Temporal profile of serum neurofilament light in multiple sclerosis: Implications for patient monitoring.

OBJECTIVE: To understand how longitudinal serum neurofilament light chain (sNfL) patterns can inform its use as a prognostic biomarker in multiple sclerosis (MS) and evaluate whether sNfL reflects MS disease activity and disease-modifying therapy usage. METHODS: This was a post hoc analysis of longitudinal data and samples from the ADVANCE trial (NCT00906399) of patients with relapsing-remitting MS (RRMS). sNfL was measured every 3 months for 2 years, then every 6 months for 4 years. Regression models explored how sNfL data predicted 4-year values of brain volume, expanded disability status scale score, and T2 lesions. sNfL levels were assessed in those receiving placebo, peginterferon beta-1a, and those with disease activity. RESULTS: Baseline sNfL was a predictor of 4-year brain atrophy and development of new T2 lesions. Clinical (p = 0.02) and magnetic resonance imaging (MRI) (p < 0.01) outcomes improved in those receiving peginterferon beta-1a whose sNfL decreased to <16 pg/mL after 12 months versus those whose sNfL remained ⩾16 pg/mL. Mean sNfL levels decreased in peginterferon beta-1a-treated patients and increased in placebo-treated patients (-9.5% vs. 6.8%; p < 0.01). sNfL was higher and more variable in patients with evidence of active MS. CONCLUSION: These data support sNfL as a prognostic and disease-monitoring biomarker for RRMS.

Neurofilament light levels are associated with long-term outcomes in multiple sclerosis.

BACKGROUND: Neurofilament light chain (NfL) is a promising marker of disease activity/treatment response in multiple sclerosis (MS), although its predictive value for long-term clinical outcomes remains unclear. OBJECTIVE: We measured NfL from a phase 3 trial in relapsing-remitting MS and investigated its association with outcomes after 8 and 15 years. METHODS: NfL concentrations were measured by single molecule array assay in cerebrospinal fluid (CSF) from MS patients (n = 235) in a 2-year randomized clinical trial (RCT) of intramuscular interferon ß-1a, and in serum (n = 164) from the extension study. RESULTS: Year 2 CSF and Year 3 serum NfL were associated with brain parenchymal fraction (BPF) change over 8 years (p < 0.0001, r = -0.46; p < 0.05. r = -0.36, respectively) and were predictive of reaching Expanded Disability Status Scale (EDSS) ⩾ 6.0 at Year 8 (odds ratio (OR) (upper vs lower tertile) = 3.4; 95% confidence interval (CI) = 1.2-9.9, p < 0.05; OR = 11.0, 95% CI = 2.0-114.6; p < 0.01, respectively). Serum NfL concentration (Year 4) was predictive of reaching EDSS score ⩾6.0 at 15 years (OR (upper vs lower tertile) = 4.9; 95% CI = 1.4-20.4; p < 0.05). NfL concentrations were complementary to 2-year BPF change in predicting long-term outcomes. CONCLUSION: Serum and CSF NfL concentrations were associated with long-term clinical outcomes in MS patients and are promising biomarkers for disease severity stratification supporting treatment decisions.

Symbol Digit Modalities Test: A valid clinical trial endpoint for measuring cognition in multiple sclerosis.

BACKGROUND: The need for more robust outcomes in multiple sclerosis (MS) clinical trials has been a main priority of the field for decades. Dissatisfaction with existing measures has led to several consensus meetings and initiatives over the past few decades in hopes of defining and gaining acceptance of measures that are valid, reliable, sensitive to change and progression, and most importantly, relevant to those living with MS. The Multiple Sclerosis Outcome Assessments Consortium (MSOAC) was formed for this purpose. OBJECTIVE: The objective of this paper is to describe the results of the MSOAC plan to obtain qualification for a cognitive performance measure that meets these requirements. METHODS: Using data from 14 MS disease-modifying registration trials, we completed a comprehensive examination of the psychometric qualities of the Symbol Digit Modalities Test (SDMT) and the Paced Auditory Serial Addition Test (PASAT) with the goal of compiling evidence to support the utilization of one of these measures in future clinical trials. RESULTS AND CONCLUSION: Consistent with the published literature, the SDMT proved superior to the PASAT. The SDMT should be considered the measure of choice for MS trials in assessing cognitive processing speed.

The MSOAC approach to developing performance outcomes to measure and monitor multiple sclerosis disability.

