Optical coherence tomography versus other biomarkers: Associations with physical and cognitive disability in multiple sclerosis.

BACKGROUND: Optical coherence tomography (OCT) is a biomarker of neuroaxonal loss in multiple sclerosis (MS). OBJECTIVE: The objective was to assess the relative role of OCT, next to magnetic resonance imaging (MRI) and serum markers of disability in MS. METHODS: A total of 100 patients and 52 controls underwent OCT to determine peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell-inner plexiform layers (GCIPL). Serum neurofilament light chain (sNfL), total lesion volume (TLV), and brain parenchymal fraction (BPF) were also assessed. The associations of OCT with disability were examined in linear regression models with correction for age, vision, and education. RESULTS: In patients, pRNFL was associated with the Symbol Digit Modalities Test (SDMT; p = 0.030). In the multivariate analysis including sNfL and MRI measures, pRNFL (ß = 0.19, p = 0.044) and TLV (ß = -0.24, p = 0.023) were the only markers associated with the SDMT. pRNFL (p < 0.001) and GCIPL (p < 0.001) showed associations with the Expanded Disability Status Scale (EDSS). In the multivariate analysis, GCIPL showed the strongest association with the EDSS (ß = -0.32, p < 0.001) followed by sNfL (ß = 0.18, p = 0.024). CONCLUSION: The associations of OCT measures with cognitive and physical disability were independent of serum and brain MRI markers of neuroaxonal loss. OCT can be an important tool for stratification in MS, while longitudinal studies using combinations of biomarkers are warranted.

Wearable Sensor Technologies to Assess Motor Functions in People With Multiple Sclerosis: Systematic Scoping Review and Perspective.

BACKGROUND: Wearable sensor technologies have the potential to improve monitoring in people with multiple sclerosis (MS) and inform timely disease management decisions. Evidence of the utility of wearable sensor technologies in people with MS is accumulating but is generally limited to specific subgroups of patients, clinical or laboratory settings, and functional domains. OBJECTIVE: This review aims to provide a comprehensive overview of all studies that have used wearable sensors to assess, monitor, and quantify motor function in people with MS during daily activities or in a controlled laboratory setting and to shed light on the technological advances over the past decades. METHODS: We systematically reviewed studies on wearable sensors to assess the motor performance of people with MS. We scanned PubMed, Scopus, Embase, and Web of Science databases until December 31, 2022, considering search terms "multiple sclerosis" and those associated with wearable technologies and included all studies assessing motor functions. The types of results from relevant studies were systematically mapped into 9 predefined categories (association with clinical scores or other measures; test-retest reliability; group differences, 3 types; responsiveness to change or intervention; and acceptability to study participants), and the reporting quality was determined through 9 questions. We followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) reporting guidelines. RESULTS: Of the 1251 identified publications, 308 were included: 176 (57.1%) in a real-world context, 107 (34.7%) in a laboratory context, and 25 (8.1%) in a mixed context. Most publications studied physical activity (196/308, 63.6%), followed by gait (81/308, 26.3%), dexterity or tremor (38/308, 12.3%), and balance (34/308, 11%). In the laboratory setting, outcome measures included (in addition to clinical severity scores) 2- and 6-minute walking tests, timed 25-foot walking test, timed up and go, stair climbing, balance tests, and finger-to-nose test, among others. The most popular anatomical landmarks for wearable placement were the waist, wrist, and lower back. Triaxial accelerometers were most commonly used (229/308, 74.4%). A surge in the number of sensors embedded in smartphones and smartwatches has been observed. Overall, the reporting quality was good. CONCLUSIONS: Continuous monitoring with wearable sensors could optimize the management of people with MS, but some hurdles still exist to full clinical adoption of digital monitoring. Despite a possible publication bias and vast heterogeneity in the outcomes reported, our review provides an overview of the current literature on wearable sensor technologies used for people with MS and highlights shortcomings, such as the lack of harmonization, transparency in reporting methods and results, and limited data availability for the research community. These limitations need to be addressed for the growing implementation of wearable sensor technologies in clinical routine and clinical trials, which is of utmost importance for further progress in clinical research and daily management of people with MS. TRIAL REGISTRATION: PROSPERO CRD42021243249; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=243249.

Serum Neurofilament Light Chain Levels in the Intensive Care Unit: Comparison between Severely Ill Patients with and without Coronavirus Disease 2019.

