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, DMFR) and patients with disease activity (n = 25, DMFNR) these groups differed significantly in CD8+ cell depletion counts (DMFR: 197.7 ± 97.1/μl; DMFNR: 298.4 ± 190.6/μl, p = 0.03) and also in cortical atrophy (DMFR: −1.7%; DMFNR: −3.2%, p = 0.01). DMFR presented reduced longitudinal GM and WM modularization and less atrophy as markers of preserved structural global network integrity in comparison to DMFNR 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.
Highlights
Loss of structural integrity driven by inflammation, demyelination, and degeneration in multiple sclerosis (MS) involves white matter (WM) and gray matter (GM) compartments, the latter playing a key role in disability and disease progression [1,2,3,4]
78 patients (mean age ± standard deviation (SD) 32.7 ± 8.7 years; 28 males; mean disease duration of 51.1 ± 37.8 months) were selected out of 1,156 patients recruited at the Department of Neurology at the University Medical Center of the Johannes Gutenberg University Mainz in Germany according to the following inclusion criteria: [1] patients aged 18–60 years, [2] patients diagnosed with relapsing-remitting MS (RRMS), [3] starting dimethyl fumarate (DMF) or NAT treatment, [4] scanned with a standardized magnetic resonance imaging (MRI) protocol [14], [5] serially acquired MRI scans at several time points, [6] no corticosteroid use within 30 days prior to MRI, [7] peripheral blood samples available at baseline and followup time points for DMF-treated patients
The multivariate analysis revealed no significant differences between the DMF and NAT groups at baseline for age [F(1,76) = 2.75, p = 0.10], disease duration [F(1,76) = 0.26, p = 0.60], Expanded Disability Status Scale (EDSS) [F(1,76) = 1.31, p = 0.25], lesion volume [F(1,76) = 0.24, p = 0.62], GM volume [F(1,76) = 0.56, p = 0.45), WM volume [F(1,76) = 0.17, p = 0.67], MRI activity [F(1,76) = 2.55, p = 0.11] and relapses [F(1,76) = 1.37, p = 0.24]
Summary
Loss of structural integrity driven by inflammation, demyelination, and degeneration in multiple sclerosis (MS) involves white matter (WM) and gray matter (GM) compartments, the latter playing a key role in disability and disease progression [1,2,3,4]. MRI parameters are regarded as surrogate measures of treatment response to DMDs, cerebrospinal fluid (CSF) or peripheral blood immune response may be a valuable biomarker [10]. In this respect, treatment response to dimethyl fumarate (DMF) was reflected by reduced counts of CD4+ and CD8+ T cells in patients without disease activity [11,12,13]. 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). 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
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