Background

People with MS present disruption of structural brain networks, but the differential characteristics of such changes among MS phenotypes and their clinical impact are not well elucidated.

Objectives

To characterize diffusion-based brain connectivity abnormalities in different MS phenotypes and their relation with disability in a large cohort of patients.

Methods

In this multicenter, retrospective, cross-sectional study, we collected clinical and brain MRI data from 344 patients with MS [median Expanded Disability Status Scale, EDSS 2.0 (range 0-7.0)] and 91 healthy volunteers (HV) from four MAGNIMS centers. Cognition was assessed with the Paced Auditory Serial Addition Test (PASAT) and Symbol Digits Modalities Test (SDMT) in 298 patients. We collected 3D-T1, FLAIR, diffusion-weighted images (DWI) and T2 or field maps acquisitions. FSL and ANTs packages were used to carry out DWI preprocessing and MRtrix software to generate connectivity matrices based on fractional anisotropy values. We computed six network measures (strength, global and local efficiency, clustering coefficient, assortativity and transitivity), and applied the ComBat tool to reduce inter-site variability. We calculated age-adjusted differences in graphs between groups using Mann-Whitney with FDR correction or Kruskal-Wallis with Dunn’s Test when necessary. Associations with clinical features were explored with Spearman’s rank correlation.

Results

Thirty-eight (11%) patients presented a clinically isolated syndrome (CIS), 262 (76%) had relapsing-remitting (RR) and 44 (13%) secondary progressive (SP) MS. CIS patients showed reduced global and local efficiency, clustering coefficient and transitivity compared to HV (corrected p<0.001), whilst RRMS did not differ from CIS patients. Compared with CIS and RRMS, patients with SPMS showed larger changes for the same previous graphs measures (corrected p<0.05), and lower strength than RRMS (corrected p=0.019).

In patients, reduced measures of strength, global and local efficiency, clustering and transitivity correlated with higher EDSS (rho:-0.12–-0.16, corrected p<0.034), lower PASAT (rho:0.26–0.30, corrected p<0.001) and worse SDMT scores (rho:0.28–0.32, corrected p<0.001).

Conclusions

Structural network integrity at the whole brain level is already widely reduced in people with MS from the earliest phases of the disease and becomes more abnormal in SPMS. Network modifications may contribute to the clinical manifestations of the disease.

Background

Inflammatory demyelination in the anterior optic pathway, including the optic chiasm (OC), occurs frequently in relapsing-remitting multiple sclerosis (RRMS), aquaporin4 (AQP4) antibody (Ab) positive neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein-Ab associated-disease (MOGAD).

Objectives

To evaluate the involvement of the OC in RRMS, AQP4-NMOSD and MOGAD using Magnetization Transfer Ratio (MTR) and explore its relationship with prior optic neuritis (ON).

Methods

We recruited 25 patients with RRMS (16 F, mean age: 44.6 yrs ±11.8, median EDSS: 2.0 [range: 1.0-7.5], mean number of previous episodes of ON: 0.44±0.58, 9 unilateral, 1 bilateral), 13 with AQP4-NMOSD (10 F, mean age: 45.3 yrs ±11.2, median EDSS: 3.0 [1.0-6.5], mean number of ON episodes: 1.54±1.13, 4 unilateral, 6 bilateral), 20 with MOGAD (13 F, mean age: 33.9 yrs ±16.4, median EDSS: 2.0 [0.0-6.5], mean number of ON episodes: 2.85±2.80, 6 unilateral, 11 bilateral) and 29 healthy controls (HC) (23 F, mean age: 35.9 yrs ±12.8). We used T2-weighted, MTon and MToff images to obtain MTR maps of the OC. Age-, sex-, and disease duration-adjusted linear regression models were used to compare the measures between disease and healthy groups (p<0.05).

Results

Chiasmal MTR values in patients with previous ON were lower in AQP4-NMOSD (p=0.040) and MOGAD (p=0.001) than HC but not when compared to patients without previous ON. In patients with RRMS and previous ON, MTR values were lower than patients without prior ON (p=0.003). No differences were found either between patients without ON and HC or between the disease groups.

When considering all patients with demyelinating diseases, patients with previous ON had lower chiasmal MTR values when compared to HC (unilateral: p=0.037; bilateral: p=0.002) and to patients without ON (unilateral: p=0.019; bilateral: p<0.001). This difference persisted when comparing both monophasic and relapsing ON patients to HC (p=0.044; p<0.001) and to patients without ON (p=0.019; p<0.001). No differences were found between patients without history of ON and HC. A correlation was found between MTR values and number of ON episodes (rho=-0.55, p<0.001).

Conclusions

Microstructural damage in the OC correlated with the number of ON episodes across inflammatory demyelinating diseases. A higher number of episodes is associated with lower chiasmal MTR, supporting its role as an accessible target for the assessment of the visual pathway in inflammatory diseases.