The association between white matter tract structural connectivity and information processing speed in relapsing-remitting multiple sclerosis.

BACKGROUND: Information processing speed (IPS) deterioration is common in relapsing-remitting multiple sclerosis (RRMS) patients [1] and might severely affect quality of life and occupational activity. However, understanding of its neural substrate is not fully elucidated. We aimed to investigate the associations between MRI-derived metrics of neuroanatomical structures, including the tracts, and IPS. METHODS: Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test (PASAT), and Color Trails Test (CTT) were used to evaluate IPS in 73 RRMS consecutive patients, all undergoing only interferon beta (IFN-ß) therapy during the study. At the same time, 1.5T MRI including diffusion tensor imaging (DTI) data was acquired for each recruited subject. We analyzed volumetric and diffusion MRI measures (FreeSurfer 6.0) including normalized brain volume (NBV), cortical thickness (thk), white matter hypointensities (WMH), volume (vol), diffusion parameters: mean (MD), radial (RD), axial (AD) diffusivities, and fractional anisotropy (FA) of 18 major white-matter (WM) tracts. Multiple linear regression model with interaction resulted in distinguishing the neural substrate of IPS deficit in the IPS impaired subgroup of patients. RESULTS: The most significant tract abnormalities contributing to IPS deficit were right inferior longitudinal fasciculus (R ILF) FA, forceps major (FMAJ) FA, forceps minor (FMIN) FA, R uncinate fasciculus (UNC) AD, R corticospinal tract (CST) FA, and left superior longitudinal fasciculus FA (L SLFT). Among volumetric MRI metrics, IPS deficit was associated with L and R thalamic vol. and cortical thickness of insular regions. CONCLUSION: In this study, we showed that disconnection of the selected WM tracts, in addition to cortical and deep gray matter (GM) atrophy, might underlie IPS deficit in RRMS patients but more extensive studies are needed for precise associations.

Brain Atrophy as an Outcome of Disease-Modifying Therapy for Remitting-Relapsing Multiple Sclerosis.

Introduction: Currently, clinical trials of DMTs strive to determine their effect on neuroinflammation and neurodegeneration. We aimed to determine the impact of currently used DMTs on brain atrophy and disability in RRMS. The main goal of this review is to evaluate the neuroprotective potential of MS therapy and assess its impact on disability. Methods: We performed a systematic analysis of clinical trials that used brain atrophy as an outcome or performed post hoc analysis of volumetric MRI parameters to assess the neuroprotective potential of applied therapies. Trials between 2008 and 2019 that included published results of brain parenchymal fraction (BPF) change and brain volume loss (BVL) in the period from baseline to week 96 or longer were considered. Results: Twelve from 146 clinical trials met the inclusion criteria and were incorporated into the analysis. DMTs that presented a large reduction in BVL also exhibited robust effects on clinical disability worsening, e.g., alemtuzumab with a 42% risk reduction in 6-month confirmed disability accumulation (p = 0.0084), ocrelizumab with a 40% risk reduction in 6-month confirmed disability progression (p = 0.003), and other DMTs (cladribine and teriflunomide) with moderate influence on brain atrophy were also associated with a marked impact on disability worsening. Dimethyl fumarate (DEFINE) and fingolimod (FREEDOMS I) initially exhibited significant effect on BVL; however, this effect was not confirmed in further clinical trials: CONFIRM and FREEDOMS II, respectively. Peg-IFN-ß1a shows a modest effect on BVL and disability worsening. Conclusion: Our results show that BVL in one of the components of clinical disability worsening, together with other variables (lesion volume and annualized relapse rate). Standardization of atrophy measurement technique as well as harmonization of disability worsening and progression criteria in further clinical trials are of utmost importance as they enable a reliable comparison of neuroprotective potential of DMTs.

Skeletonized mean diffusivity and neuropsychological performance in relapsing-remitting multiple sclerosis.

