Spinal Cord Atrophy Predicts Progressive Disease in Relapsing Multiple Sclerosis.

OBJECTIVE: A major challenge in multiple sclerosis (MS) research is the understanding of silent progression and Progressive MS. Using a novel method to accurately capture upper cervical cord area from legacy brain MRI scans we aimed to study the role of spinal cord and brain atrophy for silent progression and conversion to secondary progressive disease (SPMS). METHODS: From a single-center observational study, all RRMS (n = 360) and SPMS (n = 47) patients and 80 matched controls were evaluated. RRMS patient subsets who converted to SPMS (n = 54) or silently progressed (n = 159), respectively, during the 12-year observation period were compared to clinically matched RRMS patients remaining RRMS (n = 54) or stable (n = 147), respectively. From brain MRI, we assessed the value of brain and spinal cord measures to predict silent progression and SPMS conversion. RESULTS: Patients who developed SPMS showed faster cord atrophy rates (-2.19%/yr) at least 4 years before conversion compared to their RRMS matches (-0.88%/yr, p < 0.001). Spinal cord atrophy rates decelerated after conversion (-1.63%/yr, p = 0.010) towards those of SPMS patients from study entry (-1.04%). Each 1% faster spinal cord atrophy rate was associated with 69% (p < 0.0001) and 53% (p < 0.0001) shorter time to silent progression and SPMS conversion, respectively. INTERPRETATION: Silent progression and conversion to secondary progressive disease are predominantly related to cervical cord atrophy. This atrophy is often present from the earliest disease stages and predicts the speed of silent progression and conversion to Progressive MS. Diagnosis of SPMS is rather a late recognition of this neurodegenerative process than a distinct disease phase. ANN NEUROL 2022;91:268-281.

An electronic, unsupervised patient-reported Expanded Disability Status Scale for multiple sclerosis.

BACKGROUND: In persons with multiple sclerosis (MS), the Expanded Disability Status Scale (EDSS) is the criterion standard for assessing disability, but its in-person nature constrains patient participation in research and clinical assessments. OBJECTIVE: The aim of this study was to develop and validate a scalable, electronic, unsupervised patient-reported EDSS (ePR-EDSS) that would capture MS-related disability across the spectrum of severity. METHODS: We enrolled 136 adult MS patients, split into a preliminary testing Cohort 1 (n = 50), and a validation Cohort 2 (n = 86), which was evenly distributed across EDSS groups. Each patient completed an ePR-EDSS either immediately before or after a MS clinician's Neurostatus EDSS evaluation. RESULTS: In Cohort 2, mean age was 50.6 years (range = 26-80) and median EDSS was 3.5 (interquartile range (IQR) = [1.5, 5.5]). The ePR-EDSS and EDSS agreed within 1-point for 86% of examinations; kappa for agreement within 1-point was 0.85 (p < 0.001). The correlation coefficient between the two measures was 0.91 (<0.001). DISCUSSION: The ePR-EDSS was highly correlated with EDSS, with good agreement even at lower EDSS levels. For clinical care, the ePR-EDSS could enable the longitudinal monitoring of a patient's disability. For research, it provides a valid and rapid measure across the entire spectrum of disability and permits broader participation with fewer in-person assessments.

Telomere Length Is Associated with Disability Progression in Multiple Sclerosis.

OBJECTIVE: To assess whether biological aging as measured by leukocyte telomere length (LTL) is associated with clinical disability and brain volume loss in multiple sclerosis (MS). METHODS: Adults with MS/clinically isolated syndrome in the University of California, San Francisco EPIC cohort study were included. LTL was measured on DNA samples by quantitative polymerase chain reaction and expressed as telomere to somatic DNA (T/S) ratio. Expanded Disability Status Scale (EDSS) and 3-dimensional T1-weighted brain magnetic resonance imaging were performed at baseline and follow-up. Associations of baseline LTL with cross-sectional and longitudinal outcomes were assessed using simple and mixed effects linear regression models. A subset (n = 46) had LTL measured over time, and we assessed the association of LTL change with EDSS change with mixed effects models. RESULTS: Included were 356 women and 160 men (mean age = 43 years, median disease duration = 6 years, median EDSS = 1.5 [range = 0-7], mean T/S ratio = 0.97 [standard deviation = 0.18]). In baseline analyses adjusted for age, disease duration, and sex, for every 0.2 lower LTL, EDSS was 0.27 higher (95% confidence interval [CI] = 0.13-0.42, p < 0.001) and brain volume was 7.4mm3 lower (95% CI = 0.10-14.7, p = 0.047). In longitudinal adjusted analyses, those with lower baseline LTL had higher EDSS and lower brain volumes over time. In adjusted analysis of the subset, LTL change was associated with EDSS change over 10 years; for every 0.2 LTL decrease, EDSS was 0.34 higher (95% CI = 0.08-0.61, p = 0.012). INTERPRETATION: Shorter telomere length was associated with disability independent of chronological age, suggesting that biological aging may contribute to neurological injury in MS. Targeting aging-related mechanisms is a potential therapeutic strategy against MS progression. ANN NEUROL 2019;86:671-682.

