Network Damage Predicts Clinical Worsening in Multiple Sclerosis: A 6.4-Year Study.

Objective: In multiple sclerosis (MS), clinical impairment is likely due to both structural damage and abnormal brain function. We assessed the added value of integrating structural and functional network MRI measures to predict 6.4-year MS clinical disability deterioration.

Methods: Baseline 3D T1-weighted and resting-state functional MRI scans were obtained from 233 patients with MS and 77 healthy controls. Patients underwent a neurologic evaluation at baseline and at 6.4-year median follow-up (interquartile range = 5.06-7.51 years). At follow-up, patients were classified as clinically stable/worsened according to disability changes. In relapsing-remitting (RR) MS, secondary progressive (SP) MS conversion was evaluated. Global brain volumetry was obtained. Furthermore, independent component analysis identified the main functional connectivity (FC) and gray matter (GM) network patterns.

Results: At follow-up, 105/233 (45%) patients were clinically worsened; 26/157 (16%) patients with RRMS evolved to SPMS. The treatment-adjusted random forest model identified normalized GM and brain volumes, decreased FC between default-mode networks, increased FC of the left precentral gyrus in the sensorimotor network (SMN), and GM atrophy in the fronto-parietal network (false discovery rate [FDR]-corrected p = range 0.01-0.09) as predictors of clinical worsening (out-of-bag [OOB] accuracy = 0.74). An expected contribution of baseline disability was also present (FDR-p = 0.01). Baseline disability, normalized GM volume, and GM atrophy in the SMN (FDR-p = range 0.01-0.09) were independently associated with SPMS conversion (OOB accuracy = 0.84). At receiver operating characteristic analysis, including network MRI variables improved disability worsening (p = 0.05) and SPMS conversion (p = 0.02) prediction.

Conclusions: Integration of MRI network measures helped determining the relative contributions of global/local GM damage and functional reorganization to clinical deterioration in MS.