Hospital Clinic Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Universitat de Barcelona
Center of Neuroimmunology, Laboratory of Advanced Imaging in Neuroimmunological Diseases

Author Of 5 Presentations

Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0324 - Effect of ocrelizumab treatment in peripheral blood leukocyte subsets of Primary Progressive Multiple Sclerosis patients (ID 1613)

Abstract

Background

Ocrelizumab is the first drug approved as disease modifying treatment for primary progressive (PP) multiple sclerosis (MS). As a humanized monoclonal antibody targeting CD20 cells, it is widely known that ocrelizumab treatment results in B cells depletion, but less is known about the effects of this drug in other blood leukocyte subsets of PPMS patients.

Objectives

To explore the changes induced by ocrelizumab in blood immune cells of PPMS patients to further understand their effects in the abnormal inflammatory response.

Methods

Multi-centre prospective longitudinal study including fifty‐three PPMS patients who initiated ocrelizumab treatment. Effector, memory, and regulatory cells were analyzed by flow cytometry at baseline and after 6 months of treatment. To assess differences between baseline and after 6 months, Wilcoxon matched paired tests were used and p values were corrected using Bonferroni test.

Results

Ocrelizumab decreased numbers of naïve and memory B cells (p<0.0001) and those of B cells producing interleukin (IL)-6, IL-10, granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-alpha (p<0.0001 in all cases). A reduction of CD20+ T cell numbers (p=0.02) and percentages (p<0.0001) was also observed. We also detected a clear remodelation of the T cell compartment characterized by relative increases of the naïve/effector ratio in CD4+ (p=0.002) and CD8+ (p=0.002) T cells, and relative decreases of CD4+ (p=0.03) and CD8+ (p=0.004) T cells producing interferon-gamma. Total monocyte numbers increased (p=0.002), with no changes in those producing inflammatory cytokines. All these changes resulted in a reduction of serum neurofilament light chain (sNfL) levels (p=0.009).

Conclusions

Effector B cell depletion by ocrelizumab treatment induces changes in the T cell response of PPMS patients towards a low inflammatory profile. This resulted in a decrease of sNfL levels.

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Imaging Poster Presentation

P0556 - Characterization of multiple sclerosis lesions with distinct clinical correlates through diffusion MRI properties (ID 845)

Abstract

Background

Background: Diffusion magnetic resonance imaging can reveal quantitative information about the tissue changes in multiple sclerosis. The recently developed multi-compartment spherical mean technique can map different microscopic properties based only on local diffusion signals, and it may provide specific information on the underlying microstructural modifications that arise in multiple sclerosis.

Objectives

Objective: Given that the lesions in multiple sclerosis may reflect different degrees of damage, we hypothesized that quantitative diffusion maps may help characterize the severity of lesions “in vivo” and correlate these to an individual’s clinical profile.

Methods

Methods: We evaluated a cohort of 59 MS patients (62% female, mean age 44.7 years), for whom demographic and disease information was obtained, and who underwent a comprehensive physical and cognitive evaluation. MRI protocol included conventional sequences to define focal lesions and multi-shell diffusion imaging. Quantitative diffusion properties were used to discriminate distinct types of lesions through a k-means clustering algorithm, and the number and volume of those lesions were correlated with parameters of the disease.

Results

Results: The combination of microscopic and macroscopic diffusion properties differentiated two types of lesions, with a prediction strength of 0.931. The type B lesions had larger diffusion changes compared to the type A lesions, irrespective of their location (P <0.001). The number and volume of type B lesions was related to the severity of disease evolution, clinical disability and cognitive decline (P =0.004, Bonferroni correction). Specifically, more and larger type B lesions were correlated with a worse Multiple Sclerosis Severity Score, cerebellar function and cognitive performance, and a greater need for high-efficacy treatments.

Conclusions

Conclusions: The severity of damage within focal lesions have the potential to permit more specific understanding of the mechanisms that drive disease evolution.

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Neuropsychology and Cognition Poster Presentation

P0805 - Dynamics of cognitive decline along the disease course in multiple sclerosis (ID 897)

Abstract

Background

Cognitive decline is frequent in patients with multiple sclerosis (MS). The cognitive trajectory is not well understood and a global overview throughout the disease course needs to be elucidated. Besides, predictors of future cognitive decline are still needed.

Objectives

We aim to (a) assess the temporal dynamics of cognitive function through disease course, and (b) explore different clinical and MRI predictors of cognitive decline in a large cohort of patients with MS.

Methods

Longitudinal study with 212 MS patients who performed a total of 605 neurological, cognitive and MRI examinations at different times of the disease [examinations per patient: 3 (IQR:2-3); baseline age: 40.2 (IQR:34.5-47.6) years; baseline disease duration: 8.2 (IQR:2.3-13.9) years]. A z-score for global cognition (z-BRB) and for each cognitive domain was obtained from the Rao's Battery, and a 3D-structural MRI was acquired to calculate regional gray matter (GM) volumes. We modelled the dynamics of cognition throughout the MS course using age at MS onset, education and sex adjusted mixed-effects linear spline models with knots at 5 and 15 years. An age and sex adjusted multivariate regression model was performed to determine which factors at the first examination best predict cognitive performance at last follow-up in the entire sample.

Results

In the first 5 years of MS, we detected an increase in z-BRB (β=0.050, p=0.004) and z-attention (β=0.048, p=0.013), followed by a decline in z-BRB (β=-0.029, p=0.005) and z-verbal memory (β=-0.049, p=0.001) between the 5-15 years of the disease. During the 15-30 years of MS course, the cognitive decline was maintained, but also involved z-attention (β=-0.035, p=0.012). Lower education, higher EDSS and volumetric changes at right parahippocampus, left parsorbitalis, left superior, left middle and right inferior temporal, and right superior parietal areas at the first examination were associated with worse z-BRB at the last follow-up (adjR2=0.48, β=-0.652–0.863, p=<0.001–0.024).