BACKGROUND: The Multiple Sclerosis Outcome Assessments Consortium (MSOAC) was formed by the National MS Society to develop improved measures of multiple sclerosis (MS)-related disability. OBJECTIVES: (1) To assess the current literature and available data on functional performance outcome measures (PerfOs) and (2) to determine suitability of using PerfOs to quantify MS disability in MS clinical trials. METHODS: (1) Identify disability dimensions common in MS; (2) conduct a comprehensive literature review of measures for those dimensions; (3) develop an MS Clinical Data Interchange Standards Consortium (CDISC) data standard; (4) create a database of standardized, pooled clinical trial data; (5) analyze the pooled data to assess psychometric properties of candidate measures; and (6) work with regulatory agencies to use the measures as primary or secondary outcomes in MS clinical trials. CONCLUSION: Considerable data exist supporting measures of the functional domains ambulation, manual dexterity, vision, and cognition. A CDISC standard for MS ( http://www.cdisc.org/therapeutic#MS ) was published, allowing pooling of clinical trial data. MSOAC member organizations contributed clinical data from 16 trials, including 14,370 subjects. Data from placebo-arm subjects are available to qualified researchers. This integrated, standardized dataset is being analyzed to support qualification of disability endpoints by regulatory agencies.

Validity of the Symbol Digit Modalities Test as a cognition performance outcome measure for multiple sclerosis.

Cognitive and motor performance measures are commonly employed in multiple sclerosis (MS) research, particularly when the purpose is to determine the efficacy of treatment. The increasing focus of new therapies on slowing progression or reversing neurological disability makes the utilization of sensitive, reproducible, and valid measures essential. Processing speed is a basic elemental cognitive function that likely influences downstream processes such as memory. The Multiple Sclerosis Outcome Assessments Consortium (MSOAC) includes representatives from advocacy organizations, Food and Drug Administration (FDA), European Medicines Agency (EMA), National Institute of Neurological Disorders and Stroke (NINDS), academic institutions, and industry partners along with persons living with MS. Among the MSOAC goals is acceptance and qualification by regulators of performance outcomes that are highly reliable and valid, practical, cost-effective, and meaningful to persons with MS. A critical step for these neuroperformance metrics is elucidation of clinically relevant benchmarks, well-defined degrees of disability, and gradients of change that are deemed clinically meaningful. This topical review provides an overview of research on one particular cognitive measure, the Symbol Digit Modalities Test (SDMT), recognized as being particularly sensitive to slowed processing of information that is commonly seen in MS. The research in MS clearly supports the reliability and validity of this test and recently has supported a responder definition of SDMT change approximating 4 points or 10% in magnitude.

The Nine-Hole Peg Test as a manual dexterity performance measure for multiple sclerosis.

Impaired manual dexterity is a frequently reported disability in people with multiple sclerosis (MS) and is increasingly prevalent with worsening disease. While various tests and patient-reported outcome measures are available, the Nine-Hole Peg Test (NHPT) is considered as a gold standard measure of manual dexterity and most frequently used in MS research and clinical practice. The MS Outcome Assessments Consortium (MSOAC) includes representatives from advocacy organizations, Food and Drug Administration (FDA), European Medicines Agency (EMA), National Institute of Neurological Disorders and Stroke (NINDS), academic institutions, and industry partners along with persons living with MS. Among the MSOAC goals are acceptance and qualification by regulators of performance outcomes that are highly reliable and valid, practical, cost-effective, and meaningful to persons with MS. A critical step for these neuroperformance metrics is elucidation of clinically relevant benchmarks, well-defined degrees of disability, and gradients of change that are deemed clinically meaningful. This article addresses the NHPT, the proposed MSOAC measure for upper extremity function. We find that the NHPT is reliable within and between test sessions, discriminates between healthy subjects and MS patients with different levels of upper limb impairment, and shows high convergent validity with other manual dexterity as well as more comprehensive upper limb measures. Ecological validity is established by its relation to perceived upper limb use in daily life and perceived difficulty in performing activities of daily living. The NHPT is responsive to deterioration in longitudinal studies, and research suggests that a 20% change in test score is commonly used to define clinically meaningful worsening, a definition that needs further validation in all stages of the disease.

Validity of the timed 25-foot walk as an ambulatory performance outcome measure for multiple sclerosis.

