Background: Multiple sclerosis (MS) affects both brain and spinal cord. However, studies of the neuraxis with advanced magnetic resonance imaging (MRI) are rare because of long acquisition times. We investigated neurodegeneration in MS brain and cervical spinal cord using neurite orientation dispersion and density imaging (NODDI). Objective: The aim of this study was to investigate possible alterations, and their clinical relevance, in neurite morphology along the brain and cervical spinal cord of relapsing–remitting MS (RRMS) patients. Methods: In total, 28 RRMS patients and 20 healthy controls (HCs) underwent brain and spinal cord NODDI at 3T. Physical and cognitive disability was assessed. Individual maps of orientation dispersion index (ODI) and neurite density index (NDI) in brain and spinal cord were obtained. We examined differences in NODDI measures between groups and the relationships between NODDI metrics and clinical scores using linear regression models adjusted for age, sex and brain tissue volumes or cord cross-sectional area (CSA). Results: Patients showed lower NDI in the brain normal-appearing white matter (WM) and spinal cord WM than HCs. In patients, a lower NDI in the spinal cord WM was associated with higher disability. Conclusion: Reduced neurite density occurs in the neuraxis but, especially when affecting the spinal cord, it may represent a mechanism of disability in MS.

Brain imaging is increasingly used to support clinicians in diagnosing multiple sclerosis (MS) and monitoring its progression. However, the role of magnetic resonance imaging (MRI) in MS goes far beyond its clinical application. Indeed, advanced imaging techniques have helped to detect different components of MS pathogenesis in vivo, which is now considered a heterogeneous process characterized by widespread damage of the central nervous system, rather than multifocal demyelination of white matter. Recently, MRI biomarkers more sensitive to disease activity than clinical disability outcome measures, have been used to monitor response to anti-inflammatory agents in patients with relapsing–remitting MS. Similarly, MRI markers of neurodegeneration exhibit the potential as primary and secondary outcomes in clinical trials for progressive phenotypes. This review will summarize recent advances in brain neuroimaging in MS from the research setting to clinical applications.

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The visual system offers unparalleled precision in the assessment of neuroaxonal damage. With the majority of patients with multiple sclerosis (MS) experiencing afferent and efferent visual dysfunction, outcome measures capturing these deficits provide insight into neuroaxonal injury, even in those with minimal disability. Ideal for use in clinical trials, visual measures are generally inexpensive, accessible, and reproducible. Quantification of visual acuity, visual fields, visual quality of life, and electrophysiologic parameters allows assessment of function, whereas optical coherence tomography (OCT) provides reliable measures of the structural integrity of the anterior afferent visual pathway. The technology of oculomotor biometrics continues to advance, and discrete measures of fixation, smooth pursuit, and saccadic eye movement abnormalities are ready for inclusion in future trials of MS progression. Visual outcomes allow tracking of neuroaxonal injury and aid in distinguishing MS from diseases such as neuromyelitis optica spectrum disorder (NMOSD) or myelin oligodendrocyte glycoprotein antibody–associated diseases (MOGAD). OCT has also provided unique insights into pathophysiology, including the identification of foveal pitting in NMOSD, possibly from damage to Müller cells, which carry an abundance of aquaporin-4 channels. For some study designs, the cost-benefit ratio favors visual outcomes over more expensive MRI outcomes. With the next frontier of therapeutics focused on remyelination and neuroprotection, visual outcomes are likely to take center stage. As an international community of collaborative, committed, vision scientists, this review by the International MS Visual System Consortium (IMSVISUAL) outlines the quality standards, informatics, and framework needed to routinely incorporate vision outcomes into MS and NMOSD trials.

In early multiple sclerosis, a clearer understanding of normal-brain tissue microstructural and metabolic abnormalities will provide valuable insights into its pathophysiology. We used multi-parametric quantitative MRI to detect alterations in brain tissues of patients with their first demyelinating episode. We acquired neurite orientation dispersion and density imaging [to investigate morphology of neurites (dendrites and axons)] and 23Na MRI (to estimate total sodium concentration, a reflection of underlying changes in metabolic function). In this cross-sectional study, we enrolled 42 patients diagnosed with clinically isolated syndrome or multiple sclerosis within 3 months of their first demyelinating event and 16 healthy controls. Physical and cognitive scales were assessed. At 3 T, we acquired brain and spinal cord structural scans, and neurite orientation dispersion and density imaging. Thirty-two patients and 13 healthy controls also underwent brain 23Na MRI. We measured neurite density and orientation dispersion indices and total sodium concentration in brain normal-appearing white matter, white matter lesions, and grey matter. We used linear regression models (adjusting for brain parenchymal fraction and lesion load) and Spearman correlation tests (significance level P ≤ 0.01). Patients showed higher orientation dispersion index in normal-appearing white matter, including the corpus callosum, where they also showed lower neurite density index and higher total sodium concentration, compared with healthy controls. In grey matter, compared with healthy controls, patients demonstrated: lower orientation dispersion index in frontal, parietal and temporal cortices; lower neurite density index in parietal, temporal and occipital cortices; and higher total sodium concentration in limbic and frontal cortices. Brain volumes did not differ between patients and controls. In patients, higher orientation dispersion index in corpus callosum was associated with worse performance on timed walk test (P = 0.009, B = 0.01, 99% confidence interval = 0.0001 to 0.02), independent of brain and lesion volumes. Higher total sodium concentration in left frontal middle gyrus was associated with higher disability on Expanded Disability Status Scale (rs = 0.5, P = 0.005). Increased axonal dispersion was found in normal-appearing white matter, particularly corpus callosum, where there was also axonal degeneration and total sodium accumulation. The association between increased axonal dispersion in the corpus callosum and worse walking performance implies that morphological and metabolic alterations in this structure could mechanistically contribute to disability in multiple sclerosis. As brain volumes were neither altered nor related to disability in patients, our findings suggest that these two advanced MRI techniques are more sensitive at detecting clinically relevant pathology in early multiple sclerosis.

