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Objective: Glial fibrillary acidic protein (GFAP) is expressed in astrocytes and may be a useful marker of non-active progressive multiple sclerosis (MS). We evaluate serum GFAP (sGFAP) in a large cohort of MS patients to determine if it predicts progression independent of relapse activity (PIRA), future gait aid, and conversion to secondary progressive disease (SPMS)., Methods: Adults with clinically isolated syndrome or any subtype of MS who were listed in the Brigham MS Center Research Database and had at least one sGFAP result were included. All clinic visits following first sample were analyzed for PIRA, future gait aid, and conversion to SPMS. Future cognitive dysfunction and fatigue were evaluated as secondary outcomes., Results: In total, 741 patients were included (average age: 42.3, average disease duration: 3.7 years, median EDSS: 2, and median follow-up duration: 10.0 years). Of 643 patients (86.8%) without progressive disease at baseline, 15.9% developed SPMS. Among all 741, 50.5% had PIRA and 18.6% developed a gait aid requirement. sGFAP level predicted PIRA, future gait aid, and conversion to SPMS in univariable models (p < 0.001, <0.001, and 0.002). sGFAP remained predictive for PIRA and future gait aid in multivariable models in those younger than 50 (p = 0.048, 0.003). Change in sGFAP level over time was not predictive. There was no association between sGFAP and future fatigue or cognitive dysfunction., Interpretation: sGFAP helps to predict PIRA, future gait aid, and conversion to SPMS in a large cohort of MS patients. Our data suggest that baseline levels may be more useful than the change over time., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Stigma is an undesired differentness associated with a particular characteristic or condition that distinguishes a person as being outside the norm and cueing stereotypes. Stigma is common in people with multiple sclerosis (MS) and is associated with several disease variables including disease duration, age, age of onset, and disease course. Stigma is also associated with psychological and psychosocial variables such as depression, anxiety, and quality of life. This article reviews our current understanding of stigma in people with MS with a focus on the various stigma types including anticipated, experienced, and internalized stigma, and the lack of consistent definitions across studies. It also describes the 7 instruments that are most commonly used to measure stigma in people with MS, and the limitations of each measure. We conclude that a better understanding of stigma that includes standard definitions of stigma types could lead to more direct intervention strategies aimed at reducing particular stigma concepts and resulting in improved health-related quality of life in people with MS., Competing Interests: DISCLOSURES: Sasha I. Winston-Khan, BS, has disclosed a financial relationship with Adelphi Values (employee). All other authors report no relevant disclosures., (© 2024 Consortium of Multiple Sclerosis Centers.)

Multiple system atrophy (MSA) is a fatal neurodegenerative disease of unknown etiology characterized by widespread aggregation of the protein alpha-synuclein in neurons and glia. Its orphan status, biological relationship to Parkinson's disease (PD), and rapid progression have sparked interest in drug development. One significant obstacle to therapeutics is disease heterogeneity. Here, we share our process of developing a clinical trial-ready cohort of MSA patients (69 patients in 2 years) within an outpatient clinical setting, and recruiting 20 of these patients into a longitudinal "n-of-few" clinical trial paradigm. First, we deeply phenotype our patients with clinical scales (UMSARS, BARS, MoCA, NMSS, and UPSIT) and tests designed to establish early differential diagnosis (including volumetric MRI, FDG-PET, MIBG scan, polysomnography, genetic testing, autonomic function tests, skin biopsy) or disease activity (PBR06-TSPO). Second, we longitudinally collect biospecimens (blood, CSF, stool) and clinical, biometric, and imaging data to generate antecedent disease-progression scores. Third, in our Mass General Brigham SCiN study (stem cells in neurodegeneration), we generate induced pluripotent stem cell (iPSC) models from our patients, matched to biospecimens, including postmortem brain. We present 38 iPSC lines derived from MSA patients and relevant disease controls (spinocerebellar ataxia and PD, including alpha-synuclein triplication cases), 22 matched to whole-genome sequenced postmortem brain. iPSC models may facilitate matching patients to appropriate therapies, particularly in heterogeneous diseases for which patient-specific biology may elude animal models. We anticipate that deeply phenotyped and genotyped patient cohorts matched to cellular models will increase the likelihood of success in clinical trials for MSA., (© 2022. The Author(s).)

Background: Patient reported outcome measures (PROs) are considered promising tools for use in clinical settings to measure the impact of disease on physical, mental and social well-being from the patient's perspective. The Patient Reported Outcome Measurement Information System Scale v1.1-Global Health (PROMIS-10) is a measure that is well-suited to clinical practice, but the relationships between this measure and longer PRO measures used in multiple sclerosis (MS) research are unknown., Methods: Subjects enrolled in SysteMS: A Systems Biology Study of Clinical, Radiological, and Molecular Markers in Subjects with MS at the Brigham and Women's Hospital were eligible to contribute to the study. 349 subjects completed three PRO measures at study entry: PROMIS-10, Medical Outcomes Study Short-Form 36 (SF-36), and Quality of Life in Neurological Disorders (Neuro-QoL™). All questions and global scores from PROMIS-10 were correlated with all domain and summary component scores for SF-36 and all domain scores for Neuro-QoL using Pearson's correlation coefficient. Further, the global scores from PROMIS-10 were correlated with the expanded disability status scale (EDSS) and compared between disease categories (relapsing vs progressive MS)., Results: Strong correlations were observed between PROMIS-10 questions and SF-36 domains aimed at measuring the same construct. Further, the PROMIS-10 Global Physical Health score was correlated with the Physical Component Score from the SF-36 (r = 0.798), and the PROMIS Global Mental Health score was correlated with the Mental Component Score from the SF-36 (r = 0.726). Strong correlations between PROMIS-10 questions and two Neuro-QoL domains (fatigue and lower extremity function) were observed, but other Neuro-QoL domains were not strongly correlated with PROMIS-10 questions. PROMIS-10 Global Physical Health had stronger relationship to EDSS and disease category compared to the Global Mental Health., Conclusions: PROMIS-10 questions and global scores are highly correlated with the corresponding domains of SF-36 in PwMS. Neuro-QoL provides different information regarding HRQOL since different domains are being measured., Competing Interests: Declaration of Competing Interest Brian Healy has received research support from Analysis Group, Celgene, Bristol-Myers Squibb, Verily Life Sciences, Merck-Serono, Novartis and Genzyme Yanqing Liu and Sasha Winston-Khan have nothing to disclose. Tanuja Chitnis has received compensation for consulting from Novartis Pharmaceuticals and Roche Genentech. She has received research support from the National Institutes of Health, National MS Society, US Department of Defense, I-Mab Biopharma, Novartis Pharmaceuticals, Octave Bioscience, Roche Genentech, Sanofi-Genzyme and Tiziana Life Sciences. Howard L. Weiner has received research support from Cure Alzheimer's Fund, EMD Serono, Inc., Genentech, Inc., National Institutes of Health, National Multiple Sclerosis Society, Sanofi Genzyme, and Verily Life Sciences. He has received payment for consulting from Genentech, Inc, IM Therapeutics, I-MAB Biopharma, MedDay Pharmaceuticals, Tiziana Life Sciences, vTv Therapeutics. He is on advisory boards for The Guthy Jackson Charitable Foundation, Teva Pharmaceutical Industries Ltd., Biogen Idec, Novartis, Sanofi-aventis, Tilos Therapeutics, Tiziana Life Sciences, CBridge Capital, IM Therapeutics, Magnolia Therapeutics, Genentech, Genzyme, vTv Therapeutics, MedDay Pharmaceuticals, Weston Foundation, IMAB. He owns stock in vTv Therapeutics (Board of Directors). Bonnie Glanz has received research support from Verily Life Sciences and Merck-Serono., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Nearly 1 million Americans are living with multiple sclerosis (MS) and 30-50% will experience memory dysfunction. It remains unclear whether this memory dysfunction is due to overall white matter lesion burden or damage to specific neuroanatomical structures. Here we test if MS memory dysfunction is associated with white matter lesions to a specific brain circuit., Methods: We performed a cross-sectional analysis of standard structural images and verbal memory scores as assessed by immediate recall trials from 431 patients with MS (mean age 49.2 years, 71.9% female) enrolled at a large, academic referral center. White matter lesion locations from each patient were mapped using a validated algorithm. First, we tested for associations between memory dysfunction and total MS lesion volume. Second, we tested for associations between memory dysfunction and lesion intersection with an a priori memory circuit derived from stroke lesions. Third, we performed mediation analyses to determine which variable was most associated with memory dysfunction. Finally, we performed a data-driven analysis to derive de-novo brain circuits for MS memory dysfunction using both functional (n = 1000) and structural (n = 178) connectomes., Results: Both total lesion volume (r = 0.31, p < 0.001) and lesion damage to our a priori memory circuit (r = 0.34, p < 0.001) were associated with memory dysfunction. However, lesion damage to the memory circuit fully mediated the association of lesion volume with memory performance. Our data-driven analysis identified multiple connections associated with memory dysfunction, including peaks in the hippocampus (T = 6.05, family-wise error p = 0.000008), parahippocampus, fornix and cingulate. Finally, the overall topography of our data-driven MS memory circuit matched our a priori stroke-derived memory circuit., Conclusions: Lesion locations associated with memory dysfunction in MS map onto a specific brain circuit centered on the hippocampus. Lesion damage to this circuit fully mediated associations between lesion volume and memory. A circuit-based approach to mapping MS symptoms based on lesions visible on standard structural imaging may prove useful for localization and prognosis of higher order deficits in MS., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background and Objectives: Stable patients with multiple sclerosis (MS) may discontinue treatment, but the risk of disease activity is unknown. Serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) are biomarkers of subclinical disease activity and may help risk stratification. In this study, sNfL and sGFAP levels in stable patients were evaluated before and after treatment discontinuation to determine association with disease activity., Methods: This observational study included patients enrolled in the Comprehensive Longitudinal Investigation in MS at the Brigham and Women's Hospital who discontinued treatment after >2 years disease activity-free. Two serum samples within 2 years, before and after treatment stop, were sent for sNfL and sGFAP measurements by single-molecule array. Biannual neurologic examinations and yearly MRI scans determined disease activity by 3 time-to-event outcomes: 6-month confirmed disability worsening (CDW), clinical attacks, and MRI activity (new T2 or contrast-enhancing lesions). Associations between each outcome and log-transformed sNfL and sGFAP levels pretreatment stop and posttreatment stop and the percent change were estimated using multivariable Cox regression analysis adjusting for age, disability, disease duration, and duration from attack before treatment stop., Results: Seventy-eight patients (92% female) discontinued treatment at a median (interquartile range) age of 48.5 years (39.0-55.7) and disease duration of 12.3 years (7.5-18.8) and were followed up for 6.3 years (4.2-8.5). CDW occurred in 27 patients (35%), new attacks in 19 (24%), and new MRI activity in 26 (33%). Higher posttreatment stop sNfL level was associated with CDW (adjusted hazard ratio (aHR) 2.80, 95% CI 1.36-5.76, p = 0.005) and new MRI activity (aHR 3.09, 95% CI 1.42-6.70, p = 0.004). Patients who had >100% increase in sNfL level from pretreatment stop to posttreatment stop had greater risk of CDW (HR 3.87, 95% CI 1.4-10.7, p = 0.009) and developing new MRI activity (HR 4.02, 95% CI 1.51-10.7, p = 0.005). Patients who had >50% increase in sGFAP level also had greater risk of CDW (HR 5.34, 95% CI 1.4-19.9, p = 0.012) and developing new MRI activity (HR 5.16, 95% CI 1.71-15.6, p = 0.004)., Discussion: Stable patients who discontinue treatment may be risk stratified by sNfL and sGFAP levels measured before and after discontinuing treatment. Further studies are needed to validate findings and determine whether resuming treatment in patients with increasing biomarker levels reduces risk of subsequent disease activity., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Contrast-enhancing magnetic resonance imaging (MRI) lesions (CELs) indicate acute multiple sclerosis inflammation. Serum biomarkers, neurofilament light (sNfL), and glial fibrillary acidic protein (sGFAP) may increase in the presence of CELs, and indicate a need to perform MRI., Objective: We assessed the accuracy of biomarkers to detect CELs., Methods: Patients with two gadolinium-enhanced MRIs and serum biomarkers tested within 3 months were included ( N  = 557, 66% female). Optimal cut-points from Bland-Altman analysis for spot biomarker level and Youden's index for delta-change from remission were evaluated., Results: A total of 116 patients (21%) had CELs. A spot sNfL measurement >23.0 pg/mL corresponded to 7.0 times higher odds of CEL presence (95% CI: 3.8, 12.8), with 25.9% sensitivity, 95.2% specificity, operating characteristic curve (AUC) 0.61; while sNfL delta-change >30.8% from remission corresponded to 5.0 times higher odds (95% CI: 3.2, 7.8), 52.6% sensitivity, 81.9% specificity, AUC 0.67. sGFAP had poor CEL detection. In patients > 50 years, neither cut-point remained significant. sNfL delta-change outperformed spot levels at identifying asymptomatic CELs (AUC 0.67 vs 0.59) and in patients without treatment escalation between samples (AUC 0.67 vs 0.57)., Conclusion: Spot sNfL >23.0 pg/mL or a 30.8% increase from remission provides modest prediction of CELs in patients <50 years; however, low sNfL does not obviate the need for MRI., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: G.B. has received honoraria from TEVA Pharmaceuticals, EMD Serono, and Novartis; compensation for consulting from Novartis and EMD Serono; and research support through an endMS post-doctoral fellowship award from the Multiple Sclerosis Society of Canada, a TOHAMO innovation fund grant from IFPOC, and a Collaborate 2 Commercialize award from the Ontario Centre for Innovation.B.C.H. has received research support from Analysis Group, Celgene (Bristol-Myers Squibb), Verily Life Sciences, Merck-Serono, Novartis, and Genzyme.C.B. has received a PostDoctoral Fellowship award from the Swiss National Science Foundation.V.F.M.F. reports no disclosures.S.S. reports no disclosures.B.I.G. has received grant support from Merck Serono and Verily Life Sciences.H.A.L. reports no disclosures.M.P-T. reports no disclosures.R.B. has received consulting fees from EMD Serono and research support from BMS/Celgene, EMD Serono, Novartis, the US Department of Defense, the National Institutes of Health, and the National Multiple Sclerosis Society.H.L.W. has consulted for Genentech, Inc; Tiziana Life Sciences; IM Therapeutics; MedDay Pharmaceuticals; vTv Therapeutics; IMAB Biopharma, and received research support National Institutes of Health; National Multiple Sclerosis Society; Sanofi Genzyme; and Genentech, Inc.T.C. has received compensation for consulting from Biogen, Novartis Pharmaceuticals, Roche Genentech, and Sanofi Genzyme. She has received research support from the National Institutes of Health, National MS Society, US Department of Defense, EMD Serono, I-Mab Biopharma, Mallinckrodt ARD, Novartis Pharmaceuticals, Octave Bioscience, Roche Genentech, and Tiziana Life Sciences.

