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Background and Purpose: Paramagnetic rim lesions (PRLs) are an MRI biomarker of chronic inflammation in people with multiple sclerosis (MS). PRLs may aid in the diagnosis and prognosis of MS. However, manual identification of PRLs is time‐consuming and prone to poor interrater reliability. To address these challenges, the Automated Paramagnetic Rim Lesion (APRL) algorithm was developed to automate PRL detection. The primary objective of this study is to evaluate the accuracy of APRL for detecting PRLs in a multicenter setting. Methods: We applied APRL to a multicenter dataset, which included 3‐Tesla MRI acquired in 92 participants (43 with MS, 14 with clinically isolated syndrome [CIS]/radiologically isolated syndrome [RIS], 35 without RIS/CIS/MS). Subsequently, we assessed APRL's performance by comparing its results with manual PRL assessments carried out by a team of trained raters. Results: Among the 92 participants, expert raters identified 5637 white matter lesions and 148 PRLs. The automated segmentation method successfully captured 115 (78%) of the manually identified PRLs. Within these 115 identified lesions, APRL differentiated between manually identified PRLs and non‐PRLs with an area under the curve (AUC) of.73 (95% confidence interval [CI]: [.68,.78]). At the subject level, the count of APRL‐identified PRLs predicted MS diagnosis with an AUC of.69 (95% CI: [.57,.81]). Conclusion: Our study demonstrated APRL's capability to differentiate between PRLs and lesions without paramagnetic rims in a multicenter study. Automated identification of PRLs offers greater efficiency over manual identification and could facilitate large‐scale assessments of PRLs in clinical trials. [ABSTRACT FROM AUTHOR]

Ependymal cells form a specialized brain–cerebrospinal fluid (CSF) interface and regulate local CSF microcirculation. It is becoming increasingly recognized that ependymal cells assume a reactive state in response to aging and disease, including conditions involving hypoxia, hydrocephalus, neurodegeneration, and neuroinflammation. Yet what transcriptional signatures govern these reactive states and whether this reactivity shares any similarities with classical descriptions of glial reactivity (i.e., in astrocytes) remain largely unexplored. Using single‐cell transcriptomics, we interrogated this phenomenon by directly comparing the reactive ependymal cell transcriptome to the reactive astrocyte transcriptome using a well‐established model of autoimmune‐mediated neuroinflammation (MOG35‐55 EAE). In doing so, we unveiled core glial reactivity‐associated genes that defined the reactive ependymal cell and astrocyte response to MOG35‐55 EAE. Interestingly, known reactive astrocyte genes from other CNS injury/disease contexts were also up‐regulated by MOG35‐55 EAE ependymal cells, suggesting that this state may be conserved in response to a variety of pathologies. We were also able to recapitulate features of the reactive ependymal cell state acutely using a classic neuroinflammatory cocktail (IFNγ/LPS) both in vitro and in vivo. Taken together, by comparing reactive ependymal cells and astrocytes, we identified a conserved signature underlying glial reactivity that was present in several neuroinflammatory contexts. Future work will explore the mechanisms driving ependymal reactivity and assess downstream functional consequences. [ABSTRACT FROM AUTHOR]

Background and Purpose: Multicenter study designs involving a variety of MRI scanners have become increasingly common. However, these present the issue of biases in image‐based measures due to scanner or site differences. To assess these biases, we imaged 11 volunteers with multiple sclerosis (MS) with scan and rescan data at four sites. Methods: Images were acquired on Siemens or Philips scanners at 3 Tesla. Automated white matter lesion detection and whole‐brain, gray and white matter, and thalamic volumetry were performed, as well as expert manual delineations of T1 magnetization‐prepared rapid acquisition gradient echo and T2 fluid‐attenuated inversion recovery lesions. Random‐effect and permutation‐based nonparametric modeling was performed to assess differences in estimated volumes within and across sites. Results: Random‐effect modeling demonstrated model assumption violations for most comparisons of interest. Nonparametric modeling indicated that site explained >50% of the variation for most estimated volumes. This expanded to >75% when data from both Siemens and Philips scanners were included. Permutation tests revealed significant differences between average inter‐ and intrasite differences in most estimated brain volumes (P <.05). The automatic activation of spine coil elements during some acquisitions resulted in a shading artifact in these images. Permutation tests revealed significant differences between thalamic volume measurements from acquisitions with and without this artifact. Conclusion: Differences in brain volumetry persisted across MR scanners despite protocol harmonization. These differences were not well explained by variance component modeling; however, statistical innovations for mitigating intersite differences show promise in reducing biases in multicenter studies of MS. [ABSTRACT FROM AUTHOR]

The advent of highly effective disease modifying therapy has transformed the landscape of multiple sclerosis (MS) care over the last two decades. However, there remains a critical, unmet need for sensitive and specific biomarkers to aid in diagnosis, prognosis, treatment monitoring, and the development of new interventions, particularly for people with progressive disease. This review evaluates the current data for several emerging imaging and liquid biomarkers in people with MS. MRI findings such as the central vein sign and paramagnetic rim lesions may improve MS diagnostic accuracy and evaluation of therapy efficacy in progressive disease. Serum and cerebrospinal fluid levels of several neuroglial proteins, such as neurofilament light chain and glial fibrillary acidic protein, show potential to be sensitive biomarkers of pathologic processes such as neuro‐axonal injury or glial‐inflammation. Additional promising biomarkers, including optical coherence tomography, cytokines and chemokines, microRNAs, and extracellular vesicles/exosomes, are also reviewed, among others. Beyond their potential integration into MS clinical care and interventional trials, several of these biomarkers may be informative of MS pathogenesis and help elucidate novel targets for treatment strategies. [ABSTRACT FROM AUTHOR]

Objective: To explore longitudinal changes in brain volumetric measures and retinal layer thicknesses following acute optic neuritis (AON) in people with multiple sclerosis (PwMS), to investigate the process of trans‐synaptic degeneration, and determine its clinical relevance. Methods: PwMS were recruited within 40 days of AON onset (n = 49), and underwent baseline retinal optical coherence tomography and brain magnetic resonance imaging followed by longitudinal tracking for up to 5 years. A comparator cohort of PwMS without a recent episode of AON were similarly tracked (n = 73). Mixed‐effects linear regression models were used. Results: Accelerated atrophy of the occipital gray matter (GM), calcarine GM, and thalamus was seen in the AON cohort, as compared with the non‐AON cohort (−0.76% vs −0.22% per year [p = 0.01] for occipital GM, −1.83% vs −0.32% per year [p = 0.008] for calcarine GM, −1.17% vs −0.67% per year [p = 0.02] for thalamus), whereas rates of whole‐brain, cortical GM, non‐occipital cortical GM atrophy, and T2 lesion accumulation did not differ significantly between the cohorts. In the AON cohort, greater AON‐induced reduction in ganglion cell+inner plexiform layer thickness over the first year was associated with faster rates of whole‐brain (r = 0.32, p = 0.04), white matter (r = 0.32, p = 0.04), and thalamic (r = 0.36, p = 0.02) atrophy over the study period. Significant relationships were identified between faster atrophy of the subcortical GM and thalamus, with worse visual function outcomes after AON. Interpretation: These results provide in‐vivo evidence for anterograde trans‐synaptic degeneration following AON in PwMS, and suggest that trans‐synaptic degeneration may be related to clinically‐relevant visual outcomes. ANN NEUROL 2023;93:76–87 [ABSTRACT FROM AUTHOR]

