Fatigue in early multiple sclerosis: MRI metrics of neuroinflammation, relapse and neurodegeneration

Abstract

Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disease affecting the brain and spinal cord. Fatigue is a common disabling symptom from MS onset, however the mechanisms by which underlying disease processes cause fatigue remain unclear. Improved pathophysiological understanding offers potential for improved treatments for MS-related fatigue. MRI provides insights into in vivo neuroinflammatory activity and neurodegeneration, although existing evidence for imaging correlates of MS fatigue is mixed. We explore associations between fatigue and MRI measures in the brain and spinal cord to identify neuroinflammatory and regional neurodegenerative substrates of fatigue in early relapsing-remitting MS (RRMS). Recently diagnosed (<6 months), treatment-naive people with RRMS (n = 440) were recruited to a longitudinal multi-centre nationally representative cohort study. Participants underwent 3-Tesla brain MRI at baseline and one year. We calculated global and regional white and grey matter volumes, white matter lesion (WML) load and upper cervical spinal cord cross-sectional area levels C2-3, and assessed new/enlarging WMLs visually. Participants were classed as fatigued or non-fatigued at baseline according to the Fatigue Severity Scale (>/≤36). Disability and depression were assessed with the expanded-disability status scale and Patient Health Questionnaire, respectively. MRI measures were compared between fatigue groups, both cross-sectionally and longitudinally, using regression analyses. Higher disability and depression scores were observed for participants with fatigue, with a higher number of fatigued participants receiving disease-modifying treatments at follow-up. Structural MRI data for brain were available for n = 313 (45% fatigued) and for spinal cord for n = 324 (46% fatigued). Cervical spinal cord cross-sectional area 2-3, white and grey matter volumes decreased, and WML volume increased, over time for both groups (q < 0.05). However, no significant between-group differences in these measures were found either cross-sectionally or longitudinally (q > 0.05). The presence of new/enlarging WMLs (49% in fatigued; 51% in non-fatigued) at follow-up also did not differ between groups (q > 0.05). Our results suggest that fatigue is not driven by neuroinflammation or neurodegeneration measurable by current structural MRI in early RRMS. This novel negative finding in a large multi-centre cohort of people with recently diagnosed RRMS helps to resolve uncertainty in existing literature. Notably, we showed that fatigue is prevalent in patients without brain radiological relapse, who may be considered to have inactive disease. This suggests that symptom detection and treatment should remain a clinical priority regardless of neuroinflammatory disease activity. More sensitive objective biomarkers are needed to elucidate fatigue mechanisms in RRMS, and ultimately facilitate development of effective targeted treatments for this important 'hidden disability'.

Keywords: fatigue; magnetic resonance imaging; multiple sclerosis; neurodegeneration; neuroinflammation.

Graphical Abstract

Figure 1

Visual illustration of brain tissue regions used in statistical analysis. (A) Subcortical, brainstem and cerebellar masks, (B) regional white matter masks and (C) regional grey matter masks. All masks are shown on an example subject’s axial T₁-weighted image, with the sagittal T₁-weighted image (right) indicating axial slice position. This figure was created using MRIcron (https://www.nitrc.org/projects/mricron).

Figure 2

Visual illustration of the spinal cord areas used in statistical analysis. The spinal cord with cervical layers 2 (C2) and 3 (C3) highlighted is shown on the left, and cervical spinal cord cross-sectional area (SCCSA) highlighted in green is shown on the right.

Figure 3

Brain and spinal cord structural MRI findings in fatigue groups. Mean whole-brain volume, white matter lesion (WML) volume and cervical spinal cord cross-sectional area 2–3 [mm² (SCCSA C2–3)] at baseline, 1-year follow-up and % change over time (w1–w0) for fatigue [Fatigue Severity Scale (FSS) score ≥ 36] and no-fatigue groups (FSS < 36). Whole-brain and WML volumes are expressed as total voxel count as ratio of intracranial volume (r-ICV).

Figure 4

Regional brain structural MRI findings in fatigue groups. Non-significant standardized (Z-scores) regression coefficients of the interaction effect of fatigue group and time (circles) on (A) subcortical regions, and cerebellar and cerebral normal-appearing white (NAWM) and grey matter (GM), and (B) for regional brain NAWM and GM. Standardized regression coefficients < 0 indicate a negative effect of time and fatigue on brain tissue volume, i.e. atrophy; standardized regression coefficients > 0 indicate a positive effect of time and fatigue on brain atrophy volume, i.e. volume increase. Lines indicate 95% confidence intervals for each regression coefficient. Regression coefficients were not significant after corrections for multiple comparisons (false discovery rate corrected; q > 0.05).

Figure 5

Neuroinflammatory relapse in fatigue groups. Percentage of people with relapsing–remitting multiple sclerosis (pwRRMS) without (left) or with (right) fatigue as per baseline Fatigue Severity Scale score (<36, ≥36, respectively); with (red) or without (blue) new/enlarging white matter lesions (WML) over 1 year.