Dynamics and heterogeneity of brain damage in multiple sclerosis

Multiple Sclerosis (MS) is an autoimmune disease driving inflammatory and degenerative processes that damage the central nervous system (CNS). However, it is not well understood how these events interact and evolve to evoke such a highly dynamic and heterogeneous disease. We established a hypothesis whereby the variability in the course of MS is driven by the very same pathogenic mechanisms responsible for the disease, the autoimmune attack on the CNS that leads to chronic inflammation, neuroaxonal degeneration and remyelination. We propose that each of these processes acts more or less severely and at different times in each of the clinical subgroups. To test this hypothesis, we developed a mathematical model that was constrained by experimental data (the expanded disability status scale [EDSS] time series) obtained from a retrospective longitudinal cohort of 66 MS patients with a long-term follow-up (up to 20 years). Moreover, we validated this model in a second prospective cohort of 120 MS patients with a three-year follow-up, for which EDSS data and brain volume time series were available. The clinical heterogeneity in the datasets was reduced by grouping the EDSS time series using an unsupervised clustering analysis. We found that by adjusting certain parameters, albeit within their biological range, the mathematical model reproduced the different disease courses, supporting the dynamic CNS damage hypothesis to explain MS heterogeneity. Our analysis suggests that the irreversible axon degeneration produced in the early stages of progressive MS is mainly due to the higher rate of myelinated axon degeneration, coupled to the lower capacity for remyelination. However, and in agreement with recent pathological studies, degeneration of chronically demyelinated axons is not a key feature that distinguishes this phenotype. Moreover, the model reveals that lower rates of axon degeneration and more rapid remyelination make relapsing MS more resilient than the progressive subtype. Therefore, our results support the hypothesis of a common pathogenesis for the different MS subtypes, even in the presence of genetic and environmental heterogeneity. Hence, MS can be considered as a single disease in which specific dynamics can provoke a variety of clinical outcomes in different patient groups. These results have important implications for the design of therapeutic interventions for MS at different stages of the disease

Enhancing diversity of clinical trial populations in multiple sclerosis

BACKGROUND: Demographic characteristics, social determinants of health (SDoH), health inequities, and health disparities substantially influence the general and disease-specific health outcomes of people with multiple sclerosis (MS). Participants in clinical trials do not represent all people with MS treated in practice. Objective: To provide recommendations for enhancing diversity and inclusion in clinical trials in MS. METHODS: We held an international workshop under the Auspices of the International Advisory Committee on Clinical Trials in MS (the “Committee”) to develop recommendations regarding diversity and inclusivity of participants of clinical trials in MS. Workshop attendees included members of the Committee as well as external participants. External participants were selected based on expertise in trials, SDoH, health equity and regulatory science, and diversity with respect to gender, race, ethnicity, and geography. RESULTS: Recommendations include use of diversity plans, community engagement and education, cultural competency training, biologically justified rather than templated eligibility criteria, adaptive designs that allow broadening of eligibility criteria over the course of a trial, and logistical and practical adjustments to reduce study participant burden. Investigators should report demographic and SDoH characteristics of participants. CONCLUSION: These recommendations provide sponsors and investigators with methods of improving diversity and inclusivity of clinical trial populations in MS

Retinal inner nuclear layer volume reflects inflammatory disease activity in multiple sclerosis;a longitudinal OCT study

Background: The association of peripapillary retinal nerve fibre layer (pRNFL) and ganglion cell-inner plexiform layer (GCIPL) thickness with neurodegeneration in multiple sclerosis (MS) is well established. The relationship of the adjoining inner nuclear layer (INL) with inflammatory disease activity is less well understood. Objective: The objective of this paper is to investigate the relationship of INL volume changes with inflammatory disease activity in MS. Methods In this longitudinal, multi-centre study, optical coherence tomography (OCT) and clinical data (disability status, relapses and MS optic neuritis (MSON)) were collected in 785 patients with MS (68.3% female) and 92 healthy controls (63.4% female) from 11 MS centres between 2010 and 2017 and pooled retrospectively. Data on pRNFL, GCIPL and INL were obtained at each centre. Results: There was a significant increase in INL volume in eyes with new MSON during the study (N = 61/1562, beta = 0.01mm(3), p<.001). Clinical relapses (other than MSON) were significantly associated with increased INL volume (beta = 0.005, p =.025). INL volume was independent of disease progression (beta = 0.002mm(3), p =.474). Conclusion: Our data demonstrate that an increase in INL volume is associated with MSON and the occurrence of clinical relapses. Therefore, INL volume changes may be useful as an outcome marker for inflammatory disease activity in MSON and MS treatment trials