There is emerging evidence for multifarious neurological manifestations of coronavirus disease 2019 (COVID-19), but little is known regarding whether they reflect structural damage to the nervous system. Serum neurofilament light chain (sNfL) is a specific biomarker of neuronal injury. We measured sNfL concentrations of 29 critically ill COVID-19 patients, 10 critically ill non-COVID-19 patients, and 259 healthy controls. After adjusting for neurological comorbidities and age, sNfL concentrations were higher in patients with COVID-19 versus both comparator groups. Higher sNfL levels were associated with unfavorable short-term outcome, indicating that neuronal injury is common and pronounced in critically ill patients. ANN NEUROL 2021;89:610-616.

Intrathecal Immunoglobulin M Synthesis is an Independent Biomarker for Higher Disease Activity and Severity in Multiple Sclerosis.

OBJECTIVE: We aimed to determine in relapsing multiple sclerosis (MS) whether intrathecal synthesis of immunoglobulin (Ig) M and IgG is associated with outcomes reflecting inflammatory activity and chronic worsening. METHODS: We compared cerebrospinal fluid analysis, clinical and magnetic resonance imaging data, and serum neurofilament light chain (sNfL) levels at baseline and follow-up in 530 patients with relapsing MS. Patients were categorized by the presence of oligoclonal IgG bands (OCGB) and intrathecal synthesis of IgG and IgM (intrathecal fraction [IF]: IgGIF and IgMIF ). Relationships with the time to first relapse, sNfL concentrations, T2-weighted (T2w) lesions, MS Severity Score (MSSS), and time to initiation of high-efficacy therapy were analyzed in covariate-adjusted statistical models. RESULTS: By categorical analysis, in patients with IgMIF the median time to first relapse was 28 months shorter and MSSS on average higher by 1.11 steps compared with patients without intrathecal immunoglobulin synthesis. Moreover, patients with IgMIF had higher sNfL concentrations, more new/enlarging T2w lesions, and higher total T2w lesion counts (all p ≤ 0.01). These associations were absent or equally smaller in patients who were positive for only OCGB or OCGB/IgGIF . Furthermore, quantitative analyses revealed that in patients with IgMIF ≥ median, the time to first relapse and to initiation of high-efficacy therapy was shorter by 32 and by 203 months, respectively (both p < 0.01), in comparison to patients with IgMIF < median. Dose-dependent associations were also found for IgMIF but not for IgGIF with magnetic resonance imaging-defined disease activity and sNfL. INTERPRETATION: This large study supports the value of intrathecal IgM synthesis as an independent biomarker of disease activity and severity in relapsing MS. ANN NEUROL 2021;90:477-489.

Regional Cerebellar Volume Loss Predicts Future Disability in Multiple Sclerosis Patients.

Cerebellar symptoms in multiple sclerosis (MS) are well described; however, the exact contribution of cerebellar damage to MS disability has not been fully explored. Longer-term observational periods are necessary to better understand the dynamics of pathological changes within the cerebellum and their clinical consequences. Cerebellar lobe and single lobule volumes were automatically segmented on 664 3D-T1-weighted MPRAGE scans (acquired at a single 1.5 T scanner) of 163 MS patients (111 women; mean age: 47.1 years; 125 relapsing-remitting (RR) and 38 secondary progressive (SP) MS, median EDSS: 3.0) imaged annually over 4 years. Clinical scores (EDSS, 9HPT, 25FWT, PASAT, SDMT) were determined per patient per year with a maximum clinical follow-up of 11 years. Linear mixed-effect models were applied to assess the association between cerebellar volumes and clinical scores and whether cerebellar atrophy measures may predict future disability progression. SPMS patients exhibited faster posterior superior lobe volume loss over time compared to RRMS, which was related to increase of EDSS over time. In RRMS, cerebellar volumes were significant predictors of motor scores (e.g. average EDSS, T25FWT and 9HPT) and SDMT. Atrophy of motor-associated lobules (IV-VI + VIII) was a significant predictor of future deterioration of the 9HPT of the non-dominant hand. In SPMS, the atrophy rate of the posterior superior lobe (VI + Crus I) was a significant predictor of future PASAT performance deterioration. Regional cerebellar volume reduction is associated with motor and cognitive disability in MS and may serve as a predictor for future disease progression, especially of dexterity and impaired processing speed.