Objective: To assess the effects of demographics, lifestyle factors, and comorbidities on serum neurofilament light chain (sNfL) levels in people without neurologic disease and establish demographic-specific reference ranges of sNfL.Methods: The National Health and Nutrition Examination Survey (NHANES) is a representative sample of the US population in which detailed information on demographic, lifestyle, routine laboratory tests, and overall health status are systematically collected. From stored serum samples, we measured sNfL levels using a novel high-throughput immunoassay (Siemens Healthineers). We evaluated the predictive capacity of 52 demographic, lifestyle, comorbidity, anthropometric, or laboratory characteristics in explaining variability in sNfL levels. Predictive performance was assessed using cross-validated R2 (R2cv ) and forward selection was used to obtain a set of best predictors of sNfL levels. Adjusted reference ranges were derived incorporating characteristics using generalized additive models for location, scale, and shape.Results: We included 1,706 NHANES participants (average age: 43.6 ± 14.8 y; 50.6% male, 35% non-white) without neurological disorders. In univariate models, age explained the most variability in sNfL (R2cv  = 26.8%). Multivariable prediction models for sNfL contained three covariates (in order of their selection): age, creatinine, and glycosylated hemoglobin (HbA1c) (standardized β-age: 0.46, 95% confidence interval [CI]: 0.43, 0.50; creatinine: 0.18, 95% CI: 0.13, 0.22; HbA1c: 0.09, 95% CI: 0.06, 0.11). Adjusted centile curves were derived incorporating identified predictors. We provide an interactive R Shiny application to translate our findings and allow other investigators to use the derived centile curves.Interpretation: Results will help to guide interpretation of sNfL levels as they relate to neurologic conditions. ANN NEUROL 2022;92:688-698. [ABSTRACT FROM AUTHOR]

Background and Purpose: The North American Imaging in Multiple Sclerosis (NAIMS) multisite project identified interscanner reproducibility issues with T1‐based whole brain volume (WBV). Lateral ventricular volume (LVV) acquired on T2‐fluid‐attenuated inverse recovery (FLAIR) scans has been proposed as a robust proxy measure. Therefore, we sought to determine the relative magnitude of scanner‐induced T2‐FLAIR‐based LVV and T1‐based WBV measurement errors in relation to clinically meaningful changes. Methods: This was a post hoc analysis of the NAIMS pilot dataset in which a relapsing‐remitting MS patient with no intrastudy clinical or radiological activity was imaged twice on seven different Siemens scanners across the United States. LVV was determined using the automated NeuroSTREAM technique on T2‐FLAIR and WBV was determined with SIENAX on high‐resolution T1‐MPRAGE. Average LVV and WBV were measured, and absolute intrascanner and interscanner coefficients of variation (CoVs) were calculated. The variabilities were compared to previously established annual pathological and clinically meaningful cutoffs of 0.40% for WBV and of 3.51% for LVV. Results: Mean LVV across all seven scan/rescan pairs was 45.87 ± 1.15 ml. Average LVV intrascanner CoV was 1.42% and interscanner CoV was 1.78%, both smaller than the reported annualized clinically meaningful cutoff of 3.51%. In contrast, intra‐ and interscanner CoVs for WBV (0.99% and 1.15%) were both higher than the established cutoff of 0.40%. Individually, 1/7 intrasite and 2/7 intersite pair‐wise LVV comparisons were above the 3.51% cutoff, whereas 4/7 intrasite and 7/7 intersite WBV comparisons were above the 0.40% cutoff. Conclusion: Fully automated LVV segmentation has higher absolute variability than WBV, but much lower relative variability compared to clinically relevant changes, and may therefore be a meaningful proxy outcome measure of neurodegeneration. [ABSTRACT FROM AUTHOR]

Objective: Patients with myelin oligodendrocyte glycoprotein antibody (MOG-IgG)-associated disease (MOGAD) suffer from severe optic neuritis (ON) leading to retinal neuro-axonal loss, which can be quantified by optical coherence tomography (OCT). We assessed whether ON-independent retinal atrophy can be detected in MOGAD.Methods: Eighty patients with MOGAD and 139 healthy controls (HCs) were included. OCT data was acquired with (1) Spectralis spectral domain OCT (MOGAD: N = 66 and HCs: N = 103) and (2) Cirrus high-definition OCT (MOGAD: N = 14 and HCs: N = 36). Macular combined ganglion cell and inner plexiform layer (GCIPL) and peripapillary retinal nerve fiber layer (pRNFL) were quantified.Results: At baseline, GCIPL and pRNFL were lower in MOGAD eyes with a history of ON (MOGAD-ON) compared with MOGAD eyes without a history of ON (MOGAD-NON) and HCs (p < 0.001). MOGAD-NON eyes had lower GCIPL volume compared to HCs (p < 0.001) in the Spectralis, but not in the Cirrus cohort. Longitudinally (follow-up up to 3 years), MOGAD-ON with ON within the last 6-12 months before baseline exhibited greater pRNFL thinning than MOGAD-ON with an ON greater than 12 months ago (p < 0.001). The overall MOGAD cohort did not exhibit faster GCIPL thinning compared with the HC cohort.Interpretation: Our study suggests the absence of attack-independent retinal damage in patients with MOGAD. Yet, ongoing neuroaxonal damage or edema resolution seems to occur for up to 12 months after ON, which is longer than what has been reported with other ON forms. These findings support that the pathomechanisms underlying optic nerve involvement and the evolution of OCT retinal changes after ON is distinct in patients with MOGAD. ANN NEUROL 2022;92:476-485. [ABSTRACT FROM AUTHOR]

Objective: To evaluate changes over 3 years in the thickness of inner retinal layers including the peripapillary retinal nerve fiber layer (pRNFL), and combined macular ganglion cell and inner plexiform layers (mGCIPL), in individuals with relapsing‐remitting multiple sclerosis (RRMS) versus healthy controls; to determine whether optical coherence tomography (OCT) is sufficiently sensitive and reproducible to detect small degrees of neuroaxonal loss over time that correlate with changes in brain volume and disability progression as measured by the Expanded Disability Status Scale (EDSS). Methods: Individuals with RRMS from 28 centers (n = 333) were matched with 64 healthy participants. OCT scans were performed on Heidelberg Spectralis machines (at baseline; 1 month; 6 months; 6‐monthly thereafter). Results: OCT measurements were highly reproducible between baseline and 1 month (intraclass correlation coefficient >0.98). Significant inner retinal layer thinning was observed in individuals with multiple sclerosis (MS) compared with controls regardless of previous MS‐associated optic neuritis––group differences (95% CI) over 3 years: pRNFL: −1.86 (−2.54, −1.17) µm; mGCIPL: −2.03 (−2.78, −1.28) µm (both p < 0.0001; effect sizes 0.39 and 0.34). Greater inner retinal layer atrophy was observed in individuals diagnosed with RRMS <3 years versus >5 years (pRNFL: p < 0.05; mGCIPL: p < 0.01). Brain volume decreased by 1.3% in individuals with MS over 3 years compared to 0.5% in control subjects (effect size 0.76). mGCIPL atrophy correlated with brain atrophy (p < 0.0001). There was no correlation of OCT data with disability progression. Interpretation: OCT has potential to estimate rates of neurodegeneration in the retina and brain. The effect size for OCT, smaller than for magnetic resonance imaging based on Heidelberg Spectralis data acquired in this study, was increased in early disease. [ABSTRACT FROM AUTHOR]

