Longitudinal associations between brain structural changes and fatigue in early MS

Background: Fatigue is a common and disabling symptom of multiple sclerosis (MS) patients. Structural changes in several brain areas have been reported to correlate with fatigue in MS patients but none consistently. Objective: To study the association between global and regional measures of brain atrophy and fatigue in patients with early relapsing MS. Methods: Clinically isolated syndrome and relapsing MS patients within 12 months of clinical onset were enrolled in a neuroprotection trial of riluzole versus placebo with up to 36 months of follow-up. MRI metrics included brain volumes measured by SIENAX normalized measurements [normalized brain parenchymal volume (nBPV), normalized normal-appearing white and gray matter volume (nNAWMV and nGMV)] and T2 lesion volume (T2LV). Cortical thickness, thalamic volume and cerebellar cortical volume were measured using Freesurfer's longitudinal pipeline (v5.3) and a lesion inpainting approach. Fatigue was evaluated using the Modified Fatigue Impact Scale (MFIS). Mixed model regression measured time trends and associations between imaging and fatigue severity, adjusting for age and sex. Results: Forty-three patients (mean age 36 years; 31 females) were enrolled within 7.5±4.9 months of symptom onset. Baseline and change over baseline in lesion volumes, grey matter, white matter, basal ganglia and total parenchymal volumes were not associated with change in MFIS score over time. Lower thalamic volume at baseline predicted increasing physical subscale of MFIS score during the study (p=0.017). There was a trend toward baseline thalamic volume and cerebellar cortical volume predicting subsequent change in total MFIS score (p=0.055 and 0.082 respectively). On-study change in thalamic or cerebellar cortical volume was not associated with on-study change in MFIS score. Conclusion: Global measures of tissue loss are not strongly associated with fatigue in patients with early MS. However, thalamic and cerebellar cortical atrophy may be predictive of subsequent changes in fatigue in these patients.