Diversity and representation within the literature on sexual dysfunction in multiple sclerosis: A systematic review.

INTRODUCTION: Sexual dysfunction (SD) is a common and distressing symptom for people living with multiple sclerosis (MS). Populations included in existing studies of SD may not fully reflect the diversity of people living with MS, with important implications for wider applicability. We aimed to evaluate reporting of sex, gender identity, sexual orientation, and ethnicity across studies of SD in MS. METHODS: A systematic search of four databases was performed. Two independent authors evaluated all papers. Reporting of sex and gender identity, sexual orientation, and ethnicity were recorded. RESULTS: A total of 419 papers were reviewed, and 204 studies with 77,902 participants met the criteria for evaluation. Of 204 studies, 98 (48.0%) included both male and female participants; 78 (38.2%) included females only, and 27 (13.2%) males only. In 19 (9.3%) studies, participants were asked their gender. No studies reported asking a two-step question on sex and gender identity. No studies reported including non-binary patients or gender identities other than male or female. No studies reported including intersex patients. Only 10 (4.9%) studies reported the inclusion of homosexual or bisexual participants, or participants from other sexual minority groups. The overwhelming majority of studies (181; 88.7%) did not report ethnicity or race of participants. CONCLUSION: Sex, gender identity, sexual orientation, and ethnicity are poorly reported in studies on SD in MS. These variables must be adequately evaluated to ensure research applies across diverse MS patient populations.

Reconciling lesions, relapses and smouldering associated worsening: A unifying model for multiple sclerosis pathogenesis.

The failure of relapses and white matter lesions to properly explain long-term disability and progression in multiple sclerosis is compounded by its artificial separation into relapsing remitting, secondary progressive, and primary progressive pigeonholes. The well-known epidemiological disconnection between relapses and long-term disability progression has been rediscovered as "progression independent of relapse activity", i.e. smouldering multiple sclerosis. This smouldering associated worsening proceeds despite early and prolonged use of disease modification therapies, even those that are highly effective at preventing relapses and new/enhancing white matter lesions on MRI. We recognise that smouldering associated worsening and relapse/lesion associated worsening coexist, to varying extents. The extent of cortical demyelination has been shown to correlate significantly with the severity of diffuse injury in normal appearing white matter (post mortem histopathologically (r = 0.55; P = 0.001), and in vivo with MRI (r = -0.6874; P = 0.0006)) and does so independently of white matter lesion burden. Axon loss in the normal appearing white matter explains disability in multiple sclerosis better than focal white matter lesions do. Smouldering associated worsening typically manifests as a length-dependent central axonopathy. We propose a unifying model for multiple sclerosis pathogenesis, wherein accumulation of cortical lesion burden predisposes associated normal appearing white matter to diffuse injury, whilst also intensifying damage within white matter lesions. Our novel two-hit hypothesis implicates cortical disease as a culprit for smouldering multiple sclerosis, abetted by active focal inflammation in the white matter (and vice versa). Substantiation of the two-hit hypothesis would advance the importance of specific therapeutic intervention for (and monitoring of) cortical/meningeal inflammation in people with multiple sclerosis.

Engaging a community to focus on upper limb function in people with multiple sclerosis: the ThinkHand campaign case study.

BACKGROUND: Solving complex research challenges requires innovative thinking and alternative approaches to traditional methods. One such example is the problem of arm and hand, or upper limb function in multiple sclerosis (MS), a neurological condition affecting approximately 2.9 million people worldwide and more than 150,000 in the United Kingdom. Historically, clinical trials and research have focused on mobility and walking ability. This excludes a large number of patients who are wheelchair users, limiting their quality of life and restricting access to possibly helpful medications. To address this issue, the ThinkHand campaign was launched in 2016, aiming to raise awareness about the importance of upper limb function in MS and develop alternative ways to measure, record, and account for hand and arm function changes. MAIN BODY: The campaign utilised innovative strategies at scientific conferences and online surveys to engage people affected by MS, healthcare professionals, charities, and researchers in discussing the importance of preserving upper limb function. Through co-design and interdisciplinary collaboration, the campaign developed new tools like the low-cost cardboard version of the Nine-Hole Peg Test, facilitating remote monitoring of hand function. Additionally, the campaign co-created the "Under & Over" rehabilitation tool, allowing individuals with advanced MS to participate in a remote rehabilitation program.The impact of the ThinkHand campaign has been significant, helping to shift the focus of both academic and industry-supported trials, including the O'HAND and ChariotMS trials, both using upper limb function as their primary end point. The campaign's patient-centred approach highlighted the importance of recognising patients' perspectives in research and challenged established assumptions and practices. It demonstrated the effectiveness of interdisciplinary collaboration, systems thinking, and co-creation with stakeholders in tackling complex problems. CONCLUSION: The ThinkHand campaign provides valuable insights for health research practices. By involving patients at all stages, researchers can gain a deeper understanding of the impact of disease on their lives, identify gaps and focus research on their needs. Experimentation and iteration can lead to innovative solutions, and openness to unconventional methods can drive widespread change. The ThinkHand campaign exemplifies the potential of patient-centred approaches to address complex research challenges and revolutionise the field of MS research and management. Embracing such approaches will contribute to more inclusive and impactful research in the future.