Background: Early risk-stratification in multiple sclerosis (MS) may impact treatment decisions. Current predictive models have identified that clinical and imaging characteristics of aggressive disease are associated with worse long-term outcomes. Serum biomarkers, neurofilament (sNfL) and glial fibrillary acidic protein (sGFAP), reflect subclinical disease activity through separate pathological processes and may contribute to predictive models of clinical and MRI outcomes., Methods: We conducted a retrospective analysis of the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB study), where patients with multiple sclerosis are seen every 6 months and undergo Expanded Disability Status Scale (EDSS) assessment, have annual brain MRI scans where volumetric analysis is conducted to calculate T2-lesion volume (T2LV) and brain parenchymal fraction (BPF), and donate a yearly blood sample for subsequent analysis. We included patients with newly diagnosed relapsing-remitting MS and serum samples obtained at baseline visit and 1-year follow-up (both within 3 years of onset), and were assessed at 10-year follow-up. We measured sNfL and sGFAP by single molecule array at baseline visit and at 1-year follow-up. A predictive clinical model was developed using age, sex, Expanded Disability Status Scale (EDSS), pyramidal signs, relapse rate, and spinal cord lesions at first visit. The main outcome was odds of developing of secondary progressive (SP)MS at year 10. Secondary outcomes included 10-year EDSS, brain T2LV and BPF. We compared the goodness-of-fit of the predictive clinical model with and without sNfL and sGFAP at baseline and 1-year follow-up, for each outcome by area under the receiver operating characteristic curve (AUC) or R-squared., Results: A total 144 patients with median MS onset at age 37.4 years (interquartile range: 29.4-45.4), 64% female, were included. SPMS developed in 25 (17.4%) patients. The AUC for the predictive clinical model without biomarker data was 0.73, which improved to 0.77 when both sNfL and sGFAP were included in the model (P = 0.021). In this model, higher baseline sGFAP associated with developing SPMS (OR=3.3 [95%CI:1.1,10.6], P = 0.04). Adding 1-year follow-up biomarker levels further improved the model fit (AUC = 0.79) but this change was not statistically significant (P = 0.15). Adding baseline biomarker data also improved the R-squared of clinical models for 10-year EDSS from 0.24 to 0.28 (P = 0.032), while additional 1-year follow-up levels did not. Baseline sGFAP was associated with 10-year EDSS (ß=0.58 [95%CI:0.00,1.16], P = 0.05). For MRI outcomes, baseline biomarker levels improved R-squared for T2LV from 0.12 to 0.27 (P<0.001), and BPF from 0.15 to 0.20 (P = 0.042). Adding 1-year follow-up biomarker data further improved T2LV to 0.33 (P = 0.0065) and BPF to 0.23 (P = 0.048). Baseline sNfL was associated with T2LV (ß=0.34 [95%CI:0.21,0.48], P<0.001) and 1-year follow-up sNfL with BPF (ß=-2.53% [95%CI:-4.18,-0.89], P = 0.003)., Conclusions: Early biomarker levels modestly improve predictive models containing clinical and MRI variables. Worse clinical outcomes, SPMS and EDSS, are associated with higher sGFAP levels and worse MRI outcomes, T2LV and BPF, are associated with higher sNfL levels. Prospective study implementing these predictive models into clinical practice are needed to determine if early biomarker levels meaningfully impact clinical practice., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier B.V.)

Background: Cognitive decline is inadequately captured by the standard neurological examination. Serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) are biomarkers of neuronal damage and astrocytic reactivity that may offer an accessible measure of the multiple sclerosis (MS) pathology linked to cognitive decline., Objective: To investigate the association of sNfL and sGFAP with cognitive decline in MS patients at high risk for progressive pathology., Methods: We included 94 MS patients with sustained Expanded Disability Status Score (EDSS) ⩾ 3, available serum samples and cognitive assessment performed by symbol digit modalities test (SDMT) over a median of 3.1 years. The visit for sGFAP/sNfL quantification was at confirmed EDSS ⩾ 3. Linear regression analysis on log-transformed sGFAP/sNfL assessed the association with current and future SDMT. Analyses were adjusted for age, sex, EDSS, treatment group, and recent relapse., Results: sNfL was significantly associated with concurrent SDMT (adjusted change in mean SDMT = -4.5; 95% confidence interval (CI): -8.7, -0.2; p  = 0.039) and predicted decline in SDMT (adjusted change in slope: -1.14; 95% CI: -1.83, -0.44; p  = 0.001), particularly in active patients. sGFAP was not associated with concurrent or future SDMT., Conclusions: Higher levels of sNfL were associated with cognitive impairment and predicted cognitive decline in MS patients at high risk for having an underlying progressive pathology.

Background: Patients with multiple sclerosis (MS) on some disease modifying therapies (DMTs), particularly anti-CD20 and sphingosine-1-phosphate (S1P) modulators, are at increased risk of severe Coronavirus Disease 19 (COVID-19) and death. COVID-19 vaccinations are effective in preventing infection and severe disease, but humoral response to vaccination and outcomes of COVID-19 infection after vaccination in MS patients on DMTs remain less understood., Methods: In this retrospective single-center study, patients enrolled in the CLIMB (Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women's Hospital) study and biorepository who had been vaccinated against COVID-19 and had SARS-CoV-2 spike antibody (anti-SARS-CoV-2 S Roche-Elecsys) testing were identified and compared to healthy controls. Demographic data, serum immune profiles including lymphocyte count, B-cell count, and immunoglobulins, and clinical outcome of COVID-19 infection were collected., Results: 254 patients (73.2% female, mean (SD) age 52.9 (11.2) years) were identified. When controlling for age, time since vaccination, and vaccine type, patients on fingolimod, ocrelizumab, rituximab, mycophenolate mofetil, natalizumab and teriflunomide had significantly lower levels of spike antibodies compared to healthy controls (n = 34). Longer duration of treatment was associated with lower spike antibody levels in patients on anti-CD20 therapy (p = 0.016) and S1P modulators (p = 0.016) compared to healthy controls. In patients on anti-CD20 therapy, higher spike antibody levels were associated with higher CD20 cell count (p<0.001), and longer time since last anti-CD20 therapy infusion (p<0.001). 92.8% (13/14) vaccine responders (spike antibody titer >100 ug/dL) on anti-CD20 therapy demonstrated B-cell reconstitution (mean CD20 3.6%). Only 1 out of 86 patients with CD20 of 0% had a measurable spike antibody response to vaccination. During follow-up (mean 270 days), five patients were diagnosed with COVID-19 after vaccination (incidence 1.9%), all of whom had spike antibody < 20 ug/dL. No patients required ICU care or died., Conclusions: Patients on some DMTs demonstrate reduced humoral immunity after Sars-CoV-2 vaccination. Longer duration of anti-CD20 therapy and reduced CD20 cell count is associated with blunted humoral response to vaccination. CD20 reconstitution >0.1% appears necessary, but not always sufficient, for humoral response to vaccination. Breakthrough COVID-19 infection in our cohort of MS patients on DMT was higher than in population studies. We propose that adjustment of B-cell therapy administration to allow for B-cell reconstitution prior to vaccination should be considered., (Copyright © 2022. Published by Elsevier B.V.)

