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

Serum neurofilament light chain (sNfL) levels are a promising biomarker for quantifying neuro-axonal injury in multiple sclerosis (MS). Recent studies showed sNfL levels relate to disease activity and treatment response.

Objectives

To analyze the predictive capacity of baseline (BL) sNfL levels for disease outcomes in the 15-year BENEFIT study long-term follow-up

Methods

Monofactorial regression analyses were conducted on outcomes at Year 15, including sNfL age-adjusted percentiles (80^th, 90^th, 95^th, 97.5^th and 99^th; Disanto et al., 2017).

Further BL covariates included sex; age; lowest EDSS up to Month 6; mono/multifocal onset; presence of optic nerve, brainstem, or spinal cord lesions; Paced Auditory Serial Addition Test 3 (PASAT-3), Timed 25 Foot Walk (T25W), and 9 Hole PEG test (9HPT) scores; number/volume of hypointense T1, gadolinium-enhancing T1, and T2 lesions; cerebral volume; and initial treatment assignment. On-study covariates at Years 1, 2, and 5 were annualized relapse rate; EDSS change; PASAT-3, T25W, and 9HPT scores; annualized rate of new lesions; lesion number/volume; brain volume change; and relative duration of treatment. Covariates with p≤0.1 (at ≥2 time points for on-study covariates) were entered into multifactorial models.

We assessed the predictive capacity of BL sNfL levels for the following outcomes: EDSS ≥4, clinically silent disease, T2 lesion volume, and cerebral volume.

Results

Patients with sNfL values at screening (N=258) above the 90^th (n=176), 95^th (n=157), 97.5^th (n=149), and 99^th (n=129) percentiles (adjusted for other relevant covariates) had a significantly higher risk of EDSS≥4 at Year 15 for BL model (odds ratio 2.45 [95% CI: 1.05,5.68] p=0.0376; 2.60 [1.18,5.75] p=0.0181; 2.61 [1.20,5.66] p=0.0154; 2.47 [1.19,5.13] p=0.0150, for the 90^th, 95^th, 97.5^th and 99^th percentiles, respectively), and for on-study models at Year 1 (3.86 [1.16,12.78] p=0.0272; 3.38 [1.13,10.14] p=0.0296; 2.92 [1.02,8.35] p=0.0461; 2.98 [1.11,8.00] p=0.0305, respectively) and Year 2 (5.36 [1.26,22.85] p=0.0231; 4.88 [1.34,17.77] p=0.0163; 3.86 [1.18,12.66] p=0.0259; 3.34 [1.17,9.48] p=0.0237, respectively). Covariates that remained statistically significant with EDSS≥4 as the endpoint in most percentile models were lowest EDSS value up to Month 6 for BL and Year 1, and change in brain volume at Year 1, 2, and 5.

Conclusions

Findings in this unique long-term BENEFIT study suggest that higher sNfL values in early MS disease stages are independent predictors of long-term disability.

Background

Contactin-1 (CNTN1) is a protein that is expressed in paranodal axonal domains and involved in myelin formation in the central nervous system (CNS) by way of axo-glia interaction, which is affected in multiple sclerosis (MS). Studying patients under natalizumab treatment provides a model to investigate correlations of novel biomarkers with non-inflammation induced disease progression in MS.

Objectives

To investigate longitudinal serum CNTN1 in relation to clinical and radiological disease activity and progression independent of inflammatory disease activity in relapsing-remitting MS (RRMS).

Methods

Eighty-nine natalizumab-treated RRMS patients with minimum follow-up of 3 years were selected from an ongoing observational cohort study. Serum CNTN1 was analyzed at baseline before natalizumab initiation, and at 3, 12, 24 months and last follow-up. Clinical and radiological characteristics and CNTN1 levels were compared between patients with either progressive, stable or improved disability according to ‘EDSS plus’ criteria: Expanded Disability Status Scale (EDSS), 9-hole peg test (9HPT) and timed 25-foot walk test (T25W) combined. A significant change in at least one assessment was defined as progression (increase) or improvement (decrease), and no significant changes in any assessment as stability.

Results

Forty-three subjects (48%) showed disability progression on EDSS plus between reference and last follow-up visit, 34 (38%) remained stable and 12 (13%) improved (median [interquartile range (IQR)] follow-up 5.2 [4.3-6.7] years). No statistically significant differences were found in the proportion of patients with clinical and radiological evidence of disease activity 1 year prior to baseline or during follow-up. Baseline serum CNTN1 (median [IQR], pg/mL) was significantly lower in the group with progressive disability (920 [798-1283]) compared to patients with either stable (1169 [861-1367] p=0.043) or improved disability (1133 [1046-1378], p=0.031). A 100 pg/ml increase in baseline CNTN1 was consistent with an odds ratio [95% confidence interval] of 0.809 [0.684-0.958] (p=0.014) for disability progression. Longitudinal serum CNTN1 levels remained consistently lower in the group with progressive disability compared to the non-progressive group (stable and improved group together).

