Background

Retinoid acid X receptor [RXR] gamma agonists promote oligodendrocyte progenitor cell differentiation and remyelination following experimental demyelination.

Objectives

To assess the safety and efficacy of bexarotene, a non-specific RXR agonist licensed for cutaneous T-cell lymphoma, as a remyelinating therapy in people with relapsing remitting multiple sclerosis.

Methods

In a double-blind, placebo-controlled, phase 2a trial (Cambridge Centre for Myelin Repair: CCMR-One), participants aged 18-50 years with relapsing remitting multiple sclerosis, stable on dimethyl fumarate for at least 6 months, were randomised to bexarotene 300mg/m² or placebo for 6 months. The primary efficacy outcome was change in mean lesional magnetisation transfer ratio (MTR) for lesions whose baseline MTR was below the median lesional MTR for that patient. The secondary efficacy outcome was change in full-field visual evoked potential (VEP) latency in eyes with electrophysiological evidence of optic neuropathy (baseline latency >118ms). We analysed by intention to treat.

Results

52 patients were randomised 1:1 to receive six months of bexarotene or placebo. Two placebo patients withdrew before receiving study drug and one bexarotene patient withdrew consent during the trial. All bexarotene patients experienced adverse effects, notably central hypothyroidism (26 [100%]) and hypertriglyceridaemia (24 [92%, mean maximum of 6.79 mmol/L ,SD 4.4]; as well as rash (13 [50%]) and neutropenia (10 [38%]). Two discontinued placebo because of adverse events and five discontinued bexarotene because of rash [2], neutropenia, triglyceridaemia and mood disturbance. The primary efficacy outcome was negative (mean submedian lesion MTR change was 0.25pu in the bexarotene group versus 0.09pu in the placebo group, p=0.54), but in an exploratory, lesion-level analysis, though treatment difference in submedian lesions was too small to achieve significance, it was statistically significantly greater than in supermedian lesions (p=0·007). This suggests that bexarotene has a biological effect on MTR and that this effect is dependent on baseline lesional MTR. This interpretation is supported by the finding that bexarotene treatment reduced full field visual evoked potential latency compared to placebo in the 52 eyes with delayed VEPS at baseline, by 4·66 ms/eye (95% CI -8·38 -0·93; p=0·014) and in all eyes, by a per-protocol analysis, by 4.02ms/eye (P=0.015).

Conclusions

Despite a negative primary efficacy outcome, evidence from both magnetisation transfer ratio imaging and visual evoked potentials suggest that a retinoic X receptor agonist, bexarotene, promotes remyelination in people with multiple sclerosis. We have also a heterogeneous response of MS lesions to a drug promoting remyelination. Although bexarotene’s safety profile precludes its widespread use, these data support efforts to develop a selective RXR-gamma agonist.

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

Neurometabolites measured by proton magnetic resonance spectroscopic imaging (MRSI) can be used to examine the relationship between metabolic markers of brain injury and clinical disability in secondary progressive multiple sclerosis (SPMS). Current work has shown an association between normal appearing white matter (NAWM) total N-acetyl aspartate plus N-acetyl aspartyl glutamate (tNAA) and both arm function and measures of processing speed.

Objectives

To determine if baseline tNAA and tNAA/tCr in NAWM are associated with upper limb function (9-hole peg test) and information processing speed (Paced auditory serial addition test) after 96 weeks of follow-up.

Methods

108 participants from the recently reported MS-SMART trial were included.¹ All participants had chemical shift imaging in a single slice in the brain (2D-PRESS, TE/TR = 35/2000ms) at 3T and metabolite levels were determined for grey matter and NAWM. Absolute concentrations and ratios to total creatine (tCr) were calculated with LCModel, using an unsuppressed water scan as the internal reference. Along with MRSI, baseline T2 lesion volume (T2LV) and normalised brain volume (NBV) were calculated. Clinical measures were acquired as per MS-SMART protocol at baseline and 96 weeks.² To determine the association between baseline neurometabolites and 9-hole peg test (9HPT) and Paced auditory serial addition test (PASAT) scores at 96 weeks, multiple regression analysis was used with trial arm, age, sex, disease duration, relapses preceding study entry, T2LV and NBV at baseline as the covariates.