Objective: To assess the independent contributions of clinical measures (relapses, Expanded Disability Status Scale [EDSS] scores, and neuroperformance measures) and nonclinical measures (new brain magnetic resonance imaging [MRI] activity and serum neurofilament light chain [sNfL] levels) for distinguishing natalizumab‐treated from placebo‐treated patients. Methods: We conducted post hoc analyses using data from the AFFIRM trial of natalizumab for multiple sclerosis. We used multivariable regression analyses with predictors (EDSS progression, no relapse, new or enlarging MRI activity, brain atrophy, sNfL levels, and neuroperformance worsening) to identify measures that independently discriminated between treatment groups. Results: The multivariable model that best distinguished natalizumab from placebo was no new or enlarging T2 or gadolinium‐enhancing activity on MRI (odds ratio; 95% confidence interval: 7.2; 4.7–10.9), year 2 sNfL levels <97.5th percentile (4.1; 2.6–6.2), and no relapses in years 0–2 (2.1; 1.5–3.0). The next best‐fitting model was a two‐component model that included no MRI activity and sNfL levels <97.5th percentile at year 2. There was little difference between the three‐ and two‐component models. Interpretation: Nonclinical measures (new MRI activity and sNfL levels) discriminate between treatment and placebo groups similarly to or better than clinical outcomes composites and have implications for patient monitoring. [ABSTRACT FROM AUTHOR]

Artificial intelligence (AI)‐based diagnostic algorithms have achieved ambitious aims through automated image pattern recognition. For neurological disorders, this includes neurodegeneration and inflammation. Scalable imaging technology for big data in neurology is optical coherence tomography (OCT). We highlight that OCT changes observed in the retina, as a window to the brain, are small, requiring rigorous quality control pipelines. There are existing tools for this purpose. Firstly, there are human‐led validated consensus quality control criteria (OSCAR‐IB) for OCT. Secondly, these criteria are embedded into OCT reporting guidelines (APOSTEL). The use of the described annotation of failed OCT scans advances machine learning. This is illustrated through the present review of the advantages and disadvantages of AI‐based applications to OCT data. The neurological conditions reviewed here for the use of big data include Alzheimer disease, stroke, multiple sclerosis (MS), Parkinson disease, and epilepsy. It is noted that while big data is relevant for AI, ownership is complex. For this reason, we also reached out to involve representatives from patient organizations and the public domain in addition to clinical and research centers. The evidence reviewed can be grouped in a five‐point expansion of the OSCAR‐IB criteria to embrace AI (OSCAR‐AI). The review concludes by specific recommendations on how this can be achieved practically and in compliance with existing guidelines. [ABSTRACT FROM AUTHOR]

In multiple sclerosis (MS), a subset of chronic active white matter lesions are identifiable on magnetic resonance imaging by their paramagnetic rims, and increasing evidence supports their association with severity of clinical disease. We studied their potential role in differential diagnosis, screening an international multicenter clinical research‐based sample of 438 individuals affected by different neurological conditions (MS, other inflammatory, infectious, and non‐inflammatory conditions). Paramagnetic rim lesions, rare in other neurological conditions (52% of MS vs 7% of non‐MS cases), yielded high specificity (93%) in differentiating MS from non‐MS. Future prospective multicenter studies should validate their role as a diagnostic biomarker. ANN NEUROL 2020;88:1034–1042 [ABSTRACT FROM AUTHOR]

Purpose: To investigate diffusion‐time dependency of diffusional kurtosis in the mouse brain using pulsed‐gradient spin‐echo (PGSE) and oscillating‐gradient spin‐echo (OGSE) sequences. Methods: 3D PGSE and OGSE kurtosis tensor data were acquired from ex vivo brains of adult, cuprizone‐treated, and age‐matched control mice with diffusion‐time (tD) ~ 20 ms and frequency (f) = 70 Hz, respectively. Further, 2D acquisitions were performed at multiple times/frequencies ranging from f = 140 Hz to tD = 30 ms with b‐values up to 4000 s/mm2. Monte Carlo simulations were used to investigate the coupled effects of varying restriction size and permeability on time/frequency‐dependence of kurtosis with both diffusion‐encoding schemes. Simulations and experiments were further performed to investigate the effect of varying number of cycles in OGSE waveforms. Results: Kurtosis and diffusivity maps exhibited significant region‐specific changes with diffusion time/frequency across both gray and white matter areas. PGSE‐ and OGSE‐based kurtosis maps showed reversed contrast between gray matter regions in the cerebellar and cerebral cortex. Localized time/frequency‐dependent changes in kurtosis tensor metrics were found in the splenium of the corpus callosum in cuprizone‐treated mouse brains, corresponding to regional demyelination seen with histological assessment. Monte Carlo simulations showed that kurtosis estimates with pulsed‐ and oscillating‐gradient waveforms differ in their sensitivity to exchange. Both simulations and experiments showed dependence of kurtosis on number of cycles in OGSE waveforms for non‐zero permeability. Conclusion: The results show significant time/frequency‐dependency of diffusional kurtosis in the mouse brain, which can provide sensitivity to probe intrinsic cellular heterogeneity and pathological alterations in gray and white matter. [ABSTRACT FROM AUTHOR]

Objective: Therapeutic development in progressive multiple sclerosis (PMS) has been hampered by a lack of reliable biomarkers to monitor neurodegeneration. Optical coherence tomography (OCT)-derived retinal measures have been proposed as promising biomarkers to fulfill this role. However, it is unclear whether retinal atrophy persists in PMS, exceeds normal aging, or can be distinguished from relapsing-remitting multiple sclerosis (RRMS).Methods: 178 RRMS, 186 PMS, and 66 control participants were followed with serial OCT for a median follow-up of 3.7 years.Results: The estimated proportion of peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell + inner plexiform layer (GCIPL) thinning in multiple sclerosis (MS) attributable to normal aging increased from 42.7% and 16.7% respectively at age 25 years, to 83.7% and 81.1% at age 65 years. However, independent of age, PMS was associated with faster pRNFL (-0.34 ± 0.09%/yr, p < 0.001) and GCIPL (-0.27 ± 0.07%/yr, p < 0.001) thinning, as compared to RRMS. In both MS and controls, higher baseline age was associated with faster inner nuclear layer (INL) and outer nuclear layer (ONL) thinning. INL and ONL thinning were independently faster in PMS, as compared to controls (INL:-0.09 ± 0.04%/yr, p = 0.03; ONL:-0.12 ± 0.06%/yr, p = 0.04), and RRMS (INL:-0.10 ± 0.04%/yr, p = 0.01; ONL:-0.13 ± 0.05%/yr, p = 0.01), whereas they were similar in RRMS and controls. Unlike RRMS, disease-modifying therapies (DMTs) did not impact rates of retinal layer atrophy in PMS.Interpretation: PMS is associated with faster retinal atrophy independent of age. INL and ONL measures may be novel biomarkers of neurodegeneration in PMS that appear to be unaffected by conventional DMTs. The effects of aging on rates of retinal layer atrophy should be considered in clinical trials incorporating OCT outcomes. ANN NEUROL 2020;87:885-896. [ABSTRACT FROM AUTHOR]

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

Background: MRI is the imaging modality of choice for diagnosis and intervention assessment in neurological disease. Its full potential has not been realized due in part to challenges in harmonizing advanced techniques across multiple sites.Purpose: To develop a method for the assessment of reliability and repeatability of advanced multisite-multisession neuroimaging studies and specifically to assess the reliability of an advanced MRI protocol, including multiband fMRI and diffusion tensor MRI, in a multisite setting.Study Type: Prospective.Population: Twice repeated measurement of a single subject with stable relapsing-remitting multiple sclerosis (MS) at seven institutions.Field Strength/sequence: A 3 T MRI protocol included higher spatial resolution anatomical scans, a variable flip-angle longitudinal relaxation rate constant (R1 ≡ 1/T1 ) measurement, quantitative magnetization transfer imaging, diffusion tensor imaging, and a resting-state fMRI (rsFMRI) series.Assessment: Multiple methods of assessing intrasite repeatability and intersite reliability were evaluated for imaging metrics derived from each sequence.Statistical Tests: Student's t-test, Pearson's r, and intraclass correlation coefficient (ICC) (2,1) were employed to assess repeatability and reliability. Two new statistical metrics are introduced that frame reliability and repeatability in the respective units of the measurements themselves.Results: Intrasite repeatability was excellent for quantitative R1 , magnetization transfer ratio (MTR), and diffusion-weighted imaging (DWI) based metrics (r > 0.95). rsFMRI metrics were less repeatable (r = 0.8). Intersite reliability was excellent for R1 , MTR, and DWI (ICC >0.9), and moderate for rsFMRI metrics (ICC∼0.4).Data Conclusion: From most reliable to least, using a new reliability metric introduced here, MTR > R1 > DWI > rsFMRI; for repeatability, MTR > DWI > R1 > rsFMRI. A graphical method for at-a-glance assessment of reliability and repeatability, effect sizes, and outlier identification in multisite-multisession neuroimaging studies is introduced.Level Of Evidence: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:878-888. [ABSTRACT FROM AUTHOR]