Background: Higher levels of total physical activity (PA) are associated with better health-related quality of life (HRQOL) in individuals with multiple sclerosis (MS). The benefits of PA across the activity continuum have not been well-studied. The goal of this study was to compare the associations between total PA, strenuous PA, moderate PA, and mild PA and HRQOL in a large cohort of individuals with MS using both generic and neurologic disease-specific questionnaires. Longitudinal changes in PA and HRQOL over two years were also examined METHODS: Subjects enrolled in SysteMS completed the Godin Leisure Time Exercise Questionnaire (GLTEQ) to measure PA. Subjects also completed generic (SF-36) and neurologic disease-specific (NeuroQoL) HRQOL measures. GLTEQ and HRQOL measures were administered at baseline and 24 months. The associations between the GLTEQ total leisure activity (TLA), strenuous PA, moderate PA and mild PA and scores on NeuroQoL and SF-36 were estimated using Spearman's correlation coefficient and partial Spearman's correlation coefficient adjusting for age, sex and Expanded Disability Status Scale (EDSS) measured by a provider. To further investigate the associations between mild PA and HRQOL measures, the associations between mild PA and HRQOL were estimated in participants who reported no moderate or strenuous PA in the last week. The changes in GLTEQ TLA scores and each component score were compared to the changes in NeuroQoL and SF-36 over 24 months using Spearman's correlation coefficient and partial Spearman's correlation coefficient adjusting for age, sex and EDSS., Results: Statistically significant weak correlations were observed between GLTEQ TLA and NeuroQoL and SF-36 domains, with higher levels of TLA being associated with better HRQOL outcomes. After adjusting for age, sex and EDSS, all correlations were attenuated. Strenuous and moderate levels of PA were similarly associated with many HRQOL outcomes, but mild PA was only weakly correlated with NeuroQoL Lower Extremity Function. There was limited change in PA over 24 months. In a subgroup of participants who reported mild PA, but no moderate or strenuous PA, there were no significant associations with NeuroQoL or SF-36 domains at baseline, but increases in mild PA over two years were moderately associated with improvement on NeuroQoL Upper Extremity Function and SF-36 Mental Health and Mental Component Summary., Conclusion: There were weak associations between TLA and HRQOL across a wide range of HRQOL variables. In addition, both strenuous PA and moderate PA were weakly associated with many HRQOL outcomes, but mild PA was only associated with lower extremity function. Increases in mild PA in a subgroup of individuals who reported no strenuous or moderate PA at baseline were associated with improvements in HRQOL at 24 months. These findings suggest that programs aimed at increasing PA across the activity continuum may lead to improvements in multiple areas of HRQOL in individuals with MS., (Copyright © 2022. Published by Elsevier B.V.)

Objective: Older age at multiple sclerosis (MS) onset has been associated with worse 10-year outcomes. However, disease duration often exceeds 10 years and age-related comorbidities may also contribute to disability. We investigated patients with>10 years disease duration to determine how age at MS onset is associated with clinical, MRI and occupational outcomes at age 50., Methods: We included patients enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital with disease duration>10 years. Outcomes at age 50 included the Expanded Disability Status Scale (EDSS), development of secondary-progressive multiple sclerosis (SPMS), brain T2-lesion volume (T2LV) and brain parenchymal fraction (BPF), and occupational status. We assessed how onset age was independently associated with each outcome when adjusting for the date of visit closest to age 50, sex, time to first treatment, number of treatments by age 50 and exposure to high-efficacy treatments by age 50., Results: We included 661 patients with median onset at 31.4 years. The outcomes at age 50 were worse the younger first symptoms developed: for every 5 years earlier, the EDSS was 0.22 points worse (95% CI: 0.04 to 0.40; p=0.015), odds of SPMS 1.33 times higher (95% CI: 1.08 to 1.64; p=0.008), T2LV 1.86 mL higher (95% CI: 1.02 to 2.70; p<0.001), BPF 0.97% worse (95% CI: 0.52 to 1.42; p<0.001) and odds of unemployment from MS 1.24 times higher (95% CI: 1.01 to 1.53; p=0.037)., Conclusions: All outcomes at age 50 were worse in patients with younger age at onset. Decisions to provide high-efficacy treatments should consider younger age at onset, equating to a longer expected disease duration, as a poor prognostic factor., Competing Interests: Competing interests: GB has received an endMS PostDoctoral Fellowship award from the Multiple Sclerosis Society of Canada. BCH has received research support from Analysis Group, Celgene (Bristol-Myers Squibb), Verily Life Sciences, Merck-Serono, Novartis and Genzyme. CB has received a PostDoctoral Fellowship award from the Swiss National Science Foundation. BG has received grant support from Merck Serono and Verily Life Sciences. HAL has received research support from Verily Life Sciences, Octave Bioscience and the Department of Defense. MP-T reports no disclosures. CRGG has received research funding from Sanofi, the National Multiple Sclerosis Society, the International Progressive Multiple Sclerosis Alliance, the National Institutes of Health, the US Office for Naval Research, the Bright Focus Foundation, as well as travel support from Roche Pharmaceuticals; CRGG owns stock in Roche, Novartis, GSK, Alnylam, Protalix Biotherapeutics, Arrowhead Pharmaceuticals, Cocrystal Pharma, Sangamo Therapeutics, Alcon. RB has received consulting fees from Bristol-Myers Squibb and EMD Serono and research support from Bristol-Myers Squibb, EMD Serono, Novartis, the US Department of Defense, the National Institutes of Health and the National Multiple Sclerosis Society. HW has consulted for Genentech; Tiziana Life Sciences; IM Therapeutics; MedDay Pharmaceuticals; vTv Therapeutics; IMAB Biopharma and received research support National Institutes of Health; National Multiple Sclerosis Society; Sanofi Genzyme; and Genentech. TC has received compensation for consulting from Banner Life Sciences, Biogen, Bristol Myers Squibb, Novartis Pharmaceuticals, Roche Genentech and Sanofi Genzyme. She has received research support from the National Institutes of Health, National MS Society, US Department of Defense, Sumaira Foundation, Brainstorm Cell Therapeutics, Bristol-Myers Squibb, EMD Serono, I-Mab Biopharma, Mallinckrodt ARD, Novartis Pharmaceuticals, Octave Bioscience, Roche Genentech, Sanofi Genzyme and Tiziana Life Sciences., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The objective of this study was to identify predictors in common between different clinical and magnetic resonance imaging (MRI) outcomes in multiple sclerosis (MS) by comparing predictive models., Methods: We analyzed 704 patients from our center seen at MS onset, measuring 37 baseline demographic, clinical, treatment, and MRI predictors, and 10-year outcomes. Our primary aim was identifying predictors in common among clinical outcomes: aggressive MS, benign MS, and secondary-progressive (SP)MS. We also investigated MRI outcomes: T2 lesion volume (T2LV) and brain parenchymal fraction (BPF). The performance of the full 37-predictor model was compared with a least absolute shrinkage and selection operator (LASSO)-selected model of predictors in common between each outcome by the area under the receiver operating characteristic curves (AUCs)., Results: The full 37-predictor model was highly predictive of clinical outcomes: in-sample AUC was 0.91 for aggressive MS, 0.81 for benign MS, and 0.81 for SPMS. After variable selection, 10 LASSO-selected predictors were in common between each clinical outcome: age, Expanded Disability Status Scale, pyramidal, cerebellar, sensory and bowel/bladder signs, timed 25-foot walk ≥6 seconds, poor attack recovery, no sensory attacks, and time-to-treatment. This reduced model had comparable cross-validation AUC as the full 37-predictor model: 0.84 versus 0.81 for aggressive MS, 0.75 versus 0.73 for benign MS, and 0.76 versus 0.75 for SPMS, respectively. In contrast, 10-year MRI outcomes were more strongly influenced by initial T2LV and BPF than clinical outcomes., Interpretation: Early prognostication of MS is possible using LASSO modeling to identify a limited set of accessible clinical features. These predictive models can be clinically usable in treatment decision making once implemented into web-based calculators. ANN NEUROL 2022;92:87-96., (© 2022 American Neurological Association.)