The Multiple Sclerosis Outcome Assessments Consortium (MSOAC) includes representatives from advocacy organizations, Food and Drug Administration (FDA), European Medicines Agency (EMA), National Institute of Neurological Disorders and Stroke (NINDS), academic institutions, and industry partners along with persons living with multiple sclerosis (MS). One of the MSOAC goals is acceptance and qualification by regulators of performance outcomes that are highly reliable and valid, practical, cost-effective, and meaningful in MS. This article addresses the history, application, and psychometric properties of one such MSOAC metric of ambulation or walking namely, the timed 25-foot walk (T25FW). The T25FW has strong reliability over both brief and long periods of time in MS across a large range of disability levels. The outcome of walking speed from the T25FW has obvious real-world relevance and has correlated strongly with other measures of walking and lower extremity function. The T25FW is responsive for capturing intervention effects in pharmacological and rehabilitation trials and has an established value for capturing clinically meaningful change in ambulation. Directions for future research involve validating clinically meaningful improvements on the T25FW as well as determining whether 20% change is clinically meaningful across the disability spectrum. Researchers might further consider synchronizing accelerometers and motion sensors with the T25FW for capturing walking speed in everyday life and the patient's real environment.

Validity of low-contrast letter acuity as a visual performance outcome measure for multiple sclerosis.

Low-contrast letter acuity (LCLA) has emerged as the leading outcome measure to assess visual disability in multiple sclerosis (MS) research. As visual dysfunction is one of the most common manifestations of MS, sensitive visual outcome measures are important in examining the effect of treatment. Low-contrast acuity captures visual loss not seen in high-contrast visual acuity (HCVA) measurements. These issues are addressed by the MS Outcome Assessments Consortium (MSOAC), including representatives from advocacy organizations, Food and Drug Administration (FDA), European Medicines Agency (EMA), National Institute of Neurological Disorders and Stroke (NINDS), academic institutions, and industry partners along with persons living with MS. MSOAC goals are acceptance and qualification by regulators of performance outcomes that are highly reliable and valid, practical, cost-effective, and meaningful to persons with MS. A critical step is elucidation of clinically relevant benchmarks, well-defined degrees of disability, and gradients of change that are clinically meaningful. This review shows that MS and disease-free controls have similar median HCVA, while MS patients have significantly lower LCLA. Deficits in LCLA and vision-specific quality of life are found many years after an episode of acute optic neuritis, even when HCVA has recovered. Studies reveal correlations between LCLA and the Expanded Disability Status Score (EDSS), Multiple Sclerosis Functional Composite (MSFC), retinal nerve fiber layer (RNFL) and ganglion cell layer plus inner plexiform layer (GCL + IPL) thickness on optical coherence tomography (OCT), brain magnetic resonance imaging (MRI), visual evoked potential (VEP), electroretinogram (ERG), pupillary function, and King-Devick testing. This review also concludes that a 7-point change in LCLA is clinically meaningful. The overall goal of this review is to describe and characterize the LCLA metric for research and clinical use among persons with MS.

Processing speed test: Validation of a self-administered, iPad®-based tool for screening cognitive dysfunction in a clinic setting.

BACKGROUND: Cognitive dysfunction is common in multiple sclerosis (MS) patients and has important consequences for daily activities, yet, unlike motor function, is not routinely assessed in the clinic setting. We developed the Processing Speed Test (PST), a self-administered iPad®-based tool to measure MS-related deficits in processing speed. OBJECTIVE: To determine whether the PST is valid for screening cognitive dysfunction by comparing it to the paper-and-pencil Symbol Digit Modalities Test (SDMT). METHODS: We assessed PST test-retest reliability, sensitivity of PST and SDMT in discriminating MS patients from healthy controls (HC), convergent validity between PST and SDMT, correlations between T2 lesion load and PST and SDMT, and PST performance with and without technician present during administration. RESULTS: PST had excellent test-retest reliability, was highly correlated with SDMT, was slightly more sensitive than SDMT in discriminating MS from HC groups, and correlated better with cerebral T2 lesion load than did SDMT. Finally, PST performance was no different with or without a technician in the testing environment. CONCLUSION: PST has advantages over SDMT because of its efficient administration, scoring, and potential for medical record or research database integration. PST is a practical tool for routine screening of processing speed deficits in the MS clinic.

Factors associated with clinically significant increased walking time in multiple sclerosis: results of a survival analysis of short-term follow-up data from a clinical database.