Results

At baseline, mean age of the cohort was 55 years (sd 7.1) and 67% female, mean disease duration was 22 years (sd 9.6), median EDSS 6.0 (IQR 1.0), mean PASAT score 42.8, 95% CI [40.4-45.2], mean 9HPT (sec^-1) 0.036, 95% CI [0.034-0.037] and median T2LV 9.0mL (IQR 13.6). At 96 weeks, mean 9HPT (sec^-1) was 0.034, 95% CI [0.032-0.036] and mean PASAT3 score was 43.6, 95% CI [40.8-46.3]. Baseline tNAA (β = 0.22, 95% CI [0.02-0.41], p = 0.03) and tNAA/tCr (β = 0.23, 95% CI [0.5-0.42], p = 0.02) in NAWM were associated with 9HPT at 96 weeks. Baseline NAWM tNAA and tNAA/tCr were not significantly associated with 96-week PASAT scores.

Conclusions

Baseline neuroaxonal integrity in NAWM as measured by tNAA and tNAA/tCr are associated with upper limb function at 96-weeks. Baseline neuroaxonal integrity in NAWM was not associated with a measure of processing speed at 96 weeks.

1. Chataway J et al. Efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis (MS-SMART): a phase 2b, multiarm, double-blind, randomised placebo-controlled trial. Lancet Neurol 2020

2. Connick P et al. Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial (MS-SMART): a multiarm phase IIb randomised, double-blind, placebo-controlled clinical trial comparing the efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis. BMJ Open 2018

Background

Background: Diffusion magnetic resonance imaging can reveal quantitative information about the tissue changes in multiple sclerosis. The recently developed multi-compartment spherical mean technique can map different microscopic properties based only on local diffusion signals, and it may provide specific information on the underlying microstructural modifications that arise in multiple sclerosis.

Objectives

Objective: Given that the lesions in multiple sclerosis may reflect different degrees of damage, we hypothesized that quantitative diffusion maps may help characterize the severity of lesions “in vivo” and correlate these to an individual’s clinical profile.

Methods

Methods: We evaluated a cohort of 59 MS patients (62% female, mean age 44.7 years), for whom demographic and disease information was obtained, and who underwent a comprehensive physical and cognitive evaluation. MRI protocol included conventional sequences to define focal lesions and multi-shell diffusion imaging. Quantitative diffusion properties were used to discriminate distinct types of lesions through a k-means clustering algorithm, and the number and volume of those lesions were correlated with parameters of the disease.

Results

Results: The combination of microscopic and macroscopic diffusion properties differentiated two types of lesions, with a prediction strength of 0.931. The type B lesions had larger diffusion changes compared to the type A lesions, irrespective of their location (P <0.001). The number and volume of type B lesions was related to the severity of disease evolution, clinical disability and cognitive decline (P =0.004, Bonferroni correction). Specifically, more and larger type B lesions were correlated with a worse Multiple Sclerosis Severity Score, cerebellar function and cognitive performance, and a greater need for high-efficacy treatments.

Conclusions

Conclusions: The severity of damage within focal lesions have the potential to permit more specific understanding of the mechanisms that drive disease evolution.

Background

People with MS present disruption of structural brain networks, but the differential characteristics of such changes among MS phenotypes and their clinical impact are not well elucidated.

Objectives

To characterize diffusion-based brain connectivity abnormalities in different MS phenotypes and their relation with disability in a large cohort of patients.

Methods

In this multicenter, retrospective, cross-sectional study, we collected clinical and brain MRI data from 344 patients with MS [median Expanded Disability Status Scale, EDSS 2.0 (range 0-7.0)] and 91 healthy volunteers (HV) from four MAGNIMS centers. Cognition was assessed with the Paced Auditory Serial Addition Test (PASAT) and Symbol Digits Modalities Test (SDMT) in 298 patients. We collected 3D-T1, FLAIR, diffusion-weighted images (DWI) and T2 or field maps acquisitions. FSL and ANTs packages were used to carry out DWI preprocessing and MRtrix software to generate connectivity matrices based on fractional anisotropy values. We computed six network measures (strength, global and local efficiency, clustering coefficient, assortativity and transitivity), and applied the ComBat tool to reduce inter-site variability. We calculated age-adjusted differences in graphs between groups using Mann-Whitney with FDR correction or Kruskal-Wallis with Dunn’s Test when necessary. Associations with clinical features were explored with Spearman’s rank correlation.