Purpose: To investigate patient-reported outcome (PRO) measures in patients with relapsing-remitting multiple sclerosis (RRMS) who transition to secondary progressive multiple sclerosis (SPMS)., Methods: Subjects enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women's Hospital (CLIMB) who completed PRO measures in the RRMS and SPMS phases were identified (n = 52). The PRO measures were Medical Outcomes Study Short-Form 36 Health Survey (SF-36), the Modified Fatigue Impact Scale (MFIS), and the Center for Epidemiologic Studies Depression Scale (CESD). Two control groups of RRMS CLIMB patients who did not progress to SPMS were identified based on different matching criteria related to age, sex, disease duration and Expanded Disability Status Scale (EDSS). Summary statistics for each PRO were calculated at the last RRMS measurement and first SPMS measurement, and the change over this transition was calculated using a paired t-test. Patients who transitioned were compared to the control groups using linear regression to adjust for age, disease duration and EDSS and a mixed model to further account for the matching with a random effect for matched group., Results: Patients who transitioned from RRMS to SPMS had noticeable deficits in terms of Quality of Life (QOL) and fatigue at the visit prior to the transition. Patients worsened in terms of SF-36 Role Physical (- 3.6 [- 6.6, - 0.7]), Social Functioning (- 3.7 [- 6.4, - 1.0]), and Physical Component Summary (- 2.3 [- 4.5, - 0.1]) during the transition from RRMS to SPMS. When patients who transitioned were compared to the matched subjects, they had worse scores on several outcomes, including Physical Functioning (adjusted mean difference =  - 10.8 [- 14.1, - 7.5]), Physical Component Summary (- 5.2 [- 9.3, - 1.0]), fatigue (8.9 [1.7, 16.1]), and depression (3.1 [0.3, 5.9])., Conclusions: Patients in the period closely preceding transition from RRMS to SPMS have worse physical QOL and fatigue compared to subjects who remain RRMS., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Serum neurofilament light chain (sNfL) levels are associated with relapses, MRI lesions, and brain volume in multiple sclerosis (MS)., Objective: To explore the value of early serum neurofilament light (sNfL) measures in prognosticating 10-year regional brain volumes in MS., Methods: Patients with MS enrolled in the Comprehensive Longitudinal Investigations in MS at Brigham and Women's Hospital (CLIMB) study within five years of disease onset who had annual blood samples from years 1-10 (n = 91) were studied. sNfL was measured with a single molecule array (SIMOA) assay. We quantified global cortical thickness and normalized deep gray matter (DGM) volumes (fractions of the thalamus, caudate, putamen, and globus pallidus) from high-resolution 3 T MRI at 10 years. Correlations between yearly sNfL levels and 10-year MRI outcomes were assessed using linear regression models., Results: sNfL levels from years 1 and 2 were associated with 10-year thalamus fraction. Early sNfL levels were not associated with 10-year putamen, globus pallidus or caudate fractions. At 10 years, cortical thickness was not associated with early sNfL levels, but was weakly correlated with total DGM fraction., Conclusions: Early sNfL levels correlate with 10-year thalamic volume, supporting its role as a prognostic biomarker in MS., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)

Objective: This study was undertaken to investigate the gut microbiome in progressive multiple sclerosis (MS) and how it relates to clinical disease., Methods: We sequenced the microbiota from healthy controls and relapsing-remitting MS (RRMS) and progressive MS patients and correlated the levels of bacteria with clinical features of disease, including Expanded Disability Status Scale (EDSS), quality of life, and brain magnetic resonance imaging lesions/atrophy. We colonized mice with MS-derived Akkermansia and induced experimental autoimmune encephalomyelitis (EAE)., Results: Microbiota β-diversity differed between MS patients and controls but did not differ between RRMS and progressive MS or differ based on disease-modifying therapies. Disease status had the greatest effect on the microbiome β-diversity, followed by body mass index, race, and sex. In both progressive MS and RRMS, we found increased Clostridium bolteae, Ruthenibacterium lactatiformans, and Akkermansia and decreased Blautia wexlerae, Dorea formicigenerans, and Erysipelotrichaceae CCMM. Unique to progressive MS, we found elevated Enterobacteriaceae and Clostridium g24 FCEY and decreased Blautia and Agathobaculum. Several Clostridium species were associated with higher EDSS and fatigue scores. Contrary to the view that elevated Akkermansia in MS has a detrimental role, we found that Akkermansia was linked to lower disability, suggesting a beneficial role. Consistent with this, we found that Akkermansia isolated from MS patients ameliorated EAE, which was linked to a reduction in RORγt+ and IL-17-producing γδ T cells., Interpretation: Whereas some microbiota alterations are shared in relapsing and progressive MS, we identified unique bacteria associated with progressive MS and clinical measures of disease. Furthermore, elevated Akkermansia in MS may be a compensatory beneficial response in the MS microbiome. ANN NEUROL 2021;89:1195-1211., (© 2021 American Neurological Association.)

Background: Although recovery from relapses in MS appears to contribute to disability, it has largely been ignored as a treatment endpoint and disability predictor., Objective: To identify demographic and clinical predictors of relapse recovery in the first 3 years and examine its contribution to 10-year disability and MRI outcomes., Methods: Relapse recovery was retrospectively assessed in 360 patients with MS using the return of the Expanded Disability Status Scale (EDSS), Functional System Scale and neurologic signs to baseline at least 6 months after onset. Univariate and multivariable models were used to associate recovery with demographic and clinical factors and predict 10-year outcomes., Results: Recovery from relapses in the first 3 years was better in patients who were younger, on disease-modifying treatment, with a longer disease duration and without bowel or bladder symptoms. For every incomplete recovery, 10-year EDSS increased by 0.6 and 10-year timed 25-foot walk increased by 0.5 s. These outcomes were also higher with older age and higher baseline BMI. Ten-year MRI brain atrophy was associated only with older age, and MRI lesion volume was only associated with smoking., Conclusions: Early initiation of disease-modifying treatment in MS was associated with improved relapse recovery, which in turn prevented long-term disability., (© The Author(s) 2021.)

Background: Ocrelizumab is approved for the treatment of both relapsing and progressive multiple sclerosis (MS)., Objective: To examine the impact of ocrelizumab on health-related quality of life (HRQOL) in individuals with MS., Methods: Ninety-eight individuals with relapsing and 32 with progressive MS were enrolled. Participants were administered a battery of patient-reported outcome (PRO) measures at their first ocrelizumab infusion, and infusions at 6 and 12 months. PRO measures included the Medical Outcomes Study SF-36 and Neuro-QoL., Results: At baseline, participants had low mean scores across HRQOL domains. After 12 months, increases were observed on SF-36 Role-Physical, General Health, Vitality, Role-Emotional, Mental health and Mental Component Summary. On Neuro-QoL, improvements were seen in Positive Affect, Anxiety, Emotional and Behavioral Dyscontrol and Fatigue. Several demographic and clinical characteristics were associated with HRQOL at baseline. The strongest associations were between physical HRQOL measures and measures of MS disability. Associations between the longitudinal change in HRQOL scores and baseline demographic and clinical characteristics were mild., Conclusions: We observed significant improvements across multiple mental HRQOL domains at 12 months in individuals treated with ocrelizumab. These findings support the use of HRQOL measures to provide a subjective measure of treatment impact that complements traditional outcomes., Competing Interests: Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Glanz has received research support from Merck Serono and Verily Life Sciences. Dr. Zurawski has no disclosures to report. Ms. Casady has no disclosures to report. Ms. Shamah has no disclosures to report. Ms. Weiner has no disclosures to report. Dr. Chitnis has received personal compensation for advisory board/consulting roles for Biogen Idec, Genetech-Roche, Novartis and received financial support for research activities from Mallinckrodt, Verily Life Sciences, Tiziana Life Sciences and Novartis Pharmaceuticals. Dr. Weiner has received research support from the Department of Defense, Genentech, Inc., National Institutes of Health, National Multiple Sclerosis Society, Novartis and Sanofi Genzyme. He has received compensation for consulting from Genentech, Inc, IM Therapeutics, IMAB Biopharma, MedDay Pharmaceuticals, Tiziana Life Sciences and vTv Therapeutics. Dr. Healy has received grant support from Analysis Group, Celgene (Bristol Myers Squibb), Verily, Novartis, Merck Serono, and Genzyme., (© The Author(s) 2021.)

Background: Positive psychology (PP) uses targeted activities to increase the frequency and intensity of positive feelings and may improve overall well-being in medically ill populations. In this phase 1 randomized controlled trial, we examined the feasibility, acceptability, and potential impact of a 5-week, telephone-delivered PP intervention for individuals with multiple sclerosis (MS)., Methods: Participants were randomized 1:1 to a 5-week at-home PP intervention or a waitlist control condition. Participants engaged in weekly telephone calls with a study trainer and completed one PP exercise, such as recalling a past success, each week. Feasibility was determined by the number of sessions completed, and acceptability was assessed by weekly postexercise participant ratings of ease and utility. Efficacy was explored by examining between-group differences in changes from baseline on psychological variables, health-related quality of life, and self-reported functional activities at 5 and 10 weeks., Results: Of 30 patients enrolled in the study, 28 (93%) completed all exercises. Ease scores ranged from 7.7 to 8.7 of 10 and utility scores ranged from 8.2 to 8.7 of 10. The PP intervention was associated with significantly greater increases ( P < .05) in positive affect, optimism, state and trait anxiety, general health, and resilience in the intervention group versus the control group. Approximately half of the PP participants maintained at least 50% of the improvement at 10 weeks., Conclusions: This 5-week, telephone-based PP intervention was feasible and acceptable to individuals with MS. Larger randomized controlled trials are warranted to further investigate the utility of this intervention to improve well-being and other health outcomes in MS., Competing Interests: Financial Disclosures: Dr Healy has received grants from Analysis Group, Merck Serono, Novartis, Genzyme, and Verily Life Sciences and has served on an advisory board for Biogen outside the submitted work. Dr Huffman reports that time for his participation and editing was supported by grant R21DK109313 through the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases. Dr Chitnis has received personal compensation for advisory board/consulting for Biogen, Merck Serono, Novartis, Sanofi, Bayer, Celgene, and Alexion and has received financial support for research activities from Verily Life Sciences, Merck Serono, and Novartis Pharmaceuticals. Dr Weiner has received grants from the National Institutes of Health, the National Multiple Sclerosis Society, Verily Life Sciences, EMD Serono, Biogen, Teva Pharmaceuticals, Sanofi, and Novartis; grants and personal fees from Genentech Inc and Tilos Therapeutics; and personal fees from Tiziana Life Sciences, IM Therapeutics, MedDay Pharmaceuticals, and vTv Therapeutics outside the submitted work. Dr Glanz has received research support from Merck Serono and Verily Life Sciences outside the submitted work. Ms Freedman has no disclosures to report., (© 2021 Consortium of Multiple Sclerosis Centers.)

Background: Although confirmed disability progression (CDP) is a common outcome in multiple sclerosis (MS) clinical trials, its predictive value for long-term outcomes is uncertain., Objective: To investigate whether CDP at month 24 predicts subsequent disability accumulation in MS., Methods: The Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women's Hospital includes participants with relapsing-remitting MS or clinically isolated syndrome with Expanded Disability Status Scale (EDSS) scores ≤5 (N = 1214). CDP was assessed as a predictor of time to EDSS score 6 (EDSS 6) and to secondary progressive MS (SPMS) using a Cox proportional hazards model; adjusted models included additional clinical/participant characteristics. Models were compared using Akaike's An Information Criterion., Results: CDP was directionally associated with faster time to EDSS 6 in univariate analysis (HR = 1.61 [95% CI: 0.83, 3.13]). After adjusting for month 24 EDSS, CDP was directionally associated with slower time to EDSS 6 (adjusted HR = 0.65 [0.32, 1.28]). Models including CDP had worse fit statistics than those using EDSS scores without CDP. When models included clinical and magnetic resonance imaging measures, T2 lesion volume improved fit statistics. Results were similar for time to SPMS., Conclusions: CDP was less predictive of time to subsequent events than other MS clinical features., (© The Author(s) 2021.)