Silent progression in disease activity-free relapsing multiple sclerosis.

OBJECTIVE: Rates of worsening and evolution to secondary progressive multiple sclerosis (MS) may be substantially lower in actively treated patients compared to natural history studies from the pretreatment era. Nonetheless, in our recently reported prospective cohort, more than half of patients with relapsing MS accumulated significant new disability by the 10th year of follow-up. Notably, "no evidence of disease activity" at 2 years did not predict long-term stability. Here, we determined to what extent clinical relapses and radiographic evidence of disease activity contribute to long-term disability accumulation. METHODS: Disability progression was defined as an increase in Expanded Disability Status Scale (EDSS) of 1.5, 1.0, or 0.5 (or greater) from baseline EDSS = 0, 1.0-5.0, and 5.5 or higher, respectively, assessed from baseline to year 5 (±1 year) and sustained to year 10 (±1 year). Longitudinal analysis of relative brain volume loss used a linear mixed model with sex, age, disease duration, and HLA-DRB1*15:01 as covariates. RESULTS: Relapses were associated with a transient increase in disability over 1-year intervals (p = 0.012) but not with confirmed disability progression (p = 0.551). Relative brain volume declined at a greater rate among individuals with disability progression compared to those who remained stable (p < 0.05). INTERPRETATION: Long-term worsening is common in relapsing MS patients, is largely independent of relapse activity, and is associated with accelerated brain atrophy. We propose the term silent progression to describe the insidious disability that accrues in many patients who satisfy traditional criteria for relapsing-remitting MS. Ann Neurol 2019;85:653-666.

A Precision Medicine Tool for Patients With Multiple Sclerosis (the Open MS BioScreen): Human-Centered Design and Development.

BACKGROUND: Patients with multiple sclerosis (MS) face several challenges in accessing clinical tools to help them monitor, understand, and make meaningful decisions about their disease course. The University of California San Francisco MS BioScreen is a web-based precision medicine tool initially designed to be clinician facing. We aimed to design a second, openly available tool, Open MS BioScreen, that would be accessible, understandable, and actionable by people with MS. OBJECTIVE: This study aimed to describe the human-centered design and development approach (inspiration, ideation, and implementation) for creating the Open MS BioScreen platform. METHODS: We planned an iterative and cyclical development process that included stakeholder engagement and iterative feedback from users. Stakeholders included patients with MS along with their caregivers and family members, MS experts, generalist clinicians, industry representatives, and advocacy experts. Users consisted of anyone who wants to track MS measurements over time and access openly available tools for people with MS. Phase I (inspiration) consisted of empathizing with users and defining the problem. We sought to understand the main challenges faced by patients and clinicians and what they would want to see in a web-based app. In phase II (ideation), our multidisciplinary team discussed approaches to capture, display, and make sense of user data. Then, we prototyped a series of mock-ups to solicit feedback from clinicians and people with MS. In phase III (implementation), we incorporated all concepts to test and iterate a minimally viable product. We then gathered feedback through an agile development process. The design and development were cyclical-many times throughout the process, we went back to the drawing board. RESULTS: This human-centered approach generated an openly available, web-based app through which patients with MS, their clinicians, and their caregivers can access the site and create an account. Users can enter information about their MS (basic level as well as more advanced concepts), visualize their data longitudinally, access a series of algorithms designed to empower them to make decisions about their treatments, and enter data from wearable devices to encourage realistic goal setting about their ambulatory activity. Agile development will allow us to continue to incorporate precision medicine tools, as these are validated in the clinical research arena. CONCLUSIONS: After engaging intended users into the iterative human-centered design of the Open MS BioScreen, we will now monitor the adaptation and dissemination of the tool as we expand its functionality and reach. The insights generated from this approach can be applied to the development of a number of self-tracking, self-management, and user engagement tools for patients with chronic conditions.