Classification of multiple sclerosis based on patterns of CNS regional atrophy covariance.

There is evidence that multiple sclerosis (MS) pathology leads to distinct patterns of volume loss over time (VLOT) in different central nervous system (CNS) structures. We aimed to use such patterns to identify patient subgroups. MS patients of all classical disease phenotypes underwent annual clinical, blood, and MRI examinations over 6 years. Spinal, striatal, pallidal, thalamic, cortical, white matter, and T2-weighted lesion volumes as well as serum neurofilament light chain (sNfL) were quantified. CNS VLOT patterns were identified using principal component analysis and patients were classified using hierarchical cluster analysis. 225 MS patients were classified into four distinct Groups A, B, C, and D including 14, 59, 141, and 11 patients, respectively). These groups did not differ in baseline demographics, disease duration, disease phenotype distribution, and lesion-load expansion. Interestingly, Group A showed pronounced spinothalamic VLOT, Group B marked pallidal VLOT, Group C small between-structure VLOT differences, and Group D myelocortical volume increase and pronounced white matter VLOT. Neurologic deficits were more severe and progressed faster in Group A that also had higher mean sNfL levels than all other groups. Group B experienced more frequent relapses than Group C. In conclusion, there are distinct patterns of VLOT across the CNS in MS patients, which do not overlap with clinical MS subtypes and are independent of disease duration and lesion-load but are partially associated to sNfL levels, relapse rates, and clinical worsening. Our findings support the need for a more biologic classification of MS subtypes including volumetric and body-fluid markers.

Central nervous system atrophy predicts future dynamics of disability progression in a real-world multiple sclerosis cohort.

BACKGROUND AND PURPOSE: In an era of individualized multiple sclerosis (MS) patient management, biomarkers for accurate prediction of future clinical outcomes are needed. We aimed to evaluate the potential of short-term magnetic resonance imaging (MRI) atrophy measures and serum neurofilament light chain (sNfL) as predictors of the dynamics of disability accumulation in relapse-onset MS. METHODS: Brain gray and white matter, thalamic, striatal, pallidal and cervical spinal cord volumes, and lesion load were measured over three available time points (mean time span 2.24 ± 0.70 years) for 183 patients (140 relapsing-remitting [RRMS] and 43 secondary-progressive MS (SPMS); 123 female, age 46.4 ± 11.0 years; disease duration 15.7 ± 9.3 years), and their respective annual changes were calculated. Baseline sNfL was also measured at the third available time point for each patient. Subsequently, patients underwent annual clinical examinations over 5.4 ± 3.7 years including Expanded Disability Status Scale (EDSS) scoring, the nine-hole peg test and the timed 25-foot walk test. RESULTS: Higher annual spinal cord atrophy rates and lesion load increase predicted higher future EDSS score worsening over time in SPMS. Lower baseline thalamic volumes predicted higher walking speed worsening over time in RRMS. Lower baseline gray matter, as well as higher white matter and spinal cord atrophy rates, lesion load increase, baseline striatal volumes and baseline sNfL, predicted higher future hand dexterity worsening over time. All models showed reasonable to high prediction accuracy. CONCLUSION: This study demonstrates the capability of short-term MRI metrics to accurately predict future dynamics of disability progression in a real-world relapse-onset MS cohort. The present study represents a step towards the utilization of structural MRI measurements in patient care.

Practice Effects of Mobile Tests of Cognition, Dexterity, and Mobility on Patients With Multiple Sclerosis: Data Analysis of a Smartphone-Based Observational Study.