Background: Although cognitive problems have been identified in people with multiple sclerosis (PwMS), few studies have investigated the long-term change in cognitive functioning., Objective: To identify trajectories of change in cognitive functioning for PwMS., Methods: Participants enrolled in the quality-of-life subgroup from the Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women's Hospital (CLIMB) were eligible for our analysis. In 2006, participants in this group began to complete the Symbol Digit Modalities Test (SDMT) annually. Latent trajectory models were used to identify groups of participants with similar longitudinal change in SDMT scores. Linear and quadratic trajectory models were fit, and the models were compared. Latent trajectory models were also fit adjusting for baseline age and disease duration as well as using normalized SDMT scores. The groups identified across the approaches were compared., Results: We found that classes with higher-than-average baseline values improved, classes with average baseline values remained relatively constant, and classes with lower baseline values experienced cognitive worsening. Similar results were observed in the alternative latent trajectory models accounting for other variables., Conclusion: Our models show that subjects with higher SDMT scores at baseline showed improvement, while subjects with lower SDMT scores at baseline showed worsening. Baseline age and disease duration were also associated with SDMT performance.

Objective: Social support plays a role in the well-being of persons with multiple sclerosis (PwMS). The aims of this study were to compare social support in PwMS with relapsing versus progressive disease, examine the relationships with patient reported outcomes (PROs), and investigate social support longitudinally., Methods: For this study, we have performed an analysis of data routinely collected from subjects enrolled in the CLIMB at the Partners MS Center. Subjects (n = 789) completed measures of social support, quality of life (QOL), depression, and anxiety. Relapsing and progressive PwMS were compared using a two sample t-test, and linear regression was used to adjust for other variables. Correlations between social support and PROs were assessed using partial Pearson's correlation coefficient. A random intercept and slope model with a linear trend with time estimated the change over time., Results: Subjects with relapsing MS reported higher overall social support than subjects with progressive disease (difference in means = -6.7; 95% CI: -10.3, -3.1) as well as higher levels of 3 of the 4 dimensions of social support measured. These differences remained after adjusting for age and gender only, but were attenuated adjusting for age, gender, and depression (adjusted difference in means = -1.2; 95% CI: -5.0, 2.6). Higher overall social support was associated with higher QOL (r = 0.16-0.27), lower depression (r = -0.36), and lower state (r = -0.27) and trait (r = -0.29) anxiety. Social support was mostly stable over time., Conclusion: Social support was associated with QOL, depression, and anxiety in PwMS., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background and Purpose: Cognitive impairment occurs frequently in multiple sclerosis (MS). However, the prevalence and clinical characteristics of cognitive MS phenotype are not well established. The aim of the study was to characterize the clinical course and neurocognitive impairment of patients with MS meeting an Expanded Disability Status Scale (EDSS)-defined cognitive phenotype., Methods: A total of 2302 patients from the Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women's Hospital (CLIMB) study were studied. Predominant cognitive MS phenotype was defined as EDSS Cerebral Functional System (FS) subscore ≥3 and remaining EDSS FS subscores ≤2 on at least one clinical visit. Demographic/clinical characteristics, phenotype stability and neurocognitive domain impairment of these subjects were assessed., Results: A total of 60 of 2302 (2.6%) patients (age 52.8 ± 10.8 years, 68% female, 82% relapsing MS) met criteria for phenotype designation. A total of 29 of 60 (48%) were designated within 10 years of their presenting MS symptom. The mean cohort annualized relapse rate was 0.38 and EDSS score at last clinical assessment was 3.2 ± 1.3. Cognitive phenotype status was poorly sustained, with only 27% of subjects maintaining Cerebral FS score ≥2 throughout all follow-up. However, predominant cognitive phenotype subjects with clinical neuropsychiatric testing [n = 39/60 (65%)] frequently had cognitive impairment (1.5 SD below mean) in ≥1 domain [n = 30/39 (77%) of subjects] affecting memory, attention/executive function and processing speed. A total of 11 of 39 (28%) patients had severe-range cognitive impairment (3.0 SD below mean). Cognitive phenotype designation was associated with low rate of employment at last clinical assessment., Conclusion: Predominant cognitive MS phenotype is rare, although an EDSS-based definition identifies patients with multidomain cognitive impairment and may serve as a practical screen for identification of patients who might warrant close monitoring of neurocognitive status., (© 2020 European Academy of Neurology.)

Background: Outcome measures typically used to evaluate disease modifying therapies (DMTs) provide important information regarding their effects on disease activity, but they do not capture the full impact of living with multiple sclerosis (MS). Patient reported outcome measures (PROs) are increasingly being used to capture an individual's subjective experience of disease. We compared DMTs across a wide range of PRO outcomes in individuals with MS., Methods: Subjects enrolled in SysteMS completed the computer adaptive testing version of the Neuro-QoL within four weeks of a clinical neurological exam. Neuro-QoL measures included the following 11 health-related quality of life (HRQOL) domains: Ability to participate in Social Roles and Activities, Anxiety, Cognitive Function, Depression, Emotional and Behavioral Dyscontrol, Fatigue, Lower Extremity Function (mobility), Positive Affect and Wellbeing, Satisfaction with Social Roles and Activities, Stigma, and Upper Extremity Function (fine motor). Treatments were grouped based on the three main modes of delivery: injectable, oral and infusion. The three treatment groups were compared using linear regression adjusting for two sets of covariates (set 1: age, sex, disease duration and EDSS; set 2: age, sex, disease duration, EDSS and treatment duration). We also compared the individual treatments using linear regression., Results: After adjusting for the first set of clinical and demographic features of MS, there was a difference between treatment groups for Upper Extremity Function and Stigma. Subjects using injectable treatments reported better functioning in terms of Upper Extremity Function and Stigma than subjects using infusion treatments. In addition, subjects using injectable treatments reported better Upper Extremity Function than subjects treated with oral DMTs. When all individual treatments were compared, interferon-treated subjects reported significantly better functioning in terms of Stigma than natalizumab treated subjects. When further adjusting for time on treatment, the group differences were attenuated and no longer statistically significant., Conclusion: We examined differences between MS treatment groups across a wide range of HRQOL outcomes. The results suggest that overall there are few differences between treatments on the physical, cognitive and emotional dimensions of well-being., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Technological advances in passive digital phenotyping present the opportunity to quantify neurological diseases using new approaches that may complement clinical assessments. Here, we studied multiple sclerosis (MS) as a model neurological disease for investigating physiometric and environmental signals. The objective of this study was to assess the feasibility and correlation of wearable biosensors with traditional clinical measures of disability both in clinic and in free-living in MS patients. This is a single site observational cohort study conducted at an academic neurological center specializing in MS. A cohort of 25 MS patients with varying disability scores were recruited. Patients were monitored in clinic while wearing biosensors at nine body locations at three separate visits. Biosensor-derived features including aspects of gait (stance time, turn angle, mean turn velocity) and balance were collected, along with standardized disability scores assessed by a neurologist. Participants also wore up to three sensors on the wrist, ankle, and sternum for 8 weeks as they went about their daily lives. The primary outcomes were feasibility, adherence, as well as correlation of biosensor-derived metrics with traditional neurologist-assessed clinical measures of disability. We used machine-learning algorithms to extract multiple features of motion and dexterity and correlated these measures with more traditional measures of neurological disability, including the expanded disability status scale (EDSS) and the MS functional composite-4 (MSFC-4). In free-living, sleep measures were additionally collected. Twenty-three subjects completed the first two of three in-clinic study visits and the 8-week free-living biosensor period. Several biosensor-derived features significantly correlated with EDSS and MSFC-4 scores derived at visit two, including mobility stance time with MSFC-4 z-score (Spearman correlation -0.546; p  = 0.0070), several aspects of turning including turn angle (0.437; p  = 0.0372), and maximum angular velocity (0.653; p  = 0.0007). Similar correlations were observed at subsequent clinic visits, and in the free-living setting. We also found other passively collected signals, including measures of sleep, that correlated with disease severity. These findings demonstrate the feasibility of applying passive biosensor measurement techniques to monitor disability in MS patients both in clinic and in the free-living setting., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2019.)

Background: To date, the computerized adaptive testing (CAT) version of the Neuro-quality of life (QOL) has not been assessed in a large sample of people with multiple sclerosis (MS)., Objective: The aim of this study was to assess the associations between the CAT version of Neuro-QOL and other clinical and patient-reported outcome measures., Methods: Subjects ( n  = 364) enrolled in SysteMS completed the CAT version of the Neuro-QOL and the 36-Item Short Form Survey (SF-36) within 4 weeks of a clinical exam that included the Multiple Sclerosis Functional Composite-4 (MSFC-4). The correlations between the Neuro-QOL domains and the MSFC-4 subscores and the SF-36 scores were calculated. The changes over time in the Neuro-QOL and other measures were also examined., Results: The lower extremity functioning score of the Neuro-QOL showed the highest correlations with MSFC-4 components including Timed 25-Foot Walk, 9-Hole Peg Test, and cognitive score. The expected domains of the Neuro-QOL showed high correlations with the SF-36 subscores, and some Neuro-QOL domains were associated with many SF-36 subscores. There was limited longitudinal change on the Neuro-QOL domains over 12 months, and the change was not associated with change on other measures., Conclusion: The CAT version of the Neuro-QOL shows many of the expected associations with clinical and patient-reported outcome measures.