Results

Thirty-eight (11%) patients presented a clinically isolated syndrome (CIS), 262 (76%) had relapsing-remitting (RR) and 44 (13%) secondary progressive (SP) MS. CIS patients showed reduced global and local efficiency, clustering coefficient and transitivity compared to HV (corrected p<0.001), whilst RRMS did not differ from CIS patients. Compared with CIS and RRMS, patients with SPMS showed larger changes for the same previous graphs measures (corrected p<0.05), and lower strength than RRMS (corrected p=0.019).

In patients, reduced measures of strength, global and local efficiency, clustering and transitivity correlated with higher EDSS (rho:-0.12–-0.16, corrected p<0.034), lower PASAT (rho:0.26–0.30, corrected p<0.001) and worse SDMT scores (rho:0.28–0.32, corrected p<0.001).

Conclusions

Structural network integrity at the whole brain level is already widely reduced in people with MS from the earliest phases of the disease and becomes more abnormal in SPMS. Network modifications may contribute to the clinical manifestations of the disease.

Background

Cervical spinal cord atrophy is an MRI biomarker of neurodegeneration and in MS it correlates with disability and disease progression. The Mean Upper Cervical Cord Area (MUCCA) can be used to measure this atrophy. Recently there has been an increasing interest towards calculating the MUCCA from MR brain images. It has been shown that MUCCA measurements calculated from brain T1-weighted images are comparable with those calculated from cervical cord T1-weighted images. Moreover, gadolinium (Gd) administration seems to have no effect on these measurements.

Objectives

To evaluate the correlation and the agreement between MUCCA measurements calculated from 3D-FLAIR and 3D-T1 post Gd brain images.

Methods

We used the images of 20 patients with Progressive MS who underwent a 1.5 T MRI as a routine radiological follow-up. 3D- FLAIR and post Gd 3D-T1 brain images were acquired. In our study, MUCCA was defined as the mean cross-sectional area (CSA) of a 12.8 mm long section of the cervical spinal cord, starting from the tip of the C1 vertebra. 3D-FLAIR and 3D-T1 were co-registered and resampled to the same voxel size. The MUCCA and the CSA per slice were compared.

Results

The mean difference between the MUCCA measurements from FLAIR and T1 images was 1.12 mm² (1.9 %), range -3.13 mm² (5.4 %) - 4.18 mm² (7.2%). High positive correlation was observed between the MUCCA measurements from FLAIR and T1 images (r= .976 , p < .0001) and between the CSA per slice measurements from FLAIR and T1 images (r = .940 , p < .0001). High agreement was shown also by inspection of the Bland Altman plot.

Conclusions

Excellent correlation was observed between the MUCCA from 3D-FLAIR and post Gd 3D-T1 brain images. Hence 3D-FLAIR brain images, which are largely used in routine radiological follow-up, may be used to measure the MUCCA, allowing retrospective studies on spinal cord atrophy in addition to prospective ones. Further studies are needed to validate this approach, especially comparing 3D-FLAIR brain images with 3D-T1 spinal cord images.

Background

MRI assessment in MS focuses on the presence of typical white matter (WM) lesions. Neurodegeneration characterised by brain atrophy is recognised in the research field as an important prognostic factor. It is not routinely reported clinically, in part due to difficulty in achieving reproducible measurements. Automated MRI quantification of WM lesions and brain volume could provide important clinical monitoring data. In general, lesion quantification relies on both T1 and FLAIR input images, while tissue volumetry relies on T1. However, T1-weighted scans are not routinely included in the clinical MS protocol, limiting the utility of automated quantification.

Objectives

We address this important translational challenge by assessing the performance of FLAIR-only lesion and brain segmentation, against a conventional approach requiring multi-contrast acquisition. We explore whether FLAIR-only grey matter (GM) segmentation yields more variability in performance compared with two-channel segmentation; whether this is related to field strength; and whether the results meet a level of clinical acceptability demonstrated by the ability to reproduce established biological associations.

Methods

We used a multicentre dataset of subjects with a CIS suggestive of MS scanned at 1.5T and 3T in the same week. WM lesions were manually segmented by two raters, ‘manual 1’ guided by consensus reading of CIS-specific lesions and ‘manual 2’ by any WM hyperintensity. An existing brain segmentation method was adapted for FLAIR-only input. Automated segmentation of WM hyperintensity and brain volumes were performed with conventional (T1/T1+FLAIR) and FLAIR-only methods.