Toward a low-cost, in-home, telemedicine-enabled assessment of disability in multiple sclerosis.

BACKGROUND: Remote assessment of neurological disability in people with multiple sclerosis (MS) could improve access to clinical care and efficiency of clinical research. OBJECTIVE: To develop and validate a telemedicine-based MS disability examination that does not require an in-home examiner. METHODS: Adults with MS were recruited after a standardized in-person Expanded Disability Status Scale (EDSS) evaluation, and within 1 week underwent a blinded televideo-enabled EDSS examination with a different clinician. EDSS and tele-EDSS scores were compared. RESULTS: Overall, 41 adults participated (mean (standard deviation (SD)) age: 47.0 years (11.6); median EDSS: 2 (range: 0-7)); 37 required no in-home assistance for the tele-EDSS evaluation (e.g. help positioning camera). Mean difference between EDSS and tele-EDSS was 0.34 (95% confidence interval (CI): 0.07-0.61). For 88% of evaluations, tele-EDSS and EDSS scores were within 1 point (similar to reported in-person inter-rater differences). Unweighted kappa for agreement within 0.5 point was 0.72. Correlation for individual functional systems (FS) ranged from modest (vision: 0.37) to high (bowel/bladder: 0.79). Overall correlation between EDSS and tele-EDSS was 0.89 (p < 0.0001); and 0.98 (p < 0.0001) at EDSS range: 4-7. CONCLUSION: In this proof of principle study, disability evaluation in mild to moderate MS is feasible using telemedicine without an aide at the patient's location.

Harnessing electronic medical records to advance research on multiple sclerosis.

BACKGROUND: Electronic medical records (EMR) data are increasingly used in research, but no studies have yet evaluated similarity between EMR and research-quality data and between characteristics of an EMR multiple sclerosis (MS) population and known natural MS history. OBJECTIVES: To (1) identify MS patients in an EMR system and extract clinical data, (2) compare EMR-extracted data with gold-standard research data, and (3) compare EMR MS population characteristics to expected MS natural history. METHODS: Algorithms were implemented to identify MS patients from the University of California San Francisco EMR, de-identify the data and extract clinical variables. EMR-extracted data were compared to research cohort data in a subset of patients. RESULTS: We identified 4142 MS patients via search of the EMR and extracted their clinical data with good accuracy. EMR and research values showed good concordance for Expanded Disability Status Scale (EDSS), timed-25-foot walk, and subtype. We replicated several expected MS epidemiological features from MS natural history including higher EDSS for progressive versus relapsing-remitting patients and for male versus female patients and increased EDSS with age at examination and disease duration. CONCLUSION: Large real-world cohorts algorithmically extracted from the EMR can expand opportunities for MS clinical research.

Long-term evolution of multiple sclerosis disability in the treatment era.

OBJECTIVE: To characterize the accrual of long-term disability in a cohort of actively treated multiple sclerosis (MS) patients and to assess whether clinical and magnetic resonance imaging (MRI) data used in clinical trials have long-term prognostic value. METHODS: This is a prospective study of 517 actively managed MS patients enrolled at a single center. RESULTS: More than 91% of patients were retained, with data ascertained up to 10 years after the baseline visit. At this last assessment, neurologic disability as measured by the Expanded Disability Status Scale (EDSS) was stable or improved compared to baseline in 41% of patients. Subjects with no evidence of disease activity (NEDA) by clinical and MRI criteria during the first 2 years had long-term outcomes that were no different from those of the cohort as a whole. 25-OH vitamin D serum levels were inversely associated with short-term MS disease activity; however, these levels had no association with long-term disability. At a median time of 16.8 years after disease onset, 10.7% (95% confidence interval [CI] = 7.2-14%) of patients reached an EDSS ≥ 6, and 18.1% (95% CI = 13.5-22.5%) evolved from relapsing MS to secondary progressive MS (SPMS). INTERPRETATION: Rates of worsening and evolution to SPMS were substantially lower when compared to earlier natural history studies. Notably, the NEDA 2-year endpoint was not a predictor of long-term stability. Finally, the data call into question the utility of annual MRI assessments as a treat-to-target approach for MS care. Ann Neurol 2016;80:499-510.

Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis.

Monozygotic or 'identical' twins have been widely studied to dissect the relative contributions of genetics and environment in human diseases. In multiple sclerosis (MS), an autoimmune demyelinating disease and common cause of neurodegeneration and disability in young adults, disease discordance in monozygotic twins has been interpreted to indicate environmental importance in its pathogenesis. However, genetic and epigenetic differences between monozygotic twins have been described, challenging the accepted experimental model in disambiguating the effects of nature and nurture. Here we report the genome sequences of one MS-discordant monozygotic twin pair, and messenger RNA transcriptome and epigenome sequences of CD4(+) lymphocytes from three MS-discordant, monozygotic twin pairs. No reproducible differences were detected between co-twins among approximately 3.6 million single nucleotide polymorphisms (SNPs) or approximately 0.2 million insertion-deletion polymorphisms. Nor were any reproducible differences observed between siblings of the three twin pairs in HLA haplotypes, confirmed MS-susceptibility SNPs, copy number variations, mRNA and genomic SNP and insertion-deletion genotypes, or the expression of approximately 19,000 genes in CD4(+) T cells. Only 2 to 176 differences in the methylation of approximately 2 million CpG dinucleotides were detected between siblings of the three twin pairs, in contrast to approximately 800 methylation differences between T cells of unrelated individuals and several thousand differences between tissues or between normal and cancerous tissues. In the first systematic effort to estimate sequence variation among monozygotic co-twins, we did not find evidence for genetic, epigenetic or transcriptome differences that explained disease discordance. These are the first, to our knowledge, female, twin and autoimmune disease individual genome sequences reported.

Inflammatory and neurodegenerative serum protein biomarkers increase sensitivity to detect clinical and radiographic disease activity in multiple sclerosis.

The multifaceted nature of multiple sclerosis requires quantitative biomarkers that can provide insights related to diverse physiological pathways. To this end, proteomic analysis of deeply-phenotyped serum samples, biological pathway modeling, and network analysis were performed to elucidate inflammatory and neurodegenerative processes, identifying sensitive biomarkers of multiple sclerosis disease activity. Here, we evaluated the concentrations of > 1400 serum proteins in 630 samples from three multiple sclerosis cohorts for association with clinical and radiographic new disease activity. Twenty proteins were associated with increased clinical and radiographic multiple sclerosis disease activity for inclusion in a custom assay panel. Serum neurofilament light chain showed the strongest univariate correlation with gadolinium lesion activity, clinical relapse status, and annualized relapse rate. Multivariate modeling outperformed univariate for all endpoints. A comprehensive biomarker panel including the twenty proteins identified in this study could serve to characterize disease activity for a patient with multiple sclerosis.

An autoantibody signature predictive for multiple sclerosis.

Although B cells are implicated in multiple sclerosis (MS) pathophysiology, a predictive or diagnostic autoantibody remains elusive. In this study, the Department of Defense Serum Repository (DoDSR), a cohort of over 10 million individuals, was used to generate whole-proteome autoantibody profiles of hundreds of patients with MS (PwMS) years before and subsequently after MS onset. This analysis defines a unique cluster in approximately 10% of PwMS who share an autoantibody signature against a common motif that has similarity with many human pathogens. These patients exhibit antibody reactivity years before developing MS symptoms and have higher levels of serum neurofilament light (sNfL) compared to other PwMS. Furthermore, this profile is preserved over time, providing molecular evidence for an immunologically active preclinical period years before clinical onset. This autoantibody reactivity was validated in samples from a separate incident MS cohort in both cerebrospinal fluid and serum, where it is highly specific for patients eventually diagnosed with MS. This signature is a starting point for further immunological characterization of this MS patient subset and may be clinically useful as an antigen-specific biomarker for high-risk patients with clinically or radiologically isolated neuroinflammatory syndromes.