Normative Data and Conversion Equation for Spectral-Domain Optical Coherence Tomography in an International Healthy Control Cohort

Background:Spectral-domain (SD-) optical coherence tomography (OCT) can reliably measure axonal (peripapillary retinal nerve fiber layer [pRNFL]) and neuronal (macular ganglion cell + inner plexiform layer [GCIPL]) thinning in the retina. Measurements from 2 commonly used SD-OCT devices are often pooled together in multiple sclerosis (MS) studies and clinical trials despite software and segmentation algorithm differences; however, individual pRNFL and GCIPL thickness measurements are not interchangeable between devices. In some circumstances, such as in the absence of a consistent OCT segmentation algorithm across platforms, a conversion equation to transform measurements between devices may be useful to facilitate pooling of data. The availability of normative data for SD-OCT measurements is limited by the lack of a large representative world-wide sample across various ages and ethnicities. Larger international studies that evaluate the effects of age, sex, and race/ethnicity on SD-OCT measurements in healthy control participants are needed to provide normative values that reflect these demographic subgroups to provide comparisons to MS retinal degeneration.Methods:Participants were part of an 11-site collaboration within the International Multiple Sclerosis Visual System (IMSVISUAL) consortium. SD-OCT was performed by a trained technician for healthy control subjects using Spectralis or Cirrus SD-OCT devices. Peripapillary pRNFL and GCIPL thicknesses were measured on one or both devices. Automated segmentation protocols, in conjunction with manual inspection and correction of lines delineating retinal layers, were used. A conversion equation was developed using structural equation modeling, accounting for clustering, with healthy control data from one site where participants were scanned on both devices on the same day. Normative values were evaluated, with the entire cohort, for pRNFL and GCIPL thicknesses for each decade of age, by sex, and across racial groups using generalized estimating equation (GEE) models, accounting for clustering and adjusting for within-patient, intereye correlations. Change-point analyses were performed to determine at what age pRNFL and GCIPL thicknesses exhibit accelerated rates of decline.Results:The healthy control cohort (n = 546) was 54% male and had a wide distribution of ages, ranging from 18 to 87 years, with a mean (SD) age of 39.3 (14.6) years. Based on 346 control participants at a single site, the conversion equation for pRNFL was Cirrus = -5.0 + (1.0 × Spectralis global value). Based on 228 controls, the equation for GCIPL was Cirrus = -4.5 + (0.9 × Spectralis global value). Standard error was 0.02 for both equations. After the age of 40 years, there was a decline of -2.4 m per decade in pRNFL thickness (P < 0.001, GEE models adjusting for sex, race, and country) and -1.4 m per decade in GCIPL thickness (P < 0.001). There was a small difference in pRNFL thickness based on sex, with female participants having slightly higher thickness (2.6 m, P = 0.003). There was no association between GCIPL thickness and sex. Likewise, there was no association between race/ethnicity and pRNFL or GCIPL thicknesses.Conclusions:A conversion factor may be required when using data that are derived between different SD-OCT platforms in clinical trials and observational studies; this is particularly true for smaller cross-sectional studies or when a consistent segmentation algorithm is not available. The above conversion equations can be used when pooling data from Spectralis and Cirrus SD-OCT devices for pRNFL and GCIPL thicknesses. A faster decline in retinal thickness may occur after the age of 40 years, even in the absence of significant differences across racial groups

Retinal thickness measured with optical coherence tomography and risk of disability worsening in multiple sclerosis: a cohort study

