Background

Background: An improved understanding of the impact of demyelination on multiple sclerosis (MS) related cognitive impairment is crucial for targeting and testing therapies with the potential to slow cognitive decline. Demyelination can be assessed using myelin water imaging, a quantitative magnetic resonance imaging (MRI) technique that measures signal from water in the myelin bilayers, providing a specific measure of myelin (myelin water fraction, MWF).

Objectives

Objective: To determine if there is an anatomical-functional relationship between myelin content and location with cognitive performance.

Methods

Methods: 76 MS participants (mean (SD) age:50.4y(10.6y), 51F) underwent T2 relaxation imaging to calculate MWF maps and cognitive testing (Symbol Digit Modalities Test (SDMT); Selective Reminding Test (SRT); Controlled Oral Word Association Test (COWAT); Brief Visuospatial Memory Test-Revised (BVMT-R)). Nonparametric permutation testing with FSL Randomise was used to determine which white matter (WM) MWF voxels were associated with cognitive test performance for each test (p<0.01, after multiple comparisons correction), creating test-specific maps of associated WM areas. Pearson ́s correlations assessed relationships between mean MWF in the cognitive test-specific WM areas and respective test scores. MS patients were categorized into cognitively impaired, mildly impaired and cognitively preserved groups based on published norms. Kruskal Wallis ANOVA with post hoc pairwise comparisons investigated mean MWF differences between cognitive groups.

Results

Results: MWF in several WM areas was significantly associated with SDMT, SRT and BVMT-R scores but not the COWAT. All tests found voxels within the corona radiata, posterior thalamic radiation and parts of the corpus callosum significant. Unique WM areas were the inferior longitudinal fasciculus and anterior cingulum for SDMT and the retrolenticular part of the internal capsule for the BVMT-R. Mean MWF in the test-specific WM areas correlated significantly with performance on the SDMT (r=0.58, p= 4.11 x 10^-8), SRT (r=0.56, p= 4.14 x 10^-7) and BVMT-R (r=0.56, p= 1.0 x 10^-6). Mean MWF in the test-specific WM areas was significantly lower in the cognitively impaired group relative to the cognitively preserved group (p<0.01).

Conclusions

Conclusions: There is an anatomical-functional relationship between myelin damage and cognitive performance in MS with unique WM patterns for different cognitive domains.

Background

People with antibodies to myelin oligodendrocyte glycoprotein (MOG) using reliable cell-based assays have heterogeneous course. Best management practices and outcome predictors are still uncertain.

Objectives

This study aimed to assess the treatment experience in a relapsing MOG positive cohort and the impact on disability accrual.

Methods

Retrospective chart review of (aquaporin4 negative) MOG antibody positive patients at University of British Columbia Multiple Sclerosis Clinic with relapsing disease, and minimum 1year follow-up.

Results

Of 49 MOG positive patients, 37(64.8% female) met inclusion criteria. Median age was 26 years (range 3-62; 10 pediatric cases) with median follow-up of 6years(range 1-36). Median time to second disease episode from first was 12 months (range 1-228); and to third (n=27) was 25 months (range 3-312). Median number total disease episodes was 3 (range 2-10).

For some, management decisions were initiated prior to MOG diagnosis. At first disease presentation 35/37 patients received acute therapy but only 1 started chronic therapy. First-line chronic therapies were later started in another 30 patients; in 35%(13/37) after second disease episode, and at the third in 27%(10/37). Most common were azathioprine(61%) and rituximab(19%). Sixteen patients(52%) required second line therapy, mostly due to adverse effects(62.5%) or disease activity(31%). Most common second line therapies were mycophenolate mofetil (MMF) or rituximab. Three patients required third line therapy.

17/37 patients had good outcome (EDSS<2) at last follow-up despite relapsing course, whilst 20(54%) had residual disability. Onset clinical phenotype distribution was similar between these two outcomes. 5% had persistent disability from disease onset, but mostly this developed from the second(19%) or third(16%) episode. 4/6 untreated patients had good outcome. Only 30% of the pediatric cohort vs 63% of the adult cohort had EDSS ≥2.0.

Conclusions

Chronic therapy was not typically started at disease onset, mostly due to initial absence of diagnosis. Azathioprine, MMF and rituximab were all effective therapies. Azathioprine was associated with high proportion of intolerance. Approximately half of patients recovered well from the initial episode; the rest accrued disability, typically from second or third disease episode, independent of clinical phenotype at onset. Further studies are required to identify factors influencing disability accrual, to enable earlier effective treatment in those at highest risk.

Background

Neurological disability progression occurs across the spectrum of people living with multiple sclerosis (PwMS). Currently, no treatments exist that substantially modify the course of clinical progression in MS, one of the greatest unmet needs in clinical practice. Characterizing the determinants of clinical progression is essential for the development of novel therapeutic agents and treatment approaches that target progression in PwMS.

Objectives

The overarching aim of CanProCo is to evaluate a wide spectrum of factors associated with the onset and rate of disease progression in MS, and to describe how these factors interact with one another to influence progression.

Methods

CanProCo is a prospective, observational cohort study aiming to recruit 1000 individuals with radiologically-isolated syndrome (RIS), relapsing-remitting MS (RRMS), and primary-progressive MS (PPMS) within 10-15 years of disease onset, and 50 healthy controls (HCs) from five large academic MS centers in Canada. Participants undergo detailed clinical evaluations annually. A subset of participants enrolled within 5-10 years of disease onset (n=500) also have blood, cerebrospinal fluid, and MRIs collected facilitating study of biological measures (e.g. single-cell RNA-sequencing[scRNASeq]), MRI-based microstructural assessment, participant characteristics (self-reported, performance-based, clinician-assessed, health-system based), and environmental factors as determinants contributing to the differential progression in MS.

Results

Recruitment commenced in April/May 2019 and n=536 patients have been recruited to date (RRMS=457, PPMS=35, RIS=25, HC=19). Baseline age, sex distribution, and Expanded Disability Status Scale (EDSS) scores (median, range) of each subgroup are: RRMS=38 years, 73% female, EDSS=1.5 (0-6.0); PPMS=52 years, 40% female, EDSS=4.0 (1.5-6.5); RIS=41 years, 68% female, EDSS=0 (0-3.0); HC=37 years, 63% female. Recruitment has surpassed the 50% target but has been paused due to the COVID-19 pandemic. scRNASeq on frozen blood samples has been validated.

Conclusions

Halting the progression of MS is a fundamental clinical need to improve the lives of PwMS. Achieving this requires leveraging transdisciplinary approaches to better characterize mechanisms underlying clinical progression. CanProCo is the first prospective cohort study aiming to characterize these determinants to inform the development and implementation of efficacious and effective interventions.