Background: Disease-modifying therapy (DMT) for patients with relapsing-remitting multiple sclerosis (RRMS) have been shown to reduce relapses and new MRI lesions. However, few studies have assessed the impact of discontinuing DMT after a period of disease inactivity., Objective: To investigate the impact of DMT discontinuation on clinical and radiological outcomes in RRMS patients., Methods: 69 RRMS patients who discontinued DMT after a period of disease inactivity were identified from the Comprehensive Longitudinal Investigation of MS study at the Brigham and Women's Hospital, based on the following inclusion criteria: age 18 or older; treated with DMT ≥2 years; no clinical and radiological relapse ≥2 years until the discontinuation; not restarting DMT for ≥6 months after discontinuation. Patients matched by age, gender, treatment, treatment duration, disease duration and Expanded Disability Status Scale score who remained on DMT were identified. Univariate and multivariable Cox proportional hazard models with robust standard errors to account for the paired data were used to test the differences based on DMT discontinuation with the outcome measures: time to clinical relapse, MRI event, disability progression, and disease activity (either clinical relapse or MRI event)., Results: Based on the 69 pairs of patients, discontinuation was not associated with time to clinical relapse (HR = 0.87, 95% CI = 0.44-1.72, p = 0.69), MRI event (HR = 0.95, 95% CI = 0.57 to 1.59, p = 0.84), disability progression (HR = 1.24, 95% CI = 0.61 to 2.53, p = 0.55) and disease activity (HR = 0.89, 95% CI = 0.56 to 1.42, p = 0.62). When we performed subgroup analysis to compare the impact of DMT discontinuation between older (age > 45) and younger (age ≤ 45) patients, we found a significant difference in the association between young and old for time to MRI event (p = 0.012) and time to new disease activity (p = 0.0005)., Conclusions: This study found that patients who discontinued treatment after a period of disease inactivity had a similar time to next event compared to subjects who remained on first-generation DMTs. In our cohort, we found that discontinuation after age 45 was associated with a stable disease course, while patients younger than age 45 who discontinued treatment were more likely to experience a new clinical relapse or MRI event., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Spinal cord demyelination is common in multiple sclerosis (MS) and has been linked to increased disability and progressive clinical course. Spinal cord atrophy shows an especially close relationship to MS-related physical disability, though the relationship between spinal cord lesions/atrophy and health-related quality of life (QOL) has not been explored., Methods: 62 patients (53 relapsing MS, 7 secondary progressive, 2 clinically isolated syndrome) from our center underwent 3 T MRI within 30 days of clinical examination and QOL assessment. Upper cervical (C1-C3) spinal cord area (UCCA) was obtained from 3D high-resolution MPRAGE sequences (1 mm isotropic voxels). Cervical spinal cord (C1-C7) lesion count, and cervical and brain T2 hyperintense lesion volumes were calculated. Brain parenchymal fraction (BPF) was obtained from an automated segmentation pipeline. Spearman correlations were assessed between MRI and clinical data. Partial Spearman correlations adjusting for age, disease duration, and BPF assessed the independent association between MRI variables and QOL domains., Results: UCCA showed an inverse relationship with age (r = -0.330, p = .009), disease duration, (r = -0.444, p < .001), and nine-hole peg test (r = -0.353, p = .005). The Upper Extremity Function QOL domain showed the strongest relationship to UCCA (r = 0.333, p = .008), with Lower Extremity Function QOL (r = 0.234, p = .067) and Satisfaction with Social Roles and Activities (r = 0.245, p = .055) correlations bordering significance. The association between UCCA and Upper Extremity QOL remained significant after adjustment for BPF, age, and disease duration. QOL domains reflective of psychological health (Depression, Anxiety, Emotional and Behavioral Dyscontrol, Positive Affect and Wellbeing) showed no relationship to UCCA. Cervical and brain lesion volume related to impairment in Stigma while cervical lesion count was unrelated to NeuroQOL impairment. Brain atrophy correlated with conventional markers of disability and cognition but did not have a significant relationship to QOL., Conclusion: Cervical spinal cord volume is independently associated with impaired upper extremity-related QOL in patients with MS. These findings suggest specific clinical relevance of MS-related spinal cord atrophy as compared to brain or cervical spinal cord lesions, or whole brain atrophy., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Cognitive impairment is a common symptom of multiple sclerosis (MS), yet treatment is currently limited. The primary goal of this pilot study was to assess the feasibility and acceptability of an at-home, five-week computerized speed of processing (SOP) training intervention for MS patients. In addition, we examined the utility of the intervention to improve speed of information processing, memory, executive function, and health-related quality of life (HRQOL)., Method: Fifteen subjects were assigned five weeks of SOP training, two times per week, for a total of ten sessions. Subjects were trained on five computerized SOP tasks that required processing of increasingly complex visual stimuli in successively shorter presentation times. Subjects were given a neuropsychological test battery that included measures of speed of information processing, verbal memory, visual spatial memory, and executive function. Subjects were also administered patient-reported outcome (PRO) measures to assess HRQOL, depression, and work productivity. Neuropsychological and PRO batteries were completed at baseline and after five weeks., Results: Eighty percent of subjects completed the five-week intervention (n = 12). Significant improvements were observed on some, but not all, measures of speed of information processing, verbal memory, and executive function. There were no significant changes in HRQOL., Conclusion: This pilot study supports the feasibility of an at-home SOP training intervention for individuals with MS. SOP training was associated with improvements in several cognitive domains. Larger, randomized controlled trials are warranted.

Objective: The association between allergy and multiple sclerosis (MS) is still unclear. In our study, we assessed the association between a self-reported history of allergic conditions with MS clinical and MRI disease activity., Methods: A subset of 1349 patients enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB) study completed a self-administered questionnaire on environmental, food and drug allergies. Patients were distributed among four allergy groups: (1) environmental, (2) food, (3) drug, (4) no known allergies (NKA). Clinical (number of attacks, expanded disability status scale (EDSS), MS severity score (MSSS)) and radiological variables (presence of gadolinium-enhancing lesions and lesion count), and their associations with the different allergy groups or those with NKA, were assessed., Results: The food allergy group had a 1.38 times higher rate for cumulative number of attacks compared with the NKA group (P=0.0062); this difference remained significant in the adjusted analysis (relapse rate ratio 1.27, P=0.0305). The food allergy group showed more than twice the likelihood (OR 2.53, P=0.0096) of having gadolinium-enhancing lesions on MRI. The environmental and drug allergy groups did not show significant differences when compared with the NKA group. The EDSS and MSSS were not affected by any type of allergy., Conclusions: MS patients with food allergy had more relapses and a higher likelihood of gadolinium-enhancing lesions compared with patients with no known allergy. Future prospective studies are needed to confirm our findings and investigate underlying biological mechanisms, which may unveil new therapeutic and preventative strategies for MS., Competing Interests: Competing interests: RF reports no conflict of interests. CDC reports no conflicts of interests. ASC reports no conflict of interests. CG reports no conflicts of interests. BCH reports grants from Verily Life Sciences, grants from Novartis, grants from Merck Serono, grants from Genentech, outside the submitted work. NS reports no conflicts of interests. BIG reports grants from Merck Serono, during the conduct of the study, and grants from Verily Life Sciences, outside the submitted work. HLW reports support from NIH, NMSS, Verily Life Sciences, EMD Serono, Biogen, Teva Pharmaceuticals, Sanofi, and Novartis. Research support and consulting fees from Genentech, Inc, Tilos Therapeutics, Tiziana Life Sciences, and IM Therapeutics. Personal and consulting fees from vTv Therapeutics and MedDay Pharmaceuticals. TC reports consulting fees from Biogen Idec, Novartis, Sanofi, Bayer, and Celgene, outside the submitted work., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Although the expanded disability status scale (EDSS) is the most commonly used measure of disability for multiple sclerosis, measurement of disability accumulation is complex due to the unequal steps of the scale., Objective: To estimate the time between EDSS scores in a large MS cohort from a single center and determine the impact of functional system scores on EDSS transitions., Methods: 31,394 clinical visits with EDSS scores from 2054 subjects in the CLIMB longitudinal cohort study were included in our analysis. The time to each EDSS score and the time between each EDSS score were calculated using the nonparametric maximum likelihood estimate for interval censored data. For each initial EDSS value, the association between functional status scores and subsequent EDSS value was assessed using a mixed effects linear regression model, and the association with time to EDSS increase was assessed using a Cox proportional hazards model., Results: The median time until EDSS 2, 3, 4, 5 and 6 in all subjects were 4.8, 15.1, 28.2, 31.2, and 32.4 years, respectively. The time intervals showed that the disability accumulation intervals from EDSS 4 to 6 were much shorter than the accumulation intervals from EDSS 0 to 3 or from EDSS 6 to 8. For EDSS of 1 or 1.5, pyramidal, cerebellar, sensory, bowel-bladder and mental system scores were associated with higher subsequent EDSS values. For higher EDSS values, only pyramidal and bowel-bladder scores maintained the association., Conclusions: Time between specific EDSS levels varies considerably. Certain functional system scores have greater predictive power for future EDSS-related disability despite same present EDSS level. These findings will assist in adaptation of the EDSS as an outcome measure to assess MS-related disability in clinical trials., (Copyright © 2019. Published by Elsevier B.V.)

Depression is common in multiple sclerosis (MS), affecting up to 50% of patients at some point in their lifetime. Although the rate of depression in MS is higher than that in the general population and that in patients with other chronic medical conditions, depression in MS is underdiagnosed and undertreated. Antidepressant agents are used empirically in the management of MS-related depression, but evidence specifically demonstrating the efficacy of these medications in patients with MS is sparse. Considerable work suggests that psychological interventions such as cognitive behavioral therapy (CBT) may be effective in the management of depression in MS. Recently there has been an expansion of computerized adaptations of CBT, allowing patients to complete therapy sessions remotely via online programs. This article reviews our current understanding of depression in MS and the role of CBT in its management, focusing on recent developments in computerized formats for CBT. Four computerized CBT programs that have been previously tested in patients with MS are described: Deprexis, MoodGYM, Beating the Blues, and MS Invigor8. We conclude that despite challenges inherent to computerized CBT interventions, such platforms have the potential to positively affect mental health care delivery to the MS patient population., Competing Interests: The authors declare no conflicts of interest.

Background: Increased adiposity is a risk factor for multiple sclerosis (MS) and is associated with increased disability scores. Adipokines may mediate the effects of adiposity on MS disease course., Objective: The objective of this study is to examine the association between the adipokines (leptin and fatty acid binding protein-4, FABP4) and clinical course in individuals with MS., Methods: Subjects (18-65 years) with relapsing-remitting MS or clinically isolated syndrome and <10 year disease duration were selected from a longitudinal clinical study. Cross-sectional and longitudinal models assessed the relationship between two adipokines (leptin and FABP4) and disease severity in women and men, adjusting for age, disease duration and disease type, Vitamin D level, testosterone level, and as well by body mass index (BMI)., Results: Mean age of subjects ( N = 163, 56% women) was 39.3 years. Higher FABP4 levels were associated with higher Expanded Disability Status Scale (EDSS) scores in women in both univariate and multivariate analyses (odds ratio: 1.30; p = 0.005). In men, higher FABP4 level was significantly associated with change in EDSS over time (estimate: 0.0062; p = 0.035). We found no association of FABP4 levels with time to next relapse or a measure of processing speed., Conclusion: FABP4 levels may be associated with increased disability in both men and women with MS independent of effects of BMI and other hormones. Future studies should expand these analyses and further explore downstream mechanisms of adiposity-related effects in MS.