BACKGROUND: Smartphones and their built-in sensors allow for measuring functions in disease-related domains through mobile tests. This could improve disease characterization and monitoring, and could potentially support treatment decisions for multiple sclerosis (MS), a multifaceted chronic neurological disease with highly variable clinical manifestations. Practice effects can complicate the interpretation of both improvement over time by potentially exaggerating treatment effects and stability by masking deterioration. OBJECTIVE: The aim of this study is to identify short-term learning and long-term practice effects in 6 active tests for cognition, dexterity, and mobility in user-scheduled, high-frequency smartphone-based testing. METHODS: We analyzed data from 264 people with self-declared MS with a minimum of 5 weeks of follow-up and at least 5 repetitions per test in the Floodlight Open study, a self-enrollment study accessible by smartphone owners from 16 countries. The collected data are openly available to scientists. Using regression and bounded growth mixed models, we characterized practice effects for the following tests: electronic Symbol Digit Modalities Test (e-SDMT) for cognition; Finger Pinching and Draw a Shape for dexterity; and Two Minute Walk, U-Turn, and Static Balance for mobility. RESULTS: Strong practice effects were found for e-SDMT (n=4824 trials), Finger Pinching (n=19,650), and Draw a Shape (n=19,019) with modeled boundary improvements of 40.8% (39.9%-41.6%), 86.2% (83.6%-88.7%), and 23.1% (20.9%-25.2%) over baseline, respectively. Half of the practice effect was reached after 11 repetitions for e-SDMT, 28 repetitions for Finger Pinching, and 17 repetitions for Draw a Shape; 90% was reached after 35, 94, and 56 repetitions, respectively. Although baseline performance levels were highly variable across participants, no significant differences between the short-term learning effects in low performers (5th and 25th percentile), median performers, and high performers (75th and 95th percentile) were found for e-SDMT up to the fifth trial (ß=1.50-2.00). Only small differences were observed for Finger Pinching (ß=1.25-2.5). For U-Turn (n=15,051) and Static Balance (n=16,797), only short-term learning effects could be observed, which ceased after a maximum of 5 trials. For Two Minute Walk (n=14,393), neither short-term learning nor long-term practice effects were observed. CONCLUSIONS: Smartphone-based tests are promising for monitoring the disease trajectories of MS and other chronic neurological diseases. Our findings suggest that strong long-term practice effects in cognitive and dexterity functions have to be accounted for to identify disease-related changes in these domains, especially in the context of personalized health and in studies without a comparator arm. In contrast, changes in mobility may be more easily interpreted because of the absence of long-term practice effects, even though short-term learning effects might have to be considered.

Longitudinal patterns of cortical thinning in multiple sclerosis.

In multiple sclerosis (MS), cortical atrophy is correlated with clinical and neuropsychological measures. We aimed to examine the differences in the temporospatial evolution of cortical thickness (CTh) between MS-subtypes and to study the association of CTh with T2-weighted white matter lesions (T2LV) and clinical progression. Two hundred and forty-three MS patients (180 relapsing-remitting [RRMS], 51 secondary-progressive [SPMS], and 12 primary-progressive [PPMS]) underwent annual clinical (incl. expanded disability status scale [EDSS]) and MRI-examinations over 6 years. T2LV and CTh were measured. CTh did not differ between MS-subgroups. Higher total T2LV was associated with extended bilateral CTh-reduction on average, but did not correlate with CTh-changes over time. In RRMS, CTh- and EDSS-changes over time were negatively correlated in large bilateral prefrontal, frontal, parietal, temporal, and occipital areas. In SPMS, CTh was not associated with the EDSS. In PPMS, CTh- and EDSS-changes over time were correlated in small clusters predominantly in left parietal areas. Increase of brain lesion load does not lead to an immediate CTh-reduction. Although CTh did not differ between MS-subtypes, a dissociation in the correlation between CTh- and EDSS-changes over time between RRMS and progressive-MS was shown, possibly underlining the contribution of subcortical pathology to clinical progression in progressive-MS.

Accurate, rapid and reliable, fully automated MRI brainstem segmentation for application in multiple sclerosis and neurodegenerative diseases.

Neurodegenerative disorders, such as Alzheimer's disease (AD) and progressive forms of multiple sclerosis (MS), can affect the brainstem and are associated with atrophy that can be visualized by MRI. Anatomically accurate, large-scale assessments of brainstem atrophy are challenging due to lack of automated, accurate segmentation methods. We present a novel method for brainstem volumetry using a fully-automated segmentation approach based on multi-dimensional gated recurrent units (MD-GRU), a deep learning based semantic segmentation approach employing a convolutional adaptation of gated recurrent units. The neural network was trained on 67 3D-high resolution T1-weighted MRI scans from MS patients and healthy controls (HC) and refined using segmentations of 20 independent MS patients' scans. Reproducibility was assessed in MR test-retest experiments in 33 HC. Accuracy and robustness were examined by Dice scores comparing MD-GRU to FreeSurfer and manual brainstem segmentations in independent MS and AD datasets. The mean %-change/SD between test-retest brainstem volumes were 0.45%/0.005 (MD-GRU), 0.95%/0.009 (FreeSurfer), 0.86%/0.007 (manually edited segmentations). Comparing MD-GRU to manually edited segmentations the mean Dice scores/SD were: 0.97/0.005 (brainstem), 0.95/0.013 (mesencephalon), 0.98/0.006 (pons), 0.95/0.015 (medulla oblongata). Compared to the manual gold standard, MD-GRU brainstem segmentations were more accurate than FreeSurfer segmentations (p < .001). In the multi-centric acquired AD data, the mean Dice score/SD for the MD-GRU-manual segmentation comparison was 0.97/0.006. The fully automated brainstem segmentation method MD-GRU provides accurate, highly reproducible, and robust segmentations in HC and patients with MS and AD in 200 s/scan on an Nvidia GeForce GTX 1080 GPU and shows potential for application in large and longitudinal datasets.