BACKGROUND: Because multiple sclerosis (MS) is variable and unpredictable, if symptom worsening could be predicted, patients may feel better prepared to manage changes in function. OBJECTIVE: The objective of this paper is to study the prediction of walking impairment in MS. METHODS: We retrieved data for all MS patients at our center (2008-2009), including baseline and follow-up timed 25-foot walk (T25FW) times. We assessed the incidence of ≥20% worsening in T25FW by developing two survival models: (1) disease course and (2) Multiple Sclerosis Performance Scales (MSPS) score. The outcome was days until ≥20% worsening in T25FW. Covariates were disease subtype, years since diagnosis, Patient Health Questionnaire-9 (PHQ-9) score, and demographics. Data were interval censored; missing data were handled with multiple imputation. RESULTS: Of 1544 patients, 309 (20%) experienced ≥20% worsening T25FW. For disease course, time to worsening was significantly shorter for secondary progressive vs. relapsing-remitting disease (p < 0.001). For MSPS, patients with lower baseline MSPS scores progressed more slowly (p = 0.001). In both models, sex, baseline T25W, and time since diagnosis were significantly associated with worsening. In the disease course model, PHQ 9 score may be related to worsening (p = 0.07). CONCLUSION: These findings suggest factors associated with worsening in T25FW and a potential approach to establishing indicators associated with clinically significant change.

Experience with fingolimod in clinical practice.

AIM: To report experience with fingolimod in clinical practice. DESIGN/METHODS: Patients in an academic medical center who were prescribed fingolimod from October 2010 to August 2011 were identified through the electronic medical record and followed for 12 months after fingolimod initiation. Adverse effects (AEs), clinical measures, MRI data, and quality of life measures were assessed. RESULTS: Three hundred seventeen patients started fingolimod. Eleven patients were treatment naïve (3.5%) and 76 (24.0%) had remote disease modifying therapy (DMT) use prior to fingolimod. One hundred fifty-one (47.6%) switched because of patient preference and 79 (24.9%) switched because of breakthrough disease. About 11.6% transitioned from natalizumab. Follow-up data were available for 306 patients (96.5%) with mean follow-up time 332 days. Fingolimod was discontinued in 76 of 306 patients (24.8%) at mean 248 days after fingolimod start. Discontinuation most often was due to AEs (n = 40) or breakthrough disease (n = 22). Among patients who started fingolimod with available 12 month follow-up data, 267 (87.3%) remained relapse free and 256 (83.7%) had no relapses or gadolinium enhancement. Time to first relapse occurred at mean 282 days after fingolimod initiation. Quality of life measures remained stable at follow-up. CONCLUSIONS: Fingolimod was discontinued at a higher rate in clinical practice than in clinical trials. Discontinuation was primarily due to AEs or breakthrough disease. Disease activity was adequately controlled in most patients who started fingolimod. This clinical practice cohort is consistent with efficacy data from phase 3 trials and describes the most common tolerability issues in clinical practice.

Predictors of long-term outcome in multiple sclerosis patients treated with interferon ß.

OBJECTIVE: To identify early predictors of long-term outcomes in patients with relapsing-remitting multiple sclerosis (RRMS) treated with intramuscular (IM) interferon beta-1a (IFNß-1a). METHODS: A multicenter, observational, 15-year follow-up study of patients who completed ≥2 years in the pivotal trial of IM IFNß-1a for RRMS was conducted. One hundred thirty-six patients participated in the 15-year follow-up (69 originally randomized to IM IFNß-1a and 67 to placebo). After the 2-year clinical trial, treatment was not regulated by study protocol. Disease activity during the 2-year trial was defined as: ≥2 gadolinium-enhancing lesions (cumulative) on year 1 and/or year 2 magnetic resonance imaging (MRI); ≥3 new T2 lesions on year 2 MRI compared to baseline; and ≥2 relapses over 2 years. Odds ratios were calculated for early disease activity predicting severe Expanded Disability Status Scale (EDSS) worsening (worst quartile of change, ≥4.5 EDSS points) during the 15-year interval. RESULTS: The proportion of patients experiencing early disease activity was lower in patients on IM IFNß-1a than placebo for all disease activity markers (range, 23.5-29.0% vs 41.0-45.5%). In the IM IFNß-1a group, persistent disease activity predicted severe EDSS worsening: gadolinium-enhancing lesions (odds ratio [OR], 8.96; p < 0.001); relapses (OR, 4.44; p = 0.010); and new T2 lesions (OR, 2.90; p = 0.080). In placebo patients, early disease activity was not as strongly associated with long-term outcomes (OR range, 1.53-2.62; p = 0.069-0.408). INTERPRETATION: Disease activity despite treatment with IFNß is associated with unfavorable long-term outcomes. Particular attention should be paid to gadolinium-enhancing lesions on IFNß therapy, as their presence strongly correlates with severe disability 15 years later. The results provide rationale for monitoring IFNß-treated patients with MRI, and for changing therapy in patients with active disease.

