Stigma in Multiple Sclerosis: A Narrative Review of Current Concepts, Measures, and Findings.

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.

Increasing Neurofilament and Glial Fibrillary Acidic Protein After Treatment Discontinuation Predicts Multiple Sclerosis Disease Activity.

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.

Accuracy of serum neurofilament light to identify contrast-enhancing lesions in multiple sclerosis.

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.

Association between PROMIS10, SF-36 and NeuroQoL in persons with multiple sclerosis.

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.

Multiple sclerosis lesions that impair memory map to a connected memory circuit.

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.

Early neurofilament light and glial fibrillary acidic protein levels improve predictive models of multiple sclerosis outcomes.

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.

Serum NfL but not GFAP predicts cognitive decline in active progressive multiple sclerosis patients.

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.

Clinical Trial-Ready Patient Cohorts for Multiple System Atrophy: Coupling Biospecimen and iPSC Banking to Longitudinal Deep-Phenotyping.

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.

Humoral response to COVID-19 vaccination in MS patients on disease modifying therapy: Immune profiles and clinical outcomes.

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.

Younger age at multiple sclerosis onset is associated with worse outcomes at age 50.

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.

Estimating the association between physical activity and health-related quality of life in individuals with multiple sclerosis.

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.

Early Predictors of Clinical and MRI Outcomes Using Least Absolute Shrinkage and Selection Operator (LASSO) in Multiple Sclerosis.

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.

Serum NfL levels in the first five years predict 10-year thalamic fraction in patients with MS.

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.

Patient-reported outcomes associated with transition to secondary progressive multiple sclerosis.

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.

An At-home Positive Psychology Intervention for Individuals with Multiple Sclerosis: A Phase 1 Randomized Controlled Trial.

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.

Relapse recovery in multiple sclerosis: Effect of treatment and contribution to long-term disability.

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.

Confirmed disability progression provides limited predictive information regarding future disease progression in multiple sclerosis.

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 impact of ocrelizumab on health-related quality of life in individuals with multiple sclerosis.

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.

Gut Microbiome in Progressive Multiple Sclerosis.

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 ß-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 ß-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.