Preferential spinal cord volume loss in primary progressive multiple sclerosis.

BACKGROUND: Little is known on longer term changes of spinal cord volume (SCV) in primary progressive multiple sclerosis (PPMS). OBJECTIVE: Longitudinal evaluation of SCV loss in PPMS and its correlation to clinical outcomes, compared to relapse-onset multiple sclerosis (MS) subtypes. METHODS: A total of 60 MS age-, sex- and disease duration-matched patients (12 PPMS, each 24 relapsing-remitting (RRMS) and secondary progressive MS (SPMS)) were analysed annually over 6 years of follow-up. The upper cervical SCV was measured on 3D T1-weighted magnetization-prepared rapid gradient-echo (MPRAGE) images using a semi-automatic software (CORDIAL), along with the total brain volume (TBV), brain T2 lesion volume (T2LV) and Expanded Disability Status Scale (EDSS). RESULTS: PPMS showed faster SCV loss over time than RRMS ( p < 0.01) and by trend ( p = 0.066) compared with SPMS. In contrast to relapse-onset MS, in PPMS SCV loss progressed independent of TBV and T2LV changes. Moreover, in PPMS, SCV was the only magnetic resonance imaging (MRI) measurement associated with EDSS increase over time ( p < 0.01), as opposed to RRMS and SPMS. CONCLUSION: SCV loss is a strong predictor of clinical outcomes in PPMS and has shown to be faster and independent of brain MRI metrics compared to relapse-onset MS.

Serum neurofilament as a predictor of disease worsening and brain and spinal cord atrophy in multiple sclerosis.

Neuro-axonal injury is a key factor in the development of permanent disability in multiple sclerosis. Neurofilament light chain in peripheral blood has recently emerged as a biofluid marker reflecting neuro-axonal damage in this disease. We aimed at comparing serum neurofilament light chain levels in multiple sclerosis and healthy controls, to determine their association with measures of disease activity and their ability to predict future clinical worsening as well as brain and spinal cord volume loss. Neurofilament light chain was measured by single molecule array assay in 2183 serum samples collected as part of an ongoing cohort study from 259 patients with multiple sclerosis (189 relapsing and 70 progressive) and 259 healthy control subjects. Clinical assessment, serum sampling and MRI were done annually; median follow-up time was 6.5 years. Brain volumes were quantified by structural image evaluation using normalization of atrophy, and structural image evaluation using normalization of atrophy, cross-sectional, cervical spinal cord volumes using spinal cord image analyser (cordial). Results were analysed using ordinary linear regression models and generalized estimating equation modelling. Serum neurofilament light chain was higher in patients with a clinically isolated syndrome or relapsing remitting multiple sclerosis as well as in patients with secondary or primary progressive multiple sclerosis than in healthy controls (age adjusted P < 0.001 for both). Serum neurofilament light chain above the 90th percentile of healthy controls values was an independent predictor of Expanded Disability Status Scale worsening in the subsequent year (P < 0.001). The probability of Expanded Disability Status Scale worsening gradually increased by higher serum neurofilament light chain percentile category. Contrast enhancing and new/enlarging lesions were independently associated with increased serum neurofilament light chain (17.8% and 4.9% increase per lesion respectively; P < 0.001). The higher the serum neurofilament light chain percentile level, the more pronounced was future brain and cervical spinal volume loss: serum neurofilament light chain above the 97.5th percentile was associated with an additional average loss in brain volume of 1.5% (P < 0.001) and spinal cord volume of 2.5% over 5 years (P = 0.009). Serum neurofilament light chain correlated with concurrent and future clinical and MRI measures of disease activity and severity. High serum neurofilament light chain levels were associated with both brain and spinal cord volume loss. Neurofilament light chain levels are a real-time, easy to measure marker of neuro-axonal injury that is conceptually more comprehensive than brain MRI.