Inflammatory and neurodegenerative serum protein biomarkers increase sensitivity to detect disease activity in multiple sclerosis.

Background/Objectives: Serum proteomic analysis of deeply-phenotyped samples, biological pathway modeling and network analysis were performed to elucidate the inflammatory and neurodegenerative processes of multiple sclerosis (MS) and identify sensitive biomarkers of MS disease activity (DA). Methods: Over 1100 serum proteins were evaluated in >600 samples from three MS cohorts to identify biomarkers of clinical and radiographic (gadolinium-enhancing lesions) new MS DA. Protein levels were analyzed and associated with presence of gadolinium-enhancing lesions, clinical relapse status (CRS), and annualized relapse rate (ARR) to create a custom assay panel. Results: Twenty proteins were associated with increased clinical and radiographic MS DA. Serum neurofilament light chain (NfL) showed the strongest univariate correlation with radiographic and clinical DA measures. Multivariate modeling significantly outperformed univariate NfL to predict gadolinium lesion activity, CRS and ARR. Discussion: These findings provide insight regarding correlations between inflammatory and neurodegenerative biomarkers and clinical and radiographic MS DA. Funding: Octave Bioscience, Inc (Menlo Park, CA).

Remote Observational Research for Multiple Sclerosis: A Natural Experiment.

BACKGROUND AND OBJECTIVES: Prospective, deeply phenotyped research cohorts monitoring individuals with chronic neurologic conditions, such as multiple sclerosis (MS), depend on continued participant engagement. The COVID-19 pandemic restricted in-clinic research activities, threatening this longitudinal engagement, but also forced adoption of televideo-enabled care. This offered a natural experiment in which to analyze key dimensions of remote research: (1) comparison of remote vs in-clinic visit costs from multiple perspectives and (2) comparison of the remote with in-clinic measures in cross-sectional and longitudinal disability evaluations. METHODS: Between March 2020 and December 2021, 207 MS cohort participants underwent hybrid in-clinic and virtual research visits; 96 contributed 100 "matched visits," that is, in-clinic (Neurostatus-Expanded Disability Status Scale [NS-EDSS]) and remote (televideo-enabled EDSS [tele-EDSS]; electronic patient-reported EDSS [ePR-EDSS]) evaluations. Clinical, demographic, and socioeconomic characteristics of participants were collected. RESULTS: The costs of remote visits were lower than in-clinic visits for research investigators (facilities, personnel, parking, participant compensation) but also for participants (travel, caregiver time) and carbon footprint (p < 0.05 for each). Median cohort EDSS was similar between the 3 modalities (NS-EDSS: 2, tele-EDSS: 1.5, ePR-EDSS: 2, range 0.6.5); the remote evaluations were each noninferior to the NS-EDSS within ±0.5 EDSS point (TOST for noninferiority, p < 0.01 for each). Furthermore, year to year, the % of participants with worsening/stable/improved EDSS scores was similar, whether each annual evaluation used NS-EDSS or whether it switched from NS-EDSS to tele-EDSS. DISCUSSION: Altogether, the current findings suggest that remote evaluations can reduce the costs of research participation for patients, while providing a reasonable evaluation of disability trajectory longitudinally. This could inform the design of remote research that is more inclusive of diverse participants.

A Predictive Autoantibody Signature in Multiple Sclerosis.

Although B cells are implicated in multiple sclerosis (MS) pathophysiology, a predictive or diagnostic autoantibody remains elusive. Here, the Department of Defense Serum Repository (DoDSR), a cohort of over 10 million individuals, was used to generate whole-proteome autoantibody profiles of hundreds of patients with MS (PwMS) years before and subsequently after MS onset. This analysis defines a unique cluster of PwMS that share an autoantibody signature against a common motif that has similarity with many human pathogens. These patients exhibit antibody reactivity years before developing MS symptoms and have higher levels of serum neurofilament light (sNfL) compared to other PwMS. Furthermore, this profile is preserved over time, providing molecular evidence for an immunologically active prodromal period years before clinical onset. This autoantibody reactivity was validated in samples from a separate incident MS cohort in both cerebrospinal fluid (CSF) and serum, where it is highly specific for patients eventually diagnosed with MS. This signature is a starting point for further immunological characterization of this MS patient subset and may be clinically useful as an antigen-specific biomarker for high-risk patients with clinically- or radiologically-isolated neuroinflammatory syndromes.