Solving complex research challenges requires creative thinking and new ways of doing things. One such challenge is understanding the problems with arm and hand function in multiple sclerosis (MS), a neurological condition that affects more than 150,000 in the United Kingdom. In the past, research focused mainly on walking ability, leaving out many people who use wheelchairs.To tackle this issue, we created the ThinkHand campaign in 2016. Its goal was to raise awareness about the importance of hand and arm function for people with MS (pwMS) and find better ways to measure changes in these functions such that they can become outcomes in clinical trials. This could provide a pathway to better treatments for pwMS who cannot walk.The campaign used various methods, including surveys, social media posts, exhibitions and music to involve pwMS, healthcare professionals, charities, and researchers in discussions about the issues. Working together, they created tools to support pwMS, particularly those at an advanced stage of the disease (pwAMS), to take part in research and measure their hand and arm function. Through our collaborative approach focusing on patients' perspectives, the campaign challenged old ideas and deeply embedded practices. It showed that collaboration between different areas of expertise involving pwMS at all stages of research can help solve complex problems. This campaign teaches us valuable lessons for health research. When researchers listen to patients and try new things, they can better understand how a disease affects people's lives and develop better solutions.In conclusion, we show how embracing a patient-centred approach can address complex research challenges and improve how we study and manage MS and other conditions in the future.

No association between oral contraceptive exposure and subsequent MS: A population-based nested case-control study in primary care.

BACKGROUND: Conflicting data exist around oral contraceptive exposure and subsequent multiple sclerosis (MS). OBJECTIVE: To use routinely collected primary healthcare data to explore the potential association between oral contraceptive exposure and subsequent MS in females at population level. METHODS: We performed a nested case-control study using electronic primary care data, with complete electronic ascertainment from 1990. Logistic regression was used to evaluate associations between contraceptive exposure and MS, without and with adjusting for age, ethnicity and deprivation. RESULTS: A total of 4455 females were included: 891 cases and 3564 controls. No association was seen between oral contraceptive exposure and subsequent MS, or between any contraceptive, combined oral contraceptive pill (COCP) or progesterone-only pill (POP) use 0-2, 2-5 or >5 years prior to MS. Conclusions: In the largest population-based study to date, we find no evidence of an association between oral contraceptive exposure and subsequent MS diagnosis.

Making Information About Cladribine Tablets Accessible to People with Multiple Sclerosis: A Patient-Survey-Led Narrative Review for Healthcare Professionals.

Cladribine tablets have been granted marketing authorization in Europe and approved by the Food and Drug Administration (FDA) in the USA to treat relapsing forms of multiple sclerosis (MS). However, people with MS (PwMS) may be more familiar, and therefore more confident, with treatments requiring long-term and frequent dosing. Differences in such treatment strategies can lead to questions relating to how short-course non-continuous treatments, such as cladribine tablets, can work and how well they are tolerated. In response to this, we aimed to create an evidence-based report on patient-focused aspects of treatment with cladribine. To inform development, MS experts, including healthcare professionals (HCPs) and PwMS, proposed topics that PwMS and their families and caregivers would most like to discuss with HCPs during consultations to help them better understand cladribine treatment. The statements regarding each topic were then ranked by PwMS and used to inform the topics covered in this report. We explain here the use of cladribine tablets, which includes explanations of how cladribine tablets work, how to take cladribine tablets, and considerations required prior to and while taking cladribine tablets. We also describe how cladribine tablets affect relapse rate and quality of life and detail side effects, when they are likely to happen, and for how long. We also discuss how cladribine tablets affect family planning, fertility, and the use of vaccines. Alongside each section is a brief, plain language description of what is covered and an accompanying visual to aid conversations between HCPs and PwMS. Improved understanding by PwMS of treatments, such as cladribine, can empower them to play a bigger role in shared decision-making regarding their treatment. Additionally, the open dialogue we aim to promote with this type of report could lead to treatment choices being better tailored for individuals with chronic diseases on the basis of personal experiences, preferences, and circumstances.