Serum Neurofilament light: A biomarker of neuronal damage in multiple sclerosis.

OBJECTIVE: Neurofilament light chains (NfL) are unique to neuronal cells, are shed to the cerebrospinal fluid (CSF), and are detectable at low concentrations in peripheral blood. Various diseases causing neuronal damage have resulted in elevated CSF concentrations. We explored the value of an ultrasensitive single-molecule array (Simoa) serum NfL (sNfL) assay in multiple sclerosis (MS). METHODS: sNfL levels were measured in healthy controls (HC, n = 254) and two independent MS cohorts: (1) cross-sectional with paired serum and CSF samples (n = 142), and (2) longitudinal with repeated serum sampling (n = 246, median follow-up = 3.1 years, interquartile range [IQR] = 2.0-4.0). We assessed their relation to concurrent clinical, imaging, and treatment parameters and to future clinical outcomes. RESULTS: sNfL levels were higher in both MS cohorts than in HC (p < 0.001). We found a strong association between CSF NfL and sNfL (ß = 0.589, p < 0.001). Patients with either brain or spinal (43.4pg/ml, IQR = 25.2-65.3) or both brain and spinal gadolinium-enhancing lesions (62.5pg/ml, IQR = 42.7-71.4) had higher sNfL than those without (29.6pg/ml, IQR = 20.9-41.8; ß = 1.461, p = 0.005 and ß = 1.902, p = 0.002, respectively). sNfL was independently associated with Expanded Disability Status Scale (EDSS) assessments (ß = 1.105, p < 0.001) and presence of relapses (ß = 1.430, p < 0.001). sNfL levels were lower under disease-modifying treatment (ß = 0.818, p = 0.003). Patients with sNfL levels above the 80th, 90th, 95th, 97.5th, and 99th HC-based percentiles had higher risk of relapses (97.5th percentile: incidence rate ratio = 1.94, 95% confidence interval [CI] = 1.21-3.10, p = 0.006) and EDSS worsening (97.5th percentile: OR = 2.41, 95% CI = 1.07-5.42, p = 0.034). INTERPRETATION: These results support the value of sNfL as a sensitive and clinically meaningful blood biomarker to monitor tissue damage and the effects of therapies in MS. Ann Neurol 2017;81:857-870.

SUMMIT (Serially Unified Multicenter Multiple Sclerosis Investigation): creating a repository of deeply phenotyped contemporary multiple sclerosis cohorts.

BACKGROUND: There is a pressing need for robust longitudinal cohort studies in the modern treatment era of multiple sclerosis. OBJECTIVE: Build a multiple sclerosis (MS) cohort repository to capture the variability of disability accumulation, as well as provide the depth of characterization (clinical, radiologic, genetic, biospecimens) required to adequately model and ultimately predict a patient's course. METHODS: Serially Unified Multicenter Multiple Sclerosis Investigation (SUMMIT) is an international multi-center, prospectively enrolled cohort with over a decade of comprehensive follow-up on more than 1000 patients from two large North American academic MS Centers (Brigham and Women's Hospital (Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB; BWH)) and University of California, San Francisco (Expression/genomics, Proteomics, Imaging, and Clinical (EPIC))). It is bringing online more than 2500 patients from additional international MS Centers (Basel (Universitätsspital Basel (UHB)), VU University Medical Center MS Center Amsterdam (MSCA), Multiple Sclerosis Center of Catalonia-Vall d'Hebron Hospital (Barcelona clinically isolated syndrome (CIS) cohort), and American University of Beirut Medical Center (AUBMC-Multiple Sclerosis Interdisciplinary Research (AMIR)). RESULTS AND CONCLUSION: We provide evidence for harmonization of two of the initial cohorts in terms of the characterization of demographics, disease, and treatment-related variables; demonstrate several proof-of-principle analyses examining genetic and radiologic predictors of disease progression; and discuss the steps involved in expanding SUMMIT into a repository accessible to the broader scientific community.

Central Slab versus Whole Brain to Measure Brain Atrophy in Multiple Sclerosis.