BACKGROUND Most patients with multiple sclerosis without previous optic neuritis have thinner retinal layers than healthy controls. We assessed the role of peripapillary retinal nerve fibre layer (pRNFL) thickness and macular volume in eyes with no history of optic neuritis as a biomarker of disability worsening in a cohort of patients with multiple sclerosis who had at least one eye without optic neuritis available. METHODS In this multicentre, cohort study, we collected data about patients (age ≥16 years old) with clinically isolated syndrome, relapsing-remitting multiple sclerosis, and progressive multiple sclerosis. Patients were recruited from centres in Spain, Italy, France, Germany, Czech Republic, Netherlands, Canada, and the USA, with the first cohort starting in 2008 and the latest cohort starting in 2013. We assessed disability worsening using the Expanded Disability Status Scale (EDSS). The pRNFL thickness and macular volume were assessed once at study entry (baseline) by optical coherence tomography (OCT) and was calculated as the mean value of both eyes without optic neuritis for patients without a history of optic neuritis or the value of the non-optic neuritis eye for patients with previous unilateral optic neuritis. Researchers who did the OCT at baseline were masked to EDSS results and the researchers assessing disability with EDSS were masked to OCT results. We estimated the association of pRNFL thickness or macular volume at baseline in eyes without optic neuritis with the risk of subsequent disability worsening by use of proportional hazards models that included OCT metrics and age, disease duration, disability, presence of previous unilateral optic neuritis, and use of disease-modifying therapies as covariates. FINDINGS 879 patients with clinically isolated syndrome (n=74), relapsing-remitting multiple sclerosis (n=664), or progressive multiple sclerosis (n=141) were included in the primary analyses. Disability worsening occurred in 252 (29%) of 879 patients with multiple sclerosis after a median follow-up of 2·0 years (range 0·5-5 years). Patients with a pRNFL of less than or equal to 87 μm or less than or equal to 88 μm (measured with Spectralis or Cirrus OCT devices) had double the risk of disability worsening at any time after the first and up to the third years of follow-up (hazard ratio 2·06, 95% CI 1·36-3·11; p=0·001), and the risk was increased by nearly four times after the third and up to the fifth years of follow-up (3·81, 1·63-8·91; p=0·002). We did not identify meaningful associations for macular volume. INTERPRETATION Our results provide evidence of the usefulness of monitoring pRNFL thickness by OCT for prediction of the risk of disability worsening with time in patients with multiple sclerosis. FUNDING Instituto de Salud Carlos III

Structural networks involved in attention and executive functions in multiple sclerosis

Attention and executive deficits are disabling symptoms in multiple sclerosis (MS) that have been related to disconnection mechanisms. We aimed to investigate changes in structural connectivity in MS and their association with attention and executive performance applying an improved framework that combines high order probabilistic tractography and anatomical exclusion criteria postprocessing. We compared graph theory metrics of structural networks and fractional anisotropy (FA) of white matter (WM) connections or edges between 72 MS subjects and 38 healthy volunteers (HV) and assessed their correlation with cognition. Patients displayed decreased network transitivity, global efficiency and increased path length compared with HV (p < 0.05, corrected). Also, nodal strength was decreased in 26 of 84 gray matter regions. The distribution of nodes with stronger connections or hubs of the network was similar among groups except for the right pallidum and left insula, which became hubs in patients. MS subjects presented reduced edge FA widespread in the network, while FA was increased in 24 connections (p < 0.05, corrected). Decreased integrity of frontoparietal networks, deep gray nuclei and insula correlated with worse attention and executive performance (r between 0.38 and 0.55, p < 0.05, corrected). Contrarily, higher strength in the right transverse temporal cortex and increased FA of several connections (mainly from cingulate, frontal and occipital cortices) were associated with worse functioning (r between −0.40 and −0.47, p < 0.05 corrected). In conclusion, structural brain connectivity is disturbed in MS due to widespread impairment of WM connections and gray matter structures. The increased edge connectivity suggests the presence of reorganization mechanisms at the structural level. Importantly, attention and executive performance relates to frontoparietal networks, deep gray nuclei and insula. These results support the relevance of network integrity to maintain optimal cognitive skills

Enhancing diversity of clinical trial populations in multiple sclerosis

Background:Demographic characteristics, social determinants of health (SDoH), health inequities, and health disparities substantially influence the general and disease-specific health outcomes of people with multiple sclerosis (MS). Participants in clinical trials do not represent all people with MS treated in practice. Objective:To provide recommendations for enhancing diversity and inclusion in clinical trials in MS. Methods:We held an international workshop under the Auspices of the International Advisory Committee on Clinical Trials in MS (the "Committee") to develop recommendations regarding diversity and inclusivity of participants of clinical trials in MS. Workshop attendees included members of the Committee as well as external participants. External participants were selected based on expertise in trials, SDoH, health equity and regulatory science, and diversity with respect to gender, race, ethnicity, and geography. Results:Recommendations include use of diversity plans, community engagement and education, cultural competency training, biologically justified rather than templated eligibility criteria, adaptive designs that allow broadening of eligibility criteria over the course of a trial, and logistical and practical adjustments to reduce study participant burden. Investigators should report demographic and SDoH characteristics of participants. Conclusion:These recommendations provide sponsors and investigators with methods of improving diversity and inclusivity of clinical trial populations in MS