Conclusions

Long-term disability progression in MS patients treated with natalizumab was associated with lower serum CNTN1 concentrations compared to patients with either stable or improved disability.

Background

Whilst the introduction of disease modifying treatments (DMTs) has transformed the management of people with early/relapsing MS (pwRMS), the use of DMTs in people with MS who are largely or completely wheel chair-dependent (EDSS>6.5) remains controversial. Evidence suggests that slowing or stopping disease deterioration is possible even past this arbitrary (loss of ambulatory function) threshold. Pathology and anecdotal clinical data support the hypothesis that even at an advanced stage of MS (AMS) inflammatory activity is a key driver of functional decline and that effective immunotherapy may halt this process. Cladribine tablets are a highly effective and central nervous system (CNS) penetrant DMT for people with highly-active RMS. It effectively depletes B cells, particularly memory B cells, a likely key mechanism of disease control in MS. Evidence, suggesting that (i) a significantly higher number of CNS axons supply upper compared to lower limb functions and (ii) longer axons are more vulnerable to the effects of focal inflammatory demyelination than shorter ones, corroborate our hypothesis that upper limb function can be protected even beyond EDSS=6.5.

Objectives

Primary Objective: To investigate whether cladribine tablets over 24 months is an effective DMT in people with AMS (pwAMS; EDSS=6.5-8.5) as measured using the 9-hole peg test (9HPT) peg speed.

Secondary Objectives: To establish whether there is a difference in pwAMS between treatment with cladribine tablets or placebo in (i) blood/serum biomarkers of inflammation (lymphocyte subsets) and/or neurodegeneration (neurofilament light chain), (ii) MRI loss of brain volume and spinal cord cross sectional area, (iii) T₂ lesion burden, (iv) hypo-intense lesions on T₁ weighted scans, (v) quality of life, and (vi) whether cladribine is a cost-effective treatment for pwAMS.

Methods

Randomised, double-blind, placebo-controlled phase IIb trial. To detect a 15% treatment effect in 9HPT peg speed with 90% power at 5% significance and 20% drop-out over 104 weeks n=200 pwAMS will be recruited across 20 UK MS centres.

Results

Protocol and ancillary documents have been submitted for ethics approval. So far 17 centres have agreed to recruit pwAMS for ChariotMS. Due to the COVID-19 pandemic start of recruitment has been deferred to 04 Jan 2021.

Conclusions

ChariotMS will be the first DMT-trial focussing on pwAMS. If successful, ChariotMS would expand the DMT landscape to include pwAMS and provide a platform for add-on therapies.

Background

In 2017, a revision of the 2010 McDonald criteria for multiple sclerosis (MS) diagnosis in clinically isolated syndrome (CIS) patients has been proposed. However, its validation in a large multicenter cohort of CIS patients is still needed.

Objectives

To compare the performance of 2017 and 2010 revisions of the McDonald criteria with respect to MS development in a large multicentric cohort of CIS suggestive of MS.

Methods

Brain and spinal cord magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) examination obtained ≤5 months from CIS onset and a follow-up brain MRI acquired ≤15 months from CIS onset were assessed in 626 CIS patients from 9 European MS centres. The occurrence of a second clinical attack (clinically definite [CD] MS) was recorded. Performances of the 2017 and 2010 revisions of McDonald criteria for dissemination in space (DIS), time (DIT) and DIS plus DIT, also including OCB assessment, were evaluated with a time-dependent receiver operating characteristic curve analysis. Median time to MS diagnosis for the different sets of criteria was estimated through Kaplan-Meier curves.

Results

At the last evaluation (median=61.9 months [IQR=39.1-102.5]), 319 (51%) of 626 patients had CDMS. At 36 months, for DIS, the 2017 MRI criteria had higher sensitivity (0.84 [95% CI=0.79-0.88] vs 0.77 [0.72-0.82]), lower specificity (0.33 [0.28-0.39] vs 0.40 [0.35-0.46]), and similar area under the curve values (AUC, 0.59 [0.55-0.62] for both). The 2017 DIS plus DIT MRI criteria had higher sensitivity (0.68 [0.63-0.74] vs 0.62 [0.56-0.68]), lower specificity (0.55 [0.49-0.61] vs 0.62 [0.56-0.68]), and similar AUC values (0.62 [0.58-0.66] for both). CSF-specific OCB assessment as part of the 2017 criteria revision, increased the sensitivity (0.81 [0.75-0.85]), decreased specificity (0.40 [0.34-0.46]) and preserved AUC values (0.60 [0.56-0.64]). Median time to MS diagnosis was earlier with the 2017 revision compared to the 2010 or CDMS criteria, especially with OCB assessment (2017 revision with OCBs=3.6 months [3.1-4.0], 2017 revision without OCB=11.6 months [7.8-13.5], 2010 revision=13.9 months [12.4-15.3], CDMS=56.3 months [43.8-76.0]).

