subjects (high-exposure cohort) received 9 linear gadolinium-based contrast agent administrations (30 nonionic/50 ionic) between week −4 and year 1 and a tenth administration by year 2. One hundred fifteen subjects (low-exposure cohort) received 2 administrations (40 nonionic/75 ionic) between week −4 and year 1 and a third administration by year 2. Signal intensities were measured on unenhanced T1WIs by placing sample-points on the dentate nucleus, globus pallidus, caudate, thalamus, pons, and white matter, and they were normalized using the following ratios: dentate/pons, globus pallidus/white matter, caudate/white matter, and thalamus/white matter. RESULTS: Between week −4 and year 1, subjects in the high-exposure cohort showed increased signal intensity ratios in all regions (P < .01), while the low-exposure cohort showed only an increase in the dentate nucleus (P = .003). Between years 1 and 2, when both cohorts received only 1 additional gadolinium-based contrast agent, no significant changes were observed. In the high-exposure cohort, significantly higher changes in signal intensity ratios were observed in subjects receiving linear nonionic than in those receiving linear ionic gadolinium-based contrast agents. CONCLUSIONS: Hyperintensity in deep brain structures from gadolinium deposition is related to the number of doses and the type of linear gadolinium-based contrast agent (nonionic greater than ionic) administration.

Graphical network characteristics and nonstationary functional connectivity features, both derived from resting-state functional magnetic resonance imaging (rsfMRI) data, have been associated with cognitive performance in healthy subjects. How these features jointly relate to cognition in diseased states has not been investigated. In this study, 46 relapsing-remitting multiple sclerosis subjects underwent rsfMRI scans and a focused cognitive battery. With a sliding window approach, we examined six dynamic network features that indicated how connectivity changed over time as well as six measures derived from graph theory to reflect static network characteristics. Multiset canonical correlation analysis (MCCA) was then carried out to investigate the relations between dynamic network features, stationary network characteristics, cognitive testing, demographic, disease severity, and mood. Multiple sclerosis (MS) subjects demonstrated weaker connectivity strength, decreased network density, reduced global changes, but increased changes in interhemispheric connectivity compared to controls. The MCCA model determined that executive functions and processing speed ability measured by Wechsler Adult Intelligence Scale IV (WAIS-IV) Working Memory Index, WAIS-IV Processing Speed Index, and the Verbal Fluency Test were positively correlated with education, dynamic connectivity, and static connectivity strength; while poor task switching was correlated with disease severity, psychiatric comorbidities such as depression, anxiety, and fatigue, and static network density. Taken together, our results suggest that better executive functioning in MS requires maintenance of a continued coordination between stationary and dynamic functional connectivity as well as the support of education, and dynamic functional connectivity may provide an additional cognitive biomarker of disease severity in the MS population.

Purpose:To assess the extent of demyelination in cervical spondylotic myelopathy (CSM) using myelin water imaging (MWI) and electrophysiologic techniques.Methods:Somatosensory evoked potentials (SSEPs) and MWI were acquired in 14 patients with CSM and 18 age-matched healthy controls. MWI was performed on a 3.0T whole body magnetic resonance scanner. Myelin water fraction (MWF) was extracted for the dorsal columns and whole cord. SSEPs and MWF were also compared with conventional MRI outcomes, including T2 signal intensity, compression ratio, maximum spinal cord compression (MSCC), and maximum canal compromise (MCC).Results:Group analysis showed marked differences in T2 signal intensity, compression ratio, MSCC, and MCC between healthy controls and patients with CSM. There were no group differences in MWF and SSEP latencies. However, patients with CSM with pathologic SSEPs exhibited reduction in MWF (p < 0.05). MWF was also correlated with SSEP latencies.Conclusion:Our findings provide evidence of decreased myelin content in the spinal cord associated with impaired spinal cord conduction in patients with CSM. While conventional MRI are of great value to define the extent of cord compression, they show a limited correlation with functional deficits (i.e., delayed SSEPs). MWI provides independent and complementary readouts to spinal cord compression, with a high specificity to detect impaired conduction.

Using MR imaging, perfusion can be assessed either by dynamic susceptibility contrast MR imaging or arterial spin-labeling. Alterations of cerebral perfusion have repeatedly been described in multiple sclerosis compared with healthy controls. Acute lesions exhibit relative hyperperfusion in comparison with normal-appearing white matter, a finding mostly attributed to inflammation in this stage of lesion development. In contrast, normal-appearing white and gray matter of patients with MS has been mostly found to be hypoperfused compared with controls, and correlations with cognitive impairment as well as fatigue in multiple sclerosis have been described. Mitochondrial failure, axonal degeneration, and vascular dysfunction have been hypothesized to underlie the perfusion MR imaging findings. Clinically, perfusion MR imaging could allow earlier detection of the acute focal inflammatory changes underlying relapses and new lesions, and could constitute a marker for cognitive dysfunction in MS. Nevertheless, the clinical relevance and pathogenesis of the brain perfusion changes in MS remain to be clarified.