Under & Over: A randomised controlled study to develop an upper limb rehabilitation tool for people with Multiple Sclerosis.

BACKGROUND: Impairment of upper limb function is common in Multiple Sclerosis (MS). Rehabilitation remains a key strategy to manage symptoms and improve quality of life. The Under & Over study assessed the effectiveness of a rehabilitation programme in people with advanced MS. OBJECTIVE: To determine if repeated use of Under & Over can improve upper limb function for people with MS. METHODS: One hundred and six (N = 106) people with MS participated in this 3-month study. The primary outcome measure was the cardboard 9-hole peg test (c9HPT), with secondary outcomes including the EuroQol-5Dimensions, 5-Level Questionnaire (EQ5D-5 L) questionnaire. There were three arms: Arm 1a, the 'Daily Group', engaged with the Under & Over tool daily for 30 min. Arm 1b, the 'Free Use Group', used the same tool without time constraints, with the added feature of a community sharing platform. Arm 2, the 'Delayed Start Group', initially completed the c9HPT for three months before switching to the 'Free Use' programme. RESULTS: 43/106 (41 %) of those randomised completed the primary end point. No significant difference between c9HPT at baseline and 3 months was seen in Arm 1a or 1b. Participants in Arm 2 who had been completing the c9HPT 5 days a week for 3 months showed a training effect in the dominant hand (mean speed at baseline 0.0455 (s-1), mean at 3 months 0.0341, difference 0.011; 95 % CI 0.0080 to 0.0148, p < 0.001). No significant difference was seen in c9HPT time following 3 months of active use of the Under & Over tool. The study faced significant limitations, notably in participant adherence, with fewer than half (43/106 (41 %)) completing the final assessment. CONCLUSIONS: This study demonstrates how a small, engaged, and motivated group were able to complete a remote rehabilitation programme. Future remote intervention studies could benefit from incorporating adaptive engagement strategies, such as personalised reminders and participant-tailored activity adjustments, to enhance adherence and capture a broader spectrum of patient experiences.

Targeting Epstein-Barr virus in multiple sclerosis: when and how?

PURPOSE OF REVIEW: Epidemiological evidence implicates Epstein-Barr virus (EBV) as the cause of multiple sclerosis (MS). However, its biological role in the pathogenesis of MS is uncertain. The article provides an overview of the role of EBV in the pathogenesis of MS and makes a case for targeting EBV as a treatment strategy for MS. RECENT FINDINGS: EBV potentially triggers autoimmunity via molecular mimicry or immune dysregulation. Another hypothesis, supported by immunological and virological data, indicates that active EBV infection via latent-lytic infection cycling within the central nervous system or periphery drives MS disease activity. This supports testing small molecule anti-EBV agents targeting both latent and lytic infection, central nervous system-penetrant B-cell therapies and EBV-targeted immunotherapies in MS. Immunotherapies may include EBV-specific cytotoxic or chimeric antigen receptors T-cells, therapeutic EBV vaccines and immune reconstitution therapies to boost endogenous EBV-targeted cytotoxic T-cell responses. SUMMARY: EBV is the probable cause of MS and is likely to be driving MS disease activity via latent-lytic infection cycling. There is evidence that all licensed MS disease-modifying therapies target EBV, and there is a compelling case for testing other anti-EBV strategies as potential treatments for MS.

Inhibition of CD40L with Frexalimab in Multiple Sclerosis.