Challenges to Longitudinal Characterization of Lower Urinary Tract Dysfunction in Multiple Sclerosis.

BACKGROUND: Neurogenic lower urinary tract dysfunction (LUTD) results in lower urinary tract symptoms (LUTS) that impact quality of life in people with multiple sclerosis (PwMS). The risk factors and the contribution of LUTD to multiple sclerosis (MS) disease progression are under-researched. OBJECTIVE: To identify clinical and demographic predictors of LUTS in PwMS and gaps in clinical ascertainment. METHODS: Participants were adults with MS enrolled in a prospective, multicenter study (SUMMIT, N=802), including a subset of N = 258 patients in the UCSF EPIC study for whom medical records were further reviewed. Demographic (age, sex, race, ethnicity), clinical (disease duration, MS type), and female-specific reproductive factors (e.g., parity) were evaluated to determine associations with bowel/bladder functional system score. Participants' medical records were analyzed to understand the patterns of LUTS ascertainment by physicians and the specific contribution of LUTS to overall bowel/bladder functional system scores. RESULTS: 802 participants (71.3% female) contributed to these analyses. Higher bowel/bladder functional system scores, indicating worsening symptoms and function, were significantly associated with female sex (p=0.001) and progressive MS type (p≤ 0.001). In the EPIC participants, female-specific reproductive exposures (parity, menopause) were not significantly associated with worse bowel/bladder functional system scores. Most (98%) bowel/bladder functional system scores reflected the severity of LUTS (relative to bowel dysfunction). LUTS were under-ascertained clinically, and more so in women (X2 = 5.02, p=0.08). CONCLUSIONS: Female sex and MS type are predictive of worsening LUTS. Symptoms may be less likely to be ascertained by clinicians in females compared to males.

Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis.

Multiple sclerosis (MS), a chronic disorder of the central nervous system and common cause of neurological disability in young adults, is characterized by moderate but complex risk heritability. Here we report the results of a genome-wide association study performed in a 1000 prospective case series of well-characterized individuals with MS and group-matched controls using the Sentrix HumanHap550 BeadChip platform from Illumina. After stringent quality control data filtering, we compared allele frequencies for 551 642 SNPs in 978 cases and 883 controls and assessed genotypic influences on susceptibility, age of onset, disease severity, as well as brain lesion load and normalized brain volume from magnetic resonance imaging exams. A multi-analytical strategy identified 242 susceptibility SNPs exceeding established thresholds of significance, including 65 within the MHC locus in chromosome 6p21.3. Independent replication confirms a role for GPC5, a heparan sulfate proteoglycan, in disease risk. Gene ontology-based analysis shows a functional dichotomy between genes involved in the susceptibility pathway and those affecting the clinical phenotype.

Native ancestry is associated with optic neuritis and age of onset in hispanics with multiple sclerosis.

BACKGROUND AND OBJECTIVE: Hispanics with multiple sclerosis (MS) present younger and more often with optic neuritis (ON) as compared to Whites in the western United States. Regional differences related to Hispanic genetic admixture could be responsible. We investigated the association between global genetic ancestry and ON and age at onset of MS in Hispanics. METHODS: Data were obtained for 1033 self-identified Hispanics with MS from four MS-based registries from four academic institutions across the United States January 2016-April 2017. Multivariate regression models, utilizing genetic ancestry estimates for Native American (NA), African, and European ancestry, were used to assess the relationship between genetic ancestry and ON presentation and age of MS onset, defined as age at first symptom. RESULTS: Genetic ancestry and ON proportions varied by region where NA ancestry and ON proportions were highest among Hispanics in the southwestern United States (40% vs. 19% overall for NA and 38% vs. 25% overall for ON). A strong inverse correlation was observed between NA and European ancestry (r = -0.83). ON presentation was associated with younger age of onset (OR: 0.98; 95% CI: 0.96-0.99; P = 7.80 × 10-03) and increased NA ancestry (OR: 2.35 for the highest versus the lowest quartile of NA ancestry; 95% CI: 1.35-4.10; P = 2.60 × 10-03). Younger age of onset was found to be associated with a higher proportion NA (Beta: -5.58; P = 3.49 × 10-02) and African ancestry (Beta: -10.07; P = 1.39 × 10-03). INTERPRETATION: Ethnic differences associated with genetic admixture could influence clinical presentation in Hispanics with MS; underscoring the importance of considering genetic substructure in future clinical, genetic, and epigenetic studies in Hispanics.