Objective: To determine the optimal thresholds for intereye differences in retinal nerve fiber and ganglion cell + inner plexiform layer thicknesses for identifying unilateral optic nerve lesions in multiple sclerosis. Current international diagnostic criteria for multiple sclerosis do not include the optic nerve as a lesion site despite frequent involvement. Optical coherence tomography detects retinal thinning associated with optic nerve lesions.Methods: In this multicenter international study at 11 sites, optical coherence tomography was measured for patients and healthy controls as part of the International Multiple Sclerosis Visual System Consortium. High- and low-contrast acuity were also collected in a subset of participants. Presence of an optic nerve lesion for this study was defined as history of acute unilateral optic neuritis.Results: Among patients (n = 1,530), receiver operating characteristic curve analysis demonstrated an optimal peripapillary retinal nerve fiber layer intereye difference threshold of 5μm and ganglion cell + inner plexiform layer threshold of 4μm for identifying unilateral optic neuritis (n = 477). Greater intereye differences in acuities were associated with greater intereye retinal layer thickness differences (p ≤ 0.001).Interpretation: Intereye differences of 5μm for retinal nerve fiber layer and 4μm for macular ganglion cell + inner plexiform layer are robust thresholds for identifying unilateral optic nerve lesions. These thresholds may be useful in establishing the presence of asymptomatic and symptomatic optic nerve lesions in multiple sclerosis and could be useful in a new version of the diagnostic criteria. Our findings lend further validation for utilizing the visual system in a multiple sclerosis clinical trial setting. Ann Neurol 2019;85:618-629. [ABSTRACT FROM AUTHOR]

Objective: Vibratory sensation is a quantifiable measure of physical dysfunction and is often related to spinal cord pathology; however, its association with relevant brain areas has not been fully explored. Our objective was to establish a cortical structural substrate for vibration sensation. Methods: Eighty‐four individuals with multiple sclerosis (MS) (n = 54 relapsing, n = 30 progressive) and 28 controls participated in vibratory sensation threshold quantification at the great toe and a 3T MRI evaluating volume of the thalamus and cortical thickness primary and secondary sensory cortices. Results: After controlling for age, sex, and disability level, vibratory sensation thresholds were significantly related to cortical thickness of the anterior cingulate (P = 0.041), parietal operculum (P = 0.022), and inferior frontal gyrus pars operculum (P = 0.044), pars orbitalis (P = 0.007), and pars triangularis (P = 0.029). Within the progressive disease subtype, there were significant relationships between vibratory sensation and thalamic volume (P = 0.039) as well as reduced inferior frontal gyrus pars operculum (P = 0.014) and pars orbitalis (P = 0.005) cortical thickness. Conclusions: The data show significant independent relationships between quantitative vibratory sensation and measures of primary and secondary sensory cortices. Quantitative clinical measurement of vibratory sensation reflects pathological changes in spatially distinct brain areas and may supplement information captured by brain atrophy measures. Without overt relapses, monitoring decline in progressive forms of MS has proved challenging; quantitative clinical assessment may provide a tool to examine pathological decline in this cohort. These data suggest that quantitative clinical assessment may be a reliable way to examine pathological decline and have broader relevance to progressive forms of MS. [ABSTRACT FROM AUTHOR]

Objective: Optical coherence tomography (OCT)‐derived measures of the retina correlate with disability and cortical gray matter atrophy in multiple sclerosis (MS); however, whether such measures predict long‐term disability is unknown. We evaluated whether a single OCT and visual function assessment predict the disability status 10 years later. Methods: Between 2006 and 2008, 172 people with MS underwent Stratus time domain‐OCT imaging [160 with measurement of total macular volume (TMV)] and high and low‐contrast letter acuity (LCLA) testing (n = 150; 87%). All participants had Expanded Disability Status Scale (EDSS) assessments at baseline and at 10‐year follow‐up. We applied generalized linear regression models to assess associations between baseline TMV, peripapillary retinal nerve fiber layer (pRNFL) thickness, and LCLA with 10‐year EDSS scores (linear) and with clinically significant EDSS worsening (binary), adjusting for age, sex, optic neuritis history, and baseline disability status. Results: In multivariable models, lower baseline TMV was associated with higher 10‐year EDSS scores (mean increase in EDSS of 0.75 per 1 mm3 loss in TMV (mean difference = 0.75; 95% CI: 0.11–1.39; P = 0.02). In analyses using tertiles, individuals in the lowest tertile of baseline TMV had an average 0.86 higher EDSS scores at 10 years (mean difference = 0.86; 95% CI: 0.23–1.48) and had over 3.5‐fold increased odds of clinically significant EDSS worsening relative to those in the highest tertile of baseline TMV (OR: 3.58; 95% CI: 1.30–9.82; Ptrend = 0.008). pRNFL and LCLA predicted the 10‐year EDSS scores only in univariate models. Interpretation: Lower baseline TMV measured by OCT significantly predicts higher disability at 10 years, even after accounting for baseline disability status. [ABSTRACT FROM AUTHOR]

Objective: Identify metabolic changes produced by dimethyl fumarate (DMF) treatment and link them to immunological effects. Methods: We enrolled 18 MS patients and obtained blood prior to DMF and 6 months postinitiation. We also enrolled 18 healthy controls for comparison. We performed global metabolomics on plasma and used weighted correlation network analysis (WGCNA) to identify modules of correlated metabolites. We identified modules that changed with treatment, followed by targeted metabolomics to corroborate changes identified in global analyses. We correlated changes in metabolite modules and individual metabolites with changes in immunological parameters. Results: We identified alterations in lipid metabolism after DMF treatment – increases in two modules (phospholipids, lysophospholipids and plasmalogens) and reduction in one module (saturated and poly‐unsaturated fatty acids) eigen‐metabolite values (all P < 0.05). Change in the fatty acid module was greater in participants who developed lymphopenia and was strongly associated with both reduction in absolute lymphocyte counts (r = 0.65; P = 0.005) and change in CD8+ T cell subsets. We also noted significant correlation of change in lymphocyte counts with multiple fatty acid levels (measured by targeted or untargeted methods). Interpretation: This study demonstrates that DMF treatment alters lipid metabolism and that changes in fatty acid levels are related to DMF‐induced immunological changes. [ABSTRACT FROM AUTHOR]