Fatigue is very common in multiple sclerosis (MS) and is often considered as its most disabling symptom. Over the last 20 years, an increasing number of studies have evaluated the pathogenetic bases of MS-related fatigue. Converging evidence from neurophysiology and neuroimaging research suggests that a dysfunction in a cortico-subcortical pathway, centered on thalamus, is involved in the pathogenesis of fatigue. However, type and significance of such dysfunction remain unknown, and some studies reported an increase in the activity and connectivity within the thalamic network, whereas others suggested its reduction. Hereby, we review the results of neuroimaging studies supporting the different hypotheses about the role of thalamic network in the pathophysiology of MS-related fatigue and discuss limitations and shortcomings of available data, highlighting the key challenges in the field and the directions for future research.

Background: Compared to 1.5 T, 3 T magnetic resonance imaging (MRI) increases signal-to-noise ratio leading to improved image quality. However, its clinical relevance in clinically isolated syndrome suggestive of multiple sclerosis remains uncertain. Objectives: The purpose of this study was to investigate how 3 T MRI affects the agreement between raters on lesion detection and diagnosis. Methods: We selected 30 patients and 10 healthy controls from our ongoing prospective multicentre cohort. All subjects received baseline 1.5 and 3 T brain and spinal cord MRI. Patients also received follow-up brain MRI at 3-6 months. Four experienced neuroradiologists and four less-experienced raters scored the number of lesions per anatomical region and determined dissemination in space and time (McDonald 2010). Results: In controls, the mean number of lesions per rater was 0.16 at 1.5 T and 0.38 at 3 T (p = 0.005). For patients, this was 4.18 and 4.40, respectively (p = 0.657). Inter-rater agreement on involvement per anatomical region and dissemination in space and time was moderate to good for both field strengths. 3 T slightly improved agreement between experienced raters, but slightly decreased agreement between less-experienced raters. Conclusion: Overall, the interobserver agreement was moderate to good. 3 T appears to improve the reading for experienced readers, underlining the benefit of additional training.

Background: Neurite orientation dispersion and density imaging (NODDI) and the spherical mean technique (SMT) are diffusion MRI methods providing metrics with sensitivity to similar characteristics of white matter microstructure. There has been limited comparison of changes in NODDI and SMT parameters due to multiple sclerosis (MS) pathology in clinical settings.Purpose: To compare group-wise differences between healthy controls and MS patients in NODDI and SMT metrics, investigating associations with disability and correlations with diffusion tensor imaging (DTI) metrics.Methods: Sixty three relapsing-remitting MS patients were compared to 28 healthy controls. NODDI and SMT metrics corresponding to intracellular volume fraction (vin), orientation dispersion (ODI and ODE), diffusivity (D) (SMT only) and isotropic volume fraction (viso) (NODDI only) were calculated from diffusion MRI data, alongside DTI metrics (fractional anisotropy, FA; axial/mean/radial diffusivity, AD/MD/RD). Correlations between all pairs of MRI metrics were calculated in normal-appearing white matter (NAWM). Associations with expanded disability status scale (EDSS), controlling for age and gender, were evaluated. Patient-control differences were assessed voxel-by-voxel in MNI space controlling for age and gender at the 5% significance level, correcting for multiple comparisons. Spatial overlap of areas showing significant differences were compared using Dice coefficients.Results: NODDI and SMT show significant associations with EDSS (standardised beta coefficient −0.34 in NAWM and −0.37 in lesions for NODDI vin; 0.38 and −0.31 for SMT ODE and vin in lesions; p < 0.05). Significant correlations in NAWM are observed between DTI and NODDI/SMT metrics. NODDI vin and SMT vin strongly correlated (r = 0.72, p < 0.05), likewise NODDI ODI and SMT ODE (r = −0.80, p < 0.05). All DTI, NODDI and SMT metrics detect widespread differences between patients and controls in NAWM (12.57% and 11.90% of MNI brain mask for SMT and NODDI vin, Dice overlap of 0.42).Data Conclusion: SMT and NODDI detect significant differences in white matter microstructure between MS patients and controls, concurring on the direction of these changes, providing consistent descriptors of tissue microstructure that correlate with disability and show alterations beyond focal damage. Our study suggests that NODDI and SMT may play a role in monitoring MS in clinical trials and practice.