Conclusions

In MS, cognition deteriorates after the first 5 years of the disease, with a steady decline over the next 25 years. The verbal memory is affected earlier and more markedly, followed by involvement of attention and information processing speed. Moreover, education, clinical disability and GM volume at baseline are associated with future cognitive outcomes.

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Neuropsychology and Cognition Poster Presentation

P0820 - Phase II trial of cognitive rehabilitation in patients with multiple sclerosis: preliminary results (ID 847)

Abstract

Background

Around 50% of patients with multiple sclerosis (MS) present a decline in cognitive behavior that impacts negatively on their autonomy, social and working skills. The benefits of cognitive rehabilitation on cognition and brain plasticity are not well understood due to methodological limitations of most studies, such the use of an inappropriate control group or the small number of patients included.

Objectives

To study the efficacy on attention, processing speed and working memory of a cognitive training program in patients with MS.

Methods

Multi-center, phase II, double-blind and randomized clinical trial to a treatment group (upward intensity training) or control group (low intensity static training). Patients were assessed using Rao's battery before and after 12 weeks of online training with the Guttmann, NeuroPersonalTrainer® (GNPT). The main objective was to demonstrate an improvement in attention and working memory tests (Pasat Auditory Serial Addition Test, PASAT, and Symbol Digit Modalities Test, SDMT) in the treatment group.

Results

The recruitment is still active. In an interim analysis on May 2020, 61 patients had been evaluated, of whom 35 fulfilled the inclusion criteria, and 23 had completed the follow-up period (age 48.8±7.4, disease duration 19.2±9.3 years). Ten patients had been assigned to the treatment group and 13 to the control group. The treatment group showed a significant reduction in z-scores of attention and working memory tests (z-score=-1.68±0.90 at baseline and -1.26±1.05 at follow up) compared to the control group (-1.78±0.63 at baseline and -1.45±1.06 at follow up), p corrected=0.003, and a trend for verbal memory (treatment group z-score -2.19±1.14 and -1.61±1.68 and sham group z-score -1.38±1.32 and -1.34±1.5 at baseline and follow up respectively, corrected p=0.074). There were no significant changes in other cognitive domains (verbal, visual, and fluency memory).

Conclusions

This preliminary analysis shows that intensive rehabilitation focused on attention, information processing speed and working memory can improve these cognitive functions.

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Observational Studies Poster Presentation

P0862 - Disability accrual in primary-progressive & secondary-progressive multiple sclerosis (ID 1232)

Abstract

Background

Some cohort studies have reported similar onset age and disability accrual in primary and secondary progressive MS (PPMS, SPMS); others have reported later onset and faster disability accrual in SPMS. Comparisons are complicated by differences in baseline disability and exposure to disease-modifying therapies (DMT), and by lack of a standardized definition of SPMS.

Objectives

We compared hazards of disability accrual in PPMS and SPMS patients from the MSBase cohort using multivariable Cox models, applying validated diagnostic criteria for SPMS (Lorscheider et al., Brain 2016).

Methods

Inclusion required adult-onset progressive MS; ≥ 3 recorded Expanded Disability Status Scale (EDSS) scores; and, for SPMS, initial records with EDSS ≤ 3 to allow objective identification of SPMS conversion. Phenotypes were subgrouped as active (PPMS-A, SPMS-A) if ≥ 1 progressive-phase relapse was recorded, and inactive (PPMS-N, SPMS-N) otherwise. Disability accrual was defined by sustained EDSS increases confirmed over ≥ 6 months. Hazard ratios (HR) for disability accrual were obtained using Andersen-Gill Cox models, adjusted for sex and time-varying age, disability, visit frequency, and proportion of time on DMT or immunosuppressive therapy. Sensitivity analyses were performed using (1) PPMS and SPMS diagnosed since 1995, and (2) physician-diagnosed SPMS. Cumulative probability of reaching EDSS ≥ 7 (wheelchair required) was assessed (Kaplan-Meier).

Results

5461 patients were included (1257 PPMS-N; 1308 PPMS-A; 1731 SPMS-N; 1165 SPMS-A). Age at progression onset was older in SPMS than PPMS (47.2 ± 10.2, vs. 41.5 ± 10.7 [mean ± SD]), and in the inactive subgroups of each phenotype. Hazard of disability accrual was decreased in SPMS relative to PPMS (HR 0.85; 95% CI 0.78–0.92); decreased by proportion of time on DMT (HR 0.99 per 10% increment; 0.98–0.99); and higher in males (1.18; 1.12–1.25). Relative to PPMS-N, hazard was decreased in SPMS-A (0.79; 0.71–0.87) but similar for PPMS-A (1.01; 0.93–1.10) and SPMS-N (0.94; 0.85–1.05). Sensitivity analyses corroborated these results. However, patients with SPMS-A reached EDSS ≥ 7 at younger ages (cumulative probability 30% by 57, vs. 64–66 for SPMS-N, PPMS-A, PPMS-N).

Conclusions

Progressive phase onset is later in SPMS than PPMS. Hazard of disability accrual during the progressive phase is lower in SPMS than PPMS. However, patients with SPMS-A reach wheelchair requirement younger than other progressive phenotypes, reflecting earlier progression onset versus SPMS-N, and greater disability at onset versus PPMS

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