Objective: Autoantibodies are clinically useful for phenotyping patients across the spectrum of autoimmune rheumatic diseases. Using serum from a patient with Sjögren's syndrome (SS), we detected a new specificity by immunoblotting. This study was undertaken to identify this autoantibody and to evaluate its disease specificity. Methods: A prominent 40‐kd band was detected when immunoblotting was performed using SS patient serum and lysate from rat dorsal root ganglia (DRGs). Using 2‐dimensional gel electrophoresis and liquid chromatography tandem mass spectrometry peptide sequencing, the autoantigen was identified as calponin 3. Anti–calponin 3 antibodies were evaluated in sera from patients with primary SS (n = 209), patients with systemic lupus erythematosus (SLE; n = 138), patients with myositis (n = 138), patients with multiple sclerosis (MS; n = 44), and healthy controls (n = 46) by enzyme‐linked immunosorbent assay. Expression of calponin 3 was assessed by immunohistochemistry. Results: Calponin 3 was identified as a new autoantigen. Anti–calponin 3 antibodies were detected in 23 (11.0%) of the 209 SS patients, 12 (8.7%) of the 138 SLE patients, 7 (5.1%) of the 138 myositis patients, 3 (6.8%) of the 44 MS patients, and 1 (2.2%) of the 46 healthy controls. Among SS patients, the frequency of anti–calponin 3 antibodies was highest in those with neuropathies (7 [17.9%] of 39). In this subset, the frequency of anti–calponin 3 antibodies differed significantly from that in the control group (P = 0.02). Calponin 3 was expressed primarily in rat DRG perineuronal satellite cells but not neurons. Conclusion: Calponin 3 is a novel autoantigen. Antibodies against this protein are found in SS and associate with the subset of patients experiencing neuropathies. Intriguingly, we found that calponin 3 is expressed in DRG perineuronal satellite cells, suggesting that these may be a target in SS. [ABSTRACT FROM AUTHOR]

Background and Purpose: Magnetic resonance imaging (MRI) is crucial for in vivo detection and characterization of white matter lesions (WMLs) in multiple sclerosis. While WMLs have been studied for over two decades using MRI, automated segmentation remains challenging. Although the majority of statistical techniques for the automated segmentation of WMLs are based on single imaging modalities, recent advances have used multimodal techniques for identifying WMLs. Complementary modalities emphasize different tissue properties, which help identify interrelated features of lesions.Methods: Method for Inter-Modal Segmentation Analysis (MIMoSA), a fully automatic lesion segmentation algorithm that utilizes novel covariance features from intermodal coupling regression in addition to mean structure to model the probability lesion is contained in each voxel, is proposed. MIMoSA was validated by comparison with both expert manual and other automated segmentation methods in two datasets. The first included 98 subjects imaged at Johns Hopkins Hospital in which bootstrap cross-validation was used to compare the performance of MIMoSA against OASIS and LesionTOADS, two popular automatic segmentation approaches. For a secondary validation, a publicly available data from a segmentation challenge were used for performance benchmarking.Results: In the Johns Hopkins study, MIMoSA yielded average Sørensen-Dice coefficient (DSC) of .57 and partial AUC of .68 calculated with false positive rates up to 1%. This was superior to performance using OASIS and LesionTOADS. The proposed method also performed competitively in the segmentation challenge dataset.Conclusion: MIMoSA resulted in statistically significant improvements in lesion segmentation performance compared with LesionTOADS and OASIS, and performed competitively in an additional validation study. [ABSTRACT FROM AUTHOR]

Purpose: To explore (i) the variability of upper cervical cord area (UCCA) measurements from volumetric brain 3D T1‐weighted scans related to gradient nonlinearity (GNL) and subject positioning; (ii) the effect of vendor‐implemented GNL corrections; and (iii) easily applicable methods that can be used to retrospectively correct data. Methods: A multiple sclerosis patient was scanned at seven sites using 3T MRI scanners with the same 3D T1‐weighted protocol without GNL‐distortion correction. Two healthy subjects and a phantom were additionally scanned at a single site with varying table positions. The 2D and 3D vendor‐implemented GNL‐correction algorithms and retrospective methods based on (i) phantom data fit, (ii) normalization with C2 vertebral body diameters, and (iii) the Jacobian determinant of nonlinear registrations to a template were tested. Results: Depending on the positioning of the subject, GNL introduced up to 15% variability in UCCA measurements from volumetric brain T1‐weighted scans when no distortion corrections were used. The 3D vendor‐implemented correction methods and the three proposed methods reduced this variability to less than 3%. Conclusions: Our results raise awareness of the significant impact that GNL can have on quantitative UCCA studies, and point the way to prospectively and retrospectively managing GNL distortions in a variety of settings, including clinical environments. Magn Reson Med 79:1595–1601, 2018. © 2017 International Society for Magnetic Resonance in Medicine. [ABSTRACT FROM AUTHOR]

In our study however, we were able to detect differences with meaningful effect sizes at the group level (including faster rates in progressive MS vs controls) and we reported sample size calculations (accounting for the variance of rates in INL change) for clinical trials incorporating INL thickness as an outcome with feasible sample size estimates. We would like to thank Nij Bijvank et al for their comments on our longitudinal study, in which we found that progressive retinal inner nuclear layer (INL) thinning could be detected by optical coherence tomography (OCT) in 66 healthy controls (HC) and 364 people with multiple sclerosis (MS).1 We also found that higher baseline age was associated with faster rates of INL thinning (in both MS and HC), and that age-adjusted rates of INL thinning were 38% faster in progressive MS compared to HC. This may potentially account for some of the differences in the results obtained, given that our larger sample size and more frequent OCT monitoring would be expected to allow for estimation of rates of INL thinning with greater precision. [Extracted from the article]

We evaluated the effect of dimethyl fumarate ( DMF) treatment on B-cell memory and cytokine production in 18 patients with relapsing remitting multiple sclerosis ( RRMS) using peripheral blood mononuclear cells obtained prior to and at 6 months post- DMF initiation. We noted a decline in the absolute B-cell number with DMF treatment, with a preferential depletion of memory B cells and a concurrent increase in naïve B cells. We noted significant reductions in GM- CSF, TNF- α, and IL-6 producing B cells with DMF treatment. These effects on the B-cell compartment may underlie the beneficial effects of DMF in RRMS. [ABSTRACT FROM AUTHOR]

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

Objective: The aim of this work was to determine whether atrophy of specific retinal layers and brain substructures are associated over time, in order to further validate the utility of optical coherence tomography (OCT) as an indicator of neuronal tissue damage in patients with multiple sclerosis (MS).Methods: Cirrus high-definition OCT (including automated macular segmentation) was performed in 107 MS patients biannually (median follow-up: 46 months). Three-Tesla magnetic resonance imaging brain scans (including brain-substructure volumetrics) were performed annually. Individual-specific rates of change in retinal and brain measures (estimated with linear regression) were correlated, adjusting for age, sex, disease duration, and optic neuritis (ON) history.Results: Rates of ganglion cell + inner plexiform layer (GCIP) and whole-brain (r = 0.45; p < 0.001), gray matter (GM; r = 0.37; p < 0.001), white matter (WM; r = 0.28; p = 0.007), and thalamic (r = 0.38; p < 0.001) atrophy were associated. GCIP and whole-brain (as well as GM and WM) atrophy rates were more strongly associated in progressive MS (r = 0.67; p < 0.001) than relapsing-remitting MS (RRMS; r = 0.33; p = 0.007). However, correlation between rates of GCIP and whole-brain (and additionally GM and WM) atrophy in RRMS increased incrementally with step-wise refinement to exclude ON effects; excluding eyes and then patients (to account for a phenotype effect), the correlation increased to 0.45 and 0.60, respectively, consistent with effect modification. In RRMS, lesion accumulation rate was associated with GCIP (r = -0.30; p = 0.02) and inner nuclear layer (r = -0.25; p = 0.04) atrophy rates.Interpretation: Over time GCIP atrophy appears to mirror whole-brain, and particularly GM, atrophy, especially in progressive MS, thereby reflecting underlying disease progression. Our findings support OCT for clinical monitoring and as an outcome in investigative trials. [ABSTRACT FROM AUTHOR]