Background: Optical coherence tomography (OCT) provides quantitative measures of retinal layer thickness. Cigarette smoking is a risk factor for multiple sclerosis (MS) onset and disease severity: its effects on OCT metrics have not been assessed., Objective: The objective of this study was to assess the effect of smoking history on retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform (GCIP) of MS patients by OCT., Methods: 112 MS patients were recruited from the Brigham and Women's Hospital. Spectralis OCT scans were acquired to measure GCIP, peripapillary RNFL, and total macular volume. Multivariable linear mixed effects regression model assessed RNFL and GCIP change with fixed effects for smoking history while adjusting for optic neuritis eye status, age, disease duration, sex, baseline EDSS, and disease modifying therapies (DMTs)., Results: Smoking histories were available for 102 patients: 46 (45.10%) had a history of smoking cigarettes and 56 (54.90%) never smoked. No statistically significant differences were found between ever-smokers and never-smokers with respect to GCIP, RNFL, and macular volume., Conclusion: Our study shows no significant difference in retinal thickness between ever-smokers and never-smokers. If confirmed, this result suggests mechanistic differences between the retina and other central nervous system (CNS) compartments in response to smoking and should be noted when considering OCT as a surrogate measure of CNS activity.

Background: Serum hematological indices such as the neutrophil-lymphocyte ratio (NLR) or monocyte-lymphocyte ratio (MLR) have been used as biomarkers of pathogenic inflammation and prognostication in multiple areas of medicine; recent evidence shows correlation with psychological parameters as well., Objectives/aims: To characterize clinical, neuroimaging, and psycho-neuro-immunological associations with NLR and MLR in persons with multiple sclerosis (MS)., Methods: We identified a large cohort of clinically well-defined patients from our longitudinal database that included MS-related outcomes, disease-modifying therapy, patient-reported outcome (PRO) measures, and quantified cerebral MRI at 1.5 T. We queried hospital records for complete blood counts within 2 months of each clinic visit and excluded those obtained during clinical relapses. Four hundred eighty-three patients, with a mean of 3 longitudinal observations each, were identified who met these criteria. Initial analyses assessed the association between NLR and MLR as the outcomes, and psychological and demographic predictors in univariable and multivariable models controlling for age, gender and treatment. The second set of analyses assessed the association between clinical and MRI outcomes including whole brain atrophy and T2-hyperintense lesion volume, with NLR and MLR as predictors in univariable and multivariable models. All analyses used a mixed effects linear or logistic regression model with repeated measures., Results: Unadjusted analyses demonstrated significant associations between higher (log-transformed) NLR (but not MLR) and PRO measures including increasing depression (p = 0.01), fatigue (p < 0.01), and decreased physical quality of life (p < 0.01). Higher NLR and MLR strongly predicted increased MS-related disability as assessed by the Expanded Disability Status Scale, independent of all demographic, clinical, treatment-related, and psychosocial variables (p < 0.001). Lastly, higher NLR and MLR significantly discriminated progressive from relapsing status (p ≤ 0.01 for both), and higher MLR correlated with increased whole-brain atrophy (p < 0.05) but not T2 hyperintense lesion volume (p > 0.05) even after controlling for all clinical and demographic covariates. Sensitivity analyses using a subset of untreated patients (N = 146) corroborated these results., Conclusions: Elevated NLR and MLR may represent hematopoetic bias toward increased production and pro-inflammatory priming of the myeloid innate immune system (numerator) in conjunction with dysregulated adaptive immune processes (denominator), and consequently reflect a complementary and independent marker for severity of MS-related neurological disability and MRI outcomes.

Objective: Our goal was to compare subjects treated with glatiramer acetate (GA) and interferon-beta (IFN-β) in terms of long-term clinical outcomes., Methods: Subjects enrolled in the CLIMB who initiated either GA or IFN-β within five years of disease onset and prior to 2008 were identified (n = 150 for GA and n = 144 for IFN-β). The two treatment groups were compared in terms of long-term clinical outcomes: time to EDSS 4, time to EDSS 6 and EDSS score seven years after treatment initiation. Baseline confounders included in our analysis were age, gender, disease duration, attacks in the previous year, EDSS prior to treatment initiation, and year of treatment initiation. The groups were compared using three approaches to handle confounders: multiple regression adjusting for confounders, adjustment for the propensity score, and inverse probability of treatment weighting. In addition, we assessed potential predictors of differential treatment response using multiple regression models including appropriate interaction terms., Results: Subjects initially treated with GA had a slightly higher hazard of reaching EDSS 4 and EDSS 6, but the difference between the groups was not statistically significant (adjusted HR for EDSS 4 = 1.48; 95% CI: 0.77,2.84; p = .24; adjusted HR for EDSS 6 = 1.46; 95% CI: 0.70,3.05; p = .316). For the EDSS score at year 7, there was also only a small difference between the groups. Subjects treated with GA had a longer time until treatment cessation (adjusted HR = 0.70; 95% CI: 0.53,0.93; p = .012). The interaction models did not show strong evidence for the baseline predictors being associated with treatment response., Conclusions: Subjects treated with glatiramer acetate and interferon-beta had similar long-term clinical course., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: To assess the value of annual serum neurofilament light (NfL) measures in predicting 10-year clinical and MRI outcomes in multiple sclerosis (MS)., Methods: We identified patients in our center's Comprehensive Longitudinal Investigations in MS at Brigham and Women's Hospital (CLIMB) study enrolled within 5 years of disease onset, and with annual blood samples up to 10 years ( n = 122). Serum NfL was measured using a single molecule array (SIMOA) assay. An automated pipeline quantified brain T2 hyperintense lesion volume (T2LV) and brain parenchymal fraction (BPF) from year 10 high-resolution 3T MRI scans. Correlations between averaged annual NfL and 10-year clinical/MRI outcomes were assessed using Spearman's correlation, univariate, and multivariate linear regression models., Results: Averaged annual NfL values were negatively associated with year 10 BPF, which included averaged year 1-5 NfL values (unadjusted P < 0.01; adjusted analysis P < 0.01), and averaged values through year 10. Linear regression analyses of averaged annual NfL values showed multiple associations with T2LV, specifically averaged year 1-5 NfL (unadjusted P < 0.01; adjusted analysis P < 0.01). Approximately 15-20% of the BPF variance and T2LV could be predicted from early averaged annual NfL levels. Also, averaged annual NfL levels with fatigue score worsening between years 1 and 10 showed statistically significant associations. However, averaged NfL measurements were not associated with year 10 EDSS, SDMT or T25FW in this cohort., Interpretation: Serum NfL measured during the first few years after the clinical onset of MS contributed to the prediction of 10-year MRI brain lesion load and atrophy.

Objective: To identify circulating microRNAs (miRNAs) linked to disease, disease stage, and disability in MS across cohorts., Methods: Samples were obtained from the Comprehensive Longitudinal Investigation of Multiple Sclerosis (CLIMB, Boston, MA), EPIC (San Francisco, CA), AMIR (Beirut, Lebanon) as part of the SUMMIT consortium, and Stockholm Prospective Assessment of Multiple Sclerosis (Stockholm, Sweden) cohorts. Serum miRNA expression was measured using locked nucleic acid-based quantitative PCR. Four groups were compared: (1) MS vs healthy control (HC), (2) relapsing-remitting (RR) vs HC, (3) secondary progressive (SP) vs HC, and (4) RR vs SP. A Wilcoxon rank-sum test was used for the comparisons. The association between each miRNA and the Expanded Disability Status Scale (EDSS) score was assessed using the Spearman correlation coefficient. For each comparison, the p values were corrected for multiple comparisons using the approach of Benjamini and Hochberg to control the false discovery rate., Results: In the CLIMB cohort, 5 miRNAs (hsa-miR-484, hsa-miR-140-5p, hsa-miR-320a, hsa-miR-486-5p, and hsa-miR-320c) showed a significant difference between patients with MS and healthy individuals; among these, miR-484 remained significant after accounting for multiple comparisons ( p = 0.01). When comparing RRMS with HCs, hsa-miR-484 showed a significant difference ( p = 0.004) between the groups after accounting for multiple group comparisons. When SP and HC were compared, 6 miRNAs (hsa-miR-484, hsa-miR-140-5p, hsa-miR-142-5p, hsa-miR-320a, hsa-miR-320b, and hsa-miR-320c) remained significantly different after accounting for multiple comparisons. Disability correlation analysis with miRNA provided 4 miRNAs (hsa-miR-320a, hsa-miR-337-3p, hsa-miR-199a-5p, and hsa-miR-142-5p) that correlated with the EDSS during the internal reproducibility phase. Among these, hsa-miR-337-3p was the most statistically significant miRNA that negatively correlated with the EDSS in three of the MS cohorts tested., Conclusions: These findings further confirm the use of circulating serum miRNAs as biomarkers to diagnose and monitor disease status in MS., Classification of Evidence: This study provides Class III evidence that levels of circulating miRNAs identify patients with MS.

Introduction: Amyotrophic lateral sclerosis (ALS) is a debilitating neurologic disorder with poor survival rates and no clear biomarkers for disease diagnosis and prognosis., Methods: We compared serum microRNA (miRNA) expression from patients with ALS with healthy controls and patients with multiple sclerosis and Alzheimer disease. We also correlated miRNA expression in cross-sectional and longitudinal cohorts of ALS patients with clinical parameters., Results: We identified 7 miRNAs (miR-192-5p, miR-192-3p, miR-1, miR-133a-3p, miR-133b, miR-144-5p, miR-19a-3p) that were upregulated and 6 miRNAs (miR-320c, miR-320a, let-7d-3p, miR-425-5p, miR-320b, miR-139-5p) that were downregulated in patients with ALS compared with healthy controls, patients with Alzheimer disease, and patients with multiple sclerosis. Changes in 4 miRNAs (miR-136-3p, miR-30b-5p, miR-331-3p, miR-496) correlated positively and change in 1 miRNA (miR-2110) correlated negatively with changes in clinical parameters in longitudinal analysis., Discussion: Our findings identified serum miRNAs that can serve as biomarkers for ALS diagnosis and progression. Muscle Nerve 58: 261-269, 2018., (© 2018 Wiley Periodicals, Inc.)