BACKGROUND: The CD40-CD40L costimulatory pathway regulates adaptive and innate immune responses and has been implicated in the pathogenesis of multiple sclerosis. Frexalimab is a second-generation anti-CD40L monoclonal antibody being evaluated for the treatment of multiple sclerosis. METHODS: In this phase 2, double-blind, randomized trial, we assigned, in a 4:4:1:1 ratio, participants with relapsing multiple sclerosis to receive 1200 mg of frexalimab administered intravenously every 4 weeks (with an 1800-mg loading dose), 300 mg of frexalimab administered subcutaneously every 2 weeks (with a 600-mg loading dose), or the matching placebos for each active treatment. The primary end point was the number of new gadolinium-enhancing T1-weighted lesions seen on magnetic resonance imaging at week 12 relative to week 8. Secondary end points included the number of new or enlarging T2-weighted lesions at week 12 relative to week 8, the total number of gadolinium-enhancing T1-weighted lesions at week 12, and safety. After 12 weeks, all the participants could receive open-label frexalimab. RESULTS: Of 166 participants screened, 129 were assigned to a trial group; 125 participants (97%) completed the 12-week double-blind period. The mean age of the participants was 36.6 years, 66% were women, and 30% had gadolinium-enhancing lesions at baseline. At week 12, the adjusted mean number of new gadolinium-enhancing T1-weighted lesions was 0.2 (95% confidence interval [CI], 0.1 to 0.4) in the group that received 1200 mg of frexalimab intravenously and 0.3 (95% CI, 0.1 to 0.6) in the group that received 300 mg of frexalimab subcutaneously, as compared with 1.4 (95% CI, 0.6 to 3.0) in the pooled placebo group. The rate ratios as compared with placebo were 0.11 (95% CI, 0.03 to 0.38) in the 1200-mg group and 0.21 (95% CI, 0.08 to 0.56) in the 300-mg group. Results for the secondary imaging end points were generally in the same direction as those for the primary analysis. The most common adverse events were coronavirus disease 2019 and headaches. CONCLUSIONS: In a phase 2 trial involving participants with multiple sclerosis, inhibition of CD40L with frexalimab had an effect that generally favored a greater reduction in the number of new gadolinium-enhancing T1-weighted lesions at week 12 as compared with placebo. Larger and longer trials are needed to determine the long-term efficacy and safety of frexalimab in persons with multiple sclerosis. (Funded by Sanofi; ClinicalTrials.gov number, NCT04879628.).

Efficacy and safety of autologous haematopoietic stem cell transplantation versus alemtuzumab, ocrelizumab, ofatumumab or cladribine in relapsing remitting multiple sclerosis (StarMS): protocol for a randomised controlled trial.

INTRODUCTION: Autologous haematopoietic stem cell transplantation (aHSCT) is increasingly used as treatment for patients with active multiple sclerosis (MS), typically after failure of disease-modifying therapies (DMTs). A recent phase III trial, 'Multiple Sclerosis International Stem Cell Transplant, MIST', showed that aHSCT resulted in prolonged time to disability progression compared with DMTs in patients with relapsing remitting MS (RRMS). However, the MIST trial did not include many of the current high-efficacy DMTs (alemtuzumab, ocrelizumab, ofatumumab or cladribine) in use in the UK within the control arm, which are now offered to patients with rapidly evolving severe MS (RES-MS) who are treatment naïve. There remain, therefore, unanswered questions about the relative efficacy and safety of aHSCT over these high-efficacy DMTs in these patient groups. The StarMS trial (Autologous Stem Cell Transplantation versus Alemtuzumab, Ocrelizumab, Ofatumumab or Cladribine in Relapsing Remitting Multiple Sclerosis) will assess the efficacy, safety and long-term impact of aHSCT compared with high-efficacy DMTs in patients with highly active RRMS despite the use of standard DMTs or in patients with treatment naïve RES-MS. METHODS AND ANALYSIS: StarMS is a multicentre parallel-group rater-blinded randomised controlled trial with two arms. A total of 198 participants will be recruited from 19 regional neurology secondary care centres in the UK. Participants will be randomly allocated to the aHSCT arm or DMT arm in a 1:1 ratio. Participants will remain in the study for 2 years with follow-up visits at 3, 6, 9, 12, 18 and 24 months postrandomisation. The primary outcome is the proportion of patients who achieve 'no evidence of disease activity' during the 2-year postrandomisation follow-up period in an intention to treat analysis. Secondary outcomes include efficacy, safety, cost-effectiveness and immune reconstitution of aHSCT and the four high-efficacy DMTs. ETHICS AND DISSEMINATION: The study was approved by the Yorkshire and Humber-Leeds West Research Ethics Committee (20/YH/0061). Participants will provide written informed consent prior to any study specific procedures. The study results will be submitted to a peer-reviewed journal and abstracts will be submitted to relevant national and international conferences. TRIAL REGISTRATION NUMBER: ISRCTN88667898.