Objective To determine whether African American (AA) multiple sclerosis (MS) patients exhibit more retinal damage and visual impairment compared to Caucasian American (CA) MS patients. Methods A total of 687 MS patients (81 AAs) and 110 healthy control (HC) subjects (14 AAs) were recruited at 3 academic hospitals between 2008 and 2012. Using mixed effects regression models, we compared high- and low-contrast visual acuity (HCVA and LCVA) and high-definition spectral domain optical coherence tomography measures of retinal architecture between MS patients of self-identified AA and CA ancestry. Results In HCs, baseline peripapillary retinal nerve fiber layer (RNFL) thickness was 6.1µm greater in AAs ( p = 0.047), whereas ganglion cell/inner plexiform layer (GCIP) thickness did not differ by race. In MS patients, baseline RNFL did not differ by race, and GCIP was 3.98µm thinner in AAs ( p = 0.004). AAs had faster RNFL and GCIP thinning rates compared to CAs ( p = 0.004 and p = 0.046, respectively). AA MS patients had lower baseline HCVA ( p = 0.02) and worse LCVA per year of disease duration ( p = 0.039). Among patients with an acute optic neuritis (AON) history, AAs had greater loss of HCVA than CA patients ( p = 0.012). Interpretation This multicenter investigation provides objective evidence that AA MS patients exhibit accelerated retinal damage compared to CA MS patients. Self-identified AA ancestry is associated with worse MS-related visual disability, particularly in the context of an AON history, suggesting a more aggressive inflammatory disease course among AA MS patients or a subpopulation therein. Ann Neurol 2015;77:228-236 [ABSTRACT FROM AUTHOR]

BACKGROUND: Spinal cord (SC) pathology is common in multiple sclerosis (MS), and measures of SC-atrophy are increasingly utilized. Normalization reduces biological variation of structural measurements unrelated to disease, but optimal parameters for SC volume (SCV)- normalization remain unclear. Using a variety of normalization factors and clinical measures, we assessed the effect of SCV normalization on detecting group differences and clarifying clinical-radiological correlations in MS. METHODS: 3T cervical SC-MRI was performed in 133 MS cases and 11 healthy controls (HC). Clinical assessment included expanded disability status scale (EDSS), MS functional composite (MSFC), quantitative hip-flexion strength ("strength"), and vibration sensation threshold ("vibration"). SCV between C3 and C4 was measured and normalized individually by subject height, SC-length, and intracranial volume (ICV). RESULTS: There were group differences in raw-SCV and after normalization by height and length (MS vs. HC; progressive vs. relapsing MS-subtypes, P < .05). There were correlations between clinical measures and raw-SCV (EDSS:r = -.20; MSFC:r = .16; strength:r = .35; vibration: r = -.19). Correlations consistently strengthened with normalization by length (EDSS: r = -.43; MSFC:r = .33; strength:r = .38; vibration:r = -.40), and height (EDSS:r = -.26; MSFC:r = .28; strength:r = .22; vibration:r = -.29), but diminished with normalization by ICV (EDSS:r = -.23; MSFC:r = -.10; strength:r = .23; vibration:r = -.35). In relapsing MS, normalization by length allowed statistical detection of correlations that were not apparent with raw-SCV. CONCLUSIONS: SCV-normalization by length improves the ability to detect group differences, strengthens clinical-radiological correlations, and is particularly relevant in settings of subtle diseaserelated SC-atrophy in MS. SCV-normalization by length may enhance the clinical utility of measures of SC-atrophy. [ABSTRACT FROM AUTHOR]

ABSTRACT This study was undertaken to quantify retinal and intra-retinal layer thicknesses in Parkinson's disease (PD), and to evaluate whether retinal structural changes may be related to altered discrimination of color vision and to severity and duration of PD disease. We examined 97 PD patients and 32 healthy controls (HC) with spectral-domain optical coherence tomography (OCT), including intra-retinal layer segmentation. In total, we compared 111 retinal nerve fiber layer (RNFL)-scans and 114 macula scans from 68 PD patients with 62 RNFL and 63 macula scans from 32 HC. For clinical evaluation of disease severity, we used the Unified Parkinson's Disease Rating Scale (UPDRS) motor examination. To determine color discrimination, we performed the Farnsworth Munsell 100 Hue Test (FMT) in a subgroup of PD patients. We found significant combined outer nuclear and photoreceptor layer thinning in PD versus HC (118.6 vs. 123.5 µm, P = 0.001). Differences in RNFL, total macular volume, or the other retinal layer thicknesses were not detected. The OCT measures were not associated with disease severity, duration, or color vision. By showing photoreceptor cell layer thinning, our findings support previous in vivo and autopsy studies demonstrating retinal alterations in PD. Optical coherence tomography may help to assess morphological retinal changes in PD patients; however, the utility of OCT in routine clinical practice may be limited because many PD patients have difficulties complying with OCT investigation because of disease-related symptoms such as tremor, axial rigidity, or cognitive impairment. © 2014 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Cortical atrophy has been reported in a number of diseases, such as multiple sclerosis and Alzheimer's disease, that are also associated with white matter (WM) lesions. However, most cortical reconstruction techniques do not account for these pathologies, thereby requiring additional processing to correct for the effect of WM lesions. In this work, we introduce CRUISE+, an automated process for cortical reconstruction from magnetic resonance brain images with WM lesions. The process extends previously well validated methods to allow for multichannel input images and to accommodate for the presence of WM lesions. We provide new validation data and tools for measuring the accuracy of cortical reconstruction methods on healthy brains as well as brains with multiple sclerosis lesions. Using this data, we validate the accuracy of CRUISE+ and compare it to another state-of-the-art cortical reconstruction tool. Our results demonstrate that CRUISE+ has superior performance in the cortical regions near WM lesions, and similar performance in other regions. Hum Brain Mapp 35:3385-3401, 2014. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

We would like to thank Cordano et al for their comments on our recently published article.1 Among other findings, in our longitudinal study, we found that progressive retinal inner nuclear layer (INL) thinning occurred in both healthy controls (HCs) and people with multiple sclerosis (MS), and that higher baseline age was associated with faster rates of INL thinning in both groups. In our cohort, we did not find evidence for a nonlinear relationship, however, our cohort had a higher baseline age and disease duration, a large number of participants with progressive MS, and the vast majority of the relapsing-remitting MS participants were on a disease-modifying therapy (DMT) at baseline (94.4%), whereas the DMT characteristics of the cohort reported by Cordano et al are unclear. Ocular pathology in multiple sclerosis: retinal atrophy and inflammation irrespective of disease duration. [Extracted from the article]

Diffusion tensor imaging has been widely used in studying rodent models of white matter diseases. In this study, we examined the differences between in vivo and ex vivo fractional anisotropy and diffusivity measurements in the mouse cuprizone model. In the control mouse corpus callosum, ex vivo diffusivities were significantly lower than in vivo measurements, but ex vivo fractional anisotropy values were not significantly different from in vivo fractional anisotropy values. With cuprizone induced demyelination and accompanying pathology in the corpus callosum, changes in in vivo and ex vivo fractional anisotropy and diffusivity measurements were not always in agreement. Our results suggest that ex vivo λ⟂ was a more reliable indicator of white matter demyelination than in vivo λ⟂ and in vivo λ| was a more reliable indicator of axonal injury than ex vivo λ| in this model. When comparing in vivo and ex vivo diffusion tensor imaging results of axon and myelin pathology in the rodent models, potential changes in tissue microstructures associated with perfusion fixation should be considered. Magn Reson Med, 2012. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Several disease-modifying drugs (DMDs) are currently approved for the treatment of multiple sclerosis (MS). Recently, there has been increased identification and development of potential new treatments that may modulate the MS disease process, including oral therapies. Many of the newly approved MS therapies, as well as those in ongoing clinical trials, have the advantage of improved efficacy and/or being oral and more convenient, as compared to conventional injectable first-line MS therapies. However, many of these new and emerging MS treatments are known to be associated with serious adverse events, some of which may be potentially life threatening. Of additional concern, there is limited experience and long-term safety data for many of these drugs, and thus the true potential for complications associated with these agents remains ambiguous. With an anticipated explosion in the artillery of available MS therapies in the near future, neurologists will need to carefully weigh drug efficacy, convenience, safety, and tolerability when making therapeutic decisions. In this review, we describe the known mechanisms of action, efficacy, and side-effect profiles of new and emerging MS DMDs. [ABSTRACT FROM AUTHOR]

