Selective Brain Network and Cellular Responses Upon Dimethyl Fumarate Immunomodulation in Multiple Sclerosis

Abstract

Background: Efficient personalized therapy paradigms are needed to modify the disease course and halt gray (GM) and white matter (WM) damage in patients with multiple sclerosis (MS). Presently, promising disease-modifying drugs show impressive efficiency, however, tailored markers of therapy responses are required. Here, we aimed to detect in a real-world setting patients with a more favorable brain network response and immune cell dynamics upon dimethyl fumarate (DMF) treatment. Methods: In a cohort of 78 MS patients we identified two thoroughly matched groups, based on age, disease duration, disability status and lesion volume, receiving DMF ( n = 42) and NAT ( n = 36) and followed them over 16 months. The rate of cortical atrophy and deep GM volumes were quantified. GM and WM network responses were characterized by brain modularization as a marker of regional and global structural alterations. In the DMF group, lymphocyte subsets were analyzed by flow cytometry and related to clinical and MRI parameters. Results: Sixty percent (25 patients) of the DMF and 36% (13 patients) of the NAT group had disease activity during the study period. The rate of cortical atrophy was higher in the DMF group (−2.4%) compared to NAT (−2.1%, p < 0.05) group. GM and WM network dynamics presented increased modularization in both groups. When dividing the DMF-treated cohort into patients free of disease activity ( n = 17, DMF R ) and patients with disease activity ( n = 25, DMF NR ) these groups differed significantly in CD8+ cell depletion counts (DMF R : 197.7 ± 97.1/μl; DMF NR : 298.4 ± 190.6/μl, p = 0.03) and also in cortical atrophy (DMF R : −1.7%; DMF NR : −3.2%, p = 0.01). DMF R presented reduced longitudinal GM and WM modularization and less atrophy as markers of preserved structural global network integrity in comparison to DMF NR and even NAT patients. Conclusions: NAT treatment contributes to a reduced rate of cortical atrophy compared to DMF therapy. However, patients under DMF treatment with a stronger CD8+ T cell depletion present a more favorable response in terms of cortical integrity and GM and WM network responses. Our findings may serve as basis for the development of personalized treatment paradigms.

Gray matter network reorganization in multiple sclerosis from 7‐Tesla and 3‐Tesla MRI data

“…Yet, higher values in network metrics from 7T‐data may be directly related to the differences in CT and GWc obtained between 7T‐ and 3T‐scanners. As network modules exhibit high intramodular dependencies and high intermodular independencies, increased modularity suggests increased segregation of neuronal circuitries within the cortical GM morphometric networks in MS 20,41 . Reorganization of cortical networks following disease onset indicates to act as a compensatory response of cortical GM tissue, associated with long‐term clinical outcomes in MS 20,41,42 .…”

“…As network modules exhibit high intramodular dependencies and high intermodular independencies, increased modularity suggests increased segregation of neuronal circuitries within the cortical GM morphometric networks in MS 20,41 . Reorganization of cortical networks following disease onset indicates to act as a compensatory response of cortical GM tissue, associated with long‐term clinical outcomes in MS 20,41,42 . Besides current measures of cortical GM integrity, network measures, closely reflecting ongoing tissue damage and repair processes, are promising markers for sensibly depicting disease progression.…”

Linking immune-mediated damage to neurodegeneration in multiple sclerosis: could network-based MRI help?

“… 9 , 23 , 24 Network measures have been robustly applied to closely depict progression of clinical symptoms in multiple sclerosis 10 and therapeutic outcomes. 25 Despite these findings, attempts to inclusively model neuroinflammation and neurodegeneration to explain brain circuit functioning at a global scale have remained scarce.…”

Immune regulation by mimethyl fumarate (DMF) in relapsing-remitting multiple sclerosis patients

“…Hereby, the stronger depletion of CD8 + T cells was associated with a more favorable response in terms of cortical integrity and gray and white matter network responses (365).…”

“…Moreover, the numbers of CD8 + T cells but also of lymphocytes and B cells were indicated as predictors of treatment response (364). Recently, Ciolac et al showed that DMF-treated MS patients free of disease activity presented with a lower CD8 + T cell number (365).…”