BACKGROUND: Structural Image Evaluation using Normalization of Atrophy (SIENA) is used to measure brain atrophy in multiple sclerosis (MS). However, brain extraction is prone to artefacts in the upper and lower parts of the brain. To overcome these shortcomings, some pivotal MS trials used a central slab instead of the whole brain as input for SIENA. The aim of this study was to compare the internal consistency and statistical dispersion of atrophy measures, associations with clinical outcomes and required sample sizes in clinical trials between these two approaches. METHODS: Brain volume change was assessed using SIENA in 119 MS patients with 5-years follow-up on 3D T1-weighted Magnetization Prepared Rapid Gradient Echo datasets using the whole brain or a central slab ranging from -10 to +60 mm Montreal Neurological Institute atlas coordinates. The statistical analysis included the quartile coefficient of dispersion, partial correlations with clinical outcomes and sample size calculations. Clinical outcome measures comprised the Expanded Disability Status Scale, MS Functional Composite and Symbol Digit Modalities Test. RESULTS: Annualized brain atrophy rates were higher using central slab than whole brain as input for SIENA (-0.51 ± 0.49 vs. -0.37 ± 0.39% per year, p < 0.001). Central and whole brain volume change showed comparable statistical dispersion and similarly correlated with clinical outcomes at 5-years follow-up. Sample size calculations estimated 14% fewer patients required to detect a given treatment effect when using the central slab instead of the whole brain option in SIENA. CONCLUSION: Central slab and whole brain SIENA produced comparable statistical dispersion with similar associations to clinical outcomes.

Clinical studies and anti-inflammatory mechanisms of treatments.

In this exciting era, we are coming closer and closer to bringing an anti-inflammatory therapy to the clinic for the purpose of seizure prevention, modification, and/or suppression. At present, it is unclear what this approach might entail, and what form it will take. Irrespective of the therapy that ultimately reaches the clinic, there will be some commonalities with regard to clinical trials. A number of animal models have now been used to identify inflammation as a major underlying mechanism of both chronic seizures and the epileptogenic process. These models have demonstrated that specific anti-inflammatory treatments can be effective at both suppressing chronic seizures and interfering with the process of epileptogenesis. Some of these have already been evaluated in early phase clinical trials. It can be expected that there will soon be more clinical trials of both "conventional, broad spectrum" anti-inflammatory agents and novel new approaches to utilizing specific anti-inflammatory therapies with drugs or other therapeutic interventions. A summary of some of those approaches appears below, as well as a discussion of the issues facing clinical trials in this new domain.

Individual Assessment of Brain Tissue Changes in MS and the Effect of Focal Lesions on Short-Term Focal Atrophy Development in MS: A Voxel-Guided Morphometry Study.

We performed voxel-guided morphometry (VGM) investigating the mechanisms of brain atrophy in multiple sclerosis (MS) related to focal lesions. VGM maps detect regional brain changes when comparing 2 time points on high resolution T1-weighted (T1w) magnetic resonace imaging (MRI). Two T1w MR datasets from 92 relapsing-remitting MS patients obtained 12 months apart were analysed with VGM. New lesions and volume changes of focal MS lesions as well as in the surrounding tissue were identified by visual inspection on colour coded VGM maps. Lesions were dichotomized in active and inactive lesions. Active lesions, defined by either new lesions (NL) (volume increase > 5% in VGM), chronic enlarging lesions (CEL) (pre-existent T1w lesions with volume increase > 5%), or chronic shrinking lesions (CSL) (pre-existent T1w lesions with volume reduction > 5%) in VGM, were accompanied by tissue shrinkage in surrounding and/or functionally related regions. Volume loss within the corpus callosum was highly correlated with the number of lesions in its close proximity. Volume loss in the lateral geniculate nucleus was correlated with lesions along the optic radiation. VGM analysis provides strong evidence that all active lesion types (NL, CEL, and CSL) contribute to brain volume reduction in the vicinity of lesions and/or in anatomically and functionally related areas of the brain.

Comparison between balanced steady-state free precession and standard spoiled gradient echo magnetization transfer ratio imaging in multiple sclerosis: methodical and clinical considerations.