Neutropenia following immune-depletion, notably CD20 targeting, therapies in multiple sclerosis.

Neutropenia serves as a risk factor for severe infection and is a consequence of some immune-depleting immunotherapies. This occurs in people with multiple sclerosis following chemotherapy-conditioning in haematopoietic stem cell transplantation and potent B cell targeting agents. Whilst CD52 is expressed by neutrophils and may contribute to early-onset neutropenia following alemtuzumab treatment, deoxycytidine kinase and CD20 antigen required for activity of cladribine tablets, off-label rituximab, ocrelizumab, ofatumumab and ublituximab are not or only weakly expressed by neutrophils. Therefore, alternative explanations are needed for the rare occurrence of early and late-onset neutropenia following such treatments. This probably occurs due to alterations in the balance of granulopoiesis and neutrophil removal. Neutrophils are short-lived, and their removal may be influenced by drug-associated infections, the killing mechanisms of the therapies and amplified by immune dyscrasia due to influences on neutropoiesis following growth factor rerouting for B cell recovery and cytokine deficits following lymphocyte depletion. This highlights the small but evident neutropenia risks following sustained B cell depletion with some treatments.

Use of smartphone-based remote assessments of multiple sclerosis in Floodlight Open, a global, prospective, open-access study.

Floodlight Open was a global, open-access, digital-only study designed to understand the drivers and barriers in deployment and use of a smartphone app in a naturalistic setting and broad study population of people with and without multiple sclerosis (MS). The study utilised the Floodlight Open app: a 'bring-your-own-device' solution that remotely measures a user's mood, cognition, hand motor function, and gait and postural stability via smartphone sensor-based tests requiring active user input ('active tests'). Levels of mobility of study participants ('life-space measurement') were passively measured. Study data from these tests were made available via an open-access platform. Data from 1350 participants with self-declared MS and 1133 participants with self-declared non-MS from 17 countries across four continents were included in this report. Overall, MS participants provided active test data for a mean duration of 5.6 weeks or a mean duration of 19 non-consecutive days. This duration increased among MS participants who persisted beyond the first week to a mean of 10.3 weeks or 36.5 non-consecutive days. Passively collected life-space measurement data were generated by MS participants for a mean duration of 9.8 weeks or 50.6 non-consecutive days. This duration increased to 16.3 weeks/85.1 non-consecutive days among MS participants who persisted beyond the first week. Older age, self-declared MS disease status, and clinical supervision as part of concomitant clinical research were all significantly associated with higher persistence of the use of the Floodlight Open app. MS participants performed significantly worse than non-MS participants on four out of seven active tests. The findings from this multinational study inform future research to improve the dynamics of persistence of use of digital monitoring tools and further highlight challenges and opportunities in applying them to support MS clinical care.

Plasma proteomic profiles of UK Biobank participants with multiple sclerosis.

OBJECTIVE: We aimed to describe plasma protein biomarkers of multiple sclerosis risk and to explore protein biomarkers of disease severity using radiological outcome measures. METHODS: Multiple sclerosis cases and controls were identified in UK Biobank, a longitudinal cohort study of ~500,000 British adults. Plasma proteins were assayed in ~50,000 UK Biobank participants using the Olink proximity extension assay. We performed case-control association testing to examine the association between 2911 proteins and multiple sclerosis, using linear models adjusted for confounding covariates. Associations with radiological lesion burden and brain volume were determined in a subset of the cohort with available magnetic resonance imaging, using normalized T2-hyperintensity volume or whole brain volume as the outcome measure. RESULTS: In total, 407 prevalent multiple sclerosis cases and 39,979 healthy controls were included. We discovered 72 proteins associated with multiple sclerosis at a Bonferroni-adjusted p value of 0.05, including established markers such as neurofilament light chain and glial fibrillary acidic protein. We observed a decrease in plasma Granzyme A, a marker of T cell and NK cell degranulation, which was specific to multiple sclerosis. Higher levels of plasma proteins involved in coagulation were associated with lower T2 lesion burden and preserved brain volume. INTERPRETATION: We report the largest plasma proteomic screen of multiple sclerosis, replicating important known associations and suggesting novel markers, such as the reduction in granzyme A. While these findings require external validation, they demonstrate the power of biobank-scale datasets for discovering new biomarkers for multiple sclerosis.