Multiple Sclerosis Outcome Assessments Consortium: Genesis and initial project plan.

The need for improved clinical outcome measures in multiple sclerosis trials has been recognized for two decades, but only recently has the Food and Drug Administration (FDA) created a pathway for qualification of new clinician-reported outcome (ClinRO) assessments. Additionally, drug development in multiple sclerosis (MS) has been extraordinarily active, with numerous disease-modifying drugs now on the market. This shifting therapeutic landscape, along with the unmet need for drugs to treat the progressive forms of MS and the changing expectations of clinicians, patients, and payers, have led to the call for more sensitive and meaningful disability progression measures. In response to these drivers, the Multiple Sclerosis Outcome Assessments Consortium (MSOAC) was launched. A public-private partnership, MSOAC aims to accelerate the development of new therapies for MS by generating new tools for measuring outcomes in clinical trials. At the first annual MSOAC/FDA meeting, a regulatory path was outlined for qualifying a new tool for assessing efficacy in registration trials of MS. The European Medicines Agency (EMA) and FDA will provide parallel consultation and review. The consensus approach with engagement by all of the stakeholders, prominently including patients with MS, should also increase acceptance of the measure by clinicians and patients.

The role of cell type-specific responses in IFN-ß therapy of multiple sclerosis.

The mechanism of IFN-ß therapy in relapsing-remitting multiple sclerosis (RRMS) is not well understood, but induction of apoptosis in specific leukocyte subsets is likely to be important. Enhanced expression of TNFSF10 or TNF-related apoptosis-inducing ligand (TRAIL) mRNA in unseparated leukocytes has been put forward as a therapeutic response marker, but it is unclear which leukocyte subsets express TRAIL. We investigated the basis of TRAIL expression in response to IFN-ß by studying activation of STATs 1, 3, and 5, p38 MAPK, and NF-κB in different leukocyte subsets of patients with RRMS. Monocytes, B cells, and T cells showed substantial differences in the activation of p38 and the STATs in response to i.m. injection of IFN-ß1a or stimulation in vitro. Induction of cell-surface TRAIL, analyzed in nine leukocyte subsets, was observed only on monocytes and granulocytes and correlated with the activation of p38 and/or NF-κB in these subsets only, in agreement with previous work in fibroblasts showing that the induction of TRAIL in response to IFN-ß depends on the activation of p38 and NF-κB as well as STATs 1 and 2. We propose that, in myeloid cells, the differential activation of p38 and NF-κB and induction of TRAIL, which sensitizes cells to apoptosis, can help to explain differences in responsiveness to IFN-ß therapy among patients with RRMS and, furthermore, that such differential patterns of activation and expression may also be important in understanding the therapeutic responses to IFN-α/ß in hepatitis and cancer.