High resolution diffusion tensor images of the mouse brain were acquired using the pulsed gradient spin echo sequence and the oscillating gradient spin echo sequence. The oscillating gradient spin echo tensor images demonstrated frequency-dependent changes in diffusion measurements, including apparent diffusion coefficient and fractional anisotropy, in major brain structures. Maps of the rate of change in apparent diffusion coefficient with oscillating gradient frequency revealed novel tissue contrast in the mouse hippocampus, cerebellum, and cerebral cortex. The observed frequency-dependent contrasts resembled neuronal soma-specific Nissl staining and nuclei-specific 4′,6-diamidino-2-phenylindole (DAPI) staining in the mouse brain, which suggests that the contrasts might be related to key features of cytoarchitecture in the brain. In the mouse cuprizone model, oscillating gradient spin echo-based diffusion MRI revealed significantly higher frequency-dependence of perpendicular diffusivity (λ⊥) in the demyelinated caudal corpus callosum at 4 weeks after cuprizone treatment when compared with control mice and mice at 6 weeks after cuprizone treatment. The elevated frequency-dependence of λ⊥ coincided with the infiltration of activated microglia/macrophages and disruption of axons during acute demyelination in the caudal corpus callosum. The results demonstrate the potential of oscillating gradient spin echo-based diffusion MRI for providing tissue contrasts complimentary to conventional pulsed gradient spin echo-based diffusion MRI. Magn Reson Med 67:98-109, 2012. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

BACKGROUND AND PURPOSE: Visual disability is common in multiple sclerosis, but its relationship to abnormalities of the optic tracts remains unknown. Because they are only rarely affected by lesions, the optic tracts may represent a good model for assessing the imaging properties of normal-appearing white matter in multiple sclerosis. METHODS: Whole-brain diffusion tensor imaging was performed on 34 individuals with multiple sclerosis and 26 healthy volunteers. The optic tracts were reconstructed by tractography, and tract-specific diffusion indices were quantified. In the multiple-sclerosis group, peripapillary retinal nerve-fiber-layer thickness and total macular volume were measured by optical coherence tomography, and visual acuity at 100%, 2.5%, and 1.25% contrast was examined. RESULTS: After adjusting for age and sex, optic-tract mean and perpendicular diffusivity were higher (P = .002) in multiple sclerosis. Lower optic-tract fractional anisotropy was correlated with retinal nerve-fiber-layer thinning (r = .51, P = .003) and total-macularvolume reduction (r = .59, P = .002). However, optic-tract diffusion indices were not specifically correlated with visual acuity or with their counterparts in the optic radiation. CONCLUSIONS: Optic-tract diffusion abnormalities are associated with retinal damage, suggesting that both may be related to optic-nerve injury, but do not appear to contribute strongly to visual disability in multiple sclerosis. [ABSTRACT FROM AUTHOR]

Parallel and perpendicular diffusion properties of water in the rat spinal cord were investigated 3 and 30 days after dorsal root axotomy, a specific insult resulting in early axonal degeneration followed by later myelin damage in the dorsal column white matter. Results from q-space analysis (i.e., the diffusion probability density function) obtained with strong diffusion weighting were compared to conventional anisotropy and diffusivity measurements at low b-values, as well as to histology for axon and myelin damage. q-Space contrasts included the height (return to zero displacement probability), full width at half maximum, root mean square displacement, and kurtosis excess of the probability density function, which quantifies the deviation from gaussian diffusion. Following axotomy, a significant increase in perpendicular diffusion (with decreased kurtosis excess) and decrease in parallel diffusion (with increased kurtosis excess) were found in lesions relative to uninjured white matter. Notably, a significant change in abnormal parallel diffusion was detected from 3 to 30 days with full width at half maximum, but not with conventional diffusivity. Also, directional full width at half maximum and root mean square displacement measurements exhibited different sensitivities to white matter damage. When compared to histology, the increase in perpendicular diffusion was not specific to demyelination, whereas combined reduced parallel diffusion and increased perpendicular diffusion was associated with axon damage. Magn Reson Med 63:1323-1335, 2010. © 2010 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Objective To study antibody-independent contributions of B cells to inflammatory disease activity, and the immune consequences of B-cell depletion with rituximab, in patients with multiple sclerosis (MS). Methods B-Cell effector-cytokine responses were compared between MS patients and matched controls using a 3-signal model of activation. The effects of B-cell depletion on Th1/Th17 CD4 and CD8 T-cell responses in MS patients were assessed both ex vivo and in vivo, together with pharmacokinetic/pharmacodynamic studies as part of 2 rituximab clinical trials in relapsing-remitting MS. Results B Cells of MS patients exhibited aberrant proinflammatory cytokine responses, including increased lymphotoxin (LT):interleukin-10 ratios and exaggerated LT and tumor necrosis factor (TNF)-α secretion, when activated in the context of the pathogen-associated TLR9-ligand CpG-DNA, or the Th1 cytokine interferon-γ, respectively. B-Cell depletion, both ex vivo and in vivo, resulted in significantly diminished proinflammatory (Th1 and Th17) responses of both CD4 and CD8 T cells. Soluble products from activated B cells of untreated MS patients reconstituted the diminished T-cell responses observed following in vivo B-cell depletion in the same patients, and this effect appeared to be largely mediated by B-cell LT and TNFα. Interpretation We propose that episodic triggering of abnormal B-cell cytokine responses mediates 'bystander activation' of disease-relevant proinflammatory T cells, resulting in new relapsing MS disease activity. Our findings point to a plausible mechanism for the long-recognized association between infections and new MS relapses, and provide novel insights into B-cell roles in both health and disease, and into mechanisms contributing to therapeutic effects of B-cell depletion in human autoimmune diseases, including MS. ANN NEUROL 2010;67:452-461 [ABSTRACT FROM AUTHOR]

