B. Weinstock-Guttman
State University of New York at Buffalo Department of NeurologyAuthor Of 3 Presentations
LB01.05 - Network analysis identifies gut bacteria associated with multiple sclerosis relapse among pediatric-onset patients
Abstract
Background
Commensal gut microbes are known to affect host immune function and may be modifiable. Recent work suggests gut microbiota composition contributes to onset of MS; however, little is known about its contribution to MS disease activity.
Objectives
Estimate the association between gut microbiota and subsequent disease activity among individuals with pediatric-onset MS (pedMS) from the U.S. Network of Pediatric MS Centers.
Methods
Stool samples were collected from cases (MS symptom onset <18 years) and profiled using 16S rRNA sequencing of the V4 region. Amplicon sequence variants (ASVs) were identified using the Divisive Amplicon Denoising Algorithm-2 (DADA2). ASVs present in <20% of samples were removed. ASV clusters (modules) were identified using weighted genetic correlation network analysis (WGCNA) and sparCC transformation of ASV abundance. Cox proportional hazard recurrent event models were used to examine the relationship between individual ASVs and then ASV clusters, adjusted for age, sex, and disease modifying therapy (DMT) use.
Results
Of 53 pedMS cases, 72% were girls. At stool sample collection, the mean age was 15.5 years (SD: 2.7) and disease duration was 1.1 years (SD: 1.0). Less than half (45%) had one relapse and 30% had >1 relapse over the subsequent mean follow-up of 2.5 years (SD:1.3). Over this time, 91% used a DMT. Among 270 individual ASVs included in the analyses, 20 were nominally significant (p<0.05), e.g. the presence of Blautia stercoris was associated with higher relapse risk (hazard ratio [HR]=2.50; 95% confidence interval [CI]=1.43, 4.37). WGCNA identified 6 ASV modules. Higher values of one module’s eigengene was significantly (false discovery rate q<0.2) associated with higher relapse risk (HR=1.23, 95% CI=1.02, 1.50). Four ASVs nominally associated with higher relapse risk were in this module. These included Blautia massiliensis, Dorea longicatena, Coprococcus comes, and an unknown species in genus Subdoligranulum.
Conclusions
We found that a high relative abundance of a gut microbiota species within the Blautia genus, and its interconnected variants, was associated with a higher relapse risk in pedMS cases. While our study represents the largest of its kind in MS, findings need to be replicated. However, Blautia stercoris has been linked to disease activity in other immune-mediated diseases such as systemic lupus erythematosus.
PS04.04 - Evidence for an interaction between ozone pollution and HLA-DRB1*15 alleles in pediatric multiple sclerosis
Abstract
Background
We previously reported a relationship between air pollutants and increased risk of pediatric MS (ped-MS). Environmental risk factor research in ped-MS offers the advantage of shorter duration between exposure and disease onset. Ozone, an air pollutant, is a major global health hazard thought to have a role in MS pathoetiology. Identifying gene-environment interactions advances the understanding of biological processes at play in MS susceptibility.
Objectives
We sought to examine the interaction between ozone pollution and DRB1*15 status as the main genetic variant associated with MS susceptibility.
Methods
Cases and controls enrolled in the Environmental and Genetic Risk Factors for Pediatric MS study of the US Network of Pediatric MS Centers were analysed. County-level modeled ozone data were acquired from the CDC’s Environmental Tracking Network air pollution database. Participants were assigned ozone values based on county of residence. Values were categorized into tertiles based on healthy controls. The association between ozone tertiles and having MS were assessed by logistic regression. Interaction between tertiles of ozone level and presence of DRB1*15 alleles on odds of ped-MS was evaluated. Models were adjusted for sex, race, ethnicity, age, second-hand smoke exposure, and mother’s education. Additive interaction was estimated using relative risk due to interaction (RERI) and attributable proportion of disease were calculated.
Results
355 ped-MS cases and 565 controls contributed to the analyses. Ozone levels were associated with MS with an odds ratio (OR) of 2.35 (95%CI 1.57–3.51) and 2.21 (95%CI 1.48–3.32) in the upper two tertiles, respectively, compared with the lowest tertile. DRB1 status was also independently associated with MS (OR 1.99; 95%CI 1.43–2.78). There was a significant additive interaction between ozone and DRB1, with a RERI of 2.74 (95%CI 0.50–4.98) and 2.43 (95%CI 0.36–4.5) in the upper two tertiles, respectively. Approximately 60% of the ped-MS risk in those with HLA-DRB1*15 haplotype and high ozone exposure was attributable to the interaction between these risk factors.
Conclusions
Our data revealed additive interaction between higher exposure to ozone and DRB1 alleles on ped-MS susceptibility. Further evaluation of additional genetic variants that might play a role in ozone-induced ped-MS is underway to provide mechanistic insight.
PS07.05 - Leptomeningeal, dura mater and meningeal vessel wall enhancements in multiple sclerosis
Abstract
Background
Leptomeningeal inflammation (LMI) in multiple sclerosis (MS) can be putatively identified by leptomeningeal contrast enhancement (LMCE) on gadolinium-enhanced 3D T2-fluid attenuated inversion recovery (FLAIR) magnetic resonance (MR) images. Dura mater (DME), inclusive falx cerebri (FCE) enhancement and meningeal vessel wall enhancement (VWE) represent two other meningeal enhancement patterns in MS that have not been extensively studied.
Objectives
To investigate the frequency of LMCE, DME/FCE and VWE in patients with MS and their associations with demographic, clinical and MRI characteristics in a longitudinal retrospective study.
Methods
217 MS patients (193 relapsing-remitting MS, 24 progressive MS) were assessed at baseline and over 18 months follow-up using 3T 3D FLAIR pre- and post-contrast and subtraction images. Lesion and brain volume outcomes were additionally calculated. Analysis of covariance (ANCOVA) and regression models were used to assess the relationship between MRI variables and clinical variables, controlling for age.
Results
24% of MS patients revealed LMCE, and 47% and 24% revealed DME/FCE and VWE, respectively. LMCE presence correlated with age and higher ventricular cerebrospinal fluid (vCSF) volume. More LMCE positive subjects (38%) showed additional VWE, compared to LMCE negative subjects (20%, p=0.055). DME/FCE presence was associated with higher T1/T2 lesion load, higher vCSF volume and decreased total deep gray matter (GM) and hippocampus volumes. All three meningeal enhancement patterns showed a high persistence in shape and size at follow-up.
Conclusions
Different patterns of meningeal enhancement, i.e. LMCE, DME/FCE and VWE can be identified by gadolinium-enhanced 3D FLAIR MR imaging. LMCE positive patients show a trend for higher frequency of VWE than LMCE negative patients. DME/FCE is the most frequent meningeal enhancement pattern in MS, which correlates with imaging markers of lesion burden and brain atrophy and may indicate abnormal lymphatic drainage in these patients.