Temporal Relationship Between Serum Neurofilament Light Chain and Radiologic Disease Activity in Patients With Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Serum neurofilament light chain (sNfL) levels correlate with multiple sclerosis (MS) disease activity, but the dynamics of this correlation are unknown. We evaluated the relationship between sNfL levels and radiologic MS disease activity through monthly assessments during the 24-week natalizumab treatment interruption period in RESTORE (NCT01071083). METHODS: In the RESTORE trial, participants with relapsing forms of MS who had received natalizumab for ≥12 months were randomized to either continue or stop natalizumab and followed with MRI and blood draws every 4 weeks to week 28 and again at week 52 The sNfL was measured, and its dynamics were correlated with the development of gadolinium-enhancing (Gd+) lesions. Log-linear trend in sNfL levels were modeled longitudinally using generalized estimating equations with robust variance estimator from baseline to week 28. RESULTS: Of 175 patients enrolled in RESTORE, 166 had serum samples for analysis. Participants with Gd+ lesions were younger (37.7 vs 43.1, p = 0.001) and had lower Expanded Disability Status Scale scores at baseline (2.7 vs 3.4, p = 0.017) than participants without Gd+ lesions. sNfL levels increased in participants with Gd+ lesions (n = 65) compared with those without (n = 101, mean change from baseline to maximum sNfL value, 12.1 vs 3.2 pg/mL, respectively; p = 0.003). As the number of Gd+ lesions increased, peak median sNfL change also increased by 1.4, 3.0, 4.3, and 19.6 pg/mL in the Gd+ lesion groups of 1 (n = 12), 2-3 (n = 18), 4-9 (n = 21), and ≥10 (n = 14) lesions, respectively. However, 46 of 65 (71%) participants with Gd+ lesions did not increase above the 95th percentile threshold of the group without Gd+ lesions. The initial increase of sNfL typically trailed the first observation of Gd+ lesions, and the peak increase in sNfL was a median [interquartile range] of 8 [0, 12] weeks after the first appearance of the Gd+ lesion. DISCUSSION: Although sNfL correlated with the presence of Gd+ lesions, most participants with Gd+ lesions did not have elevations in sNfL levels. These observations have implications for the use and interpretation of sNfL as a biomarker for monitoring MS disease activity in controlled trials and clinical practice.

Serum neurofilament light-chain levels and long-term treatment outcomes in relapsing-remitting multiple sclerosis patients: A post hoc analysis of the randomized CombiRx trial.

Background: CombiRx was a randomized, double-blind, placebo-controlled phase 3 trial in treatment-naive relapsing-remitting multiple sclerosis (RRMS) patients randomized to intramuscular interferon beta-1a (IM IFN beta-1a), glatiramer acetate (GA), or both therapies. Objective: This analysis investigated changes in serum neurofilament light-chain (sNfL) levels in response to treatment and assessed baseline sNfL as a predictor of relapse. Methods: RRMS patients treated with IM IFN beta-1a 30 µg weekly + placebo (n = 159), GA 20 mg/mL daily + placebo (n = 172), or IM IFN beta-1a + GA (n = 344) were included. A linear mixed model compared sNfL values over time. Cox regression models analyzed baseline sNfL and gadolinium-enhancing (Gd+) lesions as predictors of relapse. Results: In all treatment arms, the proportion of patients with sNfL ≥16 pg/mL decreased significantly from baseline to 6 months and was maintained at 36 months. A significantly higher percentage of patients with both baseline sNfL ≥16 pg/mL and ≥1 Gd+ lesion experienced relapses within 90 days compared to patients with sNfL <16 pg/mL and/or no Gd+ lesions. Conclusion: sNfL levels were reduced within 6 months and remained low at 36 months. Results suggest that the combination of lesion activity and sNfL was a stronger predictor of relapse than either factor alone.

Magnetic resonance fingerprinting in multiple sclerosis.

BACKGROUND: In this cross sectional study, we used MRF to investigate tissue properties of normal-appearing white matter, gray matter, and lesions in relapsing remitting MS (n = 21), secondary progressive MS (n = 16) and healthy controls (n = 9). A FISP-based MRF sequence was used for acquisition, imaging time 5 min 15 s. MRF T1 and T2 relaxation times were measured from lesional tissue, normal-appearing frontal white matter, corpus callous, thalamus, and caudate. Differences between healthy controls and MS were examined using ANCOVA adjusted for age and sex. Spearman rank correlations were assessed between T1 and T2 relaxation times and clinical measures. OBJECTIVES: To examine brain T1 and T2 values using magnetic resonance fingerprinting (MRF) in healthy controls and MS. METHODS: The subjects included 21 relapsing-remitting (RR) MS, 16 secondary progressive (SP) MS, and 9 age- and sex-matched HC without manifest neurological disease participating in a longitudinal MRI study. A 3T/ FISP-based MRF sequence was acquired. Regions of interest were drawn for lesions and normal appearing white matter. ANCOVA adjusted for age and sex were used to compare the groups with significance set at 0.05. RESULTS: A step-wise increase in T1 and T2 relaxation times was found between healthy controls, relapsing remitting MS, and secondary progressive MS. Significant differences were found in T1 and T2 between MS and healthy controls in the frontal normal-appearing white matter, corpus callosum, and thalamus (p < 0.04 for all). Significant differences in T1 and T2 between RR and SPMS were found in the frontal normal-appearing white matter and T2 lesions (p < 0.02 for all). T1 relaxation from the frontal normal-appearing white matter correlated with the Expanded Disability Status Scale [ρ = 0.62, p < 0.001], timed 25 foot walk (ρ = 0.45, p = 0.01), 9 hole peg test (ρ = 0.62, p < 0.001), and paced auditory serial addition test (ρ = -0.4, p = 0.01). CONCLUSION: These results suggest that MRF may be a clinically feasible quantitative approach for characterizing tissue damage in MS.