Which aspects of tissue microstructure affect diffusion weighted MRI signals? Prior models, many of which use Monte-Carlo simulations, have focused on relatively simple models of the cellular microenvironment and have not considered important anatomic details. With the advent of higher-order analysis models for diffusion imaging, such as high angular resolution diffusion imaging (HARDI), more realistic models are necessary. This paper presents and evaluates the reproducibility of simulations of diffusion in complex geometries. Our framework is quantitative, does not require specialized hardware, is easily implemented with little programming experience, and is freely available as open-source software. Models may include compartments with different diffusivities, permeabilities, and T2 time constants using both parametric (e.g. spheres and cylinders) and arbitrary (e.g. mesh-based) geometries. Three-dimensional diffusion displacement probability functions are mapped with high reproducibility, and thus can be readily used to assess reproducibility of diffusion-derived contrasts. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Damage to specific white matter tracts within the spinal cord can often result in the particular neurological syndromes that characterize myelopathies such as traumatic spinal cord injury. Noninvasive visualization of these tracts with imaging techniques that are sensitive to microstructural integrity is an important clinical goal. Diffusion tensor imaging (DTI)- and magnetization transfer (MT)-derived quantities have shown promise in assessing tissue health in the central nervous system. In this paper, we demonstrate that DTI of the cervical spinal cord can reliably discriminate sensory (dorsal) and motor (lateral) columns. From data derived from nine healthy volunteers, two raters quantified column-specific parallel ( λ||) and perpendicular ( λ⟂) diffusivity, fractional anisotropy (FA), mean diffusivity (MD), and MT-weighted signal intensity relative to cerebrospinal fluid (MTCSF) over two time-points separated by more than 1 week. Cross-sectional means and standard deviations of these measures in the lateral and dorsal columns were as follows: λ||: 2.13 ± 0.14 and 2.14 ± 0.11 μm2/ms; λ⟂: 0.67 ± 0.16 and 0.61 ± 0.09 μm2/ms; MD: 1.15 ± 0.15 and 1.12 ± 0.08 μm2/ms; FA: 0.68 ± 0.06 and 0.68 ± 0.05; MTCSF: 0.52 ± 0.05 and 0.50 ± 0.05. We examined the variability and interrater and test-retest reliability for each metric. These column-specific MR measurements are expected to enhance understanding of the intimate structure-function relationship in the cervical spinal cord and may be useful for the assessment of disease progression. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objective Rituximab, a monoclonal antibody selectively depleting CD20+ B cells, has demonstrated efficacy in reducing disease activity in relapsing-remitting multiple sclerosis (MS). We evaluated rituximab in adults with primary progressive MS (PPMS) through 96 weeks and safety through 122 weeks. Methods Using 2:1 randomization, 439 PPMS patients received two 1,000mg intravenous rituximab or placebo infusions every 24 weeks, through 96 weeks (4 courses). The primary endpoint was time to confirmed disease progression (CDP), a prespecified increase in Expanded Disability Status Scale sustained for 12 weeks. Secondary endpoints were change from baseline to week 96 in T2 lesion volume and total brain volume on magnetic resonance imaging scans. Results Differences in time to CDP between rituximab and placebo did not reach significance (96-week rates: 38.5% placebo, 30.2% rituximab; p = 0.14). From baseline to week 96, rituximab patients had less ( p < 0.001) increase in T2 lesion volume; brain volume change was similar ( p = 0.62) to placebo. Subgroup analysis showed time to CDP was delayed in rituximab-treated patients aged <51 years (hazard ratio [HR] = 0.52; p = 0.010), those with gadolinium-enhancing lesions (HR = 0.41; p = 0.007), and those aged <51 years with gadolinium-enhancing lesions (HR = 0.33; p = 0.009) compared with placebo. Adverse events were comparable between groups; 16.1% of rituximab and 13.6% of placebo patients reported serious events. Serious infections occurred in 4.5% of rituximab and <1.0% of placebo patients. Infusion-related events, predominantly mild to moderate, were more common with rituximab during the first course, and decreased to rates comparable to placebo on successive courses. Interpretation Although time to CDP between groups was not significant, overall subgroup analyses suggest selective B-cell depletion may affect disease progression in younger patients, particularly those with inflammatory lesions. Ann Neurol 2009;66:460-471 [ABSTRACT FROM AUTHOR]

Q-space analysis is an alternative analysis technique for diffusion-weighted imaging (DWI) data in which the probability density function (PDF) for molecular diffusion is estimated without the need to assume a Gaussian shape. Although used in the human brain, q-space DWI has not yet been applied to study the human spinal cord in vivo. Here we demonstrate the feasibility of performing q-space imaging in the cervical spinal cord of eight healthy volunteers and four patients with multiple sclerosis. The PDF was computed and water displacement and zero-displacement probability maps were calculated from the width and height of the PDF, respectively. In the dorsal column white matter, q-space contrasts showed a significant ( P < 0.01) increase in the width and a decrease in the height of the PDF in lesions, the result of increased diffusion. These q-space contrasts, which are sensitive to the slow diffusion component, exhibited improved detection of abnormal diffusion compared to perpendicular apparent diffusion constant measurements. The conspicuity of lesions compared favorably with magnetization transfer (MT)-weighted images and quantitative CSF-normalized MT measurements. Thus, q-space DWI can be used to study water diffusion in the human spinal cord in vivo and is well suited to assess white matter damage. Magn Reson Med 59:1079-1089, 2008. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

We evaluated the safety, tolerability, pharmacodynamics, and activity of B-cell depletion with rituximab in patients with relapsing-remitting multiple sclerosis, receiving two courses of rituximab 6 months apart, and followed for a total of 72 weeks. No serious adverse events were noted; events were limited to mild-to-moderate infusion-associated events, which tended to decrease with subsequent infusions. Infections were also mild or moderate, and none led to withdrawal. Fewer new gadolinium-enhancing or T2 lesions were seen starting from week 4 and through week 72. An apparent reduction in relapses was also observed over the 72 weeks compared with the year before therapy. Ann Neurol 2008 [ABSTRACT FROM AUTHOR]

Objective To report the relationship between disease activity and health-related quality of life (HRQoL) in relapsing multiple sclerosis, and the impact of natalizumab. Methods HRQoL data were available from 2,113 multiple sclerosis patients in natalizumab clinical studies. In the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) study, patients received natalizumab 300mg (n = 627) or placebo (n = 315); in the Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis (SENTINEL) study, patients received interferon beta-1a (IFN-β-1a) plus natalizumab 300mg (n = 589), or IFN-β-1a plus placebo (n = 582). The Short Form-36 (SF-36) and a subject global assessment visual analog scale were administered at baseline and weeks 24, 52, and 104. Prespecified analyses included changes from baseline to week 104 in SF-36 and visual analog scale scores. Odds ratios for clinically meaningful improvement or worsening on the SF-36 Physical Component Summary (PCS) and Mental Component Summary were calculated. Results Mean baseline SF-36 scores were significantly less than the general US population and correlated with Expanded Disability Status Scale scores, sustained disability progression, relapse number, and increased volume of brain magnetic resonance imaging lesions. Natalizumab significantly improved SF-36 PCS and Mental Component Summary scores at week 104 in AFFIRM. PCS changes were significantly improved by week 24 and at all subsequent time points. Natalizumab-treated patients in both studies were more likely to experience clinically important improvement and less likely to experience clinically important deterioration on the SF-36 PCS. The visual analog scale also showed significantly improved HRQoL with natalizumab. Interpretation HRQoL was impaired in relapsing multiple sclerosis patients, correlated with severity of disease as measured by neurological ratings or magnetic resonance imaging, and improved significantly with natalizumab. Ann Neurol 2007 [ABSTRACT FROM AUTHOR]

Pulsed magnetization transfer (MT) imaging has been applied to quantitatively assess brain pathology in several diseases, especially multiple sclerosis (MS). To date, however, because of the high power deposition associated with the use of short, rapidly repeating MT prepulses, clinical application has been limited to lower field strengths. The contrast-to-noise ratio (CNR) of MT is limited, and this method would greatly benefit from the use of higher magnetic fields and phased-array coil reception. However, power deposition is proportional to the square of the magnetic field and scales with coil size, and MT experiments are already close to the SAR limit at 1.5T even when smaller transmit coils are used instead of the body coil. Here we show that these seemingly great obstacles can be ameliorated by the increased T1 of tissue water at higher field, which allows for longer maintenance of sufficiently high saturation levels while using a reduced duty cycle. This enables a fast (5-6 min) high-resolution (1.5 mm isotropic) whole-brain MT acquisition with excellent anatomical visualization of gray matter (GM) and white matter (WM) structures, and even substructures. The method is demonstrated in nine normal volunteers and five patients with relapsing remitting MS (RRMS), and the results show a clear delineation of heterogeneous lesions. Magn Reson Med, 2006. © 2006 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]