Multiple Sclerosis-Associated Changes in the Composition and Immune Functions of Spore-Forming Bacteria.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system characterized by adaptive and innate immune system dysregulation. Recent work has revealed moderate alteration of gut microbial communities in subjects with MS and in experimental, induced models. However, a mechanistic understanding linking the observed changes in the microbiota and the presence of the disease is still missing. Chloroform-resistant, spore-forming bacteria, which primarily belong to the classes Bacilli and Clostridia in the phylum Firmicutes, have been shown to exhibit immunomodulatory properties in vitro and in vivo, but they have not yet been characterized in the context of human disease. This study addresses the community composition and immune function of this bacterial fraction in MS. We identify MS-associated spore-forming taxa (primarily in the class Clostridia) and show that their presence correlates with impaired differentiation of IL-10-secreting, regulatory T lymphocytes in vitro. Colonization of antibiotic-treated mice with spore-forming bacteria allowed us to identify some bacterial taxa favoring IL-10+ lymphocyte differentiation and others inducing differentiation of proinflammatory, IFN-γ+ T lymphocytes. However, when fed into antibiotic-treated mice, both MS and control-derived spore-forming bacteria were able to induce similar IL-10-expressing Treg immunoregulatory responses, thus ameliorating symptoms of experimental allergic encephalomyelitis (EAE). Our analysis also identified Akkermansia muciniphila as a key organism that may interact either directly or indirectly with spore-forming bacteria to exacerbate the inflammatory effects of MS-associated gut microbiota. Thus, changes in the spore-forming fraction may influence T lymphocyte-mediated inflammation in MS. This experimental approach of isolating a subset of microbiota based on its functional characteristics may be useful to investigate other microbial fractions at greater depth. IMPORTANCE To address the impact of microbiome on disease development, it is essential to go beyond a descriptive study and evaluate the physiological importance of microbiome changes. Our study integrates computational analysis with in vitro and in vivo exploration of inflammatory properties of spore-forming microbial communities, revealing novel functional correlations. We specifically show that while small differences exist between the microbiomes of MS patients and healthy subjects, these differences are exacerbated in the chloroform-resistant fraction. We further demonstrate that, when purified from MS patients, this fraction is correlated with impaired immunomodulatory responses in vitro.

Multiple sclerosis risk loci and disease severity in 7,125 individuals from 10 studies.

OBJECTIVE: We investigated the association between 52 risk variants identified through genome-wide association studies and disease severity in multiple sclerosis (MS). METHODS: Ten unique MS case data sets were analyzed. The Multiple Sclerosis Severity Score (MSSS) was calculated using the Expanded Disability Status Scale at study entry and disease duration. MSSS was considered as a continuous variable and as 2 dichotomous variables (median and extreme ends; MSSS of ≤5 vs >5 and MSSS of <2.5 vs ≥7.5, respectively). Single nucleotide polymorphisms (SNPs) were examined individually and as both combined weighted genetic risk score (wGRS) and unweighted genetic risk score (GRS) for association with disease severity. Random-effects meta-analyses were conducted and adjusted for cohort, sex, age at onset, and HLA-DRB1*15:01. RESULTS: A total of 7,125 MS cases were analyzed. The wGRS and GRS were not strongly associated with disease severity after accounting for cohort, sex, age at onset, and HLA-DRB1*15:01. After restricting analyses to cases with disease duration ≥10 years, associations were null (p value ≥0.05). No SNP was associated with disease severity after adjusting for multiple testing. CONCLUSIONS: The largest meta-analysis of established MS genetic risk variants and disease severity, to date, was performed. Results suggest that the investigated MS genetic risk variants are not associated with MSSS, even after controlling for potential confounders. Further research in large cohorts is needed to identify genetic determinants of disease severity using sensitive clinical and MRI measures, which are critical to understanding disease mechanisms and guiding development of effective treatments.