Different pathological processes like demyelination and axonal loss can alter the magnetisation transfer ratio (MTR) in brain tissue. The standard method to measure this effect is to scan the respective tissue twice, one with and one without a specific saturation pulse. A major drawback of this technique based on spoiled gradient echo (GRE) sequences relates to its long acquisition time due to the saturation pulses. Recently, an alternative concept for MT imaging based on balanced steady state free precession (bSSFP) has been proposed. Modification of the duration of the radiofrequency pulses for imaging allows scanning MT sensitive and non-sensitive images. The steady-state character of bSSFP with high intrinsic signal-to-noise ratio (SNR) allows three-dimensional (3D) whole brain MTR at high spatial resolution within short and thus clinically feasible acquisition times. In the present study, both bSSFP-MT and 2D GRE-MT imaging were used in a cohort of 31 patients with multiple sclerosis (MS) to characterize different normal appearing (NA) and pathological brain structures. Under the constraint of identical SNR and scan time, a 3.4 times higher voxel size could be achieved with bSSFP. This increased resolution allowed a more accurate delineation of the different brain structures, especially of cortex, hippocampus and MS lesions. In a multiple linear regression model, we found an association between MTR of cortical lesions and a clinical measure of disability (r= -0.407, p=0.035) in the bSSFP dataset only. The different relaxation weighting of the base images (T2/T1 in bSSFP, proton density in GRE) had no effects besides a larger spreading of the MTR values of the different NA structures. This was demonstrated by the nearly perfect linearity between the NA matter MTR of both techniques as well as in the absolute MTR differences between NA matter and the respective lesions.

Cervical spinal cord volume loss is related to clinical disability progression in multiple sclerosis.

OBJECTIVE: To examine the temporal evolution of spinal cord (SC) atrophy in multiple sclerosis (MS), and its association with clinical progression in a large MS cohort. METHODS: A total of 352 patients from two centres with MS (relapsing remitting MS (RRMS): 256, secondary progressive MS (SPMS): 73, primary progressive MS (PPMS): 23) were included. Clinical and MRI parameters were obtained at baseline, after 12 months and 24 months of follow-up. In addition to conventional brain and SC MRI parameters, the annualised percentage brain volume change and the annualised percentage upper cervical cord cross-sectional area change (aUCCA) were quantified. Main outcome measure was disease progression, defined by expanded disability status scale increase after 24 months. RESULTS: UCCA was lower in SPMS and PPMS compared with RRMS for all time points. aUCCA over 24 months was highest in patients with SPMS (-2.2% per year) and was significantly higher in patients with disease progression (-2.3% per year) than in stable patients (-1.2% per year; p=0.003), while annualised percentage brain volume change did not differ between subtypes (RRMS: -0.42% per year; SPMS -0.6% per year; PPMS: -0.46% per year) nor between progressive and stable patients (p=0.055). Baseline UCCA and aUCCA over 24 months were found to be relevant contributors of expanded disability status scale at month-24, while baseline UCCA as well as number of SC segments involved by lesions at baseline but not aUCCA were relevant contributors of disease progression. CONCLUSIONS: SC MRI parameters including baseline UCCA and SC lesions were significant MRI predictors of disease progression. Progressive 24-month upper SC atrophy occurred in all MS subtypes, and was faster in patients exhibiting disease progression at month-24.

Label-fusion-segmentation and deformation-based shape analysis of deep gray matter in multiple sclerosis: the impact of thalamic subnuclei on disability.

Deep gray matter (DGM) atrophy has been reported in patients with multiple sclerosis (MS) already at early stages of the disease and progresses throughout the disease course. We studied DGM volume and shape and their relation to disability in a large cohort of clinically well-described MS patients using new subcortical segmentation methods and shape analysis. Structural 3D magnetic resonance images were acquired at 1.5 T in 118 patients with relapsing remitting MS. Subcortical structures were segmented using a multiatlas technique that relies on the generation of an automatically generated template library. To localize focal morphological changes, shape analysis was performed by estimating the vertex-wise displacements each subject must undergo to deform to a template. Multiple linear regression analysis showed that the volume of specific thalamic nuclei (the ventral nuclear complex) together with normalized gray matter volume explains a relatively large proportion of expanded disability status scale (EDSS) variability. The deformation-based displacement analysis confirmed the relation between thalamic shape and EDSS scores. Furthermore, white matter lesion volume was found to relate to the shape of all subcortical structures. This novel method for the analysis of subcortical volume and shape allows depicting specific contributions of DGM abnormalities to neurological deficits in MS patients. The results stress the importance of ventral thalamic nuclei in this respect.