Results

WM lesion volumes were comparable at 3T between ‘manual 2’, T1+FLAIR and FLAIR-only methods. For cortical GM volume, linear regression measures between conventional and FLAIR-only segmentation were high (1.5T: α=1.029, R²=0.997, standard error (SE)= 0.007; 3T: α=1.019, R²=0.998, SE=0.006). Age-associated change in cortical GM volume was a significant covariate in both T1 (p=0.001) and FLAIR-only (p=0.005) methods, confirming the expected relationship between age and GM volume for FLAIR-only segmentations.

Conclusions

FLAIR-only automated frameworks for segmentation of WM lesions and brain volumes were consistent with results obtained through conventional methods and had the ability to demonstrate biological effects in our study population. This could facilitate the integration of automated WM lesion volume and brain atrophy analysis as clinical tools in radiological MS reporting.

Background

Spinal cord atrophy is a common feature of multiple sclerosis (MS), can be detected in vivo using MRI, and is one of the main substrates of disease progression. In our previous studies, we have adapted the boundary shift integral (BSI) technique developed for the brain, to be applied to the spinal cord, obtaining the first registration-based method for longitudinal assessment of spinal cord atrophy.

Objectives

We aim to 1) compare spinal cord atrophy measurements using segmentation- and registration-based methods, with possible implications for clinical trial design (e.g., measurement variability, image noise floor); 2) compare spinal cord atrophy measurements obtained from routine brain (C1-2) and dedicated spinal cord MRI (C1-2 and C2-5), using segmentation- and registration-based methods; 3) explore possible clinical correlates, also in relation to conventional brain MRI measures; and 4) explore possible treatment effect.

Methods

We included 220 primary-progressive multiple sclerosis patients from a phase 2 clinical trial, with baseline and week-48 3DT1-weighted MRI of the brain and spinal cord (1x1x1mm³), acquired separately. We obtained segmentation-based cross-sectional spinal cord area (CSA) at C1-2 (from both brain and spinal cord MRI) and C2-5 levels (from spinal cord MRI) using DeepSeg, and, then, we computed corresponding GBSI.

Results

Depending on the spinal cord segment, we included 67.4-98.1% patients for CSA measurements, and 66.9-84.2% for GBSI. Spinal cord atrophy measurements obtained with GBSI had lower measurement variability, than corresponding CSA. Looking at image noise floor, the lowest median standard deviation of the MRI signal within the cerebrospinal fluid surrounding the spinal cord was found on brain MRI at C1-2 level. Spinal cord atrophy derived from brain MRI was related to corresponding measures from dedicated spinal cord MRI, more strongly for GBSI than CSA. Spinal cord atrophy measurements using GBSI, but not CSA, were associated with upper and lower limb motor progression. No treatment effect was detected for any spinal cord atrophy measurements.

Conclusions

Notwithstanding reduced measurement variability, clinical correlates, and possibility of using brain acquisitions, spinal cord atrophy using GBSI should remain a secondary outcome measure in MS studies, until further advancements increase the quality of acquisition and reliability of processing.

Background

MS-SMART is a recently reported phase 2b randomised placebo controlled multi-arm study of the neuroprotective potential of amiloride, fluoxetine and riluzole in secondary progressive multiple sclerosis [NCT01910259]. No change in atrophy rate was observed in any arm compared to placebo. We obtained brain metabolic data using proton magnetic resonance spectroscopic imaging (MRSI) at baseline and 96 weeks to explore postulated candidate drug mechanisms of action for the three interventions. Fluoxetine has previously shown an increase in total N-acetyl aspartate plus N-acetyl aspartyl glutamate [tNAA]; myoinositol was also examined as a marker of astrogliosis. Amiloride blocks the acid sensing ion channel-1 receptor that mediates sodium and calcium and therefore could increase neuroaxonal integrity (tNAA). It is known that riluzole decreases glutaminergic transmission.

Objectives

MRSI data at baseline and then 96 weeks was used to interrogate drug specific effects of fluoxetine on tNAA and myoinositol (mIns); riluzole on Glx (glutamate + glutamine); and amiloride on tNAA levels, all compared to placebo.