BACKGROUND: Peak width of Skeletonized Mean Diffusivity (PSMD), as a novel marker of white matter (WM) microstructure damage, is associated with cognitive decline in several WM pathologies (i.e., small vessel disorders). We hypothesized that markers combining alterations in whole WM could be associated with cognitive dysfunction in relapsing-remitting multiple sclerosis (RRMS) patients. METHODS: We used PSMD based on tract-based spatial statistics (TBSS) of diffusion tensor imaging (DTI) magnetic resonance (MR) scans. We investigated RRMS patients (n = 73) undergoing interferon beta (IFN-ß) therapy. In this cross-sectional study, we investigated the association between neuropsychological data and clinical and MRI variables: PSMD, WM hypointensities, and normalized brain volume (NBV). RESULTS: In our cohort, 37 (50.7%) patients were recognized as cognitively impaired (CI) and 36 (49.3%) patients were cognitively normal (CN). In regression analysis, PSMD was a statistically significant contributor in the California Verbal Learning Test (CVLT) list A (p = 0.04) and semantic fluency (p = 0.036). PSMD (p < 0.001, r2  = 0.35), NBV (p = 0.002, r2  = 2.6) and WM hypointensities (p < 0.001, r2  = 0.40) were major contributors to upper extremity disability (9HPT) in the CN subgroup. A significant contributor in the majority of neuropsychological measures was education attainment. CONCLUSION: We investigated PSMD as a new parameter of WM microstructure damage that is a contributor in complex cognitive tasks, CVLT performance, and semantic fluency. PSMD was a statistically significant contributor to upper extremity disability (9HPT) together with WM hypointensities and NBV. Education attainment proved to be relevant in the majority of cognitive domains. Further studies are needed to estimate PSMD relevance as a marker of CI in MS.

Retinal nerve fiber and ganglion cell complex layer thicknesses mirror brain atrophy in patients with relapsing-remitting multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is associated with progressive brain atrophy, which in turn correlates with disability, depression, and cognitive impairment. Relapsing-remitting multiple sclerosis (RRMS) is a type of MS in which relapses of the disease are followed by remission periods. This is the most common type of the disease. There is a significant need for easy and low-cost methods to these cerebral changes. Changes in retinal layer thickness may reflect alterations in brain white and gray matter volumes. Therefore, this paper aims to determine whether retinal layer thickness, measured using optical coherence tomography (OCT), correlates with volumetric brain assessments obtained by magnetic resonance imaging (MRI). METHODS: This retrospective cohort study recruited 53 patients with relapsing-remitting MS who underwent MRI and OCT examinations for evaluation of brain compartment volumes and thickness of retinal layers, respectively. OCT parameters, including central retinal thickness; retinal nerve fiber layer thickness (RNFL, peripapillary thickness); ganglion cell complex thickness (GCC, macular thickness); and Expanded Disability Status Scale (EDSS) results were compared with MRI parameters (cerebral cortex; cerebral cortex and basal ganglia combined; brain hemispheres without the ventricular system; and white matter plaques). We also checked whether there is a correlation between the number of RRMS and OCT parameters. OBJECTIVE: Our primary objective was to identify whether these patients had retinal thickness changes, and our secondary objective was to check if those changes correlated with the MRI brain anatomical changes. RESULTS: RNFL and GCC thicknesses were strongly (p-value < 0.05) associated with (i) cerebral cortex volume, (ii) combination of brain cortex and basal ganglia volumes, and (iii) the hemispheres but without the ventricular system. White matter plaques (combined) showed only weak or no correlation with RNFL and GCC. There was no correlation between central retinal thickness and brain compartment volumes, and there were weak or no correlations between the summary EDSS scores and OCT results. CONCLUSIONS: Retinal layer thickness measured by OCT correlates with select volumetric brain assessments on MRI. During the course of RRMS, the anatomo-pathological structure of the retina might serve as a surrogate marker of brain atrophy and clinical progression within selected domains.