Associations of sNfL with clinico-radiological measures in a large MS population.

OBJECTIVE: Evaluation of serum neurofilament light chain (sNfL), measured using high-throughput assays on widely accessible platforms in large, real-world MS populations, is a critical step for sNfL to be utilized in clinical practice. METHODS: Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) is a network of healthcare institutions in the United States and Europe collecting standardized clinical/imaging data and biospecimens during routine clinic visits. sNfL was measured in 6974 MS and 201 healthy control (HC) participants, using a high-throughput, scalable immunoassay. RESULTS: Elevated sNfL levels for age (sNfL-E) were found in 1238 MS participants (17.8%). Factors associated with sNfL-E included male sex, younger age, progressive disease subtype, diabetes mellitus, impaired renal function, and active smoking. Higher body mass index (BMI) was associated with lower odds of elevated sNfL. Active treatment with disease-modifying therapy was associated with lower odds of sNfL-E. MS participants with sNfL-E exhibited worse neurological function (patient-reported disability, walking speed, manual dexterity, and cognitive processing speed), lower brain parenchymal fraction, and higher T2 lesion volume. Longitudinal analyses revealed accelerated short-term rates of whole brain atrophy in sNfL-E participants and higher odds of new T2 lesion development, although both MS participants with or without sNfL-E exhibited faster rates of whole brain atrophy compared to HC. Findings were consistent in analyses examining age-normative sNfL Z-scores as a continuous variable. INTERPRETATION: Elevated sNfL is associated with clinical disability, inflammatory disease activity, and whole brain atrophy in MS, but interpretation needs to account for comorbidities including impaired renal function, diabetes, and smoking.

Epsilon toxin-producing Clostridium perfringens colonize the multiple sclerosis gut microbiome overcoming CNS immune privilege.

Multiple sclerosis (MS) is a complex disease of the CNS thought to require an environmental trigger. Gut dysbiosis is common in MS, but specific causative species are unknown. To address this knowledge gap, we used sensitive and quantitative PCR detection to show that people with MS were more likely to harbor and show a greater abundance of epsilon toxin-producing (ETX-producing) strains of C. perfringens within their gut microbiomes compared with individuals who are healthy controls (HCs). Isolates derived from patients with MS produced functional ETX and had a genetic architecture typical of highly conjugative plasmids. In the active immunization model of experimental autoimmune encephalomyelitis (EAE), where pertussis toxin (PTX) is used to overcome CNS immune privilege, ETX can substitute for PTX. In contrast to PTX-induced EAE, where inflammatory demyelination is largely restricted to the spinal cord, ETX-induced EAE caused demyelination in the corpus callosum, thalamus, cerebellum, brainstem, and spinal cord, more akin to the neuroanatomical lesion distribution seen in MS. CNS endothelial cell transcriptional profiles revealed ETX-induced genes that are known to play a role in overcoming CNS immune privilege. Together, these findings suggest that ETX-producing C. perfringens strains are biologically plausible pathogens in MS that trigger inflammatory demyelination in the context of circulating myelin autoreactive lymphocytes.

Beta-interferon for multiple sclerosis.

Interferon beta is widely used as first-line treatment for relapsing remitting multiple sclerosis (RRMS). Several products are marketed world-wide, and biosimilar products are emerging. Interferon beta reduces relapse rates by about 1/3, and reduces the appearance of new MRI lesions by about 2/3, and some studies have shown reduced disability progression, and reduced rates of brain atrophy. The mechanism of action of interferon beta in MS is poorly understood, partly due to the complex nature of the biological response to interferon injections. This mini-review succinctly summarizes clinical effects, possible mechanism of action, physiochemical properties of the different interferon products, issues related to immunogenicity, and biomarkers of the interferon beta response, and proposes important unresolved issues for future research.