Background: Positive psychology uses targeted activities to increase the frequency and intensity of positive emotional experiences. Positive psychology interventions that increase positive constructs may facilitate adjustment and improve well-being in patients with multiple sclerosis (MS). The primary goal of this study was to assess the feasibility and acceptability of a 5-week group positive psychology intervention for patients with MS. In addition, we examined the utility of the group intervention to increase positive psychological constructs and health-related quality of life (HRQOL)., Methods: 11 patients completed 5 weeks of group positive psychology training, one time per week (session duration, 45-60 minutes). Each week, patients completed one of the following positive psychology exercises: gratitude for positive events, personal strengths, gratitude letter, enjoyable and meaningful activities, and remembering past successes. Patients completed patient-reported outcome measures, including measures of positive affect, optimism, depression, anxiety, and HRQOL, at baseline and after 5 weeks., Results: All the participants completed the 5-week group positive psychology intervention, and 82% attended four or more sessions. Improvements in fatigue (vitality) and depression after the group intervention were significant (P = .016 and .049, respectively). There were no statistically significant changes in positive or negative affect, optimism, anxiety, HRQOL, or cognition., Conclusions: The 5-week group positive psychology intervention was feasible and acceptable to patients with MS. A randomized controlled trial is necessary to further explore the effectiveness of the group intervention., Competing Interests: Dr. Healy has served as a consultant for Biogen Idec and receives research support from Merck-Serono, Novartis, Genzyme, and Verily Life Sciences. Dr. Chitnis has received personal compensation for advisory board/consulting from Novartis, Bayer, and Biogen and receives financial support for research activities from Merck-Serono, Novartis, and Verily Life Sciences. Dr. Weiner has served as a consultant for Genentech and Tiziana Life Sciences and has received research support from EMD Serono, Miragen Therapeutics, Sanofi, Teva Pharmaceuticals, and Verily Life Sciences. Dr. Huffman's time for scientific input and editing was supported by grants R01HL113272 and R21DK109313 to him from the National Institutes of Health. Dr. Glanz has received research support from Merck-Serono and Verily Life Sciences. Mss. Leclaire, Cecil, LaRussa, and Stuart and Dr. Hemond have no conflicts of interest to disclose.

Background: There is uncertainty regarding the effect of oral hormonal contraceptives (OC) on multiple sclerosis (MS) course., Objective: To evaluate the hypothesis that OC use is associated with decreased risk of relapses in an observational study of women of childbearing age with new-onset MS starting a first-line injectable disease-modifying therapy (DMT)., Methods: From our CLIMB longitudinal observational study, we identified 162 women with MS or CIS with known OC use who initiated injectable DMT within two years of symptom onset, and categorized OC use at DMT onset as past, ever or never. Our primary analysis was comparison of annualized relapse rate from baseline DMT start across the three OC use categories using a negative binomial regression model., Results: In this cohort of 162 women, 81 were treated with interferon therapy and 81 with glatiramer acetate. Mean ages for current-, past-, and never-OC users were 31.4 ( n = 46), 40.3 ( n = 66), and 37.9 ( n = 50) years, respectively ( p < 0.05); mean disease duration (1.0 years) and median baseline EDSS (1.0) did not differ between groups. Prior OC users had significantly lower relapse rates than never-users ( p = 0.031); the lower annualized relapse rate in current-users relative to never-users was not significant ( p = 0.91). Annualized relapse rate was not significantly different across the OC groups ( p = 0.057, three-group comparison)., Results: These observations provide reassurance for women newly diagnosed that OC use, past or current, does not appear to be associated with greater risk of relapses.

Background: The recent approval of oral disease-modifying therapies (DMTs) for multiple sclerosis (MS) has provided patients with a new route of therapy administration. Little research has compared patients' experiences with and perceptions of injectable, infusion and oral MS therapies., Methods: Three hundred fifty-seven treated MS patients enrolled in the CLIMB study completed the Treatment Satisfaction Questionnaire for Medication (TSQM). The TSQM provides information regarding perceived effectiveness, side effects, convenience and overall satisfaction. The patients were treated with either interferon beta-1a intramuscular (IFNβ-1a IM) (n = 40), interferon beta-1a subcutaneous (IFNβ-1a SC) (n = 45), glatiramer acetate (GA) (n = 118), natalizumab (NTZ) (n = 44), fingolimod (n = 66), or dimethyl fumarate (BG-12) (n = 44). Multivariable linear regression models were used to compare treatment satisfaction across all DMTs and between patients treated with injectable (n = 203), infusion (n = 44), and oral (n = 110) DMTs. All models were adjusted for sex, age, EDSS, and time on treatment., Results: Patients taking oral DMTs reported significantly higher convenience scores compared to patients taking either injectable or infusion DMTs. The adjusted difference in the mean overall convenience score was 26.87 (95% CI: 21.4, 32.34) for the comparison of orals and injectables and 17.53 (95% CI: 11.15, 23.9) for the comparison of orals and infusion. In addition, the proportion of patients reporting a side effect was significantly lower for orals compared to injectables (adjusted OR= 0.35; 95% CI: 0.18, 0.68) and infusion compared to injectables (adjusted OR= 0.14; 95% CI: 0.05, 0.35)., Conclusion: Patients reported treatment with the oral medications as more convenient than the injectable and infusion DMTs., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Alcohol and in particular red wine have both immunomodulatory and neuroprotective properties, and may exert an effect on the disease course of multiple sclerosis (MS)., Objective: To assess the association between alcohol and red wine consumption and MS course., Methods: MS patients enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB) who completed a self-administered questionnaire about their past year drinking habits at a single time point were included in the study. Alcohol and red wine consumption were measured as servings/week. The primary outcome was the Expanded Disability Status Scale (EDSS) at the time of the questionnaire. Secondary clinical outcomes were the Multiple Sclerosis Severity Score (MSSS) and number of relapses in the year before the questionnaire. Secondary MRI outcomes included brain parenchymal fraction and T2 hyperintense lesion volume (T2LV). Appropriate regression models were used to test the association of alcohol and red wine intake on clinical and MRI outcomes. All analyses were controlled for sex, age, body mass index, disease phenotype (relapsing vs. progressive), the proportion of time on disease modifying therapy during the previous year, smoking exposure, and disease duration. In the models for the MRI outcomes, analyses were also adjusted for acquisition protocol., Results: 923 patients (74% females, mean age 47 ± 11 years, mean disease duration 14 ± 9 years) were included in the analysis. Compared to abstainers, patients drinking more than 4 drinks per week had a higher likelihood of a lower EDSS score (OR, 0.41; p = 0.0001) and lower MSSS (mean difference, - 1.753; p = 0.002) at the time of the questionnaire. Similarly, patients drinking more than 3 glasses of red wine per week had greater odds of a lower EDSS (OR, 0.49; p = 0.0005) and lower MSSS (mean difference, - 0.705; p = 0.0007) compared to nondrinkers. However, a faster increase in T2LV was observed in patients consuming 1-3 glasses of red wine per week compared to nondrinkers., Conclusions: Higher total alcohol and red wine intake were associated with a lower cross-sectional level of neurologic disability in MS patients but increased T2LV accumulation. Further studies should explore a potential cause-effect neuroprotective relationship, as well as the underlying biological mechanisms., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Previous research has examined the components of depression and fatigue in multiple sclerosis (MS), but the findings have been inconsistent. The aim of this study was to explore the associations between overall and subscale scores of the Center for Epidemiologic Studies-Depression Scale (CES-D) and the Modified Fatigue Impact Scale (MFIS) as well as the longitudinal changes in scores in a large cohort of MS patients., Methods: MS subjects who completed a battery of patient reported outcome (PRO) measures including the CES-D and MFIS (N=435) were included in our analysis. At the first available MFIS measurement, Pearson's correlation coefficient was used to estimate the association between the CES-D and MFIS in terms of both total scores and subscale scores. In addition, the longitudinal change in each total score and subscale score was estimated using a linear mixed model, and the association between the measures in terms of longitudinal change was estimated using Pearson's correlation coefficient and linear mixed models., Results: At baseline, 15% of subjects were classified as high on both depression and fatigue scales, 16% were classified as high on the fatigue scale only, and 9% were classified as high on the depression scale only. There was a high correlation between CES-D and MFIS total scores (r=0.62). High correlations were also observed between the somatic and retarded activity subscales of the CES-D and each of the MFIS subscales (r≥0.60). In terms of longitudinal change, the change over the first year between the CES-D and MFIS total scores showed a moderate correlation (r=0.49). Subjects with high fatigue scores but low depression scores at baseline were more likely than subjects with low baseline fatigue and depression scores to develop high depression scores at follow-up., Conclusions: Our study demonstrated that depression and fatigue in MS share several features and have a similar longitudinal course. But using cut-off scores to define depression and fatigue, our study also found that non-depressed subjects with high fatigue may be at a greater risk for developing depression., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background and Purpose: Two common approaches for measuring disease severity in multiple sclerosis (MS) are the clinical exam and brain magnetic resonance imaging (MRI) scan. Although most patients show similar disease severity on both measures, some patients have clinical/MRI dissociation., Methods: Subjects from a comprehensive care MS center who had a concurrent brain MRI, spinal cord MRI, clinical examination, and patient reported outcomes were classified into three groups based on the Expanded Disability Status Scale (EDSS) and cerebral T2 hyperintense lesion volume (T2LV). The first group was the low lesion load/high disability group (LL/HD) with T2LV < 2 ml and EDSS ≥ 3. The second group was the high lesion load/low disability group (HL/LD) with T2LV > 6 ml and EDSS ≤ 1.5. All remaining subjects were classified as not dissociated. The three groups were compared using regression techniques for unadjusted analyses and to adjust for age, disease duration, and gender., Results: Twenty-two subjects were classified as LL/HD (4.1%; 95% CI: 2.6%, 6.2%), and 50 subjects were classified as HL/LD (9.4%; 95% CI: 7.0%, 12.2%). Subjects in the LL/HD group were more likely to have a progressive form of MS and had significantly lower physical quality of life in adjusted and unadjusted analysis. Subjects in HL/LD had significantly more gadolinium-enhancing lesions, and subjects in the LL/HD group had significantly more cervical spinal cord lesions., Conclusions: Our results indicate that dissociation may occur between physical disability and cerebral lesion volume in either direction in patients with MS. Type of MS, brain atrophy, and spinal cord lesions may help to bridge this dissociation., (© 2017 The Authors. Journal of Neuroimaging published by Wiley Periodicals, Inc. on behalf of American Society of Neuroimaging.)