Background

In early multiple sclerosis, a clearer understanding of normal-brain tissue microstructural and metabolic abnormalities will provide valuable insights into its pathophysiology. Here, we studied the brain of patients with their first demyelinating episode using neurite orientation dispersion and density imaging (NODDI), for information about neuro-axonal density and spatial distribution, and ²³Na MRI, for total sodium concentration reflecting neuro-axonal metabolic dysfunction and loss.

Objectives

To detect, using a multi-parametric quantitative MRI approach, clinically relevant alterations in the brain of early patients not captured by conventional MRI.

Methods

We enrolled 42 patients with clinically isolated syndrome or multiple sclerosis within 3 months from the onset and 16 healthy controls. We assessed physical and cognitive scales. On a 3T scanner, we acquired brain and spinal cord structural scans, and brain NODDI. Thirty-two patients and 13 healthy controls also underwent brain ²³Na MRI. In the brain normal-appearing white matter, white matter lesions, and grey matter, we measured, from NODDI, the neurite density index (NDI), a marker of neuro-axonal density, and the orientation dispersion index (ODI), reflecting the fanning and crossing of neurites, and, from ²³Na MRI, the TSC. We used linear regression models, adjusted for brain parenchymal fraction and lesion load, and Spearman correlation tests. For robust regression estimates, we used a p≤0.01.

Results

Patients showed higher ODI in normal-appearing white matter, including the corpus callosum, where they also showed lower NDI and higher TSC, compared with controls. In grey matter, compared with controls, patients had lower ODI in frontal, parietal and temporal cortex; lower NDI in parietal, temporal and occipital cortex; and higher TSC in limbic and frontal cortex. Brain volumes did not differ between patients and controls. In patients, higher ODI in corpus callosum was associated with worse performance on timed walk test (p=0.009, B=0.01, 99% Confidence Interval=0.0001-0.02), independent of brain and lesion volumes. Higher TSC in left frontal middle gyrus was associated with higher disability on Expanded Disability Status Scale (r_s=0.5, p=0.005).

Conclusions

We found increased axonal dispersion in normal-appearing white matter, particularly corpus callosum, where we found also reduced axonal density and total sodium accumulation suggesting that this structure can be early affected by neurodegeneration. The association between increased axonal dispersion in the corpus callosum and worse walking performance implies that morphological and metabolic alterations in this structure may contribute to disability in multiple sclerosis. Brain volumes were neither altered nor related to disability in patients, so these two advanced MRI techniques can be more sensitive at detecting clinically relevant pathology in very early multiple sclerosis.

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.