The International Multiple Sclerosis Visual System Consortium - Advancing Visual System Research in Multiple Sclerosis

The International Multiple Sclerosis Visual System Consortium (IMSVISUAL) was formed in November 2014 with the primary goal of improving research, care, and education regarding the role of the visual system in multiple sclerosis (MS) and related disorders. In this review, we describe the formation, goals, activities, and structure of IMSVISUAL, as well as the relationship of IMSVISUAL with the Americas Committee for Treatment and Research in MS (ACTRIMS). Finally, we provide an overview of the work IMSVISUAL has completed to date, as well as an outline of research projects ongoing under the auspices of IMSVISUAL. IMSVISUAL has 140 members worldwide and continues to grow. Through IMSVISUAL-related research, optical coherence tomography (OCT)-derived peripapillary retinal nerve fiber layer (pRNFL) thinning has been established as a predictor of future disability in MS. IMSVISUAL has also developed guidelines for reporting OCT studies in MS. Moreover, a systematic review performed by IMSVISUAL found that not only are pRNFL and ganglion cell + inner plexiform layer (GCIPL) thicknesses reduced in patients with MS (particularly in eyes with prior optic neuritis [ON]), but that inner nuclear layer measures may be higher among MS ON eyes, relative to healthy control eyes. Currently, there are several ongoing IMSVISUAL projects that will establish a role for visual outcomes in diagnosing MS and quantifying the effects of emerging therapies in clinical trials. The development of IMSVISUAL represents a major collaborative commitment to defining the role of visual outcomes in high-quality, large-scale studies that generate definitive and instructive findings in the field of MS. As a consortium, IMSVISUAL has completed several international collaborative projects, is actively engaged in numerous ongoing research studies, and is committed to expanding the role of vision research in MS and related disorders

Magnetic resonance markers of tissue damage related to connectivity disruption in multiple sclerosis

Patients with multiple sclerosis (MS) display reduced structural connectivity among brain regions, but the pathogenic mechanisms underlying network disruption are still unknown. We aimed to investigate the association between the loss of diffusion-based structural connectivity, measured with graph theory metrics, and magnetic resonance (MR) markers of microstructural damage. Moreover, we evaluated the cognitive consequences of connectivity changes. We analysed the frontoparietal network in 102 MS participants and 25 healthy volunteers (HV). MR measures included radial diffusivity (RD), as marker of demyelination, and ratios of myo-inositol, N-acetylaspartate and glutamate+glutamine with creatine in white (WM) and grey matter as markers of astrogliosis, neuroaxonal integrity and glutamatergic neurotoxicity. Patients showed decreased global and local efficiency, and increased assortativity (p < 0.01) of the network, as well as increased RD and myo-inositol, and decreased N-acetylaspartate in WM compared with HV (p < 0.05). In patients, the age-adjusted OR of presenting abnormal global and local efficiency was increased for each increment of 0.01 points in RD and myo-inositol, while it was decreased for each increment of 0.01 points in N-acetylaspartate (the increase of N-acetylaspartate reduced the risk of having abnormal connectivity), all in WM. In a multiple logistic regression analysis, the OR of presenting abnormal global efficiency was 0.95 (95% confidence interval, CI: 0.91–0.99, p = 0.011) for each 0.01 increase in N-acetylaspartate, and the OR of presenting abnormal local efficiency was 1.39 (95% CI: 1.14–1.71, p = 0.001) for each 0.01 increase in RD. Patients with abnormal efficiency had worse performance in attention, working memory and processing speed (p < 0.05). In conclusion, patients with MS exhibit decreased structural network efficiency driven by diffuse microstructural impairment of the WM, probably related to demyelination, astroglial and neuroaxonal damage. The accumulation of neuroaxonal pathological burden seems to magnify the risk of global network collapse, while demyelination may contribute to the regional disorganization. These network modifications have negative consequences on cognition. Keywords: Structural connectivity, Spectroscopy magnetic resonance, Frontoparietal network, Multiple sclerosis, Cognitio