Modifiable risk factors for multiple sclerosis have consistent directions of effect across diverse ethnic backgrounds: a nested case-control study in an English population-based cohort.

BACKGROUND: Multiple sclerosis is a leading cause of non-traumatic neurological disability among young adults worldwide. Prior studies have identified modifiable risk factors for multiple sclerosis in cohorts of White ethnicity, such as infectious mononucleosis, smoking, and obesity during adolescence/early adulthood. It is unknown whether modifiable exposures for multiple sclerosis have a consistent impact on risk across ethnic groups. AIM: To determine whether modifiable risk factors for multiple sclerosis have similar effects across diverse ethnic backgrounds. METHODS: We conducted a nested case-control study using data from the UK Clinical Practice Research Datalink. Multiple sclerosis cases diagnosed from 2001 until 2022 were identified from electronic healthcare records and matched to unaffected controls based on year of birth. We used stratified logistic regression models and formal statistical interaction tests to determine whether the effect of modifiable risk factors for multiple sclerosis differed by ethnicity. RESULTS: We included 9662 multiple sclerosis cases and 118,914 age-matched controls. The cohort was ethnically diverse (MS: 277 South Asian [2.9%], 251 Black [2.6%]; Controls: 5043 South Asian [5.7%], 4019 Black [4.5%]). The age at MS diagnosis was earlier in the Black (40.5 [SD 10.9]) and Asian (37.2 [SD 10.0]) groups compared with White cohort (46.1 [SD 12.2]). There was a female predominance in all ethnic groups; however, the relative proportion of males was higher in the South Asian population (proportion of women 60.3% vs 71% [White] and 75.7% [Black]). Established modifiable risk factors for multiple sclerosis-smoking, obesity, infectious mononucleosis, low vitamin D, and head injury-were consistently associated with multiple sclerosis in the Black and South Asian cohorts. The magnitude and direction of these effects were broadly similar across all ethnic groups examined. There was no evidence of statistical interaction between ethnicity and any tested exposure, and no evidence to suggest that differences in area-level deprivation modifies these risk factor-disease associations. These findings were robust to a range of sensitivity analyses. CONCLUSIONS AND RELEVANCE: Established modifiable risk factors for multiple sclerosis are applicable across diverse ethnic backgrounds. Efforts to reduce the population incidence of multiple sclerosis by tackling these risk factors need to be inclusive of people from diverse ethnicities.

Development and multi-center validation of a fully automated digital immunoassay for neurofilament light chain: toward a clinical blood test for neuronal injury.

OBJECTIVES: Neurofilament light chain (NfL) has emerged as a promising biomarker for detecting and monitoring axonal injury. Until recently, NfL could only be reliably measured in cerebrospinal fluid, but digital single molecule array (Simoa) technology has enabled its precise measurement in blood samples where it is typically 50-100 times less abundant. We report development and multi-center validation of a novel fully automated digital immunoassay for NfL in serum for informing axonal injury status. METHODS: A 45-min immunoassay for serum NfL was developed for use on an automated digital analyzer based on Simoa technology. The analytical performance (sensitivity, precision, reproducibility, linearity, sample type) was characterized and then cross validated across 17 laboratories in 10 countries. Analytical performance for clinical NfL measurement was examined in individual patients with relapsing remitting multiple sclerosis (RRMS) after 3 months of disease modifying treatment (DMT) with fingolimod. RESULTS: The assay exhibited a lower limit of detection (LLoD) of 0.05 ng/L, a lower limit of quantification (LLoQ) of 0.8 ng/L, and between-laboratory imprecision <10 % across 17 validation sites. All tested samples had measurable NfL concentrations well above the LLoQ. In matched pre-post treatment samples, decreases in NfL were observed in 26/29 RRMS patients three months after DMT start, with significant decreases detected in a majority of patients. CONCLUSIONS: The sensitivity characteristics and reproducible performance across laboratories combined with full automation make this assay suitable for clinical use for NfL assessment, monitoring in individual patients, and cross-comparisons of results across multiple sites.