Conclusions

The 2017 revision of the McDonald criteria showed overall similar accuracy to the 2010 McDonald criteria in predicting CDMS development. The suggested modifications are expected to simplify the clinical use of MRI criteria without reducing accuracy and allow an earlier diagnosis of MS.

Background

Ocrelizumab (OCR) is an alternative therapy for relapsing-remitting multiple sclerosis (RRMS) patients with an increased risk of natalizumab (NTZ) associated progressive multifocal leukoencephalopathy (PML). We developed a switch protocol for PML surveillance and prevention of rebound disease activity.

Objectives

To evaluate clinical, radiological and biochemical markers in patients switching from NTZ to OCR using the locally developed switch protocol of the MS Center Amsterdam.

Methods

All patients with previous NTZ and current OCR treatment were selected from an ongoing observational cohort study with regular collection of blood samples in the Amsterdam University Medical Center (UMC) MS Biobank. Reasons for therapy switch were discriminated between patients with (indirect switchers) and without (direct switchers) use of other disease modifying treatment (DMT) during interval. Clinical, biochemical and radiological endpoints were prospectively collected from first NTZ to last OCR infusion. Serum neurofilament light (sNfL) was analyzed in direct switchers, using baseline and last follow-up samples during NTZ treatment and samples taken before every OCR infusion.

Results

Forty-one patients with current OCR and previous NTZ treatment were included with a median follow-up of 7.7 years. Twenty-eight patients switched directly, of which 21 due to PML risk. Three direct switchers suffered from a relapse, of which 1 patient showed evidence of disease activity on brain Magnetic Resonance Imaging (MRI). Two other male patients were diagnosed with carry-over PML with favorable outcomes. Before OCR became available, 13 patients switched from NTZ to other DMT due to PML risk but eventually escalated to OCR because of disease activity, progression or adverse events. Among these indirect switchers, 4 patients showed evidence of clinical or radiological disease activity. Excluding carry-over PML, OCR treatment maintained or established complete disease activity suppression in 84% of patients. Clinical measures of disability showed no significant changes. Mean sNfL significantly decreased during NTZ treatment and remained stable during OCR treatment.

Conclusions

A stringent protocol can contribute to an effective switch from NTZ to OCR in RRMS. In this observational cohort study of direct and indirect switchers, disease activity suppression was maintained or established in 84% with concurrent stability of clinical measures and sNfL.

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

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

Standardized magnetic resonance imaging (MRI) protocols are important for the diagnosis and monitoring of patients with multiple sclerosis (MS). The Consortium of Multiple Sclerosis Centers (CMSC) convened an international panel of MRI experts to review and update the current guidelines.

Objectives

The goal is to update the standardized MRI protocol and clinical guidelines for diagnosis and follow-up of MS and develop strategies for advocacy, dissemination and implementation.

Methods

The CMSC convened an expert panel in October 2019 to update the standardized MRI protocol. Conference attendees included neurologists, radiologists, magnetic resonance technologists, and imaging scientists with expertise in MS. Representatives from CMSC, Magnetic Resonance Imaging in MS (MAGNIMS), North American Imaging in Multiple Sclerosis Cooperative, National MS Society, Multiple Sclerosis Association of America, MRI manufacturers, and commercial image analysis companies were present. Before the meeting, CMSC members were surveyed about standardized MRI protocol, gadolinium, diffusion weighted imaging, and the central vein sign.

Results

95 neurologists completed the survey. 34% use the CMSC protocol. 48% use a standardized MRI protocol but are uncertain if it is similar to CMSC guidelines. 51% continue to use gadolinium for routine imaging. 58% wanted the central vein sign to be included in the diagnostic work up of MS. 87% were interested in monitoring brain volume and 10% were doing it routinely. The panel worked to harmonize CMSC and MAGNIMS MRI protocols so the updated guidelines could ultimately be accepted by international consensus. Advocacy efforts will promote the importance of standardized MRI protocols. Dissemination will include publications, meeting abstracts, educational programming, webinars, “meet the expert” teleconferences and exam cards. Implementation will require comprehensive and coordinated efforts to make the protocol easy to access and use.

Conclusions

The international expert group developed revised clinical MRI guidelines with the vision and action plans for them to be universally useful and useable and become the standard of care for patients with MS.

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.