Background

We have limited understanding of the risks and impact of COVID-19 in neuroinflammatory diseases (NID) of the central nervous system, particularly among patients receiving disease modifying therapies (DMTs).

Objectives

To report initial results of a planned multi-center year-long prospective study examining the risk and impact of COVID-19 among persons with NID.

Methods

In April 2020, we deployed online questionnaires to individuals in their home environment to assess the prevalence and potential risk factors of COVID-19 symptoms in persons with and without NID.

Results

Our cohort included 1,115 participants (630 NID, 98% MS; 485 reference) as of April 30, 2020. 202 (18%) participants, residing in areas with high COVID-19 case prevalence, met the April 2020 CDC symptom criteria for suspected COVID-19, but only 4% of all participants received testing given testing shortages. Among all participants, those with suspected COVID-19 were younger, more racially diverse, and reported more depression and liver disease. Persons with NID had the same rate of suspected COVID-19 as the reference group. Early changes in disease management included telemedicine visits in 21% and treatment changes in 9% of persons with NID. After adjusting for potential confounders, increasing neurological disability was associated with a greater likelihood of suspected COVID-19 (OR_adj=1.45, 1.17-1.84).

Conclusions

Our study of real-time, patient-reported experience during the COVID-19 pandemic complements physician-reported MS case registries that capture an excess of severe cases. Overall, persons with NID seem to have a risk of suspected COVID-19 similar to the reference population.

Background

Genetic studies suggest that peripheral immune dysfunctions occurs first in the causal chain of events leading to MS. However, these changes are typically not appreciated when patients present with their first symptom or with an asymptomatic inflammatory lesion; we have only sparsely characterized individuals before they develop disease. Thus, the earliest molecular events leading to damage of the CNS parenchyma remain unknown.

Objectives

To investigate the correlation between a marker of neuronal integrity (Neurofilament light chain, NfL) and the transcriptional profile of peripheral immune cells during the pre-symptomatic phase in a cohort of first-degree family members of MS patients.

Methods

Blood samples were collected from 124 asymptomatic first-degree relatives of MS patients part of the Genes & Environment in MS (GEMS) study, 7 MS patients, and 11 patients with other neuroimmune diseases (ONID), age (20-54). Serum samples were used to assess NfL levels using the SIMOA platform. Cryopreserved peripheral blood mononuclear cells (PBMC) were used to generate RNA-sequencing data. ‘CIBERSORT’ was used to estimate the proportions of major PBMC cell types (CD4 and CD8 T, monocyte, B, and NK) from the gene expression data. ‘WGCNA’ was used to to identify PBMC co-expressed gene modules. Available genotyping data were used to calculate a polygenic MS risk score for each individual.

Results

Serum NfL levels from GEMS individuals increased with age (p=2E-14), and were significantly lower than MS and ONID patients, adjusting for the effects of age and sex. NfL was not elevated in high-risk (high polygenic score) vs. low-risk family member subgroups.

After batch variation and technical variable correction 114 GEMS subjects qualified for PBMC bulk RNA-sequencing analysis. ‘WGCNA’ identified 37 co-expressed gene modules, 4 of which were associated with NfL levels (FDR-adjusted p<0.05), adjusting for effects of age, sex and estimated cell type proportions. One particular module is enriched in myeloid cells, and myeloid-mediated immunity and myeloid activation pathways; an association that persisted after accounting for the proportion of different cell types. The other 3 modules were all enriched for genes upregulated in chronic myelogenous leukemia and downregulated gene targets of KLF1 transcription factor.

Conclusions

The transcriptional programs of some peripheral immune cells strongly correlate with NfL levels; ongoing data replication. These results implicate a cross-talk between the peripheral immune system and the CNS that could provide additional insights into MS pathophysiology; the direction of the association is being explored.

Background

The gut microbiota is emerging as a critical regulator of immune responses and appears to play an important role in MS. The International Multiple Sclerosis Microbiome study (iMSMS) is a global collaboration aimed at elucidating the role of commensal gut bacteria in MS by acquiring and analyzing samples from 2000 patients and 2000 household healthy controls.

Objectives

The iMSMS focuses on identifying the microbes, genes and pathways that are involved in MS pathogenesis and on investigating how the microbiome changes response to treatment.

Methods

A total of 576 case and household healthy control pairs were recruited from 7 centers located in the US (West and East coasts), Europe and South America. Stool samples were collected and evaluated by both 16S and shallow whole metagenome shotgun sequencing. Univariate and multivariate linear regression analyses were conducted to understand patterns of variation on gut microbiome.

Results

This is the largest MS microbiome study reported to date. Our results showed a statistically significant difference of beta diversity between MS and healthy controls for the first time in MS. Intriguingly, multiple species of Akkermansia, including the known mucin-degrading bacterium Akkermansia muciniphila, were significantly enriched in untreated MS patients after adjusting for confounding factors, but the difference was not detected in treated MS group versus control. Ruminococcus torques and Eisenbergiella tayi were also among the top significantly enriched bacteria in MS. Inversely, a main butyrate producer, Faecalibacterium prausnitzii, was significantly decreased in the untreated MS group. Functional pathways of L-tryptophan biosynthesis and L-threonine biosynthesis were slightly increased in untreated MS patients, while 5-aminoimidazole ribonucleotide biosynthesis I was increased in the treated group.

Conclusions

Our large household-controlled study allowed us to identify modest but statistically robust MS-associated changes in bacterial composition and functions. It provides the foundation for all future studies of the gut microbiota in MS. The strain-level genomic variation and microbiome-derived molecules need to be further explored for understanding microbial adaptation and pathogenicity.

Background

We have limited understanding of the risks and impact of COVID-19 in neuroinflammatory diseases (NID) of the central nervous system, particularly among patients receiving disease modifying therapies (DMTs).

Objectives

To report initial results of a planned multi-center year-long prospective study examining the risk and impact of COVID-19 among persons with NID.

Methods

In April 2020, we deployed online questionnaires to individuals in their home environment to assess the prevalence and potential risk factors of COVID-19 symptoms in persons with and without NID.

Results

Our cohort included 1,115 participants (630 NID, 98% MS; 485 reference) as of April 30, 2020. 202 (18%) participants, residing in areas with high COVID-19 case prevalence, met the April 2020 CDC symptom criteria for suspected COVID-19, but only 4% of all participants received testing given testing shortages. Among all participants, those with suspected COVID-19 were younger, more racially diverse, and reported more depression and liver disease. Persons with NID had the same rate of suspected COVID-19 as the reference group. Early changes in disease management included telemedicine visits in 21% and treatment changes in 9% of persons with NID. After adjusting for potential confounders, increasing neurological disability was associated with a greater likelihood of suspected COVID-19 (OR_adj=1.45, 1.17-1.84).

Conclusions

Our study of real-time, patient-reported experience during the COVID-19 pandemic complements physician-reported MS case registries that capture an excess of severe cases. Overall, persons with NID seem to have a risk of suspected COVID-19 similar to the reference population.