Methods

108 participants from the MS-SMART trial were included and had chemical shift imaging in a single slice in the brain (2D-PRESS, TE/TR =35/2000ms) at 3T. Metabolite levels and ratios to creatine (tCr) were determined for normal appearing white matter (NAWM) and grey matter (GM) with LCModel using an unsuppressed water scan as the internal reference. Multiple regression models adjusting for age, sex and baseline Expanded Disability Status Scale (EDSS) were used.

Results

Mean age of the entire cohort was 55 (sd 7.1) years, 67% female, mean disease duration was 22 years (sd 9.6), median EDSS 6.0 (range 4.0-6.5) and median T2 lesion volume 9.0mL (IQR 6.0).

In the fluoxetine arm, there was no significant change in tNAA (or tNAA/Cr) in NAWM or GM; mIns/tCr (but not mIns) was lower at 96 weeks (β = -0.21, 95% CI [-0.40 to -0.02], p = 0.03) in NAWM (but not GM).

In the riluzole arm, there was a reduction in GM Glx (β = -0.25, 95% CI [-0.47 to -0.04], p = 0.02) and Glx/tCr (β = -0.29, 95% CI [-0.50 to -0.08], p = 0.007), but no change was seen in NAWM.

In the amiloride arm, there was no change in tNAA (or tNAA/tCr) in NAWM or GM.

Conclusions

Neither fluoxetine nor amiloride had any effect on proposed measures of neuroaxonal integrity in NAWM or GM as reflected in tNAA levels. There was a fluoxetine reduction in NAWM mIns/tCr perhaps reflecting some decrease in astrogliosis. Riluzole decreased GM Glx levels as anticipated. However, despite these target effects for these drugs, ultimately they did not translate into a reduction in atrophy rate in the trial.

Background

Clinical and imaging features of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) may overlap with those of aquaporin 4-neuromyelitis optica spectrum disorder (AQP4-NMOSD) and relapsing remitting multiple sclerosis (RRMS). There is an unmet need for MRI biomarkers which reflect biological mechanisms involved in MOGAD and can help in the differential diagnosis.

Objectives

We aim to identify imaging features able to differentiate between non-acute MOG-antibody disease, AQP4-NMOSD and RRMS.

Methods

In this ongoing retrospective, cross-sectional MAGNIMS study, we analyzed data collected from 8 centers. All subjects (n=352) had brain and cervical cord 3T MRI. Quantification of MRI biomarkers included brain white matter lesions (WMLs), cortical lesions (CL), brain parenchymal fraction (BPF), white matter fraction (WMF), cortical and deep grey matter fractions (GMF) and cross-sectional cervical cord area (CSA) at C1-C2. Linear regression models were used to compare MRI measures between groups, corrected for age, sex, and centre. Statistical significance was considered when p was <0.05.

Results

91 patients with MOGAD (50F, mean age: 41yrs [±15]), 85 with AQP4-NMOSD (68F, 49yrs [±14]), 90 with RRMS (56F, 41yrs [±11]) and 87 healthy controls (HCs) (54F, 36yrs [±11.6]) were collected. The most common phenotypes at onset were optic neuritis and transverse myelitis in MOGAD (93%) and AQP4-NMOSD (87%). WMLs were detected in 57% MOGAD, 79% AQP4-NMOSD, all RRMS (100%) patients, and in 15% HCs. The mean lesion load and number of lesions were higher in RRMS than both MOGAD (p=0.007, p<0.001) and AQP4-NMOSD (p=0.001, p<0.001). At least one CL was seen in 8% patients with MOGAD (total n=8), 10% patients with AQP4-NMOSD (n=7), and in 69% patients with RRMS (n=150). All patient groups showed lower BPF than HCs, with lower WMF in MOGAD and RRMS than HCs (all p<0.01). Between groups, deep GMF was lower in RRMS than MOGAD (p<0.001) and AQP4-NMOSD (p=0.001). CSA was reduced in all disease groups when compared to HCs (all p<0.01) and lower in AQP4-NMOSD than RRMS (p=0.01).

Conclusions

This ongoing study indicates that MOGAD and AQP4-NMOSD share similar MRI features, and no specific MRI biomarker can distinguish between them. Patients with AQP4-NMOSD showed greater spinal cord atrophy than RRMS, and RRMS patients had a higher number of cortical lesions, and greater deep GM atrophy than AQP4-NMOSD and MOGAD. The next step is to investigate whether lesion distribution differs